(not at apex)

C h a p t e r 13
Metabolic Diseases

CONTENTS

13.1 Disorders of a m i n o a c id 13.5 Disorders of bone. m in er al

metabolism metabolism and in o r g an ic ions
13.1.1 Alkaptonuria (ochronosis) 13.5.1 Calcium homeostasis
13.1.2 Cystinosis 13.5.2 I-lypercalcaemia
13.1.3 Cystinuria 13.5.3 Hyperparathyroid bone disease
13.1.4 Homocystinuria 13.5.4 Hypocalcaernia
13.1.5 Primary hyperoxaluria (oxaiosis) 13.5.5 Hypercalciuria
13.1.6 Phenylketonuria IPKU) 13.5.6 Osteomalacia
13.5.7 Pagets disease
13.2 Disorders of p u r i n e 13.5.8 Osteoporosis
m etabolis m 13.5.9 Disorders of magnesium
13.2.1 Gout 13.5.10 Disorders of phosphate
13.2.2 Lesch-Nyhan syndrome
13.6 Nutritional a nd v itamin
13.3 Di sorders of m e ta ls a n d di sorders
m etallopr oteins 13.6.1 The obesity and diabetes
13.3.1 V\/ilsons disease epidemic
13.3.2 Haemochromatosis 13.6.2 Protein-energy malnutrition
13.3.3 Secondary iron overload (PEM)
13.3.4 The porphyrias 13.6.3 Vitamin deficiencies

13.4 Di sorders of lipid metabolism 13.7 Metabolic a c id~ ba s e

13.4.1 Lipid metabolism disturbances (non-renal)
13.4.2 The hyperlipidaemias 13.7.1 Metabolic acidosis
13.4.3 Lipid-lowering drugs 13.7.2 Metabolic alkalosis
13.4.4 Rare lipid disorders
13.8 H y p o th er mia
13.8.1 Treatment of hypothermia

317

Metabolic Diseases
I3] DISORDERS OF AMINO ACID
METABOLISM
Most of the inherited metabolic diseases are
mendelian, single-gene defects, transmitted in an
autosomal recessive manner. Disease expression
requires the affected individual to be homozygous
- inheriting a mutant gene from each of their
parents, who are both heterozygous for the defect,
Although heterozygotes may synthesise equal
amounts of normal and defective enzymes they are
usually asymptomatic.
0 Even the major inborn errors of amino acid
metabolism are rare - phenylketonuria, one of
the most common, has an incidence of 1/20 000
0
Complete penetrance is common and the onset
is frequently early in life
0 The consequences of these enzyme deficiencies
are varied and frequently multisystem but
expression tends to be uniform
The more common of these conditions are listed in
the box below and the major inborn errors of amino
acid metabolism are then discussed.
nwmiafremiw _ 0
Albinism
Alkaptonuria
Cystinosis
Cystinuria
Homocystinuria
Histidinaemia
Maple syrup urine disease
Oxalosis
Phenylketonuria
Metabolic Diseases
13.1.1 Alk ap to n u ria (ochronosis)
This is a rare autosomal recessive disease with an
incidence of 1/100 O00. Homogentisic acid accu-
mulates as a result of a deficiency in the enzyme
homogentisic acid oxida se ,
0 The homogentisic acid polymerises to produce
the black-brown product alkapton, which
becomes deposited in cartilage and other tissues
tochronosisi
0 Classic features include pigmentation (dark
blue, grey or blacki of the sclerae, ears, arthritis,
intervertebral disc calcification and dark sweat-
stained clothing
0 Life expectancy is norrnal but there is significant
morbidity from joint complications. Onset of
back pain is around 30 years
0 Rarer manifestations include renal stone disease
as well as aortic valve and ocular involvement
0 The urine darkens on standing because
homogentisic acid conversion to alkapton is
accelerated in alkaline conditions
There is a high prevalence of alkaptonuria in
Slovakia (1/19 O00) due to novel mutations,
which have resulted in geographical clustering
The molecular basis of the disorder is known
but there is no specific treatment. Arthritis may
require joint replacement
13.1.2 Cyst i nosi s
Cystinosis is an autosomal recessive lysosomal
storage disease which occurs with an approximate
frequency of 1/100 O00 to 1/200 O00 live births. ln
Cystinosis, cystine accumulates in the reticulo-
endothelial system, kidneys and other tissues. There
319
Essential Revision Notes for MRCP
is a defect of cystine transport across the lysosomal
membrane resulting in widespread intralysosomal
accumulation of cystine. The causative gene
(CTMST, which encodes for an integral membrane
protein called cystinosin, has been identified on
chromosome l7pl3. Unlike cystinuria, stones do
not occur in this condition.
0 Fanconi syndrome (often with severe
hypophosphataemia and consequent
vitamin D-resistant rickets)
Lymphadenopathy
Severe growth retardation
Insulin deficiency
Corneal opacities and photophobia
Abnormalities of cardiac conduction
Hypothyroidism
Bone marrow failure
Central nervous system involvement
Onset is usually in the first year of life and chronic
kidney disease (CKD) is progressive, often resulting
in end~stage renal disease by the age of 10 years.
Corneal or conjunctival crystals usually suggest the
diagnosis, which can be confirmed by measuring
the cystine content of neutrophils or cultured fibro-
blasts. Specific therapy with cysteamine bitartrate is
effective at reducing cystine accumulation and de-
laying CKD. Cysteamine eye drops can be used to
help with corneal disease. Supportive care, includ-
ing dialysis and transplantation, is usually needed.
Cystinosis does not recur in the transplant but extra-
renal disease is progressive. Antenatal testing for
cystinosis can be performed by measuring cystine
levels in chorionic villi or cultured amniotic fluid
cells.
Ocular non-nephropathic cystinosis: this is a
variant of the classic disease and is due to
different mutations of the cystinosis gene CT/\/5,
lt is an autosomal recessive lysosomal storage
disorder characterised by photophobia due to
corneal cystine crystals
320
13.1.3 Cy stin u ria
Cystinuria is an autosomal recessive disorder with a
prevalence of about 1/7000. The transport of cystine
and the other dibasic amino acids lysine, ornithine
and arginine is abnormal in the pro><imal renal
tubule and the jejunum.
0 No malnutrition occurs as sufficient dietary
ami no acids are absorbed as oligopeptides
0 Presentation is usually in the second or third
decade of life with renal stones
0
Cysline accumulates in the urine. lt is highly
insoluble at acid pH and this results in the
formation of radio-opaque calculi. (Cystine
stones account for 1/0-2% of all urinary tract
s t o n es )
A urinary cystine concentration >1 mmol/l (at pl-l
7.0) is supersaturated and leads to calculi forma-
tion.
Diagnosis requires measurement of urinary cystine
and/or chromatographic analysis of the stone ,
Pathognomic hexagonal crystals can be found on
urine microscopy,
Man a g e me n t
Management involves large fluid intake, alkalinisa-
tion of urine and impenicillamine (which chelates
cystine and increases its solubility). Tiopronin is
a newer cystine chelator that is better tolerated
than D-penicillamine. Captopril is a thiol
angiotensin-converting enzyme (ACE) inhibitor and
consequently can bind to cystine and increases its
solubility.
13.1.4 Ho mo cy stin u ria
This rare autosomal recessive abnormality results
from reduced activity of cystathionine [5-synthase.
The resulting homocystine and methionine accumu-
lation interferes with collagen cross-linking. Nearly
a quarter of patients die as a result of vascular
thrombosis before the age of 30.

Qlinicnl features of y,,_,
0 Downward lens dislocation
0 Venous and arterial thromboses
0 Spontaneous retinal detachment
0
Developmental and mental retardation
0
Osteoporosis
l Seizures and psychiatric syndromes
0 Skeletal abnormalities [eg marfanoid
stature, arachnodactyly, chest deformities)
The main differential diagnosis is Marfan syndrome,
as patients can have similar skeletal manifestations
and ectopia lentis (although this is classically up-
ward lens dislocation in Marian syndrome), Osteo-
porosis, mental retardation and vascular thrombosis
do not occur in patients with Marian syndrome,
Investigations
Tests show elevated plasma free methionine and
homocystine. Diagnosis is established by the cya-
nide-nitroprusside test that detects elevated urinary
homocystine and reduced cystathionine B-synthase
enzyme activity in tissue (liver or skin biopsy).
Heterozygous carriers have elevated serum homo-
cystine but no homocystinuria. Premature cardio-
vascular risk is also increased in heterozygotes.
M an ag em en t
I
Early detection (of younger siblings)
I Methionine restriction and cystine-
supplemented diets
I Pyridoxine supplements (effective in 50%)
0 Some variants are responsive to folate or
vitamin B12 supplements
I Antenatal screening for enzyme deficiency is
available
Other cau s es of elevated p l a s ma
h o mo cy s t i n e
Plasma homocystine levels can be elevated in the
elderly, in postmenopausal women and in patients
with advanced CKD and hypothyroidism. Drug
treatments such as methotrexate can also increase
levels. Elevated homocystine levels have been asso-
Metabo/ic Diseases
V, ciated with an increased risk of cardiovascular
disease (eg in dialysis populations) and deep vein
thrombosis.
13.1.5 Primary h y p ero x alu ria
(oxalosis)
There are two inborn errors of metabolism that
cause overproduction of oxalate. Both are auto-
somal recessive and can lead to hyperoxaluria with
stones and tissue deposition of calcium oxalate,
Type I is due to a deficiency of hepatic
peroxisomal alanine:glyoxylate aminotransferase
0
Type IIis due to a deficiency of D-glyceric acid
dehydrogenase
Chnienl features of oxalosh
0 Oxalate renal stones
0 Severe arterial disease (due to deposition of
oxalate crystals in the vessel wall]
0
Nephrocalcinosis
Cardiac disease (conduction delay)
0 Bone disease (and bone marrow invasion
leading to pancytopenia and fractures)
Di agnosi s
Oxalosis should be suspected if there is increased
urinary oxalate excretion, but the latter can also
occur with pyridoxine deficiency (as this is a neces-
sary co-enzyme in oxalate metabolism), ileal dis-
ease, ethyl glycol poisoning and excess oxalate
ingestion.
Confirmation of diagnosis requires:
0 Plasma oxalate
U Liver biopsy to demonstrate enzyme deficiency
in type I
I Demonstration of enzyme deficiency in
peripheral blood leucocytes in type ll
I Genetic testing by mutation and linkage analysis
is useful for identifying other affected family
members, as well as in prenatal diagnosis and
carrier testing
321
Essential Revision /\/otes for MRCP
Treatment of oxa losis
This initially involves high fluid intake, urinary
calcium crystallisation inhibitors (eg citrate) and the
use of pyridoxine. Only iO%~3O% of patients re-
spond to pyridoxine. ln primary hyperoxaluria type l
early diagnosis and pre-emptive isolated liver trans-
plantation can be curative. In patients who already
have advanced CKD l,Cl<D stages 4 and 5), intensive
dialysis therapy is appropriate. Concomitant liver
and renal transplantation is often performed, but in
this situation the renal transplants can be lost due to
rapid oxalate crystal deposition (prior liver trans-
plantation is preferable as it would allow clearance
of the oxalate load before consideration of renal
transplantation).
13.1.6 Phenylketonuria (PKU)
There are several variants of PKU due to different
allelic mutations. For example, mutations of the
gene that encodes phenylalanine hydroxylase (and
associated enzymes) are found on chromosome 12.
Only severe deficiency of the enzyme results in
classic PKU with neurological damage. PKU affects
between i/10 OO() and i / i 4 000 live births.
The biochemical abnormality is an inability to con-
vert phenylalanine into tyrosine due to lack of
phenylalanine hydroxylase. This results in hyper-
phenylalaninaemia and increased excretion of its
metabolite, phenylpyruvic acid (phenylketone) in
the urine.
`:`.`::-fi" <`I>-ff'f`.-l;`~L-,\2l`. T,T,\~'.,- .~,~I.:5{`." If
0 Affects children, usually manifesting by
6 months of life
0
irritability
0 Decreased pigmentation* (pale skin, fair-
haired and blue-eyed phenotype)
I Eczema
Mental retardation
* This is due to reduced melanin formation
322
. "'> .if/,>,~ `\ t-.5
D i ag n o s i s
The Guthrie screening test is a bacterial inhibition
assay named after its inventor. Blood applied from
a heel prick is applied to filter paper that is
subsequently incubated with Baci//us subtilis in
the presence of [32-thienylalanine (an analogue
that inhibits utilisation of phenylalanine). The
amount of bacterial growth is proportional to the
phenylalanine concentration in the neonatal
blood.
Phenylalanine levels can also be measured by spec-
trofluorornetric methods or using a form of mass
spectrometry that has the ability to analyse many
amino acids, fatty acids and short-chain organic
acid metabolites simultaneously.
Management
A diet low in phenylalanine, with tyrosine supple-
mentation in infancy and childhood is now also
recommended for adults. Commencing the diet as
soon as possible after birth can prevent the deleter-
ious consequences, which are irreversible. PKU
females should be advised to reinstitute strict dietary
control prior to conception and throughout preg-
nancy and breast-feeding. Fish oil supplementation
can also improve symptoms.
13.2 DISORDERS OF PURINE
METABOLISM
Uric acid is the end product of purine metabolism.
Purines can be synthesised de novo or salvaged
from the breakdown of nucleic acids of endogenous
or exogenous origin. Increased de novo synthesis of
purines is thought to be responsible, at least partly,
for primary gout. Deficiency of hypoxanthine gua-
nine phosphoribosyl transferase (HGPRT), which is
involved in the salvage pathway, results in the
Lesch-Nyhan syndrome.

~ to complete lack of hypoxanthine guanine phos-
0
Primary gout
O
Lesch-Nyhan syndrome
0
Secondary hyperuricaemia
(See also Chapter 20, Rheumatology.)
13.2.1 Gout
More than 10% of the population of the western
world has hyperuricaemia, which can be due to a
variety of genetic and environmental iactors, Gout
develops in less than 0.5% of the population, (See
also Chapter 20, Rheumatology.)
0 Primary hyperuricaemia is more common in
males and postmenopausal females than in pre-
menopausal females
0 It is rare in childhood
0 It is probably polygenic, involving both
increased purine synthesis and reduced renal
tubular secretion of urate
I Gout can be precipitated by thiazide diuretics,
alcohol and high purine (meat) intake
0 Treatment is with non-steroidal anti-
inflammatory drugs (NSAIDs) and colchicine for
acute episodes. NSAIDS or colchicine may be
contraindicated or poorly tolerated by some
groups of patients (eg CKD); short courses of
oral steroids, or a long-acting IM steroid
injection, can be prescribed as an alternative.
Longer-term lowering of uric acid is achieved
with allopurinol. The Selective non-purine
xanthine oxidase inhibitor febuxostat has also
been shown to effectively lower serum uric acid
levels
I Hyperuricaemia is associated with increased
cardiovascular risk
U
Hyperuricaemia is also a sensitive marker for
pre-eclampsia. Elevated levels correlate with
maternal and fetal mortality and morbidity
13.2.2 L esch - Ny h an s y n d r o m e
Lesch-Nyhan syndrome is an uncommon X-linked
recessive disease (therefore seen only in males) due
Metabo/ic Diseases
phoribosyl transferase (HPRT). This resulm in accu-
mulation of both hypoxanthine and guanine, both
of which are metabolised to xanthine and subse-
quently I0 uric acid,
cimut mmm '
i
Mental retardation
Self-mutilation
Athetosis
Renal calculi
Gout
CKD due to crystal nephropathy
Spasticity
0
Neurological manifestations are usually present
in early infancy and consequently patients
present with delayed motor development; death
from end-stage renal disease in adolescence is
common
0
Kelley-Seegmiller syndrome is a variant, with
mild neurological symptoms, due to a partial
deficiency of HPRT
0 Treatment of the uric acid overproduction is
with allopurinol, Treatments for the neurological
and behavioural symptoms are limited
0 Carrier and prenatal diagnosis is possible by
mutation detection and linkage analysis for
probands and their families. Biochemical
measurement of HPRT enzyme activity is also
possible for at-risk pregnancies
13.3 DISORDERS OF METALS AND
METALLOPROTEINS
lron and copper play central roles in the function of
a number of metalloproteins, including cytochrome
oxidase, which is essential in cellular aerobic re-
spiration; haem, based on iron, ls the key molecule
in oxygen transport. Excessive accumulation can,
however, promote free radical injury (eg Wilsons
disease and haemochromatosis) and disorders of
haem synthesis result in porphyria.
323
Essential Revision Notes for MRCP

~
0 Fanconi syndrome
0 Musculoskeletal
Wilson's disease v Degenerative arthropathy resembling
Secondary iron overload premature osteoarthritis
Haemochromatosis ~ Osteopenia (50%)
The porphyrias Osteoporosis
Chondrocalcinosis

13.3.1 Wilson`s d isease

This autosomal recessive disorder has a gene fre-
quency of l/400 and a disease prevalence of ap-
proximately 1/200000. The responsible defective
gene (ATP 7B) is on chromosome 13, and this codes
for a copper-transporting P-type adenosine tri-
phosphate.
ln normal subjects 50% of ingested copper is
absorbed and transported to the liver loosely bound
to albumin. Here copper is incorporated into an
L12-globulin to form caeruloplasmin, which is the
principal transport protein for copper, and necessary
for biliary excretion. In V\/ilson's disease copper
absorption is normal but intrahepatic formation of
caeruloplasmin is defective. Total body and tissue
copper levels rise due to failure of biliary excretion
and urinary excretion of copper is increased.
Ctinical,fqnmes of
0 Onset in childhood or adolescence
0
Hepatic dysfunction
~ Acute hepatitis
~ Cirrhosis (most c om m on)
~ Chronic hepatitis
Massive hepatic necrosis
0 relatives should be screened for V\/ilsons disease.
Hypoparathyroidism
0 Haemolysis
0 CNS involvement (often presents later than
hepatic dysfunction)
Behavioural problems/psychosis
Mental retardation
~ Tremor/chorea
Seizures
0
Kayser-Fleischer corneal rings
~ Due to copper deposition in Descemets
membrane
Di ag n o s i s
Wilsons disease should be considered in any pa-
tient with unexplained hepatic dysfunction and
neurologicaI/neuropsychiatric symptoms. Diagnosis
is based on a decrease in serum caeruloplasmin
and increases in hepatic copper content and urinary
excretion of copper. However, biochemical diag-
nosis is increasingly recognised to have low sensi-
tivity. Molecular diagnosis is now available to
identify presymptomatic individuals. Serum copper
levels are of no diagnostic value.
M an ag em en t
Early detection permits lifelong use of medications
that can prevent the deleterious effects of copper
accumulation. Copper chelators (eg penicillamine
and trientine) are used to remove copper in sympto-
matic patients ln patients vvho have no symptoms,
zinc is used to prevent the build up of copper. Zinc
works by preventing copper absorption in the gut. It
is also used in patients who have responded to
treatment with chelators as maintenance therapy.
Fulminant hepatic failure and end~stage liver dis-
ease necessitate liver transplantation, which is cura-
tive (but CNS sequelae may persist). First-degree
(See also Chapter 6, Gastroenterology.)
l3.3.2 H aemochromatosis
ln the normal adult the iron content of the body is
closely regulated. Haemochromatosis is the exces-
sive accumulation of ir on, Primary (or idiopathic)
haemochromatosis is a common autosomal reces-
sive disorder in which iron accumulates in parench-
ymal cells, leading to damage and fibrosis.
Haemosiderin is an insoluble iron-protein complex

324

ll
i
a found in macrophages (it is relatively harmless to
them) in the bone marrow, liver and spleen. Sec-
1
ondary iron overload, which has many causes, is
often referred to as haem0sider0sis'.
I
I The gene for haemochromatosis (HFE) is located
on chromosome 6 close to the HLA locus. HFE
codes for a transmembrane glycoprotein that
modulates iron uptake. Ninety per cent of
Caucasian patients are homozygous for the HFE
CZBZY mutation
0 The gene frequency is 6"/J and disease
frequency 1/220 people, but the severity of the
disease seems to vary
I Males are affected earlier and more severely
than females (as menstrual loss/pregnancy
protects females)
0
Heterozygotes are at greater risk of secondary
haemosiderosis than non-carriers if they have a
predisposing condition
0
Thirty per cent of patients with cirrhosis develop
hepatocellular carcinoma. (See also Chapter 6,
Gastroenterology)
I Presentation above the age of 40 years
0
Hepatomegaly preceding micronodular
cirrhosis
Chondrocalcinosis and pseudogout
Cardiomyopathy and arrhythmias
Bronze skin pigmenmtion
Diabetes mellitus and (rarely) exocrine
pancreas failure
l
I
Hypopituitarism, hypogonadism and
testicular atrophy
Di agnosi s
Serum iron is elevated with greater than 60% trans-
ferrin saturation. Serum ferritin is >5OO pg/I but it is
important to note that the most common causes of
elevated ferritin (an acute phase r e a c ta nt) are in-
flammation, alcohol and many other conditions.
Molecular genetic diagnosis for HFE mutation is
now widely used. Liver iron concentration > i 8 ( )
pmol/g is also indicative of haemochromatosis.
Metabolic Diseases
Liver biopsy is novv used as a prognostic indicator
rather than a diagnostic one. Factors associated with
increased progression of hepatic fibrosis include
increased serum ferritin and alcohol abuse.
Managtrment
Venesection
Chelation therapy with desferrioxamine
Screening of first-degree relatives (serum ferritin)
Screening cirrhotic patients for hepatocellular
carcinoma is recommended [6-monthly
ultrasound and serum ot-fetoprotein)
O Liver transplantation (for end-stage liver disease)
13.3.3 Se c o n d a r y iron overload
Secondary haemochromatosis is due to iron over-
load, which can occur in a variety of conditions.
The pattern of tissue injury is similar to that in
primary haemochromatosis. ln the inherited haemo-
lytic anaemias iron overload can present in adoles-
cence; the features are often modified by the
underlying disease. Treatment is with desferrioxa-
mine.
Secondary causes of im a overload _
0 Anaemia due to ineffective erythropoiesis
Beta-thalassaemia
~ Sideroblastic anaemia
~ Aplastic anaemia
~ Pyruvate kinase deficiency
0 Parenteral iron overload
Transfusions
Iron-dextran
0 Liver disease
Alcoholic cirrhosis
o Chronic viral hepatitis
Porphyria cutanea mrda
0 Increased oral iron intake (Bantu siderosis)
0
Congenital transferrinaemia
13.3.4 Th e por phyr i a s
The porphyrias are a rare heterogeneous group of
conditions caused by abnormalities of enzymes
325
Essential Revision Notes for MRCP

involved in the biosynthesis of haem, resulting in 0

Uroporphyrinogen accumulates in blood and
overproduction of the intermediate Compounds U|'l|'|!
called porphyrins. Most porphyrias are hereditary, 0 Manifests as photosensitivity rash with bullae.
although some can be acquired. Excess production Porphyrins produce free radicals when exposed
of porphyrins can occur in the liver or bone marrow to ultraviolet light which results in damage to
and is classified as acute or non~acute. sun-exposed skin
The haem metabolic pathway and the type of por-
phyria resulting from different enzyme deficiencies Diagnosis
are shovvn in Figure 13.1. The two most important Based on elevated urinary uroporphyrinogen (urine
is normal in colour).
porphyrias are porphyria cutanea tarda and acute
intermittent porphyria - these are described in more
detail. Treatment
0 The underlying liver disease
Chloroquine
0 Venesection
P orphyria cutanea tarda
This is the most common hepatic porphyrin, There
is a genetic predisposition but the pattern of inheri- Acute intermittent porphyri n
tance is not established, lt is more common in men This causes attacks of classic acute porphyria, often
and usually presents after the age of 40. Many presenting with abdominal pain and/or neuropsy-
sporadic cases are due to chronic liver disease, chiatric disorders. It is an autosomal dominant dis-
usually alcohol-related. order.
0 There is reduced uroporphyrinogen 0 There is reduced hepatic porphobilinogen
decarboxylase activity deaminase activity

Figure 13.1 Haem synthesis and the porphyrias

Acuta p o rp h y ri n Non-acute p o rp h y rlaa
Succinyl CoA + Glycine

l ALA synthetase

Delta-aminolavulinic acid
l
Porphobilinogen
ALA uehyan-iss

PB S deaminase e Acute intermittent porphyrin*

UPGIII co-synthetase 4- Congenital erythropoietic porphyrin
Umporphyrinogen III
l UPG decarboxylase <l
Coproporphyrinoqen ill
Porphyria cutanea tard a'

CPG o x i d a s e < - - - - 1 Hereditary co p o fp h y rir

Protodorphyrinogen IX
1 PPG o x i d a s e < - e Variegate porphyri i r
Protopofphyrin IX
F e r m c n e I a r s s Erythropoietic protopofphyria
Haem

'
Heparic parpnyrras

326
 Metabolic Diseases

The gene (and disease) frequency is between
1/10 OOO and 1/50 OOO
Episodes of porphyria are more common in
females (?due to the effects of oestrogens)
There is no photosensitivity or skin rash
There is increased urinary porphobilinogen and
aminolaevulinic acid, especially during attacks
Urine turns deep red on standing
0 Sertraline and other psychotropic drugs have
been used without precipitating acute porphyria,
but care is advisable with use of all drugs
0
Early detection of the signs and symptoms of an
acute episode
0 Acute episodes are treated vvith daily haem
arginate infusions for 3 - 4 days as well as
treatment/withdrawal of any precipitating agents
0 1 0 % of patients die as a result of hepatocellular
carcinoma

Clinical features of acute intermittent

porphyri a
13.15 t)lS()Ri)l'f~Z5 ( l t t . i P l l )
Onset in adolescence lVlliTAB(_ll.l5l`\l
Females more affected
Hyperlipidaemia, especially hypercholesterolaemia,
Polyneuropathy (motor) is associated with cardiovascular disease (Table
Hypertension and tachycardia 13.1).
Episodic attacks
Tubulointerstitial nephritis TabIe13.1. Cholesterol level and relative risk
Abdominal pain occurs in 95% of acute of myocardial infarct
episodes, vomiting, constipation
I
Neuropsychiatric disorders
Total cholesterol (mmol/I) Relative risk of
myocardial infarct
Precipitating drugs:
Alcohol 5,2 1
Benzodiazepines 6,5 2
Rifampicin 7.8 4
Oral contraceptives
Phenytoin
Sulphonamides Although lipid metabolism is complex, and many
inherited or acquired disorders can disrupt it, the
O ther precipitating factors: end result is usually elevated cholesterol and/or
triglyceride concentrations. These can he managed
Stress by dietary and pharmacological means.
Pregnancy
Changes in the menstrual cycle (especially
premenstruali 13.43 Lipid metab o tism
infection
Cholesterol and triglycerides are insoluble in
Fasting
plasma and circulate hound to lipoproteins. The
lipoproteins consist of lipids, phospholipids and
Management
proteins. The protein components of lipoproteins
Supportive: maintain high carbohydrate intake; are called apolipoproteins (or apoproteins) and they
avoid precipitating factors act as cofactors for enzymes and ligands for recep-
Conadotrophin-releasing hormone analogues to tors. Figure 13.2 is a schema of lipoprotein structure
prevent cyclical attacks and lipid metabolism is shown in Figure 13.3.
1

327
 Essential Revision Notes for MRCP

Figure 13.2`Schema of lipoprot'ein structure

.
There are four major lipoproteins:

`\\\\\
Apolipopruleins
Chylomicronsz large particles that carry dietary
lipid (mainly triglycerides) from the
gastrointestinal tract to the liver, ln the portal
Core lipids
circulation lipoprotein lipase acts on
Cholesterol esters chylomicrons to release free fatty acids for
Triglycerides energy metabolism
Lipids with pol a r group
Very |0w~density lipoprotein (VLDL): carries
,\_ Phospholiplds endogenous triglyceride (60%), and to a lesser
extent cholesterol (20%), from the liver to the
\\\\\\ Free cholesterol
tissues. The triglyceride core ofthe VLDL is also
hydrolysed by lipoprotein lipase to release free

_
Figure 13.3 Llp_i_d_metabo|ism

u?n
Systemic Circulation
Portal Circulation
I
K
T9
LlP9Df0lif\
lipase
on -
i
|
T9
Ts Q
T9 Llpoprotein Tg
lipase
l Reverse Cholesterol
Hepatic
lipase Tg
,
y

Pathway Intermediate
`
Fleluming cholesterol .-density.

9
to the liver l' pp' le' "

Intracellular Metabolism
Direct uptake via the LDL
- AHM -
De " w o
- - _ LDLreoept'-
receptor
x
l ' A
synthesis
c0 R
choferzfeml
4
mediated
cholesterol U lnhibits upda te

LDL receptor

l
Lipoprotein particles Main lipid content Lipoprotein
Chylomicrons Trigyoeride (diet) Apo C,E,B48
VLDL Triglyoeride Apu C,E,B100
LDL Cholesterol Apo B100
HDL Cholesterol APU A.C.E

328

fatty acids. The VLDL remnants are called
intermediate-density lipoprotein
0
Low-density lipoprotein (LDL): formed from the
intermediate-density lipoproteins by hepatic
lipase. LDL contains a cholesterol core (50%)
and lesser amounts of triglyceride (10%). LDL
metabolism is regulated by cellular cholesterol
requirements via negative feedback control of
the LDL receptor
I
High-density lipoprotein (HDL): carries
cholesterol from the tissues back to the liver.
HDL is formed in the liver and gut and acquires
free cholesterol from the intracellular pools.
Within the HDL, cholesterol is esterified by
lecithin cholesterol acyltransferase (LCAT), HDL
is inversely associated with ischaemic heart
disease
The LDL recep t o r
Circulating LDL is taken up by the LDL receptor.
Cells replete in cholesterol reduce LDL receptor
expression. ln contrast, inhibition of 3-hydroxy-3-
methylglutaryl co-enzyme A (HMG CoA) reductase,
the enzyme that controls the rate of de novo choles-
terol synthesis, leads to a fall in cellular cholesterol
and an increase in LDL receptor expression,
Lipoprotein (ai)
Lpta) is a specialised form of LDL. Lp(a) inhibits
fibrinolysis and promotes atherosclerotic plaque for-
mation. lt is an independent risk factor for ischae-
mic heart disease.
13.4.2 The h y p erlip id aem ias
Population studies have consistently demonstrated a
strong relationship between both total and LDL
cholesterol and coronary heart disease, HDL is
protective. A total cholesterol:HDL ratio of >4 .5 is
associated with an increased risk. Inten/ention trials
(for example, the Cholesterol Treatment Trialists'
(CTT) Collaborators) have shown that a reduction of
LDL cholesterol of 1 mmol reduces cardiovascular
events by 21% and reduces mortality by 12%.
Metabo/ic Diseases
Triglycerides are also associated with cardiovascular
risk; very high triglycerides are also associated with
pancreatitis, lipaemic serum and eruptive xantho-
mata. Triglycerides must he measured fasting.
A genetic classification of lipid disorders has now
replaced the Fredrickson (Vt/HO) classification,
which was based on lipoprotein patterns. The pri~
mary hyperlipidaemias can be grouped according
to the simple lipid profile. Secondary causes of
hyperlipidaemia need to be excluded and are dis-
cussed below.
Prima ry hypercholesterolaemia (without
hypertriglyceridaemia)
Familial hypercholesterolaemia (FH) is a moi-iogenic
disorder resulting from LDL receptor dysfunction.
0 There are many different mutations in different
families, all resulting in LDL receptor deficiency/
dysfunction and producing isolated
hypercholesterolaemia
0
Heterozygote prevalence is 1/500; these
individuals have cholesterol levels of 9 4 5
mmol/I and sustain myocardial infarctions at
about age 40 years (M F)
1
0
Homozygous FH is rare. Cholesterol levels are
in excess of 15 mmol/l and patients suffer
myocardial infarction in the second or third
decades
0 Other typical clinical features are Achilles
tendon xanthomata (can also occur in other
extensor tendons) and xanthelasma
All patients with FH should have lipid-lowering
therapy titrated upwards until there has been at
least a 50% reduction in LDL cholesterol
LDL-lowering apheresis (plasma exchange)
LDL apheresis can lower plasma LDL by up to 65%
after each treatment. This procedure involves the
extracorporeal removal of LDL in a process similar
to dialysis. The treatment is lifelong and is per-
formed weekly to fortnightly. lt can be used to lower
LDL cholesterol in homozygous FH patients who
have not responded to drug treatment or have
evidence of coronary heart disease. lt can also be
used in exceptional cases for patients with hetero-
329
Essential Revision Notes for MRCP

zygous FH, ie progressive coronary heart disease 0

despite maximal medical and surgical intervention.
ACE inhibitors should not be used in patients under-
going LDL apheresis due to the increased risk of
anaphylaxis.
Liver transplantation
Patients who have had maximal medical
treatment and LDL apheresis can be considered
for liver transplantation. The nevv liver provides
functionally normal LDL receptors, thereby
reducing plasma cholesterol levels
In polygenic hypercholesterolaemia the precise nat-
ure ofthe metabolic defectls) is unknown,
These individuals represent the right-hand tail of the
normal cholesterol distribution, They are at risk of
premature atherosclerosis, Depressed HDL levels
are a risk factor for vascular disease,
Factors modifying HDL levels
0
Decreasing
Familial deficiency of HDL
o
Hyperandrogenic state
lipoprotein lipase deficiency and apoprotein
CII deficiency are both rare. They result in
elevated triglycerides due to a failure to
metabolise chylomicrons
0 These patients present in childhood with
eruptive xanthomata, lipaemia retinalis, retinal
vein thrombosis, pancreatitis and
hepatosplenomegaly
0
Chylomicrons can be detected in fasting plasma
P ri m ary mixed ( or combined)
hyperlipidaemia
0 Familial polygenic combined hyperlipidaemia
results in elevated cholesterol and triglycerides
0 The prevalence is I/200
0 There is premature atherosclerosis
0 Remnant hyperlipidaemia is a rare cause of
mixed hyperlipidaemia tpalmar xanthomata and
tuberous xanthomata over the knees and elbows
are characteristic). It is associated with
apoprotein E3. There is a high cardiovascular
risk
Secondary hyperlipidaemias are usually mixed but

--


Post-pubertal males
Obesity
Hypertriglyceridaemia
~ Diabetes mellitus
either elevated cholesterol or triglycerides may pre
dominate.

Sedentary states Causes of se c onda ry hyperlipldaemias

-
Cigarette smoking
Increasing
Familial hyperaot-lipoproteinaemia
Low triglyceride levels
0
Predominantly increased triglycerides


Alcoholism
Obesity
Thin habitus 0 CKD

-
~
~
Exercise
Oestrogens
Alcohol
0
~


Diabetes mellitus
Liver disease
High~dose oestrogens
Prednminantly increased cholesterol
e
Pr i ma r y hypert ri gl yceri daem i a (w ithout Hypothyroidism
hypercholesterolaemia)
0
Polygenic hypertriglyceridaemia is analogous to
polygenic hypercholesterolaemia. Some cases
-
o

o
Renal transplant
Cigarette smoking*
Nephrotic syndrome
Cholestasis
are familial but the precise defect is not known.
There is elevated VLDL *Cigarettesmoking reduces HDL

330
 Metabolic Diseases

13.4.3 L ipid- lower ing d r u g s
Cholesterol and triglyceride levels should be con-
sidered in combination with other risk factors (also
see Chapter 1, Cardiology). Potential secondary
causes of hyperlipidaemia should be corrected.
Dietary intervention can be expected to reduce
serum cholesterol by a maximum of 30%. Dietary
measures should be Continued with pharmaC0~
logical therapy, Table 13.2 shows the impact that
can he expected with the various agents.
The side-effect profile of the older agents (see Table
13.3) made them unpopular and reduced com-
pliance. ln the majority of cases, hypercholestero-
laemia will respond to dietary intervention and
statin therapy; and mixed or isolated hypertriglycer-
idaemla, to diet and a fibrate. Treatment of hyperli-
pidaemia can reduce the risk of coronary heart
disease by 30%. The side-effects and interactions of
lipid-lowering drugs are given in Table 13.3,
HMG-CoA re duc ta se inhibitors (st at i ns)
Statins are widely used to lower cholesterol and
have been shown to reduce cardiovascular events.
Simvastatin is now available in a generic formula-
tion; consequently many patients are having their
current statin treatment 'switched' to simvastatin on
the assumption that all statins are the same, which
they are not. Whilst switching patients to generic
simvaslatin is more often than not complication-
free, care should be taken to avoid potential drug
interactions, eg protease inhibitors used in antiretro-
viral regirnens inhibit the metabolism of simvastatin
and are contraindicated. However, protease inhibi-
tors do not interact with atorvastatin or pravastatin.
Ezelimibe
Ezetimibe is a new class of drug that selectively
inhibits intestinal absorption of cholesterol. It is
indicated for patients with primary hypercholestero-
laemia who are intolerant of statins or when there is
a contraindication to statin use. lt is also used in
combination with a statin to enable patients to
lower LDL cholesterol to the target level.
Sterols and stanols, eg Flora Pro-activm
Benecolm
These substances inhibit cholesterol absorption in
the gut and thereby lower LDL cholesterol. They are
found naturally in a number of foods including extra
virgin olive oil. They have no effect on HDL choles-
terol or triglycerides. Sterols and stanols are being
increasingly used commercially as an additive to
margarines. Although studies have shown a reduc-
tion in LDL cholesterol, further research is required
to show whether this translates into a reduction in
cardiovascular events.

Table 13.2. Impact of lipid-lowering drugs

Drug class 1LDL (%) THDL (%) LTGS (%)

HMG-CoA reductase inhibitors ZO~4O 5 -1 0 1 0 -2 0

Fibrates 1 0 -1 5 l 5 -2 5 3 5 -5 0
Ezetimibe 1 5 -2 0 No change No change
Sterols and stanols T0-20 No change No change
Anion-exchange resins 15f3O No change No change
Nicotinic acid T 0 -2 5 l 5 -3 5 2 5 -3 0
Probucol lUl5 i2o-25 No change
Neomycin 2Of25 No change No change
Fkhod 5-TO No change 30-5()

331
Essential Revision Notes for MRCP

Table 13.3. 5ideet`fects and drug interactions of lipid-lowering drugs

Drug class Side-effects/ interactions

HMG-CoA reductase Headache, nausea, insomnia, abnormal LFTs. Myositis and rhabdomyolysis
inhibbdors (when in combination with gemfibrozil or ciclosporin A)
Simvastatin (but not pravastatin) potentiates warfarin and digoxin
Fibrates
Gemfibrozil Potentiates warfarin, Gemfibrozil absorption is impaired by anion-exchange
Bezafibrate i! Sll'lS

Ezetimibe Headache, abdominal discomfort. Rarely, hypersensitivity, thrombocytopenia,

rnyositis, pancreatitis and abnormal LFTs

Sterols and stanols Well tolerated as naturally occurring substances but may cause lower GI
symptoms; diarrhoea, constipation

Anion-exchange resins (aka

bile acid sequestrants)
Colestyramine GI side-effects; nausea, cramping, abnormal LFTs
Cholestipol Impaired absorption of digoxin, warfarin, thyroxine and fat-soluble vitamins
Nicotinic acid Flushing, headaches, upper GI symptoms, acanthosis nigricans and myositis
Probucol Diarrhoea, eosinophilia, long QT syndrome, angioneurotic oedema

Neomycin Ototoxicity, nephrotoxicity

Fish oil Halitosis, bloating, nausea
Impaired glycaemic control in non~insulin-dependent diabetes mellitus

P ri m ary p rev en t i o n
Statins can be prescribed for primary prevention 0 There is no target LDL or cholesterol and
in patients who are at high risk (>2O%) of consequently high-dose statins are not
developing cardiovascular disease,* eg diabetes. recommended
lf patients are unable to tolerate a statin then 0 All patients with familial hyperlipidaemia should
ezetimibe, fibrates or anion-exchange resins be offered lipid-lowering therapy
should be offered
* Current UK guidelines recommend that cardiovascular risk should be estimated using the Framingham 1991 TU-year risk
equations. However the Framingham risk equation was developed from North American patients and consequently they have
been shown to overestimate cardiovascular risk in northern European populations by up to 50% and underestimate cardiovascular
risk in patients who are socially deprived. Alternative risk equations are available, eg QRISK (UK), ASSIGN t5cotlandi, The QRISK
equations have been developed using data from the UK population. Published data suggest QRISK equations may be better
predictors of cardiovascular events than the Framingham equation in the UK. The QRlSl< equations take family history and social
deprivation into consideration. These equations are currently in evolution and it is likely that future guidelines will use QRISK or
similar equations to calculate cardiovascular risk in England and Wales.

332
 Metabolic Diseases

5"'V """ 13.5 D i s o n o m s or BONE.

0 lt is recommended that all patients with MINERAL METABOLISM AND
established cardiovascular disease should be INORGANIC IONS
treated with a statin as first-line agent
D Iftotal cholesterol is above 4 mmol/l ur LDL Bone is a unique type of connective tissue that
remains above 2 mmol/l statin treatment should
mineralises. Biochemically it is composed of matrix
135%) and inorganic calcium hydroxyapatite (65%).
be titrated upwards
Bone and mineral homeostasis are tightly regulated
13_4_4 Rare lipid d iso rd ers by numerous factors, so as to maintain skeletal
integrity and control plasma levels.
A multitude of rare inborn errors of lipid metabolism
can lead to multisystem diseases. The most common
tall very rare) are shown in Table 1 3 , 4 ,

Table 13.4. Rare inborn errors of lipid metabolism

Disorder Serum lipid Clinical features Pathogenesis Treatment

abnormality

Abetalipoproteinaemia Low cholesterol Onset in childhood Defective ApoB Vitamin E

Low triglycerides Fat malabsorption synthesis
Acanthocytosis
(of RBCs)
Retinitis pigmentosa
Ataxia and peripheral
neuropathy

Tangier disease Low cholesterol Onset in childhood Increased /\poA None

Large orange tonsils catabolism
Polyneuropathy
No increased IHD
risk

LCAT deficiency TTriglycerides Affects young adults Reduced LCAT Low-fat diet
Variable CKD activity
cholesterol

Cerebr0~tendinous None Affects young adults Not known None

xanthomatosis Cerebellar araxia
Dementia, cataracts
Tendon xanthomata

B-Sitoslerolaemia None Affects adults increased [5- Low plant~fat diet

sitosterol
I
absorption

l
(c ontinue d)

333
Essential Revision Notes for MRCP

Table 13.4. (continued)

Disorder Serum lipid Clinical features Pathogenesis Treatment

abnormality
Fabrys disease None Affects young male Deficiency of oz- Human
adults [mild disease galactosidase A recombinant oi -
in females] galactosidase A
therapy
Angiokeratornas X-linked recessive Renal replacement
therapy if end-
stage renal failure
develops
Periodic crises
Thrombotic events
CKD

Adrenoleukodystrophy None Children <2 years X-linked Lorenzos oil la

(ALD) combination of
oleic acid and
euric acid) can
reduce or delay
symptoms
Addison's disease Accumulation of
and progressive very long-chain
brain damage fatty acids (VLC FA)
in the brain and
adrenal cortex

Adrenomyeloneuropathy A milder form of Restrict dietary

ALD that can be VLCFA intake
seen in men in Hormone
their 205 and 305. replacement for
Presentation is adrenal
similar to multiple insufficiency
sclerosis

13.5.1 Calcium homeostasis other stimuli to PTH release include

Calcium homeostasis is linked to phosphate homeo
stasis to maintain a balanced calcium phosphate
product.
0 Hypocalcaemia activates parathyroid hormone
(PTH) release to restore serum ionised calcium;
.
0
hyperphosphataemia and decreased vitamin D
levels
Hypercalcaemia switches off PTH release
Vitamin D promotes calcium and phosphate
absorption from the GI tract
0 Bone stores of calcium butler the serum changes

334
 Metabolic Diseases

The metabolism and effects of vitamin D, and the 9

actions of PTH are shown schematically in Figures
13.4 and l 3 .5 .
13.5.2 Hy p er calcaem ia
In over 90% of cases hypercalcaemia is due to either
hyperparathyroidism or malignancy, Hypercalcaemia
normally suppresses PTH and so PTH is therefore the
best first test to identity the cause of hypercalcaemia
Primary hyperparathyroidism is common/
especially in women aged 4 0 - 6 0 years. lt is
usually due to an adenoma of one of the four
parathyroid glands
0 PTHrelated protein (PTH-rPl is responsible for
upto 80% of hypercalcaemia in malignancy'
0 PTH-rP acts on the same receptors as PTH and
shares the first (N-terminal) 13 amino acids with
PTH; however, they are coded from two
separate genes

if it is detectable (in or above the normal range) the 0 Common malignancies secreting PTHrP are
patient must have hyperparathyroidism. squamous cell tumours, breast and kidney

Figure 13.4 Metabolism and the actions of vitamin D

DIET orsr
UV'-F9"-> Cholacalciterol v
7_Dehy:,**;es|e,| -> Skin
(D3)

Relative conversion
to 1,25-D3
l
K I D N E Y 4 * 25-hydroxy D3
LIVER

Promoted byfPTH,
PO4B and ~|Calcium

24,25-D3
(inactive)
l
1 .25-D3
(active vitamin D)

1 - 5 11
Kidney Bone Small
Bowel

FCa2"' and 1*Bone T Ca2+ and

'|P043 mineralisalion 1'P043 7

excretion absorption

335
Essential Revision Notes for MRCP

lv _
Figure 1 3 .5 Control and actions of_;;arathyr-gd hormone (Pig)
i Plasma J, Ca2+ l; 1 PTH

`
Kidney tie
l
Osteoclastic
1~PO43' TCa2+ TVitamin D
Excretion Fteabsorption 1-hydroxylation
Resolrpuon
Release of
T _llzoa Ca and P043-

T Intestinal
Ca2* and
P043- absorption

Sarcoidosis causes hypercalcaemia due to excess

Production of i.25D3 b Ymacro PhaSes in the sarcoid

-
0 Increased calcium absorption lesions
Increased calcium intake Familial hypocalciuric hypercalcaemia (FHH) is an
increased vitamin D autosomal dominant condition. Most cases of FHH are a
I Increased bone reabsorption result of mutations in the calcium-sensing receptor.
~ Primary and tertiary Patients are often incorrectly diagnosed with primary
hyperparathyroidism hyperparathyroidism. ln contrast to primary
Malignancy hyperparathyroidism FHH does not require any
treatment
Hyperthyroidism
0 Miscellaneous unusual causes "Hypercalcaemia can be seen in patients who
Lithium consume excess quantities of 'Rennies' bought over the
Thiazide diuretics counter
Addisons disease

- Sarcoidosis*
The symptoms of hypercalcaemia are often mild but
Phaeochromocytoma a range of manifestations can occur. The mnemonic
Familial hypocalciuric hypocalcaemia" stones, bones, abdominal groans and psychic
o Theophylline toxicity moans' can be used to describe these symptoms.
Milk-alkali syndrome***
Vitamin A toxicity (rarely)

336

Cliniealmanifestatiansof .
a .
Malaise/depression
Lethargy
Muscle weakness
Confusion
Peptic ulceration*
Pancreatitis
Constipation
Nephrolithiasis
Nephrogenic diabetes insipidus
Distal renal tubular acidosis (RTA)
CKD**
Short QT syndrome
Band keratopathy
Diabetes insipidus
*Peptic ulceration is due to excess gastrin secretion
"CKD is due to chronic tubulointeistitial calcification
and fibrosis
The management of acute hypercalcaemia (serum
calcium >3 mmol/I) involves:
0
Adequate rehydration - 3 - 4 litres saline/day
0 intravenous bisphosphonates (eg pamidronate
d isodium)
0 Identification of the cause, and its subsequent
specific treatment (eg corticosteroids for sarcoid)
if indicated
13.5.3 Hy p er p ar ath y r o id b o n e
disease
Hyperparathyroidism has a prevalence of about
l/1000. lt results in bone reabsorption due to excess
PTH action.
Primary hyperparathyroidism is caused by a single
<80"/a+) or multiple (5%) parathyroid adenomas or
by hyperplasia (10%). Parathyroid carcinoma is rare
(<20/Q). lt results from abnormal regulation of PTH
by calcium because of an increase in the calcium
set point. Familial cases (as seen in MEN type l)
have a higher incidence of hyperplasia and, like
parathyroid carcinoma, can be associated with ab-
Metabo/ic Diseases
normalities of chromosome tl (usually deletions in
,
the little q I 3 region).
Biochemically there is increased PTH, serum and
urinary calcium, reduced serum phosphate and in-
creased alkaline phosphatase. Histologically there is
an increase of both osteoblasts and osteoclasts
resulting in 'woven' osteoid, increased resorption
cavities ( oste itis fibrosa cystica') and marrow fibro-
sis. The definitive treatment of primary hyperpara-
thyroidism is by surgical parathyroidectomy.
Secondary hyperparathyroidism is physiological
compensatory hypertrophy of all four glands due to
hypocalcaemia (eg CKD, malabsorption). PTH levels
are raised, calcium is low or normal. The secondary
hyperparathyroidism in CKD is controlled by phos-
phate restriction, phosphate binders and with use of
1-a-hydroxylated vitamin D preparations ( se e also
Chapter 15, Nephrology). Cinacalcet is a calcimi-
metic which acts on calcium sensing receptors to
increase receptor sensitivity to calcium, which in
turn results in a decrease in PTH. Cinacalcet is
licensed for the treatment of advanced secondary
hype-rparathyroidism.*
Tertiary hyperparathyroidism is the development of
autonomous parathyroid hyperplasia in the setting
of long-standing secondary hyperparathyroidism -
usually in CKD. Calcium levels are raised. Treat-
ment is in the form of parathyroidectomy or cinacal
c e t*
13.5.4 H ypoc a l c a e mi a
Hypocalcaemia is usually secondary to CKD (in~
creased serum phosphate), hypoparathyroidism or
vitamin D deficiency.
' UK NICE
guidelines do not recommend cinacalcet for the
routine treatment of secondary hyperparathyroidism as it has
not been shown to be cost-effective. lt can be used in patients
who have failed to respond to other treatments or in patients
with tertiary hyperparathyroiclism in whom parathyroidectomy
is not possible.
337
Essential Revision Notes for MRCP

! \iD`i`iof lsypocalcauaisia `
0 Decreased calcium absorption
Hypoparathyroidism
o Hypovitaminosis D
0
Malabsorption
U CKD (failure of i-or-hydroxylation)
0
1-tx-hyroxylase deficiency
(vitamin-D-dependent tickets type ll
1 Vitamin D-receptor defect (vitamin D-dependent

-
~

o
ivtalabsorption
Sepsis
Fluoride poisoning
Hypomagnesaemia*
Acute respiratory alkalosis
rickets type ll)
Rickets without vitamin D deficiency and with nor-
mal calcium may be due to hypophosphataemia, as
in X-linked dominant hypophosphataemic vitamin
D-resistant tickets.
0
Hyperphnsphataemia (by reduction in
ionised calcium) The symptoms of hypocalcaemia are mainly those
1 CKD of neuromuscular irritability and neuropsychiatric
a
Phosphate administration manifestations. Signs include Chv0stel<'s (tapping
~ Rhabdomyolysis
. Tumour lysis syndrome
the facial nerve causes twitching) and Trousseaus
(precipitation of tetanic (carpopedali spasm in the
0 Deposition of calcium hand by sphygmomanometer-induced ischaemia).
o Pancreatitis Trousseau's sign is a more specific test for hypocal-

Hungry bone syndrome caemia. The development of symptoms depends on
EDTA infusion how quickly the level of calcium falls as well as the
Rapidly growing osteoblastic metastases serum concentration.
*Cause of functional hypoparathyroidism
Clinical manifestations of

Hypoparathyroidism can be spontaneous ( au t o - hypocalcaemia

immune), post-surgical or due to a receptor defect
ipseudo-hypoparathyroidism), Autoimmune hypo- 0 Neuromuscular
parathyroidism may be part of autoimmune poly- o Tetany
glandular failure type I ( m uc oc uta ne ous candidiasis, ~ Seizures
with adrenal, gonadal and thyroid failure). Treatment
is with calcium and vitamin D supplements.
--
~ Confusion
Extrapyramidal signs
Recombinant human 1-34-PTH (teriparatide) is
available but is not used in clinical practice for
hypoparathyroidism because of its cost, need for
parenteral administration and short half-life. It has
- Papilloeclema
Psychiatric
Myopathy
Prolonged QT syndrome
0 Ectodermal
been used for post surgical hypoparathyroidism over ~
a short-term period but it is more routinely used in
the management of osteoporosis.
In pseudohypoparathyroidism there is a characteris- U
-
0
Alopecia
Brittle nails
Dry skin
Calarads
tic phenotype with short stature, short metacarpals 0 Dental hypoplasia
and intellectual impairment. The disorder is due to
a G-protein abnormality (see Chapter i4, Molecular Table 13.5 lists the causes of hypocalcaemia and
Medicine). the related biochemical findings
Vitamin D deficiency can occur in several settings, The management of hypocalcaemia involves:
including: I Intravenous calcium gluconate if severe (tetany/
0
Dietary deficiency/lack of sunlight seizures)
338
 Metabo/ic Diseases

Table 13.5. Causes of hypocalcaemia - biochemical findings

Cause Serum PTH Vihamin D levels Phosphate Alkaline

phosphatase
Low Normal
Hypoparathyroidism High Normal
Vitamin D deficiency High Low Low High
i
Pseudohypoparathyroidism High Normal High Normal
i CKD High Low High High

0 Oral calcium supplements 0

0 Vitamin D (for hypoparathyroidism, vitamin D
deficiency and CKDl
0 Normalise serum magnesium levels,
Hypocalcaemia is difficult to correct if serum
magnesium levels are low
0 Thiazide diuretic and low-sodium diet
13.5.5 Hypercalciuria
Hypercalciuria is the commonest cause of kidney
stones and contributes to the development of osteo-
porosis. Hypercalciuria occurs as a result of exces-
sive duodenal calcium absorption (normally the
duodenum only absorbs 20% of ingested calcium),
renal calcium leak or excessive bone absorption (eg
hyperparathyroidisrn) resulting in excess serum cal-
cium and subsequent hypercalciuria. Excessive
calcium absorption is the commonest cause of
hypercalciuria, although the causes often overlap,
Resorptive
Hyperparathyroidism
~ MEN-1 (with hyperparathyroidism)
0 Miscellaneous
Hyperthyroidism
~ Renal tubular acidosis
~ Prolonged immobilisation
Paget's disease
~ Pregnancy
'Excess 1,25-vitamin D; production resulm in
hypercalcaemia and hypercalciuria
"Rare autosomal recessive condition caused by
mutations in the genes involved in the active absorption
of chloride in the loop of Henle. This results in excess
sodium and potassium loss in the urine. Secondary
hypefaldostemnism occurs with hypokalaemic alkalosis,
Blood pressure is usually normal
al<a X-linked recessive hypophosphataemic rickets
"""Mutation in the calcium-sensing receptor

Investigations
0
Absorptive
0 24-hour urinan/ calcium
~ Excess calcium ingestion
-~
Serum calcium, phosphate, creatinine and PTH
Milk-alkali syndrome 0 Calcium loading test in patients who have not
Vitamin D excess responded to dietary calcium restriction. Patients

--Sarcoidosis* are fasted and then administered a calcium

0 Renal hypercalciuria (renal leak) load. Urine calcium is checked at intermittent

- Medullary sponge kidney (30%-50%) periods to distinguish the cause of

Bartter syndrome" hypercalciuria, eg patients with renal leak
Dent's disease*** hypercalciuria will not change the amount of
~ Autosomal-dominant hypercalciuric calcium excreted, whereas patients with
hypocalcaemia**** absorptive hypercalciuria will increase calcium
excretion in response tothe calcium load

339
Essential Revision Notes for MRCP

Treatments 0 Defective 1oi-hydroxylation

0 Most hypercalciuria can be managed with
dietary calcium restrictions
.
Hypoparathyroidism
CKD#>k>*
Defective target organ response
0 Reduce sodium intake (elevated sodium intake 0

increases calcium excretion/ raises urinary pH Vitamin D-dependent rickets (type ll)
and reduces urinan/ citrate excretion, thereby Mineralisation defects
Abnormal matrix
increasing stone formation)
0 Thiazide diuretics are used in patients with renal Osteogenesis imperfecta

-
leak or who have not responded to dietary CKD=|<*>k
restriction alone. Thiazide diuretics reabsorb
Enzyme deficiencies
calcium in the renal tubule Hypophosphatasia
0
Bisphosphonate can be used in patients who
0 Inhibitors of mineralisation
have hypercalciuria as a result of excessive ~ Fluoride
bone resorption [especially patients with Aluminium
osteoporosis)
Bisphosphonates
0
0
Onhophosphates reduce hypercalciuria by Phosphate deficiency
reducing vitamin D3levels and increasing
tubular reabsorption of calcium, Side-effects
include GI disturbance -
Decreased Gi intake
Antacids (reduce absorption)
Impaired renal reabsorption
~ Fanconi syndrome
~ X-linked hypophosphataemic rickets
13.5.6 O s teomalacia
(vitamin D-resistant rickets)
Osteomalacia (adults) or rickets (children) result Vegans in particular may not benefit from dietary
from inadequate mineralisation of osteoid. The vitamin D
biochemical features are: elevated alkaline "Asia n immigrants in Western countries are at
phosphatase (95%), hypocalcaemia (50%) and hy- increased risk because melanin in skin decreases D3
pophosphataemia (25%), lt is usually caused by a formation and certain foods (eg chapattis) bind calcium,
defect of vitamin D availability or metabolism. unmasking vitamin D deficiency
Approximately 1 billion people have osteomalacia "*speciaI|y phenytoin
worldwide. ln the UK the prevalence increases with
"***Patients with CKD can have mixed bone disease
age, with a prevalence of 30% in the over65s_ where there is hyperparathyroid bone disease in
` combination with osteomalacia

0
-.
Vitamin D deficiency
Drewiy*
Sun exposure"
The management of osteomalacia involves:
0
Diagnosis and treatment of the underlying
disorder
v
Malabsorption 0 Vitamin D therapy to correct hypocalcaemia
~ Gastrectomy and hypophosphataemia
~ Small-bowel disease 0 Beware iatrogenic hypercalcaemia when
Pancreatic insufficiency alkaline phosphatase begins to fall at the time of
0 Defective 25-hydroxylation bone healing
Liver disease
~ Anticonvulsant treatment*** On co g en i c osteomalacia
I
.
Loss of vitamin D-binding protein
Nephrotic syndrome
This is a paraneoplastic syndrome usually caused
by benign tumours of mesenchymal origin. Patients

340
 Metabolic Diseases

have osteomalacia, bone pain, phosphaturia and 0

Bisphosphonates
hypophosphataemia. 0 Calcilonin
0
Surgery
13.5.7 P a g e f s d isease ` "

fff=*i.1iiil;"1.
Pagets disease is a focal (or multifocali bone dis-
order characterised by accelerated and disorganised
bone turnover resulting from increased numbers With high calcium
and activity of both osteoblasts and osteoclasts. A ~
viral aetiology has not been confirmed. Hyperparathyroidism
0 With high or normal calcium
Rare in patients aged under 40 years v
0 Malignancy
0 Prevalence of l%~2/0 in Caucasians over the ~ Pagets disease
age of 55 years, The UK has the highest
0 With normal calcium
Puberty
prevalence (4.6%) in Europe
0 Familial clustering and HLA linkages ( 15% have o Fracture
a positive family history) o Osteogenic sarcoma
0 Biochemically characterised by raised alkaline 0 With low calcium
Osteomalacia
phosphatase, osteocalcin and urinary
hydroxyproline excretion, X-rays and
radionuclide bone scans aid diagnosis
13.5.8 O s t e opor os i s
Paget's disease is usually diagnosed because of
asymptomatic sclerotic changes (which can mimic A very common disorder characterised by reduced
sclerotic bone metastases) but a number of compli- bone density and increased risk of fracture. The most
cations can arise. common form is postmenopausal osteoporosis, which

.
affects 5 0 % of women aged 70. Common sites of
'f
. , -:;;, > fs. ,(1 '
_` fracture are the vertebrae, neck of femur (trabecular
" , . _ , ,
`

`
bone) and the distal radius and humerus (conical
bone); these fractures can occur with minimal trauma.
Bone pain Diagnosis is by bone mineral densitometn/, meas-
Fractures (and pseudofractures) ured by dualsenergy X-ray absorptiometry (DEXA),
Secondary arthritis single-photon absorptometry (SPA) or quantitative
Neurological compression syndromes* computed tomography (QCT) (Table 13.6).
Osteosarcoma (rare)
The measured bone density is compared with the
High-output congestive cardiac failure mean population peak bone density (ie that of
Hypercalcaemia (only with immobilisation)
Skeletal deformity young adults of the same sex) and expressed as the
number of standard deviations from that mean, the
*including deafness, other cranial nerve palsies and T score. The bone mineralisation and serum bio~
spinal stenosis chemistry are normal.
0 T scores down to -1 are regarded as normal
Treatment is indicated for bone pain, nerve com- 0 T scores between -l and - 2 .5 represent
pression, disease impinging on joints and immobili- osteopenia
sation hypercalcaemia. Options include: 0 T scores below - 2 .5 are osteoporotic

341
Essential Revision Notes for MRCP

Table 13.6. Comparison of DEX/\,* SPA and QCT

Method Measurements Pros and cons Cost

oem Spine, hip, radius Most widely available
Qcr Spine, hip, radius Most accurate
Better for patients with extensive osteoarthritis
increased radiation
Expensive
SPA Radius, calcaneum Not as accurate as DEXA and QCT

Fracture risk Drugs: steroids, heparin, ciclosporin A,

The risk of future fractures is dependent on both anticonvulsants
bone quality (strength and resilience) and the risk of Malignancy: multiple myeloma,
failing. Fractures increase twofold with each stan- leukaemia
dard deviation of the T score and independently ~ Inflammatory: rheumatoid arthritis,
with age by 1.5-fold per decade, ulcerative colitis
~ GI: gastrectomy, malabsorption, primary
biliary cirrhosis

-
Aetiologg 0 CKD
From the age of 30, bone loss occurs at about 1% o Immobilisation, eg space flight
per year. This is accelerated to about 5% per year in Other. osteogenesls imperfecta,
the 5 years after the menopause. Persistent eleva- homocystinuria, Turner syndrome
tions of parathyroid hormone will accelerate bone (oestrogen deficiency), rheumatoid
loss further. This occurs both in primary hyperpar- arthritis*, scurvy
athyroidism but also in secondary hyperparathyroid- I Additional risk factors for osteoporosis
ism arising in vitamin D deficiency, or in negative Race: white/Asian
calcium balance (eg hypocalcaemia, hypercalci- Short stature and low body mass index
uria). o Positive family history

Multiparity

0
Primary
~ Type 1: postmenopausal
-
~ Amenorrhoea >6 months (other than
pregnancy)
Poor calcium and vitamin D intake
Excess alcohol and smoking

Type 2: age-related or involutional In rheumatoid arthritis osteoporosis is multifactorial but

Osteoporosis of pregnancy conicostefoids and immobility are major contributors
0
.
Secondary
Endocrine: premature menopause,
Cushing syndrome, hypopituitarism, In the absence of a recent fracture or secondary
hyperparathyroidism, prolactinomas, cause of osteoporosis, bone biochemistry should be
hypogonadism, hyperthyroidism normal.

342
 Metabo/ic Diseases

Treatmem of o n o o p o m s i s '
'

Hypom agnes aem i a

0 General measures Hypomagnesaemia is frequently accompanied by

Correct any
hypocalcaemia, hypophosphataemia and hypoka-
secondary cause laemia. Patients are often asymptomatic but may
Weight-bearing exercise
Adequate dietan' calcium and vitamin complain of weakness or anorexia, and features of
neuromuscular irritability have been described. Hy-
D intake
pomagnesaemia is an important risk factor for ven-
0
Specific drug treatments tricular arrhythmias.
(These may reduce fractures by
approximately 50%) Causes of hypomagnasaemln

0
Oestrogens (HRT)
1 Vitamin D 0 Gastrointestinal losses
o Testosterone (in males) ~ Diarrhoea
~ Bisphosphonates* Malabsorption
~ Selective oestrogen receptor modulators ~ Small-bowel disease
(SERMs), eg raloxifene Acute pancreatitis*
Teriparatide (1-34-PTH) 0
Loop of Henle dysfunction
1 Strontium ~ Acute tubular necrosis"
Denosumab (novel human monoclonal ~ Renal transplantation
antibody) ** ~ Post-obstructive diuresis
0 Other v Bartter syndrome
~ Fluoride (increases bone density, but ~ Gitelman syndrome
reduces bone microstructure quality). 0 Renal losses
Fluoride accumulates in peripheral ~ Loop and thiazide diuretics
bone and increases the risk of Volume expansion
microfractures (stress fractures) and ~ A|cohol***
fracture in peripheral weight-bearing Diabetic ketoacidosis

o
bones
Calcitonin 0
-
Hypercalcaemia****
Nephrotoxins
Aminoglycosides

-
*Prophylaxis with bisphosphonates is now Amphotericin B
recommended for patients receiving high-dose (eg
relapsing nephrotic syndrome) or long-term (eg asthma)
~ Cisplatin
steroids Pentamidine
Ciclosporin A
"Denosumab is a human monoclonal antibody against
RANKL (receptor activator of nuclear factor KB ligand).
I
Primary renal magnesium wasting*****
RANKL is involved in bone resorption, The drug is Due to the formation of magnesium soaps in the areas
of fat necrosis
currently undergoing phase Ill drug trials
" Diuretic phase
/ilcohol acutely increases urinary magnesium
13.5.9 Diso rd ers of m a g n e s i u m excretion; in chronic alcoholism this is compounded by
ketoacidosis and phosphate depletion
Magnesium is principally found in bone ( 5 0 % -
60%) as an intracellular cation and plasma levels **Hypercalciuria increases magnesium excretion; if
saline and diuretics are given to treat hypercalcaemia
are maintained within the range 0 . 7 - 1 , 1 mmol/l. lt
then the three stimuli together predispose to
plays an important role in many metabolic path~ hypomagnesaemia
ways. Disorders of magnesium balance usually oc-
cur in association with other fluid and electrolyte *Primary magnesium wasting is a rare familial,
disorder
disturbances/ in particular calcium and potassium.
343
Essential Revision Notes for MRCP
H y p ermag n es aemi a
Hypermagnesaemia is rare. It is usually due to
magnesium ingestion or infusion in the setting of
CKD (ie when the kidney cannot excrete a magne
slum load).
0 At concentrations above 4 mmol/l symptoms
develop, including lethargy, drowsiness,
areflexia, paralysis, hypotension, heart block
and finally cardiac arrest
0 Toxic effects can be temporarily reversed by
intravenous calcium (antagonises the
neuromuscular and cardiac effects of
hypomagnesaemia). in patients with normal
renal function, intravenous normal saline with
forced diuresis using loop diuretics can increase
renal magnesium loss, Dialysis can also be used
in patients with CKD or in severe
hypermagnesaemia
CKD
Adrenal insufficiency
Magnesium infusion
Milk-alkali syndrome
Oral ingestion
Lithium
Magnesium enemas
Theophylline intoxication
Familial hypocalciuric hypercalcaemia
Tumour lysis syndrome (release of
intracellular magnesium)
0
Rhabdomyolysis
13.5.10 Disorders of p h o s p h ate
Serum phosphate is maintained between 0_8 and
1.4 mmol/l largely by renal regulation of excretion.
Bone accommodates 85% of body stores; the rest is
found extracellularly as inorganic phosphate and
intracellularly as phosphate esters, eg phospho-
lipids, nucleic acids and high-energy compounds
such as adenosine triphosphate (ATP).
344
Hypophos phat aem i a
Hypophosphataemia can occur in a variety of set-
tings, due to redistribution, renal losses or de-
creased intake.
Symptoms rarely develop unless phosphate is
below 0.6 mmol/l; below 0.3 mmol/l
rhabdomyolysis is likely
U
Hypophosphataemia leads to reduced oxygen
delivery ( via reduced levels of 2,3-
diphosphoglycerate (2,3-DPG)) and also impairs
intracellular metabolism (by depleting ATP)
0
Symptoms include weakness (especially
-
respiratory muscles a particular problem
when weaning certain ICU patients from
respiratory support), confusion, coma, heart
failure and rhabdomyolysis
Count: oi hypophospha ia e mh
0 Internal redistribution
Acute respiratory alkalosis
Hyperinsulinaemia
Post renal transplantation
0 Decreased intestinal absorption
~ Inadequate intake (especially
alcoholism, persistent vomiting)
Antacids containing aluminium or
magnesium
~ Steatorrhoea and chronic diarrhoea
-
0 Increased urinary excretion (phosphate
wasting)
Primary and non-renal secondary
hyperparathyroidism
~ Vitamin D deficiency/resistance
~ Fanconi syndrome
X-linked
hypophosphataemic rickets
~ Miscellaneous - osmotic diuretics,
- thiazide diuretics
Acute volume expansion
Heavy metal poisoning
Oncogenic osteomalacia
0 Treatment is dependent on the underlying
condition and phosphate supplementation
is commonly used. Vitamin D levels should
be corrected

H ype rphospha ta e mia
l tries, protein-energy malnutrition is common.
Hyperphosphataemia is common in acute and ad-
vanced CKD. lt can also occur in massive tissue
breakdown (eg rhabdomyolysis) and if there is in-
creased tubular reabsorption of phosphate.
0 lt is usually asymptomatic. lf symptoms do
occur, they are secondary to a reduction in
ionised calcium
I In acute hyperphosphataemia (with normal
renal function), saline infusion to volume replete
with forced diuresis using a loop diuretic can be
used to increase phosphate excretion
0 In CKD a low-phosphate diet, phosphate
binders and dialysis may be required, The high
serum phosphate in CKD is a major vascular
risk factor in this population
Gfeivofhvpwvwwwmh
-
0 Massive acute phosphate load
o Tumour lysis syndrome*
--
i tries such as Brazil, India and China, WHO projects
~ Rhabdomyolysis
Lactic and ketoacidosis
Exogenous phosphate
i Vitamin D intoxication
0 CKD
0 Increased tubular reabsorption of
phosphate
i Hypoparathyroidism
i
Pseudohypoparathyroidism
Severe hypomagnesaemia (results in
PTH resistance)
Acromegaly
~ Thyrotoxicosis
~ Bisphosphonates
i
*The tumour lysis syndrome results in release of
phosphate, potassium, purines (metabolised to uric acid)
and proteins tmetabolised to urea). It can result in acute
kidney injury due to uric acid crystal deposition
l (PI;lVl}
13.6 N l l T RI" l `l ()l \ IM. AYiE`r VE'fJti\/i[i,\t
D ISO RD E RQ
In the developed countries the most common nutri-
tional problem is obesity ( se e also Chapter 4,
Metabolic Diseases
Endocrinology). ln contrast, in the developing coun-
0 In developed countries the long-term sequelae
of fetal and childhood undernutrition are
increased cardiovascular disease in adult life
E31;-.i Th e o b esity a n d fiiabetes
vpirle mir;
I
Body mass index (BMI) = weight (kg)/(height in
metres);
0
Obesity is defined as a BMI of > 3 0 kg/m2 in
males and >28.6 kg/ml in females
Obesity is associated with increased risks of cardio-
vascular disease, diabetes mellitus, osteoarthritis
and gallstones. A BMI of 25 kg/ml has been esti-
mated to reduce life expectancy by 2 years in
English men.
Previously obesity was more often than not a
problem of high-income countries; however, the pre-
valence of obesity is now increasing in other coun-
that by 2015 the number of overweight adults will be
2.3 billion and over 700 million people will be
obese. As the rate of obesity has increased, so too
has the prevalence of diabetes. In 2000 it was
estimated that 171 million adults had diabetes. This
is projected to rise to 366 million by 2030 ( 4/1% of
the world population). WHO has also projected that
the number of deaths attributable to diabetes will
increase by 50% between 2005 and 2015.
Cc-nain countries will also face a 'double burden of
disease. Middle-income countries (eg India) are see-
ing an increase in obesity in urban settings whilst
still having to manage problems associated with
undernutrition.
23.6.2 P rot e i n-e ne rggi maln u tr itio n
Stan/ation is common in the developing world. In
the developed countries PEM frequently compli-
cates severe sepsis, cachexia, liver cirrhosis,
advanced CKD and malabsorption. ln these circum-
stances undernutrition is a risk factor for death. The
345
Essential Revision Notes for MRCP
elderly and in particular the institutionalised indivi-
dual are at a markedly increased risk of malnutri-
tion. Protein-energy malnutrition in both adults and
children can be divided into undernutrition,
kvvashlorkor and marasmus (Table 13.7).
Table 13.7. Wellcome Trust classification of
protein-energy malnutrition
Weight (% of Oedema present Oedema absent
standard for
age)
60-80 Kwashiorkor* Undernutrition
< 60 Marasmic Marasmus
kwashiorkor
*Kwashiorkor literally means 'disease of the displaced
child
Marasmus results from severe deficiency of both
protein and calories
I Kwashiorkor results primarily from protein
deficiency (ie diet entirely of carbohydrate)
I Oedema ls the cardinal sign separating
marasmus from kwashiorkor; fatty liver also
develops in kwashiorkor
C Growth failure is more severe in marasmus
13.6.3 Vitamin deficiencies
Multiple vitamin deficiencies frequently accompany
PEM. Isolated or grouped vitamin deficiencies (for
example, of fat-soluble (Table 13.8) or vvater~soluble
(Table 13.9) vitamins) can also occur in specific
circum stances,
i3.7 IVIETABOLIC, F\Ut}*BAs
DlS'l`URBANCl:S i'l\lON-Rtf..l\if\L]1
The kidneys and the lungs are intimately involved
in the regulation of hydrogen ion concentration.
Metabolic acid-base disturbances arise from ab-
normalities in the regulation of bicarbonate and
other buffers in the blood. Acidosis results from an
increase in hydrogen ion concentration and alkalo-
346
sis from a fall in H+. pH is the negative logarithm of
H* ~ a small change in pH represents a large
change in H* concentration - this is often poorly
appreciated in clinical practice.
l`.`} t Metabolic. acitioss
The metabolic acidoses are conveniently divided on
the basis of the anion gap.
Amon gap : Nat + K+f ( c | ' + H c o f )
The normal anion gap is 10- 18 mmol/I and repre-
sents the excess of negative charge (unmeasured
a nions) present on albumin. phosphate, sulphate
and other organic acids, eg lactic acid.
Rllattonship of metabolic meld to a nion
0 Normal anion gap
Diarrhoea (or other Cl loss)
Renal tubular acidosis
~ Hypoaldosteronism
~ Treatment of ketoacidosis
Increased anion gap
~ Lactic acidosis
~ Ketoacidosis
-
Acute kidney injury and advanced CKD
~ Hepatic failure
Toluene ingestion
Intoxications, eg methanol, aspirin,
ethylene glycol
S pecifi c metabolic a c idose s
Metabolic acidosis with diarrhoea
The gastrointestinal secretions (below the stomach)
are relatively alkaline and have a high potassium
concentration. There is usually hypokalaemia, low
urinary potassium loss ( < 2 5 mmol/l) and low urine
pH ( <5 5 ) . Causes include:
Villous adenoma
Enteric fistula
Obstruction
Laxative abuse
 Metabolic Diseases
l
Table 13.8. Deficiencies of fahsoluble vitamins

Vitamin Causes of deficiency Roles of vitamin Deficiency

syndromes
Vitamin A Severe PEM* Component of visual pigment Night blindness
Maintenance of specialised epithelia Xerophthalmia***
Bitots spots" Follicular hyperkeratosis
l<eratomalacia****
Vitamin D Vegansl Absorption of calcium and phosphate Rickets
Elderly with poor diet Bone mineralisation Osteomalacia
CKD

Vitamin E Severe (near-total) fat Antioxidant Spinocerebellar degeneration

malabsorption
Abetalipoproteinaemia Scavenger of free radicals
Vitamin K Oral antibiotics Cofactor in carboxylation of Bleeding tendency
coagulation cascade factors
Biliary obstruction
*
Although vitamin A is fat-soluble and deficiency can occur in any chronic malabsorptive state, this is rare unless
there is severe protein-energy malnutrition
**
Conjunctival foamy patches are an early sign of vitamin A deficiency
Xerophthalmia - dryness of the cornea
***
* M *
Keratomalacia - corneal ulceration and dissolution
l
Vitamin D; is produced in the skin by photoactivation of 7-dehydrocholesterol. If sun exposure is sufficient,
dietary vitamin D is not essential
ll
Vitamin E deficiency is rare. lt can complicate biliary atresia. In abetalipoproteinaemia ( s ee earlier section)
chylornicrons cannot be formed
* Antibacterial
drugs interfere with the bacterial synthesis of vitamin K

347
 Essential Revision Notes for MRCP

Table 13.9. Deficiencies of water-soluble vitamins

Vitamin Causes of deficiency Roles of vitamin

Deficiency syndromes
Vitamin B1* Alcoholism Nerve conduction Dry beri-beri - symmetrical
(thiarnine)
Dietary Co-enzyme in Polyneuropathy
Bariatric surge ly decarboxylalion Wernicke~Korsal<off syndrome
Wet beri-beri** peripheral
e

vasodilatation, heart failure

Vitamin B2 Severe PEM*** Enzyme cofactor Angular stomatitis
(riboflavin) Clossitis
Corneal vascularisation
Niacin (nicotinic Carcinoid incorporated into NAD Pellagra- dementia, dermatitis and
acid) syndrome and NADP diarrhoea (the three Ds)
Alcoholism
Low-protein diets
Isoniazid
Vitamin B5* lsoniazid Enzyme cofactor Peripheral neuropathy
(pyridoxine) Hydralazine Dermatitis
Glossitis
Vitamin B12 Pernicious anaemia Co-enzyme for DNA Pernicious anaemia
(cyanocobalamin) Post-gastrectomy synthesis; co-enzyme in Subacute combined degeneration of
Vegan diet myelin metabolism the spinal cord
Terminal ileal disease
Blind loops

Vitamin C Dietary Redox reactions Scurvy - bleeding, joint swelling,

Collagen formation hyperkeratotic hair follicles, gingivitis
* Thiamine
deficiency is confirmed by reduced red cell transketolase activity
** ln alcoholics, wet beri-beri must be
*** distinguished from alcoholic cardiomyopathy
" lnRiboflavin deficiency usually occurs with multiple deficiencies
the carcinoid syndrome (and to a lesser extent in phaeochromocytoma) tryptophan metabolism is diverted
from nicotinamide to form amines
i
Isoniazid can lead to deficiency of pyridoxine, which is needed for the
synthesis of nicotinamide from

tryptophan
Dietary deficiency of pyridoxine is extremely rare
it
Deficiency of vitamin C is confirmed by low white cell [buffy coat) ascorbic acid levels

348

Renal tubular acidosis
Renal tubular acidosis (RTA) describes diseases/con-
ditions in which there is a net urinary reduction in
acid excretion, resulting in metabolic acidosis. This
can be due to reduced acid excretion (reduced H
secretion in type i), increased bicarbonate excre-
tion (as a result of loss of bicarbonate reabsorption
in type 2 RTA) or reduced ammonia production
(type 4 RTA). In type 4 RTA the kidney is either
resistant to aldosterone or plasma aldosterone levels
are low. This results in hyperkaiaemia, reduced
ammonia production and acidosis. It is the most
common RTA and occurs in patients with tubulo-
interstitial disease such as diabetes, The RTAs are
covered in more detail in Chapter 15, Nephrology,
Metabolic acidosis with ureteric diversion and
ileal loop diversion
This results in hyperchloraemic acidosis in 80% of
ureterosigmoid diversions. The mechanism is due to
urinary chloride exchange for plasma bicarbonate,
which is then lost in the urine. Urinary ammonia is
also absorbed across the sigmoid epithelium. Ileal
loop diversions also result in significant hyperchlor-
aemi c acidosis but less so than ureterosigmoid
diversions.
Metabolic acidosis accompanying poisoning
Metabolic acidosis often accompanies poisoning
(eg toluene, ethylene glycol, salicylates, paraceta-
mol). See also Chapter 2, Clinical Pharmacology,
Toxicology and Poisoning,
13.7.2 Metabolic alkalosis
Metabolic alkalosis is less common than metabolic
acidosis because metabolic processes produce acids
as by-products, and also because renal excretion of
excess bicarbonate is very efficient. Many causes of
metabolic alkalosis are associated with hypokalae
mia,
Metabolic Diseases
0 Gastrointestinal hydrogen ion loss
Vomiting/pyloric stenosis
~ Nasogastric suction
Antacids (in CKD)
0 Intracellular shift of hydrogen ion
v
Hypokalaemia
0 Alkali administration
0 Renal hydrogen ion loss
~ Mineralocorticoid excess, eg Cushing
syndrome
Loop or thiazide diuretics
Post~hypercapnic alkalosis
Hypercalcaemia and the milk-alkali
syndrome
0 Contractional alkalosis
Volume depletion
Specifi c metabolic alkaloses
Gastric loss of hydrogen ions
ln protracted vomiting (eg pyloric stenosis) or naso-
gastric suction there can be complete loss of up to
3 litres of gastric secretions per day. The gastric
secretions contain:
0
Hydrogen ions: TOO mmol/I
0 Potassium: 15 mmol/l
O Chloride: 140 mmol/I
Alkalosis will result but, paradoxically, acid urine is
produced due to renal tubular sodium bicarbonate
reabsorption to maintain plasma volume, Patients
respond to volume expansion with normal saline
and correction of hypokalaemia.
Milk-alkali syndrome
This is defined as the triad of hypercalcaemia, meta-
bolic alkalosis and ingestion of large amounts of
calcium with absorbable alkali (traditionally for
peptic ulcer pain). The hypercalcaemia increases
349
Essential Revision Notes for MRCP

renal bicarbonate reabsorption, exacerbating the Mild hypothermia (32-35C) causes shivering and
alkalosis. Clinical presentation is with symptoms of intense feeling of cold, altered judgement and
hypercalcaemia or metastatic calcification. ataxia.

Post-hypercapnic alkalosis Moderate hypothermia (28~32C): patients are of-

Chronic respiratory acidosis leads to a compensa~
tory increase in urinary hydrogen ion secretion,
resulting in a rise in plasma bicarbonate concentra
tion. Rapid lowering of a raised pCO; (usually by
mechanical ventilation) is not immediately accom-
panied by a fall in plasma bicarbonate. There is
often an accompanying chloride loss that must be
replaced before bicarbonate can fall to normal,
13.8 HYPOTH ERMIA
Hypothermia is defined as a fall in core temperature
to below 35C. lt is frequently fatal if the core
temperature falls below 32C,
_ :~-Q ,.\._>'<',-.;f..._f.1;; ,f,gf-,;;,;_~f_t 1/ e y
0
Exposure to low external temperatures
Elderly with inadequate heating
Immersion in cold water
~ Mountaineers
ten unconscious and lose the ability to shiver. The
risk of arrhythmias increases.
Severe hypothermia (<28C] increases the risk of
asystole, coma, apnoea, fixed pupils, pulmonary
oedema and death.
' Clinical features of hypothermia include
bradycardia, hypoventilation, muscle stiffness,
cold diuresis, hypotension and loss of reflexes.
The pupils can be fixed and dilated in
recoverable hypothermia
0 Metabolic acidusis due to lactate accumulation
is common; pancrearitis can complicate
hypothermia
0
Electrocardiograph changes: include I waves,
prolonged PR interval, prolonged QT and QRS
complexes, Death results from ventricular
- , f , . arrhythmias or asystole
In certain medical situations therapeutic hypother
mia (cooling to 32-34C) can be induced (eg after
cardiac arrest, complex cardiac surgeiy). This re-
duces tissue oxygen requirements and can improve
patient outcomes.

-
0 Medical conditions
Hypothyroidism
Hypoglycaemia 13.8.1 Treatment of h y p o th ermia
CNS disorders, eg stroke,
hypopituitarism Hypothermia >30C: Surface rewarming is usually
Post cardiac arrest and unconscious adequate with removal of wet clothes, and pro-
patients vision of warm blankets and heaters.
0
Drugs
Hypothermia <30C: Active internal warming until
.
General anaesthetics
Alcohol core temperature is at least 32C using warm IV
fluids and warm humidified oxygen. If necessary,

350

peritoneal lavage, pleural lavage and haemodialysis
can also be helpful. Cardiac bypass can be used in
patients who are in ventricular fibrillation or who
have profound hypothermia and are deteriorating.
Cardiac arrest in t he hypothe rmic p at i en t
Severe hypothermia can mimic death. Consequently
cardiopulmonary resuscitation should be continued
in hypothermic patients until the patient has been
Metabo/ic Diseases
rewarmed or until all attempts have failed to im-
prove core temperature. The hypothermic heart has
reduced responsiveness to cardiac drugs, pace-
makers and defibrillation. Cardioactive drugs can
also accumulate as drug metabolism is decreased.
Therefore, IV drugs are often withheld until core
temperature is above 30C, Hypotherrnia protects
the brain during cardiac arrest, so patients can have
a full neurological recovery despite prolonged car-
diac arrest.
351

l. CONTENTS
14.1 Molecular d iag n o s tics
14.1.1 Genomes, transcriptomes,
proteomes and metabolomes
14.1.2 The polymerase chain
reaction (PCR)
14.1.3 Reverse transcription PCR
(rt PCR)
14.1.4 Monoclonal antibodies
14.1.5 Antibody-based assays
14.2 Cell s ig n allin g
14.2.1 Types of receptor
14.2.2 Protein kinases and
phosphatases
14.2.3 Nuclear hormones
14.2.4 Transcription factors and the
regulation of gene expression
14.3 T he m o l e c u l a r p ath o g en es is
of c a n c e r
14.3.1 Somatic evolution of cancer
t.
14.3.2 Oncogenes
14.3.3 Tumour suppressor genes
14.4 Ap o p to s is a n d dise a se
L 1410. 5 Mitochondrial disorders
14.5 Molecular r egulation of
va sc ula r t o n e
C
14.5.1 Nltl'lC Oxide (NO)
14.5.2 Endothelin-1
L 353
C h a p t e r 14
Molecular Medicine
14.6 Molecular m ediators of
infl ammation, da m a ge and
r ep air
14.6.1 Interleukin 1 (lL-1)
14.6.2 Tumour necrosis factor (TNF)
14.6.3 Transforming growth factor [5
<TGF[5)
14.6.4 Heat shock proteins (HSPs]
14.6.5 Free radicals and human
disease
14.7 Transmissible s p o n g if o n n
e n c e p h a l o p a t h i e s (TSES)
14.8 Adhesion molecules
14.9 Stem cells
14.10 The m olecular ba s is of s o m e
i m p o r t a n t dise a se s
1410. 1 Amyloidosis
1 4 ,1 0 .2 Alpha-1~antitrypsin deficiency
14. 103 Alzheimers disease
14.10.4 Trinucleotide repeat disorders
14.10.6 Myasthenia gravis
14.10.7 Duchenne muscular dystrophy
1 4 1 0 . 8 Sickle cell disease
14.11 G los s ary of t erms in
molecular medicine
 Molecular Medicine

Molecular Medicine

14.1 MOLECULAR DIAGNOSTICS are orthologues (have a common ancestral gene

The diagnostic process in medicine is entering a
new and imponant historical phase, increasingly,
diagnostic entities are being reclassified according
to the molecules that are central to the disease
process and also according to changes in the ex-
pression of genes which code for these molecules.
With the advent of the complete human gene se-
quence we now have the tools for a complete
understanding of how cells develop and how they
function in health and disease.
14.1.1 Genomes, tr an scr ip to m es.
p r o teo m es and metabolomes
The genome of an organism is its complete comple-
ment of coding genes. Comparing the organisms in
Table 14.1 reveals that the level of complexity of an
organism is not explained by the number of genes
predicted to code for protein. Fruit flies (Drosophila
melanogaster, a favourite organism for geneticists)
have more complex behaviours than nematode
worms (Caenorhabditis elegans) but fewer genes.
One reason for this is that flies process genes in a
more complex way. Humans and mice have the
same number of predicted genes and 98% of these
and code for equivalent proteins). Biological com-
plexity is explained by:
0 The transcriptome: this is the name given to the
total complement of expressed mRNA
sequences in an organism. In lower organisms
this will be the same as the number of genes. ln
mammals genes are transcribed in a more
complex way, with transcription being initiated
from different exons in different tissues and
alternative splicing (post-transcriptional
processing). The temporal (when in
development) and spatial (in which cells)
expression of genes allows significant diversity
which is not evident just from looking at gene
number. lt is likely therefore that the
transcriptomes of mice and humans contain
significant differences
0 Processed mRNA is translated into protein.
Similarly, differences in mRNA transport,
localisation and stability mean that the
proteome cannot be inferred directly from the
transcriptome
0 Posl-translational processing: proteins can be
modified by glycosylation, sialydation, etc.
Protein stability and turnover may be very

Table 14.1. The genomes of various organisms

Organism Number of proteins Approx. genome size Introns Splicing

Human 30 OOO 3 x 10 <3Gb) Yes Highly complex
Mouse 30 OOO 3 Gb Yes Complex
L. Fruit fly
y
13 500 40 ><10 (40 Mb) Yes Yes
3 Nematode 19 000 96 Mb Very few Very little
Fission yeast 6 OOO 12 Mb Rare Absent
,
Bacterium 2 OOO-6 OOO 2 - 6 Mb Absent Absent

r
li 355

l
Essential Revision Notes for MRCP
different in different cell types and between
similar cells in different organisms
I
Finally, the progressive diversity ofthe proteome
with evolution leads to an exponential
amplification of combinatorial possibilities
between proteins. Therefore, while the human
genome may have 30 O00 information units
(genes) the final number of information units
needed to explain human biological complex is
theoretically several orders of magnitude greater
The Human G enome P roj ect
The Human Genome Project (HCP) was possibly
the greatest scientific undertaking in recent history,
The project began in 1990 and sequencing was
completed in 2003. Analysis of the vast amounts of
data generated by the project is still ongoing, but
medical science has already profited from the re-
sults. As a direct consequence of the HCP, genetic
tests are now available that show predisposition to a
range of diseases, including breast cancer, cystic
fibrosis and liver diseases.
The main goals ofthe HCP were to:
0
Identify all the approximately 20 O00-25 OOD
genes in human DNA
0 Determine the sequences of the 3 billion
chemical base pairs that make up human DNA
0 Store this information in databases
I
Improve tools for data analysis
I Transfer related technologies to the private
sector
0 Address the ethical, legal, and social issues
(ELSI) that may arise from the project
356
i
?
The HGP created the field of genomics, that of
understanding genetic material on a large scale, The
field of medicine is profiting from the HCP as we
learn more about the genetic contribution to dis-
ease.
5
K
W
Fluorescent in-situ hybridisation
Fluorescent irl-situ hybridisation (FISH) is a tech-
nique that, using fluorescently labelled DNA probes
(often derived from fragments of DNA that were
isolated during the HCP), can detect and confirm
gene and chromosome abnormalities beyond the
resolution of routine cytogenetics.
Sample DNA is first denatured, converting double-
stranded to single-stranded DNA. The fluorescently
labelled probe (complementary to the DNA se-
quence of interest) is then added to the single-
stranded DNA. lf the DNA sequence of interest is
present in the sample the probe hybridlses with the
complementary bases as the DNA re-forms back
into a double helix. The probe signal can then be
detected through a fluorescence microscope and
the sample DNA scored for the presence or absence
of the signal.
FISH can be performed using two sample types:
metaphase chromosomes and interphase nuclei. l
Metaphase FISH
FISH can be performed on metaphase chromosomes
to detect specific microdeletions undetectable by
routine cytogenetics, or to identify chromosome
translocations or extra material of unknown origin.
y Molecular Medicine

I 0 Cri-du-chat syndrome
A syndrome that results from the deletion of part of the short arm of chromosome 5. The main
1 clinical feature is the presence of a high-pitched 'cat-like cry present in the newborn that may
r disappear with age. Other features include a round, full face, widely spread eyes (hypertelorism),
1
an extra fold of skin at the inner corners of the eyes (epicanthal folds), a flattened and widened
nasal bridge and ears that are positioned low on the head, severe cognitive, speech and motor
delays and feeding problems from birth which may lead to poor growth
0 Miller-Dieker syndrome
A congenital malformation syndrome that results from the deletion of several adjacent genes in
the short arm of chromosome 17 (17p]. Clinical features include lissencephaly and a
characteristic facial appearance (prominent forehead with bitemporal hollowing, short nose with
upturned nares, thickened upper lip with a thin vermilion upper border, widely spaced eyes, low
ears, and small jaw). The syndrome may result in mental retardation, epilepsy, pre- and postnatal
'

growth retardation, and reduced lifespan. There may also be multiple abnormalities ofthe brain,
kidneys, heart, and gastrointestinal tract
0
Smith-Magenis syndrome
e Results from a microdeletion in the short arm of chromosome 17 [del(17)(p1 1.2 p11.2)l. Aswell
as characteristic facial abnormalities [short flat head, prominent forehead, broad square face,
upslanting eyeslits, deep-set eyes, underdeveloped midface, broad nasal bridge, short nose and
tented upper lip) the syndrome may also cause mild to moderate mental retardation
I Steroid sulphatase deficiency
~ Also known as X-linked ichthyosis, it is a genetic disorder of the skin that occurs only in males.
The condition develops in infancy and manifests as tan or grey scales on the skin that are a result
of a deficiency in the enzyme steroid sulphatase due to genetic mutations of the gene
0
DiGeorge syndrome (also known as velo-cardio-facial/CATCH-22/Shprintzen syndrome) (see
Chapter 7, Section 7.1.3 and Chapter 10, Section 10.9.4)
0 Kallman syndrome (see Chapter 4, Section 4.8.3)
0 Williams syndrome (see Chapter 1, Section 1.3.5 and Chapter 7, Section 7.1.3)
0 Wolf-Hirschhorn syndrome
~ Results from a partial deletion of the short arm of chromosome 4. Many parts of the body are
affected by this syndrome as the deletion affects fetal growth and development. Common
features include profound mental retardation, microcephaly, seizures, low muscle tone and poor
muscle development, heart defects and cleft lip and/or palate
U Prader-Willi/Angelman syndrome (see Chapter 7, Section 7.6]

can be performed very rapidly as cell growth is not

Interphase FISH required.

FISH can be used in interphase cells to determine
the chromosome number of one or more chromo-
somes as well as to detect some specific chromo-
s o me rearrangements characteristic of certain
cancers. The advantage of interphase FISH is that it
An example of interphase FISH is the aneuploid
screen test performed on amniotic fluid cells to
determine the presence of the common trisomies.
Sample nuclei are denatured and incubated with
probes for chromosomes 13, 18, 21, X and Y,

357
Essential Revision Notes for MRCP
Transcri pt om i cs
The gene expression profile (transcriptome) of a
particular tissue is the key to understanding the cell
phenotype in health and disease. An average cell
expresses about 16 000 genes throughout its lifetime
but clearly the range of genes expressed in the
lifetime of an individual cell will vary during
development, maintenance and ultimately cell
death. inevitably the genes expressed by a neurone
in the cerebellum will be very different from those
expressed by a lymphocyte, though housekeeping
genes are common to many cells and encode con-
stitutive cellular processes.
The transcriptome of a cell can be captured using a
technique known as microarray analysis, This de-
pends on the same hybridisation reaction as other
nucleic acid techniques but represents dramatic
scaling up of the procedure such that many thou-
sands of hybridisation reactions occur on a single
medium and changes in transcription in many genes
can be assessed simultaneously. RNA is prepared
from the tissue of interest (for example, a tumour
biopsy specimen) and from a control sample (eg
normal tissue from the same organ from which the
biopsy was obtained), The RNA is hybridised to a
'DNA chip. This consists of a silicon slide i - 2 cm
in size onto which have been spotted oligonucleo-
tides, 2 0 -3 0 base pairs long. Each oligonucleotide
represents a particular gene. The RNAs from the
abnormal and control tissues are labelled with dif-
ferent colour fluorescent dyes (eg red and green)
and the level of expression of many thousands of
genes can then be analysed by computer software
which compares the differences in intensity gener-
ated bythe hybridisation reaction.
0 The power of this technology is such that it is
not necessary to know anything about the
function of the particular gene spotted onto the
chip
0 As the sequence of every gene is now known,
DNA chips with a representative coverage of the
whole human genome can be produced
commercially
0 It is also possible to produce tissue-specific
chips (eg human CNS) or chips with a limited
358
number of genes of interest for use in
diagnostics, when a specific question is being
asked
I DNA microarrays can in principle identify a
whole array of downstream genetic
consequences of a particular gene mutation and
provide a molecular profile of a disease state
that can act as a marker of therapeutic effect
Practical ap p l i cat i o n s
0
Rapid sequencing for many genetic mutations
can be performed simultaneously in a high-
throughput approach. For example, specific
oligonucleotides that recognise all of the
mutations responsible for a particular disease
can be spotted onto a chip and DNA from an
affected individual analysed
0 Tumours or other abnormal tissue can undergo
molecular profiling in order to identify patterns
of gene expression. For example, it is now
possible in clinical practice to use microarrays
to analyse the expression of panels of key genes
that determine the clinical response to
chemotherapeutic agents in lymphoma. Also,
tissue or fluid from infections can be analysed
for the expression of genes conferring antibiotic
resistance before organisms have even been
cultured
0
Though still a research tool it is likely that
microarrays will be routinely used in the near
future in genotyping large numbers of genes
simultaneously' to look at specific disease risk
(eg cardiovascular) associated with single
nucleotide polymorphisms (SNPs) or other
genetic variants
0 Individual responses to common drug
treatments (eg antihypertensive agents) are likely
to have a basis in genetic va r ia tion, The
application of knowledge acquired through
genetic profiling such as with microarrays is
known as pharmacogenomics
Proteomics
As discussed above, the total protein content of a
cell or tissue may be a more meaningful target for
analysis in certain situations than either the genome

or transcriptome. Protein from whole tissue or from
subcellular fractions (eg membrane, nuclear, mito-
chondrial] can be separated by physical methods,
such as on a 2-D gel, in which proteins are resolved
by charge and mass to produce individual spots on
a polyacrylamide gel which can then be silver-
stained. Individual spots of interest can be removed
and eluted from the gel. The protein within can then
be identified using tandem mass spectrometry
which can sequence short peptides, A known pro-
tein can then be identified by reference to protein
sequence databases.
Where the oligopeptide does not produce a match,
a search can be made of the human genome
sequence databases - computer programmes have
been used to predict genes and therefore protein
sequences from the primary data (an example of
what is known as bioinformatics), Currently, proteo-
mics is largely a research tool, but with time and
improved technology it will inevitably be used in
clinical practice.
Potential applications include
0 The identification of all of the proteins
expressed in a particular cell, groups of cells or
whole tissues throughout the whole
development of an organism from conception to
death. Ultimately a complete description of the
ontogeny of the cell will be possible allowing
virtual modelling and computer-based drug
design
ogy, preclinical drug trials, toxicology, transplant
Comparisons can be made between healthy and
diseased tissue in the same way as for mRNA
with microarrays. However, the advantage with
proteomics is that it may be possible to detect
differences at the protein level which are not
reflected at the transcriptional level due to
changes in turnover or post-translational
processing. As with RNA techniques, protein
from different sources can be differentially
labelled with fluorescent dyes to aid the
detection of differences
U Protein chips contain antibodies spotted onto
silicon-based media similar to microarrays.
Several hundred targeted proteins can be
analysed in this way
Molecular Medicine
Metabolomics
Metabolomics is the study of the specific and
unique metabolite profile left behind by cellular
processes. ln different disease states it is thought
that this profile of small metabolites changes. If
characteristic profiles for specific diseases can be
determined, it may be used as a diagnostic tool.
The metabolome is the complete set of small-
molecule metabolites found in an organism. Like
the transcriptome and proteome, the metabolome
is constantly changing. At present the Human
Metabolome Project (http://'metabolomicscai has
identified and quantified over 300 metabolites in
cerebrospinal fluid, over 1000 metabolites in ser-
um, over 4O0 metabolites in urine and approxi-
mately 300 metabolites in other tissues and
biofluids, but the major limiting factor in the appli-
cation of this technology is the incomplete charac-
terisation of the human metabolome. With many of
the molecules being small and difficult to extract,
further work is required so we can use the 'whole'
metabolome in disease diagnosis. The metabolome
of an organism is related to both its genotype and
physiology and can also be affected by its environ-
ment (what it eats and breathes). This complex
interaction therefore allows us to look at geno-
type-phenotype as well as phenotype-envirom
ment relationships.
Metabolomics technology is increasingly used in a
variety of health applications, including pharmacol-
monitoring, newborn screening and clinical chem-
istry.
There are four key steps:
1. Efficient and unbiased extraction of the
metabolites from biological samples
2. Separation ofthe analytes (typically by
chromatography, either gas or high-performance
liquid chromatography)
3. Detection of the metabolites following
separation (usually by either mass spectrometry
(MS) or nuclear magnetic resonance (NMR))
4. Identification and quantification of detected
metabolites
359
Essential Revision Notes for A/(RCP
Physicians are now coming to understand that meta-
bolic profiling can be used in the diagnosis, predic~
tion, prevention and monitoring of many genetic,
infectious and environmental diseases, In practice,
complex computer software looks for patterns and
changes in the metabolic profile from samples taken
from patients with a particular disease compared
with healthy controls. Having been 'taught' that a
particular pattern is characteristic of a disease, sam-
ples from patients with unknown disease status can
then be screened comparatively.
14.1.2 The polymerase chain reactio n
(PCR)
PCR is an amplification reaction in which a small
amount of target DNA (the template) is amplified to
produce enough to perform analysis, This might be
the detection of a particular DNA sequence, such
as that belonging to a pathogenic microorganism or
an oncogene, or the detection of differences in
genes, such as mutations causing inherited disease.
Therefore, the template DNA might consist of total
human genomic DNA derived from peripheral
blood lymphocytes, amniocentesis or chorionic vil-
lus sampling; alternatively, it might consist of a
tumour biopsy or a biological fluid from a patient
with an infection.
I Two unique oligonucleotide sequences, known
as primers, are mixed with a DNA template and
a thermostable DNA polymerase (Taq
polymerase, derived from an organism that
inhabits thermal springs). Sometimes more than
two primers can be used if more than one gene
is to be amplified (multiplex PCR) or the region
of DNA to be amplified needs special definition
('nested' PCR) for example, if it is similar to
other sequences in the genome which may give
spurious reaction products
0 ln the initial stage of the reaction the DNA
template is heated (typically for about 30
seconds) to make it single-stranded and then as
the reaction cools the primers will anneal to the
template if the appropriate sequence is present
0 Then the reaction is heated to 72C (for about a
minute) and the DNA polymerase synthesises
360
new DNA between the two primer sequences.
During 30 or so cycles (each typically lasting a
few m inutes) the target sequence will have been
amplified exponentially
The crucial feature of PCR is that to detect a given
sequence of DNA it only needs to be present in one
copy (ie one molecule of DNA); this makes it
extremely powerful.
U Mutation detection
0 Detection ofviral and bacterial sequences
in tissue (herpes simplex virus in CSF,
hepatitis C, HIV in peripheral blood,
meningococcal strains)
0
Single-cell PCR of in vitro fertilised embryo
to diagnose genetic disease before
implantation
In the example in Figure 14.1, some CSF from a
patient suspected of having herpes simplex ence-
phalitis is used in a PCR reaction in an effort to
detect the presence of the virus directly,
Small amounts of target DNA are amplified with a
thermostable DNA polymerase.
14.1.3 Reverse t r a n s c r i p t i o n PCR
(rt PCR)
Conventional PCR looks at genomic DNA. Every
cell in our body contains our total genome in two
copies. However, the phenotype of a cell (what
makes a hepatocyte different from a Purkinje cell)
depends on which genes are being expressed at any
one time. To look at the expression of genes we
must therefore analyse only those genes that are
being transcribed into mRNA,
0 RNA is too unstable to be used in PCR so it
must first be converted to complementary DNA
(cDNA) using reverse transcriptase, a retroviral
enzyme that makes a precise copy of the mRNA
0 PCR is then performed in the normal way but,
because the template reflects the mRNA of the
 Molecular Medicine

Figure 14.1 The polymerase chain reaction (PCR)

Cerebrospinal fluid from a patient with en cep h alitis is healed 5' ]

I up and any viral DNA is liberated and s ep ar ated into single- 3` S
stranded DNA

s-is

i

The primers sp ecifi c for herpes simplex virus DNA bind lo

the virusspecil'|c sequences if present
s' -
_l i s
J ' _ * * l i

5 ' l _ _ _ - L ->
i
i lac DNA polymerase synthesises a new daughter strand on
the DNA template, resulting in double the number of copies
oi the starting DNA < - - - - _ -
3' S'

i.
After 30 cycles, the PCR product is analysed by agarose
i
electrophoresis. In this example, lane 1 contains a DNA siz e
marker, lane 2 a PCR reaction product using pure viral DNA
as a control. Lane 3 was generated using CSF from a
patient with HSV encephalitis and lane 4 is a control with no
CSF in the reaction to assess contamination

starting material, this technique can look at
gene expression in individual tissues
. useful diagnostic and therapeutic antibodies must
0 Detection of the expression of particular
genes in tumour tissue carries important
prognostic information
0 Basic scientific research into normal
function of disease genes by understanding
their spatial and temporal expression
high specificity for the target protein. An immune
response to an antigen consists of a polyclonal
proliferation of cells giving rise to antibodies with a
spectrum of specificity for the target. Therefore,
be selected from this complex immune response
before they can be used.
Myeloma is a malignantly transformed B-cell lineage
that secretes a specific antibody. This fact is used to
produce unlimited amounts of specific antibodies
directed towards an antigen of choice.

0 A laboratory animal is injected with the antigen

1/1.1.4 Monoclonal an tib o d ies of choice (Figure 14.2); it mounts an immune
response and its spleen, which contains B-cell
The detection of specific proteins in molecular diag- precursors with a range of specificity for the
. nosis relies on the fact that the antibody used has a antigen, is harvested

361
l
Essential Revision Notes for /VIRCP
l Figure 14.2 Monoclonal antibody production
l Antigen ?>
l munised sple e n cells
Purify a n t i l > o d y < i G'W *Ve
clones
0 The spleen cells are fused en masse to a
specialised myeloma cell line that no longer
produces its own antibody
0 The resulting fused cells, or hybridomas, grow
in individual colonies/ are immortal and
produce antibodies specified by the
lymphocytes of the immunised anim al, These
cells can be screened to select for the antibody
of interest which can then be produced in
limitless amounts
,Ciisricatappticatiournofmnnodonal
slrtibdin~~ s
..
Diagnosis of cancer and infections
Imaging of tumours, radiotherapy
As a 'magic bullet to direct drugs to target
Transplantation and other immune
modulations (eg OKT3)
14.1.5 /Xntibody-based a s s a y s
An assay is defined as a procedure where a property
or concentration of an analyte is measured. In
medicine the specific binding of labelled antibodies
362
l
g
. _ /
Myeloma Cells
\` /Fusion
` Hybridoma cells
Isolate cells +ve for antibody
by dilutional cloning
/
is used to assay for a huge range of analytes that
may aid in the diagnosis of disease. Assays are
available for numerous serum proteins (growth fac-
tors, cytokines, clotting factors, etc) as well as for
proteins found on infectious organisms (bacterial
and viral). Previous radioactive methodology (radio-
immunoassay (RIA) and immunoradiometric assay
(lRMA)l is being replaced by enzyme immuno-
assays, the most common of which is the enzyme-
linked immunosorbent assay (ELISA).
~
l. A plate is coated with capture antibody specific
to the analyte of interest (Figure 14.3)
2. Sample is added and incubated for sufficient
time to allow any analyte present to bind to the
capture antibody; non-specific, unbound
proteins are washed off
3. Secondary antibody is added that also
recognises the antigen, but which has been
raised against a different part of the protein so
~
both antibodies can bind at the same time.
Excess secondary antibody is washed off
4. Enzyme-linked tertiary antibody is added that
recognises the secondary antibody; excess
tertiary antibody is washed oft
 Molecular Medicine

Figure 1 4 .3 The ELISA assay process

3

i
& _ Q
/" i
`\
i
;
.

5. Substrate is added and is convened by the
linked enzyme to a detectable form [fluorescent
or colorimetric). The intensity of signal is
directly proportional to the amount of analyte
present. Concentration is calculated by
constructing a standard c u n / e with known
amounts of analyte
signals can only effect changes inside the cell by
interaction with membrane-bound receptor mod-
ules. This biologically ubiquitous system of signal
transduction by receptors underlies the action of
many hormones, growth factors and drugs.

Figurel4.4 A typical signalling pathway (the

rod receptor). This involves a G-protein- f
14.2 CELL SIGNALLING couPled membrane rece Ptor which activates a
Central to all cellular processes is the conversion of
second messenger pathway I
I

external signals (first messengers) via intermediates

l

Hrsl messenger Photon

(second messengers) into changes that alter the state
of that cell. This often involves adjustment in the
Seven helix mutit R hodops in
expression of genes in the cell nucleus and new receptor
protein synthesis. in the following example (see
Figure 14.4) a photon of light is the external stimu Transclucin L

lus that produces, via second messengers, a change G-protein

in the resting state Of the rod cell, leading it to
P hos phcdies teras s
transmit a signal to the visual cortex.

cGMP Amplification
14.2.1 Types of r e c e pt or l
V
Seoond rnnxenger
The chief function of the cell membrane is to Closure of cGMP-dependent ion channels
provide a barrier to ion flu>< and therefore to main
tain the internal milieu of the cell. There are, as
described below, certain lipophilic modules which Hyperpolaris ation of the rod cell
travel freely into the cell. However, most external

363
Essential Revision Notes for MRCP
Li gand-gat ed i o n c ha nne l
For example, acetylcholine receptor (nicotinic):
0 Five non-covalently assembled subunits (d;B~/6)
are located at the post-synaptic neuromuscular
junction
I Each subunit is coded for by a different gene
which enables mixing and matching of subunits
between different tissues and in embryological
development to generate a repertoire of
responses
0 On binding of acetylcholine to the or subunits
the whole complex undergoes a conformational
change leading to the passage of sodium ions
into the cell and cellular depolarisation
Other examples include some glutamate receptors
(excitatory), y-aminobutyric acid (GABA) and gly-
cine (inhibitory: the passage of chloride ions into
the cell renders it more resistant to depolarisation),
R ecep t o rs t ha t co n t ai n cy t o p l as mi c doma ins
w ith p ro t ei n -t y ro s i n e-k i n as e act i v i t y
0 Insulin binds to its receptor which then
undergoes dimerisation and
autophosphorylation at a tyrosine residue
0 The tyrosine kinase activity intrinsic to the
receptor is then activated and the result is the
phosphorylation of cytoplasmic proteins and
initiation of an intracellular cascade
0 This ultimately leads to the action of insulin on
glucose uptake, etc
Figure 1 4 .5 G-proteins are activated by ligand binding to a transmembrane receptor
iiga na
cell membrane
G-protein
, _
\ D-\_>activation
GDP
364
Other examples include platelet-derived growth fac-
tor, insulin-like growth factor i (IGF-1), macrophage
colony-stimulating factor, nerve growth factor.
G-protein-coupled re c e ptors
Cuanine nucleotide-binding proteins are a ubiqui-
tous cellular mechanism for coupling an extracellu-
lar signal to a second messenger, such as cyclic
AMP (Figure 14.5).
0
G-proteins have three non-covalently associated
subunits: ci, B,y. ln the inactive state GDP is
bound tothe oi subunit of the G-protein
0 When the receptor is activated by ligand
binding, the G-protein is activated by the
hydrolysis of GTP to GDP
O In this active state the <1 subunit dissociates from
the [3and 7 subunits. Either of these two
complexes (the GTP-0. or the [3-y) can then
interact with second messengers
0 The ct subunit is rapidly inactivated by
hydrolysis of GDP to GTP (this is an intrinsic
property ofthe or subunit, which is therefore
known as fi - G TPa se ) and then re-associates with
the [5and y subunits, resetting the whole system
to the inactive state
C-proteins can be inhibitory (Gi) or stimulatory (Cs)
and the overall activity of a second messenger such
as adenylate cyclase is likely to be regulated by the
diiterential activation of these different forms, The
muscarinic acetylcholine receptor, the oi and [5
adrenergic receptor and the retinal photoreceptor
rhodopsin are all G-protein-coupled receptors.
oi second
messengers
GTP

These can be linked to a variety of second messen-
ger systems or sometimes directly to ion channels.
Diseases auswtazui with G -pmt e m
sy.
I Cholera: Vibrio cholerae secretes an
exotoxin that catalyses ADP-ribosylation of
an arginine residue on Gsa. This makes the
subunit resistant to hydrolysis and the
second messenger (in this case cAMP)
remains activated and this ultimately leads
to the fluid and electrolyte loss
characteristic of the disease
0
Pituitary adenomas*
0
McCune-Albright syndrome*
0 The human genome is present in two copies in
Alhrights hereditary osteodystrophy* (or
pseudohypoparathyroidism)
*See Chapter 4, Endocrinology
14.2.2 Pr ote in kinas es a n d
phospha t a se s
Protein kinases catalyse the transfer of a phosphate
group from ATP to a serine, threonine or tyrosine
residue on a target protein (the substrate). Phosphor-
ylation of this amino acid residue results in an
alteration in the conformation of the target protein
and thus leads to its activation or inactivation. Many
growth factor receptors are protein tyrosine kinases
(see above). Many of the 'downstream' intracellular
pathways that are initiated by the activation of a
second messenger system involve protein kinases
(usually serine kinases in the cytoplasm). In this way
an external signal can, through the activation of one
receptor, influence a vast array of cellular processes
due to a cascade of protein inte r a c tions,
14.2.3 Nuclear hormones
Not all extracellular signals use second-messenger
systems to effect changes to the cell. important
exceptions are steroid hormones that bind to an
intracellular receptor, allowing the receptor to be
freed from its cytosolic membranebound anchor
(Figure 14.6), The receptor-hormone complex then
Molecular Medicine
travels to the nucleus where it binds to specific
regions of DNA called hormone-responsive ele-
ments (HRE), thereby effecting alterations in the
transcription of DNA,
Exam pl es of nuclear homlones
Corticosteroids
Vitamin D
Relinoic acid
Sex steroids
14.2.4 Tran scrip tio n factors a nd the
regulation of g en e e x p re s s i o n
every cell in the body, and is estimated to consist of
around 30000 genes. The spatial and temporal
expression of a proportion of these genes (typically
10000- I 5 OOO genes are expressed in any one cell
at any time) determines the differentiation, morph-
ology and functional characteristics of each cell
type (the cellular phenotype), Clearly, for cells to
maintain a specific identity, this process must be
very tightly regulated.
Eukaryotic genes consist of exons, which are tran-
scribed into the mRNA template, which is translated
into protein (Figure 14.7). Exons are separated by
introns, which do not code for protein but have a
role in mRNA stability and are spliced out of the
premRNA prior to translation. Sometimes exons are
also spliced out to produce variant forms of the
protein with tissue-specific functional elements
(splice variants).
Clearly some genes have a fundamental biological
role and will be expressed in all cells at all times
(housekeeping genes). However, the transcription
of most genes only proceeds when a macromolecuf
lar complex (the initiation complex) binds to a
region of the 5 end of genes called the promoter.
The assembly of this complex is directed by the
presence of transcription factors and facilitates the
binding of RNA polymerase, which leads to tran-
scription. Muscle, for example, will contain specific
transcription factors that lead to the expression of
365
Essential Revision Notes for MRCP

Figure 1 4 .6 The nuclear hormone superfamily of receptors act by conlrollinggne transcription in the
nucleus
Steroid hormone
#ie
Steroid h o rm o n es ar e lipid-soluble so
can easily diffuse across the cell m em b ran e Cell membrane
.H , . . . . . t . .

li ~.
1 . . . . . -. . _ ; . .
`,t ..........f.........,.t ...-.,.,-....1 .............~.........i M .

Steroid hormone
feCSPlOi Upon ligand binding the r noptor
to form an acflvo tran scrip tio n factor
menus

Actlvahd transcription factor binds

to its spocifh: n t p o n u clemont In DNA
T

av Activation/repression of cell transcription

and alteration of cell state

-i
HRE

366
 Figure 14.7 Structure o fa typical gene
DNA

T-
Promote r
Exon 1

Pre-RNA

\ _ _ /
5' UTR
Intron 1

Mature mRNA
Exon 2

1
Intron 2

_
EKOII 3

Transcription

Splicing
Intron 2
r
Molecular Medicine

EXOI1 4

la
3' UTR
_
\

;
l
5

P
Translation
l
I Protein

l
l

muscle-specific genes which determine the muscle 0 Enhancers are not obligatory for the initiation of
phenotype, transcription but alter its efficiency in such a
way as lo lead to an increase in gene expression
T h e p ro m o t er
0 A modular arrangement of different elements
that act as a binding site for RNA polymerase ll 5 untra nsla te d r e g i o n (5 ' UTR)
and the initiation of transcription

i
0 The initiation of transcription involves a large The five prime untranslated region <5' UTR) is a
l section of mRNA and the DNA that codes for it. lt
complex of multimeric proteins (RNA
i
starts at the transcription start site and ends just
polymerase ll plus the general transcription before the transcription start codon (usually
factors (GTFs): TFll A -H )
r
0 The GTFs can activate transcription of any gene AUC). The region can contain several regulatory
that has a TATA box (see below) sequences:

I A ribosome-binding site
Enha nc e rs 0
Binding sites for proteins that may affect the
I Elements that can be at the 5' or the 3' end of stability or translation rate of the mRNA
genes and can vary in distance from the coding 0
Sequences that promote the initiation of
sequence itself translation

367
Essential Revision Notes for MRCP
3 untra nsla te d reg i o n (3' UTR)
The three prime untranslated region (3 UTR), like
the 5' UTR, is a section of mRNA and the DNA that
codes for it. it starts after the stop codon (usually
UAG, UAA or UGA) and may contain several
regulatory sequences:
0 A polyadenyiation signal. This initiates the
cleavage of the transcript, which usually
happens about 30 base pairs downstream. This
is then followed by the addition of several
hundred adenine residues (poly-A tail)
U
Binding sites for regulatory proteins, These
proteins may af-fect the stability or cellular
localisation of the mRNA. AU-rich elements
(AREs) are sequences in the 3' UTR rich in
adenine and uridine nucleotides which can
stabilise or destabilise the mRNA depending on
the protein bound
Poly-A tall
The addition of a stretch of adenine residues (typi-
cally 5()-ZOO) at the 3' end of mRNAs protects
them from degradation by exonucleases present in
the cytoplasm, and aids in transcription termination,
export from the nucleus and translation. The length
of the adenine repeat may also have an effect on
stability; when the tail is shortened the mRNA is
enzymatically degraded.
T ran s cri p t i o n fa c tors
Transcription factors are proteins that bind to se-
quence-specific regions of DNA at the 5' end of
genes called response elements to regulate gene
expression. These elements can form part of promo-
ters or enhancers. They can be divided into:
I Basal transcription factors - involved in the
constitutive activation of so-called
'housekeeping genes
0 inducible transcription factors - involved in the
temporal and spatial expression of genes that
underlie tissue phenotype and developmental
regulation
368
They fall into a number of groups based on their
structure:
Helix-loop-hel ix
Helix-turn-hel ix
Zinc finger
Leucine zipper
The TATA box is a promoter element that is always
located 25~30 base pairs from the start of transcrip-
tion and serves to anchor RNA polymerase il.
Q
it
_Wil
0 An increasing number of diseases are being
described where an inherited mutation in
transcription factors leads to a
developmental disorder. These are usually
complex congenital malformations
Transcription factors can be oncogenes,
eg c-myc, TP53 ( se e Section 14.3.2)
0
Many future drugs will be developed to
alter gene transcription by acting directly or
indirectly on gene transcription in the
manner described above for steroids
l 4_3 THE MOLECULAR
PATHOGENESIS OF CANCER
14.3.1 So m atic evolution of can cer
Cancer cells are a clonal population. The accumu-
lation of mutations in multiple genes results in
escape from the strictly regulated mechanisms that
control the growth and differentiation of somatic
cells. it will be evident that some of these genetic
'errors' will be inherited and form the basis of a
familial tendency to C a n c e r. For cancer to develop,
in most cases, an environmentally driven genetic
mutation is necessary, Genotoxic damage from ion-
ising radiation and some of the constituents of
tobacco smoke fall into this category. in addition,
all somatic cell division requires the copying of

DNA and this can result in the spontaneous muta-
tions of genes. It is a combination of these three
types of genetic mutation (inherited, spontaneous
and environmentally determined) which leads to
cancer. Therefore, cancer evolution is a complex,
multifactorial process.
Most tumours show visible abnormalities of
chromosome banding on light microscopy, suggest-
ing that as tumours develop they become more
bizarre and more prone to genetic error. Although
there are some cancer genes that lead to Mendelian
(ie monogenic) inheritance of specific tumours,
most cancers result from a complex mixture of
polygenetic and environmental influences.
14.3.2 On co g en es
Originally identified as genes carried by cancer~
causing viruses that are integrated into the host
genome and, when expressed, lead to loss of
growth control (viral oncogenes are denoted v-onc)_
They have cellular homologues, proto-oncogenes
(denoted c-onc), found in the normal human gen-
o me and expressed in normal tissue, that are usually
highly conserved in evolution and have central roles
Figure 14.8 Activation of the oncoprotein ras is under reciprocal control by GNRF and GAP
GNRF: stimulates the exchange
of GDP for GTP
ras
/\ activated ras
GDP l*
g/
:`f:;:i:E;;_
1T:5:51:::.'
:I-I-' the inactive form
Molecular Medicine
in the signal-transduction pathways that control cell
growth and differentiation. They can be thought of
as exerting a dominant effect in that they cause
C a n c e r in the presence of the normal gene product
because, in mutating, they have gained a new func-
tion.
0 Ras is a small, monomeric G-protein and is
likely to be involved in the transduction of
growth-promoting signals. The relative
abundance of the active and inactive forms of
Ras is controlled by positive and negative
regulators of GTP-GDP exchange (CAP and
GNRF) (Figure 14.8), Mutations affecting the
GTP-binding site prevent GTP hydrolysis and
prolong Ras activation. At least a third of
sporadic tumours contain acquired somatic
mutations in the ras gene
Further downstream, after a number of protein
kinase steps have been activated, the
transduction of growth signals culminates in the
activation of the transcription factors Fos and
lun which in turn induce the transcription of the
proto-oncogene myc, which commits the cell to
a round of DNA replication and cell division
G]-p
GAP: stimulates hydrolysis
of GTP and the return of ras to
369
Essential Revision Notes for MRCP

Mutant forms of these proteins can induce 14.3.5 Tunlour s u p p r e s s o r g e n e s

tumour growth
The 9:22 balanced translocation (Philadelphia
chromosome) found in chronic myeloid
leukaemia (CML) generates a composite gene
comprising exons from the bcr locus on
chromosome 22 and the c-abl locus on
chromosome 9, generating a fusion protein with
distinct biochemical properties which
presumably promote tumour growth
ln Burkitt's lymphoma the cmyc gene is
transposed from its normal position into the
immunoglobulin heavy-chain locus on
chromosome 14, resulting in a gross increase in
its expression and a potent molecular signal for
cells to undergo mitosis (see Figure 14,9)
0 In contrast to oncogenes these exert a recessive
effect, in that both copies must be mutated
before tumorigenesis occurs
0 Mutation results in loss of function
I These genes normally function to inhibit the cell
cycle and therefore, when inactivated, lead to
loss of growth control
p53 is a protein that occupies a pivotal role in the
cell cycle and its gene is the most commonly
mutated gene in tumours (breast, colon, etc). lt
encodes a transcription factor, the normal function
oi which is to downregulate the cell cycle. Inactiva-
tion of p53 is the primary defect in the Li-Fraumeni
syndrome (a dominantly inherited monogenic can-

Figure 14.9 In CML the Philadelphia chromosome leads to the production of an oncoprotein

chr.9 Chr-22 Philadelphia chromosome

translocation
breakpoint
l

- /
chn9
bcr / /
a
chr.22
/ -

bcr-ab/fusion protein: a novel protein kinase

no longer subject to regulatory control

370

cer syndrome characterised by breast carcinoma,
sarcomas, brain and other tumours), ancl is a central
regulator of apoptosis (see below).
\~
i
14.4 APOPTOSIS AND DISEASE
lt has only recently been fully appreciated that
widespread cell death occurs in human develop~
i ment and in the normal regulation of cell number in
l
the adult organism. ln embryonic development cells
are lost, for example, as finger webbing disappears
or as neurones are 'selected' for survival by making
the appropriate synaptic c onta c t, In postnatal life,
L the expansion of lymphocyte numbers in response
to antigen stimulation must be regulated by the
subsequent death of these cells or clonal prolifera-
tion would continue unabated, It turns out that this
process of naturally occurring cell death is regulated
by the activation of a specific set of genes in
response to external signals in a process referred to
as programmed cell death. The morphological
change that accompanies this process is called
apoptosis (Figure 14.1 O).
0 Cells undergo shrinkage, compaction of
chromatin, nuclear and cytoplasmic budding to
form membranebound apoptotic bodies and
finally phagocytosis by surrounding
macrophages
0 The activation of intracellular nucleases can be
detected by the 'laddering ot' DNA on
Figure 14.10 Apoptosis (programmed cell death)
Activation of
Growth Factor De h pi
i/wtnarawai (9gl=as)''$
\
g e m fa i
/
Ce" D em S,g,,a,
A3
DNA Damage
Tnag
bc/ 2
Metabolic or
Cell Cycle Perturbations
Molecular Medicine
electrophoresis gels, which serves as a marker
for apoptosis
In contrast to necrosis, apoptosis does not induce
the release of destructive proteolytic enzymes and
free radicals and is thus a non-inflammatory pro-
cess. Therefore, collateral damage to neighbouring
cells is not seen. Most cells seem to rely on a
constant supply of survival signals without which
they will undergo apoptosis. These are provided by
neighbouring cells and the extracellular matrix. The
absence or withdrawal of these molecular signals is
a trigger to apoptosis.
The 'cell death programme is genetically regulated
and there are specific proteins that promote or
inhibit apoptosis.
A family of proteases called caspases (ICE, or
interleukin-l [3-converting enzyme, is the best-
studied example) is central to apoptosis in
mammals and is responsible for driving all the
structural changes in the nucleus that
accompany apoptosis. Caspases have been
shown to be present in all cells and thus to
prevent apoptosis there must be specific
inhibitors of these proteases
0 The Bcl-2 family of molecules inhibit apoptosis
by a variety of mechanisms and are thus
cytoprotective survival signals. Over-expression
of Bcl-2 specifically prevents cells from entering
apoptosis and its high expression has been
correlated with poor sun/ival from cancer
Cvtt<<ic TCe||s
Endonuclease
Activation
Protease Activation Cell Surface
Alterations
Pi-iAoocYros|s
(ICE)
Cylnskeletal
Fleorganisation
371
Essential Revision Notes for MRCP
U Fas, or CD95, is a transmembrane receptor that
belongs to the tumour necrosis factor (TNF)
receptor family. The binding of TNF-like ligands
to Fas is coupled to the activation of
intracellular caspases. Some tumours express
the Fas ligand on their surface, thus activating
Fas on cytotoxic T lymphocytes, leading to their
death (a way of evading immune surveillance)
0
|153 is required for the apoptosis of cells in
which DNA has been damaged. The failure of
tumour cells to die in the face of genotoxic
damage may be due to the accumulation of p53
gene mutations
Programmed cell death can be stimulated by a
variety of triggers and leads to the activation of
proteases such as ICE that initiate a cascade of
morphological changes (collectively known as
apoptosis) which result in inevitable phagocytosis,
Certain disorders (cancer, autoimmunity and
some viral illnesses) are associated with
increased cell survival (and therefore a failure of
programmed cell death). Metastatic tumour cells
have circumvented the normal environmental
cues for survival and can survive in foreign
environments
0
Physiological cell death is necessary for the
removal of potentially autoreactive T cells
during development and for the removal of
excess cells after the completion of the immune
response. Animal models of SLE (CD95/Fas
knockout mice) have implicated apoptosis genes
in the pathogenesis of autoimmunity
0 Death by apoptosis can be seen as an
evolutionary adaptation to prevent the sun/ival
of virally infected cells. Therefore, viruses have
ta
$5
14.5 MOLECULAR REGULATION OF
VASCULAR TONE
Both the regulation of systemic arterial blood pres-
sure and the local control of the microcirculation in
organs such as the kidney and the brain are vital for
the maintenance of homeostasis. Recently there has
been an explosion of knowledge concerning the
molecular mediators of blood flow and this is al-
ready having an impact in the therapy of some
common disorders,
Two important principles should be kept in mind:
0 The regulation of vascular tone is predominantly
a paracrine process, where molecules are
released to act in adiacent cells
0 Vascular control is often a balance between
competing vasodilators and vasoconstrictors
14.5.1 Nitric oxide (NO)
Previously called endothelium-derived relaxant fac-
tor (EDRF), NO is an important transcellular mes-
senger molecule that is involved in a diverse range
of processes.
NO is synthesised from the oxidation of nitrogen
atoms in the amino acid L-arginine by the action of
NO synthase (NOS) (Figure 14.11) .
Figure 14.11 Formation of nitric oxide
NADPH
NOS

developed strategies for circumventing this. Pox

viruses appear to inhibit apoptosis by producing L-arginine N-hydroxy-L-arginine
an inhibitor of ICE
0 Excessive cell death due to an excess of signals
promoting apoptosis has been hypothesised to
occur in many degenerative disorders where
cells have been observed to die by apoptosis.
Direct evidence that this actually occurs has yet NO + Citruliins
to be found

372

Cell types which svntheslse nitric oxide
Vascular endothelium
Platelets
Macrophages
Vascular smooth muscle
Neutrophils
Hepatocytes
Central and peripheral nerve cells
NO acts on target cells close to its site of synthesis
where it activates guanylate cyclase leading to a rise
in intracellular COMP, which acts as a second
messenger to modulate a variety of cellular pro-
cesses. It has a very short half-life.
There are at least three distinct isoforms of NO
synthase:
I Neuronal (constitutive)
I Endothelial (constitutive)
0
Macrophage (inducible)
Constitutive NO production is involved in regula-
tion of vascular tone and neurotransmission and is
calcium/calmodulin-dependent. lnducible NO pro-
duction is mainly involved in cell-mediated immu-
nity and is activated by cytokines.
Synthetic nitrates, such as GTN and sodium nitro-
prusside, act after their conversion into NO.
Functions 'of nitric oxide
I Vasodilator tone modulation in the
regulation of systemic blood pressure
0 CNS neurotransmission, including the
formation of new memories
0 Inhibition of platelet aggregation
Cytotoxic action utilised in the generation
ofthe host immune response in activated
macrophages
0
Organ-specific microregulatory control (eg
kidney)
Molecular Medicine
0
Peripheral nervous system 'non-adrenergic,
non-cholinergic neurotransmission
(NANC), mediating neurogenic
vasodilatation
Diseases related to abnormalities in t he
g e n e r a t i o n or regul at i on of NO
0
Septic shock: NO is released in massive
amounts and correlates with low blood pressure
9 Atherosclerosis: NO synthesis may be impaired
more than endothelin synthesis, leading to tonic
vasoconstriction and vasospasm
0
Primary and secondary pulmonary
hypertension: inhaled NO reverses pulmonary
hypertension
0
Hepatorenal syndrome and the hypertension of
chronic renal failure: failure of breakdown and
secretion of endogenous antagonists of NO
leads to a microcirculatory imbalance between
NO and endothelin (see below)
0 Excitotoxic cell death in the CNS: glutamate is
the principal excitatory neurotransmitter in the
CNS_ NO is the transduction mechanism when
glutamate binds to NMDA (/\/-methyl~D-
aspartate) receptors on neurones. The final event
in the presence of excess glutamate is a rise in
intracellular calcium and the cell becomes
vulnerable to dying. This process, in which NO
is now implicated, is thought to be important in
neuronal loss in many neurodegenerative
conditions such as Alzheimers disease and also
in acute brain injury such as stroke
0 Tissue damage in acute and chronic
inflammation (probably by interacting with
oxygen-derived free radicals)
0 Adult respiratory distress syndrome (ARDS)
14.5.2 Endothelin- I
This is the most potent vasoconstrictor substance yet
described. It is manufactured following vascular
endothelial 'stress' (shear, hypoxia, growth factors,
expansion of plasma volume). It is produced from
373
Essential Revision Notes for MRCP
pre-pro ET by the action of endothelin-converting
enzyme (ETCE). Very little endothelin reaches the
circulation and serum levels do not generally carry
any diagnostic significance.
There are endothelin receptors:
0 On the vascular endothelium and on some
smooth muscle cells (gut and heart), including
coronary arteries where they cause constriction
0 On capillary endothelium where they cause
vasodilatation
When ET-1 is infused intravenously it causes a
transient vasodilatation followed by a long period
of intense vasoconstriction lasting up to 2 hours,
The normal function of endothelin is in the regula-
tion of vascular tone. The endothelin-receptor
blockers sitaxsentan and bosentan have been
developed to counter pulmonary hypertension. Bo-
sentan is a non-selective endothelin-receptor block-
er whilst sitaxsentan is selective for the endothelin-
A receptor. As endothelin receptor-B activation is
thought to be beneficial, it is thought that sitax-
sentan could be a more effective treatment. More
diverse functions of endothelin are indicated by the
recent finding of mutations in the endothelin-B
receptor in some patients with Hirschsprungs
disease.
Disorde rs whose p at h o g en es i s ma y be
related to endothelium
Essential hypertension
Primary pulmonary hypertension
Renovascular hypertension
Hepatorenal syndrome
Acute renal failure
Chronic heart failure
Raynaud's phenomenon
Vasospasm after subarachnoid haemorrhage
374
14.6 MOLECULAR MEDIATORS OF
INFLAMMATION, DAMAGE AND
REPAIR
The process of tissue injury, inflammation and sub-
sequent repair is highly conserved in evolution and
represents part of the 'primitive' repertoire of protec-
tive mechanisms against invasion by foreign
organisms and other insults. This is in contrast to
the more sophisticated mechanisms of defence
mediated by the immune system. Some of the same
molecules are involved in both processes but they
are considered here to emphasise the enormous
importance of inflammation as a pathological pro-
cess central to many diseases. These molecular
interactions are to a certain extent therefore inde-
pendent of the immune system.
The principal molecules involved are termed cyto-
kines, because they function in the immune system
as products secreted by one cell to act on another
cell to direct its movement (l<inesis). ln the context
of inflammation it is the pro-inflammatory cytokines
that are relevant. (See also Chapter 10, lmmunol
0?!!/J
14.6.1 Interleukin 1 (IL-1)
This molecule has a broad spectrum of both bene~
ficial and harmful biological actions and, as a
central regulator ofthe inflammatory response, has
been implicated in many diseases,
There are three structurally related polypeptides in
the interleukin 1 family:
0 lL-ia
0 IL-iff
lL~1-receptor antagonist
IL-Ia and IL-TB are synthesised by mononuclear
phagocytes that have been activated by microbial
products or inflammation:
I lL-la stays in the cell to act in an autocrine or
paracrine fashion

0
IL-lp is secreted into the circulation and
cleaved by interleukin-1f5-converting enzyme
(ICE)
IL-IB levels in the circulation are undetectable
except:
After strenuous exercise
With sepsis
With acute exacerbation of rheumatoid arthritis
In ovulating women
With acute organ rejection
IL-1in disease
0 Rheumatoid arthritis: IL-1 is present in the
synovial lining and fluid of patients with
rheumatoid arthritis and it is thought to activate
gene expression for collagenases,
phospholipases and cyclo-oxygenases, It is thus
acting as a molecular facilitator of inflammatory
damage in the joint but is not an initiator
I Atherosclerosis: the uptake of oxidised LDL by
vascular endothelial cells results in IL-i
expression, which stimulates the production of
platelet-derived growth factor. IL-1 is thus likely
to play a role in the formation of the
atherosclerotic plaque
0 Infection; lL-l has some host defence
properties, inducing Tand B lymphocytes, and
reduces mortality from bacterial and fungal
infection in animal models
0 Septic shock: IL-1 acts by increasing the
concentration of small mediator molecules such
as platelet-activating factor (PAF), prostaglandins
and nitric oxide, which are potent vasodilators
14.6.2 Tumour n ecro sis factor (TNF)
This is a pro-inflammatory cytokine that has a wide
spectrum of actions. Either through neutralising anti
bodies (anti-TNFQ) or inhibitor drugs it is the target
of therapy in disorders such as rheumatoid arthritis
and multiple sclerosis.
Two non-allelic forms of TNF, or and [3, are ex-
pressed in different cells.
Molecular Medicine
0 TNFU is produced by macrophages, eosinophils
and NK cells
0
TNFB is made by activated T lymphocytes
Its name is derived from the early observation that it
can have a cytotoxic effect on tumour cells in vitro.
Trials with TNFct as a therapeutic agent were soon
stopped due to the severe toxicity of the substance.
ln fact in certain situations it can promote tumour
growth.
Its action in diseases such as rheumatoid arthritis
depends on a synergistic effect with IL-1. Both are
found in the synovial membrane of patients with the
disease. TNFr1 strongly induces monocytes to pro-
duce lL-1 at a level comparable to that stimulated
by bacterial lipopolysaccharide (LPSL
Actions oflNF
0 TNFu is a potent stimulator of prostaglandin
production
0 TNF is a key cytokine in the pathogenesis
of multiorgan failure
It induces granulocyte-macrophage colony
stimulating factor (GM-CSF) and thus is an
activator of monocytes and macrophages in
diseased tissue
14.6.3 T r a nsf or ming g r o w t h factor [S
(TGI-`|i)
A key cytokine that initiates and terminates tissue
repair and whose sustained production underlies
the development of tissue fibrosis.
TGFB is released by platelets at the site of tissue
injury and is strongly chemotactic for monocytes,
neutrophils, T cells and fibroblasts. It induces
monocytes to begin secreting fibroblast growth
factor (FGF), TNF and lL-i, but inhibits the function-
ing of T and B cells and their production of TNF
and IL-1. It also induces its own secretion. This
autoinduclion may be important in the pathogenesis
of fibrosis.
375
Essential Revision Notes for MRCP
TGFB in dise a se
0
TGFB-deficient (knockout) mice die of an
autoimmune disease in which levels of TNF and
IL-i are very high
0 It has a potent effect on cells to induce the
production of extracellular matrix tadynamic
superstructure of self-aggregating
macromolecules including fibronectin, collagen
and proteoglycans to which cells attach hy
means of surface receptors called integrins).
Extracellular matrix is continually being
degraded by proteases which are inhibited by
TGH5
0 In mesangioproliferative glomerulonephritis,
glomerular immunostaining for TGF|5 correlates
well with the amount of rnesangial deposition
0 In diabetic nephropathy, increased TGFIS is
found in the glomeruli, and TGFB may be
central to the pathogenesis of progression of
many chronic renal diseases
O Elevated plasma levels of TCF[5 are highly
predictive of hepatic fibrosis in bone marrow
transplant recipients. mRNA for TGH5 is found
in areas of active disease in liver biopsy samples
of patients with chronic liver disease
0 In patients with idiopathic pulmonary fibrosis,
TGFB is increased in the alveolar walls. lt is also
implicated in bleomycin lung
irem stioiili
35,451 tl tsroteins (HSPSE
The heat shock response is a highly consen/ed and
phylogenetically ancient response to tissue stress
that is mediated by activation of specific genes,
leading to the production of specific heat shock
proteins that alter the phenotype of the cell, and
enhance its resistance to stresses.
Some HSPs are extremely similar to constitutively
activated proteins that have essential roles in un-
stressed cells. Their diverse functions include:
0
Export of proteins in and out of specific cell
organelles (acting as molecular chaperones)
0
Catalysis of protein folding and unfolding
C
Degradation of proteins (often by the pathway of
ubiquitination)
376
As well as heat, HSP expression can be triggered by
cytotoxic chemicals, free radicals and other stimuli.
The unifying feature that leads to the activation of
HSPs in these situations is thought to be the accu-
mulation of damaged intracellular protein.
Clinical relevance
Tumours have an abnormal thermotolerance
which is the basis for the observation ofthe
enhanced cytotoxic effect of chemotherapeutic
agents in hyperthermic subjects
0 Stress proteins are prominent amongst the
bacterial antigens recognised by the immune
response of humans to bacterial and parasitic
infections and are thought to be involved in
some autoimmune diseases
0 Mutations in small heat shock proteins (sHSPs)
have been associated with diseases as diverse as
cataract ta-crystallin) and forms of motor
neurone degeneration (sHSPs Z2 and 27)
14.6.5 Free rad icals a n d human
d isease
Free radicals have been implicated in a large num-
ber oi human diseases and are currently the subject
of much interest. Therapeutic trials have been un-
dertaken with putative free-radical scavengers such
as vitamin E. A free radical is literally any atom or
molecule that contains one or more unpaired elec
Irons, making it more reactive than the native spe-
cies.
Free radical s p eci es p ro d u ced in th e
hum an body
-
H 00' [peroxide radical)
- C); (superoxide radical)
- HO` (hydroxyl radical)
- NC(nitric oxide)
The hydroxyl radical is by far the most reactive
species but the others can generate more reactive
species as breakdown products.

When a free radical reacts with a non-radical a
chain reaction ensues, which results in the forma-
tion of further free radicals and direct tissue damage
by lipid peroxidation of membranes. This is particu-
larly implicated in atherosclerosis, and ischaemia-
reperfusion injury (eg acute tubular necrosis within
the kidney) within tissues. Hydroxyl radicals can
cause mutations by attacking purines and pyrimi-
dines. Also:
0 Activated phagocytes generate large amounts of
superoxide within lysosomes as part of the
mechanism whereby foreign organisms are
killed. During chronic inflammation this
protective mechanism may become harmful
0
Superoxide dismutases (SOD) convert
superoxide to hydrogen peroxide and are thus
part of an inherent protective antioxidant
strategy. Catalases remove hydrogen peroxide,
Glutathione peroxidases are major enzymes
that remove hydrogen peroxide generated by
SOD in cytosol and mitochondria
0 Free-radical scavengers bind reactive oxygen
species. Alpha-tocopherol, urate, ascorbate and
glutathione remove free radicals by reacting
directly and non-catalytically. Severe deficiency
of ot-tocopherol (vitamin E deficiency) causes
neurodegeneration
Clinical relevance
There is growing evidence that cardiovascular dis-
ease and cancer can be prevented by a diet rich in
substances that diminish oxidative damage,
antioxidants
Vitamin E
Vitamin C
Beta-carotene
Flavonoids
Epidemiological studies have demonstrated an asso-
ciation between increased intake of vitamins C and
E and morbidity and mortality from coronary artery
Molecular Medicine
disease. This supports models where atherogenesis
is initiated by lipid peroxidation of LDL.
Patients with dominant familial forms of amyo-
trophic lateral sclerosis (motor neurone disease)
have mutations in the gene for Cu-Zn SOD-1,
suggesting a link between failure of oxidative
damage and neurodegeneration.
'FRANSMISSIBIF 5I?O'\lCll~`O=I,-t
ENCEPHALOP/\Ti'!lES {TSE- 5
The transmissible spongiform encephalopathies
(TSES) are a group of diseases that are characterised
by progressive spongiform degeneration in the brain
and neuronal loss. While these conditions are rare,
they are the subject of intense interest because of
an epidemic of human infection which is linked to
the cattle disease bovine spongiform encephalopa-
thy (BSE). The biologically unique features of these
diseases are, firstly, that they can be simultaneously
inherited and also infectious, and, secondly, that the
agent of transmission is thought to be a protein only
rather than an 'organism' containing DNA or RNA.
This protein has been called a prion; it is encoded
by the host genome and cannot replicate.
Diseases caused byTSEs
0
Sporadic Creutzfeldt-Iakob disease (CID): rare
(I/10), causes rapid dementia with myoclonus
and characteristic EEG
0 Variant CID (VCID): 167 cases had Occurred in
the UK up to l September 2008 with 164
deaths and 3 additional probable cases
reported. This affects young people and has a
slower course than sporadic CID; it has
characteristic pathological features
0 Autosomal dominant CID: familial form of
classic CID
0 Gerstmann-Straussler-Scheinker syndrome
(GSS): familial spongiform encephalopathy with
prominent ataxia
0 Fatal familial insomnia
377
Essential Revision Notes for MRCP
0 Kuru: previously endemic in New Guinea
highlanders who performed ritual cannibalism.
This condition is now disappearing
Molecular features ofTSEs
The accidental or deliberate inoculation of affected
brain tissue from a case of inherited or sporadic TSE
results in the passage of the disease to the recipient.
Procedures that destroy nucleic acid do not prevent
this passage, which has led to the proposition that
the prion protein itself causes the disease by inter-
acting with the host-encoded protein, leading to its
conversion to the mutant form of the protein. Other
important considerations forthe TSEs are:
0 Prion protein: This is encoded by a gene on
chromosome 20, exact function unknown.
Curiously, mice lacking this gene only have
subtle neurological defects. Prion proteins are
not destroyed by boiling, UV irradiation or
formaldehyde, nor do they elicit an immune
response of any recognisable kind
0
Species barrier: This means that the diseases
are, to some extent, species-specific, For
example, scrapie in sheep has never been
passed on to humans as far as is known.
Similarly, the transmission of a spongiform
encephalopathy from one species to another is
very difficult. lf ClD brain tissue is injected into
the brain ofa monkey then there is very little
cell death, but if brain tissue from that same
monkey is injected into another monkey
(second passage) then there is severe neuronal
loss. This suggests that the pathological process
leading to spongiform change depends on the
host protein
0 involved as cofactors in antigen presentation and
Susceptibility polymorphism: At codon 129 of
the prion protein the amino acid can either be a
valine or a glycine residue. Given that there is
one copy of the gene on each chromosome we
can either be heterozygous (valine/glycine) or
homozygous [valine/valine or glycine/glycine). It
turns out that homozygosity at this residue is
vastly over-represented in affected individuals in
sporadic CID and in variant CID. lt would
appear that the one amino acid can confer
susceptibility to the disease
378
0 Strain type: When the protein from affected
brains is electrophoretically separated and
blotted onto a membrane (Western blotting) and
then incubated with anti-prion protein antibody,
different patterns can be seen. This is what is
referred to as the strain of the infective agent
but is really a surrogate marker. lt is the fact that
the observed pattern with variant ClD is
identical to that observed with BSE, and
different from sporadic CID, that provides the
strongest evidence of a link between the two
14.8 ADHESION MOLECULES
The way in which cells communicate with each
other is fundamental to the maintenance of home-
ostasis in the developing and adult organism. In
particular, the molecular basis of neural connectiv-
ity, the immune response and the prevention of
cancer are all dependent on adhesion molecules.
Adhesion involves the interaction of one molecule,
for example a cell surface molecule, with a specific
ligand which may be on another cell or a part of
the extracellular matrix. These can be divided into
four groups on the basis of structure and function:
The immunoglobulin superfamily
The cadherin superfamily
Integrins
Selectins
The immunoglobulin superfamily is so-called be-
cause at the genetic level it has a sequence simi|ar
ity that suggests that it arose from the same set of
ancestral genes by duplication. These molecules are
are present as cell surface receptors on leucocytes
(eg CD2, CD3, T-cell receptor) and some function
as integrin ligands (eg ICAM, NCA: intercellular and
neural-cell adhesion molecule, respectively).
Cadherins are involved in the interaction between
muscle and nerve in the developing embryo.
Integrins are heterodimeric (two subunits, different
from each other) transmembrane glycoproteins
which are widely distributed in different tissues and

serve to interact with molecules of the extracellular
l matrix (laminin, fibronectin, collagen).
r cells:
Selectins are expressed on leucocytes and are
l thought to be involved in leucocyte adherence to
endothelium during acute inflammation and coagu-
l lation.
l these cells which may limit their therapeutic
i Expression of adhesion molecules is dynamic and
can be upregulated by pro-inflammatory cytokines
(IL-1, TNF), viral infection, T-cell activation and
many other stimuli.
l
Clinical relevance of adhesion molecules
Adhesion molecule expression is upregulated in
many forms of solid organ inflammation leg auto-
immune and viral hepatitis, and also in organ rejec-
tion after transplantation), The adhesion molecule
intercellular adhesion molecule-1 LICAM-1) is a
receptor for the integrin lymphocyte function-
associated molecule-1 (LFA-1) and may be involved
in the recruitment and maintenance of activated
lymphocytes in tissue inflammation.
0 lt is theoretically possible to block these
molecules to treat inflammation (eg in acute
renal failure and in transplant rejection)
0 The integrin um,[.> is the platelet receptor for
fibrinogen
I Mutations in its gene lead to the congenital
bleeding disorder Glanzmann's thrombasthenia
0 In another genetic disease, leucocyte adhesion
deficiency (LAD), lack of [$2-integrins leads to
failure of leucocyte migration to sites of
infection and hence to recurrent bacterial sepsis
0
Conversely, antibodies against 0Liihl5 are
routinely used in clinical practice (ie abciximab)
as antithrombotic agents in coronary artery
disease
14.9 STEM CELLS
A number of tissues in the body contain progenitor
cells which are capable of producing progeny, or
daughter cells, to replenish cell populations. The
most obvious example is the bone marrow where
red and white cells are constantly being replaced to
Molecular Medicine
match turnover in the peripheral blood. lt is now
known that a number of other tissues contain stem
0
Embryonic stem cells are totipotential and
hence can give rise to any tissue type. There are
ethical difficulties in the acquisition and use of
use. Embryonic stem cells from mice are a
powerful investigative tool in basic science
0 Bone marrow stem cells can be easily accessed
and purified by antigen sorting with CD34
antibodies. If these cells undergo
transdifferentiation they can then function as a
replacement for degenerating cells of n0n~
haematological origin (eg ne ur one s)
14.10 `l`llE N l O | .l f(fi i i Ni? '-i.`<..'~.ff> 4 it
S ONH; li-li-{!l, i.\.\."i _'f~` `t'~.1~ .4
The following conditions have been highlighted
either because their molecular basis is well under-
stood (eg myasthenia gravis, at-antitrypsin defi-
ciency) or because they are caused by novel
mechanisms (eg trinucleotide repeat disorders).
Others are included because the identification of
their molecular basis is historically important (as for
dystrophin in Duchenne muscular dystrophy, which
was the first disease to be worked out by identifying
the gene through positional cloning). Overall, the
following diseases serve to illustrate the importance
of the molecular mechanisms of disease outlined in
the above sections.
1-l.i0.l fftrxtyi-cxitiosts
A pathological process characterised by the accu-
mulation of extracellular fibrils of insoluble protein.
The aggregated protein is specific to the different
amyloid diseases listed overleaf, but in all cases the
fibrillar component is associated with a non~fibril|ar
constituent called amyloid-P component which is
derived from the acute phase protein serum amy-
Ioid P (SAP). Figure 14.12 outlines the classification
of amyloidosis. (See also Section 15.12,1, Chapter
15, Nephrology.)
379
Essential Revision Notes for MRCP

Figure 14.12 Classification of amyloidosis. The individual protein that associates with serum amyloid
is shown in italics
I
AMYLOID

T
/
\
SYSTEMIC

AA: 2 to chronic
inflammatory diseases
(serum amyloid A)
AL: 2 to plasma cell
E
. dyscrasia (lg light
chains)
*Amyloid
. precursor
5 protein
/
INHERITED
ACQUIFIED
Neuropathies Sporadic A|zheimers
Transthyretin Sporadic spongiform
ApoA 1
Gelsolin encephalopathies
CNS Dlalysis-associated
Familial CJD (prion protein) (B2-mlcrog/obu/in)
Familial Alzheimers (APP) Type II diabetes
Cerebral amyloid angiopathy (APF')* (amylin)
Vlsceral (mainly cardiomyopathy)
Genetic variants of transthyretin,
fibrinogen an d lysozyme

Pa thoge ne sis H 10.2 \ipha ~ l a n t i t r y p s i n defi ciency

Whilst the inherited forms of amyloid are rare, the
accumulation of amyloid fibrils is a central part of
the pathological process of a number of common
diseases such as Alzheimers and type 2 diabetes,
where amyloid is found in the islets of Langerhans.
Many individuals on long-term haemodialysis even-
tually develop amyloid arthropathy. The l<ey event
in amyloid fibril formation is a change in conforma-
tion ofthe respective precursor protein which leads
to its aggregation into an insoluble fibrillar form.
The exact mechanism of this conformational change
is unclear but it is thought to involve partial proteo-
lytic cleavage of the precursor, and/or its overpro-
duction. Using 3l-labelled SAP, amyloid deposits
can be localised using scintigraphy. Amyloid may
cause organ dysfunction by progressive replacement
of functional parenchyma or it may possibly be
inherently cytotoxic.
Deficiency of al-antitrypsin is one of the most
common hereditary diseases affecting Caucasians.
The prime function of the enzyme is to inhibit
neutrophil elastase and it is one of the serpin super-
family of protease inhibitors. Patients with defi-
ciency present with emphysema (see Chapter 19,
Respiratory Medicine) because low protein levels
fail to protect the lung from proteolytic attack, A
proportion of individuals also develop liver cirrho-
sis, but this does not appear to be directly due to
enzyme deficiency.
I The most common mutation that changes a
glutamate residue to a lysine at position 342 of
the protein (the Z mutation) results in the
accumulation of protein in the endoplasmic
reticulum of the liver

380

I The formation of these hepatic inclusions results
from a proteineprotein interaction between the
reactive centre loop of one molecule and the
[ipleated sheet of a second
I This leads to polymerisation and aggregation,
Similar mechanisms have been found to be
responsible for deficiency of C-1 esterase
inhibitor (hereditary angioneurotic
angiooedema) and antithrombin lll
0 Since not all patients who are homozygously
deficient develop liver damage, other factors,
such as the way the mutant protein is broken
down in the liver, must be relevant to the
manifestation of the liver component
14.103 Alzheimers disease
A neurodegenerative disease of inexorable cognitive
decline characterised histologically by intraneuronal
neurofibrillary tangles and extracellular amyloid
plaques. Most cases are sporadic,
I About 5% of cases are inherited as an
autosomal dominant with at least three genes
responsible
O Mutations in the amyloid precursor protein
(APP) gene on chromosome 21 are a rare cause
of familial Alzheimers disease (AD). The BA4
protein is a proteolytic product of APP and the
principal constituent of senile plaques
0 Mutations in two closely related genes, the
presenilins PS1 and P52, are responsible for
other cases of AD
I Inheritance ofthe S-4 allele of apolipoprotein E
is an important determinant of age of onset in
familial AD and a risk factor for sporadic AD.
(See also Chapter 16, Neurology)
Molecular ma rke rs
Neurofibrillary tangles consist of highly ordered
intraneuronal structures called paired helical fila-
ments (PHF) which are assembled from the micro
tubule associated protein i a u ,
This suggests that neurones die because tau is
handled in some abnormal way which leads to
dysfunction of the microtubular network. Tau pro-
Molecular Medicine
tein from PHFs is abnormally phosphorylated but it
is not yet known whether this is part of the primary
pathological process leading to AD. APP is cleaved
into a [5and a y fragment. It is thought that plaque
formation occurs when the ABfragment becomes
insoluble and aggregates. Aggregated A13 has been
shown to induce free radical-mediated damage to
neurones.
1410.4 Trinucleotide r ep eat disorders
A new class of genetic disease has been recognised
in recent years, in which the responsible genetic
mutation is a repetitive sequence of three nucleo-
tides which can undergo expansion (and occasion-
ally contraction). It has therefore become known as
a dynamic mutation.
Eaump\_ao;tr.iwuc\\otIdopeat _
0
Huntingtons disease
0
Fragile X syndrome*
0 X-linked bulbospinal neuronopathy
(Kennedy syndrome)
0
Myotonic dystrophy
0 Friedreichs ataxia
0
Spinocerebellar ataxias (there are a number
of variants)
See Chapter 7, Genetics
As a consequence of dynamic mutation, mutant
alleles arise from a population of pre-mutant alleles
that have a repeat number at the upper limit of the
normal range (usually < 3 5 ) which then become
unstable and undergo sudden expansion into the
mutant range ( > 50) . Two key genetic characteristics
are illustrated by trinucleotide repeat disorders.
Anticipation
The phenomenon whereby the severity of a disease
becomes worse, and the age of onset earlier, in
successive generations,
381
Essential Revision Notes for MRCP
Soma tic i ns t abi l i t y
The length of the expansion continues to increase
as cells divide throughout lite. This may partly
explain why a disease such as myotonic dystrophy
gets worse as the patient gets older.
For a particular disease the length of the expansion
corresponds with the age of onset of the disease.
There are two main types of trinucleotide repeats
tFigure 1 4 . 1 3 ) : trinucleotide repeats can occur in
the non-coding region or within exons, giving differ-
ent effects.
It will be evident from Figure 14.13 that the conse-
quence ofa type I expansion is loss of gene expres-
sion because the gene cannot be transcribed due to
stereochemical interference from the expanded re-
gion. Type ll disorders are thought to be so-called
gain of function dominant mutations. That is, the
trinucleotide expansion leads to the accumulation
ot' an abnormal protein which is toxic to cells. ln
several of these disorders it has now been demon-
strated that toxic protein accumulates in intraneur-
onal inclusions which stain positive for ubiquitin.
(See also Chapter 7, Ge ne tic s.)
14.105 Mitochondrial disorders
The mitochondrial genome is circular and approxi-
mately 16.5 kb in length. lt encodes genes for the
Figure 14.13 Trinucleotide repeats
Typsl : massive expansion ot the area ofthe gene
containing regulatory elements, such as
the promoter, leads to loss of expression
(GCC),,
5' non-coding region
382
mitochondrial respiratory chain and for some spe-
cies of transfer RNA. Nucleic acids cannot move in
and out of mitochondria, so all of the mRNA
synthesised from the mitochondrial genome must
be translated in the organelle itself. However, many
nuclear encoded proteins are transported into mito-
chondria and are absolutely necessary for mito-
chondrial function. (See also Chapter 7, Genetics.)
Mitochondrial DNA (mtDNA) mutates 10 times
more frequently than nuclear DNA; as there are
no introns, a mutation will invariably strike a
coding sequence
0 Maternal inheritance: no mitochondria are
transferred from spermatozoa at fertilisation and
so each individual only inherits mtDN/-\ from
the mother
0 Because there are 103-104 copies of
mitochondrial DNA in each cell teach
mitochondrion has 2 -1 0 copies of mtDNA)
normal and mutant mtDN/\ may co-exist within
one cell (known as heteroplasmy). This may be
one explanation why mitochondrial diseases
show a poor genotype-phenotype correlation
0 There is evidence that mtDNA mutations are
accumulated throughout life, as mitochondrial
DNA has no protective DNA repair enzymes,
and that this may contribute to the changes of
ageing
Typo Ilzsmaller e xpa ns i ons oi CTG nucleotides
which code tow glutamate produce a
protein toxic to neurones
(CTG) ,,
_ i i i
 Molecular Medicine

1410.6 My asth en ia g ra v i s

mtafetivmt e A

.
T
This relatively rare disease (incidence l case per
800020 000) has a molecular pathogenesis that is
Sensorineural deafness well understood, and it serves as a model for other
Optic atrophy autoimmune diseases. Specific antibodies are direc-
Stroke in young people ted against the nicotinic acetylcholine (ACh) recep-
Myopathy tor which is present on the post-synaptic membrane
Cardiomyopathy and cardiac conduction of the neuromuscular junction (Figure 14.14). This
defects results in:
0 Diabetes mellitus
0 Chronic progressive external
0
Complement-mediated destruction of
ophthalmoplegia acetylcholine receptors and a loss of the normal
I Lactic acidosis convolution of the muscle membrane (an
0 Pigmentary retinopathy important morphological hallmark ofthe
disease); this leads to the loss of surface area for
ACh to interact with its receptors
Virtually all tissues in the body depend on oxidative 0 Accelerated enclocytosis and degradation of
metabolism to a greater or lesser extent and so these
receptors
phenotypes can often occur together (for example, 0 Functional blockade of receptors
diabetes and deafness). As mentioned above the
relationship between the mutations and the clinical These abnormalities lead to fatiguable weakness (see
features is poorly understood. also Chapter 16, Neurology). Ptosls and diplopla

Figure 14.14 The neuromuscular junction in myasthenia gravis. There is loss of acetylcholine recep-
tors and a decrease in post-synaptic folds

axon

vesicles ot
acetylcholine

I 0 nerve terminal
I C

acewlcholine
receptors
$f Myasthenia g rav i s
muscle

383
Essential Revision Notes for MRCP
are the commonest symptoms. ln 10%-15% of
sufferers, symptoms are confined to the eyes [ocular
myasthenia). Fatiguability occurs because of a co m-
bination of the normal rundown of ACh release
which occurs physiologically, and a decreased num-
ber of ACh receptors.
Over 80% -90% of patients have detectable anti-
bodies to the ACh receptor and the others are
presumed to have antibodies not detectable by
current assays. Antibody negativity is more common
in the ocular form.
0 Passive transfer of antibodies from patients to
mice reproduces the disease features
0 Reduction of antibody levels by plasmapheresis
or treatment with immune globulin ameliorates
the disease
0 The antibody titre in patients does not always
correlate with disease severity, suggesting that
anti-ACh receptor antibodies have different
functional consequences depending on the
exact epitope to which they are directed
The origin of the autoimmune process is controver-
sial but 75% of patients have thymic abnormalities
[hyperplasia in 85% and thymoma in 15/Di.
14.10.7 Duchenne mus cular
dystrophy
This is a genetic disease which is X-linked; it has
the highest new mutation rate of any X-linked gene.
lt is caused by mutations in a protein called dystro-
phin, which is part of a large complex of mem-
brane-associated proteins, defects in most of which
can cause forms of muscular dystrophy.
Figure 1 4 .1 5 Dystrophin is an extremely large protein that links the cytoskeleton (actin) to the
extracellular matrix of muscle
Central rod domain
C-terminus binds
extracellular laminin
384
Dystrophin is a very large protein indeed ( > 4O0
kDa) which is attached at its C-terminus to laminin
on the inner aspect of the muscle membrane and at
its N-terminus to actin, thus providing a connection
between the extracellular matrix and the muscle
cytoskeleton (Figure 14.15) . Therefore, its role is
probably structural.
The most common mutations are large deletions
which can be either of the following:
0 In frame in which the C-terminus and N-
terrninus ofthe molecule are preserved and a
truncated form of dystrophin missing some of
the rod domain is produced leading to Becker's
dystrophy, a milder form of the disease
compatible with a normal lifespan and
prolonged ambulation
0 Out of frame which results in total abolition of
dystrophin production because one or both of
the binding sites for actin or laminin is
disrupted, This is the abnormality which leads to
typical Duchenne muscular dystrophy
The very occasional finding of affected females can
be due tothe following:
0
lyonisation: X-chromosome inactivation
occurring non-randomly and leading to
preferential inactivation of the normal
chromosome
0
Very rarely, X-autosome translocation. The
presence o fa fragment of an autosome in the
region where dystrophin is normally found leads
to the preferential activation of this chromosome
and inactivation of the normal chromosome
The clinical features of Duchenne muscular dystro-
phy are described in Chapter i 6 , Neurology.
N-terminus binds
intracellular actin
i

Molecular Medicine

14.10.8 Sickle cell disease endothelium is determined primarily by the

lt has been known for five decades that haemoglo- rapidity of polymer formation which in turn is
bin from patients with this disease undergoes ab- dependent on the rapidity of deoxygenation
normal electrophoretic mobility, The basis for this
0 The binding of sickle red cells to endothelium
is the presence, in all patients with the disease, of appears to be mediated by the interaction
a single amino acid substitution of valine for gluta-
between integrins on the cell membrane and
mic acid in the haemoglobin (HbS) B-globin sub-
adhesion molecules expressed on the vascular
unit, Haemoglobin has to be highly soluble to
endothelial surface
.li
0 The presence of pro-inflammatory cytokines
pack into red cells at high concentrations and the such as TNF stimulates this process, which
sickle mutation leads to polymerisation of HbS and
consequent loss of solubility. The reason that poly-
explains why infection of any kind can provoke
merisation takes place is that, in its deoxygenaied a sickle crisis
0 One factor that has been shown to modify the
form, the Hb5 I5-globin subunit can bind to a
rate of polymer formation is the presence of
partner Bsubunit on another strand, leading to the fetal haemoglobin (HbF), which slows the rate
l' formation of large polymers (see Figure 14,16),
which deform the red cell by damaging the mem- of polymer formation
l brane and interfering with ion flux. The polymerisa-
0 Certain ethnic subpopulations have higher
tion process is a dynamic event under the amounts of fetal haemoglobin persisting in the

influence of the oxygenation state of the cell and
the intracellular concentration of haemoglobin
l which accounts in part for the variable clinical
L manifestations of the disease.
0 The unpredictable nature ofthe vaso-occlusive
events observed in patients has been explained
v
because the SS red cells have a greater
propensity for attachment to vascular
endothelium. The degree of stickiness to
l.
circulation and milder SSdisease
0 This suggests that pharmacological upregulation
of HbF could ameliorate the disease.
Hydroxyurea has been shown to increase the
amount of HbF and is now widely used in the
prevention of sickle crises. The risk of tumours
from this cytotoxic drug appears to be small and
any myelosuppression is reversible
The clinical features of sickle cell disease are dis-
cussed in Chapter 9, Haematology.

Figure 14.16 Sickle cell disease. In sickle cell disease HbS undergoes abnormal polymerisation when
K deoxygenated
i

l
a)
E
HbA
san
L `ee@@
deoxy-H bS
nu.
li bl Hhs

i
385
y.
Essential Revision Notes for MRCP

14.11 GLOSSARY OF TERMS IN MOLECULAR MEDICINE

Allele One of several different forms of a gene occupying a given genetic locus

Annealing The pairing of complementary strands of DNA to form a double helix

Apoptosis The morphological changes accompanying the process of programmed cell death

Autocrine Secretion of substances by cells which then act on the cells themselves rather than
on a distant target

cDNA A single-stranded DNA complementary to an RNA, synthesised from it by the

enzyme reverse transcriptase in vitro
Cell cycle The period from one cell division to the next

Cytokines Act locally and their effect can be positive or negative depending on the
environment, other cytokines, the physiological state of the cell and the extra-
cellular matrix. This variable response of cytokines underlies the ability of the
organism to maintain a wide repertoire of responses to tissue injury
DNA polymerase An enzyme that synthesises a daughter strand of DNA on a DNA template

ELISA Enzyme-linked immunosorbent assay, a method of quantifying circulating proteins

Exon Any segment of an interrupted gene which is represented in the mature RNA
product
FISH Fluorescent in-situ hybridisation, a method of characterising gross chromosomal
abnormalities
Gene family Consists of a set of genes the exons of which are related; the members were
derived from a common ancestral gene by duplication and subsequent variation
Gene targeting The creation of animals (usually m ic e ) which are null mutants for a particular
gene. That is, the gene has been 'knocked out' and the 'knockout' mouse contains
no copy of the gene at all

G-protein Heterotrimeric membrane protein that is activated by the exchange of GDP for
GTP and dissociates on activation into an ot and [Sy subunits. It has intrinsic
GTPase activity which mediates its inactivation

Growth factor A hormone that induces cell division and differentiation

Heterozygote An individual with different alleles on each chromosome at a given locus

Housekeeping genes Constitutively expressed genes in all cells because they provide basic functions
needed for survival of all cell types

386
,,is
g` 93/2?
,Wi

1 -` " ii, t
lr
Molecular Medicine
l
F Hybridoma A cell line produced by fusing a myeloma with a lymphocyte; it can indefinitely
express the immunoglobulin of both cells, unless the myeloma has been selected
to be deficient in lg expression
l
Introns Sequences of DNA that are transcribed but removed from nascent mRNA by
splicing
isoform One of a number of different forms of a protein that may be derived from one
gene by splicing or from separate closely related members ofa gene family
Oligonucleotide A short sequence of (synthetic) DNA, typically l 8 f 2 2 base pairs in
length, which
y. acts as a primer for PCR reactions or a molecular probe when
sequences
detecting gene

Oncogene A gene whose protein product (the oncoprotein) has the ability to transform
eukaryotic cells so that they grow in a manner analogous to tumour cells
i Paracrine Secretion by one cell of substances that act on adjacent cells

Programmed cell death The process whereby unwanted cells die under the control of a genetic pro-
gramme
Promoter A region of DNA involved in the binding of RNA polymerase to initiate transcrip-
r tion
P
Protein kinase An enzyme that phosphorylates (adds a phosphate group) to a substrate lan amino
acid in another protein)

Protein phosphatase An enzyme that removes phosphate groups from substrates

Proto-oncogene The normal counterpart in eukaryotic genomes of retroviral genes which can
transform cells

Response elements Specific nucleotide recognition sequences in the 5' regulatory regions of genes
which recognise transcription factors that have been activated by upstream signals
such as steroid hormones
l
Somatic cells All the cells of an organism except the germ cells

Transcription factor A protein that binds to the promoter region of a gene to influence its transcription

i
Tumour suppressor gene A gene that, when activated, will produce a protein that inhibits cell division.
Mutations of these genes therefore lead to loss of control of cell division and
contribute to tumorigenesis
UTR Untranslated region

387
>

C h a p t e r 15
Nephrology
l
li
1, CONTENTS

15.1 Re na l phys iology 15.6 G lo mer u lo n ep h r itis an d

15.1.1 Glomerular filtration rate (CFR) associated syndrome s
15.1.2 Tubular physiology 15.6.1 Clinical presentation of
15.1.3 Renin-angiotensin-aldosterone glomerulonephritis
(RAA) system 15.6.2 Notes on particular
glomerulonephritides
15.2 Renal in v es tig atio n
15.2.1 Urinalysis 15.7 Inherited renal disease
15.2.2 Renal radiology 15.7.1 Autosomal dominant polycystic
kidney disease (ADPKD)
15.3 Acid-base. wat er a n d 15.7.2 Other renal cystic disorders
electr o ly te di sorders 15.7.3 Alport syndrome
15.3.1 Acidosis and alkalosis 15.7.4 Benign familial haematuria
15.3.2 Renal tubular acidosis (RTA) (BFH) and thin-membrane
15.3.3 Polyuria nephropathy
15.3.4 Hypokalaemia 15.7.5 Other inherited disorders
associated with renal disease
15.4 Acute kidney in ju r y (AKI)
15.4.1 Pathogenesis and management 1518 Re na l inte rs titia l dis orders
of acute kidney injury 15.8.1 Interstitial nephritis
15.4.2 Rhabdomyolysis 15.8.2 Analgesic nephropathy and
15.4.3 Radio-contrast nephropathy papillary necrosis

15.5 Chronic kidney disease (CKD) 15.9 Reflux ne phropa thy a n d

a n d renal r e p la c e m e n t t h e r a p y
15.5.1 Chronic kidney disease (CKD)
15.5.2 Anaemia of CKD
15.5.3 Hyperparathyroidism and CKD
mineral and bone disorder
i (CKD-MED)
l 15.5.4 Maintenance dialysis
15.5.5 Renal transplantation
u r i n a r y t ract infections
15.9.1 Vesico-ureteric reflux and
reflux nephropathy
15.9.2 Urinary tract infection (UTI)
15.9.3 Tuberculosis ofthe urinary tract

389
Essential Revision Notes for MRCP

15.10 Renal c a lc uli a n d

n e p h r o c a l c i n o si s
15.10.1 Renal calculi
(nephrolithiasis)
15.10.2 Nephrocalcinosis

15.11 Urina ry tract obstruction a n d

tumours
15.11.1 Urinary tract obstruction
15.1 1.2 Retroperitoneal fibrosis (RPF)
15. 113 Urinary tract tumours

15.12 Syste m ic disorders and t he

ki dney
15.12.1 Amyloidosis
15.12.2 Renovascular disease
15.12.3 Connective tissue disorders
and the kidney
15.12.4 Diabetic nephropathy
15. 125 Thrombotic
microangiopathies
15.12.6 Hypertension and the kidney
15.12.7 Myeloma and the kidney
15.12.8 Renal vasculitis
15. 129 Sarcoidosis and the kidney

15.13 Drugs a n d t he kidney a n d

to x ic ne phropa t hy
15.13.1 Renal elimination of drugs
15. 132 Drug nephrotoxicity
15. 133 Toxic nephropathy

390

Nephrology
15.1 RENAL PHYSIOLOGY
The chief functions of the kidneys are:
Excretion of water-soluble waste
Maintenance of electrolyte balance
Maintenance of water balance
Acid-base homeostasis
Endocrine: renin-angiotensin-aldosterone
system, erythropoietin, vitamin D activation
15.1.1 Glomerular fi ltration rate
(GPR)
Clomerular filtration is a passive process which
depends upon the net hydrostatic pressure acting
across the glomerular capillaries, countered by the
oncotic pressure, and is also influenced by the
intrinsic permeability of the glomerulus (K07 the
latter may vary due to mesangial cell contraction,
as in the response to angiotensin ll. The mean
values for CFR in normal young adults are
i s o m|~minr~i.73 rn (men) and 120 mimin"t
1.73 m'3 (Women), the 1.73 m2 being mean body
surface area of young adults. However, variation
between individuals is large and accepted ranges of
GPR at this age are 70-140 m|~min'ti.73 mr? in
health, the CFR remains stable until around 40
years of age but thereafter declines at a rate of
approximately 0.5-1 ml~minl-year'l; by the age of
80 years the mean CFR is approximately 50% of
that of a young adult.
I CFR increases by 50% during pregnancy due to
plasma volume expansion (see Chapter 12,
Maternal Medicine)
I CFR has a diurnal rhythm, values being 10%
greater in the afternoon than at midnight. This
may be partly related to protein intake (which
increases CFR)
0 CFR falls transiently during exercise
Nephrology
0 ln patients with reduced renal reserve, CFR will
be lower in the fasting than in the fully hydrated
state (relevant in the context of blood sampling)
There are several means of estimating CFR:
0 Plasma creatinine: creatinine is produced from
muscle cells at a constant rate, and so its
plasma concentration at steady state depends
upon its excretion, which reflects CFR. Plasma
creatinine is therefore useful to crudely assess
CFR. However, when renal function is well
preserved, small changes in creatinine are
associated with large changes in CFR, and so
plasma creatinine is an insensitive marker of
early renal disease
When considering plasma creatinine values,
the patients age, sex and weight should be
taken into account - elderly and
malnourished patients may have low CFR
but plasma creatinine close to the normal
range
0 All UK laboratories now provide estimated CFR
(eCFR) routinely; it is calculated from the four-
variable MDRD (Modification of Diet in Renal
Disease (Study)) equation (which includes age
and s ex )
0 Creatinine clearance: calculated from a 24-hour
urine collection with a consecutive blood
sample - this is now used infrequently. This
tends to overestimate CFR as creatinine is not
just filtered, but also secreted into the tubule
from the post-glomerular circulation; the error
increases with declining renal function. Note
that certain drugs (eg trimethoprim and
cimetidine) compete for this secretion
mechanism, and so will increase plasma
creatinine
0 Cockcroft and Gault formula: this also assesses
eCFR (based upon creatinine clearance) and
requires knowledge of the patients age, weight
391
 Essential Revision Notes for MRCP

and plasma creatinine: 1 5 ,1 2 Tubular p h y sio lo g y

GFR (m l/mm)
_ :
( 140 ~ age in years]><weight (kg)
plasma creatinine (umol/ll
><1.23 (men) or 1 , 0 4 (women)
This formula overestimates creatinine
clearance in obese patients and in those
patients adhering to a strict low-protein diet
(in both of these groups the endogenous
creatinine production will be less than that
predicted by overall body weight). A
correction should be undertaken for body
surface area
The most accurate laboratory techniques for asses-
sing GFR are:
0 Inulin clearance; inulin is a small molecule,
freely filtered by the glornerulus, and with no
tubular secretion
Chromium-labelled EDTA: the most frequently
used isotopic technique
The renal tubule has many reabsorptive and secre~
tory functions ( se e Figure 15,1); these are energy-
consurning and hence tubular cells are those most
vulnerable to ischaemic damage (the acute tubular
necrosis (ATN) of ischaemic acute renal failure).
Proximal tubule
Fifty per cent of filtered sodium is realzzsorbed within
the proximal tubule (via I\la~l<-ATPase); the Na-H
antiporter secretes H' into the lumen and is respon-
sible for 90% of bicarbonate and some chloride
reabsorption. All of the filtered glucose and amino
acids are reabsorbed here. Other important charac-
teristics are as follows:
0
Phosphate reabsorption occurs under the
influence of parathyroid hormone (PTH)
0 Some important drugs are secreted into the
tubular filtrate here: trimethoprim, cimeticline,
most [5~lactams and most diuretics ( n o te that

Figure 15.1 Schema of a nephron showing tubular physiology

gi*

DISTAL
TUBIJLE
PROXI MAL
Aldosterone
y
TUB'-"-E NaCl co-transporter I
sg n si i i v g
Uric +
Glucose anZcid or
Amino acids creatinine {NB+ Na+ lNH; H-ATPase
Phosphate H"`}
Na-H Na+
anr:porter {HC0a' 2 2 H20
O Na+ *M9 $* Na-K-20| Na+
H+
(NGK
lf,$aj;my) '
Cf } 0 Aldosleruns
ATPase)
Organic mnspmifl K+ sensitive
acids COLLECTING

l GLOMEHULUS
_____ H20
LOOP
__ _Z H o <- l-
DUCT
yH2O}sensitive
ADH

lif/
@
Sites of diuretic action
Loop
Thiazidas H20
Spironolactone
-P Tubular secretion
41 Reabscrption

392

diuretics such as thiazides, amiloride and loop
diuretics are highly protein-bound and are not
filtered at the glomerulus)
I Creatinine and urate are secreted into the lumen
Lo o p of Henle
The medullary thick ascending limb (mTAL) is
impermeable to water, and the medullary concen-
tration gradient is generated here (allowing con-
centration ofthe urine). Forty per cent of sodium is
reabsorbed (via the Na-K-2Cl co-transporter). Loop
diuretics compete for chloride-binding sites on this
transporter.
Dlstal tubule
in this segment of the nephron 5% of sodium is
reabsorbed (NaCl co-transporter); thiazide diuretics
compete for these chloride-binding site s, As loop
diuretics increase sodium delivery to the distal
tubule, their combination with a thiazide (eg meto-
lazone) can provoke a massive diuresis in resistant
oedema. There are aldosterone receptors in both
the distal and collecting tubules (see below).
C ollecting duc t
Aldosterone-sensitive sodium channels are responsi-
ble for 2% of all sodium reabsorption; spironolac-
tone binds to the cytoplasmic aldosterone receptor.
Atrial natriuretic peptide (ANP) is also anti-
aldosterone in action [and hence is increased in
renal failure and in patients with congestive cardiac
failure (CCF), where it is thought to be counteractive
against secondary hyperaldosteronism). Other im-
portant collecting duct functions are as follows:
I H* is secreted into the lumen, so aciditying the
urine by forming ammonia/NH4
0 Antidiuretic hormone (ADH, or vasopressin)
increases water reabsorption by opening 'water
channels. Receptors on the basolateral
membrane (non-luminal) ofthe collecting duct
cell are stimulated by ADH, leading to insertion
of aquaporins into the luminal membrane. The
aquaporins then allow water uptake by the cell
Nephrology
lithium enters the collecting duct cells via the
sodium channels and inhibits the response to
ADH ( s o nephrogenic diabetes insipidus (NDI)
results)
15.1.3 R e n i n - a n g i o t e n s i n -
aldos terone (RAA) sy stem
This is covered in Chapter 4, Endocrinology. The
RAA system is very important in normal health.
helping to control blood pressure, sodium balance
and circulating volume. However, it has a central
role in the pathogenesis of secondary renal hyper-
te nsion, and also in propagating progressive chronic
kidney disease (CKD) ( se e below). Remember that
intrarenal perfusion will become critically depen-
dent upon the RAA system when hypovolaemia and
hypotension supervene; this explains why patients
can be vulnerable to acute renal failure induced by
agents blocking the RAA system (ie angiotensin-
convening enzyme (ACE) inhibitors, angiotensin-
receptor blockers (ARBsI| and renin inhibitors) even
in the absence of renovascular disease.
0 The RAA system is of key importance in the
pathogenesis of progressive renal disease,
irrespective ofthe primary disease aetiology
I
Agents which block the RAA system are
therefore now considered to be essential therapy
in patients with a variety of chronic
nephropathies
15.2 RENAL INVESTIGATION
15.2.1 U r ina lgsis
Uri n ary dipstick
Standard dipsticks assess the presence of protein,
blood and glucose. 'Multi-sti>< will also assess pH
-[range 4 .5 - 8 but normally 5 - 6 ; pH>8 suggests
renal tubular acidosis, for example) and leucocytes
( mo s t commonly raised because of vaginal contam-
ination of urine or urinary tract infection).
393
 Essential Revision Notes for MRCP
0 The sticks register positive for 'blood' in the
presence of erythrocytes, as well as free
myoglohin (eg in rhabdomyolysis) and
haemoglobin, Many cases of dipstick +ve,
microscopy -v e (absence of red cells on MSU)
haematuria are seen, and these are presumably
due to haemoglobinuria (eg exercise, low-grade
haemolysis)
I Standard dipsticks do not detect Bence jone s
proteins, and so if free urinary light chains are to
be identified immunoelectrophoresis of urine is
necessary
I
Microalbuminuria will usually not be detected
with standard dipsticks
Protelnuria
Normal urinary protein excretion is < 150 mg/day,
which should consist of < 20 mg albumin, tubular
secreted proteins (4 0 -6 0 mg), such as the Tamm-
Horsfall or tubular glycoprotein and immuno-
globulin, and various filtered low-molecular-weight
proteins.
O Microalbuminuria, which is the hallmark of
early diabetic nephropathy but which is also
prognostically important for cardiovascular
disease and mortality risk when present in
hypertensive patients, is defined as albumin
excretion of 3 0 -2 5 0 mg/day
I Proteinuria should be quantified by either
urinary albumin creatinine ratio (uACR) or
protein creatinine ratio (UPCR). As a rough
guide, average individuals pass around 10 mmol
urinary creatinine each day. Hence:
uPCR or ACR 25 = 250
mg protein or
albumin/day
uPCR or ACR 100 = 1000 mg protein or
albumin/day
e uACR 5 = 50 mg albumin/day 1
micro-
albuminuria ( note that in this instance uPCR
would be 'normal' and urine dipstick testing
-v e)
Significant non-nephrotic proteinuria (eg dipstick +
to +++, 0.2-3.5 g/24 h) is usually indicative of
renal parenchymal disease (unless due to urinary
tract infection). Nephrotic-range proteinuria ( > 3, 5
394
g/24 h, dipstick ++++) is always due to glomerular
disease.
Non-renal causes of proteinuria:
Fever
Severe exercise
Skin disease (eg severe exfoliation, psoriasis)
Lower urinary tract infection (eg cystitis)
Orthostatic p r o t e i n u r i a
This describes proteinuria detectable after the pa-
tient has spent several hours in the upright posture;
it disappears after recumbency, and so the first
morning urine should test negative. Proteinuria is
usually <1 g/24 h, there is no haematuria and renal
function and blood pressure are normal. Renal
biopsy samples are usually normal and nephrologi-
cal consensus suggests this is a benign condition.
Urine m i cros copy
Microscopic examination of a fresh specimen of
urine may yield many helpful pointers to intrinsic
renal pathology:
0 Red cells; >2-3/high-power field is
pathological (microscopic haematuria); cells are
usually dysmorphic in glomerular bleeding, but
appear normal when derived from the lower
urinary tract
I
leucocytes: infection, and some cases of
glomerular and interstitial nephritis
0
Crystals: eg oxalate, struvite (see Section
15.10.! on renal calculi), cystine and, with
polarised light, uric acid
0 Casts: there are several types of cast:
Tubular ce/is - acute tubular necrosis (ATN)
or interstitial nephritis
~ Hyaline - Tamm-Horsfall glycoprotein (ie
in healthy people)
~ Granular - non-specific
Red cell - glomerulonephritis or tubular
bleeding
~ Leucocytes - pyelonephritis or ATN

. }:i,.:;;,;j,;_
.;, :;_;._\=;~
Haematuria
Myoglobinuria (brown)
Beetroot consumption
Alkaptonuria (urine brown on exposure to
the air)
0 Obstructive jaundice (yellow)
0 Haemoglobinuria
0 Drugs (eg rifampicin, para-aminosalicylic
acid)
0
Porphyria (urine dark brown or red on
standing)
15.2.2 Renal rad io lo g y
The essential first-line radiological investigation for
acute kidney injury IAKI), chronic kidney disease
(CKD) and most other nephrological conditions is
renal ultrasound, This will demonstrate:
I
Bipolar renal length: in most cases of CKD, the
kidneys are small ( < 8 c m ) the exceptions are
polycystic kidney disease (very large with
multiple cysts), and sometimes in diabetic renal
disease and amyloid (normal size). ln AKI the
kidneys are usually normal size ( 8 . 5 - 1 3 . 5 cm),
but slight enlargement is common clue to
swelling. Asymmetry ( > 1. 5 cm disparity) is seen
in unilateral renal artery stenosis (RAS), but also
in chronic pyelonephritis and other causes of
renal atrophy
0 Obstruction
0 Cortical scarring: for example in reflux
nephropathy or following segmental ischaemic
damage
0 Calculiz within the substance of the kidney and
collecting systems
0 Mass lesions and cysts (eg renal tumour,
polycystic disease or simple renal cysts)
Doppler ultrasound is useful to assess renal blood
flow and to measure the resistive index within the
kidney; specific patterns are observed in, for exam-
ple, RAS, acute tubular necrosis and acute trans-
plant rejection.
Nephrology
. _.
r
sr., ::.-_;,- ; lntravenous urography (IVU) is reserved for investi-
at
gation of urinary tract bleeding (eg to detect urothe-
lial tumours of the renal pelvis, ureters and
bladder), UTI and for some cases of obstructive
uropathy. IVU can exacerbate A|<l (see Section
15.4.3, Radio-contrast nephropathy), and has very
limited value in advanced CKD (eg eGFR < 2 5 ml/
min) because of poor concentration of the dye.
Is o t o p e ren o g rap h y
Two major types of renograms are commonly uti~
lised:
0 Static scans (eg DMSA): the isotope is
concentrated and retained within the renal
parenchyma, and elimination is slow. DMSA
will therefore demonstrate aspects of structure
(eg scars in reflux nephropathy) and split
function ofthe two kidneys
0
Dynamic scans (eg MAG3, DTPA, hippuran):
these isotopes are rapidly taken up and
eliminated by the kidneys; such scans are used
to assess renal blood flow, split function and
A
also to investigate obstruction (eg to show
whether urinary tract dilatation is due to
obstruction)
Renal a ngiogra phy
The most frequently used techniques are:
I
Magnetic resonance angiography (MRA): non-
invasive and used in screening for RAS.
Gadolinium (Gd) is used as the 'contrast' agent,
Since 2006 there has been recognition that Gd-
MR scanning can occasionally lead to a serious
condition, nephrogenic systemic fibrosis (NSF),
which has some similarities to scleroderma and
can be fatal. The patients at greatest risk are
those with stage 5 CKD (see Section 15.5.1)
receiving dialysis, or patients who have AKI; the
nature of the Gd preparation (linear structure, eg
Magnevist"-i' and Omniscan' `) and use of
multiple doses are additional risk factors.
Current guidance recommends that Gd-MR
should only be used with caution in patients
with eGFR < 30 ml/min
395
 Essential Revision Notes for MRCP
0 CT angiography (CTA): non-invasive and readily
available, but risk of contrast nephropathy in
renal impairment, diabetics, etc
0
Digital subtraction angiography (DSA): provides
excellent detail of intrarenal vasculature;
invasive and risk of contrast nephropathy
Renal tract CT a nd MR
These imaging modalities are commonly used in
nephro-urology in the investigation of many condi-
tions, including:
I Delineation of cause of obstruction
I Assessment of renal tract tumours, including
staging
0 Assessment of renal cyst structure
15.3 ACID-BASE. WATER AND
ELECTROLYTE DISORDERS
15.3.1 Acidosis a nd alkalosis
Respiratory acidosis (eg carbon dioxide retention
due to chronic or acute-on-chronic lung disease)
and alkalosis (eg due to hyperventilation) are com-
mon, and well understood by all.
Metabolic alkalosis and metabolic acidosis are cov-
ered in detail in Chapter 13, Metabolic Diseases.
The width of the anion gap can help differentiate
the likely causes of a metabolic acidosis; the
bicarbonate will be low, and the anion gap can be
either wide (normal chloride and exogenous acid)
or normal (increased chloride and, hence, hyper-
chloraemic acidosis). Renal failure is associated
with a wide-gap acidosis (due to excess ammonia
and organic acids), whereas renal tubular acidosis
is worth consideration as a cause of a
normal-gap
acidosis.
15.3.2 Renal tubular acid o sis (RTA)
Distal or type 1 RTA is fairly common, and can
complicate many renal parenchymal disorders, par-
ticularly those which predominantly affect the me-
396
dullary regions. Note that the latter may also be
associated with nephrogenic diabetes insipidus, and
sometimes with salt-wasting states. Proximal or
type 2 RTA is uncommon. GFR is often normal in
both conditions.
I
Nephrocalcinosis and renal calculi formation:
urinary calcium excretion is increased in severe
acidosis, and calcium salts are more insoluble
in alkaline urine, and hence calculi
develop
-
frequently in distal but not in proximal RTA
(which is usually associated with a lower
urinary pH and less severe acidosis)
The two types of RTA can be differentiated by
several parameters (Table 15.1), but the hallmark
associations are severe acidosis, hypokalaemia and
renal calculi/nephrocalcinosis in distal RTA, and
proximal tubular dysfunction, osteomalacia/rickets
and less severe acidosis in proximal RTA.
Treatment of RTA: this is usually straightforward
(compared with an understanding of the conditionl),
and consists of oral potassium and bicarbonate re-
placement therapy. Close monitoring is needed to
prevent major imbalances in electrolyte concentra-
tions, especially during intercurrent illness.
0
Primary
e Genetic (dominant) or idiopathic
0
Secondary to autoimmune diseases
Systemic lupus erythematosus (SLE),
Sjogren syndrome, chronic active
hepatitis
0 Tubuloinlerstitial disease
Chronic
pyelonephritis, transplant
rejection, obstructive uropathy, chronic
interstitial nephritis
0
Nephrocalcinosis
e
Medullary sponge kidney,
hypercalcaemia
0
Drugs and toxins
~ Lithium, amphotericin, toluene
 Nephrology

Table 15.1. Differentiation between type 1 and type 2 renal tubular acidosis

Type 1 (Distal) Type 2 (Proximal)

Defect Impaired urinary ( H i ) Failure of HCO; reabsorption
acidification
Urine pH >5 .3 (ie urine never Variable
acidifies')

Plasma HCO3 < 1 0 mmol/I 1 4 -2 0 mmol/l

Plasma K Usually 1 Normal or 1

Complications Nephrocalcinosis OSleomalacia (phosphate wasting)

Calculi
Other features Growth failure
i aminoaciduria)
Urine infection
i
" 1 - ' r-"~i'i~ I, _
,
,i
0
Occurring alone
~ idiopathic
0 With Fanconi syndrome
Wilsons disease, cystinosis, fructose
intolerance, Sjogren syndrome
0 Tubulointerstitial disease
interstitial nephritis, myeloma,
amyloidosis
0
Drugs and toxins
Outdated tetracyclines,
streptozotocin,
lead and mercury (and other heavy
metals), acetazolamide, sulphonamides
l 0
Type 4 RTA: this describes a metabolic acidosis that
is associated with hyperkalaemia and mild renal
impairment (QCFR usually >3O ml/min), It is com-
monly due to mineralocorticoid deficiency:
0 Low renin, low aldosterone (hyporeninaemic
hypoaldosteronismlz diabetes mellitus, and
Rickets
Fanconi syndrome (ie phosphaturia, glycosuria,
, t
drugs (non-steroidal anti-inflammatow drugs
(NSAIDs) and ciclosporin)
0
High renin, low aldosterone: adrenal
destruction, congenital enzyme defects and
drugs (ACE inhibitors and ARBS)
Abnormal collecting duct function (eg due to
absent/defective mineralocorticoid receptor, chronic
tubulointerstitial disease or drugs such as Spirono-
lactone or amiloride) is responsible for other cases.
15.3.3 Polyuria
Polyuria (urine output >3 l/day) may result from:
Diuretic usage
0
Large fluid intake
0 Alcohol: inhibits ADH release and alcohol is an
osmotic diuretic
U Cranial diabetes
insipidus: osmolality high
0
Nephrogenic diabetes insipidus: osmolality
high; note that polyuria (often manifest as
nocturia) is often the first symptom of CKD
0
Psychogenic polydipsia: osmolality usually low

397

~
Essential Revision Notes for MRCP

I Atrial natriuretic peptide release: post- 0 Without hypertension (usually high plasma
arrhythmia, cardiac failure renin activity)
plasma renin activity
~HighDiuretic

The causes of cranial and nephrogenic diabetes

usage (urinary potassium
insipidus are listed in Chapter 4, Endocrinology; excretion may be high or low)
hyponatraemia as well as other disorders of water Gastrointestinal tract losses
balance, including syndrome of inappropriate ADH (potassium excretion < 3 0 mmol/
(SIADH), are also discussed in that chapter.
~ day)
Salt-wasting CKD (high sodium and
potassium excretion)
15.3.4 H ypoka l a e mi a Bartter syndrome (high potassium
excretion - see text)
Acute hypokalaemia can lead to muscle weakness Gitelman
~ Secondarysyndrome
0 (see text)
and direct renal tubular cell injuiy. Chronic hypoka- hyperalclosteronism (eg
laemia is a cause of interstitial nephritis. The causes cardiac or hepatic failure -
can be classified according to the presence or increased potassium excretion)
absence of hypertension with reference also to the
'I I-fl-hydroxy steroid dehydrogenase metabolises
plasma renin activity and urinary potassium excre- cortisol and prevents it from binding to the
tion. mineralocorticoid receptor. Acquired or congenital
conditions in which this enzyme is inhibited have a
Conns phenotype (including patients taking liquorice in
5- 1 it
excess, and carbenoxolone), Patients may have acidosis
rather than alkalosis
I With hypertension (potassium excretion GS H is rare and is due to a gene fusion which makes
the hyperaldostefonism completely ACTH-sensitive. The
usually >3O mmol/day)
High plasma renin activity clue to diagnosis is a strong family history (autosomal
~ Renovascular disease dominant). Treatment is with glucocorticoids, which
lower the blood pressure
Accelerated-phase hypertension
~ Cushing syndrome
. Reninsecreting tumour
Low plasma renin activity
~ Primary hyperaldosteronism
Bartter s y n d ro me
Severe hypokalaemia is consequent upon a salt-
Conn syndrome) wasting state (increased sodium delivery to the
~ (including distal tubule ) that is due to defective chloride realo

-
~
Carbenoxolone*
Liquorice excess*
11-[3-hydroxy steroid dehydrogenase
deficiency* ('apparent
sorption (at the NaK-2Cl co-transporter) in the loop
of Henle; inheritance is usually autosomal re c e ssive ,
Patients have normal or lovv blood pressure and
severe hyper-reninaemia (with hypertrophy of the
mineralocorticoid excess)
v Liddle syndrome (see text) juxlaglomerular apparatus) with consequent hyper-
GIucocorticoid-suppressible aldosteronism; CFR is usually normal. Treatment is
with large-dose potassium replacement; NSAIDs
hyperaldosteronism (GSH)**
may also be beneficial.

398
 Nephrology

Liddle s y n d ro me of renal function is seen in up to 5% of all hospital

This is an autosomal dominant syndrome of hyper-
tension and variable degrees of hypokalaemic meta-
bolic alkalosis. The patient appears to have primary
hyperaldosteronism, but renin and aldosterone are
suppressed and there is no response to spironolac~
tone. The pathogenesis is associated with enhanced
reabsorption of sodium in the distal nephron
(amiloride-sensitive sodium channel). Treatment
consists of salt restriction, potassium supplements
and use of either amiloride or tr ia mte r e ne ,
Gitelman syndrome
This condition can be either autosomal recessive or
dominant, and is characterised by hypokalaemic
metabolic alkalosis and also with hypocalciuria and
hypomagnesaemia. Patients present at a later age
than those with classic Barrier syndrome and, like
the latter, the blood pressure is low or normal and
patients have hyper-reninaemic hyperaldosteronism.
The metabolic abnormalities may lead to muscular
weakness and tetany. Treatment is with magnesium
and potassium supplements,
15.4. ACUTE KIDNEY INJURY (AKI)
15.4.1 Pathogenes is an d m an ag em en t
of acu te k id n ey i n j u ry
AKI is the term now used interchangealoly to de-
scribe acute renal failure (ARF). Acute deterioration
admissions. The incidence of severe AKI (eg creati-
nine >5 0 0 pmol/l) increases with age; the overall
annual incidence is approximately 150 per million
in the UK, but this figure is six times greater in the
>80-year-old group. Oliguria is usual, and is de-
fined as a daily urine output of <400-500 ml; this
is the minimum volume to enable excretion of the
daily waste products of metabolism.
Non-oliguric AKI accounts for about 10% of cases;
this may be associated with drug toxicity (eg genm-
micin or amphotericin), radio-contrast nephropathy
and acute interstitial nephritis.
The majority (60%) of cases of AKI result from renal
hypoperfusion and ischaemic damage; the resulting
renal histopathological lesion is acute tubular ne-
crosis (ATN). Many other patients can have similar
ischaemic insults to the kidneys, with an initial
period of oliguria, but renal perfusion can then be
restored by vigorous haemodynamic management
before severe tubular injury ensues; this is termed
pre-renal uraemia. ln the latter, physiological
mechanisms (ie stimulation of the RAA system) are
preserved within the kidney, and so the urinary
manifestations of sodium and water reabsorption
allow differentiation from established ATN (Table
15.2). ln practice, the two conditions may some-
times only be differentiated by the clinical response
to fluid resuscitation - patients with ATN will re-
main oliguric, whereas those with pre-renal uraemia
will usually start diuresing. A large number of

Table 15.2. Urinary findings in acute tubular necrosis and pre-renal uraemia

Urinary findings ATN Pre-renal uraemia

Urine sodium >4 0 mmol/I < 20 mmol/l
Urinezplasma osmolality <1 _1:1 >1.5:1
Fractional sodium excretion (FeNa)* > 1% < < 1%
Urine: plasma urea <7:1 >10:1
Urine volume Oligo-anuric or polyuria < t . 5 litres
(recovery phase)
*FeNa is the percentage of sodium that is filtered at the glomerulus
(normally 1000 mmol/h) which actually appears
in the urine (normal <6 mmol/h, ie <0.6/oi)

399
Essential Revision Notes for MRCP
patients with ATN can be managed without the
need for dialysis,
Many patients with pre-existing CKD present with
acute deterioration of renal function ( a c ute - on-
chronic kidney disease) and require similarly inten-
sive support and clinical management.
The causes of ARF, with approximate relative
frequency, are summarised below (excluding
acute-onchror|ic cases).
of ARIN V
~ of vasoconstrictors (particularly endothelin) and by
0 Pre-renal factors leading lo renal
hypoperfusion and ATN (60%)
~ Reduced circulating volume: blood loss;
excess Gi losses; burns
~ Low cardiac output states: toxic or
ischaemic myocardial depression
~ Systemic sepsis
Drugs inducing renal perfusion
shutdown: (eg ACE inhibitors; NSAIDs)
' Toxic ATN (5 %)
~ Rhabdomyolysis with urinary myoglobin
Drugs: (eg gentamicin; amphotericin)
~ Radio-contrast nephropathy
-
Structural abnormalities of renal
0
vasculature (5 %)
Large~vessel occlusion (renovascular
disease]
~ Small-vessel occlusion: accelerated-
phase hypertension; disseminated
intravascular coagulation (DlC);
haemolytic uraemic syndrome ll-IUS);
thrombotic thrombocytopenic purpura
(TTP); pre-eclampsia; systemic sclerosis
Acute cortical necrosis
0 Acute glomerulonephritis and vasculitis
---
(15%)
~ idiopathic crescentic glomerulonephritis
ANCA-positive vasculitis
Goodpasture syndrome
Other proliferative glomerulonephritis
(eg SLE; endocarditis; Henoch-
Schonlein nephritis]
400
0 Interstitial nephritis (<5 % )
idiopathic, immunologically mediated
Drug-induced hypersensitivity
Infection (eg pyelonephritis;
leptospirosis; Hanta virus)
0
Myeloma/tubular cast nephropathy (<5 %)
0
Urinary tract obstruction (10%)
P athophysiology of ATN
After an ischaemic insult there is intense afferent
arteriolar vasoconstriction, mediated by the release
loss of intrinsic vasodilators (nitric oxide and prosta-
glandin IZ(PCI2)); this contributes to the loss of CFR
and the redistribution of blood flow within the
kidney. Hypoxic injury to the energy-consuming
cells of the proximal tubule and thick ascending
limb of Henle occurs; calcium- and oxygen-free
radical-mediated cell necrosis results in cell shed-
ding from the tubular basement membrane, with the
formation of casts that block urine fl ow,
Investigation of AKI
The history may point to the cause of AKI (eg drugs,
skin rash); assessment of the haemodynamic status
is imperative, and appropriate fluid resuscitation
should be given.
0
Urinary examination: ATN and pre-renal
uraemia can sometimes be differentiated by
urinary biochemistry (see Table 15.2);
microscopic haematuria and red cell casts will
point to acute glomerulonephritis as the cause
0 A renal ultrasound scan will usually show
normal-sized kidneys, and will identify
obstruction (the latter should be urgently treated
to reduce irreversible renal injury)
Auloantibody profile: ANF, ANCA, anti-GBM,
I
complement and plasma and urinary
electrophoresis should all be routinely
performed (unless the cause of AKI is obvious,
eg post-myocardial infarction or renal
obstruction)
0 Percuhaneous renal biopsy is essential if an
intrinsic lesion (eg vasculitis, glomerulonephritis,

interstitial nephritis) is suspected, or if no
ischaemic cause is apparent, especially if there
is no sign of improvement in renal function and/
or ifthe oliguric phase is delayed
Management of AKI
The mainstay of treatment involves optimisation of
fluid balance and avoidance of either hypovolaemia
or fluid overload. Patients with
singleorgan /-\Kl are
best managed in an HDL] setting. Blood pressure
should be controlled, haemoglobin maintained
above 9 g/dl and sepsis should be promptly and
vigorously treated. 'Renal dose' dopamine and loop
diuretics are often given in ATN, although there is
no evidence that they alter the outcome of AKI in
humans. Some cases of ATN can be managed with-
out dialysis, with the adoption of careful fluid
balance and dietary control; however, many
patients with ATN also have multi-organ failure
(MOP) and they can only be managed on an ICU.
Key to AKI management is attention to intensive
nutritional support of the sicker patients, and the
use of continuous renal replacement therapies (eg
CVVl-l: continuous veno-venous haemofiltration)
which are less likely to provoke haemodynamic
instability.
Other more specific treatments in AKI depend upon
the causative condition and include the following:
0
Specific immunosuppressive therapy, and
sometimes plasma exchange, may be
appropriate for some conditions (eg
Goodpasture syndrome, ANC/-\ +ve vasculitis)
I Obstruction: bladder catheterisation for bladder
outflow obstruction; nephrostomy drainage for
renal obstruction
0 Ot her; eg steroids in acute interstitial nephritis
(AIN), plasma exchange in HUS and TTP,
chemotherapy in myeloma
Nephrology
0 Severe uraemia
v eg vomiting, encephalopathy, urea > 60
mmol/l
0
Hyperkalaemia
v K+> 6.5 mmol/l [or less, if ECG
changes apparent)
0 Severe acidosis
pH <7.1
0 Uraemic pericarditis
0
Pulmonary oedema
Prognosis of AK!
The overall survival for patients with AK! remains
relatively poor; 55%-60% of patients who require
dialytic therapy survive, but this figure partly reflects
the very poor outcome of patients who have ATN as
a component of MOF who are managed on the
|CU_ For example, only l 0 %-2 0 % of those with
three- or four-organ failure will survive, yet 90% of
patients who have AKI in isolation survive.
The prognosis for recovery of renal function varies
according to the causative condition; renal recovery
occurs in < 50% of cases with autoimmune vasculi-
tis. In survivors of ATN, renal function will return to
the normal range in 60/0, whereas 30% will be left
with CKD and 10% will be dialysisdependent.
1 5 ,4 2 R ha bdomyol ys i s
Muscle damage with release of myoglobin can
cause severe, hypercatabolic /\l<l, Serum potassium
and phosphate (released from muscle) rapidly rise,
calcium is typically low and the creatine kinase
massively elevated; serum creatinine may be dispro-
portionately higher than urea. Primary management
involves intravascular fluid expansion with the en-
couragement of diuresis; alkalinisation of the urine
401
Essential Revision Notes for /VIRCP
(with l\/ bicarbonate) may help to solubilise the
myoglobin pigment within the renal tubules. S om e
times the source of the rhabdomyolytic process
requires specific therapy (eg fasciotomy for com
partment syndrome, debridement of dead tissue and
amputation of nonviable limbs).
` high-risk patients
T
lil;{f.
0 Crush injury
~ Trauma; unconsciousness with
compression
0 Metabolic myopathies
eg McArdle syndrome
0 Infections
Viral necrotising myositis, infectious
mononucleosis (eg coxsackie influenza)
I Uncontrolled fitting
0 Drugs
eg statins
0 Overdose
Barbiturates, alcohol, heroin
0 Severe exercise, heat stroke, burns
0
Inflammatory myopathies
Polymyositis
0
Malignant hyperpyrexia
P rognosi s of rha bdomyolysis
Patient survival in rhabdomyolysis depends upon
the nature and extent of the underlying causative
pathology. However, in survivors the prognosis for
full renal functional recovery is usually good.
15.4.3 Radio-contrast n ep h r o p ath y
Mild renal dysfunction may complicate up to i ( ) %
of angiographic procedures and lV U s, Radio~
contrast nephropathy is manifest by non-oliguric
AKI, typically occurring i - 5 days after the proce-
dure. lntrarenal vasoconstriction, mediated largely
by endothelin, and tubular cell toxicity (with ATN)
are important in the pathogenesis. The AKI is usual-
ly fully reversible. Recent attention has been direc-
402
ted to prevention of radio-contrast nephropathy:
Pre-hydrate patients at greatest risk (eg with N-
saline infusion before and during the procedure)
0 There is some limited evidence that N-acetyl
cysteine (given orally for 2 - 3 days, from before
to 24 hours post-procedure) may be of benefit in
=; t>t":";.=2_,2:I'-wg .r
:'>f.t`*-=?_=:f
, . '
'c'f<$--".>`,t> 1 .- 5 .< ~~ , - : <
High contrast load
High iodine content ofcontrast
Hypovolaemia
Diabetes mellitus'
Myeloma
Hypercalcaemia
Age
Pre-existing CKD
Hyperuricaemia
'Especially if the patient is taking metformin ~ this
should be withdrawn before injection of radiocontrast
15.5 c H R o N |c KIDNEY DISEASE
(CKD) AND RENAL
uEPLAcEMENT THERAPY
1 5 .5 .] Chronic ki dne y d isease (CKD)
CKD is defined as evidence of kidney damage (eg
urinary abnormality such as haematuria or protein
uria; scars or polycystic change on a renal scan) or
eGFR < 60 ml/min (see below). lt is very common,
and latest data suggest that it affects about 8% of
the UK adult population. The incidence of end-
stage renal disease (ESRD) patients joining renal
replacement therapy (RRT) programmes in the UK is
about 125/million each year; the figure is almost
300/million in parts of the USA (because of racial
factors and increased population prevalence of dia~
betes mellitus and hypertension). The prevalence of
patients on UK RRT programmes is around 600/
million, but as ageing constitutes one of the major
risk factors for CKD and ESRD, the prevalence is

greatest in people aged > 6 5 years (eg 1000/million,
or 0.1%, receiving RRT).
There are several recognised stages of CKD (Table
15.3):
0
Stage 1 ~
although renal function is entirely
normal (eCFR > 9 0 ml/min) this group should be
identified, as a proportion of patients will be at
risk of progression of CKD in the future (eg
type 1 diabetics with microalbuminuria)
Stage 2 - the same argument applies for
identification and then follow-up of patients
with eCFR 6 0 -9 0 ml/min and urinary/renal
structural abnormalities. Note that patients with
CKD stages 1 and 2:
Will not have renal-related anaemia if -
anaemia is present, another cause should be
sought
Will not have renal bone disease
e May have hypenension
I
Stage 3 - accounts for the largest proportion of
CKD patients (eg 5% of the UK adult
population), Over 95% of this group will not be
at risk of future progressive CKD, being classed
as having CKD simply because they are
elderly
(age being a denominator in the MDRD eCFR
equation). ln recognition of this, stage 3 has
been divided into 3A (eCFR 45~59 ml/min) and
3B (eCFR 3 0 -4 4 ml/min), with 3A patients
being considered at low risk (unless they have
associated proteinuria). However, a high
proportion of stage 3 patients will be
hypertensive, as this too is associated with
ageing
Table 15.3. Classification of CKD
Stage Description
1 Kidney damage with normal or TCFR
2 Kidney damage with mild 1 CFR
3A Moderate l CFR
3B
5 Severe 1 CFR
5 Kidney failure
Nephrology
~ Renal-related anaemia and secondary
hyperparathyroidism may begin during stage
3B CKD, as it is at this level of renal
function that perturbations in erythropoietin
production and vitamin D metabolism start
to occur (see below)
Stage 4 - most patients will be hypertensive,
and many are anaemic. Hyperphosphataemia
may develop during this stage. A far higher
proportion of stage 4 patients will be at risk of
progression compared to those with stage 3
CKD. Hence, the majority of patients will be
referred to the nephrology service, and those
with progressive CKD will be given patient
education with discussion of treatment options
(ie RRT or conservative care)
-
Stage 5 this is ESRD. The majority of patients
will have progressive renal dysfunction such that
consideration of treatment options becomes
essential. The patient will normally be managed
in secondary care, and attention will be given to
the following:
In patients opting for haemodialysis
therapy,
a goal of management is to have a mature
arteriovenous fistula in situ before dialysis
needs to commence
Suitable
patients will be activated on the
renal transplant waiting list (by eCFR 15 ml/
-
min), or, where relevant, transplantation
from a live kidney donor arranged
In those who have opted for treatment, and
where a renal transplant is not imminent,
most need to commence dialysis when
eCFR falls below 10 ml/min
eGFR (ml~min"~1.73 m2)
290
6O~89
4 5 -5 9
3 0 -4 4
1 5 -2 9
S1 5
403
Essential Revision Notes for MRCP
Although many cases of CKD progress insidiously,
such that very abnormal biochemistry is relatively
well tolerated by the patient, about 25% of dialysis
patients initially present as uraemic emergencies
(which carries a twofold worse prognosis). The key
parameters that differentiate CKD from AKI are:
Small kidneys at imaging
Anaemia
Renal bone disease
Clinical tolerance of very severe uraemia
,`i`,s~\,f<_.~ v '\a'vt~ it _>, Y
1
0 Most common causes of ESRD in UK*
Diabetic nephropathy (25%)
Chronic glomerulonephritis (15%)
Hypertension (15%)
Chronic pyelonephritis (12%) - most
often due to reflux nephropathy, but
also renal calculi (nephrolithiasis) with
. infection
Polycystic kidney disease (8%)
~ Obstructive uropathy (5%)
~ Chronic interstitial nephritis (4%) - eg
sarcoidosis, lithium toxicity, myeloma
Post-acute kidney injury (3%)
~ studies; for example, diabetic patients with
0
-
~
Amyloidosis (1%)
Rarer causes of CKD
Analgesic nephropathy
- Other hereditary disorders - eg Alport
syndrome
Toxic nephropathy
Following nephrectomy for renal
tumours
' ln at least 10% of cases of ESRD, the aetiology remains
unknown. These are patients presenting with small
kidneys on ultrasound, and in whom renal biopsy will
be diagnostically unhelpful. Most likely diagnoses are
hypertension, chronic glomerulonephritis or
pyelonephritis, or dysplastic kidneys
404
i
t
P at hogenes i s a nd ma na ge me nt of
p r o g r e s s i v e re na l dysfunct i on in CKD
Although the majority of cases of CKD are slowly
progressive towards ESRD, patients with particular
i
pathologies (eg post-obstructive atrophy, and hyper-
tension - when controlled) may manifest stable
CKD for many years. When progression occurs its
pathogenesis is multifactorial. It is thought that the
RAA system plays a major role: the vasoactive F
mediator angiotensin and aldosterone exacerbate
the intraglomerular hypertension seen in remaining
nephrons, and they probably stimulate fibrosis with-
in the tubulointerstitium and increase proteinuria,
which itself may also directly damage tubular cells
(see Figure 15.2). Hence the management of pa~
tients with CKD requires attention to:
0 Control of blood pressure: it is imperative to
optimise blood pressure control. Target blood
pressures for patients with CKD are <130/80
mmHg (without significant proteinuria) and
<1 25/75 mmHg if significant proteinuria (eg
uACR > 5 0 ) is present. Hypertension control can
slow the progression towards ESRD, and ACE
inhibitors and ARBs are logical agents to choose
because of their effects upon the RAA system.
The imponance of optimal blood pressure
control has been shown in observational
optimal control may lose GPR at a rate of only
1 - 2 ml/min per year whereas those with poor
blood pressure and glycaemic control
0
deteriorate rapidly towards ESRD, losing CFR at
8 - 1 6 ml/min per year
Reduction of proteinuria: heavy urinary protein
losses are associated with an increased rate of
progression in many cases of CKD. Amelioration
of proteinuria by blockade of the RAA system
may also slow progression
I
Dietary modification: patients with advanced
CKD should maintain a normal protein and high
calorie intake to avoid malnutrition (and a
consequent increased likelihood of morbidity) in
 __
Nephrology
\;
l Figure 15.2 Role of angiotensin ll (All) in the pathogenesis of progressive CKD

TANGIOTENSIN ll o iAll release from damaged

renal tissue
o leads to intraglomerular
hypertension in remaining
nephrons
l "`&J?f?T eren o Leads to iproteinuria
to tubules) and further
(toxic
H arteri ole
glomerular injury
GLOMERULI 0 Problem exacerbated by
systemic and intrarenal
hypertension

l co u / t o
FIBROBLAST o All inc r e a se s release
"" fi
, eo
/ of aldosterone from
zona glomerulosa of

l
1 fs -
A|_>5;;371.`f~;__@ ru au t f
- E - \ \
adrenal gland
o Both have deleterious
effects in the renal

l lAldosterone
/- tubulointerstitium
mediated in part by
l release pro-scarring
cytokines (eg TGFB)
TUBULOINTERSTITIUM

i the phase leading up to RRT. Restricted protein

intakes are now only used as a conservative
means of limiting uraemia in a minority of
patients, However, phosphate restriction and
dietary modification of salt and potassium
intake should be instituted at an early stage of
l CKD
Endocrine complications; anaemia and renal
I osteodystrophy may begin during CKD smges 3
and 4, and hence early attention should be
directed to these endocrine complications (see
i below]
Cardiovascular disease prevention: CKD creates
a pro-atherosclerotic environment due to factors
such as hypertension, mixed hyperlipidaemia,
hyperhomocystinaemia, anaemia,
hyperparathyroidism and, when present,
diabetes mellitus, The resulting accelerated
atherogenesis will result in coronary artery
disease, stroke and peripheral vascular disease
but other cardiovascular complications include
congestive cardiomyopathy, left ventricular
hypertrophy (LVH), and vascular calcification
(which results in arterial stiffness). Patients with
CKD therefore have a marked increase in CVS
mortality compared to the general population;
the importance of early treatment with statins is
now the subject of a multicentre trial
15.5.2 An aemia of CKD
The anaemia of CKD usually first appears when
GFR is < 50 ml/min; if untreated, it is a major
contributor to morbidity in patients with advanced
CKD. The major cause is the lack of endogenous
erythropoietin secretion by the damaged kidneys,
but other factors which predispose to the anaemia
are listed in the box overleaf.

405
l
Essential Revision Notes for MRCP
0 Reduced dietary iron intake due to anorexia
0 Impaired intestinal absorption of iron
0 Uraemia has a toxic effect upon precursor
cells in bone marrow
I Blood loss due to capillary fragility and
platelet dysfunction (probably of minor
importance)
l Reduced RBC survival (particularly in
haemodialysis patients)
ln general, haemodialysis patients have more severe
anaemia, and a poorer response to erythropoiesis-
stimulating agents (ESA) than their counterparts re-
ceiving continuous ambulatory peritoneal dialysis
(CAPD]. This may be because haemodialysis repre-
sents an 'inflammatory state' with cytokine release
being stimulated by interaction of blood cells with
the artificial dialysis membranes.
Recombinant erythropoiesis-stimulating
ag en t s (ESA)
Endogenous erythropoietin is normally synthesised
by renal peritubular cells; it stimulates proliferation
and maturation of erythroid lines within the marrow.
Recombinant ESA preparations are now widely
available and are used to correct anaemia in pa-
tients with CKD_ lt is imperative that these patient
groups avoid repeated blood transfusion, so that
future renal transplantation will not be precluded by
allosensitisation.
Before initiation of an ESA the patient should be
iron-replete. The serum ferritin and the transferrin
saturation need monitoring as most patients require
supplemental IV iron, Targets for treatment include:
0
Haernoglobin;10.5-12.5 g/dl
0 Ferritin: >20O pg/I in haemodialysis patients, or
> i 0 0 ug/l in CAPD and pre-dialysis patients
0 Transferrin saturation: >2O% ia figure of less
than this may indicate functional iron
deficiency)
One of the key aims of therapy is to limit or reverse
the LVH which is prevalent in RRT patients. Haemo-
globin correction will also have a positive effect
406
upon sexual function and other quality of life meas-
Uf! S.
Iron deficiency
Hyperparathyroidism
Sepsis or chronic inflammation
Aluminium toxicity (rare)
Occult GI tract blood loss
Pure red cell aplasia (PRCA; see below)
Main side-effects of ESA therapy: accelerated
hypertension with encephalopathy (aim for a
monthly Hb increase of <1 .5 g/dl), bone aches, flu-
like syndrome, fistula thrombosis (rare) and, most
recently, PRCA (see below).
Pure red cell ap l as i a (PRCA)
A few cases of unresponsive and progressive severe
anaemia have been identified in patients treated
with ESA, who have antibodies directed at endogen-
ous and exogenous erythropoietin; they become
transfusiomdependent. Other marrow functions re-
main intact.
15.5.3 Hy p erp arath y ro id ism an d
CKD min eral a n d bone
disorder (CKD-MBD)
The regulation of vitamin D and parathyroid hor-
mone (PTH) metabolism are discussed in Chapter
13, Metabolic Diseases. Renal bone disease (Cl<D-
MBD) is common in patients with CKD and those
receiving dialysis. The pathogenesis is fairly intricate
(see Figure 1 5 3 ) but the most important compo-
nents are:
0
High serum phosphate: phosphate clearance is
reduced in renal failure
0 Low plasma ionised calcium: due to several
factors. There is lack of l,25-dihydroxy-
vitamin D (the l-or-hydroxylation, which
markedly increases activity of vitamin D,
normally occurs in the kidney). Malnutrition may
contribute, but hyperphosphataemia
 Nephrology

l Figure15.3 Pathogenesis of CKD-bone mineral disorder (CKD-BMD). ln CKD there is phosphate

retention and reduced l-or-hydroxylation of 23-hydroxy vitamin D. These abnormalities both lead to
reduced plasma [Ca2+i and all three factors independently stimulate PTH release from the parathyroid
glands. The net effect is demineralisation of bone with release of calcium and more phosphate into
`
the crrcu lation, bony abnormalities include osleomalacia and high-turnover bone disease. (Figure
courtesy of Dr Helen Eddington, Salford Royal Hospital)

turnover TPTH / posltlve

(g
Q/ ibfirre
__1 feedback
4 4

sheomaiacia

.___-"'r':KD
" :ilcaicium
, .
l

$4Pl1osphate
|115rolriiiznf/
l
(imbalancing the ionic product of C a p ><PO43)
is also very important
Stimulation of PTH release: secondary
hyperparathyroidism is very common and is the
direct response of the glands to hypocalcaemia,
hyperphosphataemia and low i,25-dihydroxy-
vitamin D levels. The latter three factors feed
back independently on the parathyroid glands to
stimulate PTH release, and hence correction of
all of them (phosphate perhaps the most
important) is necessary before the
hyperparathyroidism can be optimally
controlled. PTH has end-organ effects on bones
(leading to osteoclastic resorption cavities) and
also the heart, contributing to LVH, and it is also
I cause of ESA resistance. Tertiary
a ma`or
hyperparathyroidism is defined by the presence
of elevated PTH and non-iatrogenrc
hypercalcaemia; it is due to autonomous PTH
secretion from generally hyperplastic
parathyr oi'd g lands (90%) or an adenoma (10%).
Note that primary hyperparathyroidism is only
rarel Yassociated with renal failure (due to the
nephrotoxic effects of hypercalcaemra or to
renal calculus disease)
Low vitamin D levels: this not only results in
reduced absorption of calcium by the gut, but
also in osteomalacia
Acidosis: increases the severity of bone
disease

4 O7
Essential Revision Notes for MRCP
Hi s t o l o g i cal fi ndings at bone bi opsy in
os t eodys t rophy
Several different histological lesions often co-exist
in the same patient:
U Osteomalacia: due to vitamin D deficiency
0
Hyperparathyroid bone disease: osteoporosis
and cystic resorption: also termed 'osteitis
fibrosa cystica ( von Recklinghausens disease of
bone). Subperiosteal erosions on the radial
border of phalanges are characteristic
Osteoporosis: due to relative malnourishment;
steroid use
U Osteosclerosisz a component ofthe 'rugger
jersey spine appearance at X-ray [bone denser
at the vertebral end-plates and thin in the
middle of the vertebrae)
I
Adynamic bone disease: bone with low
turnover; PTH levels (and serum alkaline
phosphatase) are usually subnormal, Over-
treatment of secondary hyperparathyroidism
with excess vitamin D (totally suppressing PTH
release) may be contributory. Although the exact
clinical significance is uncertain there is
perhaps a greater likelihood of fracturing
0 Aluminium bone disease: now much less
common with the use of specially treated water
supplies for dialysis (reverse osmosis) and non-
aluminium-containing phosphate binders
Prev en t i o n a n d tre a tme nt of CKD-MBD
The basic principles are to improve the diet, reduce
hyperphosphataemia and acidosis, and to reduce
the PTH level (see below). This is brought about by
use of phosphate binders, oral bicarbonate, dialysis
where necessary, and by giving vitamin D at doses
that do not provoke hypercalcaemia
408
0
Phosphate binders: aluminium-containing
binders are now infrequently used and the
mainstay of treatment has been calcium-based
binders (calcium carbonate or calcium acetate).
However, practice is changing, and with the
awareness that CKD patients are at risk of
vascular calcification and aortic valve
calcification, non-calcimimetic agents (eg
sevelamer, a polymer, and lanthanum
c a r bona te ) are increasingly used
0 Treatment targets: serum phosphate < i .7
mmol/l, calcium low-normal range ( 2. 2- 2. 45
mmol/l) and PTH <3 times above the normal
range (eg <2O0 pg/ml when range is 25-65 pg/
ml)
Most cases ( > 97%) of secondary hyperparathyroid-
ism can be controlled with this standard medical
treatment. For resistant cases (usually those with a
large parathyroid gland mass (eg >1 emi), who
have had chronic and poorly treated secondary
hyperparathyroidism) and in patients with tertiary
disease, the treatment options are now:
0 Cinacalcet (a calcium-sensing receptor agonist)
0 Selective vitamin D receptor agonist (eg
paricalcitol)
0
Parathyroidectomy
15.5.4 Maintenance di a l ysi s
ln the UK, the dialysis population is approximately
25000, or 450/million. In the UK approximately
70% of patients receive haemodialysis, and the
remainder peritoneal dialysis (CAPD, or automated
PD, APD). Ideally, a patient should be given the
opportunity to choose dialysis modality according
to lifestyle factors (employment, home environ-
ment), their capability and local resources.

Factors 'whielnvould favour
haemodlaiysis in p r d c n n e e to V
p eri t o n eal dialysis
0 Recent abdominal surgery, or irremediable
hernia
* Recurrent or persistent peritonitis (eg
Pseudomonas or fungal)
0 Peritoneal membrane failure: inability to
ultra-filtrate the necessary fluid volume to
maintain fluid balance in the patient
0
Age and general frailty (ie physically or
mentally incapable of PD)
0 Severe malnutrition: protein losses in the
dialysis effluent may be 3-10 g/day on
CAPD (>1 5 g/day during peritonitis)
I lntercurrent severe illness with
hypercatabolism
0 Chronic severe chest disease: resp~
iratory function may be compromised by
PD
0 Loss of residual renal function: it is now
recognised that many patients only obhain
adequate dialysis with CAPD during the
early stages after development of ESRD. As
residual function is lost, underdialysis
becomes a reality, especially in larger body
weight patients
Pe ritone a l dialysis
A standard CAPD regime would involve four 2-litre
exchanges/day. The concentration of dextrose with
in the dialysate can be altered so that differing
ultrafiltration requirements can be addressed.
Although a few patients manage CAPD for many
years, in most there is a finite length of time (eg 3~
6 years) for its efficacy as a form of RRT. This is
determined by gradual loss of residual renal func-
tion (ie a patient will commence CAPD with a CFR
of 1 0 -1 5 ml/min, which is a major contributor to
wasteproduct clearance; over time, the CFR falls to
zero, with corresponding inadequacy of the CAPD
technique) and deterioration of peritoneal mem-
brane function. Automated peritoneal dialysis
(APD) is performed overnight, and can maintain
Nephrology
fluid homeostasis in patients with ultrafiltration fail-
ure lsee below). APD may also be chosen for its
convenience by some patients with normal perito-
neal membrane characteristics.
The main complications of PD treatment are:
0 Bacterial peritonitis: most cases are treatable.
The most common infecting organisms are
coagulase-negative staphylococci, Gram-
ncgative bacteria and Staphylococcus aureus.
The rate of PD-peritonitis should be no greater
than 1 episode/30 patient-months. Patients who
have repeated episodes of peritonitis, and hence
several courses of intraperitoneal antibiotics, are
prone to develop resistant organisms (eg
Pseudomonas or fungal peritonitis) and catheter
loss, necessitating a switch to haemodialysis. lf
the dialysis fluid culture yields more than one
organism (especially Gram-negatives and
anaerobes] during a peritonitis episode, then
intra-abdominal pathology (eg bowel
perforation, diverticular abscess) should be
suspected and expediently diagnosed and
treated
Ullrafiltration failure: some patients are
identified as 'high transporters of glucose; the
osmolar benefit of their PD dialysate is rapidly
lost and hence these patients have difficulty
with fluid removal (ultrafiltration). The latter may
also develop after several years of PD treatment.
APD may help maintain fluid balance in such
patients, but polymer-based dialysis solutions
can also be beneficial
Encapsulating peritoneal sclerosis (EPS): an
increasingly recognised and serious
complication of long-term PD. Risk factors
include repeated episodes of peritonitis and
duration of PD (eg 5% incidence in patients
treated with PD for >3 years). The peritoneal
membrane thickens and encases the bowel.
Clinical features include CAPD ultrafiltration
failure, but, in more severe cases, life-
threatening bowel obstruction and malnutrition.
Surgery can be of benefit in some cases
0 Malnutritionz renal failure is an anorexic
condition; patients often need nutritional
supplements
409
Essential Revision Notes for MRCP
H aemo d i al y s i s
This therapy has been available for several decades;
it is an intrinsically more efficient means of RRT
than PD and so many patients have lived for >2O
years whilst being supported by haemodialysis. As
this is an intermittent therapy (typically, 4 hours of
dialysis three times each week) water restriction and
dietary modification are even more important than
tor patients receiving PD (who with CAPD would be
receiving continuous dialysis), Successful haemo-
dialysis relies upon adequate vascular access:
0 This is ideally provided by arterio-venous
fistulae. An appropriate blood flow rate would
be 250-400 ml/min into the dialyser circuit.
Fistulae take 4 - 6 weeks to mature and so
vascular access surgery should be planned in
timely fashion, when at all possible
0 Patients who present late with severe uraemia
and patients with fistula complications inevitably
require use of temporary or semi-permanent
(tunnelled) vascular access catheters. The most
frequent complication is line-related sepsis (in
particular, 5. aureus and coagulase-negative
staphylococci), and the incidence of bacterial
endocarditis is increased in haemodialysis
patients. Repeated use of antibiotic courses
increases the risk ofMRSA and Clostridium
difficile infection in dialysis patients
0 The other main complication of haemodialysis
catheters is venous stenosis or occlusion, most
commonly seen after subclavian insertion.
Consequently, most temporary catheters are
now inserted into the femoral (for the very ill) or
internal jugular veins, and the jugular veins are
the preferred sites for tunnelled catheter
insertion
0
Complications relating to insertion can be
minimised by using ultrasound scanning to
locate the vein for all insertions, and the use of
fluoroscopy with left internal jugular vein
insertion (as anatomical variants are c om m on)
Long-te rm com pl i cat i ons in dialysis p at i en t s
Although dialytic therapies will keep patients alive
and, with the additional use of ESA, relatively well,
410
many of the metabolic abnormalities of the uraemic
condition persist and these patients are at increased
risk of:
0 Vascular disease: dialysis patients have a high
risk of cardiovascular events and death
compared to the general population, the relative
risk of mortality being >l O0 in dialysis patients
aged < 3 0 years, and it remains three times that
of the general population even in patients aged
> 8 0 years. The risk is increased further in
diabetic dialysis patients (eg mean sun/ival of
Z years). Pathogenetic factors have been
discussed earlier in this section. The majority of
deaths are due to cardiac disease but this is
more often due to arrhythmia or congestive
cardiomyopathy (which is exacerbated by fluid
overload) than to overt myocardial infarction.
Vascular calcification is a major component of
the vascular disease affecting patients with renal
failure; it is associated with arterial stiffness and
LVH, which in turn correlate with increased
mortality
0 Cardiac valve calcificationz this affects the
aortic valve in particular, and is frequently seen
in haemodialysis patients. As with vascular
calcification, it is thought to be associated with
perturbations in serum phosphate and calcium
product
0
Dialysis-related amyloid: [52-microglobulin is a
small~molecular-weight (about ll 000 Da)
protein normally metabolised and excreted by
the kidney. Plasma levels increase greatly in
patients on long-term (eg > 10 years)
haemodialysis, and the protein is deposited as
amyloid within carpal tunnels, joints and bones.
Dialysis with more biocompatible membranes
can alleviate the B2-microglobulin burden
U Arthritis: pyrophosphate arthropathy
(pseudogout) and gout (see Section 15.5.5 on
transplantation below) are common in patients
with renal failure
15.5.5 Renal tr an sp lan tatio n
About 2000 UK patients benefit from renal trans-
plantation each year, and over half of transplants

derive from cadaveric donors. However, a shortage
of organs available for transplantation persists and
the rate of living-donor transplants (related or un-
related) is ever-increasing, All potential living renal
donors have to be screened carefully to ensure that
they are clinically fit; absolute contraindications
include pre-existing renal disease, a disease of un-
known aetiology [eg multiple sclerosis or sarcoido-
sis), recent malignancy and overt ischaemic heart
disease. Hypertensive patients may be considered
provided that they have no evidence of end-organ
damage, and the blood pressure is well controlled.
All donors require careful counselling before the
donor operation,
Screening a nd p rep arat i o n of p o t en t i al
reci pi ent s
All dialysis patients and those with advanced CKD
are considered for transplantation, However, less
1 than half will be suitably fit for listing,
0 Exclusion criteria include current or recent
malignancy (eg <2 years) and severe co-
morbidity (debilitating chronic obstructive
pulmonary disease (COPD) or stroke, dementia,
etc). Advanced age is not a contraindication but
few patients aged > 75 years are eventually listed
I As the transplant is inserted in the iliac fossa,
anastomosed to the iliac vessels, vascular
calcification ofthe latter should be sought with
pelvic X-ray. This is especially important in
patients with a history of peripheral vascular
disease
0 Patients with major risk factors (long-standing
diabetes, previous IHD, heavy smoking) should
undergo CVS screening prior to referral. This
would include echocardiography (LV ejection
fraction must be >30"/0) and non-invasive
imaging for reversible coronary ischaemia (eg
myocardial perfusion imaging or stress
echocardiography). Selected patients then
undergo coronary angiography and, if necessary,
L angioplasty or coronary artery bypass grafting
(CABG) prior to transplantation
l 0 Patients with obstructed and persistently or
recurrently infected urinan/ tracts (eg severe
Nephrology
reflux, patients with spina bifida) need bilateral
native nephrectomy prior to transplantation
Matching a nd inc ompa tible t ran s p l an t s
The majority of cadaveric organs are transplanted to
blood group-compatible patients with the best avail
able tissue match, but the national allocation
scheme will give preference to long~waiters' who
are often highly sensitised to the majority of HLA
allotypes.
0 HLA antigens are coded from chromosome 6
(see also Chapter 10, Immunology)
0 Class I antigens are A, B and C; class ll are the
D group antigens
0 Relative importance of HLA matching:
DR>B>A>C; most centres accept 1 DRor 1 B
mismatch
0
Transplants to incompatible' recipients (eg
blood group incompatibility or those pre-
sensitised to donor antigens) are possible with
use of 'desensitisation therapy teg plasma
exchange and B-lymphocyte suppressive
therapy) for the recipient a week or so before a
planned living donor transplant
Combined k i d n ey - p a n c r e a s t ran s p l an t at i o n
This is now increasingly performed for patients with
type i diabetes mellitus; recipient fitness is of para-
mount importance. The pancreas is usually trans-
planted onto the opposite iliac vessels to the kidney,
with its duct draining into the bladder.
0 Acute rejection of the pancreas is manifest by
worsening of glycaemic control and by a rise in
urinary amylase, but responds to pulsed steroid
therapy
Long-term results are encouraging -
normalisation of glycaemic status is expected,
and most diabetic microvascular complications
(particularly retinopathy and neuropathy) can be
stabilised, although not reversed
411
Essential Revision /\/otes for MRCP

sponsible for the majority of graft losses beyond

0
Pyonephrosis or any suppuration within the
urinary tract (see above), lf this is due to
bladder dysfunction (eg spina bifida) a
resting ileal conduit will need to be created
prior to transplantation
0 Massive polycystic kidneys
O Uncontrollable hypertension (rare with
modern drug therapies)
0 Renal/urothelial malignancy: patients must
remain free of recurrence for >Z years
before transplantation
1 year after transplantation, The causes of acute and
chronic graft dysfunction are shown in Table 15.4.
Acute t ran s p l an t rej ect i o n
This is very common, and should be anticipated in
the early weeks after transplantation. The risk of
acute reiection episodes may be less with use of
tacrolimus rather than ciclosporin. Most cases re-
spond rapidly to pulsed IV methylprednisolone ther-
apy. Steroid-resistant rejection occurs in about 5%
and usually requires therapy with monoclonal anti-
body therapy (eg ATC or Ol<T3l.

Chronic a llogra ft ne phropa thy (CAN)

P ost -t ranspl ant at i on renal function
lt is common to see acute renal transplantation
dysfunction, especially in the first 2 weeks after
engraftment. Nevertheless, overall graft survival is
90% at 1 year, 70% at 7 years and 50% at 14 years.
Chronic graft dysfunction is common and is re-
This accounts for the majority of graft losses occur-
ring beyond the first year after transplantation. It is
usually manifest by the development of proteinuria
and slowly progressive graft dysfunction, and is
thought to be due to both low-grade immunological
and non-immunological (hypertension, hyper-

Table 15.4. Causes of graft dysfunction after transplantation

Acute graft dysfunction (1 day to 4 months after transplantation)

Delayed graft function (ATN of the graft): increased with prolonged cold ischaemia time (seen in about
25% of all transplants usually resolves by 2 ~3 weeks)
~

0 Ureteric
leakage (breakdown of a n a sto mo sis)
0 Vascular thrombosis
(arterial or venous thrombosis of the transplant vessels - usually irremediable); this
be
may associated with primary non-function (ie the transplant never functions)
0
Urinary tract infection
0 Acute
ciclosporin or tacrolimus toxicity - resolves rapidly with alteration in dosage
0 CMV infection
(diagnosed with PCR for the virus)
0 Acute
rejection: occurs in about 30% ot all transplants
Chronic graft dysfunction (4 months after transplantation onwards)
I Chronic
allograft nephropathy: by far the most common cause of chronic dysfunction of the transplant
0 Recurrent primary disease within the graft
I Calcineurin inhibitor (CNl; ciclosporin or tacrolimus) nephrotoxicity: changes on transplant biopsy are
rarely pathognomonic. Withdrawal of the calcineurin inhibitor in such patients will often stabilise graft
function
0
Polyomavirus infections (eg BKo r)C virus)

412

cholesterolaemia, vascular disease within the graft,
CNI toxicity) factors. Management involves:
I
Optimising hypertension control
0 Limiting proteinuria (use of ACE inhibitors and
ARES)
I Modification of immunosuppressive therapy:
despite their excellent track record in
transplantation, CNls are associated with CAN,
partly because of their tendency to provoke
vasoconstriction and vasculopathy (and
consequent ischaemia) within the graft. There is
increasing evidence that reduction in CNI dose
or complete withdrawal, with introduction of
antiproliferative therapy [eg mycophenolate
mofetil (MMF) or sirolimus; see below), can
ameliorate, or even stabilise, progressive graft
dysfunction in patients with CAN
Polyomavirus infection
Subacute graft dysfunction is increasingly recog-
nised in association with polyomavirus infection
within the graft, BKand JC virus are named after the
initials of the patients in whom they were first
identifi ed, The mainstay of treatment is a reduction
in immunosuppressive therapy, particularly the anti-
proliferative drugs (eg MMF); specific antiviral ther-
apy with cidofovir may be beneficial in selected
cases, but this agent can be nephrotoxic and doses
must be reduced according to eGFR. Successful
treatment allows stabilisation of graft function at the
level noted at the time of polyomavirus diagnosis;
return to baseline graft function is r ar e,
P ost -t ranspl ant at i on: non-renal
complications
Although the quality of life of most patients is
significantly improved after transplantation, patients
are still at risk of:
I Malignancy: non-Hodgkins lymphoma (usually
EBvirus-associated) is 20-50 times and skin
cancer 5 -2 0 times commoner in transplant
recipients than in age-matched general
populations, and the increased incidence is
thought to be due to the effects of
immunosuppression (especially azathioprine
Nephrology
with skin and CNIs with lymphoma). All other
malignancies are slightly more prevalent (1.5-
fold increase)
Cardiovascular: ischaemic heart disease is
10-Z0 times more prevalent (due to effects of
irnmunosuppression and hyperlipidaemia, as
well as persistence of the CVS risk
accompanying the patients previous 'uraemic
sta te ' ) than in an age/sex-matched equivalent
population. Mortality is 2% in the first year after
transplantation, half of which is due to CVS
disease, and half to infection (see below)
Infections: all infections are commoner but
patients are also at risk from opportunistic
infections such as Pneumocystis carinii
pneumonia (PCP), and especially
cytomegalovirus (CMV)
~ CMV occurs in about 30% and is
anticipated in CMV antibody-negative
recipients of a CMV-positive graft at 6-12
weeks after transplantation. Patients at risk of
CMV receive prophylaxis with oral
ganciclovir, and oral valganciclovir is used
to treat mild infections (leucopenia and mild
pyrexia are typical). Severe infections occur
in 10%, and can be associated with
myocarditis, encephalitis, retinitis and renal
dysfunction; these patients require treatment
with systemic ganciclovir
~ PCP is uncommon, but patients receive co-
trimoxazole prophylaxis for the first
6 months post-transplantation
Patients of Asian origin, or those with a
previous TB history, are given anti-
tuherculous prophylaxis with isoniazid for
the first year after transplantation
Osteoporosis; the risk is increased because of
immunosuppressant (particularly steroid) usage.
Many patients receive bisphosphonate
prophylaxis
Gout: all patients with reduced renal function
are at increased risk of hyperuricaemia and
acute gout. However, prophylaxis with
allopurinol is not widely implemented, largely
because this agent has many unwanted effects.
Treatment of acute gout in patients with CKD is
problematicz there are no non-nephrotoxic
413
 Essential Revision Notes for MRCP
NSAIDs available, and patients with transplants
(or with CKD) are at risk of serious renal
dysfunction with their usage. Colchicine can be
used, but it also has frequent GI side-effects;
temporary treatment with moderate-dose
steroids (eg a single IM injection of 125 mg
methylprednisolone, or 30 mg prednisolone
orally for 1 month) will provide an excellent
anti-inflammatory effect and provides cover for
the introduction of allopurinol
0 New-onset diabetes after transplantation
(NODAT): the incidence is increased in
transplanted patients ( 3 % - 5 % may develop it
per year); immunosuppressants (particularly
tacrolimus) are thought to be responsible
Recurrent renal disease after t ran s p l an t at i o n
Patients with Alport syndrome are at risk of develop-
ing anti-glomerular basement membrane antibody
syndrome after transplantation, as they have no
prior tolerance to the Goodpasture antigen. vasculi-
tis may recur, and monitoring of serum ANCA is
recommended in these patients. All types of primary
glomerulonephritis may recur in the graft, but pani-
cularly:
0 Focal segmental glomerulosclerosis (FSGSI -
15% recurrence rate, with graft loss in 50% of
these
0
IgA nephropathy - 30%-60% have evidence of
histological recurrence; graft loss in 1 5 % of
these
0 Membranous glomerulonephritis - <10/0
recurrence rate, but 5 0 % graft loss if affected
0
Mesangiocapillary glomerulonephritis: 3 0 %-
80% risk of recurrence
Co mmo n l y used i mmu n o s u p p res s an t s for
re na l t ran s p l an t at i o n
Immunosuppressive regimes vary from centre to
centre. Most now involve induction with monoclo-
nal antibody (eg basiliximab, directed against
CD25, given at induction and day 4), followed by a
CNI-based regime (eg tacrolimus with MMF).
Patients who have at least two steroid-responsive
acute rejections will usually receive oral cortico-
414
steroids for up to 12 months after transplantation.
Particular considerations with immunosuppressants
are:
0
Citlosporin A: this agent inhibits a T-cell
phosphatase, calcineurin, which is needed for
T-cell activation, and hence the term CNl, Its
introduction around 1980 completely
revolulionised the outcome of transplantation.
Common side-effects include hirsutism, liver
dysfunction and gum hypertrophy, hypertension
and CAN
0 Tacrolimusz this is also a CNI. Compared with
ciclosporin, it reduces the incidence of acute
rejection episodes in the initial post-transplant
period. Also, the number of steroid-resistant
rejection episodes is seen to be reduced, and
hypertension may be less frequent or severe.
However, the risk of CAN with long-term use
appears to be similar to that of ciclosporin.
Approximately 5% ot' patients receiving this
agent develop diabetes mellitus (NODAT) per
year
Azathioprine: this traditional antiproliferative
agent is commonly associated with mild bone
marrow suppression. It should only be used with
caution in patients receiving allopurinol
because of the risk of life-threatening bone
marrow suppression
0
Mycophenolate mofetil (MMF): the main side-
effects of this antiproliferative agent are gastro-
intestinal, in particular diarrhoea, and bone
marrow suppression (but less frequently than
azathioprine). It is usually used in combination
with a CNI; it has a major role in the
management of CAN, being used to facilitate
reduction or withdrawal of the CNI
O Sirolimus (rapamycin): this is related to
erythromycin, and it inhibits T-cell division. It is
not associated with nephropathy, but it can
provoke hyperlipidaemia
0 Corticosteroids: these agents have been the
mainstay of immunosuppressive regimes for
several decades, but now there is concern about
long-term dosing. This is particularly relevant to
cardiovascular complications after
transplantation, as well as to post-transplant

bone metabolism (osteoporosis). Some centres
now use regimes that withdraw steroid at 6 -1 2
months post-transplantation
Op t i m al i mmu n o s u p p res s i v e reg i me
Some centres now try to tailor immunosuppressive
regimes in order to maximise the chances of good
long-term graft function, but with limitation of reci-
pient vascular risk; this involves reducing or co m-
plete withdrawal of CNI dose, and sparing steroid
use. Although there is no current consensus view,
the following would be a logical strategy:
0 Induction with monoclonal antibody and large
CN! dose
0 Maintenance therapy with CNI coupled with
either MMF or sirolimus
I ifmore than one steroid-sensitive acute
rejection episode, prednisolone for 6 -1 2
0
months
At 1 - 2 years post-transplant, reduce CNI dose
I IfCAN develops, then reduce/withdraw CNI,
and introduce MMF or sirolimus (if not receiving
one or other)
15.6 GLOMERULONEPHRITTS AND
ASSOCIATED SYNDROMES
15.6.1 Clinical p re s e n t a t i o n of
gl ome r ul one phr i t i s
The term glomerulonephritis implies inflammatory
disease primarily affecting the glomeruli (but note
that no inflammation is seen in minimal-change
disease) - lout other glomerular diseases exist which
do not involve glomerulonephritis (eg diabetic ne-
phropathy). Most glomerulonephritis develops as a
result of immune dysregulation, either due to an
inappropriate immune response to a self-antigen
(autoimmunity, eg anti glomerular basement mem-
brane tanti-GBM) disease, ANCA +ve vasculitis), or
to an inappropriate or exaggerated response to a
foreign antigen (eg membranous glomerulonephritis
secondary to hepatitis B infection).
Nephrology
0 This 'immune dysregulation pathogenesis
explains why there is a genetic predisposition to
some forms of glomerulonephritis (eg lgA
nephropathy)
9 Immune complexes are often deposited in the
glomeruli (eg SLE nephritis, mesangiocapillary
glornerulonephritis), but in some
glomerulonephritides immune complexes form
in situ within the glomerulus (eg anti-GBM
disease)
0 Inflammation leads to proliferation of cellular
structures (mesangial, endothelial or epithelial
cells) and/or scarring
0
Clomerulonephritis may be idiopathic
(primary), or secondary to systemic disease (eg
malignancy, infections), drugs, etc
0 The long-term clinical outcome often depends
more upon the severity of tubulointerstitial
damage rather than on the extent of glomerular
injury
The type ofglornerulonephritis is defined by
light microscopic, immunofluorescent and
electron microscopic (ultrastructural)
characteristics (see below)
Screening for glome rulone phritis
0 Dipstick for proteinuria; urinary ACR ( o r PCR)
Dipstick for haematuria; urine microscopy for
red cells and casts
0
Hypertension
Atte nua tion of p ro g res s i o n of
gl om erul onephri t i s
0 Control blood pressure: for all types of
glomerulonephritis. The target blood pressure
for patients with chronic renal disease and
significant proteinuria is <i 25/ 75 mmHg
0 ACE inhibitors and ARBs; decrease proteinuria
and blood pressure, and may ameliorate
progressive scarring (See Section 1 5 , 5 on CKD)
I
Progression depends on degree of co-existent
scarring in the tubulointerstitium
415
Essential Revision Notes for MRCP

Classification of glome rulone phritis
Diabetes mellitus is the most common cause of
glomerular pathology but it causes glomerulosclero-
sis and is therefore not a glomerulonephritis. The
commoner forms of glomerulonephritis (GN) are:
Minimal-change disease
Membranous glomerulonephritis
Focal segmental glomerulosclerosis (FSGS)
IgA nephropathy tmesangioproliferative
glomerulonephritis)
0 Crescentic glomerulonephritis (eg associated
with Goodpasture syndrome or vasculitis)
I Focal segmental proliferative glomerulonephritis
(eg associated with vasculitis or endocarditis)
l
Mesangiocapillary glomerulonephritis
0 Diffuse proliferative glomerulonephritis (eg post-
streptococcal)
present during the course of the disease. However:
* Certain glomerulonephritides are
characteristically associated with typical clinical
presentations (eg minimal-change disease and
nephrotic syndrome, IgA nephropathy and
recurrent macroscopic haematuria)
0 it should also be borne in mind that a particular
syndrome can be due to some conditions other
than glomerulonephritis (eg the nephrotic
syndrome can be due to accelerated-phase
hypertension, pre-eclamptic toxaemia or
amyloid)
Definitions ofthe common renal
syndrome s

-
0
Asymptomatic proteinuria
<3 g/day
0
Renal syndrome s and their relationship to Nephritic syndrome
Characterised byhypertension, oliguria,
glome rulone phritis
haematuria and oedema
There is often confusion regarding the relationship 0
Hypertension
of the various glomerulonephritides to the different 0
Nephrotic syndrome
renal syndromes. A particular type of glomerulone- ~ >3 g proteinuria/day with serum
phritis may manifest several different clinical syn- albumin < 2 5 g/l; oedema;
dromes (see Table 15.5). For example, membranous hypercholesterolaemia
glomerulonephritis may be responsible for CKD, 0 Haematuria
persistent proreinuria, nephrotic syndrome and
Microscopic or macroscopic
hypertension; any combination of these may be 0 Acute or chronic kidney disease
(Discussed in previous sections)

Table 15.5. Clinical presentation of glomerulonephritis

Proteinuria Nephrotic Nephritic Haematuria AKI CKD

tvtinimal-change disease + +++

Membranous GN +++ ++ 1 + 4-
Focal segmental glomerulosclerosis ++ ++ i ++
Mesangioproliferative (Ig/X) ++ + + +++ ++
Mesangiocapillary CN ++ ++ + + ++
Diffuse proliferative GN + i +++ ++ +++ +
Diabetic glomerulosclerosis +++ + 4. +++
Crescentic nephritis + i +++ ++ +++ +
Focal segmental proliferative GN + ++ ++ ++ ++ +
+++ \/ery common presentation; - = Never
1
seen/extremely rare

416
 Nephrology

Causes-'ofthe -uaphroitii: syndr ome

'
15.6.2 No tes on pa r t i c ul a r
gl ome r ul one phr i t i de s
l
0 Common Minimal-change disease

Primary glomerulonephritis
~ Diabetes mellitus The clinical presentation is almost always nephrotic,
,if Basement membrane nephropathy
Alport syndrome]
(eg Although most common in children (causing >80/0
of nephrotic syndrome due to glomerulonephritis in
Infections (eg leprosy, malaria, hepa- under-15-year-olds), it also accounts for 28% of
titis B - associated with secondary GN) nephrotic syndrome in adults. Highly selective pro-
Pre-eclampsia teinuria tie loss of mainly smaller protein molecules
Accelerated hypertension as evidenced by IgG/transferrin < 0 . l ; see below] is
~ Myeloma typical, and the majority of cases are steroid-respon-
Amyloidosis sive. Other features include:
Drugs (eg gold, penicillamine, captopril
Normal renal function and renal histology (by
NSAIDs, mercury - associated with
i f 0

light microscopy - but epithelial cell foot-

secondary GN)
y 0 Connective tissue disease (eg SLE -
t anther secondary GN)
0 Rare
Vesico-ureteric reflux
Constrictive pericarditis
~ Sickle cell disease
Allergies [eg bee sting, penicillin)
Hereditary glomerulonephritis [eg
'Finnish type nephrotic syndrome)
process fusion on electron microscopy]
0
May be due to NSAIDs or gold; rare
associations are with Hodgl<in's lymphoma and
thymoma
0
May frequently relapse (10%), but renal
prognosis is excellent
Monitoring: patients with frequently relapsing dis-
ease are taught to dipstick their urine on a regular
basis; three consecutive days of +++ proteinuria is
the trigger to commence steroids, which are contin-
ued at high dose until urinalysis has remained nega-
tive for 3 consecutive days.

Clusvzef Treatment: the mainstay is with short courses of

high-dose prednisolone. Most relapses are steroid-
l Urinary infections sensitive; cyclophosphamide (usually orally in chil-
f Renal papillary necrosis dren, pulsed IV in adults) is used for frequent
l Acute glomerulonephritis relapsers or steroid-resistant disease. A distinct sub-
y Loin-pain haematuria syndrome group of frequently relapsing (eg 2 - 4 relapses/year)
IgA nephropathy teenagers enter adult nephrological care and prove
'_ Prostatic hypertrophy (dilated prostatic quite difficult to manage. Avoidance of long-term
veins) steroid side-effects (particularly osteoporosis) is im-
l 0 Renal calculi portant and so the relapse rate can be reduced by
L l
0
Urinary tract malignancy treatment with ciclosporin (taken for several years),
in the knowledge that, in the majority of these
*It is usually imperative to exclude urinary tract
malignancy [urine cytology, cystoscopy, IVU and
patients, the presumed underlying immune pertur-
ultrasound) in patients aged > 40 years presenting with
bation resolves by their late 20s. However, a small
i
macroscopic haematuria group of these patients are eventually found to have
i
FSCS (see below).

417
Essential Revision Notes for MRCP
U ri n ary p r o t e i n s el ect i v i t y
The index of urinary protein selectivity is used
mainly in paediatric nephrological practice; highly
selective proteinuria is likely to result from minimal-
change disease, and so its detection may obviate
the need to perform renal biopsy of the child. In
adults the range of possible renal diagnoses in pa
tients with significant proteinuria usually makes
biopsy essential. The index is calculated from the
respective concentrations of different molecular
weight proteins within the urine:
|gG(mol,wt,150 kDa)
Transferrin (mol,
wt, 40 kDa)
Highly selective (ie minimal-change) proteinuria is
defined as an index of <O ,i ; unselective proteinuria
>0.3.
Membranous glome rulone phritis
This is o n e of the commonest types of glomerulone-
phritis in the adult; there are two peaks of disease
(patients in their mid-20s and those aged 6 0 -7 0
years). The clinical presentation may be nephrotic
syndrome, asymptomatic proteinuria or CKD.
Renal histology is characterised by granular IgG
and complement deposition on the glomerular
basement membrane; immune complexes are
subepithelial (oute r aspect of basement
membrane) and appear as 'spikesl with Silver
stain
0
Immunosuppressivetherapies have been trialled
in patients with nephrotic syndrome and/or
evidence of progressive CKD. About a third vvill
progress through CKD to ESRD, a third respond
to immunosuppressive therapy (eg cytotoxic
regimes such as the Ponticelli regime:
chlorambucil alternating with corticosteroids),
and the disease remits spontaneously in a
similar proportion of patients
418
In all proteinuric patients a cornerstone of
treatment is optimal blood pressure control and
limitation of proteinuria with ACE inhibitors
and/or ARBS
Renal vein thrombosis may occur in up to 5% of
patients. Patients at greatest risk are those with
serum albumin < 20 g/l, and these should
receive prophylactic-dose heparin.
Unfractionated heparin is generally safe, but
note that there have been reports of serious
haemorrhagic complications in patients with
renal failure who have been treated with
'normal' doses of low-molecular-weight heparin
(reduced doses can safely be used)
Membranous glomerulonephritis may be
idiopathic, or secondary to other conditions ( se e
below)
As stated before, the condition can recur in
renal transplants
Malignanqf
Bronchus, stomach, colon, lymphoma,
chronic lymphoid leukaemia (CLL) (high
suspicion of these in elderly patients)
Connective tissue disease
SLE, rheumatoid arthritis, Sjogren
syndrome, mixed connective tissue
disease
O Chronic infections
~ [eg hepatitis B or C, malaria, syphilis)
Drugs
~ Cold, penicillamine, captopril, NSAIDS
I Others
~ Sarcoidosis, Guillain-Barr syndrome,
primary biliary cirrhosis [all rare)

|
> (lg/\ n ep h ro p at h y or Berg ers disease)
i 0 Acute thrombosis
~ infantile gastroenteritis
0 Acute pyelonephritis (high mortality)
v ~ Renal cell carcinoma (with renal vein
invasion)
0 Chronic thrombosis
~ Amyloidosis
l ~ Nephrotic syndrome due to
glomerulonephritis (particularly
membranous glomerulonephritis)
Focal se gme nta l glomeruiosclerosis (FSGS)
The primary form of FSGS accounts for < iO% of
nephrotic syndrome in children and the elderly, but
up to 20% in young adults, It can also frequently
present with proteinuria and/or CKD, In childhood
the clinical pattern is often identical to minimal-
change disease, and it may be misdiagnosed as
such. There are also familial forms of FSGS. Focal
glomerular deposits of IgM are seen at biopsy.
Secondary FSGS: this can be seen in patients with
heroin abuse, those with HIV infections and AIDS,
and it is recognised in patients with obesity or when
the functioning renal mass is reduced (eg after
nephrectomy). in the latter cases, the glomerulo-
sclerosis probably occurs as a result of haemo-
dynamic stress and/or ischaemic changes within the
glomeruli, which also explains why it has been
associated with renovascular disease.
Treatment of primary FSGS: it is important to distin-
guish this clinically from secondary FSGS, as
patients with the latter should not be treated with
immunosuppression, but with optimal blood pres-
sure control with RAA bloc ka de , In nephrotic
patients with primary disease >4O% will respond to
moderate-dose steroids given for 3 - 6 months. Fre-
quent relapsers are treated in a similar way to those
with minimal-change nephropathy.
Outcome of FSGS: a rapidly deteriorating clinical
course is seen in 2%, and 25% of all patients will
l eventually progress to ESRD. There is a high rate of
recurrence in transplants.
Nephrology
Mesangioproliferative gl om erul onephri t i s
This is a very frequent condition, the commonest
primary glomerulonephritis in adults. It typically
affects young adults, presenting with microscopic or
recurrent macroscopic haematuria, The haematuric
episodes are usually synpharyngitic (ie occurring
0 - 3 days after upper respiratory tract infection
(URT|)). There are likely to be many undiagnosed
cases as most nephrologists would not undertake
renal biopsy in patients with isolated microscopic
haematuria. The serum IgA is increased in 50% of
patients; the condition is considered to be auto-
immune, perhaps due to dysregulation of IgA meta-
bolism. Other features of IgA nephropathy are:
0 An increased incidence in the Far East
(associated with HLA DQW7)
0
IgA nephropathy can be associated with
cirrhosis, dermatitis herpetiformis, coeliac
disease and mycosis fungoides. It occurs in the
Wiskott-Aldrich syndrome
0 Renal biopsy features show proliferation of
mesangial areas of the glomerulus;
immunological staining is strongly positive for
IgA in these areas. A similar histological picture
may be seen in Henoch-Schiinlein nephritis,
and the pathogenesis is thought to be similar in
the two conditions. Crescents may be present
during haematuric episodes
Treatment of IgA nephropathy: nephrotic presenta-
tions should be treated as for minimal-change ne-
phropathy. Patients with progressive CKD may show
stabilisation of renal function with a 6-month re-
gime ot alternate-day steroids. The possible benefi-
cial effects of fish oil (to-3 fatty acids) remain
unc e r ta in, Otherwise the mainstay of treatment is
optimal blood pressure control with RAA blockade,
as for other chronic nephropathies.
Outcome of IgA nephropathy: 25% of patients will
progress to ESRD by 20 years after disease onset;
however, the overall prognosis for IgA nephropathy
is certain to be better than this as the mildest cases
are likely to remain undiagnosed. Clinical criteria
help identify patients with better prognosis - those
with proteinuria <1 g/24 h at presentation have
419
Essential Revision /\/otes for MRCP
98% renal survival at t5 years, compared to 65% of
patients with proteinuria >1 g/24 h. The disease
frequently recurs in transplants,
Mesangiocapillary glomerulonephritis
(MCGN)
There are three forms of mesangiocapillary (also
termed membranoproliferative) glomerulonephritis:
0
Type I: immune deposits in the subendothelial
space and mesangium, This can occur in
association with or without mixed
cryoglobulinaemias, and hepatitis C may
underlie the problem in 70%-90%; other
causes are hepatitis B, subacute bacterial
endocarditis (SBE), shunt nephritis, malaria, SLE,
Sjogren syndrome, sickle cell disease, ot-
antitrypsin deficiency, hereditary complement
deficiencies and malignancy (CLL, non-
Hodgkins lymphoma)
I
Type Il: dense deposits in the mesangium
(dense deposit disease) leading to characteristic
double-contouring of the basement membrane
on renal biopsy. This is usually familial, and
associated with partial lipodystrophy or factor H
deficiency. Patients have reduced serum
complement and the presence of circulating C3
nephritic factor. The latter binds to the
alternative pathway C3 convertase, preventing
its inactivation by factor H, continued
complement activation results
I
Type Ill: immune deposits diffusely present in
subendothelial space and mesangium. Often
associated with hepatitis C or B infections (and
the secondary causes as for type I MCGN)
Patients present with microscopic haematuria and
dipstick proteinuria (m ost common), nephrotic syn~
drome (35%), CKD, or with rapidly deteriorating
renal function (10%), The overall prognosis is fairly
poor, with 50% progressing to ESRD; steroids are
only occasionally effective, but are used in child-
hood nephrotic presentations. There is a high rate of
recurrence of MCGN in transplants.
420
i
5
Diffuse p ro l i ferat i v e gl om erul onephri t i s
This is the histological pattern of the classic post-
streptococcal glomerulonephritis which usually pre-
sents with the nephritic syndrome or AKI; children
and young adults are most often affected. The
t
disorder is typically preceded (by i 0 ~2 t days) by a
sore throat, or (most often in third world countries)
skin disease (impetigo).
0 Serum C3 is low and there is diffuse
proliferation within glomeruli at biopsy
0 Posbinfective cases usually recover
spontaneously with restoration of full renal
function
0 The same histological picture may be seen in
patients with SLE nephritis (but immune
complex deposition is characteristic in the latter)
-
Rapidly progressi ve glome rulone phritis
(RPGN) including Goodpastur e syndrome
The term 'rapidly progressive' glomerulonephritis is
a clinical description of rapidly deteriorating renal
function due to an underlying glomerulonephritis.
The histological counterpart is a crescentic glomer-
ulonephritis, and so the two terms are (sometimes
incorrectly) used interchangeably, They refer to the
renal lesions which excite great interest from the
nephrologist, not least because patients are often
very sick with hypercatabolic AKl and possibly
associated systemic disease (eg pulmonary haemor-
rhage), but also because the underlying disease
processes are potentially treatable provided that
investigation and therapy are expedient. All age
groups may be affected and the presentation is
usually with AKI or nephritic syndrome.
0 Causes
ofEPGN linclude Coodpasture
syndrome, ANCA +ve vasculitis and lupus
ne hritis
c
may be 'idiopathic' but is
more o en associated with Goodpasture
syndrome, ANCA +v e vasculitis or SLE
ANCA +ve vasculitis and lupus nephritis are both
considered in detail in Section 15.12, 'Systemic
disorders and the kidney, and hence the remainder
of this section will concentrate on Goodpasture

syndrome and its treatment, which is similar to that
for the former conditions.
Go o d p as t u re syndrome
This is characterised hy the presence of circulating
anti-GBM antibodies (the GBM antigen is a compo-
nent of t e IV colla en), which localise to the
glomerular and pu monarv capillary basement
membranes. The condition is rare [<1 case/million
per year), tends to affect the elderly or patients in
their 20-305,
*T
is commoner in smokers and in some
1 - 1 -
cases may be triggered by inhaled
hydrocarbons.
0
Pulmonary haemorrhage occurs in 50% of
patients with Coodpastures; the most
vulnerable are young male smokers. lt is also
seen in ANCA +ve disease (\/Vegeners and
microscopic polyangiitis), which is considered
later. The occurrence of pulmonary
haemorrhage confers a greater mortality and is a
definitive indication for plasma exchange
0
Specific biopsy changes are seen in
Goodpasture syndrome, with IgG deposited on
the glomerular basement membrane in a linear
pattern. The glomerulonephritis is of the diffuse
proliferative type, and typically there is
extensive crescent formation (epithelial cell
proliferation arising from Bowmans capsule)
0
Prognosis: renal functional recovery is rarely
seen if the patient presents with advanced AKI
(eg creatinine @@pmol/l) and/or anuria.
Overall mortality isltii/ii. Elderly patients are at
particular risk from infective complications after
immunosuppression; patients who have
pulmonary haemorrhage are at greatest risk of
mortality. Transplantation is possible once the
patient is rendered autoantibody negative
Tre a tme nt of RPGN a n d C rescentic nephri t i s
The following is applicable to most diseases causing
RPGN and/or crescentic glomerulonephritis. Treat-
ment is with early and high-dose immunosuppres-
sive therapy with or without plasma exchange, The
latter is essential for patients with pulmonary hae-
morrhage who have a circulating autoantibody (ie
Nephrology
l i n
most cases o
high titre, and it is used in
oodpasture syndrome and those
with ANCA +ve disease who have /\l<l. The aim of
plasma exchange is to rapidly remove these auto-
antibodies, allowing time for the immunosuppres-
sive drugs to act to reduce their formation (eg
cyclophosphamide) or to diminish tissue inflamma-
tion [with steroids). A typical regime for Goodpas-
lur e syndrome would be:
0 Induction therapy: h i g h , ( l V
rnethylprednisolone i g on three consecutive
days, followed by prednisolone 1 mg/kg) with
7 ><4-litre plasma exchanges within the first
10- 14 days. Pulsed |\/ cyclophosphamide ( 0. 7-
1 g each month) is given for the first 6 months,
by which stage the steroid dose will have been
tapered to around 10-20 mg/day
Maintenance therapy: low-dose steroid and
azathioprine are continued for a further 12- 18
months tor even longer in some cases of c/-\NCA
+ve vasculitis ( se e later), or Goodpastures with
persistence of anti-GBM antibody)
Plasuna e xe ha nge in renal
0
Agreed benefit
o
Goodpasture syndrome
~ ANCA +ve diseases: especially with
pulmonary-renal presentation
-
(mandatory with pulmonary
haemorrhage); also for severe AKI
-
~
idiopathic crescentic glomerulonephritis
Cryoglobulinaemias
Myeloma: cases with hypen/iscosity
Thrombotic thrombocytopenic purpura
(WP)
0 Possible benefit
~ SLE nephritis: severe lupus with /-\l<|
Henoch-Schonlein nephritis: with
crescentic forms and AKI
~ Myeloma: with AKI due to cast
nephropathy (see later)
~ Haemolyticuraemic syndrome (HUS)
421
Essential Revision Notes for MRCP
H y p o co mp l emen t aemi a a n d
glome rulone phritis
The following disorders are often associated with
glomerulonephritis coupled with T/ow serum com-
T T
pIement(C3).
0 SLE
0 Shunt nephritis (rare)
o Focal segmental proliferative
glomerulonephritis (or MCGN);
classically associated with coagulase-
_ , ~ f
yentriculo-atrial shunts
0
Primary complement deficiency (eg C1q,
C2 or C4 deficiency)
o Associated with lupus-like
syndromes,
glomerulonephritis (usually
mesangiocapillary type) and increased
- risk of bacterial infection
0 Endocarditis
Focal segmental proliferative
glomerulonephritis
--
0
Post-streptococcalglomerulonephritis
I
Mesangiocapillary glomerulonephritis
(See earlier section)
I
Cryoglobulinaemia
Especially type ll (see below)
C ryoglobulinaem ia
Immunoglobulins which precipitate on cooling may
be monoclonal or polyclonal (see Chapter 10,
immunology). They can induce a small-vessel
vasculitis, particularly affecting skin and
kidneys. Type ll (mixed monoclonal) and type lll
(polyclonal) cryoglobulinaemias are associated
with glomerulonephritis (rnesangiocapillary or
memlsranoproliferative).
its? f;i_i`i'`.t~lD }itfN/st., DiSll%\.~ifi
The commonest inherited renal diseases are poly-
cystic kidney disease and Alport syndrome. Rarer
disorders include other renal cystic disease, disor~
ders of amino acids and familial glomerulonephritis;
422
the latter conditions are encountered much more
often in paediatric nephrology.
`
23 E Au to so mal d o min an t polycystic
kidney disease (ADPKD)
Autosomal dominant polycystic kidney disease
(ADPKD) is the most common inherited renal con-
dition, and the genes have now been identified:
1
0 PKD1: chromosomeiin 8 6 % of PKD patients
( m ean age of ESRD: 57 years)
0 PKD2: chr0mosom@n 10%
_._ (ESRD mean a 3ez
69 vears)
. _ . _ i
The diagnosis is usually made by ultrasound; cysts
usually develop during the teenage years so that
first-degree relatives aged,_>_;_QA_ea.r.s__with a normal
scan, can be >90% confident of being dise2@Fe_e;
the confidence level rises to 98% at 3Q yea`r_s of
age. Cysts develop from all segments of the ne-
phron. The prevalence of ADPKD is_] in i000; the
condition accounts for about 10%
in the ui<_
` of nts
Di agnost i c cri t eri a for ADPKD
In a patient known to be at 50% risk because of
family history, diagnosis would be suggested by the
following ultrasound findings:
I Two cysts, either unilateral or bilateral, if aged
< 3 0 years
0 Two cysB in each kidney in patients aged 3O
59 years
U Four cysts in each kidney in patients >6 ( ) years
Sporadic cases ( no family history) are also com-
monly seen.
Clinical features
Patients may present with abdominal pain or mass,
hypertension, urinary tract infection (UTI), renal
calculi (10%), macroscopic haematuria or Ci<D_
0 The age of onset of CKD varies widely (eg 25~
60 years); not all patients develop ESRD
0 ln patients known to have ADPKD, intermittent
presentation with severe abdominal pain is

common, but, apart from UTI and calculi, the
exact cause may be difficult to identify (cyst
expansion, cyst rupture, intracystic
haemorrhage)
0 Treatment of the progressive CKD in ADPKD is
as for other chronic nephropathies (ie
hypertension control, R/-\/-\ blockade, prevention
of CVS complications). New therapeutic agents
that limit cyst development and expansion, and
possibly progressive CKD, are currently under
investigation
T
ot,ADPKD"'
Liver cysts: ,,
Hepatic fibrosis (ra_Le) \!3 -l>! l<'p
Qpyaneurysmsz 8% (see below)
Diverticular disease
Pancreatic cysts: 10%
Mitral va ve prolapse or
incomm aorticjfc
_ _ __ _
There is no increased incidence of renal malignancy
_/\
ADPKD (see von HippelLindau syndrome below)
in
M
J#
lntra c ra nia l a n e u r y s ms in ADPKD
These occur in 5% of ADPKD patients, but familial
.
clustering is seen tie if family history of aneuwsms,
then > 20% of patients with ADPKD will have
them). The majority are asymptomatic; the risk of
rupture increases with aneurysm size (eg 4% per
Rupture is associated with a
30% -50% chance of severe morbidity/mortality.
Most patients have normal renal function at the
of rupture. There is currently some debate as totim?/(c
the
value of screening (with MR angiography) for intra-
cranial aneurysms in ADPKD.
15.7.2 Oth e r ren al c y s t i c d iso rd ers
0 Autosomal recessive PKD: rare (1/10 000 births).
The gene is localised to chromosome'6L',ESRD
develops early in childhood; 100% have hepatic
mfilorosis. The prognosis is poor
0 von Hippel-Lindau (VHL) syndrome: autosomal
dominant, the gene is localised on chromo-
Nephrology
some_K3')Renal cysts are premalignant ( > 50%)
and pro h lactic bilateral ne hrectom is often
necessary. lt is likely that patients previously
thought to have renal malignancy in association
with ADPKD actually had VHL. Patients are also
at risk of multiple spinogeigeloellar
haemangioblastomas (which can be severely
debilitating and are the main determinant of
outcome in patients who are successfully
transplanted), r tinal angiomas, pancreatic cysts,
islet cell tumours and p h a e o c h r o m o
Tuberous sclerosis: domi ther
chromosome 9 or i6) , arid affects l in T0 O00
individuals; patients develop epilepsy (80%),
mental retardation 6_O_/9), hamartornas, rena
cysts and angiomyolipomas (usually do not
require surgery). S in lesions include shagreen
patches, ash-leaf spots and adenoma sebaceum
luvenile nephronophthisis-medullary cystic
disease complex: two different terms are used
for two similar diseases which differ only in
their age of onset and mode of transmission.
Cysts occur in the renal medulla, and patients
have chronic tuhulointerstitial nephritis, salt-
wasting and progressive CK D , juvenile
nephronophthisis (NPH) occurs in children, is
autosomal recessive, and accounts for up to
15% ofchildhoocl ESRD; 10%-15% of children
have retinal abnormalities (a form of retinitis
pigmentosa). In adults a histopathologically
identical disease, autosomal dominant
medullary cystic disease, leads to ESRD in the
third and fourth decades: it is uncommon and is
not associated with extrarenal abnormalities
0
Medullary sponge kidney (MSK): sporadic; the
cysts develop from ectatic collecting ducts,
These may calcify, leading to the classic
nephrocalcinosis associated with MSK. The
disease runs a benign course except that renal
calculi and upper urinary tract infections are
commonly associated
Acquired cystic disease: cystic change is
common in the rudimentary kidneys of dialysis
patients, and especially in scarred kidneys; most
cysts develop from pgtximal tubules. They are
present in > 5% of patients at the onset of RRT,
and in > 80% after 10 y e a r s of dial sis.
T
423
 Essential Revision Notes for MRCP
Malignant change is though o occur with an
annual incidence of
0 about
Simple cysts: fluid-filled, so i ary or multiple,
these are usually harmless, incidental findings at
ultrasound or lVl,l. The cysts may grow to a
considerable size (eg > i 0 c m) . They
occasionally require percutaneous drainage
because of persistent loinpain. Simple cysts are
very commgiy affecting Zi/Qof
< 5 0 years,'l 1% aged 50-7U years patient;_d\
an \>_2Off@
g of the elderly.`The_:isniak system is used
classify the malignant risk of renal cysts
to
M (categorisation depends upon the presence of
C cyst wall thickening, calcification, septations
rj and solid components). A Bosniak I cyst is
5 simple; categon/ IV malignant. Category II and
lll cystsiiare 'indeterminate' and may require
more investigation and follow-up
lfi.7.3 Alp er t s~nilri.\me
The prevalence of Alport syndrome is l/SOOO indivi-
duals. Genetic associations vary; 85% have X-linked
dominant inheritance, but other f
dominant or recessive inheritance. The primary de
fect is an abnormal GBM (seen at electron micro-
scopy) with variable thickness and splitting (basket
weave appearance); the Goodpasture antigen is
algeni in the GBM t h e n
patients to anti-GBM glomerulonephritis after trans-
plantation),
0 Clinical presentation is with deafness (see
below), persistent microscopic haematuria,
proteinuria and CKD; 30% develop nephrotic
syndrome J \ m -
0 Renal failure develops in adl affected males; the
rate of progression is h e t e n
families (ie ESRD before 30 years in some, yet
only by 60 years in others)
424
0 Carrier females may have urinary abnormalities
lhaernaturia, proteinuria), and usually do not
develop renal failure
0 Bilateral sensorineural deafness is characteristic,
but the hearing loss may only be mild; familial
progressive nephritis may occasionally occur
without deafness
0 Other extrarenal manifestations: ocular
abnormalities occur in 40% (lenticonus -
Conical or spherical protrusion oi the surface of
the lens into the anterior chamber, retinal flecks
or cataracts);
macrothrombocytopenia;%_
leiomyomata (rare)
0 The molecular defect involves the gene
encoding for thegchain of type IV collagen;
alteration of this chain is thought to prevent
integration of the f_z_3_chain into the CBM
`l?}.7,'3 Ben ig n familial haematuria
(BPH) a n d thin-membrane
ne phr opa t hy
Up to 25% of patients referred to a nephrologist for
investigation of microscopic haematuria have this
condition. It is common in families, when it is
termed 'benign familial haematuria; the inheritance
c pattern is dominant although the gene has not been
identified. Sporadic cases are designated as 'thin-
membrane nephropathy/'. The normal thickness of
the CBM is around 450 nm; patients with BFH/thin-
membrane nephropathy have an average CBM
thickness of < 2 5 ( ) n m , Patients usually have normal
blood pressure and renal function; long-term fol~
low-up is recommended as there appears to be a
very small risk of renal failure (perhaps because
some patients represent variants of Alport syndrome,
or IgA nephropathy may co-exist).

15.7.5 O ther inherited disorders
asso ciated w i t h r e na l d isease
The list is far from comprehensive as many rare
disorders have been described.
0 Conditions associated with renal structural
disorders
Cystic renal diseases (see above)
v Brachio-oto-renal syndrome (AD)
~ Dandy-Walker syndrome (polycystic
kidneys (AR))
v Inherited conditions with glomerular
disease
~ Alport syndrome and variants (see
above)
~ Congenital nephrotic syndrome (eg
Finnish-type (AR))
Nail-patella syndrome (AD)
Familial glomerulonephritis (eg some
- forms of FSGS or IgA nephropathy;
Wiskott-Aldrich syndrome (XL))
Inherited complement deficiency
~ Charcot~Marie-Tooth disease (?AD)
0 Metabolic disorders with renal involvement
~ Fabry disease (XL)
Primary amyloidosis (AD)
Familial Mediterranean fever (AR)
Cystinosis (AR)
Primary oxalosis (AR)
0 Inherited tubular disorders
Cystinuria (AR)
~ Shwachman syndrome (AR)
~ Marble brain disease (AR)
Hypophosphatasia (AR)
0 Renal diseases which have genetic
influence
Benign familial haematuria (AD)
Reflux nephropathy
AD = autosomal dominant; AR : autosomal recessive;
XL= X-linked
Nephrology
15.8 RENAL INTERSTITIAI.
DISORDERS
15.8.1 I nter stitial n e p h ri t i s
Inflammation of the renal tubulointerstitium may be
acute or chronic; a recognised precipitating cause
can be found in the majority of patients.
Acute interstitial nephri t i s (AIN)
AIN accounts for about 2% of all AKI cases, but for
25% of all drug-induced AKI. Most cases are due to
an immunologically induced hypersensitivity reac-
-
tion to an antigen classically a drug (see below)
or an infectious agent. The presentation is usually
with mild renal impairment and hypertension or, in
more severe cases, AKI which is often non-oliguric.
Systemic manifestations of hypersensitivity may oc-
cur and include fever, arthralgia, rash, eosinophilia
and raised IgE.
0
Diagnosis: urinalysis may be unremarkable (eg
minor proteinuria), although urinary eosinophils
may be present. If> l % of urinary white cells
are eosinophils, then this suggests the diagnosis.
Renal biopsy shows oedema of the interstitiurn
with infiltration of plasma cells, lymphocytes
and eosinophils; there is often ATN with
variable tubular dilatation. Occasionally there is
a granulomatous reaction (sarcoidosis can cause
AIN). Note that AIN may need to be
distinguished from acute pyelonephrltis, in
which condition most ofthe inflammatory
infiltrate will be composed of neutrophils
0 Treatment: cessation of precipitating cause (eg
drugs). Most cases will improve without further
treatment, but studies show that moderate-dose
oral steroids (eg l mg/kg, tapered over 1 month)
can hasten recovery of renal function. Most
patients make a near-complete renal functional
recovery
425
Essential Revision Notes for MRCP

Causes of acute interstitiai nephritis Causes of chronic intentitiatlilielplnritiif

0
Idiopathic (rare - can be associated with 0
Immunological diseases
anterior uveitis) ~ eg SLE, Sjogren syndrome, rheumatoid
0 Infections arthritis, systemic sclerosis
~ Viral [eg Hanta virus), bacterial (eg I
Haematological disorders
leptospirosis), mycobacterial Myeloma, light-chain nephropathy,
0
Drugs sickle cell disease
eg rifampicin, allopurinol, methicillin, ' Heavy metals (and other toxins)
penicillin, cephalosporins, ~ eg lead, cadmium, Chinese herb
sulphonamides, furosemide, thiazides, nephropathy (see Section 15. 133 Toxic
cimetidine, amphotericin, aspirin, nephropathy)
NSAIDS 0 Metabolic disorders
0 Others, eg sarcoidosis, Sjogren syndrome eg hypercalcaernia, hypokalaemia,
hyperuricaemia
Other
Chronic tubulointerstitial nephri t i s (TIN) Irradiation, chronic transplant rejection

Many diverse systemic and local renal conditions

0 Granulomatous disease
can result in chronic inflammation within the tubu- ~ Wegenefs, TB, sarcoidosls
0
lointerstitium. Patients present with CKD or ESRD; Drugs
some patients may also manifest RTA (usually type ~ Ciclosporin A, cisplatin, lithium, iron,
1), nephrogenic diabetes insipidus (DI) or salt-
wasting states. Renal biopsy findings involve a
chronic inflammatory infiltrate within the intersti-
tium (granulomatous in sarcoid and TB), often with
0

0
- analgesics (see Section 15.8.2)
Chronic infections
Chronic pyelonephritis (TB)
Hereditary disorders
extensive scarring and tubular loss; the latter indi- ~ eg nephronophthisis, Alp0rts
cates that renal function can never be fully recov- 0 Endemic disease
ered. Balkan nephropathy (see below)

Certain common causes of CKD are associated with

TiN and macroscopically abnormal kidneys - eg
reflux nephropathy, analgesic nephropathy, obstruc-
tive and cystic renal disease. However, TIN with
macrnscopically normal kidneys accounts for about
3% of all ESRD, and is seen with Sjogren syndrome,
lithium toxicity, urate nephropathy, heavy metal
nephropathy and Balkan nephropathy (see following
box).
Treatment of TIN
This is of the underlying condition (or drug/toxin
withdrawal); steroids may be beneficial in some
autoimmune or inflammatory disorders. The pro-
gressive CKD is treated as for other chronic nephro~
pathies.

426
 Nephrology

Balkan n ep h ro p at h y 0 Patients are at a threefold increased risk of CVS

A chronic interstitial renal disease endemic in vil- disease (contributed to by hypertension,
lages along the tributaries of the River Danube (eg hyperlipidaemia, smoking and formation of
in Romania, Bulgaria, Bosnia, Cr oa tia ) , There is alherogenic oxidised LDL)
extensive scarring, and patients progress to ESRD.
0 Urothelial malignancy is increased 200-fold Causes of renal papillary ne c rosis
I Patients have coppery yellow pigmentation of
palms and soles
0 Toxic
Classic
I
Aetiologyz initially thought to be a chronic toxic analgesic nephropathy
TB
nephropathy (eg trace metals in water) or viral
infection. Although recent evidence has Ischaemic
Sickle cell disease
suggested that chronic exposure to a fungal ~ Acute pyelonephritis _
toxin (eg ochratoxins, products ofthe fungus
Accelerated hypertension
Penicillium, which may grow in stored maize)
Profound shock
may be important, genetic studies suggest an ~ Diabetes mellitus
underlying dominant inheritance pattern, with a Urinary tract obstruction
marker on chromosome 3. It is suspected that
the environmental factors modify the expression ~ Hyperyiscosity syndromes
NSAID-induced
of the genetic predisposition

15.8.2 A na l ge si c n e p h r o p a t h y a n d
p ap illar y ne c r osi s
A n al g es i c n ep h ro p at h y
In the 19505 to 19705 analgesic nephropathy was
the most common cause of both AK! and CKD in
parts of Europe and Australia (eg 25% of ESRD in
Australia). The condition is now uncommon, espe-
cially since the Withdrawal of phenacetin from the
pharmaceutical market; aspirin and NSAIDs are
now the most common causative agents, The hall-
marks of the condition are the history of chronic
analgesic usage (eg for backache, pelvic inflamma-
tory disease, headache) and of addictive or depen-
dent personality traits, renal pain ldue to papillary
necrosis) and CKD. There is a classic radiological
appearance on IVU - 'cup and spill calyces due to
papillary necrosis, with renal scarring.
I Renal biopsy is of no diagnostic value
0 Women are affected more often than men (4:1)
0 As with other TIN, nephrogenic DI, salt\/vasting
and distal RTA can be associated
0 increased risk of urothelial malignancy (there
may be multiple synchronous lesions)
2.3.1* i1;1.if`l..iL3\ -`\if,l"lt?li,l~f`.`tQSi'iv -i,:s,;
tlRli\IAl! \ l`R,Xt_'l` il*~i~7"i.t',`T;1a?\;1-;
15.13.! Vesxc~our_<=tf:1t 43; ~ .
refl ux e;':-i'..<z;\;\;v
Reflux nephropathy is the term applied when small
and irregularly scarred kidneys (c hronic pyelo-
nephritis, CPN) are associated with vesico-ureteric
reflux NUR). It is the commonest cause of CPN,
but other disorders such as obstructive injury and
analgesic nephropathy can also result in CPN. Re-
nal scarring is necessary for the diagnosis of reflux
nephropathy and this almost only occurs during the
first 5 years of life. The end result of reflux nephro-
pathy is hypertension, proteinuria, CKD and, some-
times, ESRD; reflux nephropathy still accounts for at
least 10% of adult patients entering RRT pro-
grammes, and is the commonest cause of ESRD in
children.
I
Epidemiology: VUR is very common in utero,
and 0.5% of all neonates are affected. Around
1% of children will have VUR, but this
disappears in 40% by the age of 2 years. In
l

427
Essential Revision Notes for MRCP

young children VUR usually presents with a
complicating UTI. About 3 0 % of children with
UTI will have some degree of \/UR and 10%
will have evidence of reflux nephropathy; 5% of
women with symptomatic UTI will have reflux
nephropathy. However, documented UTI occurs
in <5O% of adults with reflux nephropathy
0
Grading: reflux can be graded: from grade I
(involving reflux into the ureter only) to grade V
(gross dilatation and tortuosity of ureter, renal
pelvis and calyces with severe scarring) - see
Figure I S A
0
Diagnosis is by rnicturating cystography
(radionuclides can be used in children); scarring
can be demonstrated by ultrasound and DMSA
0
Pathogenesis of renal scarring: scars will only
form if there is intrarenal reflux accompanied by
urinary infection, The scars form at the sites of
the intrarenal reflux: severity of scarring is
proportional to the degree of \/UR, Note that
there is no evidence that UTI occurring without
\/UR will lead to scarring
I Genetic predisposition: first-degree relatives of
patients with reflux have a greatly increased (eg
> 2 5 % ) chance of VUR; it is recommended that
offspring or siblings (if a child) of affected
patients undergo screening. The gene is thought
to be dominant but its effect is modified
by
environmental factors; the gene frequency has
been estimated to be I in 600
Management ofVUR a n d re fl ux ne phropa thy
/-\II children with UTI should be investigated for
VUR. The aim of treatment for patients with VUR is
to prevent renal scars. As these occur early in life
there is no place for anti-reflux surgery to prevent
renal scars in adults who have VUR. Few surgeons
operate on children with grades I-lll reflux as these
tend to resolve spontaneously; those with grade ll or
worse reflux should receive prophylactic antibiotic
theraPY leg low-dose nitrofurantoin, trimethoprim or
co-trimoxazole, or ceialexin in those with CKDI
until puberty in order to limit UTIS.

`_

Figure 1 5 .4 Classification of vesicoureteri_c reflux I

l
I II III IV V

Grade I: Ureter only

Grade II: Up to pelvis and calyces, but with no dilatation
Grade III: Mild-moderate dilatation, but with only minimal
blunting of fornices
Grade IV: Moderate dilatation, with obliteration of
of fornices
sharp angles
s Grade V: Gross dilatation and tortuosity of ureter and pelvi-
- calcyceal system. Calyces severely clubbed

428

There is now debate as to the best management of
patients with grades lV and V VUR. Surgery (eg
endoscopic injection of collagen behind the intra-
vesical ureter, lengthening of the submucosal
ureteric tunnel and ureteric re-implantation) has its
protagonists. However, other clinicians would advo-
cate long-term antibiotics (as above). Whichever the
approach, UTI should be treated promptly and, as
with all forms of chronic, potentially progressive
renal disorders, hypertension must be controlled
properly (with RAA blockade favoured). Patients
with reflux nephropathy have an increased inci-
dence of renal calculi,
15.9.2 Urin ary tract infection (UTI)
Apart from the outer one-third of the female urethra,
the urinary tract is normally sterile, UTls are the
commonest bacterial infections managed in general
practice; they predominantly affect women texcept
in infants, patients aged >6O years, and those with
co-morbid diseases). Coliforms are by far the most
common pathogens. Several important definitions
are applied:
U Acute uncomplicated UTI: acute cystitis and
acute pyelonephritis. The incidence of cystitis is
0.5% per year in sexually active w o m e n , lt may
recur in 40% of healthy women, even when
their urinary tracts are normal. Three-day
antibiotic treatment regimes are recommended
for acute cystitis because of cost, compliance
and efficacy. In those with recurrent cystitis,
attention to hygiene, post-coital micturition and
fluid intake are recommended; in post-
menopausal women, intravaginal oestrogen
pessaries may be beneficial, probably because
of alteration of vaginal flora
0 Complicated UTI: these occur in patients with
abnormal urinary tracts (eg stones, obstruction,
ileal conduits, VUR, neuropathic bladder) and
very commonly in patients with urinary
catheters (see below). The definition also
incorporates UTI in patients with advanced CKD
and renal transplants
I
Asymptomatic bacteriuria: two separate urinary
specimens showing bacterial colony counts of
Nephrology
>l05/ml of the same organism in an
asymptomatic patient. The prevalence may be
3 % -5 % in adult w o men (and 045% in men); it
increases greatly in the elderly (eg 50% of
w om e n) and in institutionalised patients. The
vast majority of cases require no treatment, but
it should always be treated if detected in
pregnant women, as 15%-20% will otherwise
develop acute pyelonephritis (see Chapter T2,
Maternal M edicine)
Urethral syndrome: patients have 'abacterial'
Cystitis. Causes include true recurrent UTI (but
with low bacterial counts), and genital (eg
Chlamydia), vaginal (eg Trichomonas or
Candida) or fastidious organism (eg Ure-ap/asma,
Lactobacillus) infections. Postmenopausal
women may develop the syndrome because of
atrophic vaginitis due to oestrogen deficiency
long-term antibiotic treatment regimes: these may
be appropriate for patients prone to recurrent UTI,
and especially in those with an underlying predis-
position (except those with urinary catheters). The
regimes may involve rotating monthly antibiotic
courses (eg amoxicillin, a quinolone and a cepha
losporin) or low-dose, once-daily, long-term nitro-
furantoin or trimethoprim.
Plodiapositions to '
u ri n ary tract
infection
Abnormal urinary tract
eg calculi, VUR, reflux nephropathy,
analgesic nephropathy, obstruction,
alonic bladder, ileal conduit, in-
dwelling catheter
0
Pregnancy [where the urinary tract
abnomality - eg ureteral dilatation - is
temporary)
U
Impaired host defences
~ Immunosuppressive therapy (including
transplanted patients), diabetes mellitus,
atrophic vaginitis
Virulent organisms
~ (eg urease-producing Proteus)
429
Essential Revision Notes for MRCP
Ot he r speci fi c forms of UTI
U
Urinary catheter-associated infection: up to 5%
of all hospital admissions may be due to
nosocomial UTI, and the majority of these occur
in patients with long-term indwelling catheters.
The incidence of bacteriuria is 3%-10% per
day of catheterisation, and so the duration of
catheterisation is the greatest risk factor. Most
infections are asymptomatic, but catheter-
associated infections are the commonest source
of Cram - v e septicaemia in hospitalised
patients. Most cases of 'infection' do not require
treatment; if lower urinary tract symptoms occur,
a single antibiotic dose may be as effective as a
full course oftherapy (which predisposes to
bacterial resistancel, and the catheter should be
changed. For prevention of UTI in patients with
long-term catheters, regular (eg 3-monthly)
catheter change is recommended as organisms
are harboured within the biofilm lining ofthe
catheter
0 Prostatitis: prostatitic symptoms are experienced
by 50% of men, but are caused by bacteria in
only a minority. Acute bacterial prostatitis is
rare; patients present with symptoms of cystitis
and the prostate is swollen and tender. There
will be pyuria and a positive urine culture. The
commonest pathogens are the Gram A v e bacilli,
Escherichia coli, Proteus and Klebsiella.
Antibiotic treatment is needed for l month.
Chronic prostatitis is manifest by recurrent UTI
with the same organism. It is characterised by a
qualitative difference in the first voided urine
(no pyuria), compared with that passed after
prostatic massage (>1O white blood cells per
high~povver field, bacterial colony count 10~fold
greater). Treatment is with quinolone antibiotics
for 1 - 3 months
0 Renal abscess; usually due to Staphylococcus
aureus after haematogenous spread to the
kidney. May present as a renal mass but renal
abscesses are often insidious and nonspecific.
CT is needed for diagnosis. Treatment is with
antibiotics, percutaneous drainage for larger
abscesses and sometimes nephrectomy
430
0
Emphysematous pyelonephritis: this is a
necrotising, lifethreatening form of acute
pyelonephritis caused by gas~forming organisms
(including E. coli, Pseudomonas, Klebsiella and
Proteus); 9 0 % of cases occur in diabetics. Plain
X-ray will demonstrate the gas, but CTwill
localise this better. Emergency nephrectomy and
broad-spectrum antibiotics are required, but
even then mortality is 20%
0
Xanlhogranulnmatous pyelonephritis: this is a
rare chronic renal infection that is associated
with obstruction. Renal tissue is replaced with
lipid-laden infiltrating macrophages (foam cells);
the xanthomatous tissue may extend beyond the
renal capsule into neighbouring structures.
Patients are usually middle-aged women with
flank pain, fever, a palpable renal mass and
positive MSU. Nephrectomy provides the only
chance of cure
15.9.3 Tuberculosis of th e u rin ary
tr act
TB reaches the urinary tract via haematogenous
spread. Most patients are 2 0 - 4 0 years of age, with
men affected twice as commonly as women.
Twenty~five per cent of patients are asymptomatic; a
further 25% have asymptomatic pyuria or micro-
scopic haematuria, and painless macrohaematuria
is common. Hypertension is unusual, but genital
involvement (epididymitis and prostatitis in men,
salpingitis and pelvic pain in wom e n) is commonly
associated.
0 The renal medullary regions are most commonly
affected. In the early stages, ulcerating lesions
and granulomas are seen in the renal pyramids
and collecting systems; renal histology shows
chronic interstitial nephritis with granulomas
0 As the disease progresses scarring occurs with
ureteric strictures, hydronephrosis, subcapsular
collections, perinephric abscesses or renal
atrophy. The bladder may be fibrotic and small.
The caseating material may eventually calcify
0 Treatment: standard anti-tuberculous therapy is
recommended. Surgery may be indicated for
obstruction and strictures. Nephrectomy for

non-functioning kidneys is no longer routine as
prolonged anti-TB therapy can render the
calcified, caseous masses (cen'1en1 l<idney')
sterile
15.10 RENAL CALCULI AND
NEPHROCALCINOSIS
15_10. 1 R enal calculi (nephrolithiasis)
Renal stones are common, with an annual inci-
dence of approximately 2 per 1000 and a preva-
lence of 3% in the UK. Calcium-containing stones
account for >70/0,
i
1 : - r
Calcium oxalate: 25%
Mixed calcium oxalate/phosphate: 40%
Calcium phosphate: 5%
Urate: 10% (radiolucent)
Cystine: 2%
Xanthine: 1% (radiolucent)
Staghorn (struvite' containing magnesium
ammonium phosphate and sometimes
calcium): 20%; associated with infection
with urease-producing bacteria (eg Proteus
SPP-l
Basic i nves t i gat i ons
This should include stone analysis, MSU, assess-
ment of renal function, serum calcium and phos-
phate, and a qualitative test for urinary cystine. The
24-hour urinary excretion of oxalate, Calcium, crea-
Nephrology
tinine and uric acid may also be helpful, and RTA
should be excluded ( ur ine pH).
Conditions pre disposing
0 Metabolic abnormalities
~ idiopathic hypercalciuria (most
Common)
~ Primary hyperparathyroidism (and other
causes of hypercalcaemia)
Renal tubular acidosis
~ Cystinuria
Hyperoxaluria (primary or secondary]
High dietary oxaiate intake (eg glutinous
rice or leafy vegetables in Thailand)
Uric aciduria
~ Hypocitraturia (eg chronic diarrhoea,
excess laxative and diuretic use)
Renal structural abnormalities
~ Polycystic kidney disease
~ Medullary sponge kidney
e Reflux nephropathy
o
Nephrocalcinosis (see Section 15.102)
Other causes
~ Chronic dehydration - common (eg
chronic diarrhoea, warm climates)
Triamterene
Industrial exposure to cadmium or
beryllium
Treatment
General measures: increased fluid intake and low
protein diet; reduced dietary oxalate intake, Asso-
ciated urinary infection should be eradicated vvhere
possible (very difficult with staghorn calculi). Treat
431
Essential Revision Notes for MRCP
other underlying causes (eg allopurinol for urate
stones, surgery for hyperparathyroidism).
Thiazide diuretics (eg chlortalidonei: increase tubu~
lar absorption of calcium in patients with hypercal-
ciuria, and will therefore reduce the likelihood of
super-saturation of calcium products within the
urine. Citrate may be beneficial for calcium oxalate
stones.
The specific treatment of patients with cystinuria is
described in Chapter 13, Metabolic Diseases.
Stone rem oval; ureteric calculi <O.5 cm may be
passed spontaneously, Lithotripsy alone may be
used for larger ureteric stones and for pelvicalyceal
stones <4 cm (obstruction being prevented by
double 1-stent insertion); larger calculi can be 'de-
bulked' by this technique before surgical e xtr a c tion,
l5.1O.2 Nephrocalcinosis
This is defined as the deposition of calcium salts
within the renal parenchyma; it may be associated
with urinary calculi,
Causes of nephr mateinuais.
0 Cortical nephrocalcinosis
Cortical necrosis ~ after very severe
acute ischaemic iniun/ to the kidneys
(see 'tram-line calcification)
Chronic glomerulonephritis
0
Medullary nephrocalcinosis
Hypercalcaemia
(eg primary
hyperparathyroidism, sarcoidosis,
hypervitaminosis D, mill<~alkali
syndrome)
idiopathic hypercalciuria
~ Renal tubular acidosis
--
~ Primary hyperoxaluria
Berylliosis
Thyrotoxicosis
~ Sulphonamides
e
Medullan/ sponge kidney
~ Tuberculosis
432
15.11 URINARY TRACT
OBSTRUCTION AND
TUMOURS
l5.l1.l U r ina r y tr act obs truction
Chronic urinary tract obstruction (most often due to
prostatic disease, calculi and bladder lesions) is a
common cause of CKD; obstruction must also be
excluded in even/ case of unexplained AKI. The
causes of renal tract obstruction are shown in the
box opposite. The term obstructive nephropathy
refers to pathological renal damage resulting from
obstruction.
Acute obstruction
This is often painful due to distension of the bladder,
ureterts) or pelvicalyceal systems, Complete ob-
struction will result in anuria and AKI; anuria may
also occur even when obstruction is unilateral, clue
to an intense afferent arteriolar vasoconstriction
(similar to that seen in ischaemic AKI),
0
Diagnosis: obstruction is one ofthe few truly
reversible causes of renal failure, but diagnosis
and treatment need to be expedient in order to
allow renal functional recovery. Ultrasound is
the chief mode of diagnosis, but it may only
show minimal pelvicalyceal dilatation in the
early stages of acute obstruction
0 Treatment and prognosis: temporary drainage
can often be achieved by percutaneous
nephrostomy or by endoscopic ureteric stenting,
pending definitive surgical correction. Relief of
obstruction may be followed by massive diuresis
(temporary nephrogenic Di), but if the
obstruction has been relieved within 2 weeks
then full renal functional r e c ove iy is likely,
unless there is complicating pyonephrosis
Chronic obstructive n ep h ro p at h y
This is usually associated with CKD or ESRD and it
is often complicated by chronic UTI, Obstruction
accounts for 5% of all cases of ESRD, Salt-wasting
nephropathy and chronic metabolic acidosis are
common, the latter contributing to the advanced
renal bone disease recognised in some patients.

Differential diagnosis: there may be diagnostic
uncertainty when the upper tracts are dilated
(but non-obstructed). This is seen in VUR, post
obstructive atrophy, congenital mega-calyces
and mega-ureters and in some cases of CPN. In
such cases diuresis renography or retrograde
pyelography will exclude obstruction.
Occasionally, the Whitaker test, which involves
puncture of the collecting system followed by
pressure flow studies, is necessary to diagnose
obstruction
Pathology and outc om e ; there is permanent
renal histopathological damage that results from
a combination of parenchymal compression,
renal ischaemia and sometimes infection, In
severe cases severe tubular loss, interstitial
fibrosis and cortical atrophy are observed, lf the
obstruction is relieved [eg in <1 2 weeks), renal
functional decline can stabilise and dialysis may
be prevented
Causes of uri na ry tract obstruction
I Within the lumen
~ Tumour (eg urothelial lesions of bladder,
ureter or renal pelvis)
~ Renal calculi
Papillary necrosis (sloughed papilla)
~ Blood clot
0 External compression
Malignancy: retroperitoneal neoplasia
including para-aortic lymphadenopathy
and pelvic cancer (eg cervical or
prostatic carcinoma)
1 Other tumours: aortic aneurysm;
pregnancy ihydronephrosis of
pregnancy is very common, is usually
asymptomatic, and resolves fully after
-
delivery); haematomas
Aberrant arteries (PU) obstruction)
Retroperitoneal fibrosis (eg malignant,
- idiopathic, peri-aortitis, drugs (see
below))
Prostatic disease: benign hypertrophy or
malignancy
Nephrology
Inflammatory disorders (eg diverticulitis,
Crohns disease, pancreatitis)
~ latrogenic, eg accidental surgical
ligation of the ureter
0 Within the wall of urinary tract structures
Neuromuscular dysfunction (eg pelvi-
ureteric junction [PUD obstruction,
neuropathic bladder (spina bifida, spinal
-
trauma see below))
~ Ureteric or vesico-ureteric stricture: TB,
schistosomiasis, previous calculi, after
surgery, congenital, irradiation (eg for
serninoma of testis), malignancy,
ureterocele
~ Urethral stricture (eg gonococcal]
following instrumentation
~ Posterior urethral valves (see below)
Congenital bladder neck obstruction
N europathic bladder
In childhood, spina bifida with myelomeningocele
is by far the commonest cause of a neuropathic
bladder. Spina bifida has an incidence of around
I - 2 per 1000 births; siblings of affected individuals
have a 10- to 2Ofold chance of having the condi-
tion. Urinary tract complications are present at birth
in 15%, and will develop in 50%, often over many
years. Most of these patients have incomplete blad-
der emptying due to urethral sphincter dyssynergia,
but those with the mildest neurological lesions are
paradoxically able to generate very high pressures
within the bladder, with greatest risk of renal
damage.
The main urinary tract abnormalities are
incontinence, infection and reflux with upper
tract dilatation, the latter leading to CKD and
ESRD
I
Patients often have associated bowel
dysfunction
Treatment is with anticholinergic drugs,
intermittent self-catheterisation and, in more
severe cases, urinary tract diversion into an ileal
conduit. Note that chronically infected urinary
tracts will need to be removed prior to renal
transplantation
433
Essential Revision Notes for MRCP
Po s t eri o r ure thra lvalves (PUV)
These occur in male infants and account for 10% of
childhood hydronephrosis; the valves are mucosal
diaphragms in the posterior urethra at the level of
the prostate. PUV can now be detected antenatally
with ultrasound, Fifty per cent of patients present
before the first year of life with poor urinary stream,
distended bladder and failure to thrive (due to renal
failure). Most have VUR and dilated upper tracts.
0 Treatment: urinary diversion should be avoided;
self-catheterisation is usually necessary.
Approximately 20% of affected individuals will
progress to ESRD, largely because of late initial
presentation
15.l1.2 Retr o p er ito n eal fibrosis (RPF)
An uncommon, progressive condition in which the
ureters become embedded in dense fibrous tissue
(the ureters are drawn rnedially) often at the junc-
tion of the middle and lower thirds of the ureter,
leading to obstr uc tion, The majority of cases are
thought to result from an immunologically mediated
peri-aortitis, and steroids are of benefit in these
'idiopathic' forms of RPF.
I Other associations: retroperitoneal malignancy
(eg colonic, bladder or prostatic cancer,
lymphoma), previous irradiation, inflammatory
abdominal aortic aneurysm, other fibroslng
conditions (eg mediastinal fibrosis, sclerosing
cholangitis), drugs (eg methysergide and some
[5-blockers) and granulomatous disease (TB or
sarcoidosis)
l
Investigation: ESR is often very high, IVU shows
medial deviation of the ureters and a peri-aortic
mass may be seen at CT scan
I Treatment: ureterolysis (with tissue biopsy) with
long-term steroid therapy' (as relapse is
com m on). Malignant RPF can be palliated with
ureteric stenting, or with percutaneous
nephrostomy
434
1511.3 Urin ary tr act tu mo u rs
Benign renal tumours: include adenomata, which
are very common (however, just as with thyroid
adenoma and carcinoma, their histological differen-
tiation from malignant lesions can be difficult),
hamartomas and renin-secreting (juxtaglomerular
cell) tumours.
Renal cell carcinoma (hypernephroma): arise from
the tubular epithelium; they are more common in
smokers, and at least 50% of patients with von
Hippel-Lindau syndrome will develop them (usual-
ly multiple and bilateral). As mentioned previously,
acquired cystic kidney disease in patients with renal
failure is also a risk factor; the cumulative incidence
of malignant change is about l%, and accounts for
80% ot' renal cell carcinomas in dialysis patients.
0 Renal cell carcinoma has a propensity to invade
the renal veins, with passage of tumour emboli
to the lung
0 Other unusual clinical features include pyrexia
of unknown origin (PUO), left varicocele (renal
vein invasion leads to left testicular vein
occlusion), and endocrine effects (secretion of
erythropoietic factor resulting in polycythaemia
(3%), PTH-like substance, renin and ACTH).
Five-year survival is about 50%
Wilms tumour (nephrob|astoma): these are tu-
mours of early childhood, and are derived from
embryonic renal tissue (so containing combinations
of poorly differentiated epithelium and connective
tissues). They can become enormous and metasta-
sise early. Treatment is with nephrectomy and acti-
nomycin D, providing a 3-year survival rate of 65%.
Urothelial tumours: very common and usually de-
rived from transitional epithelium, although squa-
mous carcinoma (worse prognosis) is recognised.
The usual presentation is with bleeding or urinary
tract obstruction. Tumours are often multiple, and
so investigation of the complete urinary tract is
indicated.

0 Several carcinogens (eg smoking, rubber and
aniline dye exposure, analgesic nephropathy)
have been aetiologically linked to this type of
malignancy
0 Other risk factors include renal calculi, cystic
kidney disease, chronic cystitis and
Schistosoma haematobium infection ( note that
Schistosoma mansoni is associated with
glomerulonephritis)
O
Nephro-ureterectomy is indicated for lesions of
ureter or renal pelvis, and cystectomy with
resection of urethral mucosa for advanced
bladder cancer; surgery combined with
radiotherapy provides a 5-year survival rate
Of50/o
Metastatic disease (involving the kidney): most
commonly from breast, lung, stomach, lymphoma
or melanoma.
15. 12 SYSTEMIC DISORDERS AND
THE KIDNEY
15.12.1 Amyloidosis
Amyloidosis occurs when certain proteins, most of
which are normal constituents of plasma, develop
a particular conformational pattern ([5-pleated
sheet) and are deposited in an organised formation
within organs. Twenty-five different amyloid pro-
teins are now recognised: some are abnormal,
others genetically derived, and in the commoner
forms of amyloid there is over-production of the
protein. Kidney involvement leads to presentation
with proteinuria, nephrotic syndrome or CKD;
biopsy demonstrates characteristic Congored-stain-
ing extracellular fibrillar material within the mesan-
gium, interstitium and vessel walls. Radionuclide
scan (amyloid fibrils labelled with ml localise to
amyloid deposits after injection) is used to demon-
strate the full extent of disease in all organs.
Amyloid is classified according to the amyloid
proteins involved, as well as the underlying disease
process.
Nephrology
lmmunologlobulinic amyloid
(AL-amyloidosis)
The incidence of Abamyloidosis is 9 per million/
year. Free immunoglobulin light chains (hence the
'L ') are secreted by a clone of B cells; 25% of
patients have an underlying immunoproliferative
disease (usually myeloma), but many more probably
have a monoclonal gammopathy (MGUS), Median
age of presentation is above 60 years.
0
Nephrotic syndrome, postural hypotension and
peripheral neuropathy are more likely in cases
without myeloma
0
AL-amyloid may infiltrate any organ other than
the brain - eg heart (restrictive cardiomyopathy
in 30%, sick sinus syndrome and arrhythmias),
macroglossia, GI tract (motility disturbance,
malabsorption, haemorrhage), neuropathy
(peripheral and autonomic) and bleeding
diathesis
0 Treatment: cases associated with myeloma
receive conventional therapy. In 'primary
amyloid, regimes involving prednisolone with
either melphalan or colchicine have been
shown to extend survival duration by only 50%
( se e below), Autologous bone marrow
transplantation (after high-dose chemotherapy)
provides the only prospect of cure
0
Prognosis: when patients present with renal
complications prognosis is poor, with a median
survival of 12 months, and only 25% alive at
3 years. Survival is shorter in those with mye-
loma, heart disease and autonomic neuropathy,
Cardiac involvement accounts for half of deaths
AA-amyloidosis
Chronic infections (eg TB, empyema) now account
for fewer cases than previously; 70% are due to
autoimmune inflammatory conditions (eg rheuma-
toid arthritis). ln these conditions the amyloid pro-
tein A is derived from acute phase reactants, and is
made in the liver, ln AA-amyloidosis the kidney is
the main target organ - cardiac involvement and
neuropathy are uncommon. Prognosis is conse-
quently better than for AL-amyloidosis, with median
survival of 25 months and 40% 3year sun/ival.
435
Essential Revision Notes for MRCP
Treatment: the underlying inflammatory or infective
disorder should be treated. Although previously
there has been little apparent benefit from specific
drug therapy, colchicine has been shown to prevent
disease progression in familial Mediterranean fever
(another form of AA-amyloidosis), which is encoura-
ging. It has been trialled in patients with rheumatoid
arthritis with some success. A few patients with AA-
amyloiclosis have received renal transplants; recur-
rent amyloid is seen in >1O%.
Ciassihcotion of amyloidosis
0
Primary amyloid
I ALtype, which is serum amyloid protein A
coupled with immunoglobulin light chains
0
Hereditary amyloid (eg familial
Mediterranean fever)
e Fibrils are formed from other proteins
(lysosomes, apolipoproteins, fibrinogen);
the amyloid is of AAtype
0
Secondary amyloid (this is usually AA type
(fibrils derived from acute phase proteins)
0
Secondary to chronic suppurative disorders
Tuberculosis, osteomyelitis, empyema,
bronchiectasis, syphilis, leprosy
0
Secondary to chronic inflammatory
disorders
Rheumatological conditions -
rheumatoid arthritis, psoriatic arthritis,
ankylosing spondylitis, Stills disease,
- Reiter syndrome, Sjogren syndrome,
Behcets disease
Gastrointestinal conditions - Whipples
disease, inflammatory bowel disease
~ Paraprotein-related conditions ~
myeloma (AL type), benign monoclonal
I
- gammopathy (AL type)
Other secondary amyloid
Heroin abuse, paraplegia, renal cell
carcinoma
.Dialysis-related
0
amyloid
This does notdeposit in the kidneys, as
a
it is complication of long-term
dialysis. lt is due to failure of clearance
of [52-microglobulin (see Section 15.5.4)
436
1 5 .1 2 1 R enovascular d isease
Atherosclerotic renovascular disease (ARVD)
ARVD accounts for >9O"/0 of all renovascular dis-
ease. It is increased with ageing and is associated
with common atherogenic risk factors (hyperten- E
i
sion, hypercholesterolaemia, smoking, diabetes, etc)
as well as with the presence of generalised vascular
disease it can be demonstrated in > l 0 % of pa-
~
tients undergoing coronary angiography, >4 0 %
with peripheral vascular disease, and it affects 30%
of patients with CCF aged >7O years. As older
patients are now readily admitted to RRT pro-
grammes, ARVD is commonly detected in ESRD
patients ( 15%- 20%) , although it probably only ac-
counts for the renal failure in the minority ( se e
below).
Clinical presentation is with hypertension, CKD or
ESRD, 'flash' pulmonary oedema (5%), and AKI due
to acute arterial occlusion, ischaemic ATN or re-
lated to ACE-I. Prognosis is poor (5-year survival
<20"/0) due to co-morbid vascular events. Many
cases oi ARVD are thought to be incidental, the
arterial narrowing occurring in association with
prior hypertension and CKD (pro-atherogenic state),
rather than being the cause of themt Around 90% ot'
RAS lesions are ostial (occurring within the first 1
cm of the renal artery origin).
0 Flash pulmonary oedema: sudden onset of
acute heart failure in the absence of a
myocardial ischaemic event. The mechanism
probably involves reduced natriuretic ability,
coupled with left ventricular hypertrophy and
severe hypertension, in patients who usually
have severe bilateral renal artery disease. The
episodes of pulmonary oedema are more
common at night, largely because of posture-
0
related redistribution of fluid, but possibly also
because of diurnal variations in vasoactive
peptides
Pathogenesis of CKD: the correlation between
severity of proximal lesions (ie degree of renal
artery stenosis (RAS) or occlusion) and renal
function is poor: this explains why
revascularisation procedures are only variably
successful. Parenchymal disease, manifest by

intrarenal atheroma, ischaemic change and
cholesterol embolisation (ischaemic
nephropathy'), is now being recognised as a
major determinant of renal functional outcome
0
Radiological diagnosis: MR angiography (MRA)
was the optimum non-invasive screening test for
ARVD diagnosis until the advent of cases of
gadolinium-related NSF (see Section 15.2.2,
Renal radiology). MRA can still be performed
safely in most patients with CKD stages 3 and 4.
CTangiography is commonly used, but can be
l complicated by radiocontrast nephropathy in
patients with Cl<D. Duplex ultrasound combines
measurement ofproximal renal artery blood
flow velocity with intrarenal resistive index and
although time-consuming and highly operator-
dependent, it is an accurate test for detection of
ARVD and assessing RAS severity. Conventional
intra-arterial angiography is now reserved for
patients with complex anatomy, and when
confirming RAS severity prior to
revascularisation
0 Revascularisationz around 16% of American
ARVD patients undergo revascularisation
therapy and endovascular techniques (renal
angioplasty with stenting) account for > 9 5 % of
these procedures (the remainder being surgical
reconstructions - especially indicated with
complicated lesions, eg related to aortic
l
aneurysm). The ASTRAL trial, a randomised trial
involving >8O0 patients, has shown that
revascularisation added to standard medical
therapy (statins, aspirin and antihypertensives)
l does not improve renal function, blood pressure
control, CVS event rate or mortality when
compared with medical therapy alone, This
finding is applicable to the majority of patients
with ARVD; significant RAS occurring in
patients with AKI or flash pulmonary oedema is,
however, a definitive indication for
revascularisation
Fibromuscular dyspl asi a (FMD)
FMD accounts for about 10% of all renovascular
disease; it occurs in the young ( 2 0 - 3 5 years), and the
l
Nephrology
majority of patients are female. The RAS lesions may
be long and can be distal in the renal artery; they
appear as a 'string of beads at angiography. Patients
usually present with severe hypertension, but renal
failure is unusual. As the kidney beyond a fibromus-
cular stenosis is usually healthy, revascularisation
may cure the hypertension, and it often restores renal
function completely in the subgroup of patients with
renal impairment. FMD is associated with other
arterial lesions (eg carotid stenosis in 10%),
15.123 Connective t i ssue disorders
a nd the kidney
Most of the connective tissue disorders have the
propensity to cause renal disease, and characteristic
features are described below ( se e also Chapter 20,
Rheumatology); lupus nephritis and systemic sclero-
sis merit more detailed coverage.
Mixed connective tissue disease: membranous
or diffuse proliferative glomerulonephritis
(uncommon)
0
Sjiigren syndrome: renal involvement is most
often manifest by renal tubular dysfunction (RTA
1 or 2) with interstitial nephritis;
cryoglobulinaemia and membranous or focal
proliferative glomerulonephritis are less
common
0 Rheumatoid arthritis: renal disease is common,
and usually due to amyloid or less often the
effects of drug therapy. Rheumatoid-related
glomerulonephritis (typically mild mesangio-
proliferative change) is fairly common and is
manifest by microscopic haematuria and mild
proteinuria_ Membranous glomerulonephritis is
also recognised ( n o t just an association with
gold or penicillamine therapy)
0
Semnegative spondylarthropathies: ankylosing
spondylitis and Reiter syndrome can be
associated with IgA nephropathy
0
Relapsing polychondritisz this rare disorder is
associated with cartilage inflammation leading
to destruction and deformity (eg saddle nose,
floppy ears). Crescentic, mesangioproliferative
or membranous glomerulonephritis may occur
437
Essential Revision Notes for /VIRCP
SLE nephri t i s
Over 5% of patients with SLE have renal involvement
at presentation, and around 60% of patients will
develop oven renal disease at some stage. Lupus
nephritis is commoner in black patients and in
women (IO-fold greater incidence than in men), and
90% will have ANF antibodies. Renal disease can be
manifest by any syndromal picture (eg proteinuria,
nephrotic syndrome, rapidly progressive glornerulo-
nephritis with AKI, CKD) but proteinuria is present in
almost all patients with nephritis. Similarly, many
different patterns of glomerular disease are recog-
nised (the histological picture may even change,
over time, within the same individual). Note that
drug-induced SLE only rarely affects the kidneys.
Although lupus nephritis can present with marked
patient morbidity, most patients respond well to
prompt immunosuppressive treatment.
-
Renal histology WHO classification: the histolo-
gical pattern has some prognostic value, with focal
proliferative disease having a favourable renal out-
come; diffuse proliferative or crescentic glomerulo-
nephritis predicts the worst renal prognosis. 'Wire
loop lesions (thickened capillary walls - EM shows
electron-dense deposits) are characteristic; immuno-
fluorescence is positive for most immunoglobulins
(IgG, IgM, IgA) and complement components (C3,
C4, CIq).AsynopsisoftheWHOclassificationis :
0 Class I: mild changes
I Class Il: mesangioproliferative changes
0 Class Ill: focal proliferative glomerulonephritis
(variable severity)
I Class IV: severe diffuse proliferative
glomerulonephritis
0 Class V: membranous glomerulonephritis
Treatment: Patients with mild disease (eg WHO
classes I and II) usually require no treatment. How-
ever, irrespective of the WHO class, most patients
with significant proteinuria are likely to receive at
least prednisolone and ACE inhibitor therapy. Acute
SLE with AKI (classes Ill and IV - usually diffuse,
crescentic or severe focal proliferative glomerulo-
nephritis) should be treated as for RFGN/crescentic
nephritis ( s e e Section 15.6, Glomerulonephritis and
associated syndromes), with an intense induction
438
regime (high-dose steroid, and usually pulsed IV
cyclophosphamide) followed by maintenance ther-
apy. Patients with class V histology who present
with the nephrotic syndrome are treated similarly,
although there is less evidence of conclusive bene-
fit. Although plasma exchange has been used in
patients with crescentic disease, and in those with
severe extrarenal manifestations of SLE, there is
again little evidence of improved outcome.
0 Trials have shown a benefit with treatment
regimes involving MMF; this is favoured over
cyclophosphamide in the treatment of women
of child-bearing age
0 In many patients the immunosuppression can be
tapered, and withdrawn by 5 years, even in
those presenting with severe AKI
Prognosis of renal lupus: <1O% of patients with
nephritis now progress to ESRD (historically, renal
disease used to be the commonest cause of death in
SLE). The SLE syndrome often becomes quiescent
once the patients reach RRT. Lupus nephritis rarely
TQ C U F S In I! n3l ifanSpl3i1LS.
Sy s t emi c sclerosis
Renal disease is always accompanied by hyper-
tension; the hallmark presentation is scleroderma
renal crisis with accelerated hypertension, microan~
giopathic haemolytic anaemia and AKI. Prominent
pathological changes are seen in the interlobular
arteries (se ve re intimal proliferation with deposition
of mucopolysaccharides - so-called 'onion skin'
appearance); fibrinoid necrosis of afferent arterioles
and secondary glomerular ischaemia are common.
The essential treatment is with RA/\ blockade for
hypertension control; some patients develop ESRD,
but renal function can recover, particularly in those
patients who presented with renal crisis. The overall
prognosis is poor because of other organ involve-
ment (especially restrictive cardiomyopathy and pul-
monary fibrosis).
15.l2.1i Diab etic nephropathy
Diabetic nephropathy is now the most common
cause of ESRD in the UK, accounting for 25% of

patients, In recent years there have been advances
in the understanding of the natural history, patho-
genesis and treatment of diabetic nephropathy, but
the mortality of this group remains high, largely
because of associated CVS disease.
Epidemiology
Established or clinical nephropathy (see below) is
associated with macroalbuminuria ( > 3O 0 mg/24 h,
which equates to >50O mg/24 h of total protein-
uria), and occurs with a cumulative incidence of
30% after 40 years in type 1 diabetics. ln type 2
diabetics, nephropathy is already prevalent in 10%
at the time of diabetes diagnosis [reflecting previous
subc|inical hyperglycaemia), and there is a 25%
20-year cumulative incidence of nephropathy.
About one-fifth of these latter patients will develop
CKD and be at risk of ESRD [ie 5% of all type 2
diabetics) - the remainder succumb to other com-
plications (usually CVS or infections) of diabetes
before they develop significant CKD. As type 2
diabetes is 1 0 -1 5 times more common than type 1
in Western populations, it accounts for 75% of the
diabetics seen in Cl<D clinics or on RRT pro-
grammes. ln a UK diabetic clinic, the prevalence of
nephropathy is about 5% at any time.
I Genetic influence: diabetics in certain racial
groups have afar greater risk of developing
nephropathy (eg Asians, Pima Indians). In the
UK, the likelihood of ESRD is three times greater
in Asian and AfroCaribbean diabetics than in
Caucasians
0
Nephropathy is usually associated with
retinopathy (common basement membrane
pathology); renovascular disease and other
arterial pathology are common
Na tura l hi st ory of n ep h ro p at h y
ln type 1 diabetes the stages of development of
nephropathy have been well characterised:
0
Stage 1; at the time of diabetes diagnosis the
CFR is elevated by >2O% compared to age-
matched controls. Urinary albumin excretion
rate (UAER) is also increased; both are reduced
by commencement of insulin
Nephrology
C
Stage 2: CFR remains elevated (due to
hyperfiltration) and kidneys are hypertrophied
but blood pressure and UAER are normal. The
CFR appears to be linked to glycaemic control,
with greatest hyperfiltration associated with
worse control. There are early histological
Changes with thickening of glomerular basement
membranes and mesangial expansion, This
stage typically lasts for 5 - 1 5 years after diabetes
diagnosis
0
Stage 3: microalbuminuria (or 'incipient
nephropathy) is present (UAER 30-300 mg/day,
or uACR 3- 30) . The CFR remains elevated or
returns to the normal range. Blood pressure
starts to rise (in 60%) . tvticroalbuminuria occurs
in 30%-50% of patients at 5 -1 0 years after
diabetes onset. and 80% of these patients go on
to develop overt nephropathy [stage 4) over
1 0 -1 5 years. Histological changes progress
from those seen in stage 2
0
Stage 4: 'estab|ished, (also known as 'clinical'
or overt') nephropathy is associated with
increasing macro-proteinuria, which may
become nephrotic in 30%, and declining CFR
(eg average 5 - 1 0 ml/min per year) in all
patients. Hypertension is present in 80% and is
correlated with the rate of decline of CFR. Renal
histology typically shows diffuse glomerular
sclerosing lesions (all patients) and vascular
changes; 10% have Kimmelstiel-V\/ilson
nodules (focal glomerular sclerosis)
0
Stage 5: development of ESRD occurs at an
average of 7 years from onset of stage 4
lt is thought that the development of nephropathy
occurs in a similar fashion in type 2 diabetes.
Screening a n d p rev en t i o n
Patients should be screened for microalbuminuria in
the diabetic clinic; the ACR can be assessed in an
early morning specimen or equally well in random
spot urine samples. An ACR ot' >2 .5 is generally
mken as the cut-oft' for microalbuminuria (equiva-
lent to a UAER of > 30 mg/24 h).
0 Studies in type 1 diabetics have shown that tight
glycaemic control can reduce the likelihood of
439
Essential Revision Notes for MRCP
patients developing microalbuminuria (by 40%),
and there is emerging evidence that intensive
insulin regimes may prevent some
microalbuminuric patients progressing to overt
nephropathy
0 The latter has been clearly shown in trials using
ACE inhibitors in type 1 diabetes, and with
/-\RBs in type 2. These agents also slow the time
of doubling of serum creatinine and the time to
ESRD in patients with established nephropathy;
comparisons with other antihypertensive agents
suggest that their renoprotective effects are
partly independent of hypertension control
I lt is now accepted that blood pressure should be
targeted to 125/75 mmHg in patients with stage 4
nephropathy -this will slow, but not prevent, the
inexorable decline of GPR in patients with oven
nephropathy
Outcome
The mortality of these patients is very high (eg
patients with type i diabetes have a 20-fold greater
mortality than the general population) and this rel-
ative risk may be magnified a further 25-fold in
those with proteinuria (eg 2-year mortality of 30%
in patients with ESRD), largely due to co-morbid
cardiovascular disease. Most patients with stage 4
nephropathy in type 2 diabetes will die before they
reach ESRD.
0 Microalbuminuria confers an excess risk of
mortality compared to patients with
normalbuminuria - eg 4-year mortality 28% in
type 2 diabetics with microalbuminuria,
compared to 4% in those without. lt is thought
that microalbuminuria represents the renal
manifestation of a generalised vascular
endothelial dysfunction
0 All patients who reach ESRD are considered for
RRT. Most patients require screening for
coronary artery disease before listing for
transplantation; combined renal and pancreatic
transplantation is now feasible in selected
patients (see Section l 5 .5 .5 Renal
transplantation). Five-year survival of
transplanted diabetics is 45%-75%, compared
to around 20% for those who remain on dialysis
440
1512.5 Thrombotic
mi c r oa ngi opa t hi e s
Haemolylic uraemic syndrome and thrombotic
thrombocytopenic purpura share similar renal his-
tological features and pathophysiology (see also
Chapter 9, Haematology). In both conditions there
is a microangiopathic haemolytic anaemia (MAHA),
with anaemia, RBC fragments and schistocytes.
Platelet clumping occurs within the intravascular
thrombi, and hence thrombocytopenia is a major
feature. The typical renal histological lesions in-
clude intraglomerular thrombi with ischaemia and
arteriolar lesions.
Haemolytic ura e mic s yndrom e (HUS)
HUS is the commonest cause of AKI in children
(because AKI is rare in children), but it is also seen
in adults (5 cases per million/year). Children aged
<4 years account for 90% of cases. Two main forms
of HUS are recognised:
Typical or diarrhoea-associated (D+) HUS: the onset
is explosive, with AKI, and epidemics of the disease
occur. A third of UK cases are due to verotoxin-
producing E. coli Oi57:H7 (VTEC); the toxin da-
mages vascular endothelium, predisposing to the
microangiopathy. Shigella dysenteriae can also be
associated, The intravascular abnormalities are lar-
gely confined to the kidneys. Ninety per cent of
patients with D`HUS make a good recovery, but
5% die during the acute illness; up to 40% of
patients have decreased GFR at long-term follow-
up.
Atypical HUS: tends to affect older children and
adults; most patients have no diarrhoea (DHUS).
Many D'HUS cases are thought to be familial, and
there is progressive renal dysfunction with neurolo-
gical episodes that can resemble TFP, Familial forms
of HUS/ITP can be associated with factor H defi-
ciency (which may limit cleavage of unusually large
von Willebrand factors, leading to continued plate-
let activation and hence the pathogenesis of HUS or
TTP). These forms have a poorer prognosis, with
ESRD or death occurring in >5O% of patients.

0
Monitoring of disease: in typical HUS red cell
fragmentation and the platelet count are the best
means of monitoring disease activity, LDH
levels are high (due to haemolysis), but this may
also represent tissue infarction
U Treatment: the mainstay of therapy is infusion of
fresh frozen plasma (FFP) and plasma exchange.
These are more effective in adult D H l, lS than
in childhood forms. ln atypical HUS, FFP and
plasma exchange may lower the risk of ESRD
and mortality
Thrombotic t hrom bocyt openi c p u rp u ra
(TFP)
In TTP, explosive AKI is less prominent, but neuro-
logical abnormalities are usual (due to formation
and release of microthrombi within the brain vascu-
lature). Again two main forms are recognised:
0 Acute TTP: 90% of patients with TTP present
with abrupt onset with neurological signs, fever
and purpura. Plasma exchange and FFP infusion
are indicated for this condition. Previously
invariably fatal, survival now approaches 90%
0
Relapsing TTP: adults are usually affected and
chronic disease is more likely - the condition
can appear similar to atypical HUS. Some of
these cases are probably familial HUS/TTP
S e c onda ry cau s es of HUS a ndTTP
These include:
0
Pregnancy-associated thrombotic
microangiopathy (see Chapter 12, Maternal
Medicine)
TFP
HELLP syndrome
Post-partum HUS
0 HIV-associated thrombotic microangiopathy
0 Cancer-associated thrombotic microangiopathy
I
Drugs (eg ciclosporin)
15.12.6 Hy p er ten sio n an d t h e kidney
A detailed description of hypertension is beyond the
scope of this chapter; but s ee Chapter 1, Cardiology.
The kidney is often damaged by essential hyper-
Nephrology
tension, or it can be central to the pathogenesis of
many cases of secondary hypertension.
P ri m ary (essential) hypert ens i on a nd re na l
da ma ge
End-organ renal damage is common and is usually
manifest as asymptomatic proteinuria and/or CKD
(hypertensive nephrosclerosis). Microalbuminuria
develops in 20%-40% of patients with essential
hypertension, and persistent proteinuria (occasion-
ally nephrotic) in a smaller proportion. Typical
histological lesions include vascular wall thickening
and luminal obliteration, with widespread interstitial
fibrosis and glomerulosclerosis.
0 Elevated creatinine develops in 10%-20% of
patients; the risk is greater in African Americans,
the elderly and those with higher systolic blood
pressure
0
Progression to ESRD occurs in 2% -5% over
1 0 - I 5 years. Isolated hypertension accounts for
about 30% of all ESRD in the USA and 15% in
the UK
It is thought that many patients who present
with ESRD of unknown aetiology, especially
with small, smooth kidneys visible at
ultrasound, actually have long-standing
hypertensive renal disease
Treatment and targets: all patients should have
their blood pressure controlled to <140/85 mmHg.
In those with CKD, or with significant proteinuria,
the targets should be <13O/B0 and 125/75 mmHg,
respectively, RAA blockers are specifically indi-
cated for the reasons described earlier in the
chapter.
'Malignant' or accelerated hypertension: this refers
to presentation with severe diastolic hypertension
(eg DBP >12O mmHg) with grade 3 or 4 retino-
pathy (haemorrhages and/or exudates (grade 3)
with/without papilloedema). Patients may have /\l<l,
significant proteinuria and non-renal complications
such as encephalopathy or cardiac failure, The con-
dition constitutes a medical emergency, Typical
histological lesions include arterial fibrinoid necro-
sis (which also accounts for the retinal abnormal-
441
Essential Revision Notes for MRCP
ities)coupled with severe tubular and glomerular
ischaemia.
S eco n d ary hypert ens i on
Over 90% of hypertension is idiopathic, approxi-
mately 5% is due to renal disease, 2 %-3 % due to
primary hyperaldosteronism, and <1/0 has either
an alternative rare endocrine or other cause.
Hypert ens i on due to re na l disease
Renal disease accounts for the majority of cases of
secondary hypertension. The pathogenesis involves
stimulation of renin release with activation of the
RAA system, reduced natriuretic capacity (in ad-
vanced CKD), and disorganisation of intrarenal vas-
cular structures. The majority of patients with CKD
are hypertensive, and it is evident in at least 90% of
the dialysis population and over 60% of transplant
patients. lt is the chief contributor to the LVH and
associated high cardiovascular mortality of these
patients.
0 Most forms of renal disease are complicated by
hypertension, but exceptions are some patients
with chronic pyelonephritis who have salt
wasting (typically with normal blood pressure
although some can develop postural
hypotension)
0
Although ARVD is invariably associated with
hypertension it may only be pathogenetically
significant in the minority
0 Coarctation of the aorta: hypertension is seen
in the upper limbs only. Rib-notching may be
seen on X-ray
0 Endocrine: Cushing syndrome,
phaeochromocytoma, acromegaly and apparent
mineralocorticoid excess ( s e e Section 15.3.4
Hypokalaemia) are all rare causes. It is now
believed that primary hyperaldosteronism
(associated with bilateral or unilateral adrenal
hyperplasia) may account for about 3% of all
hypertension (see Chapter l, Cardiology and
Chapter 4, Endocrinology)
Other secondary hypertension: alcohol, obesity
442
15.12.7 Myeloma an d t h e kidney
Myeloma occurs with an incidence of 3 0 -4 0 cases/
million, and at a median age of 70-80 years. Renal
involvement may present with AKI, CKD and/or
proleinuria. Note that Bence jone s proteinuria is not
detected by standard urinary dipsticks.
Renal failure d u e to m yelom a
AKI: some degree of renal impairment is observed
in 50% of patients with myeloma; this is reversible
in the majority [in those where it is secondary to
hypercalcaemia, hypovolaemia, infection or ne-
phrotoxic drugs), but 10% of patients may need
dialysis. The latter cases are usually due to light-
chain or 'cast' nephropathy.
CKD: due to amyloidosis, and cast
nephropathy
associated with chronic interstitial nephritis.
Cast nephropathy
ln this, free kappa (the most nephrotoxic) and lamb-
da light chains excreted in the urine damage the
tubules by direct nephroto><icity and by cast forma-
tion. The intratubular casts are composed of hard,
needle-shaped crystals and excite an interstitial in-
filtrate, often with multinucleate giant cells, ATN
and tubular atrophy occur, and hence the potential
for some recovery from an AKI episode.
0 Patients with light-chain-only myeloma are more
likely to have renal involvement
0 Cast nephropathy may also be seen in patients
with MGUS [see below)
Treatment is with rehydration and supportive ther-
apy. Hypercalcaemia should be treated with IV bi-
sphosphonates. AKI may improve with plasma
exchange - a clinical trial is currently ongoing.
The myeloma should be treated with conventional
regimes (eg dexamethasone, melphalan and thalido-
mide if the prognosis is >6 months; in younger
patients, and those with lower tumour bulk and
complications, VAD regimes are used, and patients
may be considered for autologous stem cell trans-
plantation).
Prognosis: renal recovery is only seen in about
15/a~20% of patients with cast nephropathy who

require dialysis. The remainder need RRT - the
prevalence of myeloma patients on dialysis pro-
grammes is about 2%. Renal transplantation is not
appropriate. Patients with myeloma and ESRD have
poor survival ( < 5 0 % at 1 year). Those with the
greatest tumour mass have the worst prognosis.
B eni gn monoclonal ga mmopa thy (MGUS)
(See also Chapter 9, Haematology.) This may be
associated with light-chain nephropathy, interstitial
nephritis, amyloid and also mesangiocapillary glo-
merulonephritis, A proportion of patients with
MGUS will develop myeloma during long-term fol-
low-up.
15.12.8 Renal vasculitis
The kidney is often involved in systemic vasculitic
illness. Several disorders are recognised (see also
Chapter 20, Rheumatology),
Small-vessel pauci -i m m une vasculitis
These conditions affect small vessels (arterioles and
veins) and are associated with glomerulonephritis,
and pulmonary and skin vasculitis. They are usually
associated with +ve serum ANCA. Incidence is 1 0 -
20 cases/million each year. The major conditions
are defined as:
0 Wegeners granulomatosisz respiratory tract
disease is characteristic and this involves
necrotising granulomata within the upper
respiratory tract (leading to sinusitis and nasal
discharge, as well as damage to the nasal
septum) and lungs (with haemoptysis). About
70% of patients are CANCA +ve, and 25%
pANC/\ +ve
0
Churg-Strauss syndrome: vasculitis that is
associated with asthma, eosinophilia and
necrotising inflammation; 60% have +ve
pANCA; 30% are ANCA -v e
0
Microscopic polyangiitis (MPA): vasculitis
occurring in the absence of evidence for the
above two conditions (ie no asthma,
eosinophilia or necrotising granulomatous
Nephrology
inflammation); 50% are pANCA +ve, and 40%
CANCA +ve
ln all conditions, AKI is the usual renal presentation;
renal histology shows necrotising glomerulitis typi-
cally associated with focal proliferative and/or cres-
centic glomerulonephritis (see 'Treatment of RPGN
and crescentic nephritis in Section 15.6.2). Pul-
monary involvement is common, lout blood pressure
may be normal. Various forms of vasculitic skin rash
(ranging from purpura to skin necrosis) are seen.
Treatment; all of the above three conditions nor-
mally merit high-dose immunosuppressive therapy;
typical regimes are described in 'Treatment of
RPCN and crescentic nephritis' in Section 15.6.2.
Patients with CANCA +ve disease are more likely to
relapse after the cessation of maintenance therapy.
In such cases, immunosuppression is continued for
several further years.
Prognosis: 1-year renal and patient survival is
>80%. Poorer renal prognosis is seen in patients
with highest creatinine and/or oligo-anuria at pre-
sentation. Mortality is increased in patients with
pulmonary haemorrhage, The risk of vasculitic re-
lapse in transplanted patients is 20%.
P olyarteritis nodosa (PAN)
PAN is a rare, medium-sized arterial vasculitis
which results in microaneurysm formation; hyper-
tension is usually severe, and renal infarcts rather
than glomerulonephritis are characteristic. Patients
are usually ANCA - v e (unless there is also small-
vessel involvement, ie PAN-MPA overlap - these
patients can develop glomerulonephritis). Pulmon-
ary (infiltrates and haemorrhage), Cl tract (infarcts),
neurological (mononeuritis multiplex) and systemic
features (myalgia, PUO) are recognised, but the
condition is notoriously difficult to confirm. A few
cases are associated with hepatitis B infection.
Treatment is as for small-vessel vasculitis/crescentic
nephritis.
Other vasculitides t ha t c a n affect t h e ki dney
0
nephritis: in addition to the
H e noc h- S c hijnle in
typical systemic features of this condition, some
'
443
Essential Revision Notes for MRCP

patients develop renal disease as a result of 15. 13. ] Renal elimination of d r u g s

small-vessel (typically post-capillary venulitis
with IgA deposition) vasculitis. Glomerular
lesions range from mild mesangial
hypercellularity (similar to idiopathic lgA
nephropathy) through to crescentic nephritis
0 Kawasaki disease: acute febrile illness, usually
in children, associated with a desquamating
erythematous rash and necrotising arteritis in
some patients. lt is the commonest cause of
myocardial infarction in childhood, hut
significant renal disease is uncommon
0
Takayasu arteritis; this can be associated with
RAS and renovascular hypertension
0 Giant-cell arteritis: has been associated with
Drugs may be eliminated via the kidneys by two
main mechanisms:
0
Glomerular filtration: a passive process; such
drugs will be vvatersoluble
0 Active tubular secretion: drugs act as substrates
for secretory processes that are designed to
eliminate endogenous molecules; the tubular
pathways are different for organic anions
(basolateral tubular membrane) and cations
(located on the luminal brush border)
`

rapidly progressive glomerulonephritis (RPGN), ku ~

F4125
but such cases may represent V\/egeners
granulomatosis with temporal anery
0 Anionic drugs
involvement Acetazolamide
Cephalosporins

-~
v Penicillin

1512.9 Sarcoidosis an d t h e kidney Loop diuretics

Thiazide diuretics
Sarcoidosis ( se e Section 15.8.1 interstitial nephritis) Probenecid
can be associated with: Salicylates
0

0
AKI: due to AN. Ninety per cent of patients
have systemic manifestations of sarcoidosis (eg
hepatosplenomegaly, hypercalcaemia)
CKD: associated with Cil\i and hypercalcaemia.
0

--
Cationic drugs
e

~
Amiloride
Cimetidine
Ranitidine
Glomerular disease (membranous or Metformin

proliferative glomerulonephritis) may rarely Morphine
Quinine
occur, and is associated with microscopic
haematuria and significant proteinuria

Treatment: most patients respond promptly to oral 15.132 Dr u g nephrotoxicity

steroids, which can be tapered at 3 - 6 months.
Relapses occur, but are usually steroid-responsive.
Serum ACE may be useful for monitoring disease
activity and predicting likelihood of relapses_
15.13 DRUGS AND THE KIDNEY
AND TOXIC NEPHROPATHY
(See alsoChapter 2, Clinical Pharmacology, Toxi-
cology and Poisoning.)
Drugs can lead to renal damage in a number of
different ways, and examples are given below.
Alterations in re na l bl ood flow
NSAIDS: alteration in prostaglandin metabolism
can lead to a critical reduction in glomerular
perfusion (particularly when there is reduced
renal reserve or CKD). Interstitial nephritis may
also result from NSAIDs
0 ACE inhibitors (and ARBS): AKI or renal
impairment occurring in patients who are

444

critically dependent upon the RAA system
(those with reduced renal perfusion (eg CCF,
loop diuretics, hypovolaemia and severe ARVD)
is well recognised with these agents
0
Ciclosporin A: toxicity can be acute (due to
renal vasoconstriction) or chronic. The latter is a
common cause of transplant dysfunction, and is
associated with arterial damage (intimal
proliferation and hyaline degeneration of the
vascular media), tubular vacuolation and
atrophy and interstitial fibrosis
Direct tubular toxicity
0
Aminoglycosides: disturbance of renal function
is seen in up to a third of patients receiving
arninoglycosides. Five per cent of filtered
gentamicin is actively reabsorbed by proximal
tubular cells, within which the drug is
concentrated; binding to phospholipid results in
disturbed intracellular regulation with inhibition
l of microsomal protein synthesis and, eventually,
ATN
I
Cisplatin: selectively toxic to proximal tubular
cells, by inhibiting nuclear DNA synthesis; ATN
results. The platinum component may not be the
major damaging influence as carboplatin is less
nephrotoxic
U
Amphotericin: this is toxic to distal tubular cells
in a dose-dependent manner; ATN results, and
is accompanied by non-oliguric AKI. Liposomal
formulations minimise the nephrotoxic risk
Nephrology
Glome rulone phritis
0 Gold: although now much less commonly used
in rheumatoid treatment, gold can lead to
proteinuria in about 5% of patients, and this is
not dose-related; proteinuria usually occurs
within 6 months of the start of therapy. On
cessation of the gold, resolution of proteinuria is
seen by 6 months. Gold is found in the
mesangial cells at renal biopsy; it is believed to
induce an immune-complex glomerulonephritis
(usually membranous, but occasionally
minimal-change nephropathy)
0 Penicillaminez risk of membranous
glomerulonephritis is greater than with gold; it is
dose-related, and the onset of proteinuria may
be delayed to I8 months after the start of
treatment
Other ne phrotoxic effects of drugs
Interstitial nephritis and retroperitoneal fibrosis are
covered in earlier sections, and drug-induced SLE
syndromes in Chapter 20, Rheumatology. Lithium is
commonly associated with CKD due to an inter-
stitial fihrosis; this usually stabilises with dose re
duction or drug withdra wa l, Nephrogenic Dl can
also occur.
1513.3 Toxic n ep h ro p ath y
This refers to renal damage resulting from drugs (as
above) or radio-contrast media (see Section 15.4.3)
or environmental toxins (eg heavy metals) and poi-
sons (eg paraquatl.
445
Essential Revision Notes for MRCP

Call see nfei\vlronmen\al'a|'1`d o ccu p at i o n al toxie nephropathy

.
Heavy metals
Mercury
AKI, proteinuria and nephrotic syndrome (minimal-change or membranous nephropathy)
Lead
Acute poisoning leads to Al<l with ATN; chronic interstitial nephritis and Fanconi syndrome

-are seen with chronic exposure

Cadmium
Similar renal pathology and clinical presentation as for lead
Arsenic
Acute poisoning causes AKI with ATN and cortical necrosis; interstitial fibrosis leads to CKD
with chronic exposure
~ Bismuth
Proteinuria, Fanconi syndrome and AKI have been described
Hydrocarbons and organic solvents
Carbon tetrachloride
1 AKl
Ethylene glycol
~ This is rapidly metabolised to oxalic acid, which crysiallises within the renal tubules; ATN

- results
Petroleum-based
hydrocarbons
These can predispose to glomerulonephritis (eg Coodpasture syndrome or membranous
glomerulonephritis)

Paraquat
~ AKI, usually lethal due to irremediahle pulmonary disease

-
Plant and animal toxins
Snake, spider and hornet venoms

- Directly nephrotoxic, or induce ATN, conical necrosis [often associated with DIC), or muscle
necrosis and rhabdomyolysis
Bee sting

. Rare cause of
nephrotic syndrome

- Mushroom poisoning
AKl
Poison ivy or oak
Rare causes of nephrotic syndrome

4 46
 C h a p t e r 16
Neurology

CONTENTS

16.1 Cerebral cort ex 16.5 S p in al c ord di sorders

16.1.1 Cortical localisation 16.5.1 Neuroanatomy
16.1.2 Dementia 16.5.2 Brown-Squard syndrome
16.1.3 Multiple sclerosis IMS) 16.5.3 Motor neurone disease
16.1.4 Epilepsy 16.5.4 Absent knee ierks and extensor
planters
16.2 Movement di sorders
16.2.1 Tremors, myoclonus, dystonia 16.6 Vascular disorders, cerebral
and chorea tumours an d ot he r CNS
16.2.2 Parkinsonism
16.2.3 Huntingtons disease
p ath o lo g ies
16.6.1 Transient ischaemic attacks
(Huntingtons choreal 16.6.2 Stroke
16.2.4 Wilsons disease 16.6.3 Subarachnoid haemorrhage
16.6.4 Headache
16.3 Neuro-opht hal mol ogy 16.6.5 Benign intracranial
16.3.1 Visual fields hypertension (BIH)
16.3.2 Pupils 16.6.6 Wernickes encephalopathy
16.3.3 The oculomotor system and its 16.6.7 Cerebral tumours
disorders
16.3.4 Nystagmus 16.7 CNS infections
16.3.5 Cavernous sinus syndrome 16.7.1 Encephalitis
16.7.2 Lyme disease
16.4 Other brainstem an d cranial
n er v e disorders 16.8 P eripheral n e r v e lesions
16.4.1 Facial nerve 16.8.1 Mononeuropathies
16.4.2 Trigeminal neuralgia 16.8.2 Polyneuropathies
16.4.3 Vestibulocochlear nerve
16.4.4 Lateral medullary syndrome 16.9 Di sorders of m usc le a n d
16.4.5 Other causes of cranial nerve neuromuscular j u n c t i o n
palsies 16.9.1 Myopathies
16.9.2 Neuromuscularjunction

447
Essential Revision Notes for MRCP

16.10 Inve stiga tions us e d in

neurological disease
16.10.1 Cerebrospinal fluid
16. 102 Neuroradiology
16.1O.3 Electrophysiologicai
investigations

48
 Neurology

Neurology

16.1 CEREBRAL CORTEX In general, primary sensory cortices receive input

from subcortical structures. Signals reach the soma-
16.1.1 C o r tical localisation tosensory cortex via the posterior limb of the inter-
The conical surface is divided into frontal, parietal, nal capsule (the anterior limb carries descending
motor output in the form of the corticospinal tra c ts).
temporal and occipital lobes (Figure 16,1). Primary
motor and sensory cortices are located as follows, Auditory signals reach the temporal cortex via the
medial geniculate nucleus of the thalamus. Visual
signals reach the calcarine sulcus (Vi) from the
0 Motor lateral geniculate nucleus (the geniculostriate path-
~ Precentral gyrus (frontal lobe) way) although some also reach the visual cortex via
0
Auditory the superior colliculus (the retinotectal pathway).
~ Superior temporal lobe
(Heschl's gyrus) After processing in primary sensory areas/ cortico-
0 cortical connections carry signals into secondary
Olfactory

-
Frontal lobe lorbitofrontal cortex) association cortices. The pattern of connections of
0 the visual cortex is best understood in the following
Somatosensory
0
- Postcentral gyrus
Visual
Occipital cortex (calcarine sulcus)
way. From primary visual cortex (Vi), parallel path-
ways carry signals to different cortical areas that
carry out different types of processing (eg for colour
or for motion). These areas are broadly
organised
Figure 16.1 Lateral surface of the human brain

Central sulcus (Rolandlc) Postcentral sulous

Precentral sulcus

Frontal
cortex
` Parietal cortex

Oocipital cortex

Cerebellum

Orbital gyri

Lateral fissure (Sylvian) rclulla oblongata

449
Essential Revision Notes for MRCP
into two streams: a dorsal 'where' stream, passing
into the parietal cortex and concerned with the
location of objects in the environment, and a ventral
'what' stream passing into the temporal cortex and
concerned with object identity. Damage to the
dorsal stream can cause disorders of object localisa-
tion such as visual neglect; damage to the ventral
stream leads to difficulties with identifying objects,
such as agnosia.
A distributed network of cortical areas in the domi-
nant hemisphere (usually the left in right-handed
individuals; equally likely to be left or right hemi-
sphere in left-handers) subserves language function.
Two areas are especially important:
0 Brocas area: in the dominant frontal lobe,
which is concerned with speech output
0 Wernickes area: in the dominant posterior
superior temporal gyrus, which is concerned
with word comprehension
Frontal lobe lesions may cause:
0 Anosmia
0 Abnormal affective reactions
0 Difficulties with planning tasks or those
requiring motivation
I Primitive release reflexes (eg grasp, pout,
rooting)
0 Broca's aphasia (/telegraphic' output aphasia)
I Perseveration
0
Personality change (apathetic versus
disinhibited)
Parietal lobe lesions tend to cause disorders of
spatial representation or apraxias (disorders of
learned movement unrelated to muscular weak-
ness), such as those described below, Parietal lobe
lesions may also cause visual field defects, usually a
homonymous inferior quadrantanopia, as the upper
loop of the optic radiation (see Section 16.3 on
neuro-ophthalmology) runs through the parietal
lobe.
Parietal lobe lesions may cause:
0
Visuospatial neglect or extinction (both usually
associated with right parietal lobe lesions)
450
0
Astereognosis (failure to recognise common
objects by feeling them)
* Gerstmann syndrome (dominant parietal)
consisting of alexia (inability to read), agraphia
(inability to write), right/left confusion and finger
agnosia (inability to identify fingers by name)
0
Apraxia (dominant)
0 Acalculia (inability to perform mental
arithmetic; dominant)
Agraphia (dominant)
Dressing apraxia (dominant)
Constructional apraxia (nun-dominant)
Anosognosia (denial of illness; non-dominant)
Occipital lesions may cause:
Cortical blindness
Homonymous hemianopia
Quadrantanopia
Visual agnosia (inability to comprehend the
meaning of objects despite intact primary visual
perception)
Specific visual processing defects, eg
akinetopsia (impaired perception of visual
motion), achromatopsia (impaired perception of
colour)
Temporal lobe lesions may cause:
Wernicke's aphasia
Impaired musical perception
Auditory agnosia
Memory impairment (eg bilateral hippocampal
pathology)
C Cortical deafness (bilateral lesions of auditory
c orte x)
0 Emotional disturbance with damage to limbic
cortex
Temporal lobe lesions may also cause visual field
defects, usually a homonymous superior quadranta-
nopia, as the lower loop of the optic radiation (see
Section 16.3 on neuro-ophthalmology) runs through
the temporal lobe.

16.1.2 Demen tia
Dementia is an acquired, progressive loss of cogni-
tive function associated with an abnormal brain
condition. It is not a feature of normal ageing.
Other disorders may masquerade as dementia, in-
cluding depression, post-ictal states, acute confu-
sional states (including druginduced) and psychotic
illnesses of old age.
By far the commonest cause of dementia in adults is
A|zheimer's disease. Other important dementias in-
clude:
0 Dementia with Lewy bodies
0 Vascular dementia
U
Frontotemporal dementia (Picl<s disease)
Rarer causes of dementia include:
Creutzfeldt-jacob disease
Progressive supranuclear palsy
AIDS-associated dementia
Huntington's disease
Traatable causes of cognitive
i mp ai r men t (which can m as q u erad e as
dementia)
intracranial tumour
Normalpressure hydrocephalus
Thiamine (vitamin B() deficiency
Vitamin B12 deficiency
Hypothyroidism
Acute confusional state
Depression
Chronic drug intoxication
Dementia normally presents in primary care, and
NICE guidelines suggest that a dementia screen
should be carried out at initial presentation. This
would include:
0
Biochemistry tests (including electrolytes,
calcium, glucose, and renal and liver function)
0
Thyroid function tests
I Serum vitamin B1; and folate levels
Neurology
In making the diagnosis, structural imaging
(using
magnetic resonance imaging (MRD) and clinical
cognitive assessment (including formal neuropsych-
ological testing in cases of mild or questionable
dementia) is required.
Alzheimerk dise a se
The earliest symptom of Alzheimers disease (AD) is
typically forgetfulness for newly acquired informa-
tion. The disease progresses to disorientation, pro-
gressive cognitive decline with multiple cognitive
impairments and disintegration of personality.
The neuropathology consists of:
Macroscopic: the brain is atrophied with
enlarged ventricles. Hippocampal atrophy is
particularly prominent and can be one of the
first signs of AD
0
Microscopic: there is neuronal loss throughout
the cortex and two distinctive pathological
features: plaques (which contain a core of |3-
amyloid) and neurofibrillary tangles (which
contain hyperphosphorylated tau protein).
Tangles and plaques occur throughout the
cortex in overlapping but separate distributions.
The density of tangles can correlate with
dementia severity
0 Neurotransmitter changes: there is a loss of
cholinergic neurones and a loss of choline
acetyltransferase activity throughout the cortex,
although other neurotransmitter systems are also
affected
Genetic abnormalities associated with
Alzheimer's disease
Fewer than 5% of AD cases are familial (typically
autosomal dominant) and three main mumtions are
described. A point mutation to the presenilinl gene
(chromosome 14) accounts for up to 50% of familial
AD. Less common are mutations to the [3-amyloid
precursor protein (APP) gene (chromosome 21) or
the presenilin-2 gene ( c hr om osom e T).
0 Down syndrome (trisomy 21) is associated with
mental retardation and the formation of senile
plaques and neurofibrillary tangles in the same
brain regions commonly affected by AD.
451
Essential Revision Notes for MRCP
Clinically, people with Down syndrome develop
progressive cognitive impairment from their fifth
or sixth decade. The gene coding for amyloid
precursor protein is located on chromosome 21
and it is thought that there is overproduction of
[5-amyloid in these individuals
0
Apolipoprotein E (Apoli) is a protein synthesised
in the liver that serves as a cholesterol
transporter. There are three major forms of ApoE
that are specified by different alleles of the ApoE
gene on chromosome 19 (T12, r]3, 114). The 114
allele has a greatly increased frequency (around
50%) in patients with AD. The effect of this
allele is to decrease the age of onset of AD.
After the effect ofage, ApoE4 is the most
significant risk factor for AD
Pharmacological treatment of A|zheimers dis-
ease
ln recent years pharmacological agents have be-
come available for the treatment of AD, In the UK,
NICE guidelines (http://vvww.nice.org.ul</Cuidance/
CG42) recommend the use of three acetylcholines-
terase inhibitors (donepezil, galantamine and rivas-
tigmine) in mild to moderate AD (Mini Mennal State
Examination (MMSE) score of between 10 and 20].
Treatment must be initiated by a dementia
specialist
0 Review should occur every 6 months, and this
should include an MMSE score
0 Treatment should be discontinued if MMSE
drops below 10. (It is recognised in NICE
guidelines that the MMSE score should not be
relied upon in all circumstances (for example,
where significant functional impairment is
present despite moderately preserved MMSE)
and so some professional discretion is allowed)
F ront ot em poral de me ntia (Picks disease)
Frontotemporal lobar degeneration (also known as
Picks disease) is a progressive dementia that is asso-
ciated with focal atrophy ofthe frontal and temporal
lobes. The disorder has histopathology that is distinct
452
from that of AD, but quite heterogeneous. ln a
minority of patients with frontotemporal lobar degen-
eration, Pick bodies are seen within the cellular
cytoplasm on light microscopy. Clinically, patients
present with progressive language disturbance, often
affecting output rather than comprehension, and be-
havioural changes. Frontal lobe features are
prominent. Clinical variants include frontotemporal
dementia, semantic dementia and progressive non-
fluent aphasia.
Recently, advances in molecular genetics and im-
munohistochemistry have suggested that the micro-
tubular protein tau plays a central role in the
pathophysiology of frontotemporal lobar degenera-
tion. This suggests the possibility of common pathol-
ogies (or tauopathies) with other neurodegenerative
diseases, including corticobasal degeneration and
progressive supranuclear palsy,
Creutzfeldt-Jakob disease
Creutzfeldt-lakob disease (CID) is clinically charac-
terised by:
Rapidly progressive dementia
0
Myoclonus
0
Young age of onset
Cerebrospinal fluid (CSF) examination is usually
normal, though CSF protein may be mildly elevated.
There is a characteristic EEG with biphasic high-
amplitude sharp waves.
The most common cause is sporadic, but there are
familial forms. A new-variant CID (nvClD) is recog-
nised with a neurobehavioural presentation (often
depression) in people aged under 40; this form is
associated with interspecies transmission of the bo-
vine spongiform encephalopathy (BSE) Hg9\'1l~
Invasive brain biopsy is currently the only definitive
way of diagnosing C)D antemortem, though serolo-
gical tests show some promise. The disease is
rapidly progressive and most patients die within a
year of diagnosis.
CID is a prion disease.

'
1, it
I Prion protein is a normal product of a gene
found in many organisms
0 It is membrane-bound
0 An abnormal isoform accumulates in the
spongiform encephalopathies, and this
abnormal isoform is thought to be the
infectious agent
0 The infectious agent is resistant to heat,
irradiation and autoclaving
See also Chapter 9, Haematology (transfusion-
transmitted infection) and Chapter 14, Molecular
Medicine, which contain further discussion of prion
diseases.
Norrna l-pre ssure h y d ro cep h al u s
This should be considered in the differential diag-
nosis of dementia and consists of the triad of
dementia, gait abnormality and urinary inconti-
nence. Urinary symptoms are initially of urgency
and frequency, and progress to frontal lobe incon-
tinence (patients indifferent to their incontinence).
Gait and posture may mimic Parkinsons disease.
The syndrome appears to be due to a defect in
absorption of CSF due to thickening of the basal
meninges, or in the cortical channels over the con-
vexity and near to the arachnoid villi. The aetiology
may be secondary to meningitis, head injury or
subarachnoid haemorrhage. The ventricles are di-
lated and radiologically hydrocephalus is found, but
the pressure is only intermittently high.
Headaches are not usually a complaint and papil-
loedema is not found. Treatment with a ventriculo-
peritoneal shunt may improve symptomatology,
16.1.3 Multiple sclerosis (MS)
Clinical p res en t at i o n of MS
Multiple sclerosis (MS) is thought to be a cell-
mediated autoimmune disease associated with im-
mu n e activity directed against central nervous
system (CNS) antigens, principally myelin, Clinical
/\/euro/ogy
.
consensus identifies four different subtypes of MS,
which may reflect dinerent immunological sub-
I)/|3851
0
Relapsing-remitting disease is the most common
form of MS (8 0 % -8 5 % of patients). Short-lasting
acute attacks ( 4 - 8 weeks) are followed by
remission and a steady baseline state between
relapses. The average number of relapses is
around 0.8/year
Secondary progressive disease: about 3 0 % -
50% of patients with relapsing/remitting disease
will subsequently show progressive deterioration
with relapses becoming less prominent within
about 10 years of MS disease onset
0
Primary progressive disease: 10%-15% of
patients show progressive deterioration from
onset without any superimposed relapses. Age
of onset is typically later than for relapsing/
remitting disease
0
Progressive-relapsing disease: a small number of
patients with primary progressive disease also
experience superimposed relapses associated
with gradual disease progression
Good prognostic factors are:
0
Relapsing-remitting course
0 Female sex
0
Early age at onset
I Presence of sensory symptoms
The aetiology of MS is still unclear but there is
undoubtedly a genetic component, with an in-
creased relative risk (2O"/0-4O%) in siblings com-
pared to the general population. However, as the
concordance rate in monozygotic twins is only
25%, there appears to be a substantial environmen-
tal component as well,
Optic neuritis is a common presentation of MS;
Isolated optic neuritis: 40%-60% chance of
subsequent MS
0 A cause of painful visual loss
I Treat with methylprednisolone
0 Colour vision is affected early and residual
abnormality may persist after recovery
'
453
Essential Revision Notes for A/(RCP
Di agnosi s of M5
This typically requires the demonstration of brain or
spinal cord lesions that are disseminated in time
and anatomical location. A definitive diagnosis,
therefore, is hard to make at the time of the first
neurological episode, although if MRI reveals typi-
cal lesions this is highly suggestive. Supportive
investigations may include:
I
T2-weighted MRI showing demyelinating
plaques. The presence of gadolinium enhancing
lesions is the most predictive MRI parameter,
although these are not always present
0
Delayed visual-evoked response potentials
(VEPS)
I
Oligoclonal bands in the CSF (but not the serum
- see below)
Diagnosis of primary progressive disease is often
hardest, as clear evidence for lesions disseminated
in time and (anatomical) space is often obscured by
the progressive course of the disease, Brain MRI
may be normal in this form of MS, although multi-
ple lesions may be visible in the spinal cord,
Oligoclonal bands in the CSF
Oligoclonal bands in the CSF indicate intrathecal
immunoglobulin synthesis. These are not specific to
MS and other causes include neurosarcoidosis, CNS
lymphoma, systemic lupus erythematosus (SLE),
neurosyphilis, subarachnoid haemorrhage (rare),
subacute sclerosing panencephalitis (SSPE) - a rare,
late complication of measles - and Guillain-Barr
syndrome.
Treatments available for MS
Significant advances have been made in the treat-
ment of MS in recent years, principally in the use of
interferon preparations for relapsing-rernitting MS.
In the UK, treatment consensus guidelines have
been prepared by NICE (http://www.nice.org_uk/
Guidance/CCB) and by the Association of British
Neurologists (http://www.theabn.org/downloads/
patients). These antibodies are associated with a
ABN-Ms-ouideimes-2oo7.pd0.
Steroids
NICE guidelines suggest that individuals suffering an
acute relapse should be treated with methylpredni-
454
solone, either orally ( 500 mg to 2 g daily) or intra-
venously ( 5 0 0 mg to I g daily) for 3 -5 days.
Steroids have no effect on the incidence of relapses,
and are not useful other than for treatment of acute
attacks.
[5-lnterieron a nd gl at i ram er acetate
Clinical trial results guide recommendations for
therapy, which should be offered to patients (aged
18 years or older), who are amhulant and have no
contraindications to therapy, in the following clin-
ical situations:
I. Patients with a clinically isolated syndrome (one
episode) and an abnormal MRI typical of MS
should be offered B-interferon (reduces relapses
by about one-third over 2 years) ifthey are
within 1 year of presentation
2. Patients with relapsing-remitting MS and active
disease (two or more relapses in the last 2 years,
or one disabling relapse, or MRI with new
lesions in the last year) should be offered [5-
inlerferon or glatiramer acetate (reduces the
relapse rate by one-third in relapsing-remitting
MS)
In patients with relapsing secondary progressive
MS, treatment (glatiramer acetate, and [3-interferon
reduce relapses) should only be considered when
relapses are the dominant cause of the increasing
disability. Treatment for primary progressive MS is
not recommended.
Decisions on discontinuation of treatment are gen-
erally made clinically, on the basis of:
0
Increasing severity of relapses
0 Lack of relapse reduction on treatment
compared to pre-treatment
I The development of non-relapsing secondary
progressive MS with loss of ability to walk
Neutralising antibodies can develop to both interfer-
on IFNB-ib ( 40% of patients) and IFNB-ia ( 20% of
reduction in the drug effects on relapse rate and
also MRI lesions; in some patients the antibodies
disappear subsequently, but in others they persist, It
is unclear whether neutralising antibodies influence
the progression of disability' in any way.

These treatments modify disease and may reduce
the development of disability through preventing
relapses, although any effect has, to date, been
modest. They do not affect progression of disability
that is unrelated to relapse,
Ot he r immunomodula tory ag en t s for MS
treatment
Copolymer 1 (glatiramer acetate) and IV
immunoglobulin therapy both significantly
reduce the frequency of attacks of relapsing-
remitting MS
0 Oral low-dose methotrexate therapy also slows
clown the progression of disability in secondary
progressive MS(and possibly in primary
progressive MS)
I A number of other treatments, eg mitoxantrone
and natalizumab, are under study
16.1.4 E pile psy
An epileptic seizure is a paroxysmal discharge of
neurones sufficient to cause clinically detectable
events apparent either to the subject or an observer_
Epilepsy is a disorder where more than one such
seizure ( not including febrile seizures) has occurred.
The prevalence of epilepsy is relatively constant at
different ages and is around 0.7%, whereas the
incidence follows a U-shaped curve with the high-
est incidence inthe young and elderly.
A ~
0
-
Generalised seizures
Tonic-clonic
~ Absences (3l-lz spike-and-wave activity
in ictal EEG)
Partial seizures secondarily generalised
0 Partial seizures
Simple partial seizures
~ Complex partial seizures
I Others
eg myoclonic or atonic
l
Neurology
0 A typical tonic-clonic seizure begins without
warning. After loss of consciousness and a short
tonic phase, the patient falls to the ground with
generalised clonic movements. There may be
incontinence and there is post-ictal confusion
0
Simple partial seizures may affect any area of
the brain, but consciousness is not impaired and
the ictal EEG shows a local discharge starting
over the corresponding cortical area. Any
simple seizure may progress (for example, motor
seizures may show a lacksonian march) and
become secondarily generalised with a
supen/ening tonic-clonic seizure
0 Consciousness is impaired by complex partial
seizures that typically have a medial temporal
(often hippocampal) focus An aura ( se nse of
deja vu, strong smell or rising sensation in the
abdomen) may precede the seizure, followed by
loss of consciousness. There may be
automatisms (repetitive stereotyped semi-
purposeful movements]
Imaging is usually carried out in most if not all
patients with seizures; focal seizures usually imply a
focal pathology and imaging is mandatory in such
circumstances.
Anticonvulsant agents are discussed in Chapter 2,
Clinical Pharmacology, Toxicology and Poisoning.
Treatment of epilepsy
Patients presenting with a first seizure have an over
all risk of recurrence of about 3 5 % at 2 years. Most
neurologists do not therefore advocate routine treat
ment for a first se iz ur e , However, some groups have
a higher recurrence risk (eg 65% at 2 years for
patients with a remote neurological insult and an
EEG with epileptiform features) and in these sub-
groups treatment may be considered.
0 After the second or subsequent seizures, drug
treatment is routinely advised as the recurrence
risk is much higher
Carbamazepine and sodium valproate are
widely accepted as drugs of first choice for
partial and generalised seizures, respectively
455
Essential Revision /\/otes for MRCP
Note that 40% of patients with epilepsy will be
w o men of child-bearing age. As valproate is
associated with a higher incidence of neural
tube defects than other agents, the choice of
monotherapy may need to be reviewed (see
Chapter 2, Clinical Pharmacology, Toxicology
and Poisoning)
Any anti-epileptic should be introduced at a low
dose and the clinician must be vigilant for idiosyn-
cratic reactions. The dosage can then be escalated
until either control is achieved or the maximum
allowed dose is reached, lf control is not achieved
with monotherapy, then at least one additional trial
of monotherapy is recommended before combina-
tion therapy ls considered.
Epilepsy a nd driving
Current regulations are such that following a first
seizure (whether diagnosed as epilepsy or not),
driving is not permitted for 1 year with a medical
review before restarting driving. Loss of conscious-
ness in which investigations have not revealed a
cause is treated in the same way as for a solitary fit.
Patients with epilepsy may be allowed to drive if
they have been free from any epileptic attack for
1 year, or if they had an epileptic attack whilst
asleep more than 3 years ago and attacks subse-
quently only when asleep.
To obtain a vocational (HCV, e tc ) driving licence
patients should have been free of epileptic attacks
AND off all anti-epileptic medication AND free
from a continuing liability to epileptic seizures (eg
structural intracranial lesion) for i t ) years.
Epilepsy a nd p r e g n a n c y
Seizure rate in pregnancy is predicted by seizure
rate prior to pregnancy. All epileptic drugs have
teratogenic effects including:
Cleft-lip/palate
Congenital heart defects
Urogenital defects
Neural tube defects (especially valproate)
456
Teratogenic effects are more likely if more than one
drug is used. Nevertheless, anti-epileptic drugs are
not contraindicated in pregnancy, as the effects of
uncontrolled epilepsy may be more risky.
There is no increase in infant mortality for epileptic
mothers. Folic acid supplementation decreases the
incidence of malformations.
16.2 MOVEMENT DISORDERS
16.2.1 Tremors, myoclonus, dys tonia
an d chorea
Essential tremor is a postural tremor of the hands in
the absence of any identifiable cause such as drugs.
0 Autosomal dominant with incomplete
penetrance ( 35% will have no family history)
0
Propranolol is the most effective medication
0 Stress will worsen the tremor
0 Alcohol will improve the tremor
Resting tremor is seen when the limbs are comple-
tely supported and relaxed, and is typical of Parkin-
sonism |'pi|l-rolling').
An action tremor is typically caused by an ipsilat-
eral cerebellar hemisphere lesion. Myoclonus is
characterised by the occurrence of sudden involun-
tary jerks i'fragmentary epilepsy').
0
Physiological (normal) hypnic jerks whilst
falling asleep
Drug-induced (eg amitriptyline)
Alzheimers disease
juvenile myoclonic epilepsy
Inherited as part of other myoclonic
epilepsies (eg Lennox-Castaut syndrome)
I Metabolic (liver or renal failure)
0 Creutzfeldt-lakob disease
0
Following anoxic cerebral injury (eg cardiac
arrest)
0 As part of a progressive myoclonic
encephalopathy (eg Gauchers disease)

Dystonia is characterised by prolonged spasms of
muscle contraction; focal dystonias include spasmo-
dic torticollis, writers cramp and lolepharospasm.
Myntonic dystrophy is discussed in Section 16.9.1.
Chorea is a continuous flow of small, jerky move-
ments from limb to limb.
L3., y
g
;_l/}./,-Ml. . .
Huntingtons disease
Rheumatic (Sydenhams) Chorea
SLE
Polycythaemia rubra vera
Neuroacanthocytosis
Thyrotoxicosis
Drug-induced (eg oral contraceptives,
phenytoin, neuroleptics)
0 Chorea gravidarum (during pregnancy)
Athetosis is a slow sinuous movement of the limbs,
and is often seen after severe perinatal brain injury.
In the past, athetosis was also used to describe
movements that would now be called dystonic.
16.2.2 Parkinsonism
Parkinsonism refers to a triad of symptoms:
0
Resting tremor
0 Bradykinesia
0
Rigidity
This pattern of symptoms comprises an akinetic-
rigid syndrome.
1.. tt. _ -= .1
idiopathic Parl<insons disease
Drug~induced parkinsonism
Normal-pressure hydrocephalus
Progressive supranuclear palsy (PSP)
Diffuse Lewy body disease
Dementia pugilistica (secondary to boxing
or chronic minor head injury)
0
Postencepl-ialitic parkinsonism
I
Depression with psychomotor retardation
Neurology
0 'Parl<insons plus syndromes
0
Multiple system atrophy (eg Shy-Drager
syndrome, olivopontocerebellar atrophy)
0 lntoxications (eg carbon monoxide, MPTP,
illegal narcotic, manganese)
< ) Y
The diagnosis of idiopathic Parl<inson's disease is
often inaccurate and there is no single diagnostic
test.
Pointers include:
0 An asymmetric onset
0 Persistent asymmetry _
0 Good therapeutic response to levodopa initially
(ove r 90% will improve symptomatically)
Pharmacological treatment of Parkinson's
disease
In the UK, treatment follows NICE guidelines (http://
www.nice.org.uk/CuidancdCG35).
levodopa has been the mainstay of symptomatic
treatment of Parl<insons disease since the 19705.
However, in recent years levodopa has been used
less frequently as a first-line treatment, particularly
for young patients, because of its involvement in the
generation of long-term motor complications (eg
end-of-dose wearing-off effect, unpredictable on/off
switching). Such complications adect 1 0 % of
patients for every year of levodopa treatment.
0 Modified-released levodopa has a similar rate of
long-term motor complications
.tt ~'
Selegiline was commonly added to levodopa in
later disease as initial studies suggest that it
might have neuroprotective effects. However,
this was not confirmed in subsequent trials and
indeed one trial found increased mortality with
selegiline (although this was not confirmed at
follow-up)
U
Anticholinergics (eg benzhexol) are frequently
used for the control of tremor, but they are
probably less efficacious than levodopa in
respect of other motor symptoms (and they have
a worse side-effect profile)
457
Essential Revision Notes for MRCP
More recently, modern dopamine agonists (eg ropi-
nirole, pramipexole, cabergoline and pergolide)
have been introduced. Initial trial results suggest
that monotherapy with these agents may be margin-
ally less efficacious than with levodopa, but these
agents generate fewer long-term motor complica-
tions. Many neurologists would now recommend
that Parkinsons disease is initially treated with such
dopamine agonist monotherapy, particularly for
young patients, with small amounts of levodopa
added as the disease progresses.
However, there is no single drug of choice for
treating early-stage idiopathic Parkinsons disease
and so the choice of drug prescribed must take into
account clinical and lifestyle characteristics plus
patient preference.
Similarly, in later idiopathic Parkinsons disease
there is no single drug of choice. Most patients will
develop motor complications over time and will
require treatment with levodopa. A number of ad-
juvant drugs can be taken alongside modified-
release levodopa preparations, including dopamine
agonists, monoamine oxidase B (MAO-B) inhibitors,
catechol-O-methyltransferase (COMT`i inhibitors (eg
entacapone, tolcapone), amantadine and apomor-
phine injections. The purpose of adjuvant therapy is
to reduce motor complications and improve quality
of life.
S urgi cal treatment of Parkinson`s disease
interventional surgery with deep brain stimulation,
involving placing stereotactic electrodes surgically
in the basal ganglia, has recently become available
as a potential therapeutic option. Either subthalamic
nucleus stimulation or globus pallidus interna stimu-
lation may be considered as a therapeutic option in
late-stage Parkinsons disease in patients with motor
complications refractory to pharmacological treat-
ment, who remain responsive to levodopa and who
have no significant co-morbidities. At present it is
not possible to decide which of these two surgical
458
procedures is preferred, or if one form of surgery is
more effective than the other.
Parkinson's plus syndromes
In the differential dia Snosis of Parkinsonism, two
8rou Ps of Parkinsons Plus 5)fndromes are of Particu-
lar importance: progressive supranuclear palsy and
the multiple system atrophies.
Progressive supranuclear palsy (PSP)
Also known as Steele-Richardson syndrome, this
presents in the seventh decade with parkinsonism,
characteristic ophthalmoplegia and dementia.
The ophthalmoplegia is described in Section 16.3.3.
Other features of PSP may include pseudobulbar
palsy, and dementia late in the course ofthe illness.
Multiple system atrophies
A number of disorders fall into this category, includ-
ing Shy-Drager syndrome and olivopontocerebellar
atrophy. They are clinically characterised by:
0 Parkinsonism
Autonomic failure
0 Cerebellar and pyramidal features
(olivopontocerebellar atrophy; OPCA)
1 6 2 . 3 Htln tin g to lfs disease
(I-luntingtoris chorea)
Huntington"s disease is inherited as an autosomal
dominant disorder that normally begins in the third
or fourth decade and which is clinically charac-
terised bythe triad of:
0 Chorea (which patients can temporarily
suppress)
0
Cognitive decline
0 Positive family history
Other motor symptoms include dysarthria, dyspha-
gia, ataxia, myoclonus and dystonia. Childhood
onset is atypical and may be associated with rigid-
ny.

Genetics of H uutlngtods disease
Autosomal dominant with complete
penetrance
0 There is expansion of the CAG trinucleotide
repeat within this gene (see Chapter 14,
Molecular Medicine)
0 Gene is on chromosome 4 and codes for a
protein, huntingtin
l Genetic testing in asymptomatic individuals
is now available
Neuropathologically the disease causes neuronal
l loss in the cortex and striatum, especially the cau-
date. Treatment is unsatisfactory and relies on neu-
roleptics, which partially relieve chorea through
interfering with dopaminergic transmission.
L.
Other causes of chores
Levodopa-induced chorea in parkinsonism
Antiphospholipid syndrome
Wilsons disease
Sydenhams chorea (autoim m une, preceded
by group A Streptococcus infection)
I
Neuroacanthocytosis
1..
16.2.4 \fVilson's t i i se a se
t This is an autosomal recessive condition. The re-
sponsible gene is ATP7B, located on chromosome
l3. The gene sequence is similar to sections ofthe
L gene ATP7/l, which is defective in Menke's disease
(another disease caused by defects in copper trans-
port). The similar sequences code for copper-bind-
ing regions, part of a P-type ATPase transmembrane
protein. Clinically, the disease is characterised by
abnormal copper deposition in the basal ganglia, as
well as elsewhere in the brain, the eye and in the
liver. This disorder should be considered in any
t,
young person presenting with an extrapyramidal
syndrome. Psychiatric symptoms are particularly
common in adults. (See also Chapter 13, Metabolic
L Diseases and Chapter 6, Gastroenterology).
l
Neurology
?vEtR.G~ff)tH'lH.~\i..`~1f.tif .rr.,~~
This section should be read in conjunction with
Chapter 17, Ophthalmology.
iI=,t.f; tftstsai .>it~
The optic pathways, and the visual defects resulting
from various lesions at different sites are illustrated
in Figure 16.2.
Optic nerve fibres leave the retina, and travel in the
optic nerve to the optic chiasm. Lesions of the retina
and optic nerve produce field defects in the ipsilat-
eral eye alone. Lesions at the optic chiasm typically
produce hitemporal hemianopia. Causes include:
Pituitary tumour (compression from below)
Craniopharyngioma
intracranial aneurysm
Meningioma
Dilated third ventricle
From the optic chiasm fibres run in the optic tract to
the lateral geniculate nucleus (thalamus). Retro-
chiasmal lesions produce homonymous field de-
fects, the degree of congruity increasing with more
posterior lesions. From the lateral geniculate nu-
cleus fibres pass in the optic radiation to the
primary visual cortex, located in the occipital cor-
tex. The fibres from the lower and upper quadrants
of the retina diverge, the upper fibres (lower half of
the visual field) passing though the parietal lobes,
the lower fibres (upper half of the visual fi eld)
through the temporal lobes. Hence:
0
Temporal lobe lesions may cause superior
quadrant homonymous hemianopia
0 Parietal lobe lesions may cause inferior quadrant
homonymous hemianopia
Note that the decussation of fibres at the optic
chiasm means that the right visual field is repre-
sented in the left occipital cortex and vice versa.
Within the calcarine sulcus, there is a
topographic representation of the visual field
with more peripheral regions represented
anteriorly, and more central (foveal) regions
located posteriorly
459
Essential Revision Notes for MRCP

Figure 16.2 Optic pathway abnormalities and associated defects

Visual Flslda
L R

I Central sc o l o ma , ipsilateral lesion due

to opt i c nerve disease, eg optic neuritis

1 \ optic
2 Convwie loss ot ipsilateral lielri, eg
due to optic nerve transeclion
2
3 5 5
\ t_
nerve
optic
chiasni
-
:i Biiemporal nemlanopla chiasmal
lesion, Pituitary craniapriaryngioma

4 ~," _ late ral

geniculate
NUCleus

6 f
optic
radia lions
-
4 Homofvymous superior quadrantariopia
(pl e in the sky) temporal tone iesion
7
7
7

KEY 5. Homnnyrriocs inferior quadrantanopia

-parietal lobe lesion
Vision Area ot
spared vision loss

6, Homonyrnous tiemianopia -les s

congruous rellects more anterior lesion

7 Homonymous nemianopia highly -

-
conquous posterior lesion

0 At the very tip of the occipital lobe, the features are:

representation of the fovea trnacula) is a
vascular watershed, supplied by the posterior
and middle cerebral arteries. Sparing of this area
(foveal sparingl may therefore occur with a
posterior cerebral artery cerebrovascular
accident
Cortic a l blindness
This is usually due to bilateral occipital infarcts and
it results in severe or complete loss of vision, Other
Pupillary responses are preserved
The patient may deny that they have visual loss
(Anton syndrome)
Macular sparing may occur and the patient may
have a tiny island of preserved central field
which will allow some useful reading vision.
However, this central field may be so small as to
be useless for distance vision
16.3.2 Pu p ils
Pupil size depends on both pupillodilator (sym-
pathetic) and pupilloconstrictor (parasympathetic)

460

fibres. Pupilloconstrictor fibres travel from the Edin-
ger-Westphal nucleus in the midbrain to the Orbit
on the third nerve. The path of sympathetic fibres is
described below.
The pupillary light reflex pathway has two parts:
0 Afferent: retina, optic nerve, lateral geniculate
body, midbrain
0 Efferent: Edinger-Westphal nucleus (midbrain)
to third nerve
Affe re nt pupi l l ary defect
This is detected by the 'swinging flashlight' test, If
the amount of light information carried by one eye
ls less than that from the contralateral side when the
light is swung from the normal to the abnormal side,
pupil dilatation is observed. This is also known as a
Marcus Gunn pupil,
An afferent pupillary defect is a sign of asymmetric
disease anterior to the chiasm.
Causes:
0 Retinal disease (eg vascular occlusion,
detachment)
Table 16.1. Causes of Horner syndrome
Anatomical structures
Brainstem or spinal cord
First-order neurone
Pre-ganglionic lesion
Secon dorder neurone: anterior roots (C8-T3), sympathetic
chain
Post-ganglionic lesion
Third-order neurone: stellate ganglion, carotid sympathetic
plexus, fibres to eyelid in branch of lll, fibres to
pupil ciliary sinus lesions, orbital apex disease
l'l! FV!
Neurology
0
Optic nerve disease (eg optic neuritis,
glaucoma) with asymmetric nerve damage
Causes o f a small pupi l (miosis)
Miosis can be caused by:
Senile miosis
Pontine haemorrhage
Horner syndrome: see below
Argyll Robertson pupil: bilateral (may be
asymmetrical) small irregular pupils which do
not react to light but accommodate normally.
They dilate poorly in the dark and in response
to mydriatics. Lesion is in the rostral midbrain
near the Sylvian aqueduct, such that the light
reaction fibres are interfered with, but the more
ventral near fibres are spared
0
Drugs: systemic (opiatesu topical (pilocarpinel
0
Myotonic dystrophy
Horner s yndrom e
Horner syndrome is caused by interruption of
sympathetic pupillomotor fibres (see Table l6_i),
and is one of the causes ofa small pupil (miosis).
Causes
Vascular, trauma, neoplastic demyelination,
syringomyelia, ependymoma
Chest lesion: apical carcinoma, cervical rib,
mediastinal mass
Cervical lesion: lymphadenopathy, trauma,
thyroid neoplasm
Surgical: thyroidectomy, carotid
angiography, endarterectomy
Internal carotid artery dissection, cavernous
in
461
Essential Revision Notes for MRCP

Clinical characteristics of Horner s y n d ro me Disorde rs of co n j u g at e g a z e

0 Miosis: hydroxyamphetamine differentiates Symmetrical and synchronous movements of the
between pre- and post-ganglionic (miosis more two eyes together are known as conjugate eye
evident in dim light 'dilation lag) movements.
0
Enophihalmos; apparent, clue to narrowing of
the palpebral aperture by ptosis and elevation of Causes of oculomotor p al s l es
the lower lid
0 Ptosis: partial - levator palpebrae is 30% Ischaemic infarction of a nen/ e
supplied by sympathetic Intracerebral aneurysm
0 Anhidrosis: whole face means lesion proximal Head trauma
to common carotid artery Neurosarcoidosis
I Vasodilatation
Myasthenia gravis
Tumours at the base ofthe brain (eg glioma,
Congenital Horner syndrome is associated with metastasis, carclnomatous meningitis)
difference in iris colour (heterochromia),
Ophthalmoplegic migraine
Arteritides
Meningitides (eg syphilitic or tuberculousi
Causes of a large pupil (mydriasis) Orbital lymphoma
Mydriasis can be due to: Orbital cellulitis
AdieS (tonic) pupil: idiopathic dilated pupil
`
with poor reaction to light and slow constriction Causes of bilateral ophthalmoplegia
'

to prolonged near effort. Seventy per cent

female, 80% initially unilateral, 4% per year Dysthyroid disease
becoming bilateral. Associated with decreased Myasthenia gravis
deep tendon reflexes (Holmes-Adie syndrome) Myositis
0 Third nerve palsy: see later Midbrain tumour or infarction
G 'll -B '
`
cirome
Yn
C Drugs: systemic (eg antidepressants,
amphetamines); mydriatrics (eg tropicamide, Basal meningiti es (eg tuberculous)
atropine) Wernicke's encephalopathy
0 Trauma: sphincter pupillae rupture
The effects of paresis on diplopia are predicted by
three rules:
16.3.3 The o cu lo mo to r s ys t e m an d 0 Paresis of horizontally acting muscles tends to
i t s disorders cause horizontal diplopia, and vertical paresis
A mnemonic to remember oculomotor innervation leads to vertical diplopia
is: 0 The direction of gaze in which the separation of
the images is maximum is the direction of
|-Rs(504)s action of the paretic muscles

The sixth nerve supplies the lateral rectus, the fourth

I
T'hTrnage seen f e of gaze
(the false image) usually belongs to the paretic
supplies the superior oblique and the third nerve eye, so when covering the palgigqe, this
innervates the others. image will disappear

462
 Neuro/ogy

Third nerve 0 Orbital apex disease, such as tumours,

The third nerve nucleus is a large nucleus located
in the midbrain at the level of the superior coll}u-
lus_ Fibres pass through the red nucleus and the
pyramidal tract in the cerebral peduncle. The nerve
then passes between the posterior cerebral and
superior cerebellar arteries, through the cavernous
sinus and into the orbit via the superior orbital
fissure. The large nuclear size of the third nerve
means that it is rarely entirely damaged by lesions
and complete third nerve palsies tend to be caused
by peripheral lesions. Complete third nerve palsy
CBUSSSI
thyroid disease, orbital cellulitis,
granulomatous disease; often associated
with palsies of cranial n e n / e s lV~Vl and
optic nerve dysfunction
U Trauma
0 Uncal herniation; the third n e n / e travels
anteriorly on the edge ofthe cerebellar
tentorium and may be compressed by the
uncal ortion of the tem oral with
increase intracranial pressure du/e to a
supratentorial cause

0 Ptosis Fourth nerve

0 Eye deviated down (preserved superior oblique)
and out (preserved lateral rectus> The fourth nerve nucleus lies in the midbrain at the
0 All other movements reduced or absent,
level of the inferior colliculus. The fourth nerve has
the longest intracranial course; passing between the
dependent on whether partial or complete
I
Pupil fixed and dilated posterior cerebral and superior cerebellar arteries,
' e s lateral to the third nerve and into the orbit through
Lateral gaze is intact and attempted downward gaze the cavernous sinus and superior orbital fissure. It is
causes intorsion (inwards rotation of the eye); nor-
mal downgaze requires not only superior oblique
but also inferior rectus.
the
a s p e c t of the
brainstem. A fourth n e n / e e s i o n is the commonest
cause of vertical diplo ia. Looking down and in is
The pupil may be normal (pupil-sparing or 'medical'
most diHi cally stairs or
the patient notices
diplopia descending reading.
third) or dilated and t (so-called
'surgical' third), This is because parasympathetic Causes of a fourth nerve pa lsy
pupilloconstrictor fibres run on the surface of the
nerve; these are fed by the pial vessels and are
therefore spared in palsies of vascular aetiology. 0 Vascular (20%)
Diabetes
However, they are affected early by a compressive 0 Vasculitis
lesion rwhen the p u p I Cavernous sinus syndrome
Caitsasoiathirdfnarve p a l q f
0
Congenital (decompensation causes
symptoms) (30%)
0 Trauma (susceptible to contrecoup injury,
0 Posterior communicating artery aneurysm for example whiplash because ofdgrial
(usually but not always painful)
(75%) 0
Qrainstem exit) (30%)
Orbital apex syndrome
0 Arteriosclerotic
0 Cavernous sinus pathology (eg thrombosis,
aneurysm, fistula, pituitary mass). Sixth nerve
Frequently associated with lesions of cranial The sixth nerve nucleus lies in the mid-pons inferior
nerves l\/, V and VI (see Section 1 6 3 .5 )
to the fourth ventricle, and is motor to the lateral

463
Essential Revision Notes for MRCP

rectus. A sixth nerve palsy causes convergence of Ot he r disorders of co n j u g at e g a z e

the eyes in primary position and diplopia maximal
on lateral gaze towards the side of the lesion. The Internuclear ophthalmoplegia is a disorder of hori
affected eye deviates medially due to the unop- zontal eye movement due to a lesion in the medial

_
* _ "
posed a c tion of medial rectus.
_ longitudinal fasciculus which connects the lllrd and
Vlih cranial nerve nuclei in the pons ( se e Figure
16.3) .

Features of internuclear ophtha lmople gia

0
impaired adduction of the eye l to the
*qt* "_VJ.-1 ;,t_.,-"_..:,_iI-3,,-.i.__,,..t._.iaf,-_i_._.::_-,.t-.,_. -, . `, -. t f lesion (complete paralysis - minor slowing)
0 Horizontal nystagmus in the ghd; cfng eye
Vascular contralateral to the lesion
Trauma 0 differentiates it from a
Convergence normal (this
Cavernous sinus syndrome medial rectus lesioni i l l

Orbital apex syndrome

Increased intracranial pressure [false
0
Ve m u s occasionally present
Bilateral internuclear ophthalmoplegia results in de-
localising sign due to stretching ofthe
nerve) fective adduction ibilaterallyi, with nystagmus in the
abducting eye.

Figure 16.3 Pathology of internuclear ophthalmoplegia

l

" Lesion ol left MLF G

6 0

MH = medial rectus
LR = lateral rectus
PPFIF = parapontine reticular formation
MLF = medial longitudinal fasciculus
This causes deficient adduction
dunng attempted conjugate
gaze away irom side of MLF lesion

-464

-.
most common; may be
i ateral in
ygyger adults)
Vascular
Trauma
Occlusion of the basilar artery
L5
Miller-Fisher syndrome
Drug ovegose (barbiu@_tes, phgnytoin or
amitgigtyli ne)
I Wernicke's encephalopathy
Causes of impaired vertical conjugate gaze include
progressive supranuclear palsy, Parinaud syndrome
and thalamic or midbrain pathology,
Progressive supranuclear palsy [Steele-Richardson
syndrome): the ophthalmoplegia is a paresis of
vertical conjugate gaze which is supranuclear;
downgaze cannot be elicited voluntarily but if the
patient is allowed to fixate whilst the head is moved
passively, the eyes have a full range of movements
(dolls head mo v e me n t) . This pattern implies that
while the oculomotor nuclei are intact, in that the
eyes can be driven into eccentric positions within
the orbit, the supranuclear descending control of
voluntary eye movements is impaired.
Parinaud syndrome is also known as the dorsal
midbrain syndrome, with damage to the midbrain
and superior colliculus. lt leads to:
0
Impaired upgaze and accommodation
D Retraction of the eyelids
I Loss of light reflex with presen/ed convergence
reflex
I
Convergence retraction nystagmus
I Relative mydriasis
Possible causes include pineal tumour, stroke or
haemorrhage, hydrocephalus or dernyelinating disf
ease.
Neurology
"
Progressive supranuclear palsy
Parinauds syndrome
Myasthenia gravis
Miller-Fisher syndrome
Thyroid eye disease - mimics upgaze
weakness by causing fibrosis of inferior
recti
16.3.4 Ny stag m u s
Nystagmus is a defect of control of ocular position
that leads to a rhythmic involuntary to~and-fro oscil-
lation of the eyes. There are three types:
0 Pendular: no distinct fast and slow phases, both
being of equal velocity
0 lerkz distinct fast and slow phases; the
amplitude usually increases with gaze towards
the direction of the fast phase
Rotatoryz combination of vertical and horizontal
nystagmus
Causes of congeni t al nys t agm us
0 X-linked or autosomal dominant; usually
horizontal
0
Secondary to poor vision (eg albinism, untreated
congenital cataract, congenital optic atrophy)
Ca use s of acq u i red nys t agm us
0 Vestibular lesions: the lesion may be in the
Vllith nerve, inner ear, brainstem or vestibular
pathway; jerky nystagmus with fast phase away
from the side of the lesion and made worse by
gaze in that direction; typically' improves with
visual fixation
I Cerebellar lesions: fast phase towards the side
of the lesion
D
Drug-induced (eg alcohol, barbiturates,
phenytoin)
465
Essential Revision Notes for MRCP

Downbeat nystagmus (where the fast phase is 0

down) is associated with foramen magnum lesions
(eg Arnold-Chiari malformation, spinocerebellar
degeneration, syringobulbia, platybasiai, whereas
upbeat nystagmus is typically due to intrinsic brain-
stem disease, or, rarely, cerebellar vermis lesions or
organophosphates.
16.3.5 Cavernous s i nus s y n d r o m e
The major structures passing through the cavernous
sinus are the_|LI_rg, Ifh and \/gh cranial nerves, the
ophthalmic division of the Q nerve, the sympa-
thetic carotld plexus and the intracavernous carotid
artery (see Figure 16,4) , Lesions in this region may
therefore produce a total internal and external
ophthalmoplegia. The main causes of cavernous
sinus syndrome are:
0 Trauma
I Vascular: aneurysm of intracavernous carotid
artery or the posterior communicating artery;
cavernous sinus thrombosis; carotico-cavernous
fistula
Neoplasticz primary intracranial tumours, direct
spread from nasopharyngeal tumours or
metastatic
U
Inflammatory: due to infection (eg sinusitis,
tuberculosis, or inflammatory disease such as
Wegeners granulomatosis).
Carotico~cavernous fi stula
This may be either a high' or low-pressure shunt.
0
High pressure, high flow: shunt due to a fistula
between the cavernous sinus and the
intracavernous carotid artery. Usually traumatic
in origin, producing marked proptosis which
may be pulsatile, palsies otthe Illrd, |\/th and
Vlth nerves, an orhital bruit with an injected
chemotic eye and elevated intraocular pressure
secondary to raised episcleral venous pressure
0 Low pressure, low flow: shunt occurs because
of communication between the dural branches
of the internal or external carotid arteries and
the cavernous sinus. This type is more common
in elderly patients, often occurring
spontaneously in arteriosclerotic individuals,
and results in a milder clinical picture

Figure 16.4 Main structures passing through the cavernous sinus

At the level of the At the level of the
pituitary fossa anterior elinnid process
Ophthalmic artery
l f

JQRQ Anterior
Pituitary
tossa _ 31% G,;_,
_ l'"'d

( D H
IV
qw H N

*
y

@5992
l

S he a

W <> \
s

all
vi
vi
isnt?

` Sphenoid `
, si nus
O \ _
if
V2
-
IC Internal carotid artery
ON Optic nerve
Numbers indicate cranial nerves

466
 Neuro/ogy

16.4 OTHER BRAINSTEM AND

CRANIAL NERVE DISORDERS Causesofafxcialnervapalsy i

The brainstem and locations of the principal cranial Brainstem tumour

nerve nuclei are illustrated in Figure 16.5. Neurosarcoidosis
Cerebellopontine angle lesions (eg acoustic
neuroma)
Cholesteatoma
F 16.4.1 Facial nerve
Lyme disease
The facial nerve has the following functions: Stroke
0 Motor to the muscles of facial expression Multiple sclerosis
0 Taste fibres from the anterior two-thirds of the Otitis media
tongue (in the chorcla tympani) Ramsay Hunt syndrome
I Taste from the palate lnerve ofthe pterygoid Diabetes
canal) Guillain-Barr syndrome
l 0 Secretomotor parasympathetic fibres to parotid,
submandibular and sublingual glands
0 Nerve to stapedius If the palsy is bilateral, exclude myasthenia gravis,
l facial myopathy llook for ptosis) and neurosarcoido-
Taste fibres, the nerve to stapedius and to the facial sis. Weakness of frontalis (forehead) indicates a
muscles leave the nerve below the geniculate gang- nuclear or intranuclear (lower motor ne urorie , LMN)
lion. lesion.
l
Figure 16.5 Locations of the principal cranial nerve nuclei within the brainstem

MU: Xll X Nucleus

. nucleus nucleus solitarius
I

l \ / a e t i ki i l -si - nucleus C

'ebellar
V
l
nucleus and tract
_Structures

_
l involved in
posterior inferior Spinocerebellar tract
7 | cerebellar artery
i
thrombosis (lateral Spinothalamic
medullary syndrome) tract

\ \\
1 nucleus
V \ /
\ \ _ /
. _ _ _ - tract
lE
_

r =.
Medial
lemniscus
t_____` _.___. . _ _ . 7 7
_ _ _ _ * . _ _ _ _ W _ _ ___

467
Essential Revision /\/otes for MRCP

Be lls p al s y sensorineural and conductive deafness are distin~

An isolated facial nerve palsy of acute onset, guished by Rinne's and Weber's tests.
thought to be secondary to viral infection.
Rinnes test
0 Unilateral facial weakness 0 Air > bone conduction normally
0 Absent taste sensation on anterior two- 0
Hearing decreased and bone < air conduction
thirds of tongue in Conduction deafness
0 Pain behind the ear 0
Hearing decreased and air > bone conduction
in sensorineural deafness
Usually recovery begins by 2 weeks but the palsy
may be prolonged and lO% have residual weak- Webefs te st
ness. Electrophysiological tests can help predict the 0 Central normally l
outcome and tapering dose of steroids (given from 0 Lateralises to normal side in sensorineural
onset) improves the outcome. Tarsorrhaphy may be deafness
needed to prevent corneal damage. 0 Lateralises to deaf side in conduction deafness
Ramsay H unt syndrome V

Features include herpes zoster, affecting the genicu- t, f v

late ganglion, and facial palsy with herpetic vesicles 0 Conduction
in the auditory meatus. Deafness is a complication, Ear wax
Otosclerosis

16.4.2 Trigeminal neuralgia ~ Middle ear infection

0 Sensorineural
This is characterised by brief lancinating pain in the ~ Acoustic neuroma

-
distribution of one of the divisions of the trigeminal Pagets disease
nerve. lt is more common in patients over the age Central lesions (MS/CVA/glioma)
of 50 and in women. Maxillaiy and mandibular
Congenital (maternal infections,
divisions are most often affected, it is almost always
congenital syndromes)
unilateral and trigger points are common. lt may be ~ Mniere's disease
a presenting symptom of MS in younger patients. Head trauma
Treatment includes: ~ Drugs and toxins (aminoglycoside
antibiotics, furosemide, lead)
I
Carbamazepine/phenytoin
Clonazepam
Baclofen Several drugs may cause tinnitus, including aspirin,
furosemide and aminoglycosides.
I
Thermocoagulation of trigeminal ganglion
I
Surgical section of nerve root
Vert i g o

16.4.3 Vestibulocochlear nerve Neurological disorders causing vertigo are typically

due to pathology of the labyrinthine structures of
Damage to the eighth cranial nerve may result in the middle ear, the brainstem vestibular nuclei, or
deafness or vertigo (see below). At the bedside, the vestibulocochlear nerve that connects the two.

468

0
Labyrinthine (peripheral)
-
Trauma (including barotrauma)
~ Mniere's disease
Acute viral infections
~ Chronic bacterial otitis media
~ Occlusion of the internal auditory artery
-
Brainstem (central)
0
~ Acute vestibular neuronitis
-
~
~
Vascular disease
MS
Space-occupying lesions (eg brainstern
gliomal
Toxic causes leg alcohol, drugs)
1
Hypoglycaemia
Ac oustic neuroma
Acoustic neuroma is a benign tumour arising on the
eighth cranial nerve as it emerges from the brain-
stem in the cerebellopontine angle. It is a common
cause of a cerebellopontine angle syndrome:
0 Cranial nerve VIII is affected early, but the
patient may not report hearing loss, tinnitus
and vertigo
0 Corneal reflex (cranial nerve V) is absent
0 Facial sensation is abnormal (V nerve)
0 The facial nerve is affected late
I Investigation is by use of MRI or high-resolution CT
scanning, and treatment is surgical removal.
16.44 Lateral medullary s y n d r o m e
The lateral medullary lfwallenbergi syndrome is
usually due to vertebral artery or posterior inferior
cerebellar artery occlusion, which damages the dor-
solateral medulla and inferior cerebellar peduncle
(see Figure 16.5).
Neuro/ogy
Featm-ua o f th e lartemahzneckxllaxy ~ -
s y n d ro m e
0
Ipsilateral loss of pain and temperature
sensation on the face (V)
U
ipsilateral paralysis of palate, pharynx and
vocal cords (IX, X)
I
ipsilateral ataxia (inferior cerebellar
peduncle)
Conlralateral loss of pain and temperature
'
0
sensation on the body ispinothalamic tract)
ipsilateral Horner syndrome (descending
sympathetic outflow]
Vertigo, nausea and vomiting, nystagmus _
(vestibular nuclei)
16.4.5 O ther cau ses of cr an ial nerve
p alsies
The cranial nerves may commonly be involved in
the following neuropathies:
0 Diabetes mellitus: CN III or other oculomotor
0 Guillain-Barr/Miller-Fisher: CN VII,
oculomotor
0
Diphtheria: classically CN IX
Neumsarcoidosis: CN VII and bilateral VII
16.5 SPINAL CO RD DISORDERS
16.3.1 N e ur oa na t omy
The spinal cord ends at the lower border of L2.
There is one principal descending pathway, the
corlicospinal tract, which crosses in the midbrain.
The two principal ascending sensory pathways are
the dorsal columns and spinothalamic tracts ( s ee
below).
469
Essential Revision Notes for MRCP
Ascending sensor y pa thw a ys
--
0 Dorsal (posterior) columns
joint position sense and vibration
Carry sensation from the same side of
the body (ipsilateral uncrossed)
Synapse in the brainstem at the cuneate
- Progressive bulbar palsy: bulbar musculature
and gracilis nuclei, then decussate
0
Spinothalamic tracts
Pain and temperature
~ Incoming fibres cross immediately or
within a few segments
~ Crossed tract results in lamination, with
fibres from legs outside fibres from the
arms
` I<';?i"~,\.i~
-'ep-7i='~.\.~~\.i:t.v~->
This clinical syndrome is caused by lateral hemlsec-
tion ofthe spinal cord, resulting in:
I
ipsilateral upper motor neurone weakness
below the lesion (severed descending
corticospinal tract fibres)
0
ipsilateral loss of joint position sense and
vibration (severed ascending dorsal column
fibres)
I Contralateral loss of pain and temperature
sensation (severed crossed ascending
spinothalamic tract fibres)
Light touch sensation is often clinically normal
below the lesion, and the clinical syndrome is most
commonly (but not exclusively) caused by multiple
sclerosis.
:T6 Tilt.-or n et s rrm l ff
Motor neurone disease (MND) is a degenerative
disorder affecting both lower motor neurones (LMN)
and upper motor neurones (UMN) supplying limb
and bulbar muscles. There is no involvement of
sensory nerves, and the aetiology is unknown. There
are three principal types.
470
I
Progressive muscular atrophy: typically presents
with LMN signs affecting a single limb that then
progresses. Best prognosis (still poor)
0
Amyotrophic lateral sclerosis: both LMN and
UMN are involved; typical clinical picture
- would be LMN signs in the arms and bilateral
UMN signs in the legs. intermediate prognosis
0
affected with poor prognosis
Examination may initially show only fasciculation
but progresses to widespread wasting and weakness,
spastic dysarthria and exaggerated reflexes.
Diagnosis of MND
Diagnosis is largely clinical but confirmatory inves-
tigations include nerve conduction studies and
EMC, which show evidence of chronic partial de-
nervation and widespread fasciculation with normal
sensory nerves and preserved motor nerve conduc-
tion velocity (these latter features distinguish the
disorder from peripheral neuropathies). CSF protein
concentration may be slightly increased. Prognosis
is poor with death within 5 years typical.
Treatment of mot or n eu ro n e disease
Riluzole is a drug which affects glutamate neuro-
transmission in a complex fashion. It is usually well
tolerated, is associated with a modest improvement
in survival ( a bout 2 - 3 months at 18 months) and is
NICE-approved for treatment of probable or definite
MND. However, its effects upon quality of life
remain unknown and it should he emphasised that
the mainstay of treatment of MND remains sympto-
matic, with a multiclisciplinaq/ approach to prob-
lems such as nutrition and ventilation.
iiisvtvue
l (x .5 .4 A bse nt k n ee je r ks a n d
e xt e ns or pl-antars
The causative lesion typically produces both LMN
(diminished reflexes) and UMN (e xte nsor plantars)
signs.

Causes include:
Friedreichs ataxia
Subacute combined degeneration of the cord
Motor neurone disease
Taboparesis
Conus medullaris compression (the conus
represents the transition between spinal cord
proper and the filum terminale at the lower end
of the cord). Compression can cause UMN signs
from cord compression and LMN signs from
filum terminale (nerve root compression)
16.6 VASCULAR DISORDERS.
CEREBRAL 'IUMOURS ' -\ N [)
OTHER CNS PA'l`H()L()Gll'.`S
This section considers vascular disorders of the
CNS, the important causes of headache, cerebral
tumours and a number of metabolic disorders af-
fecting the CNS.
16.6.1 Transient ischaemic a tta c ks.
A transient ischaemic attack (TIA) is a focal CNS
disturbance developing and fading over minutes or
hours to give full recovery within 24 hours. Most
T|As are caused by embolism.
Differential diagnosis of TIA
Migraine
Malignant hypertension
MS (unusual)
Epilepsy
Hypoglycaemia
Modifiable risk factors for TlA include hypertension,
diabetes mellitus, cigarette smoking, drug use (drugs
of abuse, oral contraceptive pill, alcohol), elevated
Neurology
haematocrit and carotid stenosis. Medical manage-
ment with oral aspirin significantly decreases the
chance of subsequent TlA or stroke.
Carotid arterial s t en o s i s
lf a severe (70%-99%) carotid stenosis is present
then the existing evidence suggests that carotid
endarterectomy (by an experienced surgeon) should
be undertaken. Carotid endarterectomy carries a
relatively high (about 8%) risk of perioperative
stroke, so the patient trades a short-term increased
risk of stroke for a significant long-term reduction in
subsequent risk.
1f..'_ ? St rolex
A completed stroke is a focal CNS disturbance due
to a vascular cause where the deficit persists, The
aetiology may be embolic, thrombotic or haemor-
rhagic. The presenting symptoms depend on the
vascular territory involved.
L acuna: stroke s
Lacunar infarctions occur where small intracerebral
arteries are occluded by atheroma or thrombosis.
Typically, small low-density subcortical lesions are
seen in the area of the internal capsule.
0 Lacunar syndromes cause a pure motor,
sensorimotor or pure sensory stroke, with no
involvement of higher cortical functions
0 Lacunar intarcts have a low mortality and
relatively good prognosis for recovery; they are
primarily associated with hypertension
Other types of stroke involve either the anterior or
posterior cerebral circulation. intracerebral haemor-
rhage is primarily associated with the rupture of
microaneurysms situated in the basal ganglion or
hrainstem.
47l
Essential Revision Notes for MRCP
Risk factors for stroke
Diabetes
Hypertension
Smoking
Cocaine abuse
Previous TIA or stroke
Male sex
Increased Hb, haemoglobinopathy
Family history
Diagnosis of stroke is on clinical grounds supported
by neuroimaging. (CT is commonly used initially in
order to distinguish between haemorrhage and
ischaemic causes, but note that up to 50% of early
CT scans will be normal ln acute ischaemic strokeii
Management of stroke is initially conservative,
though patients with expanding cerebellar or cere-
bral haematoma may need surgical treatm ent, Aspir-
in is effective in secondary prevention. Mortality
from stroke is between 20% and 30%, with poorer
prognosis in old patients with depressed level of
consciousness.
Factors associated, with a poor
p ro g n o s i s in stmoke
'
0
Complete paralysis of a limb (MRC grade 0
or i)
Loss of consciousness at onset of stroke
Higher cerebral dysfunction
Coma or drowsiness at 24 hours
Old age
Treatment of str oke
ln the UK, NICE has recently published guidance
on the diagnosis and management of TIA and acute
stroke thttp://www.nice.org.uk/Guidance/CG68). For
acute stroke urgent treatment improves outcome. In
general:
0 All patients with acute stroke who have had a
diagnosis of intracerebral haemorrhage ruled
out by brain imaging should be given aspirin
300 mg as soon as possible and certainly within
24 hours
472
0
Thrombolysis vvith alteplase can be given within
appropriately equipped acute stroke services
and is indicated if presentation is less than
3 hours from symptom onset and following brain
imaging to rule out intracerebral haemorrhage
0 In addition to specific pharmacological
treatment of stroke, full supportive care
(including treatments directed at the
maintenance of cerebral blood flovv,
oxygenation and normoglycaemia) is
recommended in the context of a
multidisciplinary stroke unit
16.6.3 Subarachnoid haemorrhage
Around 5%-10% of all strokes are due to subarach-
noid haemorrhage (SAHI. Causes include:
Ruptured arterial aneurysm
Trauma
Ruptured arteriovenous malformation
Cocaine or amphetamine abuse
Hypertension
Eighty per cent of intracranial aneurysms are lo-
cated in the anterior circulation, most on the ante-
rior communicating artery, and 15% are bilateral.
Investigation of subar achnoid haemorrhage
SAH is typically investigated with CT and lumbar
puncture (LP):
0 CT may be negative in up to 20% of suspected
SAH, so a normal CT does not exclude the
diagnosis
0 LP shows xanthochromia (due to red cell
breakdown products, only visible >4 hours after
haemorrhage)
0 Other recognised findings include transient
glycosuria, low CSF glucose or lengthening of
the QT interval (leading to mchyarrhythmias or
torsades de pointes)
Treatment of SAH
The management of SAH depends upon making the
diagnosis, locating the underlying aneurysm and
occluding it. About a quarter of patients will die
 Neuro/ogy

within a day of presentation, and a third of those 16.64 H eadache

who survive the first day will subsequently die of
Headache is an extremely common symptom that
complications or rebleeding. At presentation, sev- has a multiplicity of causes. Leaving aside acute
eral factors have prognostic value for poor outc om e ,
the most important of which are decreased level oi' unexpected headaches caused by, for example, sub-
arachnoid haemorrhage, important causes of
consciousness, increasing age and amount of blood
visible on CT scan. chronic recurrent headache include:
I All patients are typically treated with oral
0 Tension headache
0 Classic (accompanied by focal neurological
nimodipine, which reduces intracranial
vasospasm and so can prevent delayed cerebral symptoms) or common migraine
ischaemia. lt probably reduces the risk of poor
0 Cluster headache
outcome by about a third
0 Headaches in association with raised
intracranial pressure
I
Early operative inten/ention to occlude the
causative aneurysm is now usual practice for
most patients in reasonable condition, but this is
not supported by randomised controlled trial Migraine
evidence
Migraine is classically preceded by a visual aura
followed by a unilateral throbbing headache with
photophobia and nausea.

0
Neurological Features of m i grai ne

-
Rebleeding
~ Hydrocephalus 0 EEC and neurovascular abnormalities
Focal ischaemic injury from cerebral associated with the headache
vasospasm 0
Rarely may result in stroke
0
Systemic 0
May have unilateral lacrimation
~ Fever 0 Can be associated with (reversible)
Tachyarrhythmias secondary to neurological signs (eg hemiplegic migraine)
catecholamine release
~ Neurogenic pulmonary oedema (rarely)
Hyponatraemia secondary to syndrome
of inappropriate antidiuretic hormone The neurological symptoms suggest a vascular ori-
gin, and a popular hypothesis is that of 'spreading
intracranial aneurysms are associated with: depression' of cortical blood flow. However, whilst
changes in cerebral perfusion undoubtedly occur, it
0
Polycystic kidney disease is presently not clear whether these are primary or
0 Ehlers-Danlos syndrome whether brainstem neuroregulatory abnormalities of
0 Fibromuscular dysplasia causing renal arteiy serotonergic or noradrenergic neurotransmitters are
stenosis more important, Therapy is aimed at stopping an
0 Medium-vessel arteritides (eg polyarteritis attack (abortive) or if the frequency of attacks is high
nodosa) enough, regular medication is given as a prophylac-
0 Coarctation of the aorta tic agent.

473
Essential Revision Notes for MRCP

Migraine the ra py lesion on imaging. The most common presentation

is in oven/veight young W o m e n and comprises;
0 Ahortive 0 Headache
Paracetamol 0 Blurred vision
Codeine i anti-emetic U Dizziness
Ergotamine* 0 Transient visual obscurations
Sumatriptan (SHT1 agonist) 0 Horizontal diplopia
I
Prophylaclic
~ Propranolol Papilloedema is found on examination, with periph-
~ Pizotifen eral constriction of the visual fields and enlarged
a
Amitriptyline blind spot. The CSF pressure is elevated.

Methysergide
latrogenic [drug-induced) causes include:
*Ergotamine is contraindicated with cardiovascular/
peripheral vascular disease as it is a vasoconstrictor: also Oral contraceptive pill
in pregnancy, Raynauds or with renal impairment Steroids
Tetracycline
Vitamin A
Cluster headache Nitrofurantoin
Cluster headache has a distinct pattern, with attacks Nalidixic acid
occurring in clusters lasting days or weeks and
remissions lasting months, Males are more often Treatment of BIH
affected than females, and onset of attacks is typi-
cally between 25 and 50 years. This consists of weight loss, acetazolamide and
repeated lumbar puncture to reduce the CSF pres-
features of cluster headache sure. In more resistant cases or those associated
Typical
with regular recurrence/ ventriculoperitoneal shunt
0 Unilateral severe headache lasting up to an may be necessary, Optic nerve sheath fenestration
hour can be performed in patients whose sight is threa-
Lacrimation tened.
Partial Horner's may occur
Pain may be retro-orbital
Redness of ipsilateral eye 16.6.6 Wernickefs en cep h alo p ath y
Nasal stuffiness This is a neurological syndrome of acute onset
characterised by:
The aetiology is not known and treatment is diffi- Ataxia
cult. Management of the acute attack includes
inhaled oxygen (face mask), ergotamine and suma- Ophthalmoplegia
Nystagmus
triptan. Steroids may be helpful, Lithium treatment Global confusional state
is used for prophylaxis.
Polyneuropathy (in some Casesl
lt may evolve into Korsakoff syndrome, with a dense
16.6.5 Eenigit i nt f a c mni a l
amnesia and confahulation. The syndrome is com-
tty,->e:ten$<>r; ilH}
monly associated with alcoholism and may be pre-
This term refers to a group of patients vvho present cipitated hy a sudden glucose load, but may also be
with headaches and profound papilloedema, yet caused by prolonged vomiting (eg hyperemesis
have no focal neurological signs or intracranial gravidarum), dialysis or gastrointestinal cancer.

474

Red cell transketolase activity is reduced. Neuro-
pathologically it is characterised by periaqueductal
punctate haemorrhage. Treatment with thiamine
should lead to rapid reversal of the neurological
symptoms, though the memory disorder may en-
dure. (See Chapter 18, Psychiatry, for further discus-
sion.)
16.6.7 C ereb ral tu mo u r s
Primary and secondary intracranial neoplasms have
an approximately equal incidence, Both produce
presenting symptoms through local neural damage
giving rise to focal neurological symptoms, epilepsy
or symptoms of raised intracranial pressure, such as
headache. The most common presenting symptoms
of a glioma are epilepsy and headache.
Gliomas
Gliomas are the most common primary intracranial
neoplasm. Most commonly gliomas are derived
from the astrocyte cell line, though less commonly
oligodendrogliomas, ependymomas and ganglio-
gliomas may occur.
0 Treatment: confirmation of diagnosis necessary
by brain biopsy, lf possible, surgical removal
should be undertaken followed by radiotherapy.
Adjuvant chemotherapy for high-grade gliomas
is under evaluation
I
Prognosis: this is relatively poor. Even grades I
and ll astrocytomas have survival rates of 1 0 %-
30% at 5 years, whereas glioblastoma
multiforme (grade l\/ astrocytoma) is usually
rapidly fatal within a year
16.7
CNS INFECTIUNS
CSF abnormalities in bacterial and viral meningitis
are discussed in Section 16.10 and causative organ-
isms are listed in Chapter i i , Infectious Diseases.
For HIV-related neurological disease see Chapter B,
Genito-urinary Medicine and AIDS.
Neuro/ogy
lltll tfttcepixaiitts
Acute viral encephalitis involves not simply the
memnges ia viral meningitis) but also the cerebral
Substance. Confusion and altered consciousness are
thus prominent, and seizures and focal neurological
signs may occur. Viral encephalitis is often second-
ary to herpes simplex, but may also be secondary to
infection with mumps, zoster, EBV or coxsackie and
echoviruses. See also Chapter 11, Infectious Dis-
eases.
He rpe s si m pl ex encephal i t i s
Clinical features of her pes simplex
encephalitis
Fever
Focal symptoms (eg musical hallucinations)
Confusion
Focal signs (eg right-sided weakness and
aphasial
Focal signs are related to anterior temporal lobe
pathology, which may be visible on CT or MRI.
Normal CSF findings are occasionally seen, but
typically there is a lymphocytosis with red cells also
present. In a minority (20%) of cases the CSF sugar
may he low. Investigation with imaging or with EEC
may confirm focal temporal lobe involvement, and
definitive diagnosis can be made with polymerase
chain reaction (PCR) to detect viral DNA in the CSF.
Treatment with aciclovir should be started on suspi-
cion ofthe diagnosis.
1.t;m<: ~.is~\.;-as
Lyme disease, caused by the spirochaete Borre/ia
burgdorferi, is discussed in Chapter 11, Section
11.8.2. The illness can be subacute or chronic and
evolves in poorly defined stages. A ring-like erythe-
matous lesion (erythema migrans) at the site of the
tick bite is accompanied by influenza-like symp-
toms, with neurological (or cardiac) symptoms
appearing weeks to months later. Usually, neuro-
logical involvement appears as 'viral-like meningitis
475
Essential Revision Notes for MRCP

with or without cranial mononeuropathies. Treat- Common p er o n eal n erv e pal s y

ment is with oral doxycycline in the initial stages
but the meningitis is usually treated with intra- This nerve is motor to tibialis anterior and the
venous ceftriaxone. peronei muscles. Patients usually present with foot
dr0P and weakness of;

Neurological almormalltiexiu Lyme

0 Inversi0n ofthe foot (L4)
disease . .
0 Dorsiflexion (L5, tibialis anterior)
0 Eversion (S1; peroneil
Cranial neuropathies
Bells palsy Sensory loss over the dorsum of the foot is usually
present, but not prominent. Distinction from an L5
Low-grade encephalitis root lesion is made by demonstrating that foot ever-
Mononeuritis multiplex
sion is intact (for a root lesion).
Meningitis
Cerebellar ataxia
Cameo-ui common pe rone a l palsy
Compression at the fibula neck, where the
nerve winds round the bone (eg below-
16.8 PERIPHERAL NERVE LESIONS knee plasters)
Connective tissue disease/vasculitis
16.8.1 Mononeuropathies
Weight loss
A peripheral lesion of a single nerve is known as a Diabetes mellitus
mononeuropathy. Commonly mononeuropathies Polyarteritis nodosa
are associated with compressive lesions or have a Leprosy
vascular aetiology, Two of the most important
morioneuropathies (other than oculomotor palsies) Other causes of (unilateral) foot drop include dia-
are carpal tunnel syndrome and common peroneal
nerve palsy. betes mellitus lother than due to C o m m o n peroneal
nerve palsy), stroke, multiple sclerosis and pro-
Iapsed inten/ertebral disc.
C a r p a l t u n n el s y n d ro me
The most C o m m o n peripheral nerve entrapment Other m o n o n eu ro p at h i es affecting t he hand
syndrome. Symptoms are of numbness and dys- a n d arm
aesthesia affecting the median nerve (lateral three-
and-a-half fingers), and weakness of median nerve- The median nerve supplies some of the muscles of
innervated muscles (see below). the thenar eminence (abductor pollicis, flexor polli-
cis brevis and o p p o n e r is pollicis) and the lateral two
Conditions associated with carpal tunnel syndrome: lumbricaIs_
Pregnancy The ulnar nerve supplies the muscles of the hy-
Obesity pothenar eminence (abductor digiti minimil, the
Hypothyroidism medial two lumbricals and all the interossei (re-
Acromegaly member dorsal abduct, palmar adduct - dab and
Amyloidosis pad').
Rheumatoid arthritis
The radial nerve does not supply muscles in the
Treatment is with wrist splints, occasionally diuretlcs hand. lt supplies primarily the extensor compart-
or surgical decompression, ment of the forearm.

476
 Neuro/ogy

of'-w aMi|s gini"tli " Causes of hndculatiun

V

f9f~&h@,1mnd=<} ~ -,
, _
Motor neurone disease
Arthritis Thyrotoxicosis
Motor neurone disease Cervical spondylosis
Other cervical cord pathology Syringomyelia
Syringomyelia Acute poliomyelitis
Polyneuropathies Metabolic severe hyponatraemia,
~

Brachial plexus injury (eg trauma, hypomagnesaemia

Pancoast's tumour) 0
Drugs (clofibrate, lithium,
anticholinesterase, salbutamol)

16.8.2 Polyneuropathies Autonomic ne uropa thie s

Polyneuropathies have a heterogeneous set of Autonomic neuropathy may present with:
causes. Typically peripheral nerves are affected in a
diffuse symmetrical fashion; symptoms and signs Postural hypotension
are most prominent in the extremities, Different Abnormal sweating
aetiologies may be associated with involvement of Diarrhoea or constipation
mainly motor, mainly sensory or mainly autonomic Urinary incontinence
fibres. Absence of cardiovascular responses leg to
Valsalva manoeuvre)
0
s
Impotence

I
Mainly sensory neuropathies of antonomic
~ Diabetes mellitus
~ Leprosy
Amyloidosis Diabetes mellitus
Vitamin Bi; deficiency
Amyloidosis
~ Carcinomatous neuropathy Chronic hepatic failure

--
Mainly motor neuropathies
I Cuillain-Barr syndrome
~ Guillain-Barr syndrome (see below) Renal failure
Porphyria Multiple system atrophies (ie Shy-Drager

- Lead poisoning
Diphtheria
Hereditary sensory and motor
neuropathy (HSMN) types I and II
syndrome/OPCA)

Palpable peripheral nerves are recognised in the

tollowing polyneuropathies:
1 Uraemic neuropathy
~ Chronic inflammatory demyelinating CharcotMarieTooth (HMSN ll)
polyneuropathy (CIDP) Amyloidosis
Lepromatous leprosy
Motor neuropathies cause partial denervation of Acromegaly
muscle. An important sign of denervation is fascicu-
Guillain-Barr s yndrom e
lation, which is particularly prominent in disorders
of the anterior horn cell in addition to the motor Guillain-Barr syndrome (CBS) is an uncommon
neuropathies described above. acute post-infective polyneuropathy. A progressive

477
Essential Revision Notes for MRCP
ascending symmetric muscle weakness (ascending
polyraoliculopathyi leads to paralysis, maximal by
lwe e k in more than half of patients. Symptoms
frequently begin after a respiratory or gastrointest-
inal infection; Campylobacter jejuni infection is
associated with a worse prognosis,
Sensory symptoms may be present but are typically
not associated with objective sensory signs. Papil-
loedema may occur. The condition may be asso-
ciated with urinary retention or cardiac arrhythmia
(autonomic involvement). Some patients will require
intubation and artificial ventilation.
Investigation typically reveals:
0 Elevated CSF protein (often very high)
0 Normal CSF white cell count
0
Slowing of nerve conduction velocity and
denen/ation on EMG
Poor prognostic features include:
Rapid onset of symptoms
Age
Axonal neuropathy on n e n / e conduction studies
Prior infection with Campylobacter jejuni
Treatments include plasma exchange and intra-
venous immunoglobulin.
Miller-Fisher syndrome is a variant of Guillain-
Barre syndrome and comprises ophthalmoplegia,
ataxia and areflexia.
16.9 DISORDERS OF MUSCLE AND
NEUROMUSCULAR JUNCTION
Disorders of muscle are known as myopathies. The
most imponant feature is muscle weakness, variably
accompanied by wasting, hypertrophy, pseudo-
hypertrophy or other symptoms, such as myotonia.
Signs are invariably symmetrical. Myopathies are
usually painless (with the exception of inflammatory
myopathies).
Note that fasciculations are signs of muscle dener-
vation, and they indicate a disorder of motor nerves
or of the neuromuscular junction. They are not a
feature of myopathy.
478
16.9.1 My o p ath ies
There are a number of different types of myopathies.
Clnultkation of myoputhios '~
.
' s i ~
ss
* Inflammatory (eg polymyositis; see Chapter
20, Rheumatology)
Metabolic (eg mitochondrial)
0
Drug-induced
0 -
Inherited dominant (eg dystrophia
myotonica; see below); recessive (eg
Duchenne; see below)
0
Secondary to endocrine disease (principally
thyrotoxicosis or hypothyroidism)
Muscular dystr ophy
Duchenne muscular dystrophy is an X-linked dis-
order affecting about l in 3500 male births, though
occasionally females may be affected (due to trans-
location of the short arm of the X chromosome,
Xp21).
0 The gene has now been isolated in this Xp2l
region, and produces a protein named
dystrophin that is normally present on the
muscle sarcolemmal membrane. The
pathogenesis is described in detail in Chapter
I4, Molecular Medicine
0 ln Duchenne dystrophy, the dystrophin protein
is absent
0 Serum creatine kinase is elevated
In Duchenne muscular dystrophy, weakness occurs
progressively from about 3 - 4 years of age. Thirty
per cent of sufferers show intellectual impairment
with the overall IQ curve being shifted to the left.
There is no effective treatment at present and death
usually occurs from cardiorespiratory failure in the
second or diird decade of life.
In the milder Beckers dystrophy, the dystrophic
protein is seen but it is dysfunctional and present at
a lower level than normal. Distinguishing features
in muscular dystrophy are shown in Table 16.2.
 Neurology

Table 16.2. Distinguishing features in muscular dystrophy

Duchenne Becker's

lmmunofluorescent dystrophin on muscle biopsy Undetectable Reduced/abnormal

Wheelchair dependence 95% at <1 2 years 5% at <12 years
Mental handicap 20% Rare

Dyst rophi a my o t o n i ca 1 in 20 000. The pathogenesis is described in detail

in Chapter I4, Molecular Medicine.
An inherited myopathy (autosomal dominant) with
onset in the third decade, Most (but not all) patients have ptosis. Many have
ophthalmoplegia, dysarthria and dysphagia, but any
Foltwna-_of dystr ophin mqotonlna muscle may be affected. The pupil is never affected,
but weakness of eye closure and ptosis is common.
0
Myotonic facies Quick lid retraction on refixation from downgaze is
0
Myotonia [delayed muscular relaxation after known as Cogans sign.
contraction)
Myasthenia gravis can mimic MND, mitochondrial
Wasting and weakness ofthe arms and legs myopathies, polymyositis, cranial nerve palsies or
Frontal baldness brainstem dysfunction.
Testicular/ovarian atrophy
Diabetes mellitus
Cataract Di agnos i s of m y as t h eai a g rav i s
Cardiomyopathy
Mild cognitive impairment 0 Tensi|on test
0 ACh receptor antibodies (present in 8 5 % -
90%)
Diagnosis depends on the characteristic myotonic 0
Electrophysiology (repetitive stimulation
discharge on EMG in association with the clinical gives rise to diminution in the amplitude of
features listed above. Usually severe disability re- the evoked EMG response)
sults within 1 0 - 2 0 years, and there is no treatment
available though phenytoin may be used for symp-
0
Thyroid function tests (up to 10% have
co-existent thyrotoxicosis)
tomatic relief of myotonia. 0 CT mediastinum

16.9.2 Neuromuscular j unc t i on

Neuromuscular transmission is dependent on choli-
nergic transmission between the terminals of motor
nerves and the motor end plate.
Myasthenia g rav i s
This is an antibody-mediated autoimmune disease
affecting the neuromuscular junction; antibodies are
produced to the acetylcholine receptors. lt is a
relatively rare disorder with a prevalence of about
Treatment of myasthenia gravis
Primary treatment is with cholinesterase (ChE) inhi-
bitors (eg pyridostigmine), and some patients will
achieve control with these agents alone, The cause
of the disease is usually modified with treatments
directed at the immune system:
0
lmmunosuppression: steroids, azathioprine,
cyclophosphamide, ciclosporin A
0
Plasmapheresis
0 Intravenous immune globulin infusion
Y

479
Essential Revision Notes for MRCP

In those with thymoma or hyperplasia of the thy-

mus, up to 60% will improve or achieve remission
after thymectomy. The benefits of surgery are great- Elevated protein
est in patients aged less than 40 years. Very high; >2 g/l
Guillain-Barre syndrome
Lambert-Eaton m yast heni c s y n d ro m e (LEMS) 0
Spinal block
LEMS is commonly a paraneoplastic syndrome, TBmeningitis
most commonly associated with small-cell carcino- Fungal meningitis
ma of the lung (also breast and ovarian cancer). High
However, in a variable proportion (up to 5 0 % ) of v Bacterial meningitis
patients no cancer is f ound, ~ Viral encephalitis
Cerebral abscess
Neurosyphilis
Subdural haematoma
Cerebral malignancy
Fatiguability
Hyporeflexia low CSF glucose
Ocular and bulbar muscles rarely affected Bacterial meningitis
Autonomic symptoms (eg difficulty with TBmeningitis
micturition, dry mouth, impotence) Fungal meningitis
Mumps meningitis (in 20% of cases)
Herpes simplex encephalitis (in 20%)
Unlike myasthenia grayis, ophthalmoplegia and pto-
Subarachnoid haemorrhage
sis are not features. Like myasthenia gravis, LEMS is
an autoimmune disorder with antibodies produced (occasionally)
to voltage-gated calcium channels in the muscle Polymorphs
membrane. On examination, reflexes are absent but Bacterial meningitis
return after exercise (cf myasthenia gravis). EMG lymphocytes
with repetitive stimulation shows an improvement
~ Viral encephalitis/meningitis
Partially treated bacterial meningitis
in response.
Behcet syndrome
CNS vasculitides
16.10 INVESTIGATIONS USED IN HIV-associated
NEUROLOGICAL DISEASE Lymphoma
Leukaemia
16.10.1 Cerebrospinal fluid Lyme disease
Systemic lupus erythematosus

O Pressure Multiple sclerosis

~ 60-150 mmof CSF (patient recumbent) Neurosarcoidosis

.
Protein CNS lymphoma

I
- 0 1 -0 . 4 g/I
Cell count
Red cells 0, white cells <5/mm3 (few
Systemic lupus erythematosus
Subacute sclerosing panencephalitis: rare,
late complication of measles
0
- monocytes or lymphocytes)
Glucose
More than 2/3rds of blood glucose
Subarachnoid haemorrhage (unusual)
Neurosyphilis
Guillain-Barr syndrome

480
 Neuro/ogy

16.10.2 Neuroradiology Nerve c onduc tion tests

CT and MRI scanning of the brain and spinal cord Nen/e conduction tests are used to investigate per-
are now widely used in the investigation of neuro- ipheral neuropathies, The technique involves stimu-
logical diseases. A comprehensive account is be- lating a peripheral nerve (sensory or mo to r ) and
yond the remit of this section. recording the action potential latency and ampli-
tude funher along the same nerve. This allows
calculation of the conduction velocity of the n e n f e .
These measures can be used to distinguish (amongst
other things) between axonal and demyelinating
neuropathies.
Oligodendroglioma
Craniopharyngioma 0 Axonalz reduced amplitude (loss of a xonsl but
Pineal gland (may be normal finding) preserved conduction velocity
Sturge-Weber syndrome 0
Demyelinating: preserved amplitude but
Aneurysm reduced conduction velocity (loss of myelin)
Meningioma
Tuberculorna Electromyography (EMG)
Tuberous sclerosis
EMG is useful in disorders of the neuromuscular
Toxoplasmosis
Hypoparathyroidism (basal ganglia) junction or investigation of myopathic processes.
The technique involves stimulating the motor nerves
while recording the compound action potential
from muscles.
1 6 1 0 .3 Electrophysiological Characteristic abnormalities:
i nve s t i ga t i ons 0
Myasthenia gravis: diminished response to
EEG repetitive stimulation
The EEG is characteristically abnormal in the follow-
0 Lambert-Eaton syndrome: enhanced response
to repetitive stimulation
ing conditions: 0
Polymyositis: fibrillation due to denervation
Absence seizures: 3-Hz spike-and-vvave hypersensitivity, reduced amplitude and
complexes duration of motor units
0
Creutzfeldt-lakobz periodic bursts of high- 0
Myolonic syndromes: 'dive bomber' discharge
amplitude sharp W a v e s thigh-frequency action potentials)

481

r
CONTENTS
. 17.1 Ba sic a n a t o m y of t h e ey e
17.1.1 Orbit
1,
l 17.1.2 Extraocular muscles
V
17.1.3 The globe
17.2 Retinal di sorders
17.2.1 Retinal venous occlusion
' 17.2.2 Retinal arterial occlusion
17.2.3 Hypertensive retinopathy
17.2.4 Diabetic retinopathy
r 17.2.5 Macular degeneration
17.2.6 Retinitis pigmentosa
17.3 Lens abnormalities
1 7.3.1 Cataract
17.3.2 Lens dislocation
r 17.4 O p tic nerve disorders
17.4.1 Optic neuritls
17.4.2 Causes of optic atrophy
17.4.3 The swollen optic nerve head
17.5 Uveitis an d scleritis
17.5.1 Uveitis
17.5.2 Scleritis
17.5.3 Causes of a painful red eye
l
C h a p t e r 17
Ophthalmology
17.6 Syste mic d r u g s a n d t he e y e
17.7 Infectious a ge nt s a n d the eye
17.7.1 Genito-urinary disease and the
eye
17.7.2 Herpetic disease and the eye
17.7.3 Tropical eye infections
17.8 Miscellaneous disorders
17.8.1 Thyroid eye disease
17.8.2 Myotonic dystrophy
17.8.3 Ocular features of the
phacomatoses
17.8.4 Sarcoidosis
17.8.5 Keratoconus
17.8.6 Glaucoma
17.8.7 Ocular tumours
1 7.8.8 Blind registration
Pupillary and eye movement disorders, nystagmus
and visual field defects are all covered in the
neuro-ophthalmology section of Chapter 16,
Neurology
483
 Ophthalmology

Ophthalmology

Pupillary and eye movement disorders, nystagmus 17.13 The g lo b e

and visual field defects are all covered in the
neuro-ophthalmology section of Chapter 16, Neu-
rology.
17.1 BASIC ANATOMY OF THE EYE
17.1.1 Orbit
The orbit houses the globe, extraocular muscles,
lacrimal gland, orbital fat and attendant arteries,
veins and nerves (Figure 17.1).
17.1.2 Extraocular muscles
The four rectus muscles and the superior oblique
arise at the orbital apex and pass forward to insen
into the globe. The inferior oblique arises from the
anteromedial orbital floor and runs along the lower
surface of the globe to insert into its posterolateral
aspect.
The innervation and primary action of each muscle
are shown in Table 17.1 note all other movements
~
Key features of the constituent parts are:
I Cornea: clarity maintained by avascularity, the
regular structural array of component fibrils and
its relative dehydrated state (maintained by
endothelium)
0
Coniunctiva: thin mucous membrane covering
anterior sclera and lining eyelids
0 Sclera: tough fibroelastic coat
0 Uveal tract: anterior uvea comprises iris and
ciliary body. Posterior uvea is the choroid, a
vascular layer lining the sclera which nourishes
outer retinal layers
0 Retinal pigment epithelium: cellular monolayer
comprising the outermost layer of the retina
Retina: light-sensitive innermost layer of the
globe. Converts light energy into electrical
energy. It comprises: (i) rods - more plentiful in
the peripheral retina, sensitive to low light and
movement detection; and (ii) cones -
concentrated within the macular region,
particularly at the fovea, important for acuity
and colour vision. Vascular supply is from the

central retinal artery. Capillaries have non-

are composite, ie due to the action of two muscles
feneslraled endothelium and tight junctions
acting together. forming a blood-retinal barrier (analogous to
the blood-brain barrier), preventing the passage
Table17.1. The innervation and primary action of large molecules
of the extraocular muscles 0 lens: positioned posterior to the iris and anterior
to the vitreous, anchored by the zonules. lt is
Muscle Nerve Primary action enclosed by a capsule, the basement membrane
supply ofthe lens epithelium. New lens fibres are
continuously produced throughout life and the
Superior rectus Ill Elevation in abduction older fibres are compressed to form the lens
Inferior rectus lll Depression in abduction nucleus. Reduced accommodation is found in
Medial rectus lll Aclduction later life because the lens becomes less
Lateral rectus VI Abduction deformable
Inferior oblique Ill Elevation in adduction
Superior oblique IV Depression in adduction

485
Essential Revision Notes for MRCP

Figure 17.1 Crosssection of the eye

<7
D Vitreous
6??
_

`
Q, 9 chamber
Zonulas: 3? ,
, l.

attach lens to
ciliary muscle
'gi'
7 7 ri (`>"*~`V
Aqueous
humor
ix

4~\
2;
'

/ Optic nerve

`\\t\\ it Central artery

Cornea
0 '._
"`-
i
and v eln
4

Pupil:
changes amount "
of light entering
the eye ,/
Lens:
bends light to Optic disc
focus it on
the retina v":'_
,Q1 Fovea

ba
his nh , - 1 r P*

Retin a;
layer that contains
Cmary m u s c l g
_
contraction alters
'

photoreceptors
curvature of lens

486
 Ophthalmology

17.2 RETINAL DISORDERS produces retinal infarction and visual loss in the
area su PPlied.
17.2.1 R etinal v e n o u s oc c l us i on
Retinal vein occlusion probably occurs due to a
dynamic change in blood flow at arteriovenous
crossings and may affect the central retinal vein
(CRVO) or one of its branches (BRVO).
0 Embolic
0 Sudden rapid increase in intraocular
Risk fa c tors pressure
To above central retinal arterial pressure
0
Systemic hypertension (most common) Arteritic
0 Increased intraocular pressure (central occlusion ~ Most commonly giantcell arteritis
only) (GCA). However, visual loss in GCA is
0 Diabetes mellitus only due to central retinal artery
Hyperviscosity states
`
0
occlusion in 10% ofcases; it usually
0 Vasculitides affects vision by producing anterior
ischaemic optic neuropathy, which
= '
damages the optic nerve head
t
_ *\,,~jz:';,`=3f"L ,`,;`"\v,' ,l i 1

0
-
Loss of vision
Variable extent depending on macular
involvement and degree of retinal
ischaemia produced
1;;.
I Relative afferent pupillary defect Sudden, profound, painless loss of vision
With retinal ischaemia (Corresponding sector field loss if
0
Multiple retinal haemorrhages branch occlusion)
1
Mainly superficial, in n e n / e fibre layer Pale oedematous retina with cherry-red
(blood and thunder appearance) spot at fovea (only lasts around 48 hours)
Retinal venous dilatation This is due to the choroidal reflex
Cotton-wool spots
showing through at the fovea as the
Vascular sheathing retina is thinner here
Neovascularisation 0 Relative afferent pupillary defect
~ May occur in 20% of CRVO and 1% of Neovascular complications (occur later)
BRVO due to ischaemia, ie similar Much rarer than with venous
pathogenesis to diabetic retinopathy. occlusions, probably because the retina
This may affect the anterior segment is too severely damaged to produce
producing neovascular glaucoma, or the angiogenic factor
retina causing vitreous haemorrhage or
retinal traction. Treatment is by retinal
laser to abolish the ischaemic stimulus
Treatment is sometimes possible to dislodge the
embolus if presentation occurs within a few hours
17.2.2 R etinal ar ter ial o cclu sio n of onset. Aims of treatment are to induce vascular
dilamtion secondary to hypercarbia by rebreathing,
As the central retinal artery is an end artery, occlu- or more usually, inducing a rapid drop in intraocu-
sion of the central artery or one of its branches lar pressure either pharmacologically or surgically.
'

487
Essential Revision Notes for MRCP

17.2.3 Hy p erten siv e r e t i nopa t hy
Retinal abnormalities represent the severity of
hypertension and are characterised loy:
0 Vascular constriction causing focal retinal
ischaemia
0
Leakage leading to retinal oederna,
haemorrhage and lipid deposition
Arteriosclerotic changes reflect the duration of the
hypertension. These include vessel wall thickening
secondary to intimal hyalinisation, medial hypertro-
phy and endothelial hyperplasia.
Diabetic retinopathy is a microvascular disease. The
phase hypertension). Treatment is aimed purely to-
wards the hypertension and any underlying cause.
17.2.4 D ia be tic r e t i nopa t hy
Diabetic retinopathy is related to the duration and
control ol the disease. lt is the most common cause
of blindness in patients aged 3 0 -6 0 years. lt is
unusual in type l diabetes until l0 years after diag-
nosis, bul eventually occurs in nearly all patients. lt
is present in 10% of type 2 patients at diagnosis,
5 0 % after 10 years' disease and 80% after 20 years'
disease.
following pathological changes are known to occur:

-
- ~
1'
~r',;\/<;i.':2-iJia.. i';z;,;1_
0 loss of vascular pericytes: thought to be
I Grade 1 responsible for the structural integrity of the
Arteriolar attenuation vessel wall. A decrease therefore results in
0 Grade 2 disruption ofthe blood-retinal barrier and
e Focal arteriolar attenuation (with leakage of plasma constituents into the retina
'arteriovenous nipping') 0
Capillary endothelial cell damage
0 Grade 3 0 Basement membrane thickening with
~ Haemorrhages, cotton-wool spots (due carbohydrate and glycogen deposition
to infarction of nerve fibre layer of
retina) Changes in red cell oxygen-carrying capabilities
0 Grade 4 and increased platelet aggregation are also thought
to contribute. The production of an angiogenic
Disc
swelling - 'malignant' or
'accelerated phase factor by ischaemic retina is the likely cause of
neovascularisation. At all stages, good control of
diabetes and of any co-existing hypertension and
Grades 3 and 4 are associated with severe target stopping smoking have been shown to reduce ser-
organ damage and high mortality (accelerated- ious sequelae.

488
 Ophthalmology

Diabetic retinopathy may progress rapidly in some

situations:

I
0

-
Background retinopathy
o Does not affect visual acuity
Microaneurysms - first clinical change,
saccular pouch, either leaks or resolves
due to thrombosis
0

0
Pregnancy - 5% of patients with background
changes develop proliferative retinopathy'
Sudden improvement in control in previously
poorly managed disease
Haemorrhages - dot, blot and flame-
Diabetic p ap i l l o p at h y
i shaped
Exudates - leakage of lipid and
Typically bilateral process in young type 1 diabetic
lipoprotein patients, Associated with mild to moderate visual
~ No local treatment required; adequate loss. Fundal examination reveals disc swelling,
I
-

control of diabetes only
Diabetic maculopathy
Most common cause of visual loss
More common in type 2 diabetes
v Retinopathy within the macular region
macular oedema with exudates and macular star.
There is no specific management apart from control
of the diabetes. Usually spontaneous recovery with-
in 6 months.

Oedematous retina that is in close

Non-retinal a ye disease Indiabetics
proximity to the fovea may require laser
0
- treatment
Preproliferative retinopathy
Cotton-wool spots - represent areas of
axonal disruption secondary to
The eye may be affected by diabetes in several
other ways:
0 Visual changes
Secondary to osmotic lens changes with
ischaemia

- Venous changes - dilatation and beading fluctuating glucose levels

1

~ Large deep haemorrhages 0

Treatment controversial: some advocate
prophylactic laser treatment, others
recommend improving disease control
and more frequent monitoring
0 Proliferative retinopathy
~ More common in type 1 diabetes
~ Retinal neovascularisation: new vessels
occur in thin-walled friable clumps on
the venous side of the retinal
circulation; new vessels on the disc are
more ominous than those on the
vascular arcades; vitreous haemorrhage,
y fibrosis and tractional retinal
detachment may occur
~ Iris neovascularisation: may be
l complicated by glaucoma
Treatment with laser
photocoagulation
to retina is designed to abolish the
production of angiogenic factor from
ischaemic retina and induce regression
of new vessels
Mononeuropathies
~ Leading to ophthalmoplegia
0 Snowflake cataract
~ Poorly controlled juvenile diabetes
Early~onset senile cataract
I Increased external eye infections
~ (eg conjunctivitis, styes)
l7.2.5 Macular de ge ne r a t i on
Macular degeneration is the commonest cause of
blindness in people aged >65 years, lt can be
broadly classified into 'wet' or 'dry' forms, accord-
ing to the presence or absence of retinal oedema.
Wet degeneration occurs due to subretinal choroi-
dal neovascularisation. Dry macular degeneration
can predispose tothe wet form of disease.
Risk factors for macular degeneration include:
0
Family history
0
Myopia
0
Smoking
489
Essential Revision Notes for MRCP
Central visual loss, which may be severe, with
preservation of the peripheral field occurs in both
types, Dry degeneration tends to be slowly progres-
sive, whereas the onset of wet degeneration may
result in acute visual loss. There is no treatment for
dry macular degeneration. Vt/et macular degenera-
tion has previously been treated with laser therapy,
either alone or more latterly in combination with
photodynamic therapy. A new treatment involving
the repeated intraocular injection of anti vascular
endothelial growth factor (\/EGF) substances, for
example Lucentisiv rranibizumabl, has recently
been approved for use in selected individuals with
recent-onset wet macular degeneration.
17.2.6 Retinitis pi gme nt os a
Retinitis pigmentosa (RP) is a term describing a
group of progressive inherited diseases affecting the
photoreceptors and the retinal pigment epithelium.
These conditions are more correctly termed photo-
receptor dystruphies. RP is characterised by the
triad of:
0
Night blindness: clue to loss of rod function
I Tunnel vision: loss of peripheral field, also due
to rod dysfunction; central visual acuity loss due
to cone disease may also occur but tends to be
a later feature
0
Pigmented 'bony spicule fundal appearance
with associated disc pallor and blood vessel
attenuation
There are three inheritance patterns: autosomal
recessive, autosomal dominant and X-linked reces-
sive.
Disease onset and progression vary between differ-
ent groups and also between affected members
within families. Autosomal recessive and X-linked
recessive forms tend to be more severe.
important systemic associations include:
0
Abetalipoproteinaemia (Bassen-Kornzweig
syndrome): autosomal recessive disease
490
typically affecting Ashkenazi jews. Treatment
with high-dose vitamin E may help neurological
and retinal disease. (See Chapter i 3 , Metabolic
diseases)
0 Refsum's disease: autosomal recessive disorder
of phytanic acid metabolism leading to its
accumulation in tissues, causing peripheral
neuropathy, cerebellar ataxia, ichthyosis and
deafness. Serum phytanic acid levels are
elevated and examination of the cerebral spinal
fluid (CSF) reveals elevated protein in the
presence of a normal cell count. Refsums
disease is responsive to a phytanic-acid-free diet
which excludes animal fats, dairy products and
green leafy vegetables
0 Usher syndrome: autosomal recessive condition
with non-progressive sensorineural deafness
0
Bardet-Biedl(Laurence-Moon-Biedl)
syndrome: autosomal recessive disease with
mental retardation, obesity, hypogonadism,
polydactyly, deafness and renal cystic disease
0
Keams-Sayre syndrome: disorder of
mitochondrial inheritance with progressive
external ophthalmoplegia, ptosis and heart
block
17.3 LENS ABNORMALITIES
17.3.1 Cataract
Cataract is an opacity of the lens. lt is the most
common cause of blindness worldwide, Many clas-
sifications exist according to type, aetiology and
associations. Surgical intervention is indicated:
0 When patient function is impaired because of
decreased vision
0 lf the view of the fundus is impaired when
monitoring or treating another condition (eg
diabetic retinopathy)

`
~ ~ Gu u s s>af 1
<
0
Congenital
Autosomal dominant (25%)
~ Maternal infection - rubella,
toxoplasmosis, cytomegalovirus (CMV),
herpes simplex, varicella zoster
Maternal drug ingestion -
corticosteroids, thalidomide
Metabolic -
galactosaemia,
hypocalcaemia, Lowe syndrome,
hypoglycaemia
Chromosomal abnormalities (eg Down
syndrome, Turner syndrome)
0
Toxic/drug-induced
~ (eg steroids, chlorpromazine, busulfan,
gold, amiodarone)
I Senile
0
Secondary to ocular disease
-
0
(eg uveitis, high myopia)
I Metabolic
Diabetes, hypoglycaemia,
mannosidosis, Fabrys disease, Lowe
syndrome, Wilson's disease,
hypocalcaemia, galactokinase
deficiency
0 Traumatic
1
Penetrating or blunt injury, infrared
radiation, radiotherapy, electric shock
0 Miscellaneous
~ Myotonic dystrophy, progeria, atopic
dermatitis
17.32 Lens dis location
Lens dislocation results from disruption of the
zonules that anchor it in position. Depending on
the lens shift this may produce myopia or hyperme-
tropia, or elevated intraocular pressure.
Ophthalmology
Ca use s of lens dislocation
Marian syndrome: up and out
Homocystinuria: down and in
Ehlers-Danlos syndrome
Autosomal recessive ectopia lentis
Trauma
Uveal tumours
17.4 OPTIC NERVE DISORDERS
17.4.1 O pt i c ne ur i t i s
inflammation of the optic nerve may affect the:
0 Nerve head: producing papillitis with optic disc
swelling, hyperaemia and haemorrhages
0 Retrobulbar portion of the nerve: producing
retrobulbar rieuritis in which the nerve appears
normal (the patient sees nothing, the doctor
sees nothing')
It is the presenting feature of 2 5 % of patients with
multiple sclerosis (MS); the cumulative probability
of developing MS by i5 years after an attack of
optic nerve nueritis has been found to be 50%
(strongly correlated to the presence of lesions on
MRI of the brain). The clinical signs of optic neuritis
are shown in Table 17.2.
Causes of o p t i c neuritis/papillitis
0
Demyelination
0 Post-viral syndromes
0 Infections; viral encephalitis (measles, mumps,
chickenpox), infectious mononucleosis, herpes
z osle r
0
Inflammatory: contiguous with orbital
inflammation, sinusitis or meningitis secondary
to granulomatous Optic nerve inflammation (eg
TB, sarcoid, syphilis)
I Other systemic disease, eg diabetes
491
Essential Revision Notes for MRCP

Table 17.2. Clinical signs of optic neuritis (in order of frequency of o ccu rren ce)

Reduced visual acuity
In classic demyelination this is usually monocular (90%) and
progresses rapidly
over a few days; improves over 4 - 6 weeks,
achieving virtually normal vision in
90%, although an RAPD usually persists

Pain Present in demyelination, precedes visual loss by a few days, worsened by eye
movements

Red colour desaturation Red appears darker or brown to the

patient
Relative afferent Swinging flashlight test - see Section 16.3.2
pupillary defect (RAPD)
Paracentral or central Cornmonest defect, although any type ofscotoma may occur
scotoma
Visual-evoked potential Reflecting delayed conduction in optic pathway
prolonged
Optic atrophy Develops within weeks, may be seen in contralateral eye as a sign of previous
asymptomatic episode

17.4.2 Caus es of o p t i c atr o p h y

Post-optic neuritis
.1 ' was->::#[e< -i, _fre-`5, ;,.! i`;f%=f?
See above
Post-trauma
Toxic neuropathy
0
Congenital (eg tobacco (cyanide), arsenic, lead,
~ Dominant or recessive methanol)
0
Secondary to optic nerve compression Nutritional
~ (eg pituitary mass, meningioma, orbital Vitamins B1, B2, B6, Bn, folic acid and

I
- cellulitis)
Drugs
Ethambutol, isoniazid, chloramphenicol,
digitalis, chlorpropamide
Radiation neuropathy
niacin deficiencies
~ Tobacco-alcohol amblyopia may be
toxic or nutritional (mechanism not fully
understood) with a good prognosis for
recovery with withdrawal of tobacco
0 Carcinomatous and alcohol, and vitamin B and folate
~ Due to microscopic infiltrates of the supplementation
nerve and its sheath Infiltrative neuropathy
I
Post-papilloedema ~ (eg sarcoid, lymphoma, leukaemia)

492
 Ophthalmology

17.4.3 The swollen o p t i c nerve head which giant-cell arteritis affects vision (90%), retinal
P api l l oedem a artery occlusion occurring in the other 1 0 % of
cases. It is essential to exclude this condition as it
Papilloedema means optic nerve head swelling sec- rapidly becomes bilateral. Giant cells and loss of

-
ondary to increased intracranial pressure. This may the internal elastic lamina are evident histologically
be due to: on temporal artery biopsy.
Space-occupying lesion Ischaemic optic neuropathy is not always due to
i
Hydrocephalus inflammatory arteritis; it may be due to arterio-
CO2 retention sclerosis or to hypotensive events. If visual loss is
>
idiopathic intracranial hypertension incomplete an altitudinal (ie horizontal) field defect
results.
Papilloedema is usually bilateral. Features include:
I

0
0
Hyperaemia of the disc: due to capillary
dilatation
Splinter haemorrhages of retina
Blurring of the disc margins: due to nerve fibre
.
i . "

..
`

.
._
> f ,*~,:;., <
i=.;i...J
..,.='., ._ Mft?
~- t

0 Central retinal vein occlusion

layer swelling
0 Exudates and cotton-wool spots
0 Loss of spontaneous venous pulsation: absent in
20% of normal people
s
I Loss of the cup is a late feature
On clinical examination papilloedema produces an
enlarged blind spot. Transient visual obscurations,
with blacking out of vision lasting a few seconds
often due to positional change, also occur. Visual
loss occurs late.
Foster-Kennedy syndrome is unilateral papilloe-
dema with contralateral optic atrophy. lt is due to a
mass lesion compressing the optic nerve on one
side causing ipsilateral atrophic changes and result-
ing in increased intracranial pressure and contralat-
eral papilloeclerna.
Papillitis
This refers to inflammation of the optic nerve head
(as distinct from retrobulbar neuritis) and is most
frequently due to a demyelinative episode ( se e Sec-
tion 17.4.1 above).
Anterior ischaemic o p t i c n eu ro p at h y
i
> infarction of the anterior portion of the optic nerve
l results in acute severe visual loss which generally
does not improve. This is the usual method by
l
0 Orbital mass (eg optic nerve glioma, nerve
sheath meningioma, thyroid eye disease
and metastases)
0
Accelerated-phase hypertension (see above)
0 Infiltrative neuropathy (eg lymphoma)
0 Toxic neuropathy
17.5 UVEITIS AND SCLERITIS
17.5.1 Uveitis
Uveitis is inflammation of the uveal tract/ which
may affect the anterior (iris and/or ciliary body) and/
or posterior uvea (choroid).
Anterior uveitis typically presents with pain, photo-
phobia, a red eye, lacrimation and decreased
vision.
Posterior uveitis presents with floaters (due to in-
flammatory debris in the vitreous) or impaired vision
[secondary to choroiditis if the inflammatory lesion
is within the macula).
Uveitis of any cause may be complicated by catar-
act or glaucoma. Anterior uveitis is most commonly
idiopathic but there are also many associations with
systemic diseases.

493
Essential Revision Notes for MRCP

conjunctivitis and keratitis; 85%-95% of

uvmsmfauafjasqam~.yf~l patients with ocular involvement have HLA B27
0
Behcel syndrome: ocular disease occurs in 70%
of patients. Anterior uveitis is often severe and
HLA-B27-associated uveitis bilateral. Conjunctivitis and episcleritis are seen
Ankylosing spondylitis and the retina is frequently affected by retinal
Sarcoidosis vasculitis with infarction, secondary venous
Inflammatory bowel disease occlusion, retinal oedema, exudates and
Iuvenile idiopathic arthritis neovascularisation
(Previously termed juvenile chronic 0 Iuvenile idiopathic arthritis: ocular involvement
arthritis) typically occurs in pauci-articular disease,
0 Reiter syndrome particularly those patients who are ANA
I Infections positive. Uveitic activity bears no relation to that

TB, syphilis, herpes simplex, herpes of the arthropathy. The disease is usually
zoster, toxoplasmosis, toxocariasis, bilateral and asymptomatic and therefore
AIDS, leprosy regular screening is required because ofthe
0 Behcet syndrome high incidence of complications. These are
0
Malignancy cataract in 35% of patients, secondary
e
Non-Hodgkins lymphoma glaucoma in 20% and band keratopathy in 40%
e Leukaernia tcalcified band across cornea)
~ Retinoblastoma
Common causes of posterior uveitis (chorio-
~ Ocular melanoma
retinitis) are:
0
Idiopalhic
Characteristics of uveitis associated with particular
0
Inflammatory: sarcoid
0 Infections: ( se e box above) TB, syphilis
systemic diseases are:
(congenital and tertiary), leprosy, toxoplasmosis,
0 HLA B27 genotype: present in 50/0-60% oi toxocariasis and AIDS
0
patients with anterior uveitis as compared to 6% Malignancyz leukaemia, lymphoma
of the population
0
Ankylosing spondylitis: recurrent anterior uveitis Treatment of uveitis
occurs in approximately 30% of patients with
Anterior uveitis is treated with topical steroids and
ankylosing spondylitis, and about 30% of males often with cycloplegia. This dilation of the pupil
with unilateral uveitis will have ankylosing
spondylitis. The uveitis may precede or follow helps reduce posterior synechiae formation which
the joint involvement and does not correlate can be associated with elevated pressure; it also
with disease severity; 88% of those with uveitis reduces pain produced by ciliary spasm.
also have HLA B27 Posterior uveitis is treated according to the extent
0 Sarcoidosis: acute or granulomatous. Anterior or of visual involvement, for example whether the
posterior. Frequently bilateral and complicated. macular area of the retina is threatened. Treatment
(See Section 1 7 8 . 4 ) varies according to the nature of the underlying
0 Reiter syndrome: anterior uveitis occurs in 30% cause but generally involves steroids and/or other
of patients. Other ocular features include immunosuppression,

494

1 :'.;w.Z
. . - f
Sciet itis;
Inflammation of t he a d a m m a y be ~
canned by ,
Herpes zoster
Ankylosing spondylitis
Sarcoidosis
Inflammatory bowel disease
Gout
Vasculltis: PAN, SLE, Wegeners
granulomatosis, relapsing polychondritis,
dermatomyositis, Behcet syndrome
17.5.3 Causes of a pa inf ul red
eg/'.>
I
Conjunctivitis (bacterial is irritable, viral is
painful)
0 Uveitis
I Scleritis (causes listed above) severe boring pain
which disturbs sleep
0 Corneal damage (abrasion, keratitis, eg herpes
simplex and herpes zoster)
0 Acute glaucoma (due to angle closure or
rubeosis)
. opacities, which are associated with a mild
17.6 SYSTEMIC DRUGS AND THE
EYE
Blurred vision is very frequently reported as a side-
effect of systemic medication. The following are
common or sight-threatening complications. The list
is not intended to be comprehensive of all ophthal-
mic side-effects.
0 Steroids: the eye can be affected by systemic,
local (eg to eyelids) or topical steroids. They
c cause cataract and can elevate intraocular
pressure in some individuals, leading to
glaucoma. For this reason steroid creams to the
periocular skin are best avoided and the
intraocular pressure should be monitored in all
patients receiving steroid eye drops
Ophthalmology
Amiodarone: causes vortex keratopathy in
almost all patients. Epithelial deposits, which
are reversible on cessation of the drug, occur.
These swirl out from a point below the pupil but
are inconsequential to vision
Chloroquine and hydroxychloroquine:
classically cause 'Bulls eye maculopathy. There
is central hyperpigmentation at the fovea
surrounded by concentric rings of hypo- and
hyperpigmentation. Fundal changes occur after
Subjective visual loss. Baseline visual function
(corrected near and distance acuity, colour
vision, visual fi elds) should he established and
these parameters monitored throughout
treatment. Toxicity is rare with a cumulative
chloroquine dose of less than 300 g, and it is
much less likely to occur with
hydroxychloroquine. Once visual loss occurs it
may be progressive despite cessation of the drug
Ethambutol: causes optic neuropathy, more
frequently when used in high doses or with
renal impairment. The earliest feature is
subjective reduction in visual acuity. Toxicity is
usually reversible with early withdrawal of the
drug Visual acuity should be checked pre-
treatment and during the course of drug usage
Tamoxifen: causes maculopathy and refractile
reduction in vision
Vigabatrin: causes constriction of visual fields
which may be severe. The onset is reported to
occur from 2 months to 5 years after starting the
drug. The field defect starts nasally and
progresses to become concentric: the eyes are
affected symmetrically. The aetiology is thought
to be related to retinal toxicity, but this is not
fully understood; the visual field defects usually
persist on cessation of vigabatrin
Drugs with anticholinergic effects (eg tricyclics
and anaesthetic agents such as atropine,
glycopyrrolate and hyoscine): these can
precipitate angle-closure glaucoma in
susceptible patients (usually those who are long-
sighted)
495
Essential Revision /\/otes for MRCP
17.7 INFECTIOUS AGENTS AND THE
EYE
The following conditions may all be caused by
infectious agents, as discussed in previous sections:
Congenital cataracts (maternal infection)
Optic neuritis/papillitis
Uveitis
Scleritis
Conjunctivitis
17.7.1 Genito-urinary disease an d t h e
eye
All patients with genito-urinary disease affecting the
eye warrant evaluation at a genito-urinary clinic for
systemic investigation and treatment. Ophthalmic
features of HIV/AIDS are covered in Chapter 8,
Genito-urinary Medicine and AIDS.
C hl am ydi al conj unct i vi t i s
This is sexually transmitted and most commonly
found in young adults. lt may be associated with
non-specific urethritis or cervicitis. Typical features
are:
0 lt causes bilateral acute conjunctivitis which can
persist for several weeks
0 This is often associated with pre-auricular
lymphadenopathy
0 lt may lead to ophthalmia neonatorum_ Affected
newborns will require systemic treatment to
prevent pneumonitis
0
Diagnosis is by chlamydial culture or
immunofluorescence
Gonococcal conj unct i vi t i s
There is typically a hyperacute conjunctivitis with
marked chemosis and lid swelling accompanied by
copious discharge. This may be associated with
corneal ulceration and the risk of perforation. A
diagnostic swab may show Gram-negative diplo-
cocci, which may be grown on culture. Topical and
systemic treatment are indicated.
496
Sy p h i l i s
The ophthalmic abnormalities are related to the
particular stage of syphilis:
0
Congenital: interstitial keratitis [leads to
clouding of the corneas in the second decade of
life), iritis, chorioretinitis and optic atrophy
0
Primary: chancre may occur on the eyelid
0
Secondary: iritis occurs in 4% of patients with
secondary syphilis, usually bilateral; optic
neuritis, Chorioretinitis and scleritis are all
associated
0
Tertiary: associated with optic atrophy,
chorioretinitis, iritis, interstitial keratitis and the
Argyll Robertson pupil (small irregular pupils
which react to accommodation but not light)
17.7.2 Herp etic disease an d the ey e
Herpes simplex (HSV)
Most HSV infections are subclinical as 90% of the
adult population are seropositive.
0
Primary infection with HSV: this usually occurs
in children and causes conjunctivitis with lid
swelling. Lesions heal without scarring
0 HSV reactivation: this is associated with
epithelial keratitis. The corneal ulceration may
be dendritic', when lesions appear like the
branch of tree, or 'geographic' when the lesions
become much larger with an amoeboid shape.
The corneal stroma may subsequently become
involved. Treatment is with topical or long-term
low-dose systemic antiviral agents, dependent
on severity
He rpe s zoster
The painful acute vesicular rash follows a dermatom-
al pattern, and so disease affecting the fifth cranial
nerve can affect the eye. lf the rash is present on the
tip of the nose (Hutchinsons sign) this indicates
involvement of the nasociliary nerve and implies a
higher risk of ophthalmic involvement.
I The eye may be affected by conjunctivitis,
corneal ulceration, uveitis, scleritis, retinitis and
oculomotility abnormalities because of cranial
nerve involvement

17.7.3 Tropical e ye infections
Trachoma
Trachoma is the second commonest cause of blind-
ness worldwide and the commonest infective cause.
It is responsible for blindness in 6 million people
but 146 million have active trachoma, Chlamydia
trachomatis is spread through poor hygiene, close
personal contact and flies. Geographically affected
areas include Africa, Asia, the Middle East and parts
of Aboriginal Australia. The resulting conjunctivitis
clears after about a month but repeated infections
occur with conjunctival and subconjunctival scar-
ring. This C a u s e s :
0 Reduced tear production
0 Trichiasis - the eyelids scar such that the lashes
abrade the c or ne a , This causes corneal
epithelial damage, allowing secondary
infection
0 Blindness - due to corneal opacification,
generally occurs in adulthood
Onchocerciasis (River blindness)
Caused by the filarial nematode Onchocerca volvu-
lus and transmitted by flies in Africa and South
America. The larval form of the worm is transmitted
from host to host by the black fly, Over 1 - 3 months
the larvae develop into adult worms, which can
release up to 2000 microfilariae per day for up to
10 years. When the microfilariae die they produce
an intense inflammatory reaction. Ocular involve-
ment produces tearing, light hypersensitivity and
foreign body sensation.
Signs include:
0
Conjunctivitis
0 intraocular microfilariae - may be seen on slit
lamp examination
0 Keratitis snowflake opacitles
v
I Anterior uveitis and chorioretinitis
0 Optic neuropathy or atrophy resulting in visual
loss
Ophthalmology
17.8 MISCELLANEOUS DISORDERS
17.8.1 T hyr oi d e ye d isease
The ocular manifestations of Graves disease may
pre-date, coincide with or follow the systemic dis
ease. In patients with no history of thyroid disease
thyroid autoantibodies are frequently positive. The
only treatment modality known to worsen or pre-
cipitate thyroid eye disease is radioactive iodine.
The classic triad of thyroid eye disease includes the
association of ocular changes with thyroid acropa-
chy (a form of pseudo-clubbing) and pretibial myx-
oedema (both of the latter are now rare). For ease of
memory, eye disease may be divided according to
Werner's classification (NO SPECSl, although it is
important to appreciate that there is not a step-like
progression from one stage to the next, and that not
all steps occur in all patients.
No signs or symptoms
Only signs (eg lid retraction/lag)
Soft tissue swelling
Proptosis - orbital fat proliferation and muscle
changes; auto-decompresses orbital contents
Extraocular muscle changes - usually affect inferior
and/or medial recti; lymphocytic infiltrate
Corneal exposure
Sight loss - secondary to corneal disease or optic
nerve compression
Management of ocular manifestations may be
divided into;
0 Surface abnormalities: ocular lubricants,
tarsorrhaphy
0 Muscle changes: prisms or patches to control
diplopia, surgery after defect stable for
minimum of 6 months
0
Optic nerve compression: presents with visual
loss, red desaturation with/without a field
defect. lt requires urgent treatment to prevent
permanent visual loss management includes
-
systemic steroids, radiotherapy or surgical
decompression ofthe orbital apex
0 Cosmetic: improve lid position, remove
redundant tissue
497
Essential Revision Notes for MRCP
17.8.2 Myotonic dys trophy
An autosomal dominant condition characterised by
failure of relaxation of voluntary muscle fibres.
Anticipation occurs over successive generations
such that severity worsens, eg a family history of
early-onset cataract may be relevant.
' seen when phaeochromocytoma is present
0 Ptosis, poor lid closure and orbicularis
weakness
0 Retinal pigmentary changes
0 Presenile cataract
0 Miotic pupils
17.8.3 Ocular features of th e
p h aco mato s es
This group of disorders affects the nervous system,
skin, eye and other organs and they are charac-
terised bythe presence of hamartomatous lesions.
S t u r g e - W e b e r s y n d ro me
Glaucoma occurs on the ipsilateral side to cuta-
neous angioma in 50%. Cavernous haemangioma
may be seen in the choroid.
Neurofibromatosis
0 The eyelid may be affected by cutaneous
|'1! L|l'OlT1a
0 ln the anterior segment, iris nodules are seen
0
O
and glaucoma is more common
Choroidal naevi may be seen on fundoscopy
The optic n e n / e may be affected by glioma, and
a pulsati le globe suggests a defect of the greater
wing of the sphenoid
von Hi p p el -Li n d au s yndrom e
Autosomal dominant condition with incomplete pe-
netrance and variable expressivity, the abnormality
being on the short arm of chromosome 3.
I Retinal haemangiomas develop bilaterallv in
25% of patients and may leak (producing
498
exudates or a serous retinal detachment), or
rupture (leading to vitreous haemorrhage). These
are histologically identical to the cerebellar
haemangioblastomas which also occur
indirectly, increased intracranial pressure due to
posterior fossa haemangioblastoma may lead to
papilloedema; hypertensive changes may be
Tube rous sclerosis
Autosomal dominant condition linked to several
chromosomal abnormalities; 50% are new
mutations. Ocular features include retinal
hamartomas and, rarely, papilloedema or sixth
nerve palsy due to increased intracranial
pressure secondary to CNS lesions
17.8.4 Sarcoidosis
This multisystem granulomatous disease affects the
eye and ocular adnexae in about 30% of cases, and
of these 25% will have posterior segment disease.
Ocuhr effaeit`?iiQ~'all':otdnsis* `~ `
0
-
Lids
I
- Lupus pernio, cutaneous granuloma
Lacrimal glands
Granulomatous infiltrate, may cause
sicca syndrome (Mikulicz syndrome
when combined with parotid
0
- involvement]
Uveitis
Acute or granulomatous, frequently
bilateral, and complicated by glaucoma
and cataract
0 Retinal involvement
With periphlebitic 'candle wax
exudates, haemorrhages, oedema and
neovascularisation
Choroiditis and choroidal granulomata
Optic nerve granuloma
Disc oedema
Nerve palsies: Ill, IV, VI

17.8.5 Keratoconus
Keratoconus is an ectatic condition of the inferior
paracentral cornea. which produces a 'cone-
shaped cornea (Figure 17.2), Onset is usually in the
teens with progressive myopic astigmatism, Man-
agement is with spectacles and hard contact lenses
when astigmatism progresses. A corneal graft may
be required, but only in a minority of patients.
Systemic associations are:
Atopy
Down syndrome
Turner syndrome
Marian syndrome
Ehler-Danlos syndrome
Figure 17.2 Keratoconus
Normal eye Keratooonus
17.8.6 Glau co m a
Glaucoma describes the group of conditions in
which intraocular pressure is sufficient to cause
visual damage with a characteristic optic neurcv
pathy. The normal intraocular pressure is <2 2
mml-lg. Aqueous humour is formed by the ciliary
body, and passes through the pupil and drains, via
the trabecular meshwork, into the venous circula
tion through the episcleral venous system.
Acute g l au co ma
0
Rapid decrease in visual acuity associated with
severe pain and vomiting
Ophthalmology
0 More common in hypermetropes (those with
long-sightedness)
0 Due to closure of the drainage angle, resulting
in a massive sudden elevation in intraocular
pressure
0 The cornea appears cloudy (due to o ed ema) and
there is a mid-dilated non-reacting pupil
0 Failure to treat pressure rapidly results in
permanent visual loss
Chr onic g l au co ma
insidious asymptomatic disease
0 intraocular pressure elevated (usually not as
markedly as in acute glaucoma), resulting in
Cupping of the optic nerve head and loss of
visual field
0
Classically an arcuate scotoma develops, which
progresses to generalised field constriction
0 Familial tendency but no strict inheritance
More common in women and myopes (those
with short-sightedness)
S e c onda ry g l au co m a
Glaucoma is a possible complication of almost any
ocular disorder.
Secondar y glqucomas m ay be gexmrally
classified as follows
0 Pre-trabecular
(eg fibrovascular membrane in rubeosis
as may occur in diabetes)
0 Trabecular
Ciogging of meshwork by, for example,
inflammatory cells in uveitis or blood as
in cases of trauma, or meshwork
alteration due to inflammation in uveitis
or scleritis
0 Post-trabecular
Raised episcleral venous pressure
preventing outflow leg carotico-
cavernous fistula, or cavernous sinus
thrombosis)
499
Essential Revision Notes for MRCP
17.8.7 Ocular tumours
Pr i ma r y tumour s
I Choroidal melanoma: this is the commonest
primary intraocular tumour. It presents as a
unilateral lesion with variable pigmentation
iamelanotic to dark brown), lt may be
asymptomatic or can cause reduction in acuity
or loss of visual field, depending on the site of
the lesion
I Choroidal haemangioma: this appears as a red/
orange lesion most frequently seen at the
macula. A more diffuse lesion can be seen in
Sturge-Weber syndrome, which gives a deep-
red appearance to the fundus; this may only be
appreciated by comparison with the other eye
Se c onda ry tumours
The eye may be affected by metastases to the
choroid or orbit and cerebral metastases may affect
the visual pathway or cause oculomotility disorders.
500
0 Choroidal metastases occur most frequently
from breast, bronchial and renal primary
tumours. They are frequently multiple and also
bilateral. Lesions appear pale and are minimally
elevated. They are associated with metastatic
disease elsewhere. The effect upon vision 5
5*
depends on the site; macular lesions are most
common and can cause marked visual loss.
Palliative external beam radiation is usually
successful in improving vision
17.8.8 Blind r e gi st r a t i on
Blind registration is completed by ophthalmologists r
and can facilitate rehabilitation and social services
support. Monocular visual loss is not a criterion for
registration. Two levels for blind registration exist:
0 Partial sight registration: this is applicable when
the visual acuity is S6/24 in both eyes, or when
there is constriction ofvisual fields, including
hemianopia
0 Blind registration: when the visual acuity is
< 3/60 in both eyes
 C h a p t e r 18
Psychiatry

CONTENTS

18.1 Sc hiz ophre nia 18.7 Self-harm a n d suicide

18.1.1 First-rank symptoms
18.1.2 Medical co-morbidities 18.8 Orga nic psychiatry
18.1.3 Principles of treatment 18.8.1 Acute organic brain syndrome
18.8.2 Dementia
18.2 Mood di sorders 18.8.3 Physical illnesses particularly
18.2.1 Hypomania/mania (bipolar associated with mental
affective disorder) disorders
18.2.2 Depression 18.8.4 Drug-induced mental disorders
18.2.3 Depression in the elderly
18.2.4 Differentiation of depression 18.9 Alcohol a buse
from dementia 18.9.1 Social consequences of
18.2.5 Principles of treatment alcohol abuse
18.9.2 Acute withdrawal
18.3 A n x iety dis orders 18.9.3 Psychological consequences of
18.3.1 Generalised anxiety disorder alcohol abuse
18.3.2 Panic disorder 18.9.4 Neuropsychiatric
18.3.3 Phobic disorders consequences of alcohol abuse
18.4 Obse ssive c o m p u lsiv e dis order 18.10S leep di sorders
18.1O.1 Normal sleep
18.5 U n ex p lain ed phys ical 18. 102 Insomnia
s y mp to ms 18. 103 Narcolepsy
18.5.1 Somatoform disorders
18.5.2 Conversion disorder 18.11 T reatm ents in p s y ch iatr y
r 18.5.3 Factitious disorder 18. 111 Antipsychotics
18.11.2 Antidepressants
18.6 E a ting disorders 18.11.3 Benzodiazepines
18.6.1 Anorexia n e n / o s a and bulimia 18.11.4 Electroconvulsive therapy
I nervosa: diagnostic criteria (ECT)
18.6.2 Medical complications of 18. 115 The psychotherapies
anorexia nervosa
18.6.3 Principles of treatment

501
l
 Psych iatry

Psychiatry
18.1 SCHIZOPHRENIA
Schizophrenia is characterised by disturbances of
thought, perception, mood and personality. These
lead to 'positive' symptoms, such as delusions,
hallucinations and disorganisation of thoughts and
speech, and 'negative' Symptoms, including de-
creased motivation, poor selt'-care and social with-
drawal. Patients do not have a 'split personality.
The lifetime risk is about 1% for men and women,
although men consistently have an earlier age of
onset. There is strong evidence of genetic predispo-
sition, but not through a simple Mendelian model of
sively in schizophrenia. ln clinical practice they
occur in approximately 70% of schizophrenic
patients and in approximately 10% of manic pa-
tients. However, for the purpose of medical exam-
inations, including the MRCP, they should be
considered to be 'diagnostic of or 'characteristic of
schizophrenia in the absence of obvious organic
brain disease. A mnemonic for first-rank symptoms
follows.
ATPD -_~
Hrsi-r\1.\k.yu'rptoma mnemonic: `
A w w Pm D m r w y
'

inheritance (see Table 18.1).

Auditory hallucinations of a specific type:
Schizophrenia is a heterogeneous condition; signs
and symptoms present to a highly variable degree 0
ii-pe rson (ie two or more voices heard
between individuals. Despite this, generalisations discussing the patient)
can be made about certain 'core features. Schnei~ 0
Running commentary
ders first-rank symptoms were an attempt to tighten 0
Thought echo
diagnostic practice.
Thought disorder of a specific type (passivity of
thoughtl:
18.1.1 First-rank s y m p t o m s 0
Thought withdrawal
0
Thought insertion
Originally described by Schneider, these represent 0
Thought broadcasting
an attempt to identify symptoms that occur exclu
Passivity experiences (delusions of control);
Table18.1. Lifetime risk of schizophrenia in re-
latives of patients with schizophrenia
0
Actions/feelings/impulses under external
control
0
Bodily sensations being due to external
Relationship Per cent with influence
schizophrenia Delusional perception (tvvo-stage process):
ivionozygotic twin 50 0 Normal perception of commonplace object/
Children (both parents 46 sight, leads to. ._
schizophrenic) 0
Sglden, iiulse, silt-referential delusion (eg
Children 13 finding coin on the ground leads to belief of
Dizygotic twin 10 messianic role)
Sibling 10
Uncles/aunts 3
Unrelated 0.9 There are many other important clinical features
of schizophrenia, including impaired insight, sus-

'

503
Essential Revision Notes for MRCP
piciousness, flat/blunted or incongruous affect,
decreased spontaneous speech, general lack of mo-
tivation and poor self-care and abnormalities of
motor activity such as dyskinesia and catatonia.
Auditory hallucinations which are not of the type
covered by the first-rank symptoms may occur, as
can other types of delusions, often bizarre and non-
mood-congruent. These symptoms can be divided
into two categories, as follows.
Positive s ym pt om s
These include delusions, hallucinations and disor-
der of the form of thought. Temporal lobe gnilegy
is one important differential t should
be considered in individuals who experience posi-
tive symptoms and hence anQ may be useful in
certain patients,
Negative s ym pt om s
These include flat/blunted affect, decreased motor
activity and speech, poor motivation and self-care.
Patients with schizophrenia who manifest predomi-
nantly negative symptoms often have frontal cogni-
tive deficits in attention and executive function
(planning, goal-directed behaviour and monitoring
of performance). CT and/or MRI studies of the brain
in such patients have shown ventricular enlarge-
ment and cortical sulcal prominence.
18.1.2 Medical co-morbidities
There is increasing recognition that people with
schizophrenia have high levels of medical co-
morbidity and unhealthy lifestyle manifesting as
higher rates of cardiovascular disease, HIV/AIDS,
hepatitis and all malignancies. Obesity and diabetes
are particularly prevalent, which may partly be
explained by increasing prescription of atypical
antipsychotics. Standardised all-cause mortality
rates are 2 - 3 times those of the general population.
18.1.3 P r i nc i pl e s of treatment
Treatment of schizophrenia involves a biopsycho-
social model, but compliance with medication is
the best predictor of relapse.
504
B iological treatments
0
Atypical antipsychotics (eg clozapine,
olanzapine, risperidone) are now considered to
be first-line therapeutic agents. They have a
preferential side-effect profile, particularly with
regard to extrapyramidal side-effects. Use of
traditional antipsychotics (chlorpromazine,
haloperidol, trifluoperazine, etc) is limited by
extrapyramidal (tardive dyskinesia occurs in
>3 0 % of patients on long-term treatment) and
oaniafc side-effects. Antipsychotics may be
given orally, intramuscularly (IM) or depot IM;
depot preparations aid compliance and are now
available in atypical form (risperidone).
'Positive' symptoms respond better than
'negative' symptoms to antipsychotic therapy;
the y c h o t i c s are probably better
for negative symptoms. Electroconvulsive
therapy (ECT) may be needed for catatonic
stupor
0
Psychological treatments: three independent
trials have recently shown that cognitive
behavioural therapy (CBT) is a valuable
adiunctive treatment for patients with persistent
hallucinations and delusions. CBT can also aid
compliance
0 Social interventions: these should target
accommodation, finances and daytime
activities. Patients and relatives may both benefit
from supportive psychotherapy; counselling and
education. Early intervention by specialist teams
for young people with psychotic illness is key
Predictors of l ong-t erm outcome
Lack of
insight, long duration of untreated psychosis
and poor response to early treatment predict poorer
outcomes.
18.2 MOOD DISORDERS
Mood (affective) disorders are conditions in which a
pathologically depressed or elated mood is the core
feature. Depression is much more common than
mania; those who suffer with mania almost invari-
ably have one or more periods of depression at
 Psychia tn/

some stage in the course of their illness. Bipolar Perhaps the most crucial decision to make in the
disorder has high heritability associated with multi- management of bipolar disorder is the timing ofthe
ple loci for genetic susceptibility. introduction of long-term prophylactic mood-
stabilising medication (typically lithium or anticon-
vulsanls). There are no hard and fast rules; this is a
18.2.1 Hy p o m an ia/m an ia ( b ip o lar matter of clinical judgement.
affective disorder)
lilhium is the most commonly prescribed mood
Hypomania and mania are mood disorders charac- stabiliser and it is particularly important to remem-
terised by pathologically elated or irritable mood. ber its therapeutic window. (See Chapter 2, Clinical
Lifetime prevalence is about 1% with a slight female
Pharmacology, Toxicology and Poisoning.)
predominance. Hypomania is a less severe form of
mania - psychotic symptoms are absent. The major-
ity of symptoms in both are 'mood congruent, ie
understandable in the context of the pathological
mood change, There is usually a previous episode
of depression or there will be episodes of depres-
sion in the future, so hypomania/mania is pan of a
0
Short-term, acute episode
Antipsychotics (olanzapine is licensed
bipolar affective disorder. The main differential diag- for the treatment ofacute mania)
noses are usually organic psychoses or schizophre- ~ Benzodiazepines
nia. The clinical features of hypomania/mania are 0 Lithium (plasma level 1 ,0 mmol/l)
listed in the following box. ECT
._
0
- .,.y-,;1),..'.;;,;,._;a.;.:._,_,.'J _ I

long-term, prophylaxis
- Lithium
aw..-,.1/,~ .- _ t s., 5 i. . (plasma level 0.5 mmol/I)
g.t.._ _ ,<..\ J . ,
,`_.f.. ~ Carbamazepine (in patients
I Mood unresponsive to lithium, particularly
~ Predominantly elevated/elated irritable

0
o

--
Expansive (but note transient depression
c om m on)
Speech and thoughts
-

'rapid cyclers: >4 episodes per year)
Valproic acid
Lamotrigine (effective where depressive
episodes predominate)
Pressured (fast) ~ Depot antipsychotics

-
1
Flight of ideas
~ inflated self-esteem/grandiosity
Over-optimistic ideas
Poor attention, concentration
0 Behaviour 18.2.2 D e pr e ssi on
~ Insomnia
~ Overactivity Depression occurs with a wide range of severity
~ Loss of normal social inhibitions: over- and has a multifactorial aetiology. Lifetime inci-
familiar, sexual promiscuity, risk-taking, dence of depression varies from 1% to 20% accord-
overspending ing to severity, Evidence for a genetic contribution
~ increased libido is most compelling in the most severe illness,
increased whereas mild and moderate depression are usually
appetite, decreased weight
best explained by psychosocial models. These latter
Psychotic symptoms (mania)
Mood-congruent (eg delusions of disorders are rarely treated by psychiatrists unless
special ability or status, grandiose they are complicated by co-morbidity with sub-
delusions or auditory hallucinations) stance misuse or personality disorder. The variation
in severity and symptomatology of depression has

'

505
Essential Revision Notes for MRCP

led to a number of classification systems: 18.2.3 Dep r essio n in t h e elderly

0 Endogenous versus reactive (m ore closely
related to precipitating life e ve nts)
Melancholic versus neurotic
0
Unipolar (depression only) versus bipolar
(depression with mania)
Clinical fainree of rlopinnion ,
'Biological' symptoms (shown in italics) are
especially important because their presence
predicts response to physical treatments. They
are also known as somatic, 'endogenous' or
melancholicsymptoms:
Depression in the elderly is often missed. This is in
part due to the prejudice that depression is an
inevitable consequence of increasing age, but also
because older patients tend to present less with
depressed mood and more with physical com-
plaints. It is likely to be associated with social
isolation, bereavement, financial problems, physical
ill health and chronic pain. The most common
presentations are physical symptoms lor hypochon
driasis), insomnia (and psychomotor disturbances),
and most commonly agitation, but stupor may oc-
cur. Neurocognitive deficits that are secondary to
depression may mimic dementia ( se e below).

-
I Mood Treatment of de pre ssion on the elderly
o Loss of reactivity
Diurnal variation (worse in a m ) Again, a biopsychosocial model is used:
Pervasively lowered 0
Biological: selective serotonin re-uptake
Variable anxiety/irritability
inhibitors (SSRIs) are currently the most popular
I Speech and thoughts first-line agents. ln the elderly, patients may be
~ Slowed speech, low volume
sensitive to the side-effects of tricyclic agents,
Reduced attention/concentration
ECT may be preferable in severe illness
~
- Reduced self-esteem
Reduced confidence
Ideas of guilt, worthlessness,
hopelessness

0
Psychological: CBT
Social: decrease isolation

Bleak, pessimistic outlook 18.2.4 Differentiation of d ep r essio n

Ideas and acts of self-harm
0 Behaviour
Insomnia (early morning wakening)
Psychomotor agitation or retardation
~ Reduced libido
from d emen tia
The cognitive impairment seen in severe depression,
sometimes called depressive pseudodementia, can
lead to a misdiagnosis of primary dementia, particu-

-
Loss of enjoyment (anhedonia) larly in elderly patients. Conversely, it is important
Decreased appetite to recognise that organic dementia often presents
Weight loss with depressive symptoms in the early stages.
e Decreased social interactions Table 18.2 details differentiating clinical features.
Reduced energy/increased fatigue
Decreased activity
0
Psychotic symptoms
Mood-congruent
~ Delusions of guilt, physical illness
Auditory hallucinations with
derogatory
content

506
 Psychiatry

Table 18.2. Clinical features of depression and dementia

Clinical features Depression Dementia

Family history Affective disorder Alzheimers disease (in som e )

lllness duration Shon Long
Progression Rapid Slow
History of previous depression Yes No
Biological symptoms of depression Present Absent
c/o poor memory Yes No
History given Detailed Vague
Effort at testing Poor Good
Response at test results Picks on faults Pleased
Other behaviour Contrary Compatible
Examination of concentration/attention Variable Consistently poor
Orientation tests Dont know' Poor
Memory loss Global Recent
Primitive reflexes Absent Present
Apraxias Absent Present
Word intrusions Corrects Llriaware

Neuropsychological tests
Test performance Variable Always poor
Pattern Nil specific Verbal IQ > performance IQ

18.2.5 Pr in cip les of treatment symptoms are present then physical treatments are
indicated, whatever the apparent psychosocial pre~
Treatments in depression target the biological, psy- cipitants. See also Section 18,11, Treatments in
chological and social aetiologies. If biological psychiatry.
111% ., :_ :, ; , , . ' , t i t - , . ~
r<
, ,V ., -,,*_
0
,
.t /to o t/, > ft Q x

7 2-LJ fi, 1 rJ _,= s _at

0
Biological treatments
Antidepressants: for moderate to severe depression. SSRIs should be considered first-line (safer in
overdose and better tolerated than other classes). Second~|ine choices include mirtazapine and
reboxeti ne
~ Lithium (for augmentation of antidepressant effect, long-term prophylaxis or in treatment-resistant
illness)
~ ECT (for severe or resistant depression)
~ Antipsychotics (if psychotic symptoms present)
~ Thyroid hormone [T;; augmentation therapy in resistant depression)
0
Psychological treatments
~ Cognitive therapy: for mild to moderate depression
Supportive psychotherapy/counselling
0 Social interventions
0 Accommodation, finances, daytime activities

507
 Essential Revision Notes for MRCP
18.3 ANXIETY DISORDERS
18.3.1 Generalised a n x i e t y disorder
The clinical features of generalised anxiety disorder
are persistent and generalised, occurring across a
range of daily circumstances. Patients never com-
pletely return to a baseline level of zero anxiety.
Anxiety affects 1% -5% of the population (m ore
common in females) and commonly co-exists with
other psychiatric problems, particularly mood disor
ders. Organic causes of anxiety disorder include
drugs (eg caffeine) and thyrotoxicosis.
Cognitive symptoms
0 related situations and this, in turn, further reinforces
Apprehension
0 Fear of death, losing control or going mad
0
Hypervigilance
Somatic symptoms (associated with
a utonomic hyper-arousal)
0
Palpitations
0 Shortness of breath and hyperventilation
0 Butterflies in the stomach, nausea, loose bowel
motions
0
Urinary frequency
Muscle tension
0 Headaches, dizziness, light-headedness, tingling
in fingers and around mouth
Treatment of an x i et y disorders
I
Biological: specific SSRI antidepressants have
been shown to be especially useful.
Benzodiazepines (with care), [5-blockers,
buspirone (5HT1A partial agonist) and tricyclic
antidepressants are also used in the short term
0
Psychological: CBT (challenges dysfunctional
thoughts and processes) and anxiety
management (structured education, relaxation
training)
18.3.2 Panic disorder
These patients suffer paroxysms of intense anxiety
(panic) interspersed vvith periods of complete remis-
sion. Typical attacks last several minutes and occur
508
without situational cues. Somatic symptoms are
prominent. Patients may develop an anticipatory
fear ofthe next attack.
Physical treatment includes short-term use of benzo-
diazepines with care, and SSRIs. CBT is an appro-
priate psychological treatment.
18.3.3 Phobic d iso rd ers
These patients suffer from intense anxiety which is
reliably precipitated by a situational cue. The fear
they experience is out of proportion to the situation
and cannot be reasoned or explained away. This
results in the avoidance of the feared situation and
the phobia.
Specifidsimple phobias include fear of flying,
heights, animals, etc. Agoraphobia is anxiety about
being in places or situations from which escape
may be difficult (for example, in crowds, on public
transport, on a bridge), Social phobia is a persistent
fear of humiliation or embarrassment in social situa-
tions.
Appropriate physical treatments include SSRIs,
fi-blockers and occasionally short-term use of ben-
zodiazepines 'with care'. Patients may also benefit
from psychological treatments, including:
0 Behavioural psychotherapy: systematic
desensitisation (controlled exposure to the
feared situation), flooding, modelling
Supportive psychotherapy
I
Psychodynamic psychotherapy ( se e Section
18.1 T_5, The psychotherapies).
18.4 OBSESSIVE COMPULSIVE
DISORDER
Obsessive compulsive disorder may also be called
obsessional illness, or obsessional neurosis. Mild
obsessional symptoms are very common and may
actually be helpful for certain occupations (eg ac-
countancy and medicine). Pathologically severe
symptoms may be secondary to other psychiatric or
neuropsychiatric disorders (see below). The lifetime

prevalence of primary obsessive compulsive disor-
der is between 2% and 3%, with a slight excess of
females affected. It is widely considered to be a
neurobiological disorder associated with inadequate
serotonin regulation.
Obsessions are ideas, thoughts (ruminations) or
images that are:
Recurrent
Persistent and intrusive
Occurring against the patients will
Regarded as absurd, but insight is maintained
Recognised as a product of the patients own
mind (in contrast to psychosis, the patient
recognises that their thoughts are abnormal)
I Resisted -~ anxiety
Compulsions are:
0 Irresistible impulses to carry out a particular
activity
0
Usually triggered byan obsessional thought
(with the belief that the compulsion will
neutralise the thought and thus lower anxiety
levels)
OBSESSION ~> COMPULSION -> RITUAL
hands dirty must wash hands washing
Compulsions and ritualised behaviours are some-
times referred to together as compulsions. There is
a large overlap with depressive disorder, and the
t w o conditions often co-exist:
0 30% of patients with obsessive compulsive
disorder have associated depression
0 25% of patients with depression develop
obsessions
Other associations include:
0 Schizophrenia (3 % -5 % )
0 Anorexia nervosa
0
Organic brain disease (frontal lobe syndromes,
Sydenhams chorea, Tourette syndrome
tobsessional symptoms in 11%- 80%) )
Treatment of obsessive compulsive disorders
0
Psychological: in mild cases, CBT, which
includes habituation training and thought
Psychiatry
stopping (for obsessions), and exposure with
response prevention (for compulsions), is first-
line treatment
0
Biological: in moderate disease SSRIs or
clomipramine (to increase SHT
neurotransmission) combined with CBT.
Antipsychotic augmentation can be used ifthe
patient is resistant to SSRI alone. Very rarely
psychosurgery may be effective for the
extremely disabled patient
18.5 UNEXPLAINED PHYSICAL
SYMPTOMS
Within a general hospital or general practice setting
psychiatric referral may occur because no organic
cause is found for physical symptoms, Somatic
symptoms may be a manifestation of depression,
anxiety or schizophrenia (rare) and these diagnoses
should be excluded before a diagnosis of somato-
form, conversion or factitious disorder is made.
18.5.1 So matoform disorders
In this group of disorders there is repeated presenta-
tion of physical symptoms accompanied by persis-
tent requests for medical investigations. lf physical
disorders are present, they do not explain the nature
or extent of symptoms. Repeated negative
findings
and reassurance have little effect and patients usual-
ly refute the possibility of psychological c a usa tion,
In somatisation disorder the emphasis is on particu-
lar symptoms (eg back pain): in hypochondriacal
disorder, patients believe they have a specific dis-
ease process (eg cancer).
Somatisation disorder
0 More than 2 years of multiple physical
symptoms without adequate explanation
U Persistent refusal to accept advice or
reassurance that there is no physical explanation
Functional impairment due to the nature of
symptoms and resulting behaviour
Affects women much more often than men
0 ls accompanied by a tendency to excessive drug
use
509
Essential Revision Notes for MRCP

Particularly common symptoms include gastrointest- Treatment of somatoform disorders

inal sensations (pain, belching, vomiting, nausea), 9 CBT
abnormal skin sensations (itching, burning, tingling)
and sexual and menstrual complaints.
0
Psychotherapy: detection of the underlying
conflict (may require hypnosis/abreaction)
0
Antidepressants
Hy p o ch o n d ri acal disorder
0 Persistent belief in the presence of at least one
serious physical illness despite repeated 18.5.3 Factitio u s disorder
negative investigations Also known as Munchausen syndrome, this is the
0
Typical illnesses include cancer, AIDS intentional production of physical or psychological
0 Persistent refusal to accept advice or symptoms. It is usually associated with severe per-
reassurance sonality disorder and treatment is extremely diffi-
0 Fear of drugs and side-effects cult.
The principles of treatment for somatoform disorders
are to exclude an organic basis for the complaint,
acknowledge that the symptoms exist and then 18.6 EATING DISORDERS
educate the patient about basic physiology and
elicit and challenge the assumptions leading from Anorexia n e o / o s a and bulimia nervosa share many

the symptoms. Self-monitoring (by keeping a diary) clinical features (Figure 18.1, Table 18.3) and pa-
can assist with the re-attribution of physical experi- tiens may satisfy criteria for anorexia or bulimia at
ences. different stages of their illness. Eating disorders are
much more common in women, but 5% -10% of
cases of anorexia are male. They are frequently
18.5.2 Conversion d iso rd er
undiagnosed and many such patients are not known
This is a rare cause of unexplained physical symp- to the healthcare system.
t o m s , The theory is that intolerable psychic anxiety
is unconsciously 'converted' to physical symptoms,
The extent of 'motivation' or voluntary control is Figure 18.1 A schematic representation of the
usually hard to assess, but there is a clear alteration relationship between anorexia nervosa and
or loss in physical function which is usually acute, bulimia n e w o s a , ln clinical practice a diag-
but may be chronic. nosis of bulimia is restricted to those with
greater than average body weight. Those in the
Such psychogenic symptoms usually follovv an
overlap are considered to have anorexia, buli-
unresolved stressful event and their existence may mic subtype.
lead to a reduction in psychological distress ('pri-
mary gain') and to a resolution of the stressful event.
Although some patients experience the 'secondary
gain of attention from others, others may be indif-
ferent to their loss of function (la belle indiffer-
ence' ). Isolated conversion symptoms may be
associated with schizophrenia or depression.
Convincing evidence of psychological causation
may be difficult to find. It is vital to exercise caution
in making a diagnosis of conversion disorder, espe- N'\f9Xi8 Bulimia
cially in the presence of a known CNS or peripheral l'\9 N0 S3 n en / o s a
nervous system disorder.

510
 Psych ia try

Table 18.3. Differentiation of eating disorders

Anorexia nervosa Anorexia nervosa Bulimia nervosa

(restricting subtype) (bulimic subtype)

'Nervosa' psychopathology Yes Yes Yes

Behaviour to control weight Yes Yes Yes
is
Bulimic episodes No Yes Yes
Low weight ( < 1 5% average Yes Yes No
body weight)
l- Amenorrhoea Yes Yes Possible

r.
Anorexia nervosa is largely restricted to social anorexia. Outcome is highly variable but is worse if
groups in which thinness is coveted, Presentation is there is preceding anorexia or if the bulimia is part
usually in adolescence and associated with child- ofa multi-impulsive personality disorder.
hood negative self-evaluation and perfectionism.
The long-term outcome is poor, with only 20%
making a full recovery and long-term mortality is
around 1 5 % - 2 0 % , 18.6.1 Anorexia nervosa a nd bulimia
n erv o sa: di a gnos t i c criteria
Bulimia nervosa has a prevalence in young women
of 1 %-2 % and usually presents in the 20s. About The diagnostic criteria of anorexia nervosa are
one-third of patients have a previous history of shown in Table 18. 4,

Table 18.4. Diagnostic criteria of anorexia nervosa

Loss of l_>15%) normal body weight which is
self-induced:
A specific psychopathology (nervosa'):
Extreme avoidance of foods considered 'fattening'
Aggravated by self-induced vomiting, purging or exercise
Overvalued idea that fatness is a dreadful state
Extremely harsh definition of fatness
Will not let weight rise above very low threshold

Specific endocrine associations:

Female Amenorrhoea
Delayed puberty if very young (primary amenorrhoea)
Male Loss of sexual interest and potency
Delayed puberty if very young; arrest of secondary sexual
characteristics

511
Essential Revision Notes for MRCP

Bulimia nervosa: d i ag n o s t i c cri t eri a

Key features:
0 Morbid fear of fatness
0
Episodes of binge eating 0
Sharply defined weight threshold
0 Persistent preoccupation with eating 0 Earlier episode of anorexia nervosa
0 Irresistible craving for food

Self-induced vomiting
Periods of starvation
Purgatlve and diuretic abuse
Abuse of appetite suppressants
Abuse of thyroid hormones
Neglect to use insulin (diabetics)
18.6.2 Medical co m p licatio n s of
an o rex ia nervosa
The medical complications of anorexia nervosa are
mostly physiological adaptations to starvation and
usually regress with refeeding (Table 18.5).

Table 18.5. Medical complications of anorexia nervosa

Cardiovascular Bradycardia (87%)

Hypotension (85%)
Ventricular arrhythmias
ECG abnormalities (including increased QT/RR slope)
Congestive cardiac failure and cardiomyopathy

Gastrnenterological Eroded dental enamel/caries (secondary to vomiting)

Enlarged salivary glands (secondary to vomiting)
Oesophagitis, erosions, ulcers
Oesophageal rupture
Acute gastric dilatation with refeeding
Decreased gastric emptying
Constipation
Duodenal dilatation
irritable bowel syndrome
Melanosis coli (secondary to laxatives)
Renal Decreased glomerular filtration rate
Decreased concentration ability
Hypokalaemic nephropathy
Pre-renal uraemia

( continued)

512
'

Psychiatry

Table 18.5. (continued)

Haematological Pancytopenia
Hypoplastic marrow
Low plasma proteins

L
Musculoskeletal and skin Early onset leads to shorter stature
Osteoporosis and pathological fractures
Muscle weakness and proximal myopathy
l
Cramps
Tetany
Xerosis (dry scaly skin)
Lanugo hair
Hair loss
Acne
Carotenoderma (yellow-orange skin discoloration caused by increased serum
carotenoids)
Acrocyanosis
- calluses on the dorsum ofthe hand, caused by using the
Russe|l's sign
fingers and hands to induce vomiting
i Metabolic Hypothermia and dehydration
Electrolyte disturbance (especially hypokalaemia, hyponatraemia,
hypomagnesaemia)
l
Hypercholesterolaemia and carotinaernia
Hypoglycaemia and raised liver enzymes

| Neurological Reversible brain atrophy lon CT sc a n)

Abnormal EEG and seizures
Endocrine Low follicle-stimulating hormone (FSH)/ luteinising hormone (LH), Oestrogens,
testosterone
L Low tri-iodothyronine (Ti)
Raised cortisol and positive dexamethasone suppression test
I Raised growth hormone (CH)

513
Essential Revision Notes for MRCP

18.6.3 Pr inc iple s of treatment

The Princi Ples of treatment for anorexia nervosa are
given in Table 18.6.

Table 18.6. Principles of treatment for anorexia nervosa

Biological/physical treatments Psychological treatments

Anorexia nervosa Anorexia nervosa
0 Restoration of
weight as an inpatient, ideally in a specialist eating 0
Supportive psychotherapy
disorder unit 0
Family therapy
0
Drugs have a limited place in management 0 CBT
0
Enteral/parenteral nutrition is rarely indicated
Bulimia nervosa Bulimia nervosa
0 Selective serotonin
re-uptake inhibitor (SSRl> may be useful 0 CBT
0 Reduce
bingeing and self-induced vomiting 0
Cognitive analytic therapy
0 Effect not related to the
presence of depressive symptoms 0
Self-help manuals

18.7 SELF-HARM AND SUICIDE
A good deal is known about the epidemiology of,
and risk factors for, deliberate self-harm, both fatal
and non-fatal. These are presented in Table l 8 , 7 . A
decrease in the rate of suicide, particularly in
patients vvith mental illness, has been the target of
many government policies,
The incidence of completed suicide is reduced
during wartime and in certain religious groups (eg
Roman Catholics). The incidence is increased in
springtime, amongst those working in certain high-
risk occupations, such as farmers and doctors, and
amongst those who are unemployed, and those
who have a family history of suicide and have the
means available to carry lt out (ie weapons/drugs).
Although the UK Suicide Policy focuses on reducing
deaths by Suicide in younger people (particularly
young males) elderly males are still at highest risk of
completed suicide.
0 Non-fatal deliberate self-harm is a strong risk
factor for eventual completed suicide
0
Approximately 20% of non~fatal deliberate self-
harm cases repeat within 1 year
0 1%-2% per year of non-fatal deliberate self-
harm cases will lead to suicide within l year
0 10%-20% eventually commit suicide
Prevention of the above involves the identification
and treatment of mental illness, increased avvare
ness among GPS and in hospital staff, and the
removal of the means to commit suicide (firearms
restrictions, limit sales of paracetamol, catalytic
converters).

514
ii

Psychiatry

Table 18.7. Features of suicide and non-fatal self-harm

Suicide Non-fatal self-harm

Annual incidence in UK `l/10 DUO (5000 totall 20-30/10 000

Se>< M : F= 3 1 1 F> M

Age Young and old males Young, < 3 5 years

i

Socioeconomic class l, V iv, V

Childhood Parental death Broken home

Physical health Chronic or terminal illness, Nil specific

handicapped, pain
It
l Mental illness Depression ~ 60% Depression ~ 10%
Alcoholism ~ 20%
Schizophrenia 10%
Pre-morbid personality Usually well-adjusted Antisocial, borderline personality
disorder

Precipitants Guilt, hopelessness Situational

Setting Premeditated, alone, warnings Impulsive, others present

Method Drug overdose. Males use more Drug overdose and cutting
>
violent methods, eg hanging

18.8 ORGANIC PSYCHIATRY 18.8.1 Acute or ga ni c brain sy n d r o m e

Organic brain disorders can mimic any other func-
tional mental disorder. Features that raise the possi-
bility of an organic disorder include acute onset,
l visual perceptual abnormalities (illusions or halluci-
nations), cognitive deficit clearly preceding other
.
symptoms, neurological signs and fluctuating symp-
1OmS.
This is also known as acute confusional state, or
delirium. The young and the elderly are especially
vulnerable. A breakdown of the blood-brain barrier
is implicated. There are multiple possible aetiolo-
gies, both intra- and extracranial. Many of these
converge in a final common pathway of profound
cholinergic deficit.

515
Essential Revision Notes for MRCP

Causes of acute orga ni c 'brain syndr ome
0 Extracranial
~ Hypoxia (cardiac, respiratory)
~ Infection (respiratory, urinary,
- septicaemia)
Metabolic (electrolyte imbalance,
uraemia, hepatic encephalopathy,
EEG tests for this condition are sensitive but not
specific; results may be abnormal (slowing of
rhythm, low voltage trace) in the absence of clear
cognitive abnormalities.
Principles of treatment are:
0

0
Specific - to treat cause of confusional state
General - to optimise immediate environment
and reduce disorientation
E
.r
-i

porphyria, hypoglycaemia)
~ Hypovitaminosis (thiamine, B12) 0 Symptomatic - careful use of sedatives if
Endocrine (hypo/hyperthyroid, necessary
hypo/
hyperparathyroid, diabetes, Addisons/
hypopituitarism) 18.8.2 Dementia
~ Cushings,
Toxic (alcohol intoxication, alcohol
withdrawal, all other illicit drugs, Dementia is the global deterioration of higher men~
l
0
- prescribed drugs (many), heavy metals)
Intracranial
Trauma (head injury)
infection (meningitis, encephalitis)
Vascular disease (transient ischaemic
tal functioning secondary to progressive neurode-
generative disease. Characteristic clinical features of
dementia include episodic memory loss, apraxia,
deterioration in self-care skills, temporal and topo-
graphical disorientation and personality changes in
attacl</stroke) hypersensitive the presence of clear consciousness (cf acute confu-
encephalopathy, subarachnoid sional state). Delusions, hallucinations, agitation
and aggression occur, particularly in the moderate
~ haemorrhage
Space-occupying lesion (tumour, stages before the dementia is ven/ severe.
abscess, subdural haemorrhage)
~ Epilepsy Aetiology
0 Alzheimer's disease ~50%
0
Lewy body dementia ~2O%
'

at 0 Vascular dementia (multi-infarct dementia)

~20/0

Clouding of consciousness For differentiation of dementia from depression, see

Disorientation Section 18.2.4.
Poor attention (digit span) Table 18.8 lists the features of Alzheimerls disease
Memory deficits and multi-infarct dementia.
Disturbed behaviour (especially at night)
Mood abnormalities
Disordered speech and thinking
Abnormal perceptions (especially visual
misperceptions and hallucinations)
0 Abnormal beliefs
I Patients may be severely agitated or
withdrawn and stuporose

516
 Psych iatry

Table 18.8. Features of Alzheimers disease and multi-infarct dementia

Clinical feature AIzheimers disease Multi-infarct dementia

Age of onset 7 0 -9 0 years 6 0 -8 0 years

Sex F> M M> F
Family history FAD* less than 1%
Aetiology Genetic + environmental Embolic
Onset lnsidious Acute
Presenting symptoms Cognitive Emotional
Cognitive impairment Diffuse Patchy
Insight Early loss Preserved
Personality Early loss Preserved
r Course of progression Relentless Stepwise
l Focal neurological signs Unusual Common
| Previous CVA** or TlA*** +++
+++
y Hypertension
Associated ischaemic heart disease +++
Seizures + +++
Most common cause of death Infection lschaemic heart disease
l
i
Time to death from diagnosis 2 - 5 years 4 - 5 years
l *FAD 1
familial Alzheimers disease; *C\/A = cerebrovascular accident; ***T|A = transient ischaemic attack

li

>

517
Essential Revision Notes for MRCP

18.8.3 Ph y sical illnesses particularly

asso ciated with men tal
disorders

Physical illnenaemparticuhrly disorders ,

0
-
Neurological

-.Parl<inson's disease (depression, dementia)

Huntingtons disease (personality

Epilepsy (depression, psychosis)

change, depression, suicide, dementia)
Neurosyphilis (dementia, depression, grandiosity)
Multiple sclerosis (depression, elation, dementia)
Wilsons disease (affective disorder, aggression,
impairment)
~ Prion diseases (depression, personality changes,cognitive
dementia)
Brain tumour (location determines early symptoms)
o Myasthenia gravis
(depression)
~ Motor neurone disease (depression, dementia)
0 Endocrine
~ Cushing syndrome: psychiatric disturbance in about 50% of hospital cases, depression, euphoria,
confusion, paranoid psychoses, cognitive dysfunction in 66%
e Addisons disease: psychiatric features in nearly 100%, depression, withdrawal, apathy,
memory
difficulties in up to 75%
~ Hyperthyroidism: psychological disturbance in 100%, restlessness, agitation, confusional state
(rare), psychosis (very rare)
Hypothyroidism: mental symptoms universal at presentation, lethargy, cognitive slowing, apathy

I
-- > depression, irritability, confusional state, dementia, affective or schizophreniform
(very rare)
Phaeochromocytoma: paroxysmal anxiety
Other systemic causes
psychosis

Systemic lupus erythematosus (SLE) (acute confusional state, affective or schizophreniform

psychosis): may be further complicated by the effect of steroids
~ Vitamin deficiency (B1: V\/ernicke-Korsakoff syndrome; B12; acute confusional state, depression)

Porphyria (especially AIP): acute confusional state, depression, paranoid psychosis

Paraneoplastic syndrome: depression, psychosis

518
 Psychiatry

tnfug-1imiatf;c<>; -rmfmvfai : s .:r :a: :>

Many drugs can lead to psychiatric conditions
(Table 18.9).

Tahle18.9. Mental disorders induced by drugs

Anxiety Depression Psychotic symptoms

Amphetamines Reserpine Amphetamines (including MDMA, 'ecstasy)
Cocaine |3Blocl<ers LSD
Alcohol Calcium antagonists Cocaine
Phencyclidine (PCP) Oral contraceptive pill Marijuana
Corticosteroids Levodopa
Alcohol Anticholinergic drugs
Furosemide Anabolic steroids
PCP

."T~l f=.i{'O>l(.! =l"l"~ < ~--fu;-il <t i \ . s < q l w n c e s of

:.51 S'-!a:,=.~l slxizrsr'
The complications of alcohol are vvide-ranging and
cross social/ psychological and neuropsychiatric Family/ma rital problems
domains. General medical problems are not cov- Incest
ered here. Absenteeism from work

Alcohol de pe nde nc e syndrome - seven

Accidents (major factor in >l 0% of road traffic
accidents)
k ey features Crime (associated with acute abuse)
I
Vagrancy
Sense of compulsion to drink
Stereotyped pattern of drinking `- " 3
, :ana \\fithcix'a\.x_1,i
Prominent drink-seeking behaviour
Increased tolerance to alcohol Acute withdrawal causes a wide spectrum of symp
Repeated withdrawal symptoms toms. The fully developed syndrome is known as
Relief drinking to avoid withdrawal delirium tremens.
symptoms
0 Reinstatement after abstinence

519
Essential Revision Notes for MRCP

18.9.3 Psy ch o lo g ical co n seq u en ces of

alcohol a b u se

-
Definition of full syndrome
0
These include dysphoric mood, pathological jea-
Vivid hallucinations (often visual)
lousy (Othello syndrome) and sexual problems (im -
Delusions
potence, decreased libido). Other symptoms are
.
Profound confusional state
Tremor
Agitation
alcoholic hallucinosis and alcohol dependence syn-
drome. Alcohol abuse commonly occurs secondary
to other psychiatric illnesses, particularly bipolar
Sleeplessness disorder, depression, anxiety and posttraumatic
Autonomic overactivity (including stress disorder (PTSD).
pyrexia)
0 Other clinical features Suicide is more common amongst this group (16%

-
o Associated trauma or infection in 50%
~ Prodromal features may occur
Onset usually after 72 hours of
abstinence
with full dependence syndrome) as is parasuicide
(used acutely by 35%).

18.9.4 Neu ro p sy ch iatric

o Visual illusions/hallucinations
co n seq u en ces of alcohol abuse
prominent
o Duration S3 days in majority The most likely neuropsychiatric consequences of

-
Hypokalaemia common i
hypomagnesaemia
Mortality up to 5%
Treatment of a lc ohol withdrawal
0
Inpatient
0
Rehydration, antibiotics, parenteral high-
potency B-complex vitamins, sedation
I Sedative drugs which facilitate GABA-ergic
neurotransmission are cross-tolerant with
alcohol and have anticonvulsant properties (eg a
reducing dose of chlordiazepoxide,
chlormethiazole oral/IV (only when patient in
hospital)). Phenothiazine should be avoided
because of the risk of seizure. lf an
antipsychotic drug is required, then haloperidol
should be used
Relapse p rev en t i o n a nd m ai nt ai ni ng
abstinence (out pat i ent )
0
Pharmacological: disulfiram, acamprosate
0
Psychosocial: essential to maintain abstinence,
group therapy and support, ie Alcoholics
Anonymous, T2-Step Programme' (specific
principles guiding action for recovery from
addiction)
alcohol abuse are Wernickes encephalopathy and
Korsakoff syndrome/psychosis. This group is also
more likely to suffer seizures, head injury and
dementia.
Rarer conditions associated with alcohol abuse
include cerebellar degeneration, central pontine
myelinosis and Marchiafava-Bignami disease (de-
myelination of the corpus callosum, optic tracts and
cerebral peduncles).
Wen-nickes en cep h al o p at h y
A disorder of acute onset featuring:
Nystagmus
Abducens anol conjugate gaze palsies (96%)
Ataxia of gait (87%)
Global confusional state (90%)
Hypothermia and hypotension
N ote ; the 'classic triad (ocular signs, ataxia and
confusional state) of symptoms is not always pre
Sent.
lt is caused by thiamine deficiency, most commonly
secondary to alcoholism, but more rarely due to:
0 Carcinoma of the stomach
Toxaemia
0
Pregnancy

520
 Psychiatry

0
Persistentvomiting Clinical features
0
Dietary deficiency 0 Chronic disorder usually following Wernicl<e's
Pathology encephalopathy
Inability to consolidate new information
I
Macroscopic: petechial haemorrhages Retrograde amnesia of days/years
0 Microscopic: dilatation and proliferation of Patchy preservation of long-term memory
capillaries, small haemorrhages, pale-staining Confabulation, not complaints of poor memory
parenchyma, reactive change in astrocytes and Apathy
microglia, neurones relatively spared Lack of insight

Structures affected Pathology

As for Wernicl<es encephalopathy.
Mammillary bodies
Walls of third ventricle
Floor offourth ventricle Treatment
Thiamine. There may be a response in only 20% of
Periaqueductal grey matter sufferers.
Certain thalarnic nuclei - medial dorsal,
anteromedial, pulvinar
0 Brainstem
I Cerebellum anterior lobe/verrnis 18.10 SLEEP DISORDERS
0 Cortical lesions rarely seen
l8.l0.l Normal sl e e p
Treatment
i ln normal sleep, drowsiness first gives way to in-
Parenteral thiamine. Up to 80% of sufferers go on i0
i creasingly deep non-REM (rapid eye movement)
develop Korsakoff syndrome.
sleep. The first REM period occurs after 5 0 -9 0
minutes and lasts for 5 4 0 minutes. The cycle
Korsakoff s yndrom e repeats at approximately 90minute intervals so that
there are four to six REM periods each night. In
A marked memory disorder with good preservation total, REM occupies 20%-25% of a nights sleep
of other cognitive functions. ( s e e Figure 18.2).

Figure 18.2 Pictorial representation of the adult sleep cycle. Shaded areas indicate REM sleep
Awake
REM
1

3
t

i
1 2 3 4 5 6 7

rr Hours ot sleep
_

521


Essential Revision Notes for MRCP

I
--
REM sleep
Asynchronous, mixed frequency EEG
Bursts of rapid conjugate eye
loss of muscle tone leading to collapse); cataplexy
occurs in response to an emotional stimulus (eg
laughing, crying) and is pathognomic of the disease,
. movements
Prominent autonomic changes Hypersomnolence 100%

--
w

increased heart rate, blood pressure - Cataplexy 90%

penile tumescence HLA DR2 positive 99%
Decreased muscle tone Major affective disorder or
Extensor plantar responses may occur personality problems 50%
I Non-REM sleep 0
Sleep paralysis 40%
~ EEG synchronous, with sleep spindles, 0
Hypnagogic hallucinations (auditory
K-complexes, generalised slowing with hallucinations while dropping off to
delta waves Sleep) 30%
Fourstages recognised: stages3and Physical associations: Obesity,
4 characterised as 'slow wave sleep insulin-resistant diabetes, hypotension,
reduced food intake

i-_
_ ,,, _.
Insomnia is seen in a wide range of psychiatric and
medical disorders. Psychiatric disorders may ac-
count for up to 36% of patients with insomnia.
Paradoxically, sleep deprivation may be used to
treat depression and may precipitate mania.
Table 18.10 summarises the pattern of insomnia in
various disorders.
5.l"$l?.' `e>*"! .~rf.;'
Narcolepsy is a condition that is often undiagnosed.
Typically, onset is between the ages of 10 and 20,
and the increased risk in a first-degree relative is ><
40. The syndrome of narcolepsy comprises exces-
sive daytime somnolence and cataplexy (sudden
in narcolepsy, REM sleep occurs at the onset of
nocturnal sleep. Daytime attacks also consist of
periods of REM sleep occurring out of context.
_ -; .a <,s'f ~i"\. 3'. ;1 ~.',< r m ttev
Antipsychotics are indicated in schizophrenia,
mania, other paranoid psychoses and psychotic
depression. 'Atypical' antipsychotics have preferable
side-effect profiles and are now used as first-line
treatment in schizophrenia.
Antipsychotics are most effective against the 'posi-
tive symptoms of schizophrenia. They have an im~
mediate sedative action but the antipsychotic action

Table 18.10. Mental disorders and sleep disturbance

Disorder Pattern of insomnia

Major depression
Mania
Generalised anxiety disorder
Post-traumatic stress disorder
Acute confusional state
Initial (early morning waking) and late insomnia in up to 80%
Globally reduced sleep
Initial and middle insomnia
lntrusive nightmares about trauma
Disturbed sleep cycle

522
 Psychiatry

may be delayed for 3 weeks. They play an impor- l8.1l.2 A nt i de pr e s s a nt s

tant role in preventing relapse,
Clozapine is effective in treatment-resistant schizo-
phrenia and severe tardive dyskinesia. However,
there is increasing evidence that the atypical anti-
psychotics clozapine, olanzapine and, to a lesser
extent, risperidone are linked to hyperglycaemia,
impaired glucose tolerance and occasionally to fatal
diabetic ketoacidosis.
Table 18.11 gives examples of the different classes
of antipsychotic drugs and their side-effects.
Antidepressants are indicated in depressive illness,
anxiety disorders (especially panic disorder and
phobic disorders) and obsessional illness.
In depressive illness, antidepressants have a re
sponse rate of around 65%, with a delay in action
of between 10 days and 6 weeks. The presence of
'biological' symptoms can help in the prediction of
response. Antidepressants also play a prophylactic
role in recurrent depressive disorders.

Table 18.11. Side-effects of antipsychotic drugs

Class Example Side-effects

Atypical antipsychotics (highly
selective blockade of rnesolimbic D2 Olanzapine
receptors and serotonin (5HT;A)
receptors)
Typical antipsychotics (DZ-receptor
antagonists of the mesolimbic,
tuberoinfundibular and nigrostriatal
systems)
Phenoth iazines
Butyrophenones
Thioxanthenes
i Prolonged QTC interval
Sulpiride/amisulpride
Risperidone
Clozapine (also u,-receptor
antagonist)
Chlorprornazine,
thioridazine
Haloperidol, droperidol
Flupentixol, zuclopenthixol
Hyperprolactinaemia
Weight gain
Nausea, dyspepsia
Blood dyscrasias (neutropenia (3%),
agranulocytosis [1"/0)); fatal myocarditis
and cardiomyopathy
Hypersalivation
All of the following side- effects can be
seen with each of the three classes of
typical antipsychotic drugs:
Extrapyramidalz acute dystonia,
parkinsonism, akathisia, tardive
dyskinesia
Anticholinergic: dry mouth,
constipation, etc
Anti-adrenergic: postural hypotension
Antihistaminergic: sedation
Endocrine: hyperprolactinaemia,
photosensitivity (especially
phenothiazines)
Other:
lowered seizure threshold
Neuroleptic malignant syndrome

523
Essential Revision Notes for MRCP

Drugs which inhibit 5HT reuptake are particularly
useful in obsessional illness. Most antidepressants
(particularly SSRIs) are associated with hyponatrae-
mia, which is mediated via syndrome of inappropri-
ate ADH (SlADH); elderly women are particularly
vulnerable to developing this, Abrupt cessation of
paroxetine causes a discontinuation syndrome with
flu-like symptoms, dizziness and insomnia.
Table 18.12 gives examples of the different classes
of antidepressants and their side-effects.
The side-effects and toxicity of lithium are described
in detail in Chapter 2, Clinical
Pharmacology, Tox
icology and Poisoning.
18.113 Benzodiazepines
Benzodiazepines are only indicated for the short-
term relief of severe, disabling anxiety, The British
National Formulary recommends only 2 - 4 weeks of
use. They are not indicated for 'mild'
anxiety but

Table 18.12. Examples of the different classes oi antidepressants and their side-effects

Class Example Side-effects

SSRI* Citaloprarn Nausea, sexual dysfunction, headache, sleep disturbance
Fluoxetine (early), increased anxiety (early)
Fluvoxamine
Paroxetine
Sertraline

Tricyclic Amitriptyline Anticholinergicz dry mouth, constipation, etc

lmipramine
Clomipramine Anti-adrenergic; postural hypotension
Antihistaminergic: sedation
Weight gain
Lower seizure threshold
Cardiac arrhythmias
SNRI" Venlafaxine Nausea
Hypertension
MAo|*** Phenelzine Anticholinergic
Anti-adrenergic
Hypertensive reaction with tyramine-containing foods
lmponant drug interactions
RIMAMM Moclobemide Potential tyramine interaction

Presynaptic az-antagonist Mirtazapine Agranulocytosis

*SSRI = selective serotonin re-uptake inhibitor
**SNRl = selective noradrenaline re-uptake inhibitor
***MAOl = monoamine oxidase inhibitor
***R|MA reversible inhibitor of monoamine oxidase A
I

524
 Psych iatry

can be used as adjunctive treatment for anxiety, It is also indicated to treat catatonia associated with
agitation and behavioural disturbance in acute psy- schizophrenia and in treatment-resistant cases of
chosis or mania. They are only indicated for insom- mania.
nia if the condition is severe, disabling or subjecting
the patient to extreme distress. Table 18.13 shows
the pharmacokinetics of some benzodiazepines. ~**41H%%371;
- ,_ _.
,
W , s

Benzodiazepine withdrawal syndrome may not de- * Early

velop for up to 3 weeks, but can occur within a few
hours for short-acting drugs. Symptoms include in-
somnia, perspiration, anxiety, tinnitus, decreased
appetite, decreased weight, perceptual disturbances
and tremor.
The recommended withdrawal regime involves
transferring the patient to an equivalent dose of
diazepam, preferably taken at night. ideally the
dose should be decreased by approximately 1/8 of
the daily dose every 2 weeks. If withdrawal symp-
toms occur, the dose is maintained until symptoms
improve.
18.11.11 Electroconvulsive th er ap y
(EC1)
ECT is indicated in severe or treatment-resistant
depression or where there are psychotic symptoms,
life-threatening lack of food and fluid intake, or for
stupor and elderly (especially agitated) patients.
'Biological features help predict the likely response.
~ Headache
~ Temporary confusion
v
Impaired short-term memory (bilateral
ECT worse than unilateral)
~ (Rare) fractures, dislocation, fat
embolism
0 Late ( 6 - 9 months)
No memory impairment detected
~ Subjective impairment
Contfaindications to ECT
Raised intracranial pressure (the only absolute con-
traindication), cardiac arrest less than 2 years pre-
viously, other cardiac disease, pulmonary disease,
history of cerebrovascular accident.
ECT has a mortality rate of 3 deaths per 100 000 (cf
general anaesthesia in healthy adults, 1 per
1 0 0 O00). The mortality rate of untreated major
depression is 10%, however.

Table 18.13. Pharmacokinetics of benzodiazepines

Longer half-life Diazepam Half-life Shorter half-life Diazepam Half-life

equivalent (mg)* (hours) equivalent (mg)* (hours)

Diazepam 5 2 0 -9 0 Lorazepam 0.5 8 -2 4

Chlordiazepoxide 15 zo-eo Oxazepam 15 6 -2 8
Nitrazepam 5 i s -40 Temazepam 10 6 -1 0
Chlorazepate - 5 0 -1 0 0 Alprazolam -
6 -1 6
Flurazepam - s o-i oo

*Approximate equivalent doses to diazepam 5 mg

**lncludes active metabolites

525
Essential Revision Notes for MRCP

1811.5 Th e p sy ch o th er ap ies
Table 18.14 lists the different forms of psychother-
apy available, their indications and delivery.

Table 18.14. The psychotherapies

Type Frequency No. of sessions Indications

Counselling Weekly to monthly 6 -1 2 Mild depression

Anxiety
Bereavement

Cognitive behavioural Weekly 8-12 Depression

Anxiety
Somatoform disorder
Eating disorders
Behavioural Weekly 6 -1 2 Phobias
Anxiety
Obsessional illness
Sexual dysfunction
Dementia

Psychoanalytic 1-5/week 50-indefinite Neu ros is

Personality disorders
Psychosexual
Group Weekly 6 -1 2 Anxiety
Substance misuse
Eating disorders

526
l
I

l S f

s
.V
i y

_ ._.. " .
l ..
~='<'v-3

f"
~

E;
. . '
;._'='"f*?5.~*f.`.:;_
_..

l
l :,`! )l\1 fi
l 19.4.3 Silicosis
| tv.: 2.1.1115; .at\.'-1it,=;'t> m e a l . ;3~.~.a>;'i1.-gy.. 19.4.4 Berylliosis
19.1.1 Ventilation 19.4.5 Byssinosis
l 19.1.2 Perfusion 19.4.6 Occupational asthma
19.1.3 Control of respiration 19.4.7 Reactive airways dysfunction
I 19.1.4 Pulmonary function tests (PFTsi syndrome (R/-\DS)
V. 19.1.5 Gas transfer 19.4.8 Extrinsic allergic alveolitis
19.1.6 Adaptation to high altitude (hypersensitivity pneumonitis)
l
1.9.2 l)i:u..f.~uw ol ln" = tr" :~
LV 19.2.1 Asthma
l t r

19.5.1 Lung cancer

19.2.2 Chronic obstructive pulmonary 19.5.2 Mesothelioma
disease (COPD) 19.5.3 Mediastinal tumours
l 19.2.3 Alpha-1-antitn/psin deficiency
19.2.4 Long~term oxygen therapy . \ r tf < ~ -..i,.f:1.;?f:.-`
: fv1istil.*.?i1e~'1
[LTOTl i\..~~af.f ' 1' ;5;if~;>.:~
19.2.5 Respiratory failure 19.6.1 Sarcoidosis
l 19.2.6 Ventilatory support 19.6.2 Histiocytosis X
19.6.3 Pulmonary fibrosis
i. i m g ; ttlef. ?[=.1~<=.~.=. 19.6.4 idiopathic pulmonary fibrosis
F 19.3.1 Pneumonia (usual interstitial pneumonia -
19.3.2 Empyema UIP)
r 19.3.3 Tuberculosis
r 19.3.4 Bronchiectasis '="-=3ff:;':'i . ~' ffiiris mic?
19.3.5 Cystic fibrosis ttiii...
V

19.3.6 Aspergillus and the lung 19.7.1 V\/egeners granulomatosis

19.7.2 Churg-Strauss syndrome
i
was Uu:'.1p:.:ta~.>':.~ 19.7.3 Polyarteritis and Henoch-
19.4.1 Asbestoserelated disease Schonlein vasculitis
19.4.2 Coal workers pneumoconiosis 19.7.4 Connective tissue disorders
(CWP) 19.7.5 Pulmonary eosinophilia
l

l'

527
Essential Revision Notes for MRCP

19.8 Miscellaneous r e s p ir a to r y
di sorders
19.8.1 Pleural effusion
19.8.2 Pneumothorax
19.8.3 Obstructive sleep apnoea/
hypopnoea syndrome (OSAHS]
19.8.4 Adult respiratory distress
syndrome (ARDS)
19.8.5 Rare lung disorders

528

Respiratory Medicine
19.1 LUNG ANATOMY AND
PHYSIOLOGY
i lar lining fluid, increasing lung compliance and
The human lung is composed of approximately 300
l million alveoli each around 0.3 mm in diameter.
Cas exchange takes place in the alveoli, and air is
| transported to these via a series of conducting air-
ways. lt is warmed and humidified in the upper
i airways and transported through the trachea, main
bronchi, lobar and segmental bronchi to the term-
| inal bronchioles, the smallest of the conducting
i tubes. These airways take no part in gas exchange
and constitute the anatomical dead space (approxi-
l mately 150 ml). The terminal bronchioles lead to
the respiratory bronchioles, which have alveoli bud-
l ding from their walls. Lung tissue distal to the
terminal bronchiole forms the primary lobule.
|
i 19.1.1 Ventilation
The most important muscle of inspiration is the
I diaphragm, a muscular dome that moves down-
i wards on inspiration. The external intercostal mus-
cles assist inspiration by moving the ribs upwards
l and forwards in a 'bucket-handle' movement.
I The accessory muscles of respiration include the
scalene muscles, which elevate the first two
ribs, and the sternocleidomastoids, which
elevate the sternum; these are not used during
quiet breathing
O Expiration is passive during quiet
breathing
During exercise, expiration becomes active and
the internal intercostal muscles and the muscles
of the anterior abdominal wall are utilised
0 The greatest ventilation is achieved at the lung
r
bases and this is matched by increased
perfusion irr these areas
Normal lung is very compliant. Compliance is
reduced by pulmonary venous engorgement and
alveolar oedema and in areas of atelectasis. Surfac-
l
r
I
Respiratory Medicine
tanl, secreted by type 2 alveolar epithelial cells,
substantially lowers the surface tension of the alveo-
promoting alveolar stability. Lack of surfactant leads
to respiratory distress syndrome.
Resistance to airflow is related to the radius of the
airway, but the greatest overall resistance to flow
occurs in medium-sized bronchi. Airway calibre is
influenced by lung volume; at low lung volumes
small airways may close completely, leading to
areas of atelectasis, particularly at the lung bases.
19.1.2 Perfusion
The pulmonary vessels form a low-pressure system
conducting deoxygenated blood from the pulmon-
ary arteries to the alveoli where they form a dense
capillary network. The pulmonary arteries have thin
walls with very little smooth muscle; the mean
pulmonary artery pressure is 15 mmHg and the
upper limit of normal pressure is 30 mmHg.
Pulmonary vascular resistance is one-tenth
systemic vascular resistance
0
Hypoxic vasoconstriction refers to contraction of
smooth muscle in the walls of the small
arterioles in a hypoxic region of lung; this helps
to divert blood away from areas with poor
ventilation so maintaining ventilation and
perfusion matching
19.1.3 Control of re s p i ra t i o n
The respiratory centre comprises a poorly defined
collection of neurones in the pons and medulla; to
a certain extent, the cortex can override the func-
tion of the respiratory centre. Chemoreceptors are
crucial to the control of respiration, and these may
529
Essential Revision Notes for MRCP
be central or peripheral:
0 Central chemoreceptors are located on the
ventral surface of the medulla. They respond to
increased hydrogen ion concentration in the
cerebrospinal fluid (CSF), generated by
increased pCO; in the blood
Peripheral chemoreceptors are located in the
carotid bodies (at the bifurcation of the common
carotid arteries) and the aortic bodies (near the
aortic arch); they respond to hypoxaemia,
hypercapnia and pH changes
ln people with normal respiratory function the most
important factor for control of ventilation is the
pCO;, which is maintained to within 3 mmHg of
baseline (normal range 3 5 -4 5 mmi-lg), However, in
patients with severe lung disease, chronic CO;
retention develops and the hypoxic drive to ventila-
tion becomes very important.
0 Ventilation may increase by 15 times the resting
level during severe exercise
0
Cheyne-Stokes respiration is characterised by
periods of apnoea separated by periods of
hyperventilation; it occurs in severe heart failure
or brain damage and at altitude
1 9 1 .4 PulnrfJrwiu innctrfrr. i f-s i s
(Plfi s i
Peak ex p i rat o ry flow ra t e (PEFR)
This is measured in litres per minute and is a useful
guide to airways obstruction. Attention to technique
is important in order to obtain accurate, repeatable
readings.
I It is most useful in asthma as it reflects central
airways obstruction
It may underestimate disease severity in chronic
obstructive pulmonary disease (COPD)
530
Spirome try
0 FEV] refers to the volume of gas expired in the
first second of a forced expiration
0 FVC refers to the total volume of gas expired on
forced expiration (forced vital capacity)
0 The normal ratio of FEV]/FVC is 70%-80%
A reduction in FEV( with a preserved FVC
occurs in airways obstruction (eg asthma or
COPD), In patients with severe COPD a slow
vital capacity is a more accurate measurement
as it allows time for the lungs to empty fully and
hence a true FEV(/F\/C ratio can be determined
0 Restriction refers to a reduction in FVC with a
preserved FEV(/FVC ratio and occurs in
conditions such as pulmonary fibrosis,
neuromuscular disorders, obesity and pleural
disease
Flow volume l oops
A flow volume loop (Figure 19.1) is produced by
plotting flow on the y axis against volume on the x
&XIS.
If a subject inspires rapidly from residual volume
(RV) to total lung capacity (TLC) and then exhales
as hard as possible back to RV, a record can be
made of the maximum flow volume loop. This loop
shows that expiratory flow rises very rapidly to a
maximum value/ but then declines over the rest of
expiration During the early part of a forced expira~
tion the maximum effort-dependent flow rate is
achieved within 0.1 s, but the rise in transmural
pressure leads to the airways being compressed and
therefore to the flow rate being reduced. The flow
rate is then said to be etfort-independent.
A great deal can be learned by comparing the form
of the loop to that which is normally seen (triangle
sitting on a semi-circle). Several patterns can be
 Respiratory Medicine

Figure 19.1 Typical flow loop

PEFFI
FEFFI 25%

I
FEFFI 50%

Expiratory
ilow
FEFFI 75%
l

TLC RV

inspiratory
TLC
VC
RV
-Wal
~ Total lung capacity
capacity
Residual volume
flow
PIFR Peak inspiratory flow rate
PEFFI Peak expiratnry flow rate
FEFR Forced explratory flow rate

PIFR

recognised, reflecting various disorders (Figure 0 TLC, RV and functional residual capacity can be
19.2), measured using a helium dilution method,
nitrogen washout or body box

Lung volume s
I Tidal volume, inspiratory and expiratory reserve
volumes and vital capacity can all be measured
by the use of a spirometer (see Figure 19.3)
19.1.5 G a s transfer
Transfer of carbon monoxide is solely limited by
diffusion and is used to measure gas transfer, Either
a single breatlmhold or a steady-state method can
be used. Results are expressed both as total gas

531
Essential Revision Notes for MRCP

Figure 19.2 Flow volume loops in different disorders

s
5?

Pressu re-d ep en d en t co llap se Volume-dependent c ol l a ps e

ll intrathoracic airways collaps e immediately expiration begi ns ll the airways collapse progressively with expiration.
there inan abrupt early iall from peak llow, ie pressure-dependent th e scooping out oi the expiration limb is more
collapse typical Inemphysema gradual, Ie volume-dependent collapse. This is
seen Inchronic pulmonary disease

It

inspiratory l oop Flattened i ns pi rat ory e xpl ra t nry l oops

lf the lungs are abnormally stiff or s pringy, a i rwa y closure is If exiralhoracic obstruction exists, both the
delayed, as in children and young women. producing a inspiratory an d expiratory l oops will be llattened, eg
descending portion which is convex. Inspiration is oppos e d tracheal compres s ion by goltre, node s
slightly, producing a flatter inspiratory loop

532
 Respiratory Medicine

Figure 19.3 Subdivision of lung volume

-> t 1s

- au-
----_-- - - _ - - - .

al
nu

9 2
O
,DZ
LL
>
I

-
TV =Tidal volume TLC = Total lung cap acity
VC = Vital cap acity (VC = IC + ERV) -
RV = Residua volume (RV = TLC VC)
FEV( Forced explraton/ votume 1 s IC = Inspiratory capacity
FRC = Funotional residual cap acity ERV = Expiretory reserve volume
( Pac = env + Rv) -
(ERV = VC IC)

transfer (DLCO) or gas transfer corrected for lung Oxygen a n d c a rbon dioxide t ran s p o rt
volume (KCO, ie K C O : DLCO/VA where VA is
Oxygen is transported in the blood by combination

_.y
alveolar volume).
with the haemoglobin (Hb) in red cells. A tiny
amount is dissolved (0.3 ml/100 ml blood, assuming
- ~' p02 of 100 mmHg). The oxyhaemoglobin dissocia-
tion cu n f e is sigmoid in shape. Once oxygen satura-
I
Hypoventilation tion falls below 90% the amount of oxygen carried
~ Opiate overdose to the tissues falls rapidly. The p50 (the partial
~ Paralysis of respiratory muscles pressure at which haemoglobin is 50% saturated) is
I
\'//Q mismatch 26 mmHg.
~ Pulmonary embolus

I

-
Low inspired partial pressure ofoxygen
High altitude
Breathing a hypoxic mixture
0 The curve is shifted to the right by high
temperature, acidosis, increased pCO; and
increased levels of 2,3-diphosphoglycerate (2,3-
Diffusion impairment DPC); this encourages offloading of oxygen to
Pulmonary oedema the tissues
Fibrosing alveolitis The c u n / e is shifted to the left by changes
0 Bronchiolar-alveolar cell carcinoma opposite to those above, and by
Shunt* Carboxyhaemoglobin and fetal haemoglobin
~ Pulmonary AV malformations
~ Cardiac right-to-left shunts Carbon dioxide is transported in the blood as bicar-
*Hypoxaemia caused by shunt cannot be abolished by
bonate, in combination with proteins as carbamino
administering 100% oxygen compounds, and it is also dissolved in plasma,
Carbon dioxide is 20 times more soluble than oxy-

'

533
Essential Revision Notes for MRCP
gen and about 10% of all CO2 is dissolved, CO;
diffuses into red blood cells where carbonic anhy
drase facilitates the formation of carbonic acid,
which dissociates into bicarbonate and hydrogen
ions. Bicarbonate diffuses out of the cell and chlor-
ide moves in to maintain electrical neutrality.
Acid - ba se c ontrol
The normal pH of arterial blood is 7.35-7.45.
Blood pH is closely regulated and variation outside
this pH range results in compensation either by the
lung or the kidney to return pH to normal. Failure to
excrete CO2 normally results in a respiratory acido-
sis; this is usually due to hypoventilation, Hyperven-
tilation causes lowering ofthe pCO; and alkalosis,
pH can also be altered by metabolic disturbance,
Metabolic acidosis and alkalosis are considered in
Chapter 13, Metabolic Diseases. Mixed respiratory
and metabolic acid-base disturbances are com-
mon.
Arte ria l blood g a s e s
Normal values are:
U
pH 7.35~7.45
0 whilst breathing
p02 >1 ( ) . 6 l<F'a (77 mmHg)
room air
9
pCO; 4 , 7 ~ 6 . 0 l<PEt (3 5 -4 5 mmHg)
0
HCO3 (bicarbonate) 2228 mmol/l
When recording blood gases the percentage of
inspired oxygen should always be stated. The value
in kilopascal (kPa) should be multiplied by 7.6 to
convert to mmHg.
t i i i ii
A da pt a t i on to ttiglt a t t i t ude
The barometric pressure decreases with altitude: at
18 000 feet it is half the normal 760 mmHg. Hyper-
ventilation, due to hypoxic stimulation of peripheral
chemoreceptors, is an early response to altitude.
534
The respiratory alkalosis produced is corrected by
renal excretion of bicarbonate.
0
Hypoxaemia stimulates the release of
erythropoietin from the kidney, and the resultant
polycythaernia allows increased carriage of
oxygen by anerial blood
0 There is an increased production of 2,3-DPC,
which shifts the oxygen dissociation curve to
the right, allowing better offloading of oxygen to
the tissues
0
Hypoxic vasoconstriction increases pulmonary
artery pressure causing right ventricular
hypertrophy. Pulmonary hypertension is
sometimes associated with pulmonary oedema
- altitude sickness
l9.2 DISEASES OF LARGE AIRWAYS
19.2.1 Asthma
Asthma is a chronic inflammatory disorder of the
airways. In susceptible individuals this inflammation
causes symptoms that are associated with wide-
spread but variable airflow obstruction, which is
reversible either spontaneously or with treatment.
There is an increase in airway sensitivity to a variety
of stimuli.
The prevalence of asthma has been increasing in
recent years, principally among children, Appro><i~
mately 5.1 million people suffer from asthma in the
UK - 1 .4 million of these are children. Around
1500 asthma deaths occur annually in the UK.
The development of asthma is almost certainly due
to a combination of genetic predisposition and
environmental factors. Atopy is strongly associated
with asthma. The most important allergens are the
house dust mite (Dermatophagoides pteronyssinus),
dog allergen (found in pelt, dander and saliva), cat
allergen (predominantly in sebaceous glands), pol-
len, grasses and m oulds,

Exposure to sensitising agents
Exercise
Infection
Castro-oesophageal reflux
Drugs, including aspirin, non-steroiclal anti-
inflammatory agents, B-blockers
0
Cigarette smoke, fumes, sprays, perfumes,
etc
0 Failure to comply with medication
ln patients with asthma the airways are narrowed by
a combination of contraction of bronchiolar smooth
muscle, mucosal oedema and mucus plugging, ln
the early stages changes are reversible, but, in
chronic asthma structural changes (including thick-
ening ofthe basement membrane, goblet cell hyper-
plasia and hypertrophy of smooth muscle) develop
and ultimately lead to irreversible fibrosis of the
airways. Asthma is regarded as a complex inflam-
matory condition and mast cells, eosinophils,
macrophages, T lymphocytes and neutrophils are
all involved in the pathogenesis. A variety of inflam-
matory mediators are released, including histamine,
leukotrienes, prostaglandins, bradykinin and platelet
activating factor (PAF).
Chronic asthm a
The hallmark of chronic asthma is variable and
reversible airflow obstruction. This causes:
Shortness of breath
Chest tightness
Wheeze
Cough
At times the cough may be productive of sputum
which may be clear, or yellow/green, due to the
presence of eosinophils. The normal diurnal varia-
tion in airway calibre is accentuated in asthmatics
and symptoms may be worse at night.
Respiratory Medicine
Pl'|yaloa`l
Tachypnoea
Wheezing, most marked in expiration
Hyperinflation of the chest
Nasal polyps (particularly in aspirin-
sensitive asthmatics)
0
Atopic eczema
Di agnosi s of a sthma
The diagnosis of asthma is clinical and is often
confirmed by diary recordings of the peak expira-
tory flow rate (PEER). The pattern of lung function
tests may be very helpful ( s ee box below). Chal-
lenge tests with histamine or methacholine, or with
exercise, can be used to assess airways responsive-
ness where the diagnosis is unclear. Responsiveness
is expressed as the concentration of provoking agent
required to decrease the FE\/1 by 20%.
'Rmical lung funetinnttests, in asthms
0
Significant (>2O% difference) diurnal peak
expiratory flow rate IPEFR) variability on at
least 3 days per week for a minimum of
2 weeks
I
Significant improvement in PEFR ( > l 5%)
and FE\/1 (at least 400 ml) after
bronchodilator or a trial of oral or inhaled
steroids
Increased lung volumes
Reduced FEV]
FEV]/FVC ratio < 70%
Gas trapping
Other clinical features that are helpful in making a
diagnosis of asthma are:
A history of asthma in childhood or of eczema
or hay fever
0 A family history of asthma
535
Essential Revision Notes for MRCP
0 Symptoms of perennial rhinitis, nasal polyps or
chronic sinusitis
0
History of wheezing associated with aspirin,
NSAIDs or B-blockers
Skin-prick tests
Skin-prick tests can be used to assess atopy. Many
asthmatic subjects make IgE in response to common
allergens. A tiny quantity of allergen is introduced
into the superficial layers of the dermis and tests are
read at 20 minutes. The diameter of the weal is
measured in millimetres, the size of the weal corre-
lating well with bronchial challenge testing. Serum
total IgE is commonly raised in asthmatics, Specific
IgE may be measured by radio-allergosorbent testing
(RAST).
Treatment
The aims of prophylactic treatment in asthmatic
patients are to:
0 Minimise symptoms during day and night
0 Minimise the need for 'reliever' (eg
bronchodilator) medication
0 Avoid exacerbations
0 Prevent limitation of physical activity
0 Maintain normal lung function (FEVt/PEFR
>8O/0)
The mainstay of treatment is inhaled corticosteroid
with short-acting [3-agonists to relieve symptoms.
Treatment is altered in a stepwise fashion as recom-
mended in the BTS/SIGN National Guidelines. The
dose of inhaled steroid should initially be appropri-
ate to the severity of symptoms and is adjusted to
achieve c ontrol,
I
Long-acting [5-agonists (eg salmeterol or
eformoterol) should be added in patients who
are inadequately controlled on beclornetasone
dipropionate (200 mg/day) or an equivalent
steroid inhaler
I Oral theophylline preparations or [53-agonist
tablets are of benefit in some patients
0 biotics. PEFR should be measured regularly to assess
Leukotriene-receptor antagonists ( se e also
Chapter 2, Clinical Pharmacology, Toxicology
536
and Poisoning) may be particularly useful for
exercise-induced asthma, and in patients with
aspirin sensitivity
0
Long-term oral corticosteroids are reserved for
patients with very severe asthma
0
Allergen avoidance may be helpful in reducing
the severity of existing disease in patients
exposed and sensitised
0
Smoking cessation is essential and should be
advised
U Ornalizumab is a possible add-on therapy for
patients with severe persistent allergic asthma
I All inhalers are now required to be CFC-free
Acute severe asthm a
Asthma symptoms may worsen acutely necessitating
prompt treatment to relieve the attack. An immedi-
ate assessment is essential, looking for signs of
severity, which include the following:
Speech impairment
Respiratory rate > 25 breaths/min
Tachycardia (pulse >l 10 beats/min)
PEFR 33%-50% of predicted
Life-threatening asthma is associated with any one
of the following:
Hypoxaemia
PEFR <33"/0 of predicted
Exhaustion
Bradycardia (pulse < 6 0 beats/min)
Hypotension
A silent chest
A normal or raised pCO;
Arterial blood gases should be performed if the
patient is hypoxic on air ( sa tur a tions <92/1) and a
chest X-ray is necessary to exclude pneumothorax.
Management consists of high-flow oxygen therapy,
nebulised bronchodilators (ti-agonists, ipratropium),
steroids and, if infection is considered likely, anti-
the response to treatment.
 Respiratory Medicine

I Ifthere is no improvement with nebulisers, then \ c |. . . ' -ofi c gynf ,,

' = ,

intravenous infusions of either salbutamol or

aminophylline should be used
0 A single dose of intravenous magnesium can be
given to patients who have not had a good
response to bronchodilators, or to those with
life-threatening asthma
O lfthe patient is severely ill, or not improving
with treatment, they should he promptly
transferred to an Intensive Care Unit
Allergic br onchopulmonar y aspergillosis
Most patients with allergic bronchopulmonary as-
pergillosis are asthmatics but the condition may
occur in non-asthmatics. This condition is consid-
ered in detail in Section 1 9 . 3 6 ,
19.2.2 Chronic obstructive
p u lm o n ar y disease (COPD)
COPD is defined as a chronic, slowly progressive
disease characterised by airflow obstruction that
does not markedly change over several months.
Most of the lung function impairment is fixed
although s o me reversibility can be produced by
bronchodilator therapy. Long-term prognosis is de-
termined by postbronchodilator FEV1. COPD is an
inflammatory condition that progresses even if the
patient has stopped smoking.
COPD currently accounts for 6% -7% of all UK
deaths. However, the incidence of COPD is increas-
ing and it is likely to become the third commonest
cause of death worldwide (it is currently fourth] by
2020. lt is the only one of the top 1 0 ' worldwide
causes of death that is increasing,
The diagnosis is made by:
0 History of cough with sputum production,
wheeze and shortness of breath
I
History of frequent winter bronchitis and
delayed recovery from viral infections
0 Reduced FE\/1/FVC ratio without reversibility
0
Smoking (usually a history of at least 20
pack-years)
0 Air pollution
0 Low birth weight and low socioeconomic
status
0 Dust exposure
0
Alpha-1-antitrypsin deficiency
COPD is due to a combination of chronic bronchitis
and emphysema.
Chronic bronchitis is defined as chronic cough and
sputum production for at least 3 months of two
consecutive years in the absence of other diseases
recognised to cause sputum production.
Emphysema is characterised by abnormal, perma-
nent enlargement of the air spaces distal to the
terminal bronchioles, accompanied by destruction
of their walls without obvious fibrosis. Emphysema
may be centri-acinar (predominantly affecting the
upper lobes and associated with smoking), panaci-
nar, paraseptal or predominantly localised around
scars (scar ernphysema),
,, 3 . >~;='>=,=-fr-, -
Many patients with COPD will have no abnor-
mal physical signs until the disease is ad-
va nc e d;
Hyperinflation
Central cyanosis
Weight loss
Cor pulmonale: raised IVP, right ventricular
heave, loud P2, tricuspid regurgitation,
peripheral oedema, hepatomegaly
Flapping tremor
Pursed-lip breathing
Wheeze
Reduced breath sounds
Investigations
I PFTs: FEV] <80"/n predicted, FEV1/FVC <70%;
patients have large lung volumes and reduced

537
Essential Revision /\/otes for MRCP
gas transfer factor |jDLCO) in emphysema.
COPD may be graded by the FEVt:
Mild COPD: FEVt 50/<>-80% of
predicted
Moderate COPD: FEV] 30% -50% of
predicted
~ Severe C OP D; FEV1 <30/0 of predicted
l Chest X-ray: may be normal or show evidence
of hyperinflation, bullae or prominent
vasculature due to pulmonary hypertension
0 Arterial blood gases: may indicate type 1 or
type 2 respiratory' failure
I Full blond count (FBC): possible polycythaemia
0 ECG: may show P-pulmonale, right axis
deviation, right bundle branch block
I
Sputum culture: Haemophilus influenzae,
Streptococcus pneumoniae or less commonly
Staphylococcus, Moraxe/la catarrha/is or Gram-
negative organisms
Treatment of COPD
Several recent clinical trials have shown no impact
of inhaled steroids on disease
progression in COPD
although they do reduce exacerbations and improve
quality of life in those patients with moderate or
severe disease who have at least two exacerbations
each year. Pulmonary rehabilitation is increasingly
recognised as an important pan of disease manage-
ment.
0 hypercapnia persists, then non-invasive positive-
Smoking cessation
U
Lung volume reduction surgery (for patients
with severe emphysema) or bullectomy
inhaled anticholinergic drugs
inhaled short or long-acting |32-agonists
Theophyllines
inhaled steroids*
Diuretics
Long-term oxygen therapy (LTOT)
Pulmonary rehabilitation
Transplantation
*Systemic steroids awe resen/ed for very severe cases
538
Pulmonary rehabilitation
This plays a key role in the management of respira-
tory diseases causing breathlessness, particularly
COPD. A multidisciplinary team, usually
comprising
a physiotherapist, occupational
therapist, respiratory
nurse, dietician and sometimes psychologist, is
needed. Patients usually panicipate 23 times per
week over 6 - 8 weeks. Aerobic exercise including
specific upper and lower limb strengthening is fol-
lowed by educational and relaxation sessions. Pul~
monary rehabilitation has been shown to be
effective for all patients with COPD regardless of
severity and all motivated patients should be re-
ferred for this treatment.
Treatment of acute exacerbations
Antibiotics are indicated for acute exacerbations if
two ofthe following are present:
0 increased breathlessness
0 Increased sputum volume
0
Increased sputum purulence
Regular bronchodilators (nebulised or inhaled) are
g iv e n in addition to short courses of oral steroids
and controlled oxygen therapy.
if initial blood gases show hypercapnia and acido-
sis;
0 Patients should be treated along conventional
lines for an hour and arterial blood gases then
repeated
0 Ifsignificant acidosis (pH <7 .3 5 ) with
pressure ventilation iN|PPV) should be instituted
via a face mask
19.2.3 Alpha-l-antitrypsin defi ciency
Many different phenotypes of oi-antitrypsin are
known, the common ones being designated M, S
and ZZ. MM confers 100% protease inhibitor activ-
ity while the most severe deficiency is produced by
ZZ. Panlobular emphysema develops, which is most
marked in the basal areas of the lungs. Emphysema
is thought to result from an imbalance in the
lung
between neutrophil elastase (which destroys elastin)
F Respiratory Medicine

l
and the elastase inhibitor al-antitrypsin (which pro-
tects against the proteolytic degradation by elastinl.
The decline in lung function is accelerated in smo-
kers.
U PFTs show airflow obstruction, large lung
volumes and reduced KCO
0 Cirrhosis of the liver is more common,
particularly in those of ZZ phenotype
I
Smoking cessation is imperative
I
Replacement therapy with otl-antitrypsin is not
routinely given
t 0 Lung transplantation may be an option for some
patients
0 Genetic counselling should be offered and
A
siblings of index cases should be genetically
tested
r. 19.2.4 Long-term oxygen th er ap y
(LTOT)
Two trials have established the benefit of LTOT. In
the MRC trial, oxygen via nasal cannulae was given
to raise the p02 to 8 kPa ( 60 mmHg) for at least i5
hours per day compared to patients with COPD
i
receiving conventional therapy. After 3 years of
|-
treatment, survival was 50% better in the group
for at least 15 hours per day, The patient should
have stopped smoking before LTOT is c onside re d,
19.2.5 R e s p i ra t o ry faiinr-t
Respiratory failure is an inability to maintain ade-
quate oxygenation and carbon dioxide excretion.
There are two recognised types of respiratory fail-
ure:
0
Type 1 respiratory failure is present when there
is hypoxaemia with normal or low levels of
carbon dioxide
0
Type 2 respiratory failure is hypoxaemia with
Causes of res p i rat o ry failure
0 Reduced ventilatory drive
Opiate overdosage, brainstem injury
0 Mechanical problems
~ Chest trauma causing flail chest
~ Severe kyphoscoliosis
Obesity
Neurological conditions (affecting chest
wall muscles)
~ Guillain-Barr syndrome
Polio

--

receiving oxygen.
0 Alveolar problems
The NOTT trial compared 12 and 24 hours of Barriers to diffusion:
continuous oxygen therapy and was terminated pre-
maturely due to better survival in the group receiv-
ing 24-hour therapy. Patients are eligible for LTOT if
. Pulmonary oedema
Pulmonary fibrosis
o \'//Q mismatch:
they exhibit all of the following: ~ Pulmonary embolus
pO; on air < 7 3 kPa (55 mmHg) o Shunt (cardiac or pulmonary)
Normal or elevated pCO; ~ Reduced inspired partial pressure of
FEV; < l . 5 litres OX)/geflf
p 0 ; 7.343 l<Pa ( 5 5 - 6 0 mml-lg) with evidence High altitude
of pulmonary hypertension, polycythaemia Upper airway obstruction
peripheral oedema or nocturnal hypoxaemia Laryngeal tumour
l
- ObStfUCllVE Sl! Ep BPHOEH
U

Arterial blood gases must be measured when the I Lower airway obstruction
patient is clinically stable (at least 5weel<s post- Bronchospasm
exacerbation), and on two occasions that are at ~ Sputum retention
l, least 3 weeks apart. p02 on oxygen should be
>8 kPa (60 mmHg) without an unacceptable rise in Type 1 respiratory failure may be corrected by
l pCO2. Oxygen should be given via a concentrator increasing the inspired oxygen concentration
i '

539

i
 Essential Revision Notes for MRCP
6
Type 2 respiratory failure may require
mechanical ventilatory support. Respiratory
stimulants such as doxapram may be useful for
those with reduced respiratory drive
19.2.6 Ventilatory s u p p o r t
This may be invasive or non-invasive.
Non-invasive p o s i t i v e-p res s u re ventilation
(NIPPV)
This involves the use of a securely fitting nasal or
full face mask. The technique has been used to
provide long-term respiratory support in the com-
munity for patients with respiratory failure due to
conditions such as severe chest wall deformity,
neuromuscular disorders or obesity hypoventilation
syndrome.
I It ls used increasingly to manage episodes of
acute respiratory failure due, for example, to
exacerloations of COPD - as an alternative to
(and often more appropriate than) ventilation on
the Intensive Care Unit (ICU)
NIPPV can be carried out on general wards
using portable bi-level pressure support
ventilators. Supplementary oxygen can be given
via the port on the face mask. Regular
monitoring of blood gases is necessary and the
ventilator settings are altered in response. As the
patient improves, time spent off the ventilator is
lengthened until the patient is weaned
i When NIPPV treatment is instituted, a decision
as to whether ICU referral would be appropriate
if the patient were to deteriorate should be
clearly stated in the case notes
P ositive-pressure ventilation
Conventional ventilation requires access to the air-
way, by means of either an endotracheal tube or
tracheostomy. Indications for positive pressure venti-
lation are:
Type 2 respiratory failure from any cause
I
Paralysis of respiratory muscles (eg Cuillain-
Barre syndrome)
0
Multiple organ failure
540
0 Trauma cases, including injury to the chest or
cervical spine
0
Inability to maintain a clear airway
0 Reduced conscious level - Glasgow coma
scale score <5
0
During and after certain surgical procedures
Ventilation should be considered when there is
failure to maintain oxygenation (pO; <8 kPa
[ 6 0 rnmHg)) despite high inspired oxygen concen-
trations (usually associated with hypercapnia and
acidosis). It is often necessary in patients with multi-
ple organ dysfunction associated with sepsis or
trauma.
Continuous positive ai rway s p res s u re (CPAP)
CPAP is delivered through a tightly fitting face mask
or it may be used in conjunction with conventional
ventilation. It provides a pneumatic splint to the
airway and is the treatment of choice for obstructive
sleep apnoea. CPAP improves oxygenation in pa-
tients requiring high concentrations of
oxygen by
the recruitment of collapsed airways. High levels
may, however, cause hypotension, the rise in mean
intrathoracic pressure inhibiting venous return and
reducing cardiac output.
19.3 LUNG INFECTIONS
HIV/AIDS-associated respiratory disease is covered
in Chapter 8, Genito-urinary Medicine and AIDS.
19.3.1 Pneumonia
Pneumonia is an acute inflammatory condition of
the lung usually caused by bacteria, viruses or,
rarely, fungi. The chest X-ray will show consolida-
tion, the hallmark of which is an air bronchogram.
Pneumonia continues to be an important cause of
mortality across all age groups, with 50% of pneu-
monia deaths occurring in those aged I 5 - 6 4
years.
Community-acquired p n e u m o n i a
The incidence is 5/I000 to It/1000 adult popu-
lation per year, and this is much more common in
 Respiratory Medicine

the elderly. Causal organisms are given in the The presence of co-existing disease is a bad
following box. prognostic factor

., rf ~\_="@-~ `=~*~>=;'f. fx _.,-

:*.a.f`e*'12f

0
Streptococcus pneumoniae (60%-70%) S peci fi c p n eu mo n i as
0
Atypical organisms, including Mycoplasma
pneumoniae (5%-15%), Legionella Streptococcus pneumoniae
pneumophila, Chlamydia psittaci, There is an abrupt onset of illness, with high fever
Chlamydia pneumoniae and Coxiella and rigors. Examination reveals crackles or bron-
burnetii (Q fever) chial breathing, and herpetic cold sores may be
Haemophilus influenzae present in >l / 3 of cases.
Staphylococcus aureus 0
Elderly patients may present with general
Gram-negative organisms deterioration or confusion
Viruses, including influenza, varicella 0
Capsular polysaccharide antigen may be
zoster, CMV detected in serum. sputum, pleural fluid or urine
0
Increasing incidence of penicillin resistance,
General investigations for p at i en t s admitted particularly in countries such as Spain
t 0 Vaccine available
to hos pi t al with p n eu mo n i a
These include FBC, biochemical profile (including Mycoplasma pneumoniae
liver function tests), C-reactive protein (CRP), arterial Mycoplasma pneumoniae tends to affect young
blood gases, chest X-ray and blood and sputum adults; it occurs in epidemics every 3 - 4 years.
cultures. There is typically a longer prodrome, usually of 2 or
more weeks, and the vvhite cell count may be
Paired serological tests for atypical organisms and normal. Cold agglutinins occur in 50%; the morta|~
.
viruses and urinary antigen tests for Legionella and
ity is low.
Pneurnococcus should be used in selected cases
0
Extrapulmonary complications include: peri/
Si g n s of severe p n e u m o n i a (CURB- 65 myocarditis, erythema multiforme, erythema
criteria) nodosum, Stevens-lohnson syndrome,
r haemolytic anaemia, disseminated intravascular
0 Confusion (<8 / 1 0 score on abbreviated mental coagulation (DIC), thrombocytopenia, meningo-
t test (AMT)) encephalitis, cranial and peripheral
Urea >7 mmol/l neuropathies, bullous myringitis, hepatitis and
0
Respiratory rate >3O breaths/min pancreatitis
l O BPsystolic < 9 0 mmHg and/or diastolic
i' < 6 0 mmHg Legionella pneumophila
l 0
Age >6 5 Outbreaks are usually related to contaminated vvater
Patients with three or more CURB criteria are at cooling systems, showers, or air conditioning sys-
tems, but sporadic cases do occur. Legionnaires
high risk of death and are regarded as having severe disease usually affects the middleaged and elderly,
community-acquired pneumonia.
patients often having underlying lung disease. Males
0
l-lypoxaemia (pO2 <8 kPa despite oxygen are affected more than females t'3:1). Diagnosis is
therapy) and multilobe involvement also confer by direct fluorescent antibody staining or serological
a worse prognosis tests; antigen may be detected in the urine.

541
Essential Revision Notes for MRCP
Y . ; e 1 , 5 . 2%
f ; $s\-ost"
A
; , ; ='\,<'
s
f
Mts #ft as
0 Gastrointestinal upset common; diarrhoea,
jaundice, ileus and pancreatitis may occur
0 WCC often not elevated with lymphopenia;
thrombocytopenia/pancytopenia may occur
I
Hyponatraemia due to syndrome of
inappropriate antidiuretic hormone (SIADH)
0 Headache, confusion and delirium are
prominent and focal neurological signs may
develop
I Abnormal liver and renal function in
approximately 50%
I Acute renal failure, interstitial nephritis and
glomerulonephritis may develop
Staphylococcus aureus
Staphylococcus aureus pneumonia may follow a
viral illness; it has a high mortality (30%-70%). The
disease is more common in intravenous drug ad-
dicts.
Specific features include:
U Toxin production with extensive tissue necrosis
0
Staphylococcal skin lesions may develop
0 Chest X-ray shows patchy infiltrates with abscess
formation in 25% and empyema in 10%
0 > 25% of patients have positive blood cultures
Treatment of p n e u m o n i a
All patients should be given appropriate concentra-
tions of oxygen and they may require intravenous
fluids if circulating volume is depleted. Treatment is
with oral amoxicillin and a macrolide (eg clarlthro-
mycin) for non-severe cases requiring hospitali-
sation. A third-generation cephalosporin given
intravenously coupled with a macrolide is indicated
In S! V! I! C3595.
0 A single antibiotic can be used for community
patients or those admitted to hospital for non-
medical reasons
0 Newer fluoroquinolones leg moxifloxacin)
provide an alternative for patients who are
allergic to penicillin or macrolides
542
t
'<
'
7
0 Intravenous treatment should he stepped down
to oral treatment after 48 hours provided the
patient is improving
0 lfa specific organism is isolated the appropriate
antibiotic is given
Treatment should continue for 7-TO days depend-
ing upon response. Up to 21 days of treatment is
recommended for Legionella pneumonia.
Nosocomial (hospi t al -acqui red) p n e u m o n i a
This is defined as pneumonia that develops 2 days
or more after admission to hospital ( O. 5%- 5% of
hospitalised patients). The organisms usually in-
volved include:
* S. aureus
0
Gram-negative bacteria: Klebsiella,
Pseudomonas, Escherischia coli, Proteus spp.,
Serralia spp., Acinetobacter spp.
0 Anaerobes
0
Fungi
S. pneumoniae (and other streptococci) are less
common
Treatment is with broad-spectrum agents (eg third-
generation cephalosporinsi.
Aspiration p n e u m o n i a
Aspiration pneumonia may complicate impaired
consciousness and dysphagia, Particulate matter
may obstruct the airway, but also chemical pneumo-
nitis may develop from aspiration of acid gastric
contents, leading to pulmonary oedema.
I Anaerobes are the principal pathogens, arising
from the oropharynx
0 There are typically two to three separate isolates
in each case
I
Multiple pulmonary abscesses or empyema may
result
0 Treat with metronidazole in combination with
broad-spectrum agent (eg third-generation
cephalosporin)
Cavitation may develop in certain lung infections
( se e following box).

_S ,.,_*-Wi .g
b/:_,>;\;
S. aureus
at
'fr iw i_
A,
Klebsiella pneumoniae
Legionella pneumophila (rare)
Anaerobic infections
Pseudomonas aeruginosa
Mycobacterium tuberculosis and non-
tuberculous mycobacterial infections
Lung abscess
This may be suspected when the patient is slow to
improve from pneumonia, A chest X~ray will show
single or multiple fluid-filled cavities, Prolonged
courses of antibiotics are needed, sometimes with
percutaneous drainage,
19.3.2 Empyema
A collection of pus in the pleural space may com-
plicate up to 15% of community-acquired pneumo-
nias and is more common when there is a history of
excess alcohol consumption, poor dentition, aspira-
tion or general anaesthesia.
0 A diagnosis of empyema is suspected if a patient
is slow to improve, has a persistent fever or
elevation of the white cell count or CRP, and
has radiological evidence of a pleural fluid
collection. The pH of pleural fluid is <7 .2
I Untreated, extensive fibrosis occurs in the
pleural cavity, weight loss and clubbing develop
and the mortality rate is high
I The mainstay of treatment is drainage of the
pleural space combined with continuous high-
dose intravenous antibiotic treatment, Daily
intrapleural administration of streptokinase has
been shown to liquefy the pus and to facilitate
percutaneous drainage
0 For those who fail to resolve with medical
therapy, thoracotomy and decortication of the
lung may be necessary
19.3.3 Tuberculosis
Unlike Community-acquired pneumonia, the num-
ber of new cases of tuberculosis (TB) declined in
yt
Respiratory Medicine
, v
the UK throughout the 20th century, mainly due to
i
the improvement in living standards. ln recent years,
however, the incidence of TB has begun to increase
again. Those at risk include:
0 Those on low incomes
Homeless people
Alcoholics
HIV-positive individuals
Immigrants from countries with a high incidence
of TB
The rnost commonly involved site is the lung - with
lymph node, bone, renal tract and GI tract being
less common. Tuberculous meningitis is the most
serious complication.
Primary TB
Primary infection occurs in those without immunity.
A small lung lesion known as the Ghon focus
develops in the mid- or lower zones ofthe lung and
is composed of tubercle-laden macrophages. Bacilli
are transported through the lymphatics to the drain-
ing lymph nodes, which enlarge considerably and
caseate. Infection is often arrested at this stage and
the bacteria may remain dormant for many years.
The peripheral lung lesion and the nodes heal and
may calcify. The entire process is often asympto-
matic. However, specific immunity begins to devel-
op and tuberculin skin tests become positive.
Post-primary TB
Organisms disseminated by the blood at the time of
primary infection may reactivate many years later.
The most common site for post-primary TB is the
lungs, with bone and lymph node sites being less
common. Reactivation may be precipitated by a
waning of host immunity, for example due to malig-
nancy or immunosuppressive drugs (including ster-
oids).
Clinical p i ct u r e
Primary infection is often asymptomatic, but may
cause mild cough and wheeze or erythema nodo-
sum. Clinical features of reactivation or re-infection
are described in the following box.
'
543
_
Essential Revision Notes for MRCP

2-;<.g
'Q
, ,J . _ ; \ . , 5' .,- g, , _ ; \ , . / <
,....;~.t
>"~___r;.-<>

Persistent cough
Weight loss
Night sweats
Haemoptysis
Pleural effusion
Pneumonia
-'f
~ Ms- ,--9,11-1.
t-
,.

at -<3 '.;;;;,='W, tej g`?@f`~\,t if/Y 1

f.

.\ w*t"Xi\>
I
t
'tv-A, .,

aff, st;-;'si<,,. f .s
i;t>'\tf;
stains and then cultured on Lowenstein-Jensen
medium. Cultures are continued for at least 6 weeks
as the organism is slow-growing. Polymerase chain
reaction (PCR) for tuberculous DNA can be used to
provide a rapid diagnosis. This allows early differ-
entiation from non-tuberculous mycobacterial infec-
tion [which would be important before embarking
on an extensive screening programme of contacts)
and can also be used to detect multidrug-resistant
Meningitis disease.
Lymphadenopathy
Treatment
Mlliary TB
(See also Section 11.6.1 in Chapter 11 Infectious
This is caused by widespread dissemination of in- Diseases.) This is with a combination of four drugs:
fection via the bloodstream. It may present with
non-specific symptoms oi malaise, pyrexia and Rifampicin
Isoniazid
weight loss. Eventually hepatosplenomegaly devel-
ops and chnroidal tubercles may be visible on Pyrazinamide
Ethambutol
fundoscopy. The chest X-ray shows multiple
rounded shadows a few millimetres in diameter, lt is
Short courses of treatment for 6 months are now
universally fatal if left untreated.
standard. All drugs are given for 2 months and
_M , s t isoniazid and rifampicin are continued for a further
4 months.
I
-
Chest X-ray
May show patchy shadowing in the
upper zones with volume loss and
0
Sensitivity testing will identify drug resistance
and all four drugs are continued until
sensitivities are known
cavitation, and ultimately fibrosis 0 If pyrazinamide has to be discontinued due to
0 Pleural fluid aspiration and biopsy side-eftects, a 9-month regime is necessary
0 and lavage 0 Second-line agents (eg ethionamide,
~Bronchoscopy
Used for those unable to expectorate; propionamide, streptomycin, cycloserine) may
transbronchial biopsy if miliary disease be needed
is a possibility 0
Compliance can pose major problems and
0
Early morning urine specimens directly obsen/ed therapy (DOT - larger doses
For renal tract disease of drugs administered three times per week) is
Liver biopsy used when poor compliance is anticipated
Lymph node biopsy
Bone marrow aspirate Multidrug-resistant TB (MDR-TB) signifies resistance
Morning sputum collections to rifampicin and isoniazid and currently accounts
For acid and alcohol-fast bacilli smear for 2% of tuberculous infections, It is mainly con-
0 CSF culture centrated in the London area.
Once 2 weeks of antituberculous chemotherapy has
Specimens are examined for acid and alcohol-fast been completed, the patient is considered to be
bacilli (AAFB) using Ziehl-Neelsen or auramine non-infectious.

544

Side-effects of antituber culous tre a tme nt
Side-effects are common:
' O p p o rt u n i s t i c m y co b act eri al infections
Hepatitis: may be caused by rifampicin,
isoniazid and pyrazinamide
0
Optic neuritis: may be caused by ethambutol;
visual acuity should be checked before
treatment is initiated
0 Peripheral neuropathy: may be clue to isoniazid;
10 mg of pyridoxine daily is given in those at
particular risk of this complication (eg
alcoholics, diabetics and in patients with renal
failure)
Prevention
The schools BCG programme has now been with-
drawn. Babies and infants at high risk are screened
opportunistically for active disease and then offered
BCG vaccination. The efficacy of BCG varies greatly
in different communities but usually helps prevent
disseminated disease. All immigrants to the UK from
high-risk countries are screened for latent disease.
Mantoux testing is offered to all those without a
definite BCG scar, followed by BCG vaccination if
the Manotoux test is negative, or chemoprophylaxis
if it is positive. Chemoprophylaxis comprises isonia-
zid for 6 months or rifampicin and isoniazid for
3 months.
I Patients with pulmonary TB (particularly those
who are sputum smear-positive for AAFB) are
potentially infectious and close contacts should
be screened for disease. Mantoux testing is
offered to those aged < 35 years, and a chest X-
ray performed for patients aged > 3 5 years
0 More recently selective immunological
(interferon-y) tests have been developed and are
useful where Mantoux testing may be inaccurate
0 The use of anti-tumour necrosis factor alpha
(Tl\.Fo.) therapy can be associated with
reactivation of latent TB. Patients due to start
such treatment should be screened for active/
past TB. Those who have had adequately treated
past TB should be monitored closely. Where
past TB has not been treated fully a course of
chemoprophylaxis is given
Respiratory Medicine
TB is a notifiable disease.
These account for TO/0 of all mycobacterial infec-
tions. Causative organisms include the following:
Mycobacterium kansasii (commonest)
Mycobacterium xenopi
Mycobacterium ma/moense
Mycobacterium avium intrace/lulare
These organisms cause disease that is clinically and
radiologically identical to TB, and that is indistin-
guishable from TB on sputum smear. Pulmonary
disease, lymphadenitis (in children) and dissemi-
nated infection are the commonest clinical prob-
lems. Most patients are middle-aged/elderly with
significant underlying COPD, bronchiectasis or pre-
vious TB. A minimum of two positive cultures taken
a week apart in a patient with an appropriate
clinical picture is necessary to make the diagnosis.
The organisms are ubiquitous in the environment
and are low-grade pathogens. Opportunistic myco-
bacterial infections constitute a relatively higher
proportion of mycobacterial infections in patients
with acquired immunodeficiency syndrome (MDS).
The onset of symptoms is usually gradual
0 Treatment programmes are generally longer than
for TB, and are continued for at least 9 months
and often for 2 years
0
Rifampicin and ethambutol are the mainstay of
treatment; clarithromycin or ciprofloxacin may
be added
Opportunistic infections do not need to be
notified
0 Contact tracing is unnecessary as person-to-
person infection is very rare
19.3.4 B ro n ch iectasis
This is the permanent dilatation of subsegmental
airways, which are inflamed, tortuous, flabby and
partially/totally obstructed by secretions. Bronchiec-
tasis may be cystic, cylindrical or varicose, with the
cystic pattern being the most severe. The obstruc-
tion often leads to post-obstructive pneumonitis so
545
Essential Revision Notes for MRCP

that the lung parenchyma may be temporarily or Investigations

permanently damaged. 0
Sputum microbiology: most commonly shows
H. influenzae, 5. pneumoniae or Pseudomonas
: i e 1 ~ " - , .~; "\=;,"%t,:.ii'.~,,<,;;4<,r I . r
~

aeruginosa; mycobacteria and fungi may also be

seen
0
Congenital
0 Chest X-ray: may be normal or may show
I Post-infective (eg following episodes of thickening of bronchial walls and in cystic
childhood measles, pneumonia or pertussis) bronchiectasis, ring shadows i fluid levels. The
0 Immune deficiency upper lobes are most frequently affected in
0 Post-tuberculosis ABPA, cystic fibrosis, sarcoidosis and
O Allergic bronchopulmonaiy aspergillosis tuberculosis
(ABPA) - proximal Pulmonary function tests: may be normal or
0

I
Compllcating sarcoidosis or pulmonary show an obstructed/restricted pattern (or both)
0
fibrosis High-resolution CT scanning: is diagnostic in
idiopathic - 60% > 90% of cases
0 Distal to an obstructed bronchus (or a 0
Immunoglobulin levels (or antibody response
bronchus severely compressed from following vaccination, eg H. influenzae or
encroaching lymph nodes) pneumococcus): may demonstrate deficiency of
0
Secondary to bronchial damage resulting humoral immunity
from a chemical pneumonitis (eg inhalation
of caustic chemicals) u .` ., . t . - . t

0
Mucociliary clearance defects: primary
ciliary dyskinesis or associated with situs J ,; - .,.a - . . . r-,:="l:., '.
inversus (Kanagener syndrome) or
associated with azoospermia and sinusitis 0 Rheumatoid arthritis
0
in males (Young syndrome) Malignancy (childhood acute lymphoblastic
0 HIV/AIDS leukaemia, adult chronic lymphocytic
0
Alpha-1-antitrypsin deficiency leukaemia)
0
*In 60% of cases no cause is identified
Sjogren syndrome
0 Yellow nail syndrome and primary
lymphoedema
Inflammatory bowel disease (usually
ulcerative colitis)
Clinical features o infenimy
There is a history of chronic sputum production,
which is often mucopurulent and accompanied by
episodes of haemoptysis. Occasionally bronchiecta- Treatment
sis can be 'dry' with no sputum production lout with
As far as possible the aetiology of the bronchiectasis
episodic haemoptysis. Exertional dyspnoea and
wheeze may be associated. Patients complain of should be established in every case. If there is an
malaise and fatigue; one-third have symptoms of underlying immune deficiency slate, treatment with
chronic sinusitis. There may be few abnormal clin~ intravenous gamma globulin replacement therapy is
ical findings other than occasional basal crackles or beneficial. Regular physiotherapy with postural drai-
wheeze on chest examination; clubbing may be nage and using the active cycle of breathing helps
to clear the airways.
present. ln more advanced disease weight loss and
cachexia are prominent. I inhaled bronchodilators are often used

546

I Antibiotics are usually given in response to an
exacerbation, but some patients require
continuous oral therapy; azithromycin given
three times per week is one option
0 Nebulised antibiotics can be used to reduce the
microbial load and they are particularly useful
when a patient is colonised with Pseudomonas
I
Adequate hydration is important but mucolytics
are generally not helpful
0
Surgery is reserved for those with localised
severe disease; lung transplantation has been
successful
C om pl i cat i ons
infective exacerbations are the principal problem.
Haemoptysis usually settles with treatment of the
infection but occasionally embolisation of the
bleeding vessel is required. Chest pain over an area
of bronchiectatic lung is not uncommon. In the long
term, systemic amyloid may result.
19.3.5 Cyst i c fibrosis
Cystic fibrosis is the most common fatal autosomal
recessive condition in the Caucasian population,
affecting 1 in 2500 live births; i in 25 adults are
carriers of the gene. The cystic fibrosis gene has
been localised to the long arm of chromosome 7
and codes for the cystic fibrosis transmembrane
conductance regulator protein (CFTR), which func~
tions as a chloride channel (see also Chapter 7,
Genetics). Over 800 mutations have been identified,
the most common being A508. The basic defect
involves abnormal transport of chloride across the
cell membrane; in the sweat gland there is a failure
to reabsorb chloride and in the airway there is
failure of chloride secretion. Diagnosis is made by
detection of an abnormally high sweat chloride
( > 6 0 mEq/l) and by genetic analysis.
P ulmona ry disease
A significant inflammatory infiltrate may be identi~
fied in the lungs at a very early age. The airways
become obstructed by thick mucus due to de-
creased chloride secretion and increased sodium
Respiratory Medicine
reabsorption, and so bacterial infection becomes
established in early life.
Infection occurs in an age-related fashion: infants
and young children become colonised with S. aur-
eus and subsequently H. influenzae. In the teenage
years infection with Pseudomonas aeruginosa oc-
curs.
The other major pathogens involved are:
S. pneumoniae
Burkholderia cepacia complex
Mycobacterium tuberculosis
Non-tuberculous mycobacteria
Aspergillus fumigatus
Viruses
Chronic infection and inflammation cause lung da-
mage with bronchiectasis affecting predominantly
the upper lobes. Patients have breathlessness and
reduced exercise tolerance, cough with chronic
purulent sputum production, and occasional hae-
moptysis. Physical signs include clubbing, cyanosis,
scattered coarse crackles and occasional wheeze.
Slight haemoptysis is often associated with infection
but major haemoptysis may occasionally necessitate
pulmonary arterial embolisation.
0
Pulmonary function tests show airflow
obstruction; chest X-ray may show
hyperinflation, atelectasis, visible thickened
bronchial walls, fibrosis and apical bullae;
pneumothorax occurs in up to 10% of patients
I In the terminal stages of disease, respiratory
failure develops; 90% of deaths are attributable
to respiratory failure. The average life
expectancy has increased into the fourth decade
of life
Gastrointestinal tra c t
Pancreatic insufficiency is present in over 90% of
patients. Malabsorption causes bulky offensive
stools, with weight loss and deficiency of fat-soluble
vitamins (A, D, E and K). Babies may present with
meconium ileus and adults may develop an equiva-
lent syndrome with obstruction of the small bowel
due to poorly digested intestinal contents, causing
547
Essential Revision Notes for MRCP
abdominal pain, distension, vomiting and severe
constipation.
0 Obstruction of the biliary ductules in the liver
may eventually lead to cirrhosis with portal
hypertension, splenomegaly and oesophageal
varices
0 Gallstones (in 15% of patients), peptic ulcer and
reflux oesophagitis are all more prevalent
I Pancreatitis may develop in older patients
Involvement of othe r s ys t em s
0 Diabetes: eventually occurs in up to a third of
patients. There ls a gradual loss of pancreatic
islet cells with fibrosis developing, Ketoacidosis
is very uncommon
0
Upper airway disease: nasal polyps occur
frequently (up to one-third of patients); chronic
purulent sinusitis may develop
0
Fertility: virtually all males are infertile due to
abnormal development of the vas deferens and
seminiferous tubules, but fertility in w o men is
only slightly reduced. Although many women
with cystic fibrosis have had successful
pregnancies, pregnancy may lead to life-
threatening respiratory complications
0
Osteoporosis is more common with an
increased risk of fractures
0 Renal disease: renal calculi (oxalate stones) are
mo re common in people with CF. There is also
a high prevalence of urinary incontinence in
females
Treatment of cy s t i c fibrosis
Care for patients with cystic fibrosis is best given in
a specialist unit, which can provide extensive multi-
disciplinary input.
Antibiotics and respiratory treatments
ln the UK most centres give antibiotics when spu-
tum becomes increasingly purulent, pulmonary
function tests are deteriorating or the patient is
generally unwell with weight loss. Most patients
become chronically colonised with Pseudomonas
aeruginosa and so two different antibiotics (eg cefta-
548
zidime and tobramycin) are used in combination to t.
if
prevent resistance developing.
0 Up to 10% of patients become colonised with a
group of bacteria called Burkho/deria cepacia, r
some of which are highly transmissible from one
individual to another and are associated with a
worse prognosis. These patients are therefore
segregated from other patients in the hospital, at
outpatient clinics and also socially
0 Most patients need continuous anti-
staphylococcal treatment
Nebulised antibiotics reduce the microbial load and
are useful in those who need frequent courses of
intravenous antibiotics; colistin or tobramycin are
used continuously in a twice-daily regimen.
0 DNase helps to liquefy viscous sputum and is
helpful in some patients. Bronchodilators and
inhaled steroid are given to treat airflow
obstruction. Physiotherapy, using the active
cycle of breathing technique, should be tailored
to individual needs
Pancreatic enzyme supplements
Given with main meals and snacks to those with
pancreatic insufficiency. Meconium ileus equivalent
is treated with vigorous rehydration and regular oral
Gastr0grafin. Good nutritional status is associated
with improved prognosis; supplementary overnight
feeding with nasogastric tube or via gastroenterost-
omy can help to maintain hody weight.
Transplantation
Double-lung transplantation (if only single lung
transplant peiformed the new lung would be vulner-
able to infection from the remaining damaged lung)
may be appropriate for some patients with terminal
respiratory failure, Non-invasive positive-pressure
ventilation may be utilised to support a patient
before transplantation. The optimal timing of lung
transplantation must be assessed in each individual
case. Liver and occasionally pancreas transplants
are also carried out in some patients.

Future devel opm ent s in cy s t i c fibrosis
Screening of newborns for cystic fibrosis will soon
be practised throughout the UK. Extensive research
is being carried out into gene therapy, although this
is still a long way from having a clinical applica-
tion.
l9.3.6 Asp erg illu s a n d t h e lu n g
Aspergillus causes three distinct forms of pulmonary
disease: allergic loronchopulmonary aspergillosis,
colonisin E asPer Sillosis and invasive asiferEillosis.
Allergic br onchopulmonar y aspergillosis
Most patients with allergic bronchopulmonary
aspergillosis (ABPA) are asthmatics but the condi-
tion may occur in non-asthmatics.
The disease is due to sensitivity to A. fumigatus
spores mediated by specific IgE and IgG antibodies.
The allergic response results in airways becoming
obstructed by rubbery plugs of mucus containing
Aspergillus hyphae, mucus and eosinophils; plugs
may be expectorated. The following changes may
be found on investigation:
0 Lobar or segmental collapse of airways
0
Fleeting chest X-ray shadows due to intermittent
obstruction of airways
Positive skin-prick tests and RAST to Aspergillus
Positive precipitins to A. fumigatus
Raised serum IgE >i00O ng/ml
Peripheral blood and pulmonary eosinophilia
0 The condition may result in proximal
bronchiectasis
Treatment is with oral corticosteroids which may be
required long-term; itraconazole is also useful and
may allow the dose of steroid to be reduced.
Colonising aspergillosis
Fungal colonisation of cavities in the lung parench-
yma, of dilated bronchi or the pleural space.
A mass or ball of fungus develops known as an
aspergilloma. A. furnigatus is usually responsible,
but occasionally A, niger, A, flavus or A. nidulans
Respiratory Medicine
may be implicated. Cavities due to TB, sarcoidosis,
cystic fibrosis or pulmonary neoplasms may be
colonised. Cough and sputum production often oc-
cur and are features of the underlying disease.
Haemoptysis is a common complication, and this
may be massive.
0 An aspergilloma is usually suspected by chest
X-ray, which demonstrates a cystic space
containing a rounded opacity. An air space is
visible between the fungal mass and the cavity
wall - the 'halo' sign
0
Precipitating antibodies are nearly always
present but response to skin testing is variable
0
Sputum examination may reveal fungal hyphae
Many aspergillomas require no specific treatment.
Treatment is indicated for recurrent haemoptysis,
systemic symptoms and where there is evidence of
fungal invasion of surrounding tissue. Intra-cavity
instillation of amphotericin paste is sometimes use-
ful, and systemic treatment with the newer azoles
(eg voriconazolei may be helpful in some cases.
Surgical resection of the affected area of lung may
be curative but surgery can be technically difficult.
Invasive aspergi l l osi s
Fungal infection spreads rapidly through the lung
causing granulomata, necrosis of tissue and sup-
puration. It occurs most commonly in the immuno-
suppressed host and may be rapidly fatal.
Progressive chest X-ray shadowing (which may cavi-
tate), associated with fever, chest pain and haemop-
tysis that does not settle promptly with antibacterial
agents, suggests invasive aspergillosis,
0
Cough with copious sputum production, often
with haemoptysis, is usual
Examination of sputum or bronchoalveolar
lavage fluid may demonstrate fungal hyphae
0
High-resolution CT scanning shows pulmonary
infiltrates with the 'halo' sign. Treatment is with
systemic antifungal agents
549
Essential Revision Notes for MRCP
19:3 fL`)(,`il..i[r'-\`l"l()l\dr\.L LLJNG U There is an increased risk of lung cancer ( se e
lJlSE.f\SE.
19.4.1 Asbestos-related d isease
Exposure to asbestos was previously commonplace
in many occupations including ship builders,
laggers, builders, dockers and workers in factories
engaged in the manufacture of asbestos products.
Effe c ts of a sbe stos on t h e l ung
Pleural plaques
These appear 20 years or more after low-density
exposure. They develop on the parietal pleura of
the chest wall, diaphragm, pericardium and medias-
tinum, and commonly calcify, Pleural plaques are
usually asymptomatic but they may cause mild
restriction.
Diffuse pleural thickening
This can extend continuously over a variable pro-
portion of the thoracic cavity, but is most marked at
the lung bases. It causes exertional dyspnoea; PFTs
show restriction, decreased compliance and re-
duced total lung capacity, but the KCO is normal.
Pleural effusions may occur in asbestos-related dis-
ease, usually within i5 years of exposure. They
often resolve spontaneously, leaving thickening of
the visceral pleura.
Ashestosis
The onset of asbestosis is usually > 20 years after
exposure (but with higher levels of exposure fibrosis
occurs earlier). Fihrotic changes are more pro-
nounced in the lower lobes; patients present with
slowly worsening exertional dyspnoea and clinical
examination reveals fine inspiratory crackles in the
lower zones. Clubbing may occur.
0 Chest X-ray shows small irregular opacities,
horizontal lines and, in more advanced disease,
honeycomb and ring shadows
0
High-resolution CT (HRCT) confirms fibrosis
associated with pleural disease
0 PFTs show a restrictive defect with reduced
KCO
550
be low ) -
0 The disease is untreatable and death is usually
due to respiratory failure or malignancy
lung cancer
Mesothelioma is the commonest malignancy asso-
ciated with asbestos exposure, The risk of lung
cancer is also substantially increased, particularly in
smokers ( se e below).
C om pensat i on claims for o ccu p at i o n al lung
disease
Patients with all of the above asbestos-related dis-
eases texcept pleural plaques) are entitled to state
compensation and a disability pension. Patients can
also claim against their employers for negligently
exposing them to asbestos for any of the above
asbestos-related conditions (including pleural pla-
ques). They should be advised to begin legal action
within 3 years of being told that they have an
asbestos-related condition.
0 The same applies for patients with coal workers
pneumoconiosis and occupational asthma and
a small number of other industrial diseases
19.4.2 C o al workers p n e u m o c o n i o s i s
(CWP)
The incidence of this pneumoconiosis is related to
total dust exposure. Dust particles 2 - 5 umin dia-
meter are retained in the respiratory bronchioles
and alveoli. Simple CWP is characterised by small
rounded opacities ( < 1 5 mm in diameter) on chest
X-ray, and is associated with focal emphysema. The
lesions are asymptomatic.
P rogressive mas s i v e fi brosis (PMP)
Progressive massive fibrosis involves the develop-
ment of larger opacities ( > 3 cm in diameter) on a
background of simple CWP,
0 PMF lesions are usually in the upper zones and
may cavitate

0
Cough, sputum production and dyspnoea occur
with reduced life expectancy, deaths occurring
from progressive respiratory failure
l PFTs show a mixed obstructive/restrictive
pattern with reduced KCO
Coal mining is recognised as a cause of COPD.
Caplan syndrome is the development of multiple
round pulmonary nodules in patients with rheuma-
toid arthritis and a background of CWP. Nodules
may develop before the joint disease, and occur in
crops in the periphery of the lung. They may be
associated with pleural effusion and may ultimately
calcify.
19.4.3 Silicosis
This is caused by inhaling silicon dioxide, a highly
fibrogenic dust; those commonly affected are quarry
workers, hard-rock miners and civil engineers.
Silicosis was commonly associated with TB in the
first half of the 20th century,
0 An acute illness characterised by dry cough and
breathlessness occurs within a few months of
exposure to very high levels of dust
I With more chronic exposure silicotic nodules
form, which are 3 - 5 mm in diameter and
predominantly affect the upper lobes
I Eggshell calcification occurs around enlarged
hilar glands
0
Gradually worsening breathlessness is
associated with restrictive lung physiology and a
fall in gas transfer
0 There is no effective treatment (other than lung
transplantation in patients with respiratory'
failure), but the disease is compensable
I Silicosis is associated with an increased
incidence of tuberculosis
Respiratory Medicine
1*), l i l Ber ylliosis
The inhalation of fumes from molten beryllium
C a u s e s an acute alveolitis. However, most cases of
berylliosis are due to chronic low-level exposure,
causing a tissue reaction similar to sarcoidosis.
Non-caseating granulomata form in the lungs and
lymph nodes surrounded by fibrous tissue; the chest
X-ray shows fine nodulation evenly distributed
throughout the lung fields with bilateral hilar lym-
phadenopathy.
0 A positive blood and bronchoalveolar lavage
beryllium lymphocyte proliferation assay is
strongly associated with the presence of chronic
beryllium disease
0 Interstitial fibrosis develops, with shrinking of
the lungs
0 Patients develop progressive breathlessness with
death ultimately occurring due to respiratory
and right heart failure
1 9 . 4 5 Byssi nosi s
This is caused by exposure to cotton dust, flax and
hemp. Acute exposure causes airways narrowing in
a third of affected individuals. However, chronic
byssinosis develops after years of heavy exposure to
cotton dust; symptoms are worse on the first day
back after a break from work, and include chest
lightness, cough, dyspnoea and wheeze.
0 There is a progressive decline in FEVr during the
working shift, most marked on the first day of
the week
0 Prevention is by reducing the levels of cotton
dust to which employees are exposed
0 Bronchodilators may provide some relief of
symptoms
551
Essential Revision Notes for MRCP
i*}/it{r.= {`}(,r11:pa1iotaa`tasthma
Occupational asthma is now the commonest indus-
trial lung disease in developed countries. A large
number of agents encountered at work cause asth-
ma and are officially recognised for industrial com-
pensation, as listed in the following box.
`
Causes of oe e upa tiona l asthma
0
lsocyanates
U Acid anhydride and amine hardening
agents
Platinum salts
Stainless steel welding
Resin used in soldering flux
Epoxy resins
Proteolytic enzymes
Azodicarbonamide (PVC, plastics)
Pharmaceuticals
Glutaraldehyde
Many other chemicals
Wood dust
Any known sensitising agent in the
workplace
0
Laboratory animals and insects
0
Dyes
'
0
Flour/grains
Occupational asthma develops after a period of
asymptomatic exposure to the allergen, but usually
within 2 years of first exposure. Detection depends
on a careful history, and PEFR monitoring both at
work and at home, Once occupational asthma has
developed, bronchospasm may be precipitated by
other non-specific triggers such as cold air, exercise,
etc. Occupational asthma may develop in workers
with previously diagnosed asthma. ln order to iden-
tify the substance involved, specific IgE levels may
be measured or occasionally bronchial provocation
testing may be performed. Early diagnosis and re-
moval ofthe individual from exposure to the aller-
gen are essential if they are to make a full recovery.
Asthma symptoms may persist despite termination
of exposure.
552
l'9.4.7 Reactive a i rw a y s d y sfu n ctio n
s y n d r o m e (RADS)
This reactive airways dysfunction syndrome (RADS)
refers to bronchial hyper-responsiveness following
the inhalation of high Concentrations of irritant gas,
aerosols or particles. Asthma-like symptoms usually
develop within minutes to hours after exposure and
airways hyper-reactivity persists over a prolonged
period of time. 'Irritant asthma' occurs following
rnultiple exposures to lower concentrations of irri-
tants.
19.4.8 Extrinsic allergic alveolitis
(h y p ersen sitiv ity p n eu mo n itis)
This is a hypersensitivity pneumonitis caused by a
specific immunological response tusually IgG-
mediated) to inhaled organic dusts.
0 Farmers lung is due to the inhalation of
thermophilic actinomycetes (usually
Micropolyspora faeni and Therrnoactinomyces
vulgaris), when workers are exposed to mouldy
hay
0 Bird fanciers lung is caused by inhaled avian
serum proteins, present in excreta, and in the
bloom from feathers; it primarily affects those
who keep racing pigeons and those keeping
budgerigars as pets
0 Ventilation pneumonitis occurs in inhabitants of
air-conditioned buildings where thermophilic
actinomycetes grow in the humidification
system
0
Bagassosis is due to exposure to
Thermoactinomyces sacchari in sugar cane
processors
0 Mall worker's lung is due to the inhalation of
Aspergillus clavatus
0 Mushroom worker's lung is due to the
inhalation of thermophilic actinomycetes
Clinical features of ex t ri n s i c allergic
alveolitis
The clinical features depend on the pattern of
exposure. An acu t e allergic alveolitis develops sev-
eral hours after exposure to high concentrations of

dust, Breathiessness and 'flu-like symptoms occur,
sometimes associated with fever, headaches and
muscle pains, The symptoms are short-lived and
usually resolve completely within 48 hours.
0
inspiratory crackles may be heard on chest
auscultation
0 The disease may present in a sub-acute or
chronic form characterised by cough,
breath lessness, fatigue and weight loss
0
Clubbing may occur in association with
irreversible pulmonary fibrosis
Investigation and treatment
The diagnosis of extrinsic allergic alveolitis is made
by establishing a history ot' exposure to antigen and
the demonstration of precipitating antibodies in the
patients serum.
U Chest X-ray may show a generalised haze
sometimes associated with nodular shadows, In
chronic cases, progressive upper zone fibrosis
and loss of lung volume occurs
U
Spirometry becomes restrictive and gas transfer
is reduced
0
Histology of lung hiopsy tissue shows a
mononuclear cell infiltrate with the formation of
non-caseating granulomata
0 Fluid obtained from bronchoalveolar lavage
(BAL) has a high lymphocyte count
0
Precipitins; the demonstration of specific IgG
antibodies in serum against the identified
antigen, Precipitins may be present in the
absence of clinical disease
Once the diagnosis is established the patient should
be isolated from the antigen; if this is impossible
respiratory protection should be worn. Cortico-
steroids accelerate the rate of recovery from an
acute attack but are generally not helpful once
established fibrosis develops,
P ulmona ry fibrosis in ext ri nsi c allergic
alveolitis
Multi le e Pisodes of acute ex osure to a ents caus-
ing extrinsic allergic alveolitis, or long-term low-
grade exposure, as occurs in budgerigar owners,
Respiratory Medicine
can lead to irreversible lung fibrosis. These chronic
cases present with progressive dyspnoea, weight
loss and fatigue. The chest X-ray will show lung
shrinkage but calcification or cavitation does not
develop. HRCT demonstrates reticular, nodular and
ground-glass opacities. Prompt diagnosis of extrinsic
allergic alveolitis is important as the disease is
reversible when diagnosed early.
l ) .' $ TUMOURS
l}.;`>f m i n g can cer
Lung cancer is the most prevalent cancer worldwide
and accounts for i in 3 cancer deaths in men and i
in 6.5 cancer deaths in women. Female mortality
from lung cancer now exceeds that from breast
cancer. Twenty per cent of smokers will develop
lung cancer. The prognosis is poor, with a i-year
sun/ival of 20%. The 5-year survival rate is only
5.5%. Lung cancer is rare under the age of 40 but
the incidence rises steeply with age, peaking in the
70-74-year age group,
Causes of l ung 'canon
0
Smoking
Over 90% of lung cancers occur in
0
- current or ex-smokers
Atmospheric pollution
Persistently higher lung cancer rates in
urban populations; passive smoking
industrial exposures
~ Asbestos fibre, aluminium industry,
arsenic compounds, benzoyl chloride,
~ beryllium
increased incidence in patients with
cryptogenic fibrosing alveolitis and
systemic sclerosis
Smoking is the leading cause of lung c a nc e r,
Although smoking rates have declined amongst
adult men and to a lesser extent among women,
there is an increasing number of teenage smokers,
particularly girls.
553
Essential Revision Notes for /\/IRCP

Hi s t o l o g i cal t ype s of l u n g cancer 0

0
Squamous cell (35%): usually arises from a
central airway
Small Cell (20%): arises in central airways and
grows rapidly, producing both intrathoracic and
metastatic symptoms
0 Adenocarcinoma (30%): may be peripheral and
slow-growing. Now the commonest form of
lung cancer
O Undifferentiated large cell ( 10%)
0 Bronchiolar-alveolar cell carcinoma (5%)
Supraclavicular and anterior cervical lymph
nodes, adrenals, bones, liver, brain and skin
Haemoptysis is one of the common presenting
symptoms of lung cancer.
Causes of ha e moptysis
Common causes
Carcinoma of the bronchus
~ Pneumonia/acute bronchitis
~ Bronchiectasis
Pulmonary tuberculosis

Clinical features of lung cancer o

Patients commonly present with cough, breathless-
ness, haemoptysis, chest pain, hoarse voice or
weight loss. Lung cancer should be suspected if a
pneumonia fails to resolve radiologically, Occasion-
ally an asymptomatic lesion will be noted on a
routine chest X-ray,
lnctrathoracic c omplic a tions of lung
cancer
I
Collapse of lung distal to obstructing
tumour
0 Recurrent laryngeal nerve palsy causing
hoarseness
I
Dysphagia due to compression of the
oesophagus by enlarged metastatic lymph
nodes or tumour invasion
0 Pericarditis with effusion
0 Phrenic n e n / e palsy with raised
hemidiaphragm
0 Pleural effusion
0
Superior vena caval obstruction causing
headache, distension of the veins in the
upper body, fixed elevation of the lVP,
facial suffusion with conjunctival oedema
0 Rib metastases
0
Spontaneous pneumothorax
Metastases can occur throughout the body but the
most commonly involved sites are:
Pulmonary embolus
o Mitral valve disease
Infective exacerbation of COPD
Rarer causes
Vascular malformations
Mycetoma
~ Connective tissue disorders
Vasculitis
Goodpasture syndrome
~ Cystic fibrosis
Bleeding diathesis
idiopathic pulmonary haemosiderosis
P aran eo p l as t i c s yndrom es
0
Syndrome of inappropriate ADH (SIADH):
chiefly associated with _small-cell lung cancer.
May resolve with chemo ut recurs with
tumour progression. Treatment involves fluid
restriction initially and demeclocycline for
resistant cases
0
Ectopic adrenocorticotrophic hormone (ACTH):
mainly associated with small-cell lung cancer
0
Hypercalcaemia: usually associated with
multiple bony metastases from squamous cell
carcinoma; ectopic parathyfroid PTH)
secretion occurs in a few squamous cancers
0
Gynaecomastiaz associated with large-cell
carcinoma and adenocarcinoma: may be
painful
0
Hyperthyroidism; rare (due to ectopic thyroid
stimulating hormone (T'_$_l-_l_))_- sguamws cell
lung cancer

554
 Respiratory Medicine

0 Lambert-Eaton syndrome: almost exclusively

associated with small~cell lung cancer; produces
Di l g n o d s of lung cancer
a proximal m y o u c e d tendon reflexes
Wherever possible, the histological type of lung
4 andTLTfo1omic features *T cancer should be confirmed and the patient
>
I
C|ubb W0~30W0 of lung cancers; should be staged, usually by computed tomo-
> may resolve after resection (see box below)
I graphy (CT) scanning. Nonsmall-cell lung can-
Hypertrophic pulmonary osteoarthropathy cers are staged using the TNM classification
(HPOA): produces periostitis, arthritis and gross

an
whilst small-cell lesions are classified as either
i
finger clubbing. HPOA is most commonl limited stage (confined to one hemithorax) or as
>
associated with adenocarcinoma extensive disease. An assessment of perform-
frequently with small-cell carcinoma. lt involves ance status is important prognostically. lncreas~
the long bones (tibia/fibula, radius/ulna or
ingly, positron emission tomography (PET)
femur/humerus). lt is associated with
scanning is being used to assess a solitary
subperiosteal new bone formation visible on pulmonary nodule or to complete staging prior
plain X-ray and is ohen painful to surgery or radical radiotherapy
li . `. \ , , , \ \ . , -, y . . . . . ,

l D iagnosis of l ung cancer

Carcinoma of the bronchus 0 CT thorax
Asbestosis 0 Percutaneous CT-guided biopsy of peripheral
Lung abscess nodules
Cystic fibrosis 0
Tuberculosis Bronchoscopy
0
Biopsy of metastatic deposit (including lymph
Cryptogenic fibrosing alveolitis nodes)
Bronchiectasis 0 Resection of peripheral nodules
Empyema 0
Sputum cytology is occasionally useful if the
Mesothelioma
patient is unfit for bronchoscopy and the tumour
is proximally situated
Pancoast s yndrom e
This is due to a tumour of the superior sulcus. The Treatment of l ung cancer
most common presenting complaint is pain (due to The management of all cases of lung cancer should
involvement of the eighth cervical and first thoracic be discussed at a multidisciplinary team meeting.
nerve roots) e x t e n d i
upper arm to the forearm and hand. The small
Surgery offers the best chance of cure. At the time
of presentation only 10%-20% of patients with
musa gof the hand may atrophy. Horner syndrome non-small-cell lung cancer will be operable. The 5-
may develop. Chest X-ray demonstrates a shadow at year survival rate depends on the clinical stage
the extreme apex, and there may be destr_L.u;tion of ( 60% for stage l tumours but only 7% for stage lllb
the first and second ribs. tumours, when disease is locally advanced). Patients
xi

555

i
Essential Revision Notes for MRCP
whose tumour is technically operable, but who are
unfit for surgery due to co~existing medical condi-
tions or poor lung function, may be treated with
radical radiotherapy.
0 Palliative radiotherapy is very effective in
relieving pain from bony metastases, controlling
haemoptysis and cough, Dysphagia due to
oesophageal compression by lymph nodes
responds well to radiotherapy
0
Superior vena caval obstruction can also be
treated with radiotherapy, although stenting
provides more immediate relief of symptoms
0
Chemotherapy for unresectable non-small-cell
lung cancer offers a small survival benefit but
has been shown to provide effective palliation
0 Unresectable tumours that compromise the
trachea or large airways may be palliated by
local techniques to maintain airway patency,
These include hrachytherapy iintraluminal
radiotherapy), laser therapy, airways stents and/
or photodynamic therapy
Small-cell lung cancer is associated with an extre-
mely poor prognosis if left untreated, with a median
survival of only 8 weeks. The tumour is, however,
much more sensitive than other types of lung cancer
to chemotherapeutic agents, and cycles of combina-
tion chemotherapy can result in remission in up to
80% of cases.
0 Median survival is now 1 4 -2 0 months for
limited disease and 8 -1 3 months for extensive
disease
0 Once the disease has relapsed, mean sun/ival is
4 months
19,52 Mesothelioma
This is most common in men between the ages of 50
and 70 years. The lesion arises from mesothelial cells
of pleura, or less commonly, the peritoneum. Asbes-
tos exposure is responsible for at least 85% of
malignant mesotheliomas, and the risk of mesothe-
lioma increases with the dose of asbestos received.
Crocidolite (blue asbestos) is more potent than amo-
site (brown asbestos) and both are more potent than
chrysotile ( white asbestos) in causing mesothelioma.
556
There is usually a latent period of > 3 0 years loe-
tvveen asbestos exposure and development of
mesothelioma. The tumour arises from the visceral
or parietal pleura, and expands to encase the lung.
Pleural mesothelioma presents with chest pain,
weight loss and dyspnoea and may cause pleural
effusion.
0
Annual incidence of mesothelioma in the UK
exceeds 1300 cases. Controls over asbestos
exposure only came into force in the 19705,
and the incidence of mesothelioma is rising and
is expected to peak around 2015. A detailed
occupational history is essential
0 Chest X-ray and CT thorax usually show an
effusion with underlying lobulated pleural
thickening and contraction of the hemithorax
0
Diagnosis is made by pleural biopsy, often done
as a video-assisted thoracic surgery (VATS)
procedure ( se e Section 19.6.4); the main
differential diagnosis is adenocarcinoma of the
pleura or benign pleural thickening
0 Treatment is unsatisfactory; radical surgical
procedures should only be performed within the
setting of a randomised trial. Radiotherapy is
helpful for pain relief and for prevention of
seeding of the biopsy track. Randomised trials of
chemotherapy for mesothelioma are currently
ongoing Pleural effusions should be drained
and talc pleurodesis considered once a tissue
diagnosis has been made. Involvement of the
palliative care team is often helpful
Median survival from presentation is 8 -1 4
months for pleural mesothelioma and 7 months
for peritoneal mesothelioma
0 Patients with mesothelioma may be eligible for
industrial compensation
19.5.3 Mediastinal tumours
Mediastinal tumours are often asymptomatic and
they may be an incidental finding on a routine
chest X-ray. In adults, 90% are benign. Clinical
presentation is with stridor, superior vena caval
obstruction, dysphagia, Horner syndrome, hoarse-
ness or pericardial effusion, The causes of mediast-
inal masses can be divided according to situation

f in the mediastinum:
0 Anterior mediastinum: thymoma, retrosternal
thyroid, lymphoma, teratoma, fibroma, lipoma,
seminoma and choriocarcinoma
5
0 Middle mediastinum: aortic arch aneurysm, left
51
ventricular aneurysm and pericardial cysts
0 Posterior mediastinum: neurogenic tumours
(neurofibroma, neuroblastoma, neurolemoma,
>
chemodectoma and phaeochromocytoma),
oesophageal tumours and diaphragmatic hernia
The initial investigation is usually chest X-ray which
will be followed by CT scan. Occasionally radio-
nuclide scans are needed to confirm the presence
of functioning thyroid tissue. Magnetic resonance
imaging (MRI) scanning may be used to define
tissue planes and operability,
19.6 GRANULOMATOUS AND
DIFFUSE PARENCHYMAL LUNG
DISEASE
19.6.1 Sar co id o sis
Sarcoidosis is a multisystem granulomatous disorder
primarily affecting young adults. The aetiology is
unknown. The prevalence varies among different
populations but in the UK it is 20/100 000 to 30/
)
100000, being highest among West Indian and
Asian immigrants. The characteristic histological
lesion is the granuloma composed of macrophages,
lymphocytes and epithelioid histiocytes which fuse
to form multinucleate giant cells, The disease may
present acutely with erythema nodosum and bilat-
eral hilar lymphadenopathy on the chest X-ray
(good prognosis with most patients showing radiolo-
gical resolution within a year) or insidiously with
multi-organ involvement. Ninety per cent of patients
have intrathoracic involvement.
Chest X-ray changes are graded as:
0
Stage 0: clear chest X-ray
0 Stage 1: bilateral hilar lymphadenopathy
(Bl-lL)
I
Stage 2: BHL and pulmonary infiltration
I
Stage 3: diffuse pulmonary infiltration
i
Respiratory Medicine
Patients may have no respiratory symptoms or com-
plain of dyspnoea, dry cough, fever, malaise and
weight loss. Chest examination is frequently normal;
finger clubbing is rare.
Diffuse parenchymal lung involvement may pro-
gress to irreversible fibrosis; the mid- and upper
zones of the lungs are most frequently affected.
Calcification of the hilar nodes or the lung parench-
yma may occur with chronic disease. Pleural effu-
SIOU IS THTQ.
Upper airway involvement (infrequent): the nasal
mucosa may become hypenrophied and cause ob-
struction, crusting and discharge; perforation of the
nasal septum and bony erosion are rare.
Extra pulmona ry disease
0
lymphadenopathy: painless, rubbery lymph
node enlargement is more common in black
patients; the cervical and scalene lymph nodes
are most frequently affected
0
Splenomegaly (25%)
0 liver involvement: this is common but, apart
from liver enlargement, is often subclinical
(derangement of liver function tests). Liver
biopsy is of diagnostic value in 90% (typical
sarcoid granulomata)
0 Skin; erythema nodosum [most commonly in
Caucasian females) in disease with BHL; skin
plaques, subcutaneous nodules and lupus
pernio (violaceous lesions on the nose, cheeks
and ears) seen in chronic disease
0 Acute anterior uveitis (25%): chronic
iridocyclitis affects older patients and responds
poorly to treatment
U H e e r f o r d t- W a ld e n s tr ijm syndrome: consists of
parotid gland enlargement, uveitis, fever and
cranial nerve palsies
0
Neurological manifestations (uncom m on):
cranial nerve palsies (facial nerve most often
affected), meningitis, hydrocephalus, space-
occupying lesions and spinal cord involvement;
granulomata infiltrating the posterior pituitary
may produce diabetes insipidus, hypothalamic
hypothyroidism or hypopituitarism
557
Essential Revision Notes for MRCP
U Cardiac sarcoid may result in cardiac muscle
dysfunction or involve the conducting system,
producing arrhythmias, bundle-branch block or
complete heart block
0 Renal involvement: renal impairment may be
associated with hypercalcaemia. Acute renal
failure can be due to granulomatous interstitial
nephritis, Glomerulonephritis is a rare
complication ( se e also Chapter T5, Nephrology)
I Bone cysts: with overlying soft tissue swelling,
bone cysts occur most often in the phalanges,
metacarpals, metatarsals and nasal bones;
arthritis is common
0
Hypercalcaemia: this occurs in at least 5% of
cases of sarcoidosis and it is due to excess
production of vitamin D and gut activity
(calcium reabsorption)
D iagnosis
The combination of BHL with erythema nodosum
(EN) in a young adult is virtually diagnostic of acute
sarcoidosis. The combination of BHL and EN in
association with fever and arthralgia is known as
Lofgren syndrome. The main differential diagnoses
are TB and lymphoma, and every effort should be
made to confirm the diagnosis of sarcoidosis histo-
logically.
0 Thoracic CTappearances are often
characteristic, showing hilar and mediastinal
lymphadenopathy, nodules along bronchi,
vessels and in subpleural regions, ground-glass
shadowing, parenchymal bands, cysts and
fibrosis
0 Tissue biopsy ttransbronchial and endobronchial
biopsy) can demonstrate non-caseating
granulomata in 85%-90"/U of cases with
respiratory involvement
0 Elevated serum angiotensin-converting enzyme
(ACE) and calcium are consistent with the
diagnosis but are non-specific. The 24hour
urinary calcium excretion is often raised
0 The Kveim-Siltzbach test lintradermal injection
of extract of spleen from a patient with active
sarcoidosis with skin biopsy at 4 - 6 weeks
demonstrating a granulomatous response) is no
longer used
558
0
Anergy to Heaf testing favours a diagnosis of
sarcoid but patients who are HIV-positive or
who have overwhelming TB may also be
anergic
Treatment of sa rc oidosis
The best prognosis is associated with acute Sarcoi-
dosis which frequently undergoes complete remis-
sion without specific therapy.
0
Stage 0 and 1 disease usually resolves
spontaneously
0 With stage 2 disease, lung function tests should
be performed serially and treatment instituted if
there is evidence of progressive deterioration
Steroids are the mainstay of therapy for chronic
disease but response is unpredictable
Steroid therapy is definitely indicated for hypercal-
caemia and hypercalciuria which persist despite
dietan/ calcium restriction, and also for ophthalmo-
logical and neurological complications, Other
immunosuppressive agents (eg azathioprine or
methotrexate) may be used as steroid-sparing
agents.
19.6.2 Histiocytosis X
Three clinical entities are recognised:
0
Eosinophilic granuloma: solitary bone lesions
occurring in children and young adults. Lung
disease is known as Langerhans cell
histiocytosis
0 Letterer-Siwe disease: a diffuse multisystem
disorder of infancy which is rapidly lethal
I Ha nd- S c hijlle r - C hr istia n disease: characterised
by exophthalmos, bony defects and diabetes
insipidus tin children and teenagers). Diffuse
nodular shadows occur in the lung with hilar
lymphadenopathy
In adults histiocytosis is often confined to the lung.
lt is rare and most likely in young adults.
Patients present with non-productive cough and
breathlessness. The chest examination is usually
normal.

0
Strongly associated with smoking
0 Chest X-ray shows multiple ring shadows on a
background of diffuse reticulonodular opacities
mainly in the upper and mid-zones; the lung
bases are spared
0 VI/ith disease progression larger cysts and bullae
form and interstitial fibrosis develops.
Spontaneous pneumothorax occurs in 25%.
Lung volumes are preserved
I Diagnosis is by high-resolution CT scanning and
occasionally lung biopsy
0 Treatment includes smoking cessation and
steroids; spontaneous remission occurs in 25%
of patients, but in a funher 25% the disease may
be rapidly fatal, Patients may progress to end-
stage fibrotic lung disease
19.6.3 Pu lm o n ar y fibrosis
Interstitial lung disease is associated with many
conditions, including the connective tissue diseases
(particularly systemic lupus erythematosus (SLE) and
systemic sclerosis), rheumatoid arthritis and sarcoi-
dosis, When pulmonary fibrosis develops without
obvious cause, it is known as idiopathic pulmonary
fibrosis. Extrinsic allergic alveolitis also causes dif-
fuse interstitial fibrosis.
19.6.4 l di opa t hi c p u l m o n a r y fi brosis
( u s u al in terstitial p n e u m o n i a
- UIP)
This is a specific form of lung fibrosis characterised
by UIP on lung biopsy. It accounts for around 80%
of patients with interstitial lung fibrosis. The preva-
Ience is increasing (currently 2 0 - 3 0 per T00 O0() in
some areas). It is a disease of the middle-aged and
elderly, more common in men, and is possibly the
result of an inhaled environmental antigen; metal
and wood dusts have been implicated but no causal
relationship has been identified. There may be an
association with Epstein-Barr virus (EBV). Patients
present with a dry cough and breathlessness, and
signs include cyanosis, finger clubbing and fine late
inspiratory crackles.
Respiratory Medicine
0
Lung function tests: small static lung volumes,
with reduction in gas transfer and restrictive
spiromelry
0 Blood gas analysis: typically shows type I
respiratory failure with hypoxaemia and a
normal or low p! O3
0
C|1esIX~ray: reveals small lung volumes and
interstitial shadowing most marked at the bases
and peripheries. HRCT is useful to determine the
degree of inflammatory change and the
likelihood of response to steroids
0 VATS (video-assisted thorascopic surgery) or
open lung biopsy can be used to confirm the
diagnosis and histology shows variable degrees
of established fibrosis and acute inflammation
Treatment of idiopa thic pulmona ry Hbrosis
Steroids and other immunosuppressive agents are
used with variable success; clinical trials are cur-
rently investigating a number of new agents. Patients
with established honeycomb fibrosis on HRCT do
not usually respond. Single-lung transplantation
should be considered in patients below the age of
65 years. Patients may benefit from pulmonary
rehabilitation, oxygen therapy and, in terminal
cases, morphine/lorazepam in order to palliate
symptoms.
Ot he r forms of interstitial l ung disease
The following conditions are recognised subtypes of
interstitial lung disease:
Non-specific interstitial pneumonia (NSIP)
Desquamative interstitial pneumonia (DIP)
Acute interstitial pneumonia (AIP)
Respiratory bronchiolitis-associated interstitial
lung disease tRB|LD)
0
Lymphocytic interstitial pneumonitis (LIP)
Of these, NSIP, DIP and RBILD are more steroid-
responsive and carry a better prognosis, AIP carries
the same poor prognosis as adult respiratory distress
syndrome (ARDSI.
559
Essential Revision Notes for MRCP

Extrinsic al l ergi c alveolitis (EAA or Causes of calcitlcation onchest X-racy

-
hypersensitivity p n eu mo n i t i s )
(This is covered in Section 19.4, Occupational lung 0
lymph node calcification
disease) Sarcoidosis
Silicosis
Tuberculosis
0
Drgugs canning pulownary Hbrosis Parenchymalcalcification
Healed tuberculous lesions
Healed
l Amiodarone fungal infections
Causes an alveolitis [which may be v Previous varicella pneumonia
reversible on drug cessation), Mitral stenosis*
o Chronic left ventricular failure*
progressing to diffuse fibrosis; v
commoner when higher doses are used Hyperparathyroidism
Sulfasalazine
o Chronic renal failure
Methotrexate o Vitamin D intoxication
Busulfan Benign tumours
Bleomycin
~ Busulfan lung
Caplan syndrome
Cyclophosphamide Alveolar microlithiasis
Nitrofurantoin
Gold
0 Pleural calcification
Calcified pleural plaques
Melphalan following
asbestos exposure, and pleural
calcifrcation due to previous
haemothorax or TB
*Results in secondary pulmonary haemosiderosis
Causes of reticulalr-nodular shadowing
_0nchstXfry, ,__

-
Upper zone
0
19.7 PULMONARY \lASCl,LlTlS AND
Extrinsic allergic alveolitis EOSINOPHILI/\
Sarcoiclosis
~ Coal workers pneumoconiosis \ ).7 .l \,\e9ener`s g r an u lo m ato sis
v Silicosis
0 Basal zone Small/medium-sized arteries, veins and capillaries
e
ldiopathic pulmonary fibrosis are involved with a granulomatous inflammation.

- Ninety per cent of Wegeners cases present with

Lymphangitis carcinomatosis
Drugs
Connective tissue disorders
upper or lower respiratory tract symptoms. Upper
airway involvement includes crusting and granula-
tion tissue on the nasal turbinates,
producing nasal

560

obstruction and a bloody discharge; collapse of the
nasal bridge produces a saddle-shaped nose;
CANCA is present is 90% of cases (see also Chapter
10, Immunology; Chapter T5, Nephrology and
Chapter 20, Rheumatology).
0 Henoch-Schonlein purpura (HSP). The disorder
Respiratory symptoms: cough, haemoptysis,
breathlessness and pleurisy. Stenosis of a main
airway may cause severe breathlessness and
stridor
Large rounded shadows may be visible on the
chest X-ray and these often cavitate. Pleural
effusions and infiltrates may develop
Seventy-five per cent develop
glomerulonephritis and eye and joint
involvement are c om m on, Patients may have a
typical vasculitic skin rash and rnononeuritis
multiplex may also develop
I Prognosis: untreated, the median survival is
5 months. Treatment with cyclophosphamide
and steroids has now reduced mortality to
around 10%
19.7.2 Ch u r g - St r a u ss sy n d r o m e
A syndrome of necrotising vasculitis, eosinophilic
infiltrates and granuloma formation, there is often a
prior history of asthma and sometimes allergic rhini-
tis. Peripheral blood eosinophilia occurs with eosi-
nophilic infiltrates of the lungs and often the
gastrointestinal tract. Vasculitic lesions appear on
the skin (purpura, erythema or nodules),
U
pANCA is positive in 50%
0 Chest X~ray shows nodular or confluent
shadows without cavitation
I Treatment is with steroids and/or
cyclophosphamide
19.7.3 Polya r te r itis a n d H e n o c h -
Sch o n lein v ascu litis
0
Microscopic polyangiitis (MPA) may involve the
lungs to produce pulmonary haemorrhage.
haemoptysis and occasionally pleurisy;
granulomata are not a feature
Respiratory Medicine
0
Lung involvement is uncommon in polyarteritis
nodosa; it consists of pulmonary infiltrates
(composed mainly of neutrophils) without
granuloma formation
0
Pulmonary involvement is a rare feature in
can be associated with streptococcal or
hepatitis B (less often with viral or fungal)
infections
19.7.4 C onnective t i s s ue disorders
9 Rheumatoid disease: has many pulmonary
associations which include bronchiectasis,
obliterative bronchiolitis, bronchiolitis obliterans
organising pneumonia (BOOP), pulmonary
fibrosis, nodules, Caplan syndrome and pleurisy
with effusion
0 SLE: pulmonary fibrosis, BOOP, pleural effusion
and shrinking lung syndrome can all occur
0
Systemic sclerosis; associated with
bronchiectasis, pulmonary fibrosis, and
aspiration pneumonia (due to dysphagia)
All may cause pulmonary hypertension but this
occurs most frequently in systemic sclerosis
patients,
Pulmonary vosculitis occurs in
a ssoc ia tion with
Ulcerative colitis
Giant~cell arteritis
Takayasu arteritis
Behcet syndrome
Multiple pulmonary emboli
Infection
19.7.5 Pu lm o n ar y eo sin o p h iiio
This describes a group of disorders characterised by
peripheral blood eosinophilia and eosinophilic infil-
trates in the lungs,
561
Essential Revision Notes for MRCP
afoattwpriiih' ~ pneumonia. Cardiac involvement occurs in 60%
0
Churg-Strauss syndrome
0 Loffler syndrome
0
Drug-induced (eg nitrofurantoin,
sulfasalazine, imipramine, phenytoin)
0
Allergic bronchopulmonary
aspergillosis (ABPA)
Chronic eosinophilic pneumonia
Hypereosinophilic syndrome
Acute eosinophilic pneumonia
Tropical pulmonary eosinophilia (associated
with parasite infection, eg Strongyloides
stercora/is, Toxacara canis)
Loffler syndrome (simple pulmona ry
eosinophilia)
Transient radiographic shadows and peripheral
blood eosinophilia are seen in association with the
passage of parasites (commonly /-tscaris lumbri-
coides) through the lungs. The illness usually lasts
less than 2 weeks and the eosinophilia is moderate.
Symptoms are mild and include cough, rhinitis,
night sweats and fever. The condition usually re
solves spontaneously.
Chronic eosinophilic p n e u m o n i a
Peripheral blood eosinophilia and persistent pul-
monary infiltrates occur without any obvious cause.
0 The chest X-ray is often described as a 'reverse
batwing', being the photo-negative appearance
of pulmonary oedema
0
Lung biopsy shows airspace consolidation with
an eosinophilic inflammatory infiltrate
0
Symptoms are more severe than in simple
pulmonary eosinophilia. The condition responds
to steroids
Hypereosi nophi l i c s yndrom e
Characterised by very high eosinophil counts (m ean
2O><lO/l), the syndrome has clinical manifestations
(weight loss, fever, night sweats, hepatomegaly and
lymphadenopathy) similar to chronic eosinophilic
562
(producing arrhythmias and cardiac failure).
0 Thromboembolism occurs in two-thirds of
patients
0 Other organ involvement: central nervous
system ( inte lle c tua l deterioration and peripheral
neuropathies), Gi tract and the kidney
(proteinuria and hypertension)
0 Steroids are effective
Acute eosinophilic p n e u m o n i a
Patients present with an acute illness with fever,
myalgia, pleurisy and respiratory failure. The chest
X-ray shows diffuse infiltrates, but these are not
usually peripheral. The blood eosinophil count is
usually normal although the eosinophil count in
fluid obtained from BAL is very high. Treatment is
with high-dose steroids and ventilatory support.
19.8 MISCELLANEOUS
RESPIRATORY DISORDERS
19.8.1 Pleural effusion
Transudates are usually clear or straw-coloured,
whereas exudates are often turbid, bloody and may
clot on standing. Fluid protein content should be
examined: protein levels >3O g/l (or fluid to serum
ratio >0 .3 ) and lactic dehydrogenase (LDH) levels
>2 0 0 IU/I (fluid to serum ratio of >O.6) are consis-
tent with an exudate. pH <7 .1 also suggests an
exudate.
0 Low concentrations of glucose in the pleural
fluid compared to serum glucose are found in
infection and with rheumatoid arthritis
In pancreatitis the amylase level may be higher
in pleural fluid than in blood
I Cell content should be examined. Transudates
contain <t0O0 white cells made up of a
mixture of polymorphs, lymphocytes and
mesothelial cells. Exudates usually have a much
higher white cell count. ln bacterial infection
this is usually polymorphs but in TB,
lymphocytes predominate
 Respiratory Medicine

i
0
Malignant cells from a primary bronchial Uncommon
carcinoma or from metastatic disease may be Infections:
found in approximately 60% of malignant
Fungal
pleural effusions Viral
I
Any patient with pneumonia who develops a Parasitic
pleural effusion should have the fluid analysed
for pH, A pl-I of < 7_2 suggests a developing
~ Malignancy:
Lymphoma
empyema Pleural tumours
~ Connective tissue disorders:
- > =a V
\/Vegeners granulomatosis
.~}s,;-:W1:,t:~KfaWa<r~;;s ;~~;;-.315/\ t / , t ,V f,
v
,~ #"2 ; } ~ ; = = _f<-f-"ff:'=<<- -,fl-,"_-,-~l_'f
~ yr +
,~Qi Sjogren syndrome
lmmunoblastic lymphadenopathy
Subdiaphragmaticr
0 Transudates
Common Hepatic abscesses
Trauma:
I LVF
~ Cirrhosis ofthe liver Ruptured oesophagus
~ Nephrotic syndrome
~ Acute glomerulonephritis
~
Other causes of hypoproteinaemia < ~""' ,
Uncommon ii"~' : " 1 f A "lie/,ilf*,.'1.i~~I><>;if Ft
Myxoedema

-
Meigs syndrome

Pulmonary emboli Asbestos exposure
Sarcoidosis
Familial Mediterranean fever
Peritoneal dialysis Yellow nail syndrome
0 Exudates
r Common Post-thoracotomy syndrome
Dressler syndrome
e
Pulmonary embolism
Infections:
Bacterial pneumonia Ifthe cause of an exudative effusion is not apparent,
TB the patient should have further investigation with
~ Malignancy:
contrast-enhanced CT thorax and pleural biopsy.
Medical lhoracoscopy is increasingly' performed
Primary carcinoma of bronchus
Metastatic carcinoma and allows direct visualisation of the pleura. Biop-
~ Connective tissue disorders: sies can be taken and if the appearances are of
Rheumatoid arthritis malignancy talc pleurodesis can be performed.
Systemic lupus erythematosus
Subdiaphragmatic: 19.8.2 Pn eu mo th o r ax

- Pancreatitis
Subphrenic abscess
Trauma:
Haemothorax
Pneumothorax may be classified as either primary
or secondary, the latter complicating underlying
lung disease, Presenting symptoms are of pleuritic
chest pain and breathlessness and the degree of
Chylothorax
dyspnoea relates to the size of the pneumothorax.

563
Essential Revision Notes for MRCP
Primary spontaneous pneumothorax usually occurs
at rest and the peak age of presentation is in pa-
tients in their early twenties. Pneumothorax is much
more common in smokers,
Clinical s i gns of pnaumothssrax
0 Diminished breath sounds
0 Decreased chest excursion on the affected
side
0
Hyper-resonance of percussion note
U
Auscultatory 'clicks'
Stg m o fi e n d o n
Severe breathlessness
Hypotension
Mediastinal shift
Cardiac arrest (often electromechanical
dissociation)
Di agnosi s
This is made when a visceral pleural line is seen on
chest X-ray, ln patients with emphysema it must be
differentiated from large, thin-walled bullae. In gen
eral, the pleural line is convex towards the lateral
chest wall in pneumothorax, whereas a large bulla
tends to be concave towards the lateral chest wall.
CT scan can be used to differentiate between these
two conditions.
Treatment
0 ln a patient who has no underlying lung disease
and with no clinical distress accompanying a
small pneumothorax, no specific therapy is
required but follow-up chest X-ray should be
arranged to ensure lung re-expansion
I In all other patients, aspiration of the
pneumothorax should be attempted first, except
if there are signs of a tension pneumothorax,
when a drain should he inserted immediately
0 lf the pneumothorax recurs despite aspiration, a
smalll:>ore chest drain should be inserted. This
may he removed when the lung has fully re-
564
expanded and no air leak (bubbling) has dm
occurred for at least 24 hours
0 lf the lung fails to re-expand within a few hours
then suction should he applied to the drain.
Chest drains should not be clamped. Once the
lung has been fully re-inflated for Z4 hours, and
bubbling has ceased, the suction can be
discontinued. Provided that the lung remains
fully inflated, the drain can then be removed.
Removal ofthe drain too early is likely to result
in recurrence of the pneumothorax
0 If the lung does not re-expand with chest drain
and suction then the patient should be referred
for thoracic surgery
0 Patients with recurrent pneumothorax on the
same side will also need thoracic surgical
inten/ention
l
19.8.3 Obstructive sle e p a p n o e a /
hypopnoea syndrome (OSAHS)
it is estimated that approximately l % - 2 % of adult
men and 0.5%-1% of women suffer from obstruc-
tive sleep apnoea. The cardinal symptom is daytime
somnolence due to the disruption of the normal
sleep pattern. This leads to poor concentration,
irritability and personality changes and a tendency
to fall asleep during the day, Road traffic accidents
are more frequent in this group of patients. The
problem is exacerbated by nighttime alcohol intake
and sedative medication.
Pathogenesis
During sleep, muscle tone is reduced and the airs
way narrows so that airway obstruction develops
between the level of the soft palate and the base of
the tongue. Respiratory effort continues but airflow
ceases due to the obstructed ainivay; eventually the
patient arouses briefly and ventilation is resumed.
The cycle is repeated several hundreds of times
throughout the night.
0 Over 80% of men with OSAHS are obese (BMI
>3O kgmzi. Hypothyroidism and acromegaly
are also recognised causes. Retrognathia can
cause OSAHS, and large tonsils may obstruct

the airway. Patients with OSAHS have higher
blood pressure than matched controls
I Patients (or their partners) give a history of loud
snoring interrupted by episodes of apnoea.
There may be a sensation of waking up due to
choking. Sleep is generally unrefreshing
0 Patients suspected of sufieri ng from OSAHS
have some measure of daytime somnolence
made (eg using the Epworth scoring system).
Mental concentration is impaired
0
Diagnosis is made by demonstration of
desaturation ($aO; below 90%) associated with
a rise in heart rate and arousal from sleep,
together with cessation of airflow, The frequency
of apnoeic/hypopnoeic episodes per hour is
used to assess disease severity, The diagnosis
can be made in most patients by home pulse
oximetry recordings or by limited sleep studies,
but where the diagnosis is in doubt, full
polysomnography lsleep studies) may be needed
Tmatm1ntoF9i9 I i w oe a ~
0 Nocturnal continuous positive airways
pressure (CPAP) administered via a nasal
mask
I
Tonsillectomy if enlarged tonsils are thought
to be the cause
l Correction of underlying medical disorders
(eg hypothyroidism)
0
Weight loss for individuals who are obese
I Anterior mandibular positioning devices are
useful in some patients
0
Tracheostomy (only as a last resort)
Uvulopalatopharyngoplasty is not generally of
benefit.
Once a patient has been diagnosed as suffering
from OSAHS, and if they are suffering from exces-
sive daytime somnolence, then the Licensing Autho-
rities should be informed and the patient should
refrain from driving. Patients may resume driving
once their OSAHS has been satisfactorily treated.
Holders of heavy goods vehicle (HGV) licences
Respiratory Medicine
may also have their licence reinstated once they
have been adequately treated.
l9.8.4 Adult re s p i ra t o ry distress
s y n d r o m e (ARDS)
This is a syndrome comprising:
0 Anerial hypoxaemia
9 Bilateral fluffy pulmonary infiltrates on chest
X-ray
0
Non-cardiogenic pulmonary oedema
[pulmonary capillary wedge pressure
<18 cmH;O)
0 Reduced lung compliance
Ca\uasofARDS
Sepsis
Burns
DIC
Pneumonia
Aspiration of gastric contents
Near-drowning
Drug overdoses (eg diamorphine,
methadone, barbiturates, paraquat)
Trauma
Pancreatitis, uraemia
Cardiopulmonary bypass
Pulmonary contusion
Smoke inhalation
Oxygen toxicity
Management
No specific treatment is available and management
is essentially supportive. Supplemental oxygen is
given and patients frequently' require mechanical
ventilation Pressurecontrolled inverse-ratio ventila~
tion is used as this lowers peak airway pressure,
reduces barotrauma and creates better distribution
of gas in the lungs. With the addition of positive
end-expiratory pressure (PEEP) there is greater al-
veolar recruitment, increased functional residual
capacity, better lung compliance and reduced
shunt. Turning the patient into the prone position
intermittently allows those dependent parts of the
i
565
Essential Revision Notes for MRCP
lung which are susceptible to atelectasis to re-
expand and improves blood flow to the ventilated
parts of the lung.
0 inhaled nitric oxide (NO) is a potent vasodilator
which causes selective vasodilatation of the
ventilated areas of the lung when inhaled at lovv
concentrations
I Use of exogenous surfactant in adult patients
has no proved value
0 Corticosteroids have been shown to be
beneficial in the latter stages of ARDS
(characterised by progressive pulmonary
interstitial fibroproliferation)
19.8.5 Hare lung disorders
Lymphangioleiomyomatosis
This affects young/middle-aged women and is char-
acterised by non-neoplastic proliferation of atypical
smooth muscle resulting in airways and vascular
obstruction, cyst formation and progressive decline
in lung function, lt may occur spontaneously or as
part of the tuberous sclerosis complex. Fifty per cen t
of patients have renal angiomyolipomas.
0 Patients present with progressive breathlessness,
pneumothorax or chylous effusions
0 The chest X-ray may appear normal initially but
HRCT shows thin-walled cysts, The condition
must be differentiated from histlocytosis X
0
Pregnancy and oestrogen replacement are
associated with more rapid disease progression
0 The only known cure is lung transplantation.
Hormonal therapy with progesterone is used to
slow disease progression
0
Average survival is l0~2O years
Alveolar p r o t e i n o s i s
A disorder characterised by the accumulation of
phospholipid and proteinaceous material in the
alveoli and distal airways, The malezfemale ratio is
3:1, with age of onset 30-SO years, Patients present
with dyspnoea of effort and cough; occasionally
constitutional symptoms (fever, weight loss and
566
malaise) develop. Haemoptysis and chest pain may
OCCLIY.
0 Chest X-ray shows bilateral infiltrates with air
bronchograms in a butterfly pattern
0 Bronchoalveolar lavage establishes the
diagnosis, yielding milky fluid
0 Treatment consists of interval whole lung lavage
under general anaesthesia
P ul m onary amy l o i d o s i s
The lungs are frequently involved in systemic amy-
Ioidosis ( mo st often in primary amyloidosisi; either
the lung parenchyrna or the tracheobronchial tree
may be predominantly affected. The diagnosis is
usually confirmed by biopsy. (See also Chapter 15,
Nephrology.)
0 Bronchial tree: plaques visible on
bronchoscopy; leads to breathlessness,
wheezing, stridor and haemoptysis
I Nodules: may develop throughout the lung
parenchyma or a solitary nodule may occur
0 Diffuse parenchymal amyloidosis: may develop
with amyloid deposited along the alveolar septa
and around blood vessels; this form is extremely
rare
ldiopa thic pul m onary haemosiderosis
This condition is of unknown cause and is charac-
terised by recurrent episodes of alveolar haemor-
rhage, haemoptysis and secondary iron-deficiency
anaemia. It may present in childhood with chronic
cough, pallor and failure to thrive. Generalised
lymphadenopathy and hepatosplenomegaly may
occur.
ln the early stages the chest X-ray shows
transient blotchy shadows
I
Eventually pulmonary fibrosis develops, and
this is associated with chronic dyspnoea and
Gnger clubbing. Steroids are unhelpful and
patients die of cor pulmonale or of massive
bleeding
 terrier Ztlt
Rheumatology

CGNTENTS

20.1 Rheumatoid factor ,r

`_=_<._.~ `~.\"~'1i! .<iEi.".f
20.5.1 Overview of vasculitis
20.2 Rheumatoid .a rthritis 20.5.2 Classification of vasculitis
20.2.1 Clinical features 20.5.3 Polymyalgia rheumatica, giant-
20.2.2 Musculoskeletal features cell and other large-vessel
20.2.3 Extra-articular manifestations arteritides
20.2.4 Investigations 20.5.4 \/\/egeners granulomatosis
20.2.5 Drug therapy 20.5.5 Churg-Strauss syndrome
(allergic angiitis and
20.3 Sponcl yl oart hropat hi es granulornatosis)
(HLA-B27~ associated 20.5.6 Polyarteritis nodosa
20.5.7 Microscopic polyangiitis
disorders)
20.3.1 Ankylosing spondylitis (microscopic polyarteritis)
20.3.2 Reiter syndrome 20.5.8 Kawasaki disease
20.3.3 Psoriatic arthritis 20.5.9 Behcet syndrome

20.4 I n fl ammato r y c o i m e c t i v e 20. 6 (Irys tai art1r<>;:.trit.~\ .md

t i s s u e dis orders o5teoarih;';es-
20.4.1 Markers in inflammatory 20.6.1 Gout
connective tissue disorders 20.6.2 Calcium pyrophosphate
20.4.2 Systemic lupus erythematosus deposition disease (CPDD)
(SLEI 20.6.3 Osteoarthritis
20.4.3 Dermatomyositis and
;' ( T .fsriiirilis in fizificir <.'-"rv
polymyositis
20.4.4 Systemic sclerosis 20.7.1 juvenile idiopathic arthritis
20.4.5 Sjogren syndrome 20.7.2 Systemic (classic Still's disease)
20.4.6 Mixed connective tissue 20.7.3 Polyarticular
20.7.4 Pauci-articular
disease/overlap syndromes

567
 Rheumatology

Rheumatology
201, RHEUl\'!A'I`()lD FAC1 OR In rheumatoid arthritis, RFis an assessment of pro -
Rheumatoid factors (RF) are antibodies to human nosis rather than a diagnostic test. i
IgG, usually reacting with t h e
Ffpital tests detect lgM rheumatoid factors, but RF
may be of any immunoglobulin isotype (lgM/lgG/
rg/ft),
I
Agglutination tests (Latex/SCAT): detect only 243.2 Hilti! l\/IATOID ARTHRITIS
rgr/i RF Rheumatoid arthritis (RA) is a chronic, symmetric
I RlR7Efl'S7\ tests: can detect any class of RF(IgA,
IgG, IgM) inflammatory polyarthritis. It characteristically in~
a f * volves small joints, and can be both erosive and
deforming. Soft tissues and extra-articular structures
|!MKFllfoundin ~

may also be involved in the disease process. RA is

the most common form of inflammatory arthritis. lt
0 Normal population (4% overall; 25% of the affects 1%-3% of the population in all racial
elderly) groups, with a femalermale ratio of 3:1. It may start
Chronic infections (usually low titre) at any age but onset is most commonly in the 40s.
.~
0
_c
syphilis 10% The cause is not known but both genetic and

-
~ Leprosy 50/>
Bacterial endocarditis QA)
Pulmonary tuberculosis 5%-29%
environmental factors are thought to play a part,
with genetic factors accounting for 10%-30% of
the risk of developing RA. There is an association

-
Other 'immunological' diseases
0
~ Autoimmune liver disease
with HLA DR4 and patients with DR4 tend to have
more se'\/`e'er'le disease.
~ Sariygsis

I
- Paraproteinaemias
Cryoglobumtaemias
Transplam recipients
Connective tissue disorders (often high titre)
Prognosis is variable and difficult to predict `in
individual cases:
0 50% are too disabled to work i0 years after
diagnosis
Rheumatoid arthritis 70% 0 25% have relatively mild disease
Rheumatoid arthritis with extra-articular
/ There is excess mortality
0

`
features 100%
Slfisfen

Systemic lupus erythematosus (SLE) The following are associated with a worse prog-

-
I

~
20%-40/o
Scleroderma 20%
Polyarteritis nodosa 0% -5%
nosis:

Positive rheumatoid factor

--
Extraarticular features
Dermatomyositis 0% -5% HLA DR4
0 Miscellaneous
Relatives of rheumatoid arthritis patients Female sex
Increasing age Early erosions
Transiently during acute infections Insidious onset
Severe disability at presentation

569
Essential Revision Notes for MRCP

5532. ! rtii' at Ffcsmrf.-= lt# L' il- tx tr a- ar ticu lar manifestations

The onset of disease may take several forms:
0 insidious (weeks/months) 55%-70%
0 Intermediate 15/tr-20%
Acute (days) 8 %-1 5 %
Other rare patterns of onset:
0 Palindromic: episodic with complete resolution
between attacks
Systemic: presentation with systemic/extra~
articular features
0 disease:
Polymyalgicz symptoms initially similar to
polymyalgia rheurnatica
Z(i.L:..''f it/f|lsti:ii>s;i\2iel.1iteatimfs
Joints
Symmetric metacarpophalangeal (MCP) joint and
wrist arthritis is characteristic but any synovial joint
can be involved. RA tends to start in the hands and
feet hut, in time, most joints of the upper and lower
limbs become affected. The cervical spine is in-
volved in more than 30%. Hi or distal interphalan-
geal (DIP) joint involvement is unusual in ear y
disease.
Extra-articular features may arise in several ways:
0 True extra-articular manifestations of the
rheumatoid process
0 Non-articular manifestations of joint/tendon
disease ( r iot specific to RA)
0
Systemic effects of inflammation lnot specific to
RA) (eg amyloidosis)
Adverse drug effects
True extra-articular manifestations of rheumatoid
0 Present in approximately 30% of patients with
RA
0 R e u m a t o i factor is always o s i t i v
0 Art ritis t e n s to e more severe
Rheumatoid nodules are the most characteristic
extra-articular feature.
Rheumatoid nodule s
4 20%-30% of cases
0 Rheumatoid factor always positive
0
Any site - most commonly subcutaneous at
extensor surfaces and ressure oints

Characteristic defonnities
gaiuzate
Associated with more severe arthritis
Ulnar deviation of MCP joints 0 Sometimes induced by methotrexate
Boutonniere deformities of fingers
therapy
Swan-neck deformities of fingers 0 The pathology of a rheumatoid nodule
Z deformity of thumbs involves a central area of
surroun ded by ll' d'
fi h
i S
Sof t tissue involvement in RA p
with a fibrous capsu e
"e
%
I
Tenosynovitis
~ Tendon rupture (extensor more Eye involvement is common: 20%-30%
_ , _ _ _ of patients
have keratoconjunctivitis sicgfa (Sogren syndrome).
frequently than fl'eT-0r)*`
~ Car
"l al tun nel syndrome (common) r e d d e n i n g of the eye lasting
I
Ligament laxity
HX]
a u t a week) is l : to be as common but usually
unnoticededdening
.-
o Atlanto-axial subluxation (most are goes and pain) is a
asymptomatic) manifestation of vasculitis and is uhco Re-
Sub~axialsublu><ation
Lymphoedema
Rare
ks of Sdemls
prOdu
(blue sclera and the eye may jleiiomte scleromala-
cia perforans). This is very rare. In contrast to the
spondyloarthropathies, @;nQ1`a feature.
570
 Rheumatology

Vasculitis is usually' benign, manifesting as nail fold

infarcts and mild sensory neuropathy in association
modifying drugs. Rashes occur in
patients treated with gold or enicill
abouof
`

with active joint disease. The much rarer systemic
rheumatoid vasculitis carries a significant mortality.
its features include cutaneous ulceration, mono-
neuritis multiplex and involvement of the mesen-
teric, cerebral and coronary arteries. Renal
vasculitis is unusual.
Cardiorespiratory manifestations: pleural and peri-
cardial disease are common (30%) but asympto-
matic in all but a few cases. Less common features
include interstitial lung disease and the very rare,
and often rapidly fatal, obliteratiye bronchiolitis.
C_Rl3L'i syndrome ( m a s s i v e 1 A
patients with pneumoconiosisl is very rare,
Felty syndrome (Splenomegaly, neutropenia and
Ri) is rare. Patients with Felty syndrome usually
have a positive NA and may have associatedleg
li ujggs, ly a and mi .
effects of inflammation
0
Malaise, fever, weight loss, myalgia
0 Anaemia of chronic disease
0 increased incidence of corona[y heart
disease
U
Osteoporosis (immobility also contributes)
0
Lymphadenopathy
o
A s (now rare)
,
0 Renal impairment: due to prostaglandin
inhibition, or the much rarer acute interstitial
nephritis, may be due to NSAIDs, Proteinuria
occurs in about 10% of patients receiving gold
or penicillamine but only a few develop
nephrotic syndrome. The proteinuria usually
resolves after cessation of treatment
0 Gastrointestinal: NSAIDs commonly cause
peptic and intestinal ulceration. Gold may cause
s _
and enteroco itis (rare
Diarrhoea is common with leflunomide
0
Hypertension: this can occur with NSAIDs,
ciclosporin A and leflunomide
0
Respiratory: acute pneumonitis may occur with
methotrexate or leflunomide
0 Infection: the anti tumour necrosis factor alpha
(anti-TNF<1) agents are associated with increased
infection rages and may reactivate latent
tu rculosis
Other extra-articular features/
a ssoc ia tions of RA
Palmar erythema (common)
Recurrent respiratory infections
derma gan renosum
Depression (30%)
- 1 - _ _ _ _ . . ~

Non-a rtic ula r manifestations o fj o i n t / t en d o n 20.2.4 Inve s t i ga t i ons

disease
0
Entrapment neuropathy, most commonly carpel
tunnel syndrome, may occur in up to 30% of
patients, but is usually mild. it may be the 3"first
symptom of RA
0 Cervical myelopathy due to atlanto-axial
suloluxation (rare, but high mortality)
The diagnosis of RA is based primarily on the
history and examination. Laboratory tests and X-rays
may be helpful but are rarely diagnostic in early
disease. I clinical studies, RA can be diagnosed
when(@or more of the following are present:
0
Morning stiffness >i hour for more than

it
0 Hoarseness and stridor due to cricoarytenoid
a_rQ1_|;Lt.i5 (rare, but dangerous]
U
we
Arthritis of hand
joints (wrist, MCP or PIP) for
more than 6 weeks
Adve rse d r u g e ffe c ts
I Subcutaneous nodules
i
P O Skin rashes: may be due to non-steroidal anti- 0 Arthritis o f f o r more
inflammatory drugs (NSAIDs) or disease- than 6 weeks

l 571
 Essential Revision Notes for MRCP
f o r more than 6 weeks
U Positive rheumatoid factor
ii
R adiology
0
Early changes
Soft tissue swelling
luxta-articular osteoporosis
0 Intermediate changes
Ioint space narrowing (due to
0
-
Late changes
Bone and joint destruction
Subluxation
cartilage loss)
Ankylosis lrare nowadays)
Lab o rat o ry studies
0 Rheumatoid factor is positive in 70%
I Antibodies to cyclic citru 'mated peptide [anti-
CCP) have a high specificity for RAand can be
' '
paHicularl y use u I in RF-negative patients
'
I Most laboratory abnormalities are secondary to
active inflammation or drug effects and are not
specific to RA. They are used to monitor disease
activity and screen for adverse drug effects
I
Erythrocyte sedimentation rate (ESR), C-reactive
protein (CRP) and plasma viscosity reflect
disease activity
I Alkaline phosphatase is often mildly raised in
active disease R
0 Anaemia is common and may be:
-
Iron-deficient: gastric blood loss from
NS/\lDS
Normochromic: with active disease (often
with thrombocytosis)
Aplastic: rare drug effect (eg aurothiomalate,
. NSAIDS)
Haemolytic: rare as a manifestation of RA,
but mild forms common with sulfasalazine
0
Immunoglobulin levels may be raised,
particularly in active disease
0
Complement levels are usually normal, or
elevated as an acute phase response
I Ferritin may be elevated in an acute phase
response and cannot be usecl to assess iron
SlHlUS
l
Synovial fluid examination is rarely helpful in
diagnosis but is often done to exclude other
572
diagnoses (eg sepsis, gout). Rheumatoid
effusions, like those of most other inflammatory
arthropathies, contain large numbers of
polymorphs
Assessment
Patients are evaluated with regard to disease
activity,
joint damage and function. Disease activity can be
assessed simply by counting the number of inflamed
joints, but in clinical studies and when assessing
patients for anti-TNFC1 therapies a composite score
such as thedisease activity score using 28
joints) would be uscd. This is based on the number
of swollen joints, tender joints, ESR and the patients
self assessment:
DAS28 >5.1: hi h disease activity
DAS28 5.2 - 5.1: moderate disease activity
DAS28 <3.2: low disease activity
DASZB <2.6: remission
_ , T
20.2.5 D r u g t he r a py
Drugs used in the treatment of RA fall into two
categories: symptom-modifying and disease-modify-
ingt The diseasemodifying drugs are also referred to
as slowacting antirheumatic drugs or second-line
drugs; the newer biologic agents also fall into this
category. Corticosteroids produce rapid improve-
ment in symptoms and may have disease-modifying
actions
0
Symptom-modifying drugs: reduce pain,
stiffness and swelling (eg NSAIDs)
-~
Disease-modifying antirheumatic drugs
0
(DMARDs) have additional actions and will:
Reduce pain, swelling and stiffness
Reduce ESR and CRP
Correct the anaemia of chronic disease
Slow disease
progression
Other extraarticular features do not respond to
disease-modifying drugs, though nodules may re-
g r e s s . i s unusual in that it
the formation of rheumatoid nodules.
Methotrexate is the DMARD of choice in RA. The
aim is to begin treatment with DMARDS as soon as

RA is diagnosed and achieve control of inflamma-
tion as quickly and completely as possible. Metho-
trexate may be used alone or in combination with
other disease-modifying agents. Since DIvtARDs
take several weeks to become effective, cortico-
steroids are employed during this period. Cortico-
steroids may be given intra-articularly, parenterally
or orally.
DMARDs in common use are listed in Table 20.1,
together with the necessary parameters for monitor-
ing.
Other agents with DMARD activity include sodium
aurothiomalate (gold), azathioprine, ciclosporin and
D-penicillamine
Biologic disease-modifying a ge nts
These agents are very effective at controlling the
symptoms of RA and reducing joint damage. Their
effectiveness is enhanced when used in combina-
tion with methotrexate,
m@ infliximab, adalimumab, etanercept)
a n d ituxirnab) are routinely used in the
UK. Ot er agents that are effective but not in
routine use are interleukin l (lL-l) blockers (anakin-
ral and ( TLA4-Ig gabatacepti.
The biologic agents are used in severe active rheu-
matoid arthritis (DAS28 > 5 . l ) when standard
disease-modifying therapy has failed. The onset of
clinical effects can be rapid compared with tradi-
tional disease-modifying drugs (usually apparent
within 2 weeks). A fall in DAS28
as a good response to treatment.
of@is regarded
Table 20.1. Disease-modifying drugs in common use
Drug Monitoring
Methotrexate Full blood count (FBC), liver function tests (LFTs)
Sulfasalazine FBC, LFTs
Leflunomide PBC, LFfs, blood pressure (BP)
Hydroxych loroquine Ophthalmological
- . _ \ / \ /
Rheumatology
TNH1 blockers
0 lnfliximabz chimeric l Q I , H 2 )
monoclonal antibody against T NF Q -
administered intravenously
0 Adalimumabz c l o n a l antibody
against TNFu - administered sullcutaneously
Etanercept: TN FQ receptor fusiowprotein
consisting of a dimer of the extracellular portion
Of two p75 receptors fused to the Fc portion of
human IgG] - administered subcutaneously
Adverse effects:
0
lmmunosuppressionz severe infections (mostly
respiratory but disseminated tuberculosis can
occur). Live vaccines are contraindicated in
patients receiving these agents
0
Injection site reactions (common but rarely
significant)
0
Worsening of heart failure
0 Antinuclear antibo 'es develo in about 10% of
patients, but clinical lupus is rare
@ >
Rituximab
0 A chimeric mouse/human monoclonal antibody
directed against CD20, a cell surface marker
found on B lymphocytes. The effect is to deplete
B lymphocytes. The time to clinical effect is
slower than that for the T NF Q blockers, taking
up to tis;/_veeks to become maximal
Adverse effects:
0 Infusion reactions
0
Immunosuppression
- ` _ , .
573
Essential Revision Notes for MRCP

lnfliximab and rituximab are usually given in com- Table 20.2. Associations with HLA B27
bination with methotrexate. Adalimumab and e t a '
nercept can be used with methotrexate or as Prevalence of HLA B27 in %
monotherapy. Biologic disease-modifying agents are
also effective in psoriatic arthritis, ankylosing spon- spondyloarthropathies
dylitis and juvenile arthritis. Normal Caucasian population 8
Ankylosing spondylitis 90
Reiter syndrome 70
20.3 SPONDYLOARTHROPATHIES Enteropathic spondylitis 50
Psoriatic arthritis 20
(HLA-B27-ASSOCIATED
Psoriatic arthritis with sacroiliitis 50
DISORDERS)
This group of disorders is characterised by seronega-
tive (ie rheumatoid factor-negative inflammatory
arthritis and/or soridylitis The peripheral arthritis is
espe-
lYPlC3llYinvolving<lrerljoints,
cially the nees and ankles, Characteristic muscu- 20.3.1 Ankylosing spondylitis
loskeletal features include enthesitis (inflammation
at sites of tendon insertion), sacroiliitis and da_ctyli- Typically begins with the insidious onset of low
back pain and stiffness in a young man. The age of
_ti_s_.'These arthropathies should nofbeconfusd with
seronegative RA, which is a symmetric small-joint onset is usually between 15 and 40 years and the
arthritis. malezfemale ratio is about 5:1. lt is less common
than RA, with a prevalence of about 0.1%. The
nm .W1
prognosis is good.
`
feature# of
'

0 5
Ankylosing spondylitis (_

I Psoriatic arthritis
0 Reactive arthritis (including Reiter
0 Arlicular
0
syndrome)
Enteropathic arthritis
~ Sacroiliitis is the characteristic feature,
but radiological changes may not be
0 Many cases do not fit into these categories
and are referred to as undifferentiated evident for several years
spondyloarthritis

0
--
Sp0ndylitis(l00%)

Peripheral arthritis (35%)
lnten/ertebral discitis (rare)
Extra-articular

-
'

Asod&`df:adiox|s
Anterior uveitis (25%)
Anterior uveitis
o Aortic incompetence (4%)
Psoriasis Apical lung fibrosis (rare)
~ Aortitis (rare)
inflammatory bowel disease
Eiythema nodosum
I
Amyloidosis (rare)
Heart block (rare)
Pyoderma gangrenosum

There is an association with HLA B27 and a ten- Di agnosi s

dency for relatives to have other conditions within Definitive diagnosis requires radiological evidence
the group (Table 20.2) . of sacroiliitis, inflammatory spinal pain and limited

574
 Rheumatology
t

spinal movement or chest expansion. Since sacro- Spinal pain

iliitis may take many years to become evident on X- loint pain
rays, these criteria have a poor sensitivity in early Localised tenderness
disease and magnetic resonance imaging (MRI) evi- Morning stiffness

-
dence of sacroiliitis may be diagnostically useful in BAS-Fl (Bath Ankylosing Spondylitis
`
the early stages. Functional index)
Activities of daily living
Investigations BAS-G (Bath Ankylosing Spondylitis Patient
Global Score)
, ESR/CRP may be elevated
~ General well-being in the last week
Normochromic anaemia General well-being in the last 6 months
Alkaline phosphatase often mildly elevated
0 BAS-Ml (Bath Ankylosing Spondylitis
Radiology (see box be low)
Metrology Index]
HLA B27 in diagnosis
~ Cervical rotation
Tragus to wall distance (a measure of `
This should not be a routine test in back pain.
thoracic kyphosis, measured as the
` Although a negative result makes ankylosing spon- distance between the tragus of the ear
dylitis unlikely, a positive result is of little help, and the wall with the patient standing
with their back to the wall)
Lumbar lateral flexion
Lumbar flexion (modified Schobers test)
0 Sacroillac joints lntermalleolar distance

Irregular/blurred joint margins
~ Subchondral erosion
Sclerosis
Fusion Treatment
0 Spine
Loss of lumbar lordosis 0
Physiotherapy and regular home exercise
y

Squaring of vertebrae
NSAIDS
Romanus lesion (erosion at the corner of Sulfasalazine or methotrexate help peripheral
vertebral bodies) arthritis but are not effective for spinal disease
~ Bamboo spine (calcification in anterior 0 Anti-TNFo therapy is very effective. Used when
and posterior spinal ligaments) the BAS-DA) score is above 4 despite NSAIDs
~ Enthesitis (calcification at tendon/ 0
Surgery ijoint replacement, spinal straightening)
in end-stage disease
ligament insertions into bone)

Assessment 20.3.2 Reiter sy n d r o m e

l . . .
A number of indices and scores are used in the
assessment of patients both in clinical practice and
research. The BAS-DAI is used to identify patients
1.
suitable for treatment with anti-Tl\lFoi therapies and
to assess their response to treatment.
0 BAS-DAI (Bath Ankylosing Spondylitis
e
Disease Activity Index)
~ Fatigue
Reiter syndrome is a form of reactive arthritis
characterised by a triad of arthritis, conjunctivitis
and urethritis. Reactive arthritis usually begins
I - 3 weeks after an initiating infection at a distant
site. Antigenic material from the infecting organism
may be identified in affected joints but complete
organisms cannot be identified or grown, and the
arthritis does not respond to treatment with anti-
biotics.

575
 Essential Revision Notes for MRCP

Reiter syndrome is said to be 20 times more fre- Treatment

quent in men than in women. This is lil<ely to be an
overestimate because cewicitis may go unrecog-
0 Mild disease: NSAIDs
nised. The true malezfemale ratio is more likely to 0 Chronic disease may need disease-modifying
be 5:1. Post-dysenteric reactive arthritis has an drugs
equal sex distribution. The age of onset is 1 5 -4 0
0 Prominent systemic symptoms may need
warm- corticosteroids

Recognised precipitating infections: ''%_1

"
;~=,r?i: t-triiirt1=s.
0
Post-urethritis (Chlamydia trachomatis - 5 0 % )
0
Post-dysenteric (Yersinia, Salmonella, Shigella, Chronic synovitis occurs in about 8% of patients
with psoriasis. The arthritis may precede the diag-
Camyglqbacteri nosis of psoriasis in 1 in 6 of these patients. Males
and females are egua y afiected.

Clinical features of Reiter syndrome Patterns of poori at i c arthritis

0 Classic triad 0
Polyanhritis similar ggBAmost common
Arthritis
type)

Conjunctivitis Distal interphalangeal joints (5 %-1 0 %]
Urethritis Sacroiliitis and spondylitis (20%-40%)
0 Rare features Asymmetric oligoarthritis (20%-40%)
Heart: pericarditis, aortitis, conduction Arthritis mutilans_.___
(<5%)
defects
s
Lung: pleurisy, pulmonary infiltrates
o CNS: m e n i n g o - e n c r a l Characteristic'fzlitures of p s o ri at i c
itthrliio
neuropathy
0 Other features
~ Circinate ba_laL1i_ti_s (25%) 0 N ' | pitting and onycholysis

-

Buccal/lingual ulcers (10%)
Keratoderma blenorrhagica (10%)
I
0
oint arthritis
Telesco ing fingers in arthritis mutilans
- _ (chronic cases onl Y
_lritis
- 30%) EREFT e a cac I ificarron
0
Plantar fasciitis/Achilles tendonitis Dactyitis
o
Fever/weight loss
Drug treatment
The same approach is adopted as for treatment of
rheumatoid arthritis:
P rognosi s 0
Symptom-modifying drugs (analgesics, NSAIDs)
0
Complete resolution, no recurrence in 7 0 %- 0
Disease-modifying drugs (eg sulfasalazine,
75% methotrexate)
0
Complete resolution, recurrent episodes in 0 Anti-TNFa therapy for refractory disease (either
20%-25% (usually B27 +ve) in combination with methotrexate or as
0 Chronic disease in <5/D (usually B27 + ve ) monotherapy)

576
 Rheumatology

20.4 iNFLAt\fIl\/lATOR`' LUi\'F-Liifi i`iL'i Methods of detection

TISSUE DISURDERS
0
Radioimmunoassay (Farr assay)
2 0 ,4 3 Markers in inilaiiiiiiatoify , Crithidia Iucillae immunofluorescence
c o n n e c t i v e t i ssue d iso ru ers 0
Enzyme-linked immunosorbent assay
Antinuclear antibodies (ELISA)
Antinuclear antibodies (ANAS) are directed against
a variety of nuclear antigens and may be induced Extractable nuclear an t i g en s
by certain drugs (hydralazine . Like rheumatoid fac- These are specific nuclear antigens and therefore
tors, ANAs can be of Qimmunoglobulin class
are usually associated with positive ANA tests. They
(remember that IgG can s the lacenta .
are useful in defining the type of connective tissue

|fluorescence
for n d n c ecanthe
etectin g ANA. It
'
is
is routine method
"
I1'ig hly sensitiveancl t I'ie
disease present. Method of detection: counter im-
munoelectrophoresis or ELISA.
staining pattern give some indica-
tion ofthe type of ANA/disease present: Extroctable nuclear an t i g en s
0
0
Homogeneous staining suggests
Speckled staining suggests nligd connective
-
Anti-Ro Sjogren syndrome, congenital
tissue disease
heart block, neonatal lupus syndrome,
ANA- e ative SLE
O
0
Nggleolgr staining suggests
Centromere staining suggests CREST syndrome
(ie calcinosis, Raynaud phenomenon,
0
_ Sj9'_g|;g;i syndrome
Ami-sm SLE (2o%,Tery specific:
conferring a high risk of renal lupus)
W
oesophageal dysmotility, sclerodactyly, 0 Anti-RNP - nli_x_ed connective tissue
telangiectasia)
disease (T00%), SLE

i ' I mi g seen in a specific variant of

0

ANAS are found in

0 Anti-ScI70 - progressive systemic sclerosis
" " ` \
Zrug-induced lupus (1 0%) (20%)
Systemic lupus erythematosus (SLE) (95%)
0 Anti-centromere - CREST syndrome
- i - \
Scleroderma (90%)
Sogren syndrome (80%) Antiphospholipid a ntibodie s
Mixed connective tissue disease (93%)
Polymyositis (40%) Antiphospholipid antibodies are associated with ar-
Normal population (5%, titres usually terial or venous thrombosis, transient neurological
below 11320) deficits, fetal loss, livido reticularis and thromb -
(Hughes s e I Sectioniiii.
Eytgeuia
ifferent antibody isotypes exist: IgG and to a lesser
arthritis suggests extent IgM isotypes of anticardioli `
antibodies
/\i\lAfir;_rheumatoid
or jogren syndrome.
anti-ds WA) in
ANA against double-stranded
high titre is virtually diagnos-
(ACLA) are associated iv
tic of SLE The ANA in drug-induced lupus is presented.
KDNA
n s t DNA (anti-ssDNA). Antiphospholipid antibodies have activity against a
variety of cell membrane phospholipids, and the
single-stranded most commonly measured are those against cardio-
Anti-JSDNA
lipin. Protein complexes such as |32-glycoprotein-1,
High titres are specific r SLE; anti-dsDNA is pre- which have anticoagulant properties, are found on
sent in f patients with SLE. cell membranes, and it is the interaction between
approximately/O%
\ \ / '

577
 Essential Revision Notes for MRCP

antiphospholipid antibodies and these proteins that ~ Alowcia (up to 50%)

is likely to explain the development of throm bosis, ~
About 10% of patients with anticardiolipin-
associated thrombosis have antibodies to [52-glyco-
protein-1 itself. Antiphospholipid antibodies are
found in 2% of the normal population.
-
~
Raynauds phenomenon (10%-40%)
Oral or nasal ulcers (10%-40%)
Res iratory (10%): pneumonitis,
shrinking lung syndrome
~ Cardiac (10%): myocarditis,
Antibody levels are measured by ELISA. The pre- endocarditis (Libman-Sacks)
sence of antiphospholipid antibodies can also be
7
reflected in false-positive VDR tests and a p p ;
Investigations for SLE
.lnnged activated partial thromboplastin time which
ht ma
iS
(lupus anticoagulant test). Lupus anticoagulant
The FBC may show the following abnormalities:

and ELISA show 50% concordance. LA detects Abuormolitles of FDC in SLE

some antibodies not picked up by ELISA.
Anaemia of chronic disease (normal mean
cell volume (MCV)]
0
20.4.2 Sys temic lupus erythematos us Neutropenia
0
Thrombocytopenia
(SLE) 0
Haemolytic anaemia (high MCV,
A multisystem inflammatory connective tissue dis- reticulocytosis)
order with small-vessel vasculitis and non-organ- 0
Lymphopenia
specific autoantibodies. lt is characterised by skin 0
Aplastic anaemia (rare)
rashes, arthralgia and antibodies against dsDA.
Young women are predominantly affected, with a ESR reflects disease activity. CRP usually rises with
female:male ratio of 10:1. It is more common in active disease of the joints or serositis (pericarditis,
West lnd`an populations, Ten-year survival exceeds pleurisy), but in active lupus of other organ systems
90%.
This
K
discrepancy can be used to
i e r e ntia te et w een a flare of SLE and intercurrent
infecti ,

Clkiirehiattutes ni _SLE '

`
Low C3 and C4 suggest lupus nephritis.
0 Common ( >8 0 % of cases)

Arthralgia or non~erosive arthritis L u p u s v ari an t s
Rash (malar, discoid or
pl1o__Lo_s,nsitive) Drug-induced lupus is more common in men than
0
Fever
Others
in women. It is usually es on
stopping the drug. CNS and renal disease are La_r_e_k
Serositis (30%-60%): pericarditis, ANA is positive b u t dsDNA are not
pleurisy, effusions The is not known, and
~ R~e_rl;il: proteinuria (30%-60%),
usually present. pathogenesis
antibodies to the drug do not occur. The drugs
nephrotic syndrome less common, commonly implicated (procainamide, isoniazid and
~
glomerulonephritis (15%-20%) h ) all have a c t i g r o u p ?
- Nguropsychiatric (10%-60%):
psychosis, seizures
Haematological (up to 50%) :
leucopenia, thrombocytopenia,
Antiphospholipid antibody syndrome (Hughes syn-
drome): recurrent venous or arterial thromboses,
fetal loss and thrombocytopenia. Libman~Sacl<s en-
docarditis and focal neurological lesions (such as
haemolysis
cerebrovascular accident (CVA) or transient ischae

578

mic attack (M) in lupus are usually due to anti-
phospholipid antibodies.
Treatment of lupus depends on severity and organ
involvement.
0 Cardiovascular risk reduction
~ Cardiovascular risk is markedly
increased so risk factor reduction
(obesity, blood pressure, lipids,
smoking, exercise) is important
0 Sunscreens
0 Sunburn can provoke a generalised flare
i;di'ase
0 Corticosteroids and immunosuppressive
drugs
~ For vital organ involvement
0 Plasmaexchange
~ ln difficult cases with aggressive disease
I Rituximab (monoclonal antibodies against
B ly7FplTocytes)
0 Used in severe disease refractory to
other treatments
0
Anticoagulation
~ For thrombotic features
0
-
NSAIDs and antimalarials
`
(eg hydroxyc hior u|ne)uSed fOr
arthritis and skin- imited disease
20.4.3 Der m ato m y o sitis an d
p o ly my o sitis
Polymyositis is an idiopathic inflammatory disorder
of skeletal muscle. When associated with cutaneous
lesions it is called dermatomyositis. These condi-
Rheumatology
tions are rare (5 cases per million). Fiveyear survi-
val is 8 0 % with treatment. Myositis may also occur
with other connective tissue disorders.
Mus edisease
~ eakness
~ Swelling and tenderness of muscles
-
0 Others
Pulmonary muscle weakness
o Infgrnal lun disease
Arthralgia
Weight loss
e Fever
0 Skin rash
o discoloration of the eyelids
o Gottrons papules (scaly papules over
MCP/PIP joints)
Feriungualtelangiectasia
Erythematous macules
luvenile dermatomyositis differs from the adult
form. Vasculitis, ecto ic calcification and lipody-
strophy are commonly present.
Malignancy
The elderly with dermatomyositis and polymyositis
have a higher prevalence of malignancy than would
be expected by chance and this is most pronounced
in dermatomyositis, There between
dermatomyositis/polymyosit i sociation
d malignancy in
children or adults of young and middle age,
579
Essential Revision Notes for A/IRCP

La bora tory tests in t' `i '

s / Clinical features of systemic sclerosis
polymyooitis
0
-
Muscle
Elevated muscle enzymes: creatine
kinase (CK), aspartate transaminase
0
Raynauds phenomenon
Initial complaint in Qi
Associated
digital ulcers and calcinosis
unusual in primary Raynauds .
f

(AST), me dehydrogenase Q i ) (very
phenomenon)
/Rlmormal EMG 0 Musculoskeletal
~ ~ Arthralgia
0 A

Biopsy showing inflammation, muscle
fibre necrosis and regeneration
u t
Antinuclear antibodies may be present
-
Erosive arthritis in about 30%
Myositis (usually mild, often
asymptomatic with raised CK)
M

I
is associated with a specific
syndrome of: acute-onset myositis;
Flexion deformities of fingers due to
skin fibrosis
interstitial lung disease; fever; arthritis; 0
Pulmonaly
Raynauds phenomenon; mechanics Fibrolic interstitial lung disease
hands (fissuring of the digital pads Pulmonary hypertension
v'7m~T5ut ulceration and periungual 0 Renal
infarcts) ~ Scleroderma renal crisis (malignant I
hypertension, rapid renal impairment
Treatment
0 Corticosteroids: CKfalls rapidly but muscle
power takes many weeks to improve
0

-
S
e
with 'onion skin intrarenal vasculature)
c | e
Early oedematous phase
Later indurated and hidebound
@

Affected areas may become pigmented

e

0
Immunosuppressives: methotrexate or

Z().&.t
cyclophosphamide are used in resistant cases

bt/stenlic sclerosis
0
- and lose hair
Gastrointestinal
Motility can be impaired at any level
(smooth muscle atrophy and fibrosis)

--
Oesophagus (reflux,
Systemic sclerosis is a connective tissue disorder dysphagiai peptic
characterised by thickening and fibrosis of the skin strictures)
(scleroderma) with distinctive involvement of inter- Gastric dilatation
nal organs. lt is a rare condition/ occurring in all Intestine (bacterial overgrowth,
racial groups, with an incidence of 4-12/million malabsorption, steatorrhoea, pseudo-
per year. It is more common in women (femalezmale obstruction
ratio 4:1) and may start at any age. Colon (constipation)
Some C a s e s may be due to exposure to substances
such as vinyl chloride.
' i f

580
 Rheumatology

Invest i gat i ons Scleroderma without internal organ disease

l Plaques: morphoea
Laboratory tests include: ~ Linear:
coup
de sabre
0 Elevated ESR or CRP
0 Autoantibodies
l Rheumatoid factor positive in 30%
Antinuclear factor positive in 90% 'lieahuent
( h o m o g e n
staining) Supportive
l
& Anti-centromere and anti-Scl70 are quite
specific
~
~
~
NSAIDs for arthralgia/arthritis
Proton-pump inhibitors for reflux

-
o Anti-centromere-positive in 5 0 %-9 0 % of Intermittent antibiotics for bacterial
limited and 10% of diffuse scleroderma in the small bowel
Anti-Scl7O [anti-topoisomerase-l) positive in ~ overgrowth
Vasodilators for Raynauds phenomenon
20%-40%
Prostacyclin or iloprost infusions for _
severe Raynaud's phenomenon and
l Disease pa tte rns digital ischaemia
Specific

il
0

-
Limited scleroderma with systemic involvement
-CREST
Scleroderma limited to the face, neck and
limbs distal tothe elbow and knee
~

D-Penicillamine can slow the
progression ofsEin disease
Steroids and irnmunosuppressives for
interstitial lung disease
1 sually be ins with Raynauds phenomenon Steroids do not help the skin
~ CR oesophageal
,
1 dysmotility, sclerodactyly, telangiectasia)
l Anti-centromere antibody-positive in most
o

i
pulmonary hypertension
l'T10l'! COl'TiITlOl'\
Better prognosis (7O+% 10-year survival)
i
0 Diffuse scleroderma with limited involvement
Scleroderma involvin trunl< and roximal
limbs as well as face indfstal lirE`lTs_`
Usually begins with swelling of fingers and
1 ' " - / _ ' _ * 7
arthritis
~ Anti-Scl70 antibodies 20%-40%
Pulmonary hypertension rare, renal grisis
more common
~ Worse proggis ( 50% l0-year sun/ival)
22').-3.53 Siiigren syndrorne
A connective tissue disorder characterised by lym-
phocytic infiltration of exocrine glands, especially
the lacrimal and salivary glands, The reduced secre
tions lead to the dry eyes and dry mouth of the
sicca syndrome, Secondary Sjogren syndrome de-
scribes the presence of sicca syndrome and either
RA or a connective tissue disorder. About 3% of
rheumatoid patients have secondary Sjogren syn-
dromeT_4-_

l
581
Essential Revision Notes for MRCP

Clinical features of Sifi gr m svndmme
0
Dryness from atrophy of exocrine glands
~ Eyes (xerophthalmia), which may lead
to corneal ulceration
syndromes. One specific overlap syndrome, mixed
connective tissue disease, is associated with anti-
RNP antibodies. The clinical features are Raynauds
phenomenon, swollen hands and other features
from at least two connective tissue disorders (SLE,

-
Mouth
(xerostomia), with increased scleroderma or polymyositis).
dental caries 0
Prognosis: the 10-year survival is 80%. Patients
Respiratory, with hoarseness, dysphagia, who have features mainly of scleroclerma and
respiratory infections polymyositis fare much worse, with a 10-year
Vaginal, causing dyspareunia
survival as low as 30%
I
Arthralgia or arthritis
Can be erosive
0
Raynauds phenomenon
I
Lymphadenopathy
0 Gland swelling
ln the early stages (eg parotid) 20.5 VASCU LITIS
Vasculitic
purpura
Ne ropathles 20.5.1 Overview of vasculitis
Reiliilitilar acidosis (30%)
lfancreatitis i
Systemic vasculitis usually presents with constitu-
a tional symptoms such as general malaise, fever and
weight loss, combined with more specific signs and
La bora tory tenth r

symptoms related to specific organ involvement.

0 Anaemia and leucopenia are common
0 ANA frequently present
0 Anti-Ro or anti-La present in primary
Sjogren syndrome
0 ESR and CRP reflect disease activity
0 Rheumatoid factor positive in most cases
I
Polyclonal hypergammaglohulinaemia
Treatment
0 Artificial tears: plugging of lacrimal punctae in
severe cases
/vtoistening sprays for the mouth
0 NSAIDs and sometimes hydroxychloroquine for
arthritis
Z(}.4.(a Mixed c onne c t i ve t i ssue
disease/overlap sy n d r o m es
Some patients have features of more than one con-
nective tissue disorder and are said to have 'overlap
The diagnosis is based on a combination of clinical
and laboratory findings, and is usually confirmed by
biopsy and/or angiography.
Aetiology
Infections, malignancy and drugs may all lead to
vasculitic illness but, in many cases, the trigger for
endothelial injury is unknown. The following me-
chanisms of endothelial cell injury have been pro-
posed in the pathogenesis of vasculitis:
0 Immune complex deposition: hepatitis B-
associated polyarteritis nodosa
0 Direct endothelial cell infection: HIV
I Anti-endothelial cell antibodies: Kawasaki
disease, lQ;|g_et syndrome
0 ANCA-mediated neutrophil activation:
Wegener's granulomatosis, microscopic
polyangiitis
0 T cell-dependent injury: giant-cell arteritis
_ f _ _ f

582

,c1iata1*t,w\r~ _rrvau1m.,
General
0
Constitutional (fever, weight loss,
fatigue, anorexia)
~ Musculoskeletal (arthralgia, arthritis,
myalgia)
0 Related to specific organ involvement
~ Kidney ( g l
s manifest
-
acute renal failure, proteinuria/
by
haematuria); see Nephrology, Chapter
a
15
Respiratory (alveolitis, infiltrates,
-
haemorrhage, sinusitis)
~ Neuropathy irnononeuffs multiplex,
se_n9_ry neuropathy)
Gastrointestinal (diarrhoea, abdominal
pain, perforation, haemorrhage)
Cardiovascular (jaw or extremity
claudication, angina, mVocardial
infarction)
, _
Central nervous system (headache,
vispal loss, stroke, serzures)
- * _
~ Skin (livedo reE|cula'r`s"i
, urticaria,
vasculitlc lesions mc uding purpura and
erythema multiforme)
20.5.2 C lassifi catio n of v ascu litis
The vasculitides are classified according to the size
of vessel involved and the pattern of organ involve-
m e nt,
U
-~
Large vessels
Takayasu arteritis
Giant-cell/temporal arteritis
~ Aortitis associated with ankylosing
spondylitis
Small/m ~ium-sized vessels
-
I
Wegeners granulomatosis
Churg-Strauss syndrome
v (iranu omatous angiitis of the CNS
mi
Rheumatology
6 J
(Son-granulomatousti
Polyarteritis no osa A
v Kawasaki disease
~ Arteritis/vasculitis of i w ,
Sjogren syndrome
v
Microscopic p o |
Small-vessel vasculitis
Leucocytoclastic vasculitis: allergic or
hypersensitivity vasculitis
Henoch-Schonlein syndrome
~ (fr o lobulinaemia
~
~ D ced vasculitis
Vasculitis of RA, SLE, Sjogren syndrome
~ Microscopic polyangiitis
'
0 Others
Behcet syndrome (vasculitis and
V enll IEIS
Q/\/\
La bora tory tests _
ESR/CRP are invariably elevated in active
disease
Normochromic anaemia and leucocytosis
(usually a neutro h`|ia) are common
0
Eosinophilia is charac eristic of
Churg-Strauss syndrome but may occur in
ny vasculitis
Assessments of renal function and urinalysis are
essential if vasculitis is suspected since renal
involvement is one of the most important factors
affecting prognosis
Anti-neutrophil cytoplasmic antibodies (ANCA)
These antibodies are directed against constituents of
the neutrophil cytoplasm, proteinase 3 and
myeloperoxidase (MPO). When neutrophils are acti-
vated PR3 and MPO move to the cell surface. Anti-
bodies to either granule will cause activation of the
respiratory burst and degranulation, particularly in
the presence of TNFL1, causing endothelial cell
damage. ANCA may therefore play a role in the
pathogenesis of its associated disorders. Titres often
reflect disease activity.
` * \ _ /
583
Essential Revision /\/otes for MRCP

cANCA (cytoplasmic staining dence of 52/100 000 people aged over 50, and
pattern,(anti-PR3))
is found in Wegeners granulomatosis ( 90% o giant cell-arteritis of 18/100 OOO people over 50.
patients) and mic r o sc o p ic po ya ngii is ELIL'/A Treatment is with corticosteroids,
I . - - - /
pANCA (perinuclear staining pattern, anti-MPO)
is found in microscopic
polyangiitis (60%) Features of polymyalgia rheurnatica and
Wegener's granulomatosis (20%), connective giant-cell arteritis
tissue disorders, other vasculitides _
U
Other inflammatory disorders can be associated Polymyalgia rheumatica
vvith positive ANCA in the absence of vasculitis (eg ~ Femalermale ratio 3:1
connective tissue disorders, autoimmune hepatitis ~ Age > 50 years "_

and inflammatory bowel disease); in these condi- ~ Proximal muscle ain' (shoulder or
"-ti
as
tions the immunofluorescence staining may be aty-
pical or appear similar to pANCA patterns. Early morning stiffness
Raised acute phase response (ESR/CRP)
Treatment Abnormal liver function tests (alkaline
0
phosphatase/gamma glutamyl
Large-vessel group: corticosteroids only for most transpeptidase (GGT))
0
cases
Medium/small vessels: corticosteroids and
44. CK norma I
v
Synovitis of knees, etc may occur
immuriosugpressives (cyclophosphamide, Response to corticosteroids is
dramatic
azathioprlne, MMF) and prompt (within 24- 48 hours]
0 Small-vessel group: corticosteroids and 0 Giant-cell arteritis
immunosuppressives in some cases; certain General malaise,
weight loss, fever
conditions (eg Ieucocytoclastic vasculitis) are o
Temporal headache with tender,
benign and do not require treatment enlarged, non-gylsatlle temporal arteries

S rness
--
P rognosi s l
Visual disturbancdloss
The size of vessel involved and presence of renal
involvement are the most important factors deter- Polymyalgia rheumatica
Positive temporal artery biopsy (patchy
mining prognosis. Despite treatment with immuno-
suppressive agents and steroids, up to 20% of granulomatous necrosis with i s)
patients with systemic vasculitis of thimall/
medium-vessel group of diag-
nosis. Patients with large- or srnall-vessel vasculitis Takayasu art eri t i s (pul sel ess disease)
have a much more favourable outlook. This rare condition presents with systemic illness
such as malaise, weight loss and fever. The main
vasculitic involvement is of the aorta and its main
20.5.3 Polymyalgia rheumatica,
branches, producing arm claudication absent
gia nt- c e ll a n d o th er large-
v essel ar ter itid es Qulses andiils. Thirty per cent of patients have
visual disturbance. Diagnosis is by angiography and
Giant-cell arteritis is a vasculitis of large vessels, treatment involves corticosteroids.
usually the cranial branches arteries arising from
of
the aorta. Polymyalgia rheumatica is not a vasculitis,
but is found in 40%-60% of patients with giant-cell 2 0 5 . 4 Wegener is g r a n u l o m a t o s i s
arteritis. Both are disorders of the over-505 and both A rare disorder (incidence 0.4/100 O00) charac-
are relatively c om m on, Polymyalgia has an inci- terised by a granulomatous necrotising vasculitis.

584
 Rheumatology

Any organ may be involved but the classic
\/\/egeners triad includes:
0
Upper airways (sinuses, ears, eyes): saddle nose,
. & _ _ , l m -
proptosis
0
Respiratory: multiple pulmonary nodules
0 Renal: focal proliferative glomerulonephritis,
often with segmental necrosis (see Nephrology,
Chapter 15).
20.5.5 C h u r g - S t r a u s s s y n d r o m e
(allergic a ngi i t i s a n d
granulomatosis)
A rare systemic vasculitis with associated eosino hi-
infarcts; glomerulonephritis is less common and
i.s3n in ANCA-positive overlap syndromes
20.5.? Micro sco p icg mly an g iitis
(micro sco p ic poiya rtte ritis)
Usually presents between the ages of 40 and 60
with constitutional illness ancl renal disease. Though
classified with the medium/small-vessel disorders,
microscopic angiitis tends to affect small arteries
and arterioles of the kidney. Organs involved in-
clude:
0
Kidney: glomerulonephritis (sec Nephrology,
Chapter 15] as for Wegeners granulomatosis

lung aw
lia and as hm Any organ can be involved but the
,

are the most commonly affected.

Though corticosteroids are required, the condition
0
0
0
Skin: palpable gurpura
Lung: infiltrates, haemoptysis, haemorrhage
Gut, eye or peripheral nerves can also be
of most patients can be controlled without addi- involved
tional immunosuppressives, in some cases, the dis- ANC/\ is positive in most cases: pANC/-\ in 60%
ease is triphasic. and cANCA in 40%.
0 Prodromal: allergic features of asthma rhinitis
0
Eosinophilia: with eosinophilic prtgumpnia or
eosinophilic gastroenteritis 20.5.8 Kawasak i d isease
I Systemic vasculitis An acute febrile illness w it systemic vasculitis

20.5.6 Poiya rteritis riodosa

e hich mainly affects
peak onset is
under
at 1 .5 years
the age of
and it has an
incidence of about 6/100 000 in the under-Ss. It is
more common and more severe in males. The cause
Primary necrotising vasculitis of small/medium-sized is not known but its occasional occurrence in mini-
vessels with formation of microaneurysms. lt is
epidemics, suggests an infectious agent. (Rickettsia
uncommon, with an incidence of 5 - 9 per million, .
has been implicatedl
-f-
' Q _ - 4
but it may b s much as 10 times more frequent in
areas
usually
wher B
with
is endemic, Presentation is
constitutional symptoms. Any organ fmirmrva of Kawasaki disease
may be involved but commonly peripheral
nerves, lfitlney, gtit and J:o_ii1ts are affected. Treat- 0 Fever
ment is with corticosteroids and immunosuppres- (Followed by thrombocytosis)
s iv es , I Mucocutaneous
h red crac l<ed l 'ips, straw berr
0 Hepatitis B surface antigen is present
cases worldwide, but < l ( ) % in the UK
inof
Biggs,
ton ue, coniunctiViti"s
Mild eosingghilia may be present
0 Vase
~ W'itl`i coronary aneurysm formation
_LFTs often abnormal M o c a
2.5%
ANC/A is Ositive in <__i_of'/..
Renal disease is typically manifest by
0
L

y m
accelerated-phase hypertension and renal ( E s

585
Essential Revision Notes for MRCP

atment differs from rnos er vasculitides. 20.6 CRYSTAL ARTHROPATHIES

`
AND OSTEOARTHRITIS
creas corona i aneur sms. Anti-inflammatory
doses of aspirin are used during the acute febrile 20.6.1 Gout
phase and antiplatelet doses are given once the
fever resolves and thrombocytosis occurs. lntra Hyperuricaemia is common and usually asympto-
venous immunoglobulin is also effective. matic, but in some individuals uric acid crystals
form within joints or soft tissues, leading a variety of
diseases.
20.5.9 Be h cet s y n d r o m e
Behcet syndrome is a rare condition rnost com
monly found in Turkey and the eastern Mediterra Clinical futures of gout ~

-
nean where there is a strong association with
HLAB5. There is an equal sex ratio but the disease 0 Acute ciystal arthritis
is more severe in ma e s, he pathological findings
Particularly affecting the small joints of
are of immune-me lated occlusive vasculitis and the feet (eg first MTP, usually recurrent]
venulitis. The diagnosis is based on clinical features, 0
Gouty nephropathy
Main cllnieal features

al disease due to
parenchymal crystal deposition
Acute intratubular precipitation
Recurrent ill ulceration (100%) resulting
in acute renal failure
Recurrent @iri__ful_ge_uit.al ulceration (80%) Urate stone formation (rgdiolucent)
0 Recurrent irltis (60%-70%) 0 Chronic tophaceous arthritis
0 lesions (60%-80%) ~ These are aggregations of urate crystals
affecting articular, periarticular and non-
Other features _ articular (eg ears)
c\a\rR|ea/gi
0 Cutaneous vasculitis

_
Thrombophlebitis
0 (red papules >2 mm at
PAatherg_y\reaction_
sites of needle pricks after 48 hours)
Aetiology
Erythema
I Arthritis (usually non-erosive, asymmetric, Uric acid is a breakdown product of purine nucleo-
tides. Purines can be synthesised from precursors,
lowediybi
0 but significant amounts are ingested in normal diets
Neurolog_icQinvolvement (aseptic and released at cell death. Hyperuricaemia arises
meningitis, ataxia, pseudobulbar palsy)
, . , because of an imbalance in uric acid production/
0 Gastrointestinal involvement
, _. . ___
ingestion and excretion.

586
 Rheumatology

-
Ca me sof gnut '
Treatment of gout
0 (innate) 0 Acute attack
~Primary
Idiopathic Qty, of these are due to ~ NSAIDs (colchicine or steroids may be
under-excretion of uric acid] used if NSAID-intolerant)
Rare enzyme deficiencies: eg 0
Prophylaxis (the aim ls to reduce serum uric
hypoxanthine-guanine acid < 3 e0 pmol/ii
Allopurinol, a xanthine oxidase
-
phosphoribosyltransferase (HGPRT)

deficiency (Lesch-Nyhan syndrome) inhibitor, is the drug of first choice

0
Secondary hype'ruricaemiaf*`" Benzbromarone ia uricosuric agent) can
Increased uric acid productiorvintake be used if allopurinol is not tolerated
~
__
Myeloproliferative and Probenecid and sulfinpyrazone are less
lyrnphoprol`ferative disorders effective uricosurics
o High purine diet, eg purines in beer Losartan and fenofibrate have mild

--
(even non-alcoholic) uricosuric effects
therapy All may precipitate acute attacks at the
~ Cytolfic
Acidosis, eg the ketosis of starvation outset of treatment unless an NSAID or
or diabetes colchicine is given
~ Extr exercise, status
e Lile ticus L
, 0 Decreased uric acid excretion
~ Renal failure

-
Drugs (diuretics, low-dose aspirin,
l
ciclosporin,
`
pyrazinarmde) Other m an ag em en t issues:
Alcoho
~ Lead intoxication (saturnine gout) Lose weight if obese
1 5own'"`nsyErome "
Reduce alcohol intake
( ` _ _ - _ _
Reduce excessive dietary purine intake
Identify and treat associated factors
Di agnosi s (hyperlipidaemia, hypertension, hyperglycaemia]
I
Withdraw drugs which cause hyperuricaemia
Negatively irefringent needle-shaped crystals such as diuretics
must e ientified in joint i uid or other tissues
for a definitive diagnosis
i O ln chronic tophaceous gout the X-ray
appearances (large punched-out erosions distant

l l
m
from the joint mar in) are characteristic and

In clinical practice, a characteristic history with

Indications for prophyl axi s
Recurrent attacks of arthritis
Tophi
hyperuricaemia is often thought sufficient, but Uric acid nephropathy
there are pitfalls: uric acid may fall by up to Nephrolithiasis
,
`
30% during an acute attack; hyperuricaemia is During cytolytic therapy of leukaemia
common and may be coincidental HGPRT deficiency

587
Essential Revision Notes for MRCF

20.6.2 Calcium p y r o p h o sp liate 20.6.3 O s teoarthritis

de pos i t i on disease {CPDD)
This is a spectrum of disorders ranging from asymp-
tomatic radiological abnormalities to disabling poly-
arthritis. The underlying problem is the deposition
of calcium pyrophosphate crystals in and around
joints. This is most commonly idiopathic and age-
related, but may occur in metabolic disorders, espe-
cially those with hypercalcaemia or hypomagnesae-
mia. Calcium pyrophosphate forms positively
birefringent brick-shaped crystals,
Variants:
0
Asymptomatic: radiological chondrocalcinosis
(30% of over-805)
C Acute monoarthritis: pseudogout (usually knee,
elbow or shoulder)
0
Inflammatory polyanhritisr mimicking RA ( 10%
of CPDD)
0 Osteoarthritis: often of hips and knees but with
involvement of the index and middle MCP
Osteoarthritis (OA) is the most common joint dis-
ease. It is characterised by softening and degrada-
tion of articular cartilage, with secondary
changes
in adjacent bone. The prevalence of OA on X-ray
rises with age and affects 70% of 70-year-olds.
Many individuals with radiological OA, however,
are asymptomatic.
Common joints involved are:
0 Distal interphalangeal joints [Heberdens nodes)
0 Proximal interphalangeal joints (B0ucharcls
nodes)
Base of thumb (first carpometacarpal joint)
Hips
Knees
Spine
Metacarpophalangeal joint OA suggests a second-
ary cause (eg CPDD).
OA subsets

-
joints (rarely seen in primary osteoarthritis)
O
Primary
causes af cP oD
l

Localised ( one
'

~ Generalised (egprincipal site, eg hip)

hands, knees, spine)
0
Hyperparathyroidism Secondary
Wilson's disease ~ Inherited dysplastic disorders
Bartter syndrome Mechanical damage (eg osteonecrosis,
Hypomagnesaemia post-meniscectomy)
Haemochromatosis o Metabolic (eg ochronosis, acromegaly)
Hypophosphatasia ~ Previous inflammation (eg sepsis, gout,
Ochronosis RA)

Treatment
TmatmemnfCPDD-iW 2

Exercise
0 Chondrocalcinosis alone needs no Physiotherapy
treatment Occupational therapy
I NSAIDS for arthritis Analgesics, including NSAIDs
0 Correction of metabolic disturbances (if intra-articular injection (steroid or hyaluronic
possible) acid)
Surgery

588
 Rheumatology

20.7 ARTHRITIS [N CHILDREN 20.7.3 Po ly articu lar

ChssiBcntimn
0 iuvenile idiopathic arthritis (previously
termed 'juvenile chronic arthritis' (]CA))
0 Systemic connective tissue disease
0 Reactive arthritis (eg rheumatic fever)
0 Other (psoriatic, viral, leukaemic]
Arthritis of more than four joints. This is probably
two distinct disorders. Younger children with nega-
tive rheumatoid factor have a symmetric anhritis of
large joints (especially the knees), though the small
joints can be affected. Older children, usually teen-
agers, with a positive rheumatoid factor have, in
fact, early-onset rheumatoid arthritis.

20.7.1 Juvenile id io p ath ic ar th r itis
juvenile idiopathic arthritis is a persistent arthritis of
more than 3 months duration in children under the
age of 16. It is one of the more common chronic
disorders of children and is a major cause ot' mus-
culoskeletal disability and eye disease. The cause is
not known. A number of distinct clinical patterns of
onset are recognised (Table 2O.3l.
2074 Pauci-articular
Arthritis of between one and four joints. Again there
are two distinct groups: older boys with sacroiliitis
and HLA B27 who probably have juvenile-onset
ankylosing spondylitis; and younger girls, usually
ANA~positive, who may have uveitis. Regular
ophthalmological screening is required in this
gI'OUp.

20.7.2 Sy stem ic (classic Stills T r e a t m c m o ( llfihrith in children

disease)
Physiotherapy and splintage
The hallmark is a high spiking fever which, with the Occupational therapy
salmon-pink evanescent rash, is virtually diagnostic. NSAIDs
There is usually visceral involvement with hepatd Disease~modifying agents (eg methotrexate)
splenomegaly and serositis. Initially the arthritis may in persistent polyarticular disease
be flitting as in rheumatic fever, but in 50% of cas es Corticosteroids may be needed for systemic
this develops into a chronic destructive arthropathy. disease
This is usually a disease of the under-5s, but adult Anti-TNFa therapy for refractory disease
cases do occur.

Table 20.3. Clinical patterns of onset of] uvenile idiopathic arthritis

Systemic Polyarticular Pauci-articular

Frequency t%) I0 30 60
Number of joints involved Variable five or more four or fewer
Femalezmale ratio 1:1 3:1 5:1
Extra-articular features Prominent Moderate Rarer
Uveitis (%) Rare 5 20
Rheumatoid factor (0/0) Rare 15 Rare
Antinuclear factor (/0) 10 40 85
Prognosis Moderate Moderate Good

589
 Chapter 21
Statistics

CONTENTS

21.1 S tu d y de s ign
21.1.1 Research questions
21.1.2 Experimental studies
21 ,1 .3 Crossover studies
2 1 .1 ,4 Observational studies
2 1 .1 ,5 Confounding
21.2 Distributions
21.2,1 Types of data
21.2.2 Skewed distributions
21.2.3 Normal distribution
21.2.4 Standard deviation

21.3 C onfi dence inte rva ls

21.3.1 Standard error ofthe
mean (SEM)

21.4 Signifi c a nc e tests

21.4.1 Null hypotheses and p values
21.4.2 Significance, power and sample
size
21.4.3 Parametric and non-parametric
tests

21.5 Correlation a n d r e g r e s s i o n
L. 21.5.1 Correlation coefficients
21.5.2 Linear regression

k
21.6 Sc re e ning tests

- 591

Statistics
21.1 STUDY DESIGN
21.1.1 R esearch q u e s t i o n s
A research study should always be designed to
answer a particular research question. The question
usually relates to a specific population, For exam-
ple:
I Does taking folic acid early in pregnancy
prevent neural tube defects?
I ls a new inhaled steroid better than current
treatment for improving lung function amongst
cystic fibrosis patients?
I Are those who smoke more likely to develop
cancer?
Random samples of the relevant groups are taken.
For example, pregnant women, cystic fibrosis pa-
tients, those who do and do not smoke.
Based on the outcome in the samples, inferences
are made about the populations from which they
were randomly sampled. Statistical analysis enables
us to determine what inferences can be made.
Studies are either experimental or obsen/ational.
21.1.2
E xpe r i me nt a l s tudies
In experimental studies, individuals are assigned to
groups by the investigator. For example, pregnant
women would be assigned to take either folic acid
or a placebo; cystic fibrosis patients would be
assigned to either the new or current treatment. ln
both of these examples the second group is known
as a control group.
Note that a control group does not necessarily
consist of normal healthy individuals. In the second
example the control group comprises cystic fibrosis
patients on standard therapy.
Statistics
Individuals should be randomised to groups to
remove any potential bias. Randomisation means
that each patient has the same chance of being
assigned to either of the groups, regardless of their
personal characteristics. Note that 'random' does
not mean haphazard or systematic.
Experiments! studies ma y be
0 Double-blind: neither the patient nor the
researcher assessing the patients/treating
clinician knows which treatment the patient
has been randomised to receive
0
Single-blind: either the patient or the
researcher/clinician does not know (usually
the patient)
0 Unblinded (or open): both the patient and
the researcher/clinician know
Clinical trials are experimental studie s,
21.1.3 Crossover stu d ies
ln a crossover study, each patient receives treatment
and placebo in a random order. Fewer patients are
needed because many between-patient confounders
may be removed. For example, even though pairs of
cystic fibrosis patients may be chosen and rando-
mised to groups on the basis of their disease severity
this does not ensure that the groups will be of
similar age or s ex ,
Crossover studies are only suitable for chronic dis-
orders that are not cured but for which treatment
may give temporary relief. There should be no
carryover effect of the treatment from one treatment
period to the next.
593
Essential Revision Notes for MRCP
21.1.4 Observational s tudies
ln observational studies the groups being compared
are already defined (eg smokers and non-smokers)
and the study merely observes what happens,
Case-control, cross-sectional and Cohort are parti~
cular types of observational studies that, respec-
tively, consider features of the past, the present and
the future to try to identify differences between the
groups.
0 If we take groups of individuals with and
without cancer with the aim of identifying
different features in
thei<pastjhat might explain
a causal route for the cancer, this is a case-
control study
0 Ifwe take groups of smokers and non-smokers
and follow them forward in time to see whether
one group is more prone to cancer, then this is a
cohort study
21.1.5 Co n fo u n d in g
Confounding may be an important source of error.
A confounding factor is a background variable (ie
something not of direct interest) that:
I is different between the groups being compared
and
I affects the outcome being studied
For example, in a study to compare the effect of
folic acid supplementation in early pregnancy on
neural tube defects, age will be a confounding
factor if:
either the folic acid or placebo group tends to
consist of older women
and
I older women are more, or less, likely to have a
child with a neural tube defect
When studying the effects o f a new inhaled steroid
against standard therapy for cystic fibrosis patients,
594
disease severity will be a confounder if:
0 one of the groups (new steroid/standard therapy)
consists of more severely affected patients
and
0 disease severity affects the outcome measure
(lung function)
In the comparison of cancer rates between smokers
and non-smokers, diet will be a confounder if:
0 smokers eat less fruit and vegetables
and
0
eating more fruit and vegetables reduces the risk
or' contracting cancer
If a difference is found between the groups (folic
acid/placebo, new steroid/standard therapy and
smokers/non-smokers) we will not know whether
the differences are, respectively, due to folic acid or
age, to the potency of the new steroid or the
severity of disease in the patient, or to smoking or
diet.
Confounding may be avoided by matching indivi
duals in the groups according to potential confoun-
ders_ For example, we could a g e
and placebo pairs or deliberately recruit smokers
and non-smokers with similar fruit and vegetable
consumption. We could find pairs of cystic fibrosis
patients of similar disease severity and randomly
allocate one of each pair to receive the new steroid
while the other receives standard therapy.
21.2 DISTRIBUTIONS
21.2.1 Types of d a t a
Data may be either categoric or numeric.
I With categoric variables each individual lies in
one category
0 Numeric data are measured on a number scale
Ranks give the order of increasing magnitude of
numeric variables. For example:

Sample of seven readings:

2,3

~2.1
Ranks:
1
5.0

1.3

2.5
3 .9
ln order of magnitude:
1.3

2.5
1.3

2.3

4
f2 .1

3 .9

5
Note that there are seven values in the sample and
the largest value has rank 7. Where there are ties
1.3

4.2

6
4.2

5 .0

7
above:

Mean 1

_
215.9
7
Z 2-27

21.2.2 Sk ewed dis tributions

Sta tistics

The mean is the arithmetic average. In the example

2 .3 + 5 ,0 + 3 .9 + 1 .3 -2 ,1 + 1 .3 + 4 .2

(for example, the two values 1.3), the ranks are The distribution of a set of values may be asym-
metric or skewed (Figure 21.1i.
averaged between the tied values.
The mode is the value that occurs most often, In the In a sample of this type the mean is 'pulled wards
the values in the outlying tail of the is ribution a
example above;
is unrepresentative of the bulk of the data.
Mode = 1.3 Note that the skew is named according to the
direction in which the tail points. In Figure 21.1a,
The median is the middle value when the values are l e tail points to e left, to negative values and
ranked. In the example above: downvva rds.
Median = 2.3 If the distribution is skewed then the median is
/ T '
preferable as a summary of the data.
/

Figure 21.1 (a) Negative or downward or left skew (b) Positive or upward or right skew
Mode Mode
edia e
Mean Mean

te
- f m
we
le w w

595
Essential Revision Notes for A/(RCP
ri

21.2.3 Normal distribution 21.3 CONFIDENCE INTERV/-\LS

The normal distribution is symmetric and bell-
21.3.! Stan d ar d e r r or of tile m e a n
shaped (Figure 21.2). The normal distribution is
sometimes called the Gaussian distribution. (SEM)
Often abbreviated to 'standard error (SE), this is a
W H - _ A

measure of how precisely the sample mean approx- E

i

Figure 21.2 Normal distribution__ imates the population mean.

Stand ard error :

standard deviation
- _ - 1 *
/
li/S
E /
,R
where n is the sample size
The standard error is smaller for larger sample sizes
(ie as n increases, SEM decreases). The more obser-
vations in the sample (the bigger the value of nl the
more precisely the sample mean estimates the
population mean (ie the less the error).
The SEM can be used to construct confidence
intervals:

21.2.4 S tandard deviation

0 The interval (m ean :iz 1.96 SEM) is a 95%
confidence interval for the population mean
The standard deviation (= \/variance) gives a mea- 0 The inten/al (mean i 2 SEM) is an approximate
sure of the spread of the distribution values, The 95% confidence inten_/ or the population
smaller the standard deviation (or variance) the

mean //t
5
more tightly grouped the values (Figure 21,3). The inten/al 1.64 EM) is a 90%
lfthe values are normally distributed, then: lmearkifor th population mean
confidence inten/a

0
Approximately 68% ofthe values lie within i 1 There is a 5%, or 0.05, or a 1 in 20 chance that the
standard deviation of the mean true mean lies outside the 95% confidence interval:
0
Approximately 95% of the values lie within 1 2 0 'We are 9 5 % confident that the true mean lies
standard deviations ofthe mean inside the interval
0
Exactly 95% ofthe values lie within i 1 .9 6
standard deviations of the mean (hence 2.5% lie There is a 10%, or 0.1, or 1 in 10 chance that
in each tall) the true mean lies outside the 90% confidence

Figure 21.3 (a) Small standard deviation. (b) Large standard deviation

l
_A
596
 Statistics

interval: null hypothesis is to be correct. The measure of

0 'We are 90% confident that the true mean lies
'how likely' is given by a probability (p) value.
inside the interval Usually, the null hypothesis is that there is no
difference' between the groups.
Note the difference between the standard deviation
and the standard error:
21.4.1 Null h y p o th eses an d p- va l ue s
0 Standard deviation (SD) gives a measure of the
spread of the data values To answer the research questions in Section 21.1
0 Standard error (SE) is a measure of how we test the following null hypotheses:
precisely the sample mean approximates the 0 There is no difference in the incidence of fetuses
population mean with neural tube defects between the groups of
For example, FEV( is measured in 100 students. The pregnant women who do and do not take folic
mean value for this group is 4.5 litres with a acid supplements
standard deviation of 0.5 litres. If the values are 0
Lung function is similar in cystic fibrosis patients
normally distributed then: who receive the new inhaled steroid when
compared to the patients on current treatment
approximately 95% of the values lie in the range 0 Smokers and non-smokers have equal chances
(4.5 i 2(O_5)) of contracting cancer
= (4.5 i 1 litres)
Even if these null hypotheses were true we would
= (3.5, 5.5 litres) not expect the averages or proportions in our sam-
ple groups to be identical. Because of random
0.5 0.5 variation there will he some difference. The pvalue
Standard error = I e
= 0.05
V100 10 is the probability of observing a difference of that
magnitude if the null hypothesis istrue.
An approximate 95% confidence interval for the
Since the p-value is a probability, it takes values
population mean FEV] is given by: between 0 and 1. Values near to zero suggest that
(4.5 :l:2(0.05)) 1
(4.5 i 0.1) :
(4.4, 4.6) litres
the null hypothesis is unlikely to be true. The
smaller the p-value the more significant the result:
This means that we are 95% confident that the 0
p = 0.05, the result is significant at 5%
population mean FEV, of students lies in the range The sample difference had a 1 in 20 chance
4.4 to 4 .6 litres. of occurring if the null hypothesis were true
Confidence intervals can similarly be constructed 0
p 0.01, the result is significant at 1%
1

around other summary statistics, for example the
difference between two means, a single proportion
or percentage, the difference between two propor-
tions. The standard error always gives a measure of
the precision of the sample estimate and is smaller
for larger sample sizes.
21.4 SIGNIFICANCE TESTS
Statistical significance tests, or hypothesis tests, use
the sample data to assess how likely some specified
The sample difference had a 1 in 100
chance of occurring if the null hypothesis
w ere true
Statistical significance is not the same as clinical
significance. Although a study may show that the
results from drug A are statistically significantly
better than those for drug B, we have to consider
the magnitude of the improvement, the costs, ease
of administration and potential sideeffects of the
two drugs, etc before deciding that the result is
clinically significant and that drug A should be
introduced in preference to drug B.
4

597
Essential Revision Notes for MRCP

2it4.Z Sig n ifi can ce. p o w e r a n d Z1.-1.3 Par ametr ic a n d n o i r

s a mpi e siz e
The study sample may or may not be compatible
with the null hypothesis. On the basis of the study
results, we may decide to disbelieve (or reject) the
null hypothesis. In reality, the null hypothesis either
is or is not true (Table 21.1).
The study may lead to the wrong conclusions:
0 A low (significant) p-value may lead us to
disbelieve (or reject) the null hypothesis when it
is actually true - (I) in Table 21.1. This is
known as a type I error
0 The
p-value may be high (non-significant) when
-
the null hypothesis is false (Il) in Table 21.1.
This is known as a type II error
The power of a study is the probability (usually
expressed as a percentage) of correctly rejecting the
null hypothesis when it is false.
Larger differences between the groups can be de-
tected with greater power. The power to identify
correctly a difference of a certain size can be in-
creased loy increasing the sample size. Small sam-
ples often lead to type ll errors (ie there is not
sufficient power to detect didereiices of clinical
importance).
In practice there is a grey area between accepting
and rejecting the null hypothesis. The decision will
be made in the light of the p-value obtained. We
should not draw different conclusions based on a p
value of 0.051 compared with a value of 0.049. The
p-value is a probability. As it gets smaller the less
likely it is that the null hypothesis is true. There is
Lgsudden changeover from 'accept' to reject,
p a r a n t e t r i c t e st s
Statistical hypothesis tests are either parametric or
non-parametric. Choosing the appropriate statistical
test depends on:
* The type of data and their distribution
0 Whether the data are paired or not
Parametric tests usually assume the data are
normally distributed, Examples are:
*_
0 t-test ( som e tim e s called Students t-test or
Students paired t-test()
0 Pearson's coefficient of linear correlation
An unpaired ( or 2-sample) t-test is used to compare
the average values of two independent groups (eg
patients with and without disease, treated versus
placebo, e tc ) .
A paired tor 1-sample) t-test is used if the members
of the groups are paired. For example, each indivi-
dual with disease is matched with a healthy indivi-
dual of the same age and sex; in a crossover trial
the measurements made on two treatments are
paired within individuals.
Non-parametric tests are usually based on
ranks. Examples are:
Wilcoxon tests
Kendall tests
Sign
Spearmans rank correlation
Mann-Whitney U
Chi-squared (xl)

Table 21.1. The null hypothesis

Decision based on study results Null hypothesis

True False

'Accept' null hypothesis OK (ll)

Reject null hypothesis (I) OK

598
 Statistics

Chi-squared is used to compare proportions (or 21.5.! ( Q o r r e l a t i o n coeffi cients

percentages) between two groups, The correlation coefficient ( som e tim e s called Pear-
sons coenicient oi i n e a r Eorrelation) is denoted by
ra nd indicates hovv closely the points lie to a line,
rtakes values between -l and 1; the closer it is to
21.53 CORRELATEON AND
zero the less the linear association between the two
RE G RIi SSl ()N
variables. ( Note that the variables may be strongly
Sometimes measurements are made on two contin- associated but not linearly.)
uous variables for each study subject, eg CD4 count
and age, blood pressure and weight, FRC and Negative values of r indicate that one variable de
creases as the other increases (eg CD4 count falls
height. The data can be displayed in a scatterplot with age).
(Figure ll .4).

l
_ __ --
VFigure 21.4 Scatterplot of CD4 count versus

age
- _ - _ . _ ; - ~ - - - ~ . _ _ i . . - _ - _ _ . _ _ _ _ - -< -----
- _ -
- - _ _ _ _ - _

e
5 0

l
4 . C O
0
C
o o
3 0
0"
1
0
0
.0 0

Q
o'
2 0
0 0

i i l r-
0 1 2 3 4
mewears) y

599
Essential Revision Notes for MRCP

Values of el or +1 show that the variables are 0 Parametric correlation coefficients quantify the
perfectly linearly related, ie the scatterplot points lie extent of any linear increase or decrease
on a straight line. Non-parametric correlation coefficients quantify
Correlation coefficients (Figure 21.5) : the extent of any tendency for one variable to
increase or decrease as the other increases (for
0 Show how one variable increases or decreases example, exponential increase or decline,
as the other variable increases increasing in steps, etc)
Do not give information about the size of the
increase or decrease
0 Do not give a measure of agreement A p-value attached to a correlation coefficient
shows how likely it is that there is no linear associa-
tion between the two variables.
Pearsons r is a parametric correlation coefficient.
Spearman's rank correlation and l<endall's tests are A significant correlation does not imply cause and
non-parametric correlation coefficients. effect.

Figure 21.5 Scatterplots with different correlation coefficients

_ . _.
_..
r = `l , f =-1
o o
0
-0' `
_/
,v ~.`.
J

.. o

'-
.

. .,
..-

--

I= 0

'

l= -0.5 f =O .7
'

. 1

.'
~
,
'o
'

'-- u
__

~..' f u
. I ;

_
600
 Statistics

21.5.2 Linear r e gr e ssi on 0 If'b' is negative then Y decreases as X

A regression equation ( Y = a + bX) may be used Io
PREDICT one variable from the other (Figure 21.6) .
0 ' a' is the intercept - the value Ytakes when X is
zero
0 'b' is the slope ofthe line - sometimes called
the regression coefficient, lt gives the average
change in Yfor a unit increase in X
II'\C|'! 3S 9S
If the units of measurement change then so will the
regression equation. For example, if age is measured
in months rather than years then the value of the
slope (eg the average change in CD4 for a unit
increase in age) will alter accordingly (Figure 21.7).

Figure 21.6 Linear regression line

v=a +bx ,

Y
O

0.. .

Figure 21.7 CD4 count versus age

6

5 0 CD4 = 4.24- O,64(age)

4
oo
A

3

0 I I I I-
0 1 2 3 4
A92 (years)

601
 Essential Revision Notes for MRCP

2 1 .() SCREENING TESTS 0

Negative predictive value is the proportion of
Screening tests are often used to identify individuals those who test negative who do not have the
at risk of disease, Individuals who are positive on disease
screening may be investigated further to determine _ d
whether they actually have the disease. c+a'
I Some of those who screen positive vvill not have
Note that the positive and negative predictive values
the disease
0 Some of those who have the disease may be depend on the prevalence of the disease and may
v a iy from population to population.
missed by the screen (ie test negative)
Figure 2 1 , 8 shows an example of a contingency
table containing data for a screening test.
Likelihood ra tios
O
Sensitivity is the proportion of true positives
correctly identified by the test 0 The likelihood ratio (LR) for a positive test
a result:
8-i-C
LR+ = sensitivity
1 - specificity
0
Specificity is the proportion of true negatives
correctly identified by the test
_L
_b+d The likelihood ratio for a negative test result:
I -
I Positive predictive value is the proportion of lR_ :
sensitivity
those who test positive who actually have the specificity
disease
likelihood ratios may be multiplied by pre-test odds
a to give post-test odds. They are not prevalence-
:a + b dependent.

A _
Figur;21.B Example of a contingency tallcontaihingdata for a screening test
Y Y
w w w *

Screening test result: Diseased Disease-free

Positive - indicating possible disease a l b

Negative ~ c d

602
 Statistics

Exam pl e ' The positive predictive value is 60/(60 +

A screening test is applied to patients with and 2 0 ) : 0.75 or 75% (ie 75% of those who test

without disease X. Of 1 0 0 who have the disease, 60 positive actually have the disease in this sample)
test positive; of 200 without the disease, only 20
0 The prevalence of the disease in this sample is
100/( 100 + 2 0 0 ) 1 0.33 Or 33%
test positive.
The following table may be constructed (Table If a particular patient had a prior odds of 1.5 of
21.2): having the disease (meaning that he or she is 1.5
times more likely to have the disease than not to
have it) then 1.5/2.5 (or 60%) of patients of this type
will have the disease. The posterior odds of the
Table 21.2. patient having the disease will thus be determined
by the result of the screening test:
Screening test result Disease X Disease-free Ifthe test is positive then the odds of having the
disease will be 1.5 ><6 = 9
Positive 60 20 0 Ifthe test is negative, the odds will be
(indicating possible 1.5 ><0 , 4 4 = 0.66
disease)
Negative 40 180 Note that, as expected, the odds of having the
disease rise if the test is positive and fall if the test is
negative,
A posterior odds of 9 means that the patient is nine
Therefore, the following are true: times more likely to have the disease than not,
Sensitivity = 60/100 : 0.6 or 60% which equates to a probability of 9/10 or 0.9 (as
Specificity: 180/200 = 0.9 or 90% opposed to 0.6 before testing). A posterior odds of
LR+ 0.6/( 1- 0.9) 6
1 1
0.66 equates to a probability of 0.66/1.66, or 0.4
LR- = (1 -0 .6 )/ 0 .9 = 0.44 (as opposed to 0.6 before testing).

603

Where more than one page number appears against a heading, page numbers in bold indicate the main
treatment of a subject.
abacavir 207, 208, 2 0 9
abatacept 573
abciximab (ReoPro") 57- 58, 3 7 9
abdominal pain
acute 178
HIV/AIDS 203
abducens nerve see sixth (VI) nerve
abetalipoproteinaemia 333,347,
490
abscesses
brain 277
liver 176, 285- 286
lung 543
renal 430
absolute risk 128, 129
ABVD regimen 2 3 0 - 2 3 1
acalculia 450
acanthosis nigricans 85, 120
acanthosis palmaris 85
with nigricans 85
acarhose 61, 120, 121
accessory pathways, arrhythmias 26,
30
ACE inhibitors 58, 99
contraindications 56, 57, 58
diabetes 440
genetic variation in response 55
heart failure 39, 40, 51
hypertension 4B, 49
ischaemic heart disease 51
myocardial infarction 36
nephrotoxicity 444- 445
pregnancy 298, 303, 311
renal disease 405, 415
acetylator status 55
acetylcholine (ACh) receptors 364
antibodies 383, 384, 479
acetylcholinesteiase inhibitors 452
acetylcysteine 67, 69
N-acetyl cysteine 402
achalasia 1 4 5
achromatopsia 450
aciclovir 277, 475
acid-base control 534
acid-base disturbances 346- 350,
396- 397
acidosis
metabolic 346-349, 350, 396
renal bone disease 407
respiratory 396
acitretin 7B
acne 66, 78- 79, 113
aco u s tic neuroma 469
acrocentric chromosomes 181
acromegaly 94, 101, |0 3 , 115
ACTH
e c topic 110, 554
petrosal sinus 1 | 1
stimulation les t 111
see also Synacthen " tests
actinic skin damage 87
activated partial thromboplastin time
(APTT) 47, 237, 238, 243
activated protein C 274
activated protein C test 243
acute abdomen 178
acute confusional s t al e 515- S 16
acute coronary syndromes 35, 36
see also myocardial infarction
acute fatty liver ot pregnancy 310
acute intermittent porphyria 83,
326- 327
acute kidney injury (AKli 39' )-402,
416
causes 400
drugprescribing 57
investigation 400- 40|
malaria 284
management 401
myeloma 442
non-oliguric 399
prognosis 401
radiology 395
sarcoidosis 444
vasculitic disorders 443
vs chronic kidney disease 404
Index
see also hepatorenal syndrome
acute lymphoblastic leukaemia
(ALL) 225-226, 237
acute myeloid leukaemia tAML`| 221,
225- 226, 227, 236, 237
acute myelomonocytic
leukaemia 224, 227
acute organic brain syndrome
515- 516
acute phase proteins 218, 222
acute promyelocytic leukaemia LAML
M3) 227- 228
acute renal failure see acute kidney
injury
acute transplant rejection 412
acutetubularnecrosis(ATN) 392,
399-400, 401
acylation-stimulating protein
(ASP) 96
adalimumab 78,161,573, 574
addisonian crisis 113
Addison's disease 112, 51 B
adenosine 26, 58, 66
adenylate cyclase 93, 364
ADH see antidiuretic hormone
adhesion molecules 378- 379
Adie's pupil 462
adipokines 96
adiponectin 96
adrenal disease 109- 113
adrenal failure, acute 113
adrenal hyperplasia 110, 111
congenital (CAH) 111-112,113,
117
adrenaline 9 4 , 1 1 4
adrenal steroids 98
adrenal tumours 110,111,114
adrenarche 115- 116
adrenergic receptors 364
adrenocorticotrophic hormone
see ACTH
adrenoleukodystrophy(ALD) 334
adrenomyeloneuropathy 134
605
Essential Revision Notes for MRCP
adult respiratory distress syndrome
(ARDSl 373, 565- 566
adverse drug reactions se e drug
reactions, adverse
aerobic bacteria 267
aetiological fraction 130
affective disorders 504- 507
afferent pupillary defect 461
aflatoxin 176
African trypanosomiasis 288
afterload 39
agammaglobulinaemla 261- 262,
2 73 -2 74
agglutination tests 569
agoraphobia 508
Agouti-related protein (AgRP) 96
agrapl-iia 450
AlD$ see HIV/AIDS
airways 529
diseases of large 534- 540
resistance to airflow 529
see also upper airway disease
akinetic-rigid syndrome 457
akinetopsia 450
alanine aminotransferase (ALT) 168
Albriglits hereditary
osteoolystrophy 94, 1 89-190,
365
albumin, plasma 309
albumin creatinine ratio, urinary
(UACR) 394, 439
alcohol
anaemia 213
cardiac effects 43
health benefits 43
withdrawal 519- 520
alcohol abuse 5 1 9 - 5 2 1
hypomagnesaemia 343
liver disease 172, 173
neuropsychiatric effects
520- 521
psychological effects 520
vitamin deficiencies 348
Wernicke's encephalopathy 474,
520- 521
aldosterone 93, 98, 99
renal actions 392, 393
secreting adenoma 110
aldosterone antagonists 40
alefacept 78
alemtuzumab lCampath'`) 229, 234
aliskiren 58
alkaline phosphatase
606
bone 339, 340, 341
liver 168
alkalosis
metabolic 346, 349-350, 396
respiratory 3 9 6
alkaptonuria 319, 395
allele 386
allergic angiitis and granulomatosis
se e Churg-Strauss syndrom e
allergic bronchopulmonary
aspergillosis 5 3 7 , 5 4 ' )
allopurinol 64, 323, 413- 414, 587
all-trans retinoic acid (ATRA) 2 2 8
alopecia 88- 89
alopecia areata 88- 89
alpha-1 antitrypsin deficiency
380- 381, 538-539
u-fetoprotein (AFP) 176, 297
alpha-glucosidaseinhibitors 121
Alpon syndrome 186, 188, 414, 424
alprazolam 525
altitudesickness 534
aluminium bonedisease 408
aluminiumtoxicity 214
alveolarproteinosis 566
Alzheimers disease (AD) 451 -452,
516
clinicalfeatures 517
drugtreatrnent 452
molecular basis 381, 451- 452
amantadine 6 2 , 4 5 8
ambiguous genitalia 1 1 7 , 1 9 2 - 1 9 3
amenorrhoea 113
drug-induced 66
hyperthyroidism 106
amiloride 111
aminehormones 93
amino acid metabolism, disorders
of 319- 322
aminoglycosides 271,445
5-aminosalicylic acid (5-ASA)
compounds 6 1 , 1 5 9 - 1 6 1
arniodarone 5 6 , 5 8
arrhythmias 2 6 , 2 8
side-effects 58, 108, 495, 560
amitriptyline 524
amoebiasis 165, 285- 286
amoebic liver abscesses 176,
285- 286
amphotericin 207, 445, 5 4 9
amyloidosis 379-380
AA 435- 436
AL (immunoglobulinici 435, 436
cardiac 41
classification 380, 436
dialysis~related 410, 436
kidrieyinvolvement 435- 436
pulmonary 566
amyloid plaques 381, 451
amyloid precursor protein
(APP) 380, 381
amyotrophic lateral sclerosis 377,
470
anaemia 2 1 3 - 2 1 7
blood transfusion 246
chronic disease 214
chronic kidney disease 405- 406
macrocytic 213- 214
malaria 284
microcytic 214
normocytic 213
physiological, ofpregnancy 293
red cell morphology 214
rheumatoid arthritis 572
see also specific types
anaerobic bacteria 267
anakinra 573
analgesic nephropathy 427
anaphylactic reactions 258
ANCA-positive vasculitis 582,
583- 584, 585
renal involvement 420, 421, 443
see also anti~neutrophil
cytoplasmic antibodies
Ancylostoma duoclenale 289
androgens
adverse effects 67- 68
excess 79. 113
resistance/insensitivity 95, 116,
117, 193
aneuploid screen test 357
aneuploidy 181
aneurysms, intracranial 423,
472- 473
Angelman syndrome 189, 190, 357
angina 32,123
angiodysplasia 155- 156
angioederna
drug-induced 86
hereditary 253, 261
angiotensin ll 99
angiotensin-converting enzyme
(ACE) 99, 558
inhibitors se e ACE inhibitors
angiotensimreceptor blockers
(ARBS) 40, 56, 59

diabetes 440
renaldisease 405,415
anhidrosis 462
animaltoxins 446
anion-exchange resins 331,332
aniongap 346,396
ankylosing spondylitis 437, 494,
574- 575
juvenile-onset 589
Ann Arbor staging, Hodgkins
disease 230
annealing 386
anorectal conditions, HIV/AIDS 204
anorexia nervosa 93, 510- 514
diagnosticcriteria 511
medical complications 512- 513
treatment 514
anosognosia 450
antenatal care
cardiacdisease 299-300
diabetes 297
renaldisease 303
anti-androgens 67, 79
antibacterial agents 269-271
antibiotic prophylaxis
cysticfibrosis 548
hyposplenism/splenectomy 246,
273
infective endocarditis 19, 280,
300
meningococcal contacts 276
Pneumocystis pneumonia 202
urinary tract infections 429
antibodies
passive immunisation 263, 271
see also immunoglobulins;
monoclonal antibodies
antibody-based assays 362- 363
antibody-dependent cytotoxicity 2 5 8
anticardiolipin antibodies
(ACLA) 303, 577
anti-CD20 agent see rituximab
anti-centromere antibodies 577, 581
anticholinergic agents 457, 495
anticipation, genetic 189, 382
anticoagulation 242
atrial fibrillation 27
heart failure 40
paroxysmal nocturnal
haemoglobinuria 221
polycythaemia 234
in pregnancy 18, 299, 312, 313,
314
pulmonary embolism 47
pulmonary hypertension 45
anticonvulsants 62- 63
eclampsia 311
epilepsy 455- 456
in pregnancy 306, 4 5 6
anti-D 234, 241
antidepressants 507, 523- 524
se e also specific agents a nd classes
antidiuretic hormone (A D H ) 102.
104
renal action 392, 393
syndrome of inappropriate
(Sl/\DH) 68,104- 105, 554
anti-double-stranded DNA (a nt i -
dsDNA) antibodies 577
anti-embolic stockings 312-313
anti-endothelial cell antibodies 582
antr-epileptic drugs
see anticonvulsants
antiglobulintest 219-220
anti-glomerular basement membrane
(CBM) antibodies 421
antihypertensive drugs 48
diabetes mellitus 121, 440
pre-eclampsia 3 0 9
in pregnancy 49, 303, 311
primary l\yperaldosleronism 111
renal disease 405, 415
see also specific types
anti~lo 1 antibodies 577, 580
anti-La antibodies S77, 582
antimitochondrialantibodies 175
anti-neutrophil cytoplasmic antibodies
(ANC/tl 583- 584
cytoplasmic (cANCA) 584
perinuclear |jpANO\) 5 8 4
see also ANCA-positive vasculitis
antinuclearantibodies(ANA) 373,
577, 581
antioxidants 377
antrphospholipid antibodies 243,
577- 578
antrpbospbolipid syndrome
578- 579
pregnancy and 303, 312
antipsychotic drugs 63, 522- 523
adverse effects 63, 67, 523
atypical 504, 5 2 3
hypomanialmania 505
schizophrenia 504
traditional 504, 523
antiretroviral therapy 200, 2 0 7 - 2 0 9
Index
anti-RNPantibodies 577, 582
anti-Ro antibodies 577, 582
anti-Scl70 antibodies 577, 581
anti-Sm antibodies 577
antithrombin deficiency 243, 312,
313, 314
anti-thyroid drugs 107, 304
antituberculous drugs 282, 544- 545
anti tumour necrosis factor alpha (anti-
TNFccl agents
ankylosing spondylitis 576
Crohns disease 161
psoriasis 78, 576
rheumatoid arthritis 571, 573,
574
tuberculosisreactivation 545
Anton syndrome 460
anuria 432
anxiety disorders 508
drug-induced 519
drug treatment 523, 524-525
aortic bodies 530
aortic coarctation 21- 22, 442
aortic dissection 49
aortic regurgitation (AR) 10, 11,
16 - 1 7
aortic stenosis (AS) 17
aortography 11, 49
aphasia 450
aphthous ulcers 1 4 5
aplastic anaemia 214, 217
aplastic crisis 215
apolipoprotein E, is-4 allele 381, 452
apolipoproteins 327,328
apomorphine 62, 4 5 8
apoprotein CII deficiency 330
apoptosis 371- 372, 386
appetite, hormonal regulation 96
apraxias 450
aquaporins 393
ARDS see adult respiratory distress
syndrome
arginine-vasopressin (AVP) see
antidiuretic hormone
Argyll Robertson pupils 16, 461, 496
arm, mononeuropathies 476
arrhythmias 2 3 - 3 0
arsenic 446
artemether 234- 285
arterial blood gases 315, 534
arterial pulse 3 - 4
arterial switch operation 23
arteriosclerosis 488
607
Essential Revision Notes for MRCP

arteriovenous (AV) fistulae 13, 410 atherosclerotic renovascular disease nails 89

arthritis (AR\/D) 436- 437, 442 skin 81, 206
calcium pyrophosphate deposition athetosis 4 5 7 see also specific infections
disease 588 athletes, ECG abnormalities 7 bacterial overgrowth, small
children 589 atopie dermatitis (eczema) 78 bowel 155, 1 5 9
chronic kidney disease 410 atopy 534, 536 bacteriuria, asymptomatic 429
gouty 586 atosiban 297 bagassosis 552
psoriatic 76, 574, 577 atrial arrhythmias 26- 27 Balkan nephropathy 427
see also osteoarthritis; rheumatoid atrial fibrillation (AH 23, 2 6 - 2 7 Bardet-Biedl syndrome 490
arthritis alcohol and 43 Barretts oesophagus 146- 147
Arthus reaction 258 thromboembolic risk scoring Z7 Bartter syndrome 339, 3 9 8
asbestosis 550 treatment 26- Z7, 30, 3| hasal cell carcinoma 87
asbestos-related lung disease atrial flutter 23, 26. 30, 31 basal cell naevus syndrome 84, 192
549- 550, 556 atrial rnyxomas 42 basiliximab 414
ascites 1 6 9 - 170, 172 atrial natriuretic peptide ( ANP) 100, basophils 255
aspartate aminotransferase 393 Bassen-1<ornzweig disease see
lAST| 168, 309 atrial septal defects (ASD) 20, 24 ahetalipoproteinaemia
aspergillomas 549 atrloventricular iA\/) block Bath Ankylosing Spondylitis (BAS)
aspergillosls 549 first degree 25 scores 576
allergic brcnchopulmonary 537, high-grade 25 B cells (E lymphocytes) 256
549 second-degree Mobitz 1 disorders 261-262
colnnising 549 (\/Venckebachi 25 BCG vaccination 282,545
invasive 549 see also heart block Bcl-2 171
aspiration pneumonia 542 atrioventricular (AV) nodal re-entry BCR/ABL fusion gene 228-229, 370
aspirin tachycardia (AVNRT) 26 Beaus lines 89
acutestroke 472 atrioventricular (AV) re-entry Becker's muscular dystrophy 478,
adverse effects 66 tachycardia (AVRT) 26 479
antiphospholipid syndrome 303 atropine 34 Beckwith-Wiedemann
microangiopathic haemolytic attributable fractions 130 syndrome 1 9 0
anaemia 221 Austin Flint murmur 1 4 , 1 6 beclometasone dipropionate 536
myocardial infarction 36, 37, 51 autocrine action 386 behaviouraltherapy 526
overdose 70 autoimmune polyglandular failure Behcet syndrome 494, 586
polycythaemia 234 type I 338 Bell's palsy 468
pre-eclarnpsia prophylaxis 308 autoinduction 375 Bencelones protein 232, 394
assays, antibody-based 3 6 2 - 3 6 3 automated peritoneal dialysis benclroflumethiazide 60
associations,epidemiological 127, (APD) 408, 409 Benecolm 331
128- 129 a utonomic neuropathies 123, 477 benign intracranial hypertension
astereognosis 4 5 0 autosomal dominant (AD) (Bll-ll 474
asthma 534- 537 inheritance 184- 185 benzbromarone 587
acutesevere 536- 537 autosomal recessive (AR) benzodiazepines 508,524- 525
adverse drug effects 6 6 - 6 7 inheritance 185- 186 benzoyl peroxide 79
allergic bronchopulrnonary average risk 128 benzylpenicillin 270
aspergillosis 537,549 a waves 3, 39
Sergers disease se e IgA nephropathy
chronic 535 axonal neuropathies 481 beri-beri 348
diagnosis 5 3 0 , 5 3 5 - 5 3 6 azathioprine 64, 161, 414 berylliosis 551
'irritant' 552 azelaic acid 79 [$2-microglobulin 410
occupational 550, 551- 552 B-blockers
treatment 66, 536 babesiosis 273 adverse effects 67, 68
ASTRAL trial 437 Baci//uscereus 278 heart failure 39, 40, 51
ataxia telangiectasia 84, 2 6 2 bacteria, classification 267- 268 hypertension 48, 49
atazanavir 208 bacterial infections ischaemic heart disease 51
atenolol 37 cysticfihrosis 547 myocardial infarction 36
atherosclerosis 373, 375, 377 meningitis 275- 276 variceal haemorrhage 174

608
 Index

betamethasone 2 9 7 body mass index (BMI) 156, 345 buHae 75

bezafibrate 332 bone cysts, sarcoidosis 558 bullous eruptions 81- 82
bias 129, 137- 138 hone disease bullous pemphigoid 81f 82
bicarbonate (HCO3) 534 adynamic 408 bulls eye maculopathy 495
biguanides 121 aluminium 408 bundle branch block 7 - 8
bile 142, 169 chronic kidney disease 406- 408 Burkholderia cepacia 548
enterohepatic circulation 167 mehabolic 333-345 Burkitfs lymphoma 370
bile acid sequestrants see anion- bone marrow busulfan 228
exchange resins failure 247 byssinosis 551
bilharzia (schistosomiasis) 176, 286 megaloblastic 213
biliary disease, HlV/AIDS 203 nnrmoblastic 213 C1 inhibitor deficiency 253, 261
bilirubin 142,166,167 stem cells 3 7 9 cadherins 378
conjugated 166, 167, 168 bone marrow (stem celli cadmium 446
unconjugated 166, 168 transplantation 236- 237 Caeruloplasmin 324
bioinformatics 359 aplastic anaemia 217 calcarinesulcus 4 5 9
biological agents leukaemia 221, 225, 226, 229, calcification
psoriasis 78 237 <:hestX~ray 560
rheumatoid arthritis 573-574 myeloma 232, 233 vascular, dialysis patients 410
bipolaraffective disorder 505 Borrelia burgdorferi 290, 475 calcineurin inhibitors lCNls) 57
bird fancier's lung 552 bortezomib 232 nephrotoxicity 412,413
birth weight, infants of diabetic bosentan 46, 374 renal transplant recipients 414,
mothers 296 Bosniak system 424 415
bisferiens pulse 3 botulism 272 calcitonin 100, 107
bismuth 446 Bouchards nodes S88 calcium i'Ca1')
bisphosphonates 232, 337, 340, 343 bovine spongiform encephalopathy homeostasis 100, 334- 335
bitemporal hemianopia 459, 460 (BSE) 377 intracellularsignaling 94
biventricular pacing 30 bradyarrhythmias 2 3 - 2 5 loading test 3 3 9
Biork-Shiley heart valve 18 hradykinin 99 therapy/supplements 71, 308,
BKvirus 413 brain abscesses 2 7 7 338- 339
blackwater fever 284 brainstem lesions 466- 469 see also hypercalcaemia;
bladder branch retinal vein occlusion hypocalcaemia
neuropathic 433 (BRVOl 487 calcium-channel antagonists 46, 48
tumours 434- 435 BRC/\ 1/2 mutations 183, 191, 192 calcium gluconate 311, 338
Blalock shunt operation 23 breast cancer, hereditary 188, 191, calcium pyrophosphate deposition
hleomycin 65, 376 192 disease lCPDD) 558
blinding, randomised studies 133, breast-feeding, drug prescribing 56 Campath talemtuzumabi 229, 234
593 British Doctors' Study 135 Campylobacter infections 164, 165,
blind registration 500 Brocas area 450 278, 478
blood gases, arterial 315, 534 bromocriptine 1 0 3 cancer
blood pressure (BP) bronchiectasis 545-547 dermatomyositis/
ambulatory monitoring 13 bronchitis, chronic 537 polymyositis 579
control, chronic kidney bronchospasnmdrug-induced 66- 67 genetics 191- 192
disease 405, 415 Brown-Squard syndrome 470 Hl\//AIDS 206
measurement 306 brucellosis 289 molecular pathogenesis
normal pregnancy 293 Brugia malayi 288 368- 371
see also hypertension Bruton's X-linked renal transplantrecipients 413
blood transfusion 246- 247 agammaglobulinaemia 262 screening 192
aplastic anaemia 217 B-type natriuretic peptide (BNP) 100 skin changes 84- 85
infectionstransmitted 246-247 Budd-Chiari syndrome 173 somatic evolution 368- 369
paroxysrnal nocturnal budesonide 161 urinary tract obstruction 433
haemoglobinuria 221 bulimia nervosa 510- 511 see also specific cancers
sicklecelldisease 215 diagnosticcriteria 512 candidaloesophagitis 146
thalassaemia 216 treatment 5 1 4 Canicolafever 279

609
Essential Revision Notes for MRCP
C3l`|l'1O|'1 3 VVZIVGS 3 drugs 57- 60
capecitabine 65
Caplan syndrome 551, 571
Capnocytophaga canirnorsus 273
capsule enteroscopy 156
captopril 320
carbamazepine
epilepsy' 6 2 - 6 3 , 4 5 5 - 4 5 6
mania/hypomania 505
carbenoxolone 398
carbimazole 57, 60, 304
carbon-14 (MC) breath test 1 5 9
carbon dioxide transport 533- 534
carbon monoxide
poisoning 69-70
transfer 531-533
carbon tetrachloride 446
carcinoembryonic antigen (CEA) 164
carcinoid syndrome 154- 155, 348
carcinoidtumours 154-155
cardiac amyloidosis 41
cardiac apex 4
cardiac arrest, hypothermlc
patient 351
cardiac arrhythmias 2 3 - 3 0
cardiac catheterisation 11-12, 38
congenital heart disease 20
hypertrophic cardiomyopathy 40
normal pressures 50
valvular disease 14, 17
cardiac contusion 8
cardiac disease see heart disease
cardiac enzymes 33, 34
cardiac failure 35-39
clinical trials 51
diastolic 38
NYHA classification 39
pacing 30, 31, 40
therapy 39, 40
cardiac index 50
cardiac infections 279- 281
cardiac resynchronisation therapy
(CRT) 30, 40, 51
cardiac surgery, in pregnancy
299- 300
cardiac tamponade 4 4 - 4 5
cardiac transplantation 43, 257
cardiac tumours 42
cardiac valve calcification, dialysis
patients 410
cardiology 3- 51
clinical examination 3 - 5
clinical trials 36, 47- 48, 51
610
cell cycle 386
investigations 5 - 1 3 cell-mediated immunity
normal physiological values 50 dysfunction 262
cardiomyopathy 39- 41 cell signalling 363- 368
cardiotocography(CTG1 2 9 7 cellular phenotype 365
cardiovascular disease ( CVD) central retinal vein occlusion
chronic kidney disease 405, 4 1 0 (CRVO) 487
diabetes mellitus 122-123 cephalosporins 57, 270
primary prevention 332 cerebellar lesions 465
renal transplantrecipienls 413 cerebellopontine syndrome 469
rheumatoid arthritis 571 cerebral cortex
risk estimation 332 lesions 450
risk factors 31,32,121 localisation of functions 4 4 9 -
secondary prevention 333 450
cardiovascular system (CVSI cerebral tumours 475, 518
in pregnancy 293 cerebrospinal fluid (CSF)
screening, before renal examination 480
transplant 411 oligoclonal bands 454, 480
cardioversion 26, 27 cerebro-tendinous
Carey Coombs murmur 14 xanthomatosis 333
Carneys triad 114 cerebrovasculardisease 471-473
CaroIi's disease 177 cervical venous hum 13
carotico-cavernous fistula 465 CHADS 2 score 27
carotid arterial stenosis 471 Chagas disease 288-289
carotid bodies 530 chance association 129
carpal tunnel syndrome 476, 571 channelopathies, proarrhythmic
case-control studies 132, 135-136, 28- 29
594 charcoal haemoperfusion 69, 71
caspases 371 Charcot-Marie-Tooth disease 188
cast nephropathy 442- 443 Chediak-Higashi syndrome 84, 261
catalases 377 274
cataplexy 522 chemoreceptors 529- 530
cataracts 489, 490-491 chemotherapy
catechoI-O-methyltransferase tCOMT) colorectal cancer 1 6 4
inhibitors 4 5 8 leukaemia 225- 226, 228, 229
categoric variables 594 lungcancer 556
caudal regression 2 9 5 lymphoma 230-231
causation myeloma 232
disease 127, 129-130 polycythaemia 234
reverse 130 chestdrains 564
cavernous sinus syndrome 463, 465 chestpain
cavitation, lung infections 542-543 anginal,indiabetes 123
cavopulmonary correction, toml 23 Canadian cardiovascular
CCR5 inhibitors 208 assessment 32
CD3 255 hypothyroidism 107
CD4 (helper) T cells 255-256, 257 non-anginalcauses 32
cytokine production 2 5 9 chestXray
HIV infection 200, 209, 262, 284 aspergillosis 549
CD8 (cytotoxic) T cells 255, 256, bronchiectasis 546
257 calcification 360
CD95 372 congenital heart disease 20
CDN/\ 360, 386 COPD 538
ceftriaxone 270 diffuselungdisease 559
 Index

extrinsic allergic alveolitis 553 vaccinations 271 citalopram 524

pericardialdisease 44 chronic granulomatous disease 261 clinical trials 593
Pneumocystis pneumonia 201 chronic kidney disease (CKD) clofazimine 287
pulmonaryembolism 4 6 , 3 1 5 402- 415, 4 1 6 clomipramine 524
pulmonaryeosinophilia 562 acute-on-chronic 400 clopidogrel 36, 37, 60
reticular-nodularshadowing 560 anaemia 405- 406 clostridial infections
tuberculosis 544 bone mineral disorder 337, 340, gas gangrene 281
valvularheartdisease 14 406- 403 intravenous drug users 272- 2 73
Cheyne-Stokes respiration 530 causes of progressive 404 Clostridium difficile 162, 278
chickenpox (varicella) 269, 272 classification 403 clozapine 504, 523
chi-squared test 598- 599 cystinosis 320 clubbing 85, S55
Chlamydia infections 199, 4 9 6 drug prescribing 57 cluster headache 474
Chlamydia pneumoniae 275 hyperphosphataemia 345, 406 CNS infections see neurological
Chlamycliapsittaci 275 hypertension 373, 404, 442 infections
Chlamydia trachomatis 497 hypocalcaemia 338, 339, 406 coagulation 2 3 7 - 2 3 8
chlorambucil 229,231 management 404-405 coagulation factors 238
chloramphenicol 56 myeloma 442 changes in pregnancy 294, 311
chlorazepate 525 oxalosis 322 vitamin i<-dependent 240
chlordiazepoxide 525 pathogenesis 404, 405 coagulnpathies 238-241
chloroquine 285,495 radiology 395 hypertensive disorders of
chlorpromazine 63, 66, 67, 504, renovasculardisease 436-437 pregnancy 308
523 sarcoidosis 444 malaria 284
cholangiocarcinoma 173,176- 177 vsacute kidney injury 404 neonatal 306
cholangiopathy, HIV 203 see also end-stage renal disease coal tar 77
cholecystokinin 141,142, 169 chronic lymphocytic leukaemia coal workers pneumoconiosis
cholecystokinin-pancreozymin 143 lCLL] 229 lCWP) 550- 551
cholera 165, 365 chronic myeloid leukaemia coarctation of aorta 21- 22, 442
cholestasis, drug-induced 67, 171 (CML) 228-229, 237, 370 Cockcroft and Gault formula
cholesterol chronic myelomonocytic leukaemia 391- 392
lowering therapy see lipid- LCMML) 236 codeine 158
lowering therapy' chronic obstructive pulmonary disease coeliac disease 154
metabolism 327, 328, 329 (COPDi 45, 537-538 Cogan's sign 479
risks of elevated 327, 329 acute exacerbations 5 3 8 cognitive-behavioural therapy
target levels 60, 333 coal miners 5 5 | (CBT) 508, 509, 526
se e also hypercholesterolaemia investigations 530, 5 3 7 - 5 3 8 cognitiveimpairment 451
cholestyramine see colestyramine treatment 538, 539, 5 4 0 cohort studies 132,134-135, 594
cholinesteraseinhibitors 479 Churg-Strauss syndrome 443, 561, colchicine 64, 226, 323, 414
chondrocalcinosis 588 585 cold agglutinins 232, 255
CHOP regimen 231 Chvosteks sign 3 3 8 cold sores 269
chorea 457, 459 chylomicrons 328, 330 colectomy, prophylactic 192
choroidal tumours 500 cicatricialpemphigoid 82 colestipol 332
Christmas disease 238- 239 ciclosporin 65 colestyramine 158, 175, 332
chromium-labelled EDTA 392 inflammatory bowel disease 161 colon 143
chromosome abnormalities nephrotoxicity 57, 445 colonoscopy 156, 158, 162, 192
182- 184 psoriasis 77 colorectal carcinoma 163- 164
cancer 369, 370 renal transplant recipients 414 hereditary non-polyposis
leukaemia/lymphoma 2 2 6 , 2 2 7 cidofovir 207, 413 (HNPCC] 162,138,191,
chromosomes 181 -1 84 cimetidine 66 192
chronic allograft nephropathy cinacalcet 337, 408 inflammatory bowel disease
( CAN) 412- 413, 415 ciprofloxacin 65, 161, 165, 2 7 0 162
chronic bronchitis 537 cirrhosis 172-173, 3 2 5 common peroneal ne n/ e palsy 476
chronic disease primary biliary 173, 1 7 5 common variable
anaemia of Z14 cisplatin 65, 445 immunodeficiency 261

611
Essential Revision Notes for MRCP
compensation claims, occupational
lungdisease 550
complement 251- 252
activation 251- 252
deficiencies 252-253,261,273,
422
low serum 422
complementary DNA (cDNA) 360,
386
compliance 133
compulsions 509
computed tomography (CT)
angiography (CTA) 396, 437
aortic dissection 49
cardiac 13
chronic pancreatitis 152
liver disease 169
neurological disease 481
pulmonary angiography
(CTPA) 315
pulmonary embolism 46
quantitative (QCT) 341, 342
renal tract 396
sarcoidosis 558
stroke 472
confidenceintervals 596- 597
confounders 1 2 7 , 1 2 8
confounding 128,131,135, 5 9 4
confusional state, acute 515- 516
congenital adrenal hyperplasia
(CAH) 111-112,113, 117
congenital heart disease 19-23, 24
acyanotic 19
cyanotic 20, 24, 235
pregnancy in 2 9 9
congenital malformations
infants of diabetic mothers 295
maternal epilepsy and 306
conjugate eye movements 462
coniugate gaze disorders 462- 465
conjunctiva 485, 456
conjunctivitis 495
chlamydial 496
gonococcal 496
connective tissue disorders 577- 532
kidneyinvolvement 437- 438
markers 577-578
overlap syndromes 582
pulmonaryinvolvement 5 5 9 ,
561
rheumatoid factor 569
skin lesions 82
Conn syndrome 110, 398
612
contact dermatitis 86
continuous ambulatory peritoneal
dialysis (C/~\PD) 408, 4 0 9
continuous positive airways pressure
(CPAP) 540, 565
contraception,dialoetes 298
contrast nephropathy 402
control group 593
conus medullaris compression 471
conversion disorder 510
Coombs' test 219- 220
COPD see chronic obstructive
pulmonary disease
copolymer 1 (glatiramer
acet at e) 454- 455
copper 323, 324
cornea -185
corneal damage 495
coronary angiography It
coronary angioplasty 35, 37
coronary artery bypass grafting
lC"\BC> 9, 37
coronary artery interventional
procedures 37
coronary heart disease see ischaemic
heart disease
coronary stenting 37
cor pulmonale 537
correlation 599- 600
correlation coefficients 599-600
Corrigans pulse 16
Corrigans sign 16
conical blindness 460
corticosteroids(steroids) 57
acute interstitial nephritis 425
antenatal therapy 297
asthma 536
dermatomyositis/
polymyositis 580
eye complications 495
inflammatory bowel disease 161
microangiopathic haemolytic
anaemia 221
multiple sclerosis 454
Pneumocystis pneum onia 202
renal disease 417, 421, 4 3 8
renal transplant recipients
414-415
replacement therapy 104
rheumatoid arthritis 572, 573
sarcoidosis 558
systemic sclerosis 581
tuberculosis 282
r
f
vasculitis 584
weak topical 77 l
corticotrophin-releasing hormone
(CRHft 110,111 6
cortisol 98,109- 110, 111, 113 I
Corynebacterium diphtheriae 274
co-trimoxazole 270
HIV/AIDS 201,202, 207
renal transplant recipients 413
cottonwool spots 489
counselling 526
Cowden disease 84
Coxie/la burnetii 275, 290
coxsackie A16 virus 81
cranial nerve disorders 462-464,
466- 469
craniopharyngiomas 101-102
C-reactive protein (CRP) 222
creatine phosphokinase (CPK) 34,
creatinine. plasma 391
creatinine clearance 391
crescentic nephritis 416, 420, 421
CREST syndrome 577, 581
Creutzfeldt-lakob disease
(CID) 452-453
F
autosomal dominant 377
EEG findings 452, 481
sporadic 377, 378
variant (\/CID) 246, 377, 378,
452
cri-du-chat syndrome 357
Crigler-Najjar syndrome 165
Crohns disease 159-162
cromoglicate, sodium 67
crossing over 182
crossover studies 134, 593
crosssectiona| studies 132,
136- 137, 594
crusts 75
cryoglobulinaemia 420,422
cryoglobulins 2 3 2 , 2 5 4 - 2 5 5
cryptococcal meningitis 205, 207,
276
cryptosporidiosis 2 0 3 , 2 7 8
crystal arthropathies 586- 588
crt/t4-rg 573
C-type natriuretic peptide (CNP) 1
Cushing disease 101,110,115
Cushing syndrome 109-110,111,
518
cu tan eo u s T-cell lymphoma 87
c wave 3
cyanocobalamin see vitamin Bi;
L_
Index

If cyclic/\MP(cAMPl 9 3 - 9 4 , 3 6 4 dehydroepiandrostenedione maturity-onset, uf young

li?
cyclic citrullinated peptide (CCP) lDHEAi 113 ( MOBY) 1 1 9
antibodies 572 deiodinaseenzymes 98- 99 nevv onset, after transplantation
cyclo-oxygenase 260- 261 delayed-type hypersensitivity 258 (NOD/41) 414
cyclophosphamide delirium 515- 516 non-retinal eye disease 489
allopurinol interaction 64 delirium tremens S 19- 520 obesityand 345
glomerulonephritis 4 1 7 , 4 2 1 deltaagent 171 pregnancy and 294-298
haernatological delta waves 26 prevention (type 2) 120
malignancies 229, 232, delusions, schizophrenia 503, S04 risk factors 118- 119
236 dementia 4 5 1 - 4 5 3 , 5 1 6 secondary 117, 120
1
s
cyproheptadine 155 aetiology 516 skin signs 83
cysteamine 3 2 0 AIDS 204 treatment 61, 121- 122
cysticercosis 288 rnulti-infarct 517 type 1 117, 1 1 8 - 1 1 9
cystic fibrosis 5 4 7 - 5 4 9 vs depression 5 0 6 , 5 0 7 rype2 1 1 7 , 1 1 3 - 1 1 9
clinicalteatures 5 4 7 - 5 4 8 DeMusset'ssign I6 diabetic maculopathy 489
genetics 194,547 demyelinating neuropalhies 481 diabetic nephropathy 438-440
treatment 548 denosumab 343 epidemiology 122, 439
cystinosis 319-320 dense deposit disease 420 kidney-pancreas
cystinuria 320 Dentsdisease 339 transplantation 412
cystitis, acute 429 depression 505-507 outcome 440
cytochromeoxidase 323 drug-induced 519 pathogenesis 376
cytogenetics, leukaemia/ elderly 506 pregnancy and 302
lymphoma 226,227 treatment 507, 523- 524, 523 proteinuria 123,394, 439
cytokines 258-260, 374, 386 vs dementia 5 0 6 , 3 0 7 screening and prevention 123,
pro-inflammatory 374-376 dermatitisteczemat 78 439- 440
roleinmyeloma 232 atopic 78 stages 439
therapeutic uses 259- 260 cercarial 2 8 6 diabetic neuropathy 122, 123
cytomegalovirus (CMV) contact 86 diabetic papillopathy 489
infections 269 nailchanges 89 diabetic retinopathy 122, 123,
HIV/AIDS 2 0 5 , 2 0 7 dermatitis herpetiformis 82, 154 488- 489
pregnancy 272 dermatology 75- 89 diabetic rubeosis 83
retinitis 2 0 5 , 2 0 7 dermatomyositis 82, 85, 579-580 dialysis 408- 410
transfusion-transmitted 246, 247 juvenile 579 acute kidney injury 401, 402
transplant recipients 413 dermatophytes 81 long-term complications 410,
cytotoxic drugs 56, 6 5 - 6 6 dermatoses 76- 81 436
cytotoxic T cells see CD8 T cells derrnis 75 se e also haemodialysis; peritoneal
desferrioxamine 70, 216, 325 dialysis
danazol 253 desmopressin (DDAVP") 102, 239 Dianette 79
dapsone 207, 2 8 7 dexamethasone 98 diarrhoea 157- 158
data dexamethasone suppression test 97, antibiotic-related 162, 278
distributions 594- 596 110, 111 bloody 155
types 594- 595 diabetesins1piduS(D|) 102- 103 HIV/AIDS 203
DDAVP 102, 239 cranial (central) 102,103, hyperthyroidism 106
D-dirners 46 397- 395 infectious 165, 203, 277- 278
deafness 468 nephrogenic 95, 102, 393, metabolic acidosis 346
conduction 468 397- 398 diazepam 62, 69, 525
sensorineural 424, 468 diabetes mellitus (DM) 117-123 didanosine 208
deep brain stimulation 458 complications 122-123 diet modification, chronic kidney
deep vein thrombosis (DVTl 46-47, cranial nerve palsies 469 disease 405-406
311 cystic fibrosis 548 DiGeorge syndrome 184, 262, 3 5 7
diagnosis 46, 315 diagnostic criteria 119- 120 digital subtraction angiography
se e also venous thromboembolism gestational 118, 295, 297-298 (DSA) 396
deferasirox 216 hypoglycaemia 123- 124 digoxin 40, 46, 59

613
Essential Revision Notes for MRCP
ECG signs 8, 59
toxicity 2 8 .5 1 5 9
dilated cardiomyopathy (DCM) 41,
43
dimorphic blood picture 214
dipeptidylpeptidase-4 (DPP4)
inhibitors 61,121
diphtheria 274, 469
diploidy 181
diplopia 462, 463
disease-modifying antirheumatic drugs
(DM ARDSl 572- 574
disseminated intravascular
coagulation (D|Cl 220, 240,
310
distributions, statistical data
594-596
dithranol 77
rliuretics
contraindications 57
hypertension 48
mechanisms of action 392, 393
pulmonary hypertension 46
DMSA scans 395
DNA (deoxyribonucleic acid) 138
DNA polymerase 386
domperidone 67, 146, 150
Donahue syndrome 95
dopamine agonists 62, 67, 97, 458
dopamine-blocking drugs 66, 67
Doppler echocardiography 9
Doppler ultrasound 315, 3 9 5
dorsal columns 470
dorsal midbrain syndrome 465
dose-response association 130
double-blind 133, 593
Down syndrome 183- 184,
451- 452
doxorubicin 66
doxycycline 284, 285, 476
Dresslersyndrome 33
driving fitness
coronary heart disease 3 7 - 3 8
epilepsy 456
obstructive sleep apnoea 565
drugisi
overdose 6 9 - 7 1
placental transfer 294
prescribing 5 6 - 5 7
renal elimination 444
thyroid and 108
drug eruptions B6
drug interactions 55- 56
614
drug metabolism 55- 56
genetic polymorphisms 55
liver enzyme induction/
inhibition 56
drug reactio n s , adverse 6 6 - 6 8
eye 495
HIV/'AIDS 203, 207
immunodeficiencies 262
liver 67- 68, 171- 172
lupus 55, 86, 577, 578
mental disorders 519
nephrotoxicity 57, 444- 445
pulmonary fibrosis 560
rheumatoid arthritis 571
skin B6
DRVT (dilute Russell viper venom
time) 243
DTPA SCBDS 395
dua|~energy Xlray absorptiometry
IDEXAJ 341, 342
Dubin-johnson syndrome 168
Duchenne musculardystrophy 478
479
inheritance 187
pathogenesis 379, 384
Ducl<ett-jones criteria, rheumatic
fever 42
Dul<e's staging, colorectal
carcinoma 163
dumping syndrome 151
Duroziezs sign 16
dysentery 165, 277, 285- 286
dyskine-sia,drug-induced 67
dyspepsia 148
dystonia 67, 4 5 7
dystrophia rnyotonica se e myotonic
dystrophy
dystrophin 384, 478
eating disorders 510- 514
Ebola fever 289
Ebsteins anomaly 17
ECG se e electrocardiography
Echinococcus granulosus 175,
278- 279
echocardiography 9 - 1 0
congenital heart disease 20
hypertrophic cardiomyopathy 4 1
M-mode patterns 10, 11
normal pregnancy 293, 2 9 3
transoesophageal (TOE) 10, 27,
49
valvular disease 14, 17
eclampsia 310- 511
ecological studies 132, 1 3 7
ECT see electroconvulsive therapy
eculizumab 221
eczema see dermatitis
Edwards syndrome 184
EEG 481
efalizumab 78
efavirenz 207, 208
effect modifiers 127, 128
eformoterol 536
eicosanoids 260- 261
eighth nerve lesions 468- 469
Eisenmenger syndrome 21, 22
ejection fraction (EF) 38- 39, 50
ejection systolic murmur (ESM) 18,
39, 40
elderly
antipsychorics 63
depression 506
dermatomyositis/
polvmyositis 579
Goodpasture syndrome 421
renal function 391, 403
electrocardiography(ECG) -
common abnormalities
COPD 538
electrical alternans 9, 44
exercise stress testing 12
hypothermia 3 3 0
low voltage 7
normal pregnancy 293, 298
normal values 50
potassium and 9
prolonged monitoring 9
pulmonary embolism 46, 315
electroconvulsive therapy (ECT) 504
506, 507, 525
electroencephalography(EEG) 481
electromechanical dissociation
[El\/1D) 29
electromyographyt'EMG`) 481
electrophysiological
investigations 481
electrophysiologist, indications for
referral 31
elephantiasis 288
ELISA 362-363, 386, 569
emboli
calcified 17
paradoxical 20
systemic 27
embryonic stem cells 379
 Index

emphysema 537, 5 3 8 - 5 3 9 epidemiological study designs expiratory reserve volume tER\/ji 531,
se e also chronic obstructive 131- 138 533
pulmonary disease epidemiology' 127-138 exposure 127
empyema, pleural 543 epidermis 75 extensor plantar response 470-471
encapsulating peritoneal sclerosis epidermolysis bullosa 81 extra-ocular muscles 485
(EPS) 409 epilepsy 455-456, 475 extrinsic allergic alveolitis 552-553
encephalitis 2 7 6 - 2 7 7 , 475 mental problems 518 EYE
endocarditis pregnancy and 306, 456 anatomy 455- 487
infective see infective endocarditis treatment 62- 63, 455- 456 deviation 4 6 3 , 4 6 4
non-infective causes 18 se e also seizures painful red 495
l' endocrine disorders 1 0 0 - 1 2 4
drugs 6 0 - 6 1
episcleritis 570
eplerenone 111
tumours 500
eyedisease 487- 500
investigations 97 Epstein-Barr virus IEBV) 269, 27-1 cystinosis 320
mental disorders 5 1 8 ergometrine 300 diabetic non-retinal 489
endocrine tumours 153 ergotamine 474 drug-induced 495
endocrinology 93- 124 erythema HIV/AIDS 205
endoscopic retrograde necrolytic migratory 35 infectious 496-497
cholangiopancreatography toxic B6 rheumatoidarthritis 570
lERCP) 152,153,169 erythema gyratum repens B5 sarcoidosis 494, 498, 557
endoscopic ultrasonography 152, erythema ichronicumi migrans 290, thyroid 105,465,497
153 475 tropical infections 497
endothelin-1 373- 374 erythema rriultiforme 80, 86 eye movement disorders 462-465
endothelin-receptor blockers 46, erythema nodosum 80, 160, 557, ezetimibe 331,332
374 558
endothelium-derived relaxing factor erythema nodosum Ieprosum Fabry's disease 186- 187, 334
(EDKF) see nitric oxide (ENL) 288 facial nerve palsy 467- 468
end-stage renal disease tESRDfi erythrocyte sedimentation rate factitious disorder 510
402~403 (ESR) 222 factor \/ Leiden 242, 243, 313, 314
diabetic nephropathy 4 3 9 , 440 eiythroderma 77, 85 factor Vlll 238, 2 5 9
hypenension 441 erythromycin 57, 150, 165 factor lX 2 3 8 , 239
pregnancy 301 en/thropoiesis factorial trials 134
see also chronic kidney disease ineffective 217, 325 faecal elastase test 152, 158
enfuvirtideifT-20,1 208 rnegaloblastic 213 faecal occult blood (FOB)
enhancers 367 normoblastic 213 testing 163
enophthalmos 462 erythropoietin 234, 235, 2 4 6 Eal|ot's tetralogy 22- 23
enoxaparin 57 deficiency 405- 406 familial adenomatous polyposis
Entamoeba histolytica 165, 176, eryth ropoietimstimulating agents (polyposis coli) 151,162,192
285- 286 (ESA) 406 familial hypercholesterolaemia
enteral nutrition 1 5 7 Escherichia coli (EH) 329
enteric fever 165, 285 enterotoxigenic 278 familial hypocalciuric hypercalcaemia
enterohepatic circulation 167 verotoxin-producing ( 0157) 22 0, ( FHHI 100, 336
enteropathic arthritis/spondylitis 574 2 77,
/ 440 familial Mediterranean fever 436
enteroscopy 154, 1 5 6 etanercept 78, 573, 574 Fanconi syndrome 320, 397
enzyme-linked immunosorbent ethambutol 282, 495, 544 , 545 Fansidar'* 284
assay (ELISA) 362-363, 386, ethanol, intravenous 71 farmers lung 552
569 ethylene glycol poisoning 71, 446 Fas 372
eosinophilia 223 evidence, integrating 138 fasciculation 477, 478
parasitic infections 289 Ewart's sign 44 fatal familial insomnia 377
pulmonary 561 - 562 excitotoxic cell death, CNS 373 febuxostat 323
vasculitis with 583, 585 exenatide 60, 121 Felty syndrome 571, 577
eosinophilic granuloma 558 exercise stress testing 12 fenofibrate 587
eosinophilicoesophagitis 146 exons 365, 367, 386 ferritin, scrum 218, 325, 406
eosinophils 255 experimental studies 593 fertility problems see subfenility

615
Essential Revision Notes for MRCP
fetal assessment, pre-eclampsia 309
fetal death, in utero 2 9 6
fetal growth restriction (IUGR) 296,
300, 311
fetus
maternal diabetes and 2 9 5 - 2 9 6
maternal epilepsy and 306
thyrotoxicosisrisks 3 0 4 - 3 0 5
FEV, 530, 533
FEV1/FVC ratio 530
fibrates 331, 332
fibrinogen, plasma 294
fibrinolysis, therapeutic 244
see also thrombolysis
fibrinolytic inhibitors 239
fibromuscular dysplasia (FMD) 437
filariasis 288
FISH see fluorescent insitu
hybridisation
fish oils 308, 331, 332, 419
fistulae 161
Sq minus syndrome 236
5 untranslated regions (5 UTR) 367
fixed drug eruptions 86
flecainide 28, 59
Flora Pro-activw 131
flow volume loops 5 3 0 - 5 3 1 , 532
flucytosine 207
fludarabine 229
fludrocortisone 98
fluorescent in situ hybridisation
(FISH) 184, 356-357, 386
5-fluorouracil 164
fluoxetine 524
flurazepam 525
flushing, episodic 114
focal segmental glomerulosclerosis
(F5651 414, 416, 419
folate 144, 213
folic acid supplementation 306, 456
follicle-stimulating hormone
(FSH) 96, 116
follow-up, losses to 133, 1 3 5
fomepizule 71
Fontan operation, classic 23
food poisoning 2 7 7
foot drop 476
F05 369- 370
foscarnet 207
Foster-Kennedy syndrome 493
Fournier's gangrene 281
fourth tfl\/) nerve 462, 485
palsy 463
616
fractures, osteoporotic 341, 342
fragile X syndrome 186, 189
free radicals 3 7 6 - 3 7 7
free-radicalscavengers 377
fresh frozen plasma (FFP) 220, 247,
441
frontal lobe lesions 450
frontotemporaldemenlia 452
functional residual capacity
(FRC) 531, 533
fungal infections
nails 89
skin 81, 206
see also specific infections
fusion protein 370
F\/C 530
gabapentin 62
gadoliniurn (Gd) 395
Gaisb6i;l<'spolycythaemia 234
gaiactorrhoea 97
galibladdercarcinoma 177
gailstones 1 5 1 , 1 5 2 , 1 6 9
y-arninobutyric acid (GABA) 62
gamma glutamyl transferase tgammzi
GT) 168
ganciclovir 207
Gardner syndrome 84
gas gangrene 281
gas transfer, pulmonary 531- 533
gastric carcinoma 130
gastric inhibitory peptide -(CIP) 141
143
gastric loss, hydrogen ions 349
gastric polyps 151
gastric surgery, complications 151
gastrin 141, 143
gastrinomas 115, 149- 150, 153
gastroenteritis 1 6 4 - 1 6 5
gastrointestinal disorders 141-178
Cystic fibrosis 547- 548
drugs 61- 62
HIV/AIDS 202- 204
rheumatoid arthritis 571
gastrointestinal haemorrhage,
upper 148, 172
gastrointestinal stromal tumours
(GIST) 150
gastrointestinal (GI) tract
anatomy and physiology
141 - 1 4 4
infections 164- 166, 2 7 7 - 2 7 9
gastroparesis 150
gastroscopy 156, 158, 174
Gaussian distribution 596
gemfibrozil 3 3 2
gemtuzumab 234
g! l'1!
family 386
structure
365, 367
targeting 386
gene expression
detection lJyrtPCR 361
profiling 358
regulation 365- 368
generalisability 131
generalised anxiety disorder 5 0 8
genetic heterogeneity 187, 188
genetics 181-195
genitalherpes 269
genito-urinary disease 199,496
genome 355
sequence databases 359
genomicimprinting 189-191
genomics 356
genotyping 358
gentamicin 3 7 , 2 7 1
Gerstmann-StraussIer-Scheinker
s\,/ndrome(GSS) 377
Gerstmannsyndrome 4 5 0
gestational diabetes 118, 295,
297- 298
Ghonfocus 543
ghrelin 96
giant-cell ar1eritisiGCAi 444, 487,
493,584
giant\t1s)waves 3
giardiasis 1 6 5 , 2 7 7 - 2 7 8
Gilhertssyndrome 168
Gitelmansyndrome 399
glandularfever 269, 2 7 4 - 2 7 5
Glanzmannsthrombasthenia 379
glatirameracetate 454-455
glaucoma 4 9 5 , 4 9 9
gliomas 475
globe 4 8 5 - 4 8 7
glomerulardiseases 415
inherited conditions with 425
glomerular filtration rate (CFR)
391- 392
g|omerulonephritis[GN) 415-422
acute 400
attenuating progression 415
classification 416
clinical presentation 4 1 5 - 4 1 7
diffuse proliferative 416, 420

drug induced 4 4 5
focal segmental proliferative 416
hypocomplementaemia and 422
idiopathic (primary) 415
membranous 414, 416, 418
mesangiocapillan/(MCGN) 414,
416, 420
mesangioproliferative 376,416,
419-420
post-streptococcal 420
1 pregnancy and 301
rapidly progressive (RPGN)
420- 421
secondary 415
glomerulosclerosis
diabetic 416
focal segmental (FSGS) 414, 416,
419
glucagon 93, 142
glucagon-like peptide-1 (CLP-11 96
glucagon-like peptide-1 (GLF-ll
agonists 121
glucagonoma 153
glucocnrticoids 95
glucocorticoid-suppressible
hyperaldosteronismlCSHi 398
glucose, plasma 119- 120,123, 1 2 4
see also glycaemic control,
diabetic
glucose tolerance test (CTT)
acromegaly 103
diabetes 119- 120, 152, 293
glutamate 373
glutamate receptors 364
glutamic acid 62
glutathione peroxidases 377
gluten-sensitive enteropathy 1 5 4
glycaemic control, diabetic
assessment 122
drugs used 60, 61,121
pregnancy and labour 297
prevention ofcomplications 122,
439-4-'IO
glycated haemoglobin (Hb/\1,
HhA1C1 122,297
glycine receptors 364
glycopeptide antibiotics 271
Glypressin see terlipressin
gnid 56, 445, 571
gonococcalconjunctivitis 496
gonorrhoea 199
Goodpasture syndrome 420- 421
Gorlin syndrome 8 4 , 1 9 2
Index
Gottrons papules B2, 5 7 9 se e also leukaemia; lymphoma
Gottrons sign B2 haematological system, changes in
gout 323, 5 8 6 - 5 8 7 pregnancy 2 9 3 - 2 9 4
drug treatment 6 4 - 6 5 , 587 haematology 2 1 3 - 2 4 7
psoriasis and 76 haematuria 416
renal transplant recipients benign familial (BPH) 424
41 3 - 4 1 4 macroscopic 417, 419
G-protein-coupled receptors microscopic 394, 419, 424
364- 365 haemochromatosis
G-proteins 93- 94, 364, 365, 386 primary (hereditary) 175, 186,
graft rejection 257, 2 5 8 324- 325
graft-versus-host disease secondary liron overload) 216,
tGVl-iD) 236, 237, 246 325
graft-versus-leukaemia ( CVD haemodialysis 408, 410
effect 216, 237 overdose or poisoning 69, 70, 71
Cram staining 267 haemoglobin (Hb)
granulocyte colony stimulating factor concentrations 213, 246, 406
iG-CSF) 217, 236 F (fetal), sickle cell disease
granulocyie macrophage colony 215-216, 385
stimulating factor ( CM- globin chains 216
CSF> 232, 260, 375 glycated (HhA1, HhA1c) 122,
Graves' disease 107, 108 297
eye disease 108, 497 oxygen transport 533
pregnancy and 304 haemoglobin H (HbH] 217
group therapy 526 haemoglobin S (H175) 385
growth disorders 115- 117 haemoglobin S beta thalassaemia trait
growth factor receptors 365 tl-ll:iS Thai) 214
growth factors 386 haemoglobin SCdisease
growth hormone iGHl 97 lHlaSC1 214, 215
adult deficiency 103- 104 haemoglobinuria 219
excess 103 paroxysmal nocturnal
replacement therapy 104 lPNll> 221, 253, 261
growth hormone-releasing hormone haemolysis 219-221, 309
l.GHRH) 103 haemolytic anaemia 219- 221, 244
Guillain-Barrsyndrome(C]BSi 469 congenital 245
477- 478 microangiopathic (MAHA)
gut hormones 143 220- 221
Guthrie test 322 haemolytic uraemic syndrome
gynaecomastia 67, 98, 554 rnosi 220- 221, 247,
440- 441
HAART see highly active antiretroviral haemophilia 2 3 8 - 2 3 9
treatment Haemophilus influenzae
HACEK organisms 279 cystic fibrosis 547
liaem 142,167,323, 3 2 6 increased susceptibility 273, 274
haemangiomas meningitis 2 7 5 - 2 7 6
choroidal 5 0 0 haemopoietic stem cell
hepatic 177 transplantation
retinal 498 see bone marrow transplantation
haematinics, metabolism 144 haemoptysis 554
haematological malignancies aspergillosis 549
225- 237 hronchiectasis 546, 547
imrnunodeficiencies 262 cystic fibrosis 547
splenectomy 2 4 5 lung cancer 554
617
 Essential Revision Notes for MRCP
haemorrhage
cirrhosis 172
variceal 173- 174
haemosidcrin 324- 325
haemosiderosis 325
idiopathic pulmonary 566
hair disorders 87- 89
half and half nails 89
hallucinations,schizophrenia 503,
504
haluperidol 67, 5 0 4 , 5 2 3
Ham acid serum haemolysis test 221
hand
mononeuropathies 476
wasting of small muscles 477
Hand-Schtiller-Christian
disease 558
Hansen's disease (leprosy) 286-288
haploidy 181
haptoglobin 219
Hashimotdsthyroiditis 305
hazard ratio 129
HCC), (bicarbonate) 534
HDL see high-density lipoprotein
headache 473-474
head injury 463
Heat testing, anergy to 5 5 8
heart block
complete 17, 25
post-myocardial infarction
34- 35
see also atrioventricular (AV)
block; bundle branch block
heart disease 13- 43
alcohol and 43
arrhythmias and pacing 2 3 - 3 0
congenital 19-23, 24
ischaemic se e ischaemic heart
disease
other myocardial 35- 43
pregnancy and 298-300
sarcoidosis 558
valvular 13- 18
heart failure see cardiac failure
heartmurmurs 1 3 - 1 4
Austin Flint 1 4 , 1 6
ejection systolic (ESM) 18, 39, 40
normal pregnancy 293
Heart Protection Studyil-lPS) 51, 134
heart sounds 4 - 5
heat shock proteins (HSPS) 3 7 6
heat shock response 376
heavy metal poisoning 446
618
Heberdens nodes 588
Heerfordt-\/\/aldenstriim
syndrome 557
Helicobacter pylori 147, 148-149
HELLP syndrome 241, 309-310
helper 1 cells see CD4 (helper) T cells
Henoch-Schonlein nephritis 419,
443 - 4 4 4
He noc h- Sc hijnle in purpura
(HSP) 561
heparin
membranous
glomerulonephritis 418
myocardial infarction 35, 36
in pregnancy 299, 314
pulmonary embolism 47
see also low-molecular-weight
heparin
hepatic abscesses 176
hepatic adenoma, benign 177
hepatic encephalopathy 172,
174- 175
hepatic fibrosis 376
hepatic necrosis 172
hepatitis
autoimmune 172
drug-induced 67, 171- 172
viral 170-171
hepatitis A 170
hepatitis B 170, 173, 176
polyarteritis nodosa S85
serology 171
transmission 246, 272
vaccination 263
hepatitis C 170-171, 1 7 6
mesangiocapillary
glomerulonephritis 420
transmission 246, 272
hepatitis D 171
hepatitis E 171
hepatitis G 171
hepatobiliary tumours 1 7 6 - 1 7 7
hepatocellularcarcinoma 173,176,
1 77
hepatology 166- 177
hepatorenal syndrome(HRS) 170,
174, 3 73
hereditary motor and sensory
neuropathy 188
hereditary non~polyposis colorectal
cancer (HNPCC) 162, 188,
191, 192
herpes labialis 269
herpes simplex virus (HSV) 146, 269
encephalitis 277, 475
eye disease 496
herpesviruses B1, 2 6 9
herpes zoster (shingles) 85, 269
ophthalmic 4%
heterochromia 462
heteroplasrny 139
heterozygotes 386
hiatus hernia 146- 147
high altitude 534
high-density lipoprotein (HDL) 328,
329
drugs raising 331
factors modifying 330
highly active antiretroviral treatment
(HAARTJ 207-208, 209
hippuran scans 395
hirsutism 87,118,113
histamine 141,155
histiocytosis X 558-559
HIV/AIDS 199-209, 262
atypical mycobacteria 202,
283 -284, 545
classification 201
drug therapies 207- 209
epidemiology 200
gastrointestinal diseases
202- 204
malignant disease 206
neurologicaldisorders 204-205
prognosis 209
respiratory diseases 201 - 202
seroconversion 200-201
skin disease 77, 81, 206-207
transmission 200, 246
tuberculosis 202, 204, 281
vaccination 271
virology 200
HLA antigens 257, 412
disease associations 569, 586
HLA-B27 genotype 494, 574, 576,
589
HMG CoA reductase 329
HMC CoA reductase inhibitors
(statins) 51, 59-60, 331
primary prevention 332
secondary prevention 333
side-effects/interactions 332
Hodgl<in's disease ( HD) 229- 231
Holter monitoring 9
Holt-Oram syndrome 20
homocystine, elevated plasma 321
L
homocystinuria 313, 320- 321
homonymous field defects 459, 460
hookworrns 289
hormonelsi
gut 143
in illness 95
1 mechanismsofaction 93- 95
1
in obesity 9 5 - 9 6
physiology 9 5 - 9 7
in pregnancy 9 6 - 9 7
resistance syndromes 95
suppression and stimulation
tests 97
types 93
see also specific hormones
i
hormone replacement therapy
(HRT) 61, 242
hormone-responsive elements
(HREl 365
Horner syndrome 461- 462
HOT trial 47- 48
housekeeping genes 358, 365, 386
Howel-Evans syndrome 84
Howell-lollybodies 245,246
Hughes syndrome see
antiphospholipid syndrome
human chorionic gonadotrophin
lhCG) 97
Human Genome Project (HCP)
human herpesvirus B (HH\/81 206,
223, 269
Human Metabolome Project 359
human T-lymphotropic virus
(HTLV) 246
humoral immunity dysfunction 262
Huntingt0ns disease 458- 459, 5 1 8
Hutchinson's sign 4 9 6
hybridomas 362, 387
hydatid disease 175, 2 7 8 - 2 7 9
hydralazine 39, 44, 49
hydrocarbons, toxicity 446
hydrocephalus,normal-pressure 453
hydrocortisone 98, 2 7 4
hydrogen breath test 158
hydrogen ions, gastric loss 3 4 9
17-hydroxprogesterone 1 13
hydroxycarbamide 216, 228, 234
hydroxychloroquine 495, 573
11-hydroxylase deficiency 111- 112
21-hydroxylase deficiency 111- 112,
113
hydroxyl radicals 376
l 619
1 1-fi-hydroxysteroid
dehydrogenase 98
deficiency 3 9 8
5-hydroxytryptamine -I5-HTl
agonists 63
hydroxyurea 385
hyperaldosteronism
glucocorticoid-suppressible
(GSH) 3 9 3
primary 110- 111,398,442
secondary 398
hyperbilirubinaemia 166
congenital 1 6 8
hypercalcaemia 3 3 4 , 3 3 5 - 3 3 7
causes 336
familial hypocalciuric
fFHl-li 100,336
hypomagnesaemia 343
Iungcancer 554
MENsyndromes 115
sarcoidosis 336,558
hypercalciuria 100, 339-340
hypercholesterolaemia
farnilia|tFI-it 329-330
polygenic 330
primary 3 2 9 - 3 3 0
secondary 3 3 0
treatment 331- 333
356 hypercortisolism 109- 110
hyperemesis gravidarum 97
hypereosinophilic syndrome
223- 224,562
hyper IgE syndrome 261, 274
hyperkalaemia 9, 112-113, 401
hyperlipidaemia 329- 330
familial polygenic combined 3 3 0
primary mixed (combined) 330
remnant 330
secondary 330
treatment 331- 333
hypermagnesaemia 344
hypernephroma 434
hyperoxaluria, primary 321 - 3 2 2
hyperparathyroidism
bonedisease 337,408
chronic kidney disease 406- 408
primary 335, 337, 407
secondary 337, 407
teniary 3 3 7 , 4 0 7
hyperphosphataemia 345, 406
hyperpigmentation B 5- 86
hypersensitivity 2 5 8
Index
hypersensitivity pneumonitis
352- 553
hypersplenism 241
hypertension 4 7 - 4 9
ambulatory BPmonitoring 13
chronic kidney disease 373, 404,
442
clinical trials 47- 48
hypokalaemia with 398
malignant or accelerated
441- 442, 488
pre-eclamptic 307, 309
in pregnancy 306, 307, 311
pregnancy-induced(PlH) 307
primary lessential) 441
primary hyperaldosteronism 110,
l 11
renal damage 441-442
renal disease and, in
pregnancy 300-303
renovasculardisease 436
rheumatoid arthritis 571
risks 38, 48- 49
secondary 442
systolic 48
treatment guidelines 47, 48
see also antihypertensive drugs
hypertensive disorders ot'
pregnancy 306- 311
see also pre-eclampsia
hypertensive nephrosclerosis 441
hypertensive retinopathy 458
hyperthyroidism
lthyrotoxicosis) 105-107, 108,
109
fetal 305
lungcancer 554
neonatal 305
post-partumthyroiditis 305
pregnancyand 304- 305
psychologicaldisorders 318
hypertrichosis B7, 88, 113
hypenrichosis lanuginosa,
acquired S5
hypenriglyceridaemia 329
polygenic 330
primary 330
secondary 330
treatment 331- 333
hypertrophic cardiomyopathy
(HCM) 39-41,188
echocardiography 10, 11
Essential Revision Notes for /\/IRCP

infants of diabetic mothers 296 pregnancy and 301 congenital 271- 272
hyperuricaemia 323, 586, 587 igo 2 5 4 cytokines 375
hyperventilation 8, 32 igs 254 eye 494, 4 9 6 - 4 9 7
hyperviscosity syndrome, igc 253, 254 gastrointestinal 1 6 4 - 166,
plasma 231- 232 igrvi 253 277- 279
hypoadrenalism 105, 112- 113 ileal loop diversion 349 hyposplenism/splenectomy
hypocalcaemia 334, 337- 339 imatinib 228, 229 245-24s, 273
autosomal dominant imipramine 524 immunodeficiency
hypercalciuric 100, 339 immediate hypersensitivity 2 5 8 disorders 261, 262,
causes 338 immune cells 253-257 2 73 - 2 7 4
chronic kidney disease 338, 339, immune complex-mediated intravenous drug users 272- 273
406 hypersensitivity 258 liver 278- 2 79
infants of diabetic mothers 296 immune thrombocylopenic purpura notifiable 2 7 7
hypochondriacaldisorder 510 (ITP) 241, 247 in pregnancy 271 - 272
hypocomplementaemia, immunisation 2 6 2 - 2 6 3 , 2 7 1 reactive arthritis 576-577
glomerulonephritls and 422 immunodeficiency 261-262, renal transplant recipients 413
hypogammaglobulinaemia 261 2 73 - 2 74 respiratory tract 274-275,
hypoglycaemia 123-124,151 immunoglobulins 253-255 540- 549
malaria 284 deficiencies 261, 262 rheumatoid arthritis 571
neonatal 296 intravenous 241, 455 soft tissue 272, 281
hypogrinadism, idiopathic passive immunisation 263, 271 systemic 2 73- 2 74
hypogonadotrophic 117 see also specific classes transfusion-transmitted 246-247
hypokalaemia 9, 110, 398-399 immunoglobulin superfamily 378 treatment and prevention
hypomagnesaemia 296, 343 immunology' 251 - 2 6 ] 269-2 71
hypomania 505 in-imunosuppressants tropical 284- 289
hyponatraemia 104- 105 aplastic anaemia 217 urinary tract 429- 430
hypoparathyroiclism 338, 339 dermatomyositis/ see also specific infections
hypophosphataemia 344 polymyositis 580 infectious mononucleosis (glandular
hypopigmentation 85 inflammatory bowel disease 161 fever) 269, 274- 275
hypopituitarism 103- 104 lupus nephritis 4 3 8 infective endocarditis 18-19,
hyposplenism 245-246,273 myasthenia gravis 479 279- 230
hypothermia 350-351 in pregnancy 301 antibiotic prophylaxis 19, 280,
hypothyroidism 104, 105-107, 109 renal transplant recipients 413, 300
autoimmunity and 108 414- 415 culture-negative 280
drug-induced 67 vasculitis 584 intravenous drug users 272
posbpartumthyroiditis 305 impairedfastinggluc0se(|FG) 120 inferior vena cava filters 47
in pregnancy 3 0 5 impaired glucose tolerance inflammation
psychological disorders 518 (ICT) 120 measurement of 221 -222
transient neonatal 304, 305 in pregnancy 295, 297-298 molecular mediators 374-377
hypovolaemia 99, 104, 105, 303 implantable cardioverter defibrillators tissue damage 373
hypoxaemla 533, 5 3 9 , 541 (ICD) 23, 30, 31, 38, 40, 51 inflammatory bowel disease
hypoxanthine guanine phosphoribosyl implantable loop recorders 9 159- 162
transferase (HGPRT) imprinting, genomic 189- 191 infliximab 73, 161, 573, 574
deficiency' 322, 323 incidence proportion 128 influenza vaccine 263
hypoxic vasoconstriction 529, 534 incidence rate 127 inheritance
hypoxic ventilatory drive 530 incidence rate ratio 128 maternal 189, 382
incontinentia pigmenti 1 8 7 Mendelian 184- 187
iclithyosis incretln effect 96 inositol 1,4,5-trisphosphate (lPq) 94
acquired B5 indinavir 207, 208 insomnia 522
X-linked 3 5 7 indometacin 21, 56 inspiratory capacity 533
ig/\ 252 infections/infectious diseases insulin 142
deficiency 261 267- 290 receptor-mediated signalling 364
IgA nephropathy 414, 416, 419- 420 CNS see neurological infections therapy 121, 297

620
 Index

insulin analogues 122 intravenous urography (IVU) 395 I<aposis sarcoma-associated virus see
insuliwhypoglycaemia stress test 97, lntr0i1 365, 367, 3 8 7 human herpesvirus 8
103, 104 inulin clearance 392 Kartagencr syndrome 546
insulin-like growth factor-1 iodides 56 Katayama fever 286
(ICF-1) 97 iodine 107 Kawasaki disease 271, 444,
insulinomas 115, 124, 153 ion channels, ligand-gated 364 585- 586
insulin resistance 120 irinotecan 164 Kayser-Fleisclterrings 324
in pregnancy 96, 295 iron 217- 219, 323 Kearns-Sayre syndrome 490
integraseinhibitors 208 assessment ofslatus 217-213 Kelley-Seegmiller syndrome 323
integrins 378- 379 demand in pr egnancy' 293- 294 I<endallstest 600
intention-to-treat analysis 133- 134 membolism 144, 217, 2 1 8 keratitis
intercellular adhesion molecule-1 overload, secondary 216, 3 2 5 epithelial 496
(ICAM-1) 379 poisoning 70 interstitial 496
interferon 108,171, 228, 231 side-effects 108 keratoacanthoma 87
interferona 259 trial oforal 218 keratoconus 499
interferon-[3 (IFN-B) 260, 454-455 iron-deficiency anaemia 214, 217 keratomalacia 347
interferon-y 260 irritable bowel syndrome (IBS) 164 kidney
interferon-7 tests, tuberculosis ischaemia-reperfusion injury 377 pelvic, pregnancy and 302
281 -252, 545 ischaemic cardiomyopathy 31 physiology 391-393
interleukin 1 (IL-1] 374-375 ischaemic bean disease 31-38, 123 scarring 428
blockers 573 clinical trials 51 solitary, pregnancy and 302
interleukin 16-converting enzyme hyperlipidaemias 329-330 Klinefelter syndrome 116,117,183
(ICE) 371, 372, 375 risk factors 31, 32 knee jerks, absent 470-471
interleukin 2 (IL-2) 77, 208, 260 see also angina; myocardial Kobnerphenomenon 76,77
interleukin 5 (IL-5) 223 infarction koilonychia 89
interleukin 6 (IL-6) 42, 222, 232 islets of Langerhans 142 Korsakoff syndrome 474, 521
intermediate factors (variables) 127, isoform 387 kuru 378
128 isoniazid 281, 282, 544 Kussmaul'ssign 3
international normalised ratio adverse effects 55, 348, 545 Kveim-Siltzbachtest 558
(INR) 47, 69, 242 prophylaxis 545 kwashiorkor 346
internuclear ophthalmoplegia isoprenaline 34
464-465 isotope renography 395 labetalol 3 0 9
intersex 117,192-193 isotretinoin 79 labour management
interstitial lung disease 559- 560 itraconazole 549 cardiac disease 300
interstitial nephritis 400, 425- 426 ivabradine 60 diabetes 297
acute (AIN) 4 2 5 - 4 2 6 labyrinthine disorders 469
chronic tubulointerstitial jaundice 166- 169,172 lactase deficiency 158
(TIN) 426 haemolysis 2 1 9 Iacmte dehydrogenase (LDH) 34,
intracerebral haemorrhage 471 malaria 284 230, 309
intracranialcalcification 481 neonatal 296 lacunar stroke 471
intracranial hypertension, benign IC virus 41 3 Lady Windermere syndrome 283
(Bll-l) 474 iervell-LangeNie|sen syndrome 29 Lambert-Eaton myasthenic syndrome
intracranial pressure, raised 493 lob syndrome 261, 274 (LEMS) 480, 481, 554
intrapartum management see labour jugular venous pulse (IVP) 3, 43, 44 Iamivudine 208
management lun 3 6 9 - 3 7 0 lamotrigine 62, 505
intrauterine contraceptive device juvenile idiopathic arthritis (]IA) 494, Lancefield groups, [3-haemolytic
(IUCD) 298 589 streptococci 268
intrauterine growth retardation juvenile nephronophthisis-medullary language function 450
LIUGR) 296, 300, 311 cystic disease complex 423 large bowel 143
intravenous drug users, disorders 159- 164
infections 272- 273 Kallman syndrome 116- 117, 357 infections 277- 278
intravenousimmunoglobulin 241, l<aposi's sarcoma 202, 203, 206, 269 Laron dwarfism 95
455

621
Essential Revision /\/otes for /\/IRCP

Lassa fever 289 chronic myelomonocytic Wilson's disease 1 7 5 , 324

lateral geniculate nucleus 459, lCMML) 236 liver enzymes
460 FAB classification of acute
changes in pregnancy 294
lateral medullary syndrome 469 227- 228 induction 56
Laurence-Moon-Biedl leukaemic blast cells 225 inhibition 56
syndrome 490 Ieukotriene antagonists 66, 261, 536 liver failure
lazy leucncyte syndrome 261 leukotrienes 261 drug prescribing 57
LDL see low-density lipoprotein levodopa (L-dopa> 62, 457, 458 fulminant 170,173
lead 446 Libman-Sacks endocarditis 18, liver function tests 168- 169
Leber's hereditary optic 578- 579 liver transplantation 173, 257
neuropathy 189 lice 81 hyperlipidaemias 330
lecithin cholesterol acyltransferase lichenplanus 8 0 , 8 9 l i y ert u m o u rs 177
(LC/\Tl329 Liddlesynclrome 399 metabolic disorders 322, 324,
deficiency 333 lidocaine 2 8 , 6 8 325
leflunomide 571, 573 Li-Fraumenisyndrome 370- 371 primary biliary cirrhosis 175
left axis deviation 7 ligand-gated ion channels 364 liver tumours 67-68,176-177
left bundle branch block (LBBB) 8 light-chain icastl nephropathy Loffler syndrome 562
Legionella pneumophila 442- 443 Lofgren syndrome 558
pneumonia 275, 541- 542 likelihood ratios 602-603 long QT syndrome 6, 28, 29, 188
lenalidomide 232 lipid-loweringtherapy 59- 60, long-term oxygen therapy
lens 485-487 331-333 (LTOTl 539
abnormalities 490- 491 clinicaltrials 36,51 loop cliuretics 57, 392, 393
dislocation 491 lipid metabolism 327-329 heart failure 39, 40
lenticonus 424 disorders 3 2 7 , 3 2 9 - 3 3 3 loop of Henle 392,393
lentigo maligna melanoma 87 rare inborn errors 333- 334 Ioperarnide 158, 164
leprechaunism 95 lipidperoxidalion 377 lorazepam 525
leprosy 286- 258 lipoprotein (al 329 Lorenzo's oil 334
leptin 96 lipoprotein lipase 328- 329 losartan 587
leptospirosis 279 deficiency' 330 low-density lipoprotein (LDL) 328,
Lesch-Nyhan syndrome 322, 323 lipoproteins 327-329 329
Letterer-Siwe disease 558 5-lipoxygenase 2 6 0 lowering apheresis 329-330
leucocyte adhesion deficiency liquoriceexcess 3 9 8 loweringdrugs 331
(LAD) 261, 274, 379 Listeria monocytogenes 2 7 6 targetlevels 6 0 , 3 3 3
leucocytes lithium 63- 64 low-density lipoprotein (LDL)
disorders 2 2 2 - 2 2 5 bipolardisorder 303 receptor 329
urine 394 depression 507 low-molecular-weight heparin
leucocytosis 222-224, 294 prescribing cautions 56, 57 (LMVVH)244
leucoerythroblastic change 224 renalaction 6 3 - 6 4 , 3 9 3 in pregnancy303, 312-313, 314
leukaemia 225- 226 thyroid effects 1 0 8 Lown-Ganong-Levine syndrome 7
acute 225-226 toxic effects 64, 68, 445 Lucentis 490
acute lymphoblastic (ALL) liver 142 lung
225-226, 237 acute fatty, of pregnancy 310 abscess 543
acute myeloid (AML) 221, biopsy 169, 172, 325 529
anatomy
225- 226, 227,236, 237 infections 278- 279 compliance 529
acute myelomonocytic 224, 227 parasitic infections 175- 176 gastransfer 5 3 1 - 5 3 3
acute prornyelocytic (AML liverdisease 1 6 6 - 1 7 7 perfusion 529
M3l 227- 223 anaemia 213 lungcancer 553- 556
chromosome abnormalities 226, chronic 174,175 asbestos-related 550
22 7 drug-induced 67- 68, 171- 172 clinicalfeatures 554
chronic 225 drugprescribing 57 diagnosis 555
chronic lymphocytic (CLL) 229 ironoverload 325 paraneoplastic syndromes
chronic myeloid (CML) pre-eclampsia 309 554- 555
228-229, 237, 370 sarcoiclosis 557 treatment 555- 556

622

lung disease
asbestosrelated 549- 550, 556
cystic fibrosis 547
granulomatous and diffuse
parenchymal 557- 560
interstitial 5 5 9 - 5 6 0
obstructive 530
occupational 5 4 9 - 5 5 3
rare causes 566
restrictive 530
see also respiratory disease
lung function tests 530- 531, 533,
534
lung infections 540- 549
cavitation 542- 543
cystic fibrosis 547
see also pneumonia
lungtransplantation 548, 559
lungtumours 553-557
lung volumes 531, 533
lupus, drug-induced 55, 86, 577,
578
lupus anticoagulant 243, 303, 578
lupus erythematosus B2
discoid 82
systemic se e systemic lupus
erythematosus
lupus nephritis 420, 438, 578
luteinising hormone (LH) 9 6 , 1 1 6
Lutembacher syndrome 20
Lyme disease 290, 4 7 5 - 4 7 6
lymphaclenopathy
bilateral hilar (BHL) 557, 558
sarcoidosis 557
lymphangioleiomyomatosis,
pulmonary 566
lymphocyte function-associated
molecule-1 (LFA-11 379
lymphocytes 2 5 5 - 2 5 7
lymphocytosis 223, 229
lymphogranuloma venereum
lLGVl 199
lymphoma 225, 2 2 9 - 2 3 1
chromosome abnormalities 226,
227
HIV/NDS 2 0 3 , 2 0 6 , 2 0 9
Hodgkins disease 229- 231
non-H0dgkin's(NHL) 231,413
psoriasisand 76
renal transplant recipients 4 1 3
smallbowel 154
lymphoproliferative disorders 244,
245
Index
lyonisation 181, 384 Marfan syndrome 195, 321
mast cells 255
Mal3`1'hera se e rituximab mastectomy, prophylactic 192
l\/1cCune-Albright syndrome 94, maternal inheritance 189, 382
116,365 maternal medicine 293- 315
macrocytic anaemia 213-214 maternal mortality, causes 307- 308,
macrolide antibiotics 270 309- 310, 31 1
maculardegeneration 489- 490 maturity-onset diabetes of young
macularsparing 460 IQMODY) 1 19
macules 75 mean 595
madcowdisease 246 measurement error 129, 135
MAG; scans 395 me c onium ileus equivalent 5 4 7 - 548
magnesium median 595
disorders 343- 344 median nerve 476
primary renal wasting 343 mediastinal tumours 556-557
therapy 28, 36 mediastinitis 32
magnesium sulphate, eclampsia 31 1 medullary cystic disease, autosomal
magnetic resonance angiography dominant 423
(MRA) 395,437 medullary sponge kidney (MSK) 423
magnetic resonance medullary thyroid cancer
cholangiopancrealography (MTC) 107, 115
KMRCP) 152,169 meflnquine 285
magnetic resonance imaging (MRIi meiosis 181-182
cardiac 13 ot-melanocyte-stimulating hormone
neurologicaldisease 481 (ot-MSH) 96
renaltract 396 melanoma
major histocompatibility complex choroidal 500
(MHC) 257 malignant 87
malalosorption |5 8 -1 5 9 , | 6 5 MELAS syndrome 119, 189
cysticfibrosis 547 melphalan 232
post-infective 278 membrane attack complex
psoriasisand 76 (MAC) 251, 252
malaria 273,284-285 Mendelian inheritance 154- 187
algid 284 Mntriers disease 150
benign 285 meningitis 2 7 5 - 2 7 6
cerebral 284 HIV/AIDS 204, 205
falciparum 284- 235 susceptible individuals 273
prophylaxis 2 8 5 meningococcaldisease 275-276
Malarone 285 Menke's disease 459
malignant disease see cancer menorrhagia,hypothyroidism 106
malnutrition mental disorders see psychiatric
chronic kidney disease 409 disorders
protein-energy 345- 346 s-mephenytoin 55
maltworkerslung 552 mercury 446
mania 505 MERRF 189
mannose-binding lectin (MBL) 251, mesalazine 6 1 , 1 5 9 - 1 6 1
273 mesenteric angiography 156
Mantouxtesting 545 mesothelioma 550, 556
maranticendocarditis 18 meta-analysis 137- 138
marasmus 346 metabolic acidosis 346-349, 350,
Marburgfever 289 396
Marchiafava-Bignami disease 520 metabolic alkalosis 346, 349-350,
lv\arcusGunnpupil 461 396
623
Essential Revision Notes for MRCP
metabolic diseases 3 1 9 - 3 5 1
metalaolicsyndrome 76
metaholome 359
metabolomics 359- 360
metals and metalloproteins, disorders
Of 323- 327
metastases
choroidal 500
kidneys 435
liver 1 7 6
metformin 113,120,121
methicillin-resistant Staphylococcus
aureus(MRSA`) 267
methotrexate
adverseeffects 66
ankylosingspondylitis 576
inflammatory bowel disease 161
multiplesclerosis 455
psoriasis 77
rheumatoid arthritis 572-573
methyldopa 49, 309
methylprednisolone 229, 414, 454
methysergide 155
metoclopramide 67, 146, 150
metronidazole 79,161,162,165
metyrapone 111
microalbuminuria 394,439- 440
microangiopathic haemolytic anaemia
(MAH/\) 220- 221
microarray analysis 5 5 8
microcyticanaemia 214
microdeletion syndromes 184, 357
microscopic polyangiitis (or
polyarteritis) 443, 561, 585
migraine 6 3 , 4 7 3 - 4 7 4
milk-alkali syndrome 3 4 9 - 3 5 0
Miller-Diel<er syndrome 357
Miller-Fisher syndrome 469, 478
mineralocorticoid deficiency 397
mineralocorticoidreceptors 98
mineralocorticoids 98
minimal-change disease 416,
417- 418
miosis 461, 462
mirtazapine 524
miscarriage
indiabetes 295
recurrent 303,312
mitochondrial disorders 189,
382- 383
mitosis 181
mitral balloon valvuloplasty 15
mitral regurgitation (MR) 1 5 - 1 6
624
mitral stenosis 5, 10,11, 1 4 - 1 5 murmurs, cardiac see heart murmurs
mitral valve prolapse 8, 10, 11, muscarinic acetylcholine
15- 16, 32 receptors 364
mixed connective tissue disease 437, muscle disorders 478- 479
582 muscular dystrophy 478, 479
moclobemide 524 mushroom workers lung 552
mode 595 mutations
molecular chaperones 376 cancer generation 368- 369
molecular diagnostics 355- 363 detection 358, 3 6 0
moleculargenetics 138 dynamic 381
molecular medicine 355- 387 in frame 384
molecularprofile 358 gain of function 382
monoa mine oxidase B IMAO-B) out of frame 384
inhibitors 458 myasthenia,druginduced 68
monoamine oxidase inhibitors myasthenia gravis 479- 480
(M/\OlS) 524 diagnosis 479, 431
monoclonal antibodies mental illness 518
clinical applications 233, 234, molecular basis 383-384
362 myctc-myc) 369-370
production 361-362 mycobacterial infections 281-284
monoclonal gammopathy of atypicaliopportunistic) 202,
undetermined significance 283-284, 545
IMGUSP 233, 435, 443 skin 81
rnonocytosis 224, 236 Mycobacterium a v i u m complex
mononeuropathies 476 (MAO 202, 283- 284
montelukast 66, 261 Mycobacterium leprae 286- 287
mood disorders 504- 507 Mycobacterium tuberculosis
morphoea 82 281 - 2 8 2
mosaicism 183 see also tuberculosis
motilin 143 mycophenolate mofetil (MMF)
motor neurone disease 377, 470, lupus nephritis 438
518 in pregnancy 301
motor neuropathies 477 renal transplant recipients 413,
mouth disorders see oral disorders -'ll-1
mouth ulcers 1 4 5 Mycoplasma pneumoniae
movementdisorders 456- 458 pneumonia 275, 541
MRFIT study 47 mycosis fungoides 87
Muir-Torre syndrome 192 mydriasis 462
Miillerian ducts 192,193 myelodysplasias imyelodysplastic
Mlillerian inhibiting factor -IMIF) 192 syndromes) 213, 227,
MLiller's sign 16 235- 236
multi-infarct dementia 517 myeloma 213, 231-233
multi-organ failure (MOP) 401 amyloidosis 435
multiple endocrine neoplasia renal involvement 442-443
(MEN) 114- 115 myeloperoxidase (MPO)
iype i 101, 114, 115 antibodies 583, 584
type 2A 114- 115 deficiency 261
type 2B 84, 115 myeloproliferative disorders 214,
multiple sclerosis (MS) 453-455 223, 244, 245
mental problems 5 1 8 myocardial infarction (Ml) 32- 38
optic neuritis 453, 491 cholesterol level and risk 327
multiple system atrophies 4 5 8 complications 3 3 - 3 4
Munchausen syndrome 510 diagnosis 6, 33, 34

fitness to drive 3 7 - 3 8
heart block and pacing 34- 35
interventional procedures 37
medical therapy 35, 36, 51
non-ST-segment elevation
(NSTEMD 33, 35
postcrior 35
rehabilitation 37
ST-segment elevation tSTEMli 33,
35
myocardial ischaemia 8
myocardial perfusion imaging
(MPI) 10- 1 1
myocarditis 42, 280
myoclonus 456
myoglobin 34
myopathies 478-479
myotonia 479
myotonic dystrophy ldystrophia
myotonica) 479
genetics 189, 382
ophthalmic features 498
myotonic syndromes 481
my><omas, cardiac 42
N-acetyl cysteine 402
nail disorders B9
derrnatomyositis 82
HIV/AIDS 207
psoriasis 76, B9
nail-patella syndrome 89
narcolepsy 522
nateglinide 55, 61
natriuretic peptides 100
natural killer cells 2 5 7
Necatoramericanus 289
necrolytlc migratory en'/thema 85
necrosis 371
necrotisingfasciitis 281
negative predictive value 602
neglect, visuospatial 450
Neisseria meningitidis 273,
275- 276
Nelson syndrome 101,110
neomycin 331, 332
neonates
cystic fibrosis screening 548
infants ofdiabetic mothers 296
infants of epileptic mothers 306
ophthalmia neonatorum 199, 496
thyrotoxicosis risks 304- 305
neovascularisation, intraocular 487,
489
nephrectomy
pregnancy after 302
recipient, before renal
transplant 412
nephritic syndrome 416
nephroblastoma 434
nephrocalcinosis 396, 432
nephrogenic systemic librosis
(NSF) 395
nephrolithiasis seerenal calculi
nephrology 391 - 4 4 6
nephron 392
nephronophthisis.juvenile 423
nephrotic syndrome 416, 417
nephrotoric drugs 37, 444- 445
nerve conduction tests 481
neurocysticercosis 288
neurofibrillary tangles 381, 451
neurofihromatosis t1\F) 84, 114, 194,
495
neurologicaldisorders 449-481
drugs 62-63
HIV/AIDS 204-205
investigations 480-481
mentaldisorders 518
neurological infections 275- 277,
475- 476
l-ll\//AIDS 2 0 4 - 2 0 5
neuromuscular junction
disorders 4 7 9 - 4 8 0
neuro-ophthalmology 459- 466
neuropathicbladder 433
neuropeptideY(NPY) 96
neuroradiology 481
neurosarcoidosis 3 3 6 , 5 5 8
neurosyphilis 199,205,518
neutropenia 224- 225
neutrophilia 223
neutrophils 255
disorders 261
nevirapine 207, 208
new onset diabetes after
transplantation (NODAT) 414
New York Heart Association INYHA)
classification of heart
failure 39
Nezelofsyndrome 262
niacin see nicotinic acid
nicorandil 60
nicotinamide
phosphorihosyltransferase
(NAMPT) 96
Index
nicotinic acetylcholine
receptors 364, 383
nicotinic acid (niacin)
deficiency' 155, 348
therapy' 331, 332
nifedipine 297, 309
night blindness 490
nimodipine 473
nitrates '16, 39, 373
nitrazepam 525
nitric 0XiCl! 1NO) 46, 372- 373
inhaled 566
nitric oxide synthase (NOS) 372, 373
nodules 75
non-goriococcal uretl-iretis
(NGUJ 199
non-Hoclgkins lymphoma
(NHL1 231, 413
non-invasive positive-pressure
ventilation (NIPPVJ 540
non-nucleoside reverse transcriptase
inhibitors (NNRTIJ 208
non-parametric tests 598-599
non-steroidal anti-inflammatory drugs
(NSA|DSl 260- 261
adverse effects 66, 437, 444
gout 323, 587
liver impairment and 57
non-thyroidal illness 109
Noonan syndrome 116, 185, 188
normal distribution 596
normal-pressure hydrocephalus 453
NSAIDs see non-steroidal
anti-inflammatory drugs
nuchal translucency lNTl
screening 297
nuclearantigens,extractable 577
nuclearcardiology 10- 11
nuclear hormone receptors 365, 366
nucleoside/nucleotide reverse
transcriptase inhibitors
lr\`RTll 2 0 8
null hypotheses 597, 598
numeric data 594- 595
nutrition 156- 159
nutritional assessment 156- 157
nutritional disorders 345- 346, 492
nutritional support 157, 161
nystagmus 464, 465-466
obesity 345
endocrine causes 110
hormone changes 95- 96
625
Essential Revision Notes for MRCP
psoriasis risk 76
ob gene 96
observationalstudies 5 9 4
obsessive compulsive disorder
508- 509
obstructive nephropathy,
chronic 432- 433
obstructive sleep apnoea/hypnoea
syndrome (OSAHS) 564- 565
occipital lesions 450, 460
Occupational lung disease 549- 553
compensationclaims 550
ochronosis 319
octreotide 103,155,158
ocular non-nephropathii:
cystinosis 320
oculartumours 500
oculomotordisorders 462-465
oculomotor nerve see third itll) nerve
oculomotor palsies 462, 463-464
odds, posterior 603
odds ratio 129
oeclema
liver disease 172
periorbital 107, 108
oesophagealcarcinoma 147
oesophageal ya r i c e s 173- 174
oesophagitis 145- 146
oesophagus 141
Barretls 146- 147
disorders 1 4 5 - 1 4 7 , 203
oestrogens 56
adverse effects 6 7 - 6 8
thyroid effects 108
olanzapine 63, 504, 505, 523
nligoclonal bands, CSF 454, 480
oligomenorrhoea 113
oligonucleotides 387
oliguria 399
olivopontocerebellar atrophy 458
olsalazinc 61,159- 161
omalizumab 66, 536
omega-3 fatty acids 308, 419
onchocerclasis 497
oncogenes 369-370, 387
oncogenic osteomalacia 340- 341
owtreatmentanalyses 134
onycholysis 89
oophorectomy, prophylactic 192
ophthalmia neonatorum 199, 496
ophthalmic disease se e eye disease
ophthalmology 4 8 5 - 5 0 0
ophthalmoplegia
626
bilateral 462 PABA ip-aminobenzoic acid)
internuclear 4 6 4 - 4 6 5 testing 152
optic atrophy 492 pacing 25, 29- 30
optic nerve disease 459, 460. hean failure 30, 3 1 , 4 0
491- 493 myocardial infarction 34- 35
optic nerve head swelling 493 permanent 29, 30, 38
optic nerve sheath fenestration 474 temporary 29, 30
optic neuritis 453, 491, 492 Pagets disease 341
optic neuropathy, anterior Pancoast syndrome 555
ischaemic 493 pancreas 142
optic pathway disorders 4 5 9 - 4 6 0 disorders 1 5 1 - 1 5 3
oral contraceptive pill 46 pancreas transplantation 412
diabetes 2 9 8 pancreatic carcinoma 153
failure 56 pancreatic enzyme supplements,
liyer tur nour s and 176, 177 cystic fibrosis 548
thrombosisand 242 pancreatic polypeptide 142, 143
oraldisorders 145 pancreatitis
l'llV/AIDS 203 acute 6 8 , 1 5 1 - 1 5 2
whitelesions BO chronic 152
oral rehydration therapy tORT) 164 HIV/AIDS 203
orbit 485 pancreolauryltesting 132
orbitalapexclisease 463 panic disorder 508
organic psychiatry 515-519 papillitis 491, 493
organicsolvents 440 papilloedema 474, 493
orlistat 61,121 papules 75
ornithine transcarbamylase paracentesis, abdominal 170
deficiency 186 paracetamol overdose 69, 172,
orthologues 355 l 74
orthophosphates 3 4 0 paracrine (action) 372, 387
osteitis fibrosa cystica 403 paragangliomas 114
osteoarthritis 585 familial 114,190,191
osteomalacia 340-341, 407, 408 parametric tests 598- 599
osteomyelitis 273 paraneoplastic disorders
osteoporosis 341- 343, 413 Lambert-Eaton syndrome 48 0,
cysticfibrosis 5 4 8 554
renal bonedisease 408 lung cancer 554- 555
osteosclerosis 408 mental disorders 518
Othellosyndromc 520 oncogenic osteomalacia
outcome 127- 128 340- 341
ovarian cancer, hereditary 188, 192 skin 84- 85
overlap syndromes 582 paraquat 446
oxaliplatin 164 parasitic infections
oxalosis 321- 322 eosinophilia 223, 289
oxazepam 525 liver 175- 176
oxygen saturation 50 pulmonary eosinophilia 562
oxygen therapy, long-term skin 81
(LTOT) 539 space-occupying brain
oxygentranspon 533-534 lesions 277
oxyhaemoglobin dissociation tropical 284- 256, 288- 289
curve 533 parathyroid adenomas/
oxyntomodulin 96 hyperplasia 337
parathyroid carcinoma 337
p53 3 7 0 - 3 7 1 , 372 parathyroid hormone (PTH)
 Index
,
it
calcium homeostasis 100, pre-eclampsia 307-308
t
1 haemolytic uraernic
1 334- 335, 336 periorbttal oedema 107, 108 syndrome 441
serum 339 peripheral nerve lesions 476- 478, LDL-lowering 329- 330
parathyroid hormone (PTH) 1-34, 481 microangiopathic haemolytic
recombinant human 338 peritoneal dialysis ( PD) 408, 409 anaemia 220
parathyroid hormone-related protein peritonitis, bacterial 409 renaldisease 421,438
(PTH-rP) 335 periventricular nodular plasma hyperviscosity
paratyphoid 165, 285 hererotopia 187 syndrome 231- 232
parenteral nutrition 157 pernicious anaemia 1 4 4 , 348 plasmaviscosity 222
parietal lobe lesions 450, 459 petroleum-based hydrocarbons 446 plasma volume, changes in
Parinaud syndrome 465 Peutz-leghers syndrome 84, 151, pregnancy 293,294
parkinsonism 4 5 7 - 4 5 8 |62 platelet counts 240, 294, 308
l Parkinsons disease 62, 457-458, pH, arterial blood S34 platelettransfusions 247
l 518 phacomatoses, ocular features 498 plethysmography 315
1, Parkinsons plus syndromes 458 phaeochrornncytomas 48, 114, 1 15 pleural effusion 562- 563
paroxetine 524 51B pleural plaques/thickening,
paroxysmal nocturnal pharmacogenomics 358 asbestos-related 550
haemoglobinuria(PNl-1) 221, pharmacokinetics, in pregnancy pneumococcal [Streptococcus
253, 261 294 pneumoniae) infections
parvovirus B19 81, 215, 272, 273 pharrnacology,clinical 55-68 increased susceptibility 273-274
Patau syndrome 154 phenelzine 524 meningitis 275-276

i
patent ductus arteriosus (PDA) 21, phenoxyhenzamine 155 p n eu m o n ia 541
24 phenyIl<etonuria1Pl<U) 319. 322 pneumococcal vaccination 245, 263
patentforamenovale 20 phenytoin 57, 68, 69 pneumoconiosis, coal
pcoz 530,534 Philadelphia chromosome 226, 227, workers 550- 551
peak expiratory flow rate (PEFR) 530, 228, 3 70 Pneumocystis carinii pneum onia

1
531, 535 phobic disorders 5 0 8 l'PCPi 201- 202,207, 413
Pearson's correlation coefficient 598, phosphate pneumonia 540- 543
599 disorders 344- 345 acuteeosinophilic 562
pegvisomont 103 renal reabsorption 392 aspiration 542
pellagra 1 5 5 , 3 4 8 serum levels 339, 344 atypical 275,541
pempnigus 81 wasting 344 causes 541- 542
penetrance, reduced 184, 191 see also hyperphosphataemia community-acquired 540- 541
penicillamine phosphate binders 408 CURB-65 criteria 541
1 adverse effects 64, 68, 445, 571 phospholipase C tPLC) 94 interstitial 559
il metabolic disorders 320, 324 photoreceptor dystrophies 490 nosocomial (hospital-
i systemic sclerosis 581 photosensitivity,drug-induced 68, acquired) 542
penicillins 57, 270 86 susceptible individuals 273
pentamidine 207 physical symptomS. treatment 542
peptic ulcer disease 147- 149 unexplained 509-510 usual interstitial lUlP) 559
peptide hormones 93 Picl<s disease 452 pneumonitis
peptide YY 96 pioglitazone 61,121 hypersensitivity 552-553
percutaneous coronary intervention pituitary apoplexy 101 ventilation 532
1 (PCI) 37 pituitary failure 101 pneumothorax 29, 563- 564
perfusion, pulmonary 529 pituitary gland 100- 104 po, 534,539
i pericardial disease 43- 45 pituitary radiotherapy 103 poikilocytosis 214
pericardial effusion 44 pituitary surgery, trans- poisoning 69- 71, 349
li pericarclial knock 4, 43 sphenoidal 103 pollution, atmospheric 553
l pericarditis
constrictive 4 3 - 4 4
pituitary tumours 100,101-102,
1 10, 365
polyarteritis nodosa 302, 443, 561,
585
yi infectious causes 280 placental transfer 294 poly-Atail 368
perinatal mortality plaques 75 polychromasia 214
maternal diabetes 295 plasma exchange polycystic kidney disease
1
l
627

l
Essential Revision Notes for MRCP
autosomal dominant
(ADPKD) 188, 422-423
autosomal recessive 423
pregnancy and 302
polycystic ovary syndrome
(PCOS) 113
polycythaemia 233-234, 243
infants of diabetic mothers 296
relative 234
secondary 234, 235
polycythaemia rubra vera (PRV) 233
potydipsia 102- 103, 397- 393
polymerase chain reaction
(PCR)188, 360, 361
polymorphonuclearcells 2 5 5
polymyalgiarheumatica 564
polymyositis 481,579-580
polyneuropathies 477-478
polyomavirusinfections 413
polyposis coli, familial 151,162,
192
polyuria 397-398
pompholyx 78
population-attributable fraction 130
porphyria 325-327
acute intermittent 83, 326- 327
congenital erythropoietic 83
cutanea tarda 83, 3 2 6
mental disorders 5 1 8
skin signs 83
urine discoloration 395
portal hypertension 173- 174, 244
portal vein thrombosis 173
positive predictive value 602, 603
positive-pressure ventilation 540
positr on emission tomography
tPETl 230, 555
posterior urethral valves (PLN) 434
post-hypercapnic alkalosis 350
poststreptococcal
glomerulonephritis 420
post~translational processing
355- 356
potassium
ECC changes and 9
see also hyperkalaemia;
hypokalaemia
power, statistical 133, 598
pox viruses 81
Prader-\/Villi syndrome 159, 190,
357
pre-B cell colony-enhancing
factor 96
628
precipitins 553
pre-conception care
cardiac disease 298- 299
diabetes 297
epilepsy 306
prediabetes 120
prednisolone 98, 241, 414
pre-eclampsia 307- 309, 311
pre-excitation 7
pregnancy 293- 315
acute fatty liver 310
anticoagulation in 18, 299, 312,
313, 314
antihypertensive therapy 49, 303,
311
antiphospholipid syndrome 303
cardiac disease and 298-300
diabetes and 294-298
drugtherapies 56-57,294
epilepsy and 306, 456
hormones in 9 6 - 9 7
hypertension in 306, 307, 311
hypertensive disorders of
306- 31 1
hypertrophic cardiomyopathy 40
infections in 271-272
medical complications 306- 314
physiology of normal 293- 294
renal disease and
hypertension 300-303
thrombocytopenia 241
thrombotic complications
31 1- 314
thyroid disease 304-305
urinary tract infections 429
pregnancy-induced hypertension
(PlH) 307
pre-load 39
premutation carriers 189
presenilin-1 and -2 (PS1 and PS2) gene
mutations 381, 451
pretibial myxoedema 497
prevalence 128, 602, 603
priapism 215
primaquine 285
primary biliary cirrhosis 173, 1 7 5
primers 360
PR interval
prolonged 25
short 7
Prinzmetal's angina 32
prion diseases 377- 378, 518
see also Creutzfeldt-lakob disease
prion proteins 377, 378, 453
probenecid 587
probucol 331, 332
procainamide 68
progesterone-only pill 298
programmed cell death 371-372,
387
progressive bulbar palsy 470
progressive massive fibrosis
(PMF) 550- 551
progressive muscular atrophy 470
progressive supranuclear palsy
(PSP) 458, 465
proguanil 285
prolactin 96, 9 7 - 9 8
prolactinomas 101, 115
promoters 365, 367, 387
prophylactic surgery 192
propylthiouracil 304
prostacyclin (P0111 45- 45, 260
prostaglandin D21PGD;) 260
prostaglandin Er 21
prostaglandin E2(PCL) 260
prostaglandins 260-261
prostatitis 430
prosthetic heart valves 17-18
protease inhibitors (Pl) 208
proteinase 3 (PR3) antibodies 583,
584
protein C deficiency 243, 312- 313,
314
protein chips 359
protein creatinine ratio, urinary
(UPCR) 394
proteinenergy malnutrition
(PEM) 345- 346
protein kinases 365, 387
protein phosphatases 365, 387
protein S deficiency 243, 313, 314
protein tyrosine kinases 94, 364, 36 5
proteinuria 394
diabetic nephropathy 123, 394,
439
glomerulonephritis 416,418,
419- 420
highly selective (minimal
change] 418
management 405
orthostatic 394
pregnancy 306- 307
proteome 355, 356
proteomics 3 5 8 - 3 5 9
prothrombin gene variant 313, 314
 Index

prothrombin time (PT) 23/ idiopathic pulmonary quantitative computed tomography

proton-pump inhibitors 146, 149 haemosiderosis 566 lQCTl 341,342
proto-oncogenes 3 6 9 , 3 8 7 progressive massive (PMF) questions, research 393
pruritus, generalised 83-84, 85 550- 351 Quincl<e's sign 16
pseudodominant inheritance 1 8 6 pulmonary function tests quinidine 68
pseudogout 588 (PFls) 530- 531, 533, 534 quinine 70, 284
pseudohypoparathyroidism 94,95, pulmonary haemorrhage 421 quinolones 270
338, 339 pulmonary haemosiderosis, Qwaves 8
pseudomembranous colitis 162, 2 7 8 idiopathic 566
Pseudomonas aeruginosa pulmonary hypertension 45-46, 374 Rabson-Mendenhallsyndrome 95
infections 5 4 7 , 5 4 8 primary (PPH) 45- 46, 373 radial nerve 476
pseudopseudo- secondary 45, 373 radial pulse, absent 4
hypoparathyroidism 94 pulmonary infarction-chest radio-contrast nephropathy 402
psittacosis 275 syndrome 215 radiofrequency ablation 26, 30, 31
psoriasis 66,76-78,89 pulmonary oedema radiotherapy
psoriatic arthritis 76, 574,577 flash 436 colorectal cancer 164
psychiatric disorders 503-526 malaria 284 lung cancer 556
drug-induced 519 pulmonary vascularresistance 529 lymphoma 231
drugtreatment 6 3 - 6 4 , 5 2 2 - 5 2 5 pulmonary vasculitis 560- 561 Ramsay Hunt syndrome 468
physicalillnesses 518 pulse, arterial 3 - 4 random allocation
sleepdisturbance 522 pulseless disease seeTakayasu aneritis (randomisationi 130, 131, 133,
treatment 522-526 pulse oximetry 201 393
psychoanalytictherapy 526 pulsus alternans 3, 44 randomised trials 131-134,138
psychogenic disorders 509-510 pulsus bigeminus 59 ranibizumab 490
psychotherapies 526 pulsus paradoxus 4, 43, 44 rapamycin 414
anxietydisorders 508 pupillary light reflex 461 rapid acetylators 55
depression 5 0 6 , 5 0 7 pupils 460- 462 Ras 369
eatingdisorders 514 afferent defect 461 rate difference 129
obsessive compulsive large 462 Raynaud's phenomenon 580, 581
disorder 509 small (miotic) 461, 462 reactive ain/vays dysfunction syndrome
schizophrenia 504 third nerve palsy 463 (R/RDS) 552
psychotic symptoms, drug- pure red cell aplasia (PRCA) 406 reactive arthritis 574, 576-577
induced 519 purine metabolism, disorders recall bias 136
ptosis 4 6 2 , 4 7 9 of 322- 323 receptors, cell 363- 365
puberty 115- 117 purine nucleoside phosphorylase receptor tyrosine kinases 94, 364
delayed 116- 117 deficiency 262 recombination 182
precocious 115- 116 pustules 75 red cell aplasia, pure (PRCA) 406
publication bias 137- 138 p-values 597, 5 9 8 red cells
pulmonaryangiography 1 1 - 1 2 , 4 7 pyelonephritis morphological changes 214
computed tomography acute 429 urine 394
(CTPA) 315 chronic (CPN) 427 Reed-Sternberg cells 230
pulmonary artery (PA), emphysematous 430 reflux nephropathy 301, 427- 429
catheterisation 1 1 - 1 2 pregnancy and 301 reflux oesophagitis 145- 146
pulmonaryembolectomy 47 xanthogranulomatous 430 refractory anaemia 236
pulmonary embolism (PE) 46- 47, pyoderma gangrenosum 63, 85, refractory anaemia with excess of
311 160 blasts (RAEB) 236
diagnosis 46, 315 pyrazinamide 282, 5 4 4 Refsums disease 490
see also venous thromboembolism pyridoxine (vitamin B5) regression, linear 601
pulmonaryeosinophilia 561- 562 deficiency 348 regression coefficient 601
pulmonary fibrosis 559- 560 therapy 321, 322, 5 4 5 regression dilution bias 129, 135
drugs causing 560 pyrimethamine 2 0 7 Reiter syndrome 437, 494, 574,
extrinsic allergic alveolitis 353 576- 577
idiopathic 376, 559 Q fever 275, 2 9 |) relapsing polychondritis 437

629
Essential Revision Notes for MRCP
relative risk 128- 129
REA/1 Sleep 521, 322
renal abscess 430
renal angiography 395- 396, 437
renal angioplasty with stenting 437
renal artery stenosis (RAS) 302, 395,
436- 437
renal biopsy, percutaneous 400-401
renal calculi 431 - 4 3 2
cystine 320
hypercalciuria 339, 340
investigations 395, 431
oxalate 321
pregnancy and 302
renaltuhularacidosis 3 9 6
renal carcinoma, familial 192
renal cell carcinoma 434
renal cystic disease 422-424
acquired 423-424, 434
simple cysts 424
see also polycystic kidney disease
renal disease
chronic see chronic kidney disease
cystic fibrosis 548
end-stage see end-stage renal
disease
inherited 422- 425
interstitial 425- 427
investigations 393- 396
pregnancy in 300-303, 307
recurrence after
transplantation 414
rheumatoid arthritis 437, 571
sarcoidosis 444, 558
systemic disorders 4 3 5 - 4 4 4
see also glomerulonephritis
renal failure se e a c ute kidney injury;
chronic kidney disease
renal function 3 9 1 - 3 9 3
assessment 391- 392
pre-eclampsia 3 0 8 - 3 0 9
pregnancy 294
renal transplant recipients 412
renal papillary necrosis 427
renal replacement therapy
(RRT) 401, 402- 403, 408- 415
diabetic nephropathy 440
see also dialysis; renal
transplantation
renal stones se e renal calculi
renal transplantation 410- 415
donors 411
graftdysfunction 412- 413
630
im m u n o s u p p res s iv e
therapy 414- 415
matching and incompatible 257,
41 1
non-renal complications
41 3 - 41 4
pancreas transplant with 411
pregnancy after 301
primary hyperoxaluria 322
recurrent renal disease after 414
renal function alter 412
screening and preparation 411
renal tubular acidosis tRTA) 349,
396- 397
renal tubular function 308, 392- 393
renal tumours, benign 434
re na lya sc ulitis 443-444
renal vein thrombosis 418. 419
r e ni n 99
reninzalclosterone ratio 110-111
renin-angiotensin-aldosterone (RAAI
system 99, 393, 405
Renriies 336
renovasculardisease 436-437
repaglinide 61
research questions 593
research study designs 593- 594
residual volume (RV) 530, 531, 533
resistin 96
respiration
control of 529-530
physiology 529-530
respiratory acidosis 396
respiratory alkalnsis 396
respiratory disease 534- 566
HIV/AIDS 201 - 2 0 2
infants of diabetic mothers 2 9 6
rheumatoid arthritis 561, 571
see also lung disease; upper airway
disease
respiratory failure 539-540
respiratory medicine 529-566
respiratory muscles 5 2 9
respiratory system, changes in
pregnancy 293
respiratoiy tract infections 274- 275,
540- 549
response elements 368, 387
restrictive cardiomyopathy 41, 44
reticulardysgenesis 262
reticulocytosis 213, 219
retina 485, 486
retinal arterial occlusion 487
retinalclisorders 487- 490
hypertension 488
visual field defects 459
retinal haemorrhages 487
retinal pigmentepithelium 485
retinal venous occlusion 487
retinitis, HIV/AIDS 205
retinitis pigmentosa 188, 490
retinoids 57, 66, 78, 79
retmutations 114- 115
retrochiasmal lesions 459, 460
retroperitoneal fibrosis (RPF) 434
Rett syndrome 1 8 7
reverse transcriptase 360
reverse transcriptase inhibitors 208
reverse transcription polymerase chain
reaction (rt PCR) 360-361
reversible inhibitor of monoamine
oxidase A (RIMA) 524
rhabdomyolysis 401-402
rheumatic fever 42, 280
rheumatoid arthritis (RA) 569-574
Caplan syndrome 551, 571
clinical features 570-571
disease activity scoring 572
drug therapy 572- 574
extra-articularfeatures 570- 571
investigations 571-572, 577
pro-inflammatorycytokines 375
pulmonaryinvolvement 561,
571
renal involvement 437, 571
skin changes 82
rheumatoid factor (RF) 569, 572
rheumatoid nodules 570
rheumatology 569- 589
drugs 6 4 - 6 6
rhodopsin 364
riboflavin deficiency' 348
rickets 338, 340
vitamin D-dependent 95, 338
vitamin D-resistant 187, 338
X-linked recessive
hypophosphataemic 339
rifampicin 282, 287, 5 4 4 , 5 4 5
adverse effects 282, 545
liver disease 57
resistance 281, 544
right axis deviation 7
right bundle branch block i,RBBB) 8
right heart catheterisation 11-12
right ventricle, systemic 23, 24
riluzole 470
 Index

rimonabant 121 Schumm test 219 shock 273

ringsideroblasts 218 sclera 485, 486 short stature 1 1 6 - 1 1 7
Rinnestest 4 6 5 scleritis 495, 570 shunt nephritis 422
riskdifference 129 scleroderma 580, 581 Shy-Drager syndrome 458
riskratio 129 localised 82, 581 sibutramine 121
risperidone 6 3 , 5 0 4 , 5 2 3 pregnancy 302 sick euthyroidism 99, 109
ristocetin 239 renal crisis 438, 580 sickle Cell disease 214-216, 273,
ritodrine 297 systemic see systemic sclerosis 385
ritualised behaviours 509 screening tests 602- 603 sickle dactylitis 215
rituximab scurvy 348 sickle pain crisis 215, 216
haematologicaldisorders 221 seborrhoeic dermatitis 7 8 , 206 sideroblastic anaemia 214,
229, 231, 234, 241 second messengers 94, 363 218- 219, 236
rheumatoid arthritis 5 7 3 - 5 7 4 secretin 141,143 sigmoicloscopy 158
systemic lupus seizures significance tests, statistical
erythematosus 5 7 9 absence 481 597- 599
l rizatriptan 63 drug-induced 65, 69 silicosis 551
RNA (ribonucleic acid] 188 eclamptic 310-311 simvastatin 134, 331
Robertsoniantranslocations 182, epileptic 453 single-blind study 133, 593
i 183 fetal effects 306 single-photon absorptiometry
l Romano-Wardsyndrome 29 see also epilepsy (SP/xl 341, 342
rosacea 79-BO selectins 379 single ventricular circulation Z3, 24
rosespots 165,285 selection bias 129,136 sinus node disease 25
li rosiglitazone 61,120,121 selective noradrenaline re-uptake sinus venosus defects 20
l Rotorsyndrome 168 inhibitors (SNRIE 524 sirolimus 414
rubella 272 selective serotonin reuptake inhibitors sitagliptin 61,121
Russell-Silversyndrome 190 (SSRIs) sitaxserttan 374
Russellssign 513 anxiety disorders 508, 5 0 9 15-sitosterolaemia 333
'l Rwaves,tall,inV1 7 depression 506, 507 sixth (VI) nerve 462, 485
li sacroillitis 5 7 4 - 5 7 5
side-effects 67, 524
selegiline 62, 437
palsy 463- 464
Sjijgren syndrome 581- 582
l salbutamol 297 selenium-75 homotaurocholic acid investigations 577, 552
salicylate overdose 70 (Sel-lCAT] retention test 1 5 8 renal disease 437
salivary gland disorders 145 self-harm 514- 515 secondary 570, 581
salmeterol 536 Sengstaken-Blakemore tube 174 skewed distributions 593
l Sa/rnone//a infections skin
1, sensitivity, screening test 602, 603
N gastrointestinal 165, 203, 278, sensorimotor neuropathy, HIV/ function 75
,_ 285
osteomyelitis 273
AIDS 204 infections 81
sensory neuropathies 477 Structure 75
samplesize 598 sepsis 2 7 3 - 2 7 4 skin cancer 87,192, 413
sarcoidosis 557-358 septic shock 373, 375 skin disorders/lesions
hypercalcaemia 336,558 serotonin (5-HT) 1 5 5 bullous eruptions 81- 82
neural (neurosarcoidosisl 469, serotonin [5-HT) agonists 63 connective tissue disorders B2
557 serum amyloid P( SAP) 379, 3 8 0 dermatomyositis 579
l ocular features 494, 498, 557
renaldisease 444, 558
skin lesions 82, 557
sevelamer 408
severe combined immun0def1ciency
drug eruptions 86
HIV/AIDS 77, 81, 206- 207
(SClDl 262 internal malignancy 84- 85
scabies 81 sex chromosome aneuploidies oral lesions 145
scales 75 182 - 183 pigmeritary 85-86
Schillingtest 144 sexual development 192, 193 sarcoidosis 82, 557
schistosomiasis 176, 286 sexually transmitted infections 199 specific derrnatoses 76- 81
schizophrenia 503- 504 Sheehan syndrome 103 systemic disease 82- 83
first-rank symptoms 5 0 3 - 5 0 4 Shigella infections 165, 278, 440 terminology 75
treatment 504, 522- 523, 525 shingles see herpes zoster sl<inpricktests 536

631

I
 Essential Revision Notes for MRCP
skin tumours 87
SLE see systemic lupus erythematosus
sleep
disorders 521- 522
normal 521 - 5 2 2
sleep apnoea, obstructive 564-565
sleeping sickness 2 8 8
slow acetylator status 55, 62
small-cell lung cancer 5 5 4 , 5 5 6
small intestine 142~143
bacterial overgrowth 158, 159
disorders 153- 156
infections 2 77- 2 78
villous atrophy 154
Smith-Magenis syndrome 3 5 7
smoking
cardiovascularcomplications 32
COPD 537
lung cancer 553
psoriasis and 77
social phobia 508
sodium
renal handling 392, 393
urinary 105
see also hyponatraemia
sodium bicarbonate 69, 70, 71
sodium cromoglicate 67
sodium valproate see valproate,
sodium
soft tissue infections 272, 281
somatic cells 387
somatisation disorder 509- 510
somatoform disorders 509~ 510
somatostatin 142, 143
somatostatin analogues 1 0 3 , 1 5 0
somatostatinoma 153
sotalol 26, 28
South American
trypanosomiasis 288- 289
space-occupying lesions, infectious
causes 277
Spearman's rank correlation 600
Specificity, screening test 602, 603
spherocytes 214
spina bifida 433
spinal cord disorders 469- 471
spinothalamic tracts 470
spiruchaetes 81, 268
spirometry 530
spironolactone 111, 392, 393
spleen 244- 246
splenectomy 241, 245, 273
splenic sequestration crisis 215
632
splenic vein thrombosis 173
splenomegaly, malaria 284
spondyloanhropathies.
seronegative 437, 574-576
sputum examination 538, 546, 555
squamous cell carcinoma
cutaneous 87
lung 553- 554
standard deviation 596, 5 9 7
standard error (SEM or SE) 596-597
stanols 331, 332
staphylococcal infections
endocarditis 279, 280
Skin 81
staphylococci,classification 267
Staphylococcus aureus 267
cystic fibrosis 547
gastroenteritis 164, 278
pneumonia 542
soft tissue infections 281
toxic shock syndrome toxin-
'l 274
Staphylococcus epic/ermidis 18, 267
Starr- Edwards heart valve 18
starvation 95, 345-346
statins see HMG CoA reductase
inhibitors
statistical artefact 1 2 9
statistical significance 597
statistics 593 - 603
stavudine 208
steatorrhoea 149, 152
Steele-Richardson syndrome 458,
465
ST elevation 8 sulfinpyrazone 587
stem cells 379
stercobilinogen 1 4 2 , 1 6 7
sterilisation 298
steroid hormones 93, 95
receptors 365, 3 6 6
steroids see corticosteroids
steroid sulphatase deficiency 3 5 7
sterols 331, 332
Stevens-johnson syndrome 80, 207
Still's disease 589
St Iude heart valve 18
stomach 141
disorders 147- 151
streptococcal infections
endocarditis 18, 279, 280
skin 81
soft tissue 281
streptococci
classification 267, 268
group A 42, 268, 280, 281
group B 268
group D 268
toxic shock syndrome 274
viridans-type 18, 267, 279
Streptococcus pneumoniae infections
see pneumococcal infections
Streptococcus pyogenes
see streptococci, group A
streptomycin 282
stress hormones 95
stroke 471- 472
atrial fibrillation and 26, 27
sickle cell disease 215
stroke volume index 50
strontium 66
STsegment, abnormalities 7 -8
Students t-test 598
study designs
epidemiological 131-138
research 593- 594
Sturge-Weber syndrome 84, 498
subacute combined degeneration of
spinal cord 348
subarachnoid hemorrhage
(S/\Hl 472- 473
subfertility 106, 113, 5 4 8
subgroup analyses 134
sudden death 17, 40
Suicide 514-515, 520
sulfadiazine 207
sulfamethoxazole 270
sulfasalazine 61- 62, 159- 161, 576
sulphonamides 270
sulphonylureas 121
sumatriptan 63, 474
sunlight, diseases aggravated by 86
superior vena caval obstruction 556
superoxide dismutases (SOD) 377
supraventriculartachycardia(SVT) 6
23, 26, 31, 58
surfactant 529
survival time 128
sweating, episodic 114
swimmers itch 286
Sydenham's chorea 459
"
Synacthen tests 97, 104, 113
syncope
neurocardiogenic 25
unexplained 38
syndrome of inappropriate ADH
 Index

secretion (SIADH) 68, tears, artificial 582 systemic lupus

1 104-105, 554 teicoplanin 267 erythematosus 5 7 8 - 5 7 9
1
syndrome X 32 temazepam 525 see also venous thromboembolism
synovial fluid examination 572 temporal arteritis thrombotic microangiopathies
syphilis 199, 205 see giant-cell arteritis 440- 441
blood-borne transmission 246 temporal lobe lesions 450, 459 thrombotic thrombocytopenic purpura
eye disease 496 teriparatide 338 lTTPi Z2()-221
see also neurosyphilis terlipressin 148, 170, 174 renal involvement 440, 441
SysEurTrial (2000) 48 termination of pregnancy, renal treatment 220- 221, 247
systemic inflammatory response disease 301 thymectomy 480
syndrome (SlRSl 273 testicular feminisation syndrome 95, thyroid acropathy 4 9 7
systemic lupus erythematosus 1 16, 1 93 thyroid axis
(SLE) 578- 579 testosterone 192 in illness 95, 99
antiphospholipid antibodies 243, tetanus 272- 273 in pregnancy 97
5 78- 579 tetracyclines 79, 165, 270, 290 thyroid-bindingglobu|intTBG1 97,
investigations 577, 575 tetralogyo1Fall0t 22-23 98, 108, 304
lung involvement 561 TH1 (helper) cells 255- 256, 259 thyroid-binding pre-albumin
mental disorders 518 TH2 lhelper) cells 256, 259 ITBPA] 98
nephritis 420, 438, 578 thalassaemia 216- 217 thyroid cancer 107, 115
pregnancy 302 major 216 thyroid disease 105- 107
skin features 82 trait 214, 217 autoimmunity 108
treatment 579 thalidomide 232 pregnancy and 304-305
systemic sclerosis 580-5111 thelarche 115-116 see also hyperthyroidism;
clinical features 581 theophylline 69, 536 hypothyroidism
investigations 577, 581 thiamine thyroid eye disease 105, 465, 4 9 7
lung involvement 561 deficiency 348, 520- 521 thyroid function tests 99, 1011-109
renal disease 438, 5 8 0 therapy 475 in pregnancy 304
skin features 82 thiazide diuretics 48, 57, 60, 340 thyroid gland 105- 109
treatment 581 mechanism of action 392, 393 drugs and 108
see also scleroderma renal calculi 432 ectopic tissue 107
systemic vascular resistance thiazolidinediones 61, 120, 121 thyroid hormone metabolism
(S\/R) 50 thin-membrane nephropathy 424 98- 99
third (Ill) nerve 462, 485 thyroiditis 107
l T; 98- 99, 304
` palsy 463 post-partum 305
freetrrn 99,108,109 thought disorder, schizophrenic 503 thyroid nodules 107
reverse (rT;) 9 8 , 9 9 3 untranslated regions ( 3' UTRi 368 thyroid-stimulating hormone
T4se e thyroxine thrombin time (TT) 2 3 8 (TSH) 108, 109, 304
tachyarrhythmias 2 5 - 2 8 thrombocythaemia, primary thyrotoxicosis se e hyperthyroidism
tachycardia, broad-complex 28 (essential) 234- 235 thyroxine (T4) 93, 95, 98- 99, 304
tacrolimus 57,414 thrombocytopenia 24|)-241,247 free (FTA) 108, 109
Takayasu arteritis 444, 584 thrombocytosis 234- 235 replacement therapy 104
tamoxifen 495 thrombolysis 244 tidalvolumeiTVl 531,533
tandem mass spectrometry 3 5 9 contraindications 35 tiopronin 320
Tangierdisease 333 myocardial infarction 35, 36, 51 tissue Doppler imaging 1U
tapeworms 288 pulmonary embolism 47 tissue injury and repair, molecular
Taqpolymerase 360 stroke 472 mediators 3 7 4 - 3 7 7
tardive clyskinesia 504 thrombophilia 2 2 1 , 1 4 2 - 2 4 3 tissue plasminogen activator 35, 47
targetcells 214,245 in p reg n an cy ' 312-313, 314 tobacco-alcoholamblyopia 492
tarpreparations 77 thrombophlebitis, migratory B5 tocolytic agents 2 9 7
TATA box 368 thrombosis 242- 244 tongue, disorders 145
tau protein 381, 452 atrial fibrillation and 27 tonic pupil 462
T cells (T lymphocytes) 2 5 5 - 2 5 6 complications of Torre-Muir syndrome 84
disorders 262 pregnancy 311- 314, 3 1 5 torsade de pointes 28, 79

633

i
Essential Revision Notes for MRCP

total lung capacity' (TLC) trisomy 21 1 8 3 - | 8 4

530, 531, tyrosine kinase inhibitors 228, 229
533 trochlear nerve see-fourth (IV) nerve tyrosine kinases Q4, 364, 365
toxic epidermal necrolysis 86 tropical infections 284-289,497
toxic nephropathy 4 4 5 - 4 4 6 tropical splenomegaly UK PDS trial 48
toxicology 5 5 - 7 1 syndrome 284 ulcerative colitis 61, 159-162
toxic shock syndrome 274 tropical sprue 1 5 4 , 278 ulnar nerve 476
toxoplasmosis troponin assays 33, 34 ultrafiltration failure 409
cerebral 204, 205, 207 1rousseaus sign 338 ultrasound
in pregnancy 272 trypanosomiasis 288- 289 antenatal screening 297
trachoma 199, 497 T scores 341 intracardiac 10
transcription factors 365-368, 387 t~test 598 intravascular 10
transcriptome 355, 3 5 8 tuberculosis (TB) 281- 282, liver 169
transcriptonnics 358 543- 545 renal 395, 400, 437
transdifferentiation 379 diagnosis 281- 282, 544 ultraviolet (UV) radiation 77, 78
transferrin receptor, serum gastrointestinal 165- 166 uncal herniation 463
soluble 218 HIV/AIDS 202, 204, 281 uncertainty principle 133,134
transferrin saturation 217-218, 325, meningitis 276 undulant fever 259
406 miliary 544 uniparental disomy 189
transforming growth factor B multidrug-resistant untranslated regions (UTR)
ircrtii 375-376 LMDR-TB) 2 8 | , 544 3 6 7 - 3 6 8 , 387
transient ischaemic attack (TIA) 471 pericarditis 280 upgaze palsy 465
transjugular intrahepatic porto- post-primary 543 upper airway disease
systemic shunting (TIPSS) 174 prevention 282, 545 cystic fibrosis 548
translocations 182 primary 543 sarcoidosis 557
malignant disease 226, 227, 370 pulmonary 543 \/\/egener's granulomatosis
transmissible spongiform treatment 282, 544- 545 560- 561
encephalopathies (TSEs) urinary tract 430- 411 upper gastrointestinal
377- 378 tuberous sclerosis 194-195, 423 haemorrhage 148, 172
transoesophageal echocardiography genetics 185, 194 uraemia
(Too 10, 27, 49 ocular features 498 acute kidney injury 401
transplantimmunology 2 5 7 skin lesions 84 pre-renal 3 9 9 - 4 0 0
transposition of great vessels 23, 24 tubulointerstitial nephritis (TIN), urate oxidase 65
Traube's sign 16 chronic 426 ureteric diversion, metabolic
tremors 456 tumour lysis syndrome 344, 345 acidosis 349
treponemal tests 199 tumour necrosis factor (TNF) 3 7 5 urethral syndrome 429
trichiasis 497 tumour necrosis factor et (TNFU) 375 urinalysis 393- 394
tricuspid regurgitation (TR) 17 blockers see anti tumour necrosis urinary albumin excretion ratio
tricyclic antidepressants 69, 524 factor alpha (anti-TNFI1) (UAERl 439
trientine 324 agents urinary catheter-associated
trifascicular block 25 tumour necrosis factor B(TNFB) 375 infections 430
trifluoperazine 504 tumours urinary dipsticks 393- 394
trigeminal neuralgia 468 molecular profiling 358 urinary protein selectivity index 418
triglycerides 327, 328, 329 se e also cancer urinary tract
lowering drugs 331 tumour suppressorgenes 370- 371, changes in pregnancy 294
triiodothyronino se e T3 387 obstruction 432- 434
trimethoprirn 165 tunnel vision 490 surgery, pregnancy after 302
trinucleotide repeat disorders Turner syndrome 116, 117, tuberculosis 430-431
188- 189, 381-382 132- 183 tumours 434- 435
tripe palms 85 2-D gels 359 urinary tract infections (UTI)
triple X syndrome 183 tylosis 147 429- 430
triploidy 181 type l error 5 9 8 urine
trisomy 13 1 8 4 type ll error 598 discoloration 3 9 5 ~
trisomi,/18 184 typhoid 165, 285 microscopy 394

634
 Index

urobilinogen 142,167, 2 1 9 venlafaxine 69, 524 vitamin By seethiamine

urolithiasis see renal calculi venography 315 vimmin B2deficiency 348
urothelial tumours 4 3 4 - 4 3 5 venous thromhoembulism (VTE) vitamin Br, see pyridoxine
ursodeoxycholic acid 169, 175 46- 47, 242 vitamin By; 144
urticaria 86, 107 diagnosis 46- 47. 315 deficiency 161, 213, 348
Usher syndrome 490 in pregnancy 311- 314, 315 vitamin C 308, 377
uveal tract 485 risk factors 242 deficiency 348
ut/ellis 493-494, 557 ventilation 529 vitamin D
ventilationlperfusion (V/Q) dependent rickets 95, 338
vaccination 271 scanning 46, -17, 315 metabolism and actions 95, 100,
childhoodschedule 271,274 ventilation pneumonitis 532 334- 335
hyposplenism/splenectomy 245, ventilatory support 540 resistant rickets 187, 338
273 ventricular angiography 11 serum levels 339
vaccinetypes 263 ventricular arrhylhmias Z7- 29, 51 synthesis in skin 75
valganciclovir 207 ventricularfibrillation 23, 31 therapy 77, 339
valproate, sodium 57, 63, 66, ventricular septal defects t\/SD) 21, vitamin D deficiency 347
455-456 24 chronic kidney disease 407, 408
valvular heart disease 13-19 ventricular tachycardia (VT) 6, 23, hypocalcaemia 338, 339
vancomycin 162,267,271 27-28, 30, 31 osteomalacia 340
variables, epidemiological 127- 128 vertigo 468- 469 vitamin deficiencies 346, 347-348,
variceal haemorrhage 173-174 very low-density lipoprotein 318
varicella (chickenpox) 269, 272 l\/LDL) 328-329 vitamin E 308, 377
varicella zoster virus (VZV) 269 vesicles 75 deficiency 347
varices 173- 174 vesico-ureteric reflux N U R) vitamin K 240, 306
vascular access, haemodialysis 410 427- 429 deficiency 347
vascular disorders vestibular lesions 465, 468- 469 vitiligo 112
CNS 471- 473 vestibulocochlear nerve vomiting
majorvessels 4 5 - 4 9 lesions 4 6 8 - 4 6 9 infectious causes 278
see also cardiovascular disease Vibrio cholerae 365 metabolic alkalosis 349
vascular tone, molecular video-assisted thoracoscopic surgery see also gastroenteritis
regulation 372- 374 (\/ATS? 556,559 von Hippel-Lindau syndrome 192
vasculitis 582- 586 vigabatrin 62,495 ocular features 49B
aetiology 582 vildagliptin 12| phaeochromocytomas 114
classification 583 vinblastine 66 renal cysts 423
clinicalfeatures 583 Vincentangina 32 skin lesions B4
drug-Induced 68 vincristine 66,226 von Recklinghausens disease of
laboratory tests 5 8 3 - 5 8 4 VlPoma 153 bone 408
large-vessel 5 8 3 , 5 8 4 viral infections von Willebrand factor (vV\/F) 220,
prognosis 584 blood-borne 272 239
pulmonary 560- 561 encephalitis 2 7 7 , 4 7 5 von \/\/illellrands disease 239
renal 443- 444 haemorrhagicfevers 289 v wave 3
rheurnatoidarthritis 571 hepatitis 170- 171
scleritis 495 lymphocytosis 223 Wallenberg syndrome 469
small/medium-sized vessels 583 meningitis 276 warfarin 242
small-vessel 4 4 3 , 5 8 3 skin 8 1 , 2 0 6 liver disease 57
treatment 584 see also specific infections myocardial infarction 34, 36
vasoactive intestinal peptide viruses 2 6 9 in pregnancy 18, 57, 299, 314
(VIP) 143 visfatin 96 pulmonary embolism 47
vasodilators 39, 40, 4 5 - 4 6 visualagnosia 4 5 0 warts 81
vasopressin see antidiuretic hormone visual field defects 450, 459- 460 vvater deprivation test 102- 103
vegans 3 4 0 , 3 4 7 , 3 4 8 visual obscurations, transient 493 water intake, excessive
Ve|cade (bortezomib) 232 vital capacity (VC) 530, 531, 533 see polydlpsia
venesection, therapeutic 234 vitaminAdeficienq/ 347 Vt/eber's test 468

635
Essential Revision Notes for MRCP

Wegeners granulomatosis 302, 443 Wilsons disease 175, 324, 459, 518 X-linked Conditions 186- 187
560- 561, 5 8 4 - 5 8 5 \/Visl<ott-Aldrich syndrome 84, 262 XO l<aryot\/pe se e Turner syndrome
weight, hormonal regulation 9 5 - 9 6 Wolffian ducts 192, 1 9 3 XXX karyotype 183
weight loss agents 61, 121 Wolff-Parkinson-VV|1i|e (WPW) XXY karyotype see Klinefelter
V\/eil`s disease 279 syndrome 7, 26 syndrome
\/\/ernic ke-Korsakoff syndrome 348, Wolf-Hirschhorn syndrome 157 xylose absorption tesr 159
474 Wuchereria bancrofti 288 XYY males 183
\/\/ernickes area 4 5 0
\/\/ernicl<es encephalopaihy xanthelasma 3 2 9 ydescenr 3 , 4 4
474- 475, 520- 521 xanthochromia 472 rapid 3
wheal 75 xanlhomata 329,330 yeasts 81
V\/hipples disease 155 X-autosometranslocalion 384 yellownailsyndrome 89
\/1/hiiaker test 433 X-chromosome inactivation 181, Young syndrome 546
white blood cells see leucocytes 384
white cell count, raised 222- 224, xdescent 3,44 zidovudine 2 0 7 , 2 0 8
294 sleep 3 zinc 324
Wicl<hams striae 80 xeroderma pigmentosum 84 Zollinger-Ellison syndrome
Williams syndrome 17,184, 357 xerophthalmia 347, S82 149-150, 153
Wilms tumour 434 xerostomia 582 zoonoses 289-290

636