The Liver and Its Disorders

THE LIVER AND ITS
DISORDERS
DR. APPIAH
Outline
• Introduction
• Functions of the liver
• Bilirubin metabolism
• Jaundice
• Inherited hyperbilirubinaemia
• Neonatal jaundice
• Laboratory diagnosis
DR. APPIAH'S LECTURE SERIES 2

Objectives
• Appreciate the tests that are used to assess the liver function.
• Explain the biochemical basis of the above liver function tests.
• Explain the biochemical changes seen in main hepatobiliary diseases.
• Explain the significance of serum ALT and AST (markers of inflammation

of liver) & γ-GT (diagnosis of hepatobiliary dysfunction)
• Differentiate between the three types of jaundice using liver enzymes,

bilirubin & urobilinogen
Introduction
• The liver is the largest solid organ in the body.
• In adults, it weighs 1.0–1.5 kg and its size is

maintained in relatively constant proportion to
body weight.
• It is comprised of a large right lobe and a

smaller left lobe, and is located in the upper
right quadrant of the abdomen under the lower
edge of the diaphragm.
• It is the only organ that has the capability to

regenerate completely after it has been
damaged or following a partial hepatectomy.
Functions of the liver
❑It is the site for the following:
➢Metabolism of carbohydrates, lipids and proteins
➢Conversion of β-carotenes into vitamin A
➢Synthesis of plasma proteins except immunoglobulins and

complement
➢Synthesis of clotting factors such as fibrinogen and factors II,V,VII,

IX, XII & XIII
• Site for the synthesis of lipoproteins, VLDL and HDL
• Site for the synthesis of primary bile acids
• Site for the detoxification of drugs and toxic substances
• Site for the storage of glycogen,iron, fat-soluble vitamins and vitamin B12
• Metabolism of steroid hormones (25-hydroxylation of vitamin D)

polypeptide hormones, and bilirubin.

Bilirubin metabolism
• 80% of the daily output of bilirubin is derived from the breakdown of
erythrocytes
• The remaining 20% of the output is from red cell precursors and haem
proteins e.g myoglobin, cytochrome & peroxidase
• The breakdown commences with the removal of the iron moiety

• Haem oxygenase then converts the
porphyrin ring to biliverdin Ixα
• This is then converted to bilirubin

IXα by biliverdin reductase
• Bilirubin is then transported to the

liver for further metabolism by
binding to albumin.
• It is taken up by the liver by a

facilitated transport system

• Ligandin Y and Z are transport proteins which are associated with
intracellular binding and transport of bilirubin
• In the hepatocytes, about 85% of bilirubin is conjugated with two

molecules of glucuronic acid in the smooth endoplasmic reticulum
• Most of the rest of bilirubin is conjugated with one sugar molecule to

form monoglucuronate-bilirubin. The addition of the sugar group
increases the solubility of the molecule.
• The enzymes involved are UDP glucose dehydrogenase, UDP-

glucuronyl transferase I and II
• The activity of UDP-glucuronyl transferase may be induced by
phenobarbitone and inhibited by novobiocin.
• The liver is the main site of bilirubin conjugation but it may occur in
the kidney and intestinal mucosa
• Bilirubin diglucuronide is actively secreted into the bile

• When conjugated bilirubin gets
to the terminal ileum and the
large intestines, the intestinal
flora deconjugates the bilirubin
• Bilirubin is then converted to

urobilinogen, mesobilinogen and
stercobilinogen.
• Some of the pigments undergo

an enterohepatic circulation.

• Urobilinogen is thus a normal constituent of the urine
• The pigments stercobilin contribute to the colour of the stool
• Normal adults do not excrete bilirubin in the urine and stool

Jaundice in adults
• The reference range of bilirubin in adults is up to 17.1 µmol/l
• Jaundice is characterized by the yellowish colouration of the tissues

due to retention of pigments
• Experienced physicians discern when blood [bilirubin] is about 35

µmol/l

• It becomes overt when levels are about 55-70 µmol/l
• Jaundice is a symptom of an underlying disease
• It may be due to pre-hepatic, hepato-cellular and post-hepatic causes

Pre-hepatic jaundice
• It may be due to haemolytic or non-haemolytic causes
• Haemolytic jaundice may be due to acquired (malaria) or congenital(G6PD

deficiency) causes
• It may also be due to ineffective erythropoiesis (pernicious anaemia) or

right sided congestive cardiac failure

• Typical serum bilirubin pattern of prehepatic hyperbilirubinemia is
increased unconjugated bilirubin and normal conjugated bilirubin.
• Non haemolytic jaundice is usually of congenital origin e.g Criggler-

Najjar and Gilberts’syndrome

Hepatocellular jaundice
• This may be due to defects in conjugation of bilirubin or defects in its
hepatic uptake
• Defects in conjugation may result from diffuse hepatic injury which

may occur in the following:
✓Acute, subacute, chronic and fulminant hepatitis
✓Effects of drugs or toxins such as paracetamol, alcohol, CCl4 and

halothane

• Defects in uptake may result from the effects of flavispidic acid
• The typical serum bilirubin pattern of hepatic hyperbilirubinemia is

increased unconjugated and conjugated bilirubin.
• Serum enzymes that indicate hepatocellular inflammation and cellular

damage within the liver, including ALT and AST, are also often
elevated

Intra-hepatic cholestasis
• This may occur in subacute or chronic hepatitis
• It may also be due to the effects of drugs such as:
✓17 α-alkylated steroids e.g methyltestosterone or norethisterone
✓Phenothiazine e.g chlorpromazine

✓Antibiotics e.g oleandomycin and erythromycin
✓Penicillin sensitivity
• It may also occur in some forms of cirrhosis, especially primary biliary

cirrhosis

Post-hepatic jaundice
• This is usually due to mechanical obstruction of the biliary tree as a
result of:
✓Gallstones
✓Carcinoma of the head of the pancreas
✓Scarring from infection

• The typical serum bilirubin pattern of post hepatic hyperbilirubinemia
is increased conjugated bilirubin but normal unconjugated bilirubin.
• Serum enzymes that indicate biliary cell damage, including alkaline

phosphatase and GGT, are also often elevated.

Summary

An approach to jaundice
• Is it isolated elevation of serum bilirubin ?
• If so, is the ↑unconjugated or conjugated fraction?
• Is it accompanied by other liver test abnormalities ?
• Is the disorder hepatocellular or cholestatic?
• If cholestatic, is it intra- or extrahepatic?

• These can be answered with a thoughtful
✓History and physical examination
✓Interpretation of laboratory tests and
✓Radiological tests and procedures.

Inherited hyperbilirubinaemia
• This may be classified into unconjugated and conjugated types
• The congenital unconjugated hyperbilirubinaemias are Gilberts and

Criggler-Najjar Syndromes
• The congenital conjugated hyperbilirubinaemias are Dubin Johnson

and Rotor Syndromes

Gilbert’s syndrome
• This is a heterogenous condition and has an estimated prevalence of 3–8%
in the general population.
• The defect is a TA insertion in the TATA repeat box of the gene promoter
region. Homozygosity reduces the capacity for gene expression
• It is characterized by the defective uptake of bilirubin by the hepatocytes
• There may be an associated reduction in the life span of the erythrocytes

• Their serum [bilirubin] is usually between 20-40 µmol/l and rarely
exceeds 80 µmol/l
• Their serum bilirubin levels may rise during intercurrent illness or

during fasting
• It may present at any age but it commonly presents in the second

decade of life.

Crigler-Najjar Syndrome
• This is characterized by the deficiency of hepatic glucuronyl
transferase
• Two types of the condition have been described;
✓Type I is characterized by a marked deficiency of the enzyme which

may lead to death from kernicterus at infancy

• Type II is characterized by a partial deficiency of the defective enzyme
• The serum [bilirubin] may be reduced by drugs which induce hepatic

enzyme synthesis e.g phenobarbitone
• Crigler-najjar Syndrome usually presents at birth

Dubin- Johnson Syndrome
• This is a rare and benign condition which is characterized by defective
excretion of bilirubin but not bile salts
• It is associated with a slightly raised serum conjugated bilirubin
• Affected subjects present with bilirubinuria but the Alkaline

Phosphatase is normal

• There may be hepatomegaly
• The liver of affected persons has orange-yellow granules
• The liver of subjects is usually dark brown

Rotor Syndrome
• This is also characterized by defective excretion of conjugated
bilirubin into the biliary tree.
• The liver of affected subjects does not have orange-yellow granules

Neonatal jaundice
• The reference range of bilirubin in neonates is 8-67 µmol/l
• In the first week of a neonates life, there may be a physiological

hyperbilirubinaemia
• The serum [bilirubin] may rise to as high as 200 µmol/l and is usually
prolonged in preterm neonates.

Causes of neonatal jaundice
• Haemolytic disease e.g blood group incompatibilty and G6PD
deficiency.
• Immaturity of the hepatic processes for uptake and excretion of

bilirubin.
• Interference with hepatic transport functions by drugs e.g progesterone

or steroids with progesterone-like activity

• Neonatal hyperbilirubinaemia may be aggravated by:
✓Acid-Base disturbances
✓Hypoxia
✓hypoglycaemia

• The course and severity of neonatal jaundice may be influenced by:
✓Drugs such as salicylates and sulphonamides which compete for binding to

albumin
✓Novobiocin which inhibits the glucuronyl transferase system
✓Drugs which cause haemolysis
▪ If the level of unconjugated bilirubin exceeds the plasma binding capacity it

will lead to kernicterus

• Biliary atresia may lead to cholestatic jaundice
• It’s a blockage in the tubes(ducts) that carry bile from liver to the
gallbladder.
• This congenital condition occurs when the bile ducts inside or outside
the liver do not develop normally
• Its not known why the biliary system fails to develop normally

Lab Diagnosis of Jaundice
Prehepatic Intrahepatic Posthepatic

Features
(Heamolytic) (Hepatocellular) (Obstructive)
Unconjugated ↑ Normal Normal
Conjugated Normal ↑ ↑
AST or ALT Normal AST↑ ↑↑ Normal
Alkaline phos.
and GGT
Normal Normal ↑↑
Urine bilirubin Absent Present Increased
Urobilinogen Increased Present Absent

DR. APPIAH'S40
LECTURE SERIES
Case study
❑14-year-old boy presented to his doctor complaining of abdominal pain, nausea,
and weakness. His previous medical history included recent travel to Africa to
visit relatives. On examination he was jaundiced, had a fever, and an enlarged
liver with tenderness. The results of his biochemical tests for the liver were as
follows (reference ranges are given in brackets):
• Total protein 71 g/L (60–80)

• Albumin 40 g/L (35–80)
• Bilirubin 233 lmol/L (0–20)
• Alkaline phosphatase 307 IU/L (30–130)
• Aspartate aminotransferase 1825 IU/L (5–50)
• Gamma-glutamyl transferase 282 IU/L (5–55)
➢What is the differential diagnosis?

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THE LIVER AND ITS

• Functions of the liver

DR. APPIAH'S LECTURE SERIES 2

• Explain the biochemical basis of the above liver function tests.

• Explain the biochemical changes seen in main hepatobiliary diseases.

• Explain the significance of serum ALT and AST (markers of inflammation

• Differentiate between the three types of jaundice using liver enzymes,

• In adults, it weighs 1.0–1.5 kg and its size is

• It is comprised of a large right lobe and a

• It is the only organ that has the capability to

➢Metabolism of carbohydrates, lipids and proteins

➢Conversion of β-carotenes into vitamin A

➢Synthesis of plasma proteins except immunoglobulins and

➢Synthesis of clotting factors such as fibrinogen and factors II,V,VII,

• Site for the synthesis of primary bile acids

• Site for the detoxification of drugs and toxic substances

• Metabolism of steroid hormones (25-hydroxylation of vitamin D)

DR. APPIAH'S LECTURE SERIES 6

• The breakdown commences with the removal of the iron moiety

DR. APPIAH'S LECTURE SERIES 7

• This is then converted to bilirubin

• Bilirubin is then transported to the

• It is taken up by the liver by a

DR. APPIAH'S LECTURE SERIES 8

• In the hepatocytes, about 85% of bilirubin is conjugated with two

• Most of the rest of bilirubin is conjugated with one sugar molecule to

• The enzymes involved are UDP glucose dehydrogenase, UDP-

• Bilirubin diglucuronide is actively secreted into the bile

DR. APPIAH'S LECTURE SERIES 10

• Bilirubin is then converted to

• Some of the pigments undergo

DR. APPIAH'S LECTURE SERIES 11

• The pigments stercobilin contribute to the colour of the stool

• Normal adults do not excrete bilirubin in the urine and stool

DR. APPIAH'S LECTURE SERIES 13

• Jaundice is characterized by the yellowish colouration of the tissues

• Experienced physicians discern when blood [bilirubin] is about 35

DR. APPIAH'S LECTURE SERIES 14

• Jaundice is a symptom of an underlying disease

• It may be due to pre-hepatic, hepato-cellular and post-hepatic causes

DR. APPIAH'S LECTURE SERIES 15

• It may be due to haemolytic or non-haemolytic causes

• Haemolytic jaundice may be due to acquired (malaria) or congenital(G6PD

• It may also be due to ineffective erythropoiesis (pernicious anaemia) or

DR. APPIAH'S LECTURE SERIES 16

• Non haemolytic jaundice is usually of congenital origin e.g Criggler-

DR. APPIAH'S LECTURE SERIES 17

• Defects in conjugation may result from diffuse hepatic injury which

✓Effects of drugs or toxins such as paracetamol, alcohol, CCl4 and

DR. APPIAH'S LECTURE SERIES 18

• The typical serum bilirubin pattern of hepatic hyperbilirubinemia is

• Serum enzymes that indicate hepatocellular inflammation and cellular

DR. APPIAH'S LECTURE SERIES 19

• It may also be due to the effects of drugs such as:

✓17 α-alkylated steroids e.g methyltestosterone or norethisterone

✓Phenothiazine e.g chlorpromazine

DR. APPIAH'S LECTURE SERIES 20

• It may also occur in some forms of cirrhosis, especially primary biliary

DR. APPIAH'S LECTURE SERIES 21

✓Carcinoma of the head of the pancreas

✓Scarring from infection

DR. APPIAH'S LECTURE SERIES 22

• Serum enzymes that indicate biliary cell damage, including alkaline