ENDOCRINOLOGY FOR PRIMARY FRCA

HORMONES – TYPES, HIERARCHY, EXTRACELLULAR SIGNALLING

• 2 main types of hormones
• Exocrine
• endocrine
• Cellularly: Paracrine, autocrine, (intracrine)

Select the statement that is true:

A. Bile salts are not steroid hormones F

B. Insulin & glucagon are peptide hormones but unlike insulin glucagon acts on membrane receptors T
C. Cortisol doesn’t act at the mineralocorticoid receptor F
D. Melatonin acts on receptor tyrosine kinases F

Aldosterone, cortisol, and corticosterone act through the mineralocorticoid receptor for which they have similar binding affinity
to initiate transcriptional effects that take more than 3 hours or rapid nongenomic effects that occur in seconds to minutes.

HORMONE TYPES & RECEPTORS

Function Peptide/Protein AA Derivative Steroids Eicosanoids
Adipose & Glucose Insulin
IGF-1
FGFs
Glucagon
Ghrelin
Leptin
Thyroid TRH Thyroxine
TSH
Gonadal & Growth FSH Testosterone
LH Progesterone
GH Oestrogen
Stress ACTH Catecholamines Cortisol
Volume /BP Renin Aldosterone
ANP
Vasopressin (ADH)
Angiotensin
Electrolytes PTH Vitamin D
Calcitonin
Others CCK Melatonin Bile salts Prostanoids
Gastrin Leukotrienes
MSH Resolvins
Oxytocin
Prolactin
VIP
Red: Nuclear Receptors Green: Receptor Tyrosine Kinase (RTKs). Rest: Membrane Receptors GPCRs

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MECHANISMS OF HORMONAL CONTROL - -VE FEEDBACK CONTROL

In a negative feedback system, a stimulus elicits the release of a substance; once the substance reaches a certain
level, it sends a signal that stops further release of the substance. In this way, the concentration of hormones in blood
is maintained within a narrow range.

A negative feedback system in its simplest form is when the product from the target cells inhibits the hormone
secretion from the endocrine cells. An example is the release of thyroid stimulating hormone (TSH) from the
anterior pituitary. This stimulates the release of thyroxine (T4), and high levels of T4 feedback and inhibit the
release of TSH.

POSITIVE FEEDBACK CONTROL

Oxytocin production and secretion is controlled by a positive feedback mechanism where release of the hormone
causes an action that stimulates more of its own release. For example, when contraction of the uterus starts during
childbirth, oxytocin is released. Another example is release of prolactin by the sucking of the breast.

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 RECEPTORS

INTRODUCTION
Generally speaking, there are two types of receptors – sensory (taste bud, rods and cones etc) and those
macromolecules which are specifically related to physiology, biochemistry and especially pharmacology.
A receptor is any macromolecule or complex of macromolecules (proteins / peptide / DNA) which have a minimum
of two functional domains (ligand binding domain and effector domain).
A ligand is a substance which binds with a receptor at the ligand binding domain and lead to the production of
biological response. When the ligand binds to the receptor, it alters the structure of the receptor resulting in the
activation of the effector domain. Plasma proteins binds drug and other substances, but it does not have effector
domain, and no conformational change and therefore no specific biological response because no effector domain.
Ligand is substance which binds with a receptor and bring about conformational or functional change in the receptor
to produce some biological response. The ligand may be:
o Hormone
o Drug
o Neurotransmitter

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 o Toxins
o Other substances.
In response to binding, the receptor undergoes a conformational change (structural and functional change) and the
result of that modification will be that the effector domain is activated or inactivated.
Receptors are broadly classified into the following groups based on their location:
o Cellular
o Membrane
o Intracellular
 Cytoplasm (steroid hormones)
 Nucleus (T3 and T4).
o extracellular

The ligands can access the receptor based on their molecular weight (size), charge and lipid solubility.

Cell surface (membrane):

 Large molecular weight
o Peptide hormones
 Insulin
 Glucagon
 Growth Hormone
 Prolactin
 FSH
 LH
 TSH
 Highly polar (charged)
o Catecholamines
 Noradrenaline
 Adrenaline
 Dopamine
o Acetylcholine
o 5- HT
o Histamine
o Prostaglandin

Intracellular

 Small molecular weight.

o T3 & T4
o Retinoids (Vitamin A).
 Lipid soluble
o All steroid hormones
 Testosterone
 Progesterone
 Oestrogen
 Aldosterone
 Glucocorticoid
 Vitamin D (cholecalciferol)

CELL MEMBRANE RECEPTORS

 7 pass / serpentine / G-protein coupled receptors.
 1 pass receptor (tyrosine kinase, insulin receptor)
 4 – 5 pass receptors / ion channel
 12 pass receptors

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Transmembrane receptors take extracellular signal inside the cell and they bring about biological response inside the
cell.

7 PASS / SERPENTINE / G-PROTEIN COUPLED RECEPTOR

 Big family of receptors.

 Serpentine (snake-like)
 Passes in and out of the cell membrane 7 times
 Has two functional binding domains – ligand binding domain outside and the effector domain inside.
Extracellular domain is the ligand binding domain. When the ligand binds the receptor it activates the receptor, then
the intracellular part (effector domain) will start giving very unique signals to the cell.
Ligands for the 7-pass receptor include:
 Catecholamines
 Acetylcholine
 Prostaglandins
 Histamine
 5 -Hydroxyl Tryptamine
 TSH

The 7-pass receptor is coupled to a unique type of protein – the trimetric primary protein found in the cell.

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The -subunit binds with a high energy compound (GTP) and the compound and the complex is highly energetic
and very active. Because the intracellular protein is binding with GDP or GTP, they are simply called G-protein. The
serpentine receptor is a G-protein coupled receptor.

G-Proteins are unique type of intracellular proteins to which GTP or GDP binds. All the serpentine receptors work
through different types of G-Proteins – hence they are called G-protein coupled receptors.

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ONE PASS RECEPTOR
One pass receptor has a unique effector domain – the domain is an enzyme, so the other name for the one pass
receptor is enzyme linked receptor.

Example of 1-pass receptors include:

 Tyrosine kinase
 Insulin
When insulin binds its 1-pass receptor, it attracts another 1-pass receptor [insulin receptor dimerization] resulting in
a dimer; the intracellular change is brought about by the dimer.

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4 – 5 PASS RECEPTORS
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  May be 4 or 5 different peptide units eg ligand binding ion channels – nicotinic cholinergic receptors or
 Single peptide unit that is going in and out of the membrane.
 The effector unit is basically a canal or central pore which is opening and closing. When the ligand binds
the frequency of opening and closing of the canal changes and this brings about a biological change.

When Ach binds, it changes the frequency of opening and closing of the receptor canal. Upon ligand binding, some
ion channels undergo a conformational change that alters the flux or movement of the ions. Such receptors are called
ligand-gated or ligand operated ion channel.

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7-PASS / SERPENTINE / G-PROTEIN-COUPLED RECEPTOR
Examples of ligands that bind to the 7 – pass receptors include:
 Adrenergic receptors.
 Glucagon
 Muscarinic Ach receptors.
When adrenaline binds at the ligand binding domain, there is a change in the intracellular cAMP levels.
 Ligand binding of catecholamine is the 1st messenger.
 Ultimate biological changes in cAMP is the 2nd messenger.

When the ligand binds at the ligand binding domain (amino acid end) extracellularly the carboxylic end (effector
domain) does not change the cAMP directly. In between there are many molecular signalling pathways going on.
When the ligand binds it leads to conformational changes in the transmembrane domain component resulting in a
twist at the effector domain thereby exposing it to the signalling pathways.

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The trimetric primary G-protein then binds to the intracellular effector domain – the G-protein binds GTP or GDP.
 Monomeric – 1 peptide
 Trimetric – 3 peptides (, , ).
The effector domain changes in such a way that the trimetric G-protein will bind there. 30 – 40 % of current drugs
act by modifying the action of the 7-pass receptors.

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12-PASS SERPENTINE RECEPTORS
 Single peptide chain
 Passes through the membrane 12 times.
 The 12 pass receptors are found at the presynaptic nerve endings of neurones which release monoamines
where they bring about their re-uptake into the presynaptic nerve endings.

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NUCLEAR HORMONE RECEPTORS

Fig 1: Intracellular receptors

Nuclear hormone receptors (NHRs) are located inside the cell. These receptors are found either in the cytoplasm
(type I) or the nucleus (Type II). Nuclear receptors are a family of ligand-regulated transcription factors that are
activated by:
 Steroid’s hormones (estrogen and progesterone)
 Lipid-soluble signals (retinoic acid, oxysterols)
 Thyroid hormones

MECHANISM OF ACTION OF NUCLEAR RECEPTOR.

Small lipophilic substances such as natural hormones diffuse through the cell membrane and bind to the nuclear
receptor located in the cytosol (type I) or nucleus (type II) of the cell. Binding causes a conformational change in the
receptor which, depending on the class of receptor, triggers a cascade of downstream events that direct the nuclear
receptor to DNA transcription regulation sites which result in up or down regulation of gene expression.

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Fig 2: Mechanism of class I nuclear receptor action.
A class I nuclear receptor (NR), in the absence of a ligand, is located in the cytosol. Hormone binding to the NR triggers
dissociation of heat shock proteins (HSPs), dimerization, and translocation to the nucleus, where the NR binds to a specific
sequence of DNA known as a hormone response element (HRE). The nuclear receptor DNA complex in turn recruits other
proteins that are responsible for transcription of downstream DNA into mRNA, which is eventually translated into protein, which
results in a change in cell function.

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Fig 3: Mechanism of class II nuclear receptor action
A class II nuclear receptor (NR), regardless of ligand-binding status, is located in the nucleus bound to the DNA. For the purpose
of illustration, the nuclear receptor shown here is the thyroid hormone receptor (TR) heterodimerized to the RXR. In the absence
of ligand, the TR is bound to corepressor protein. Ligand binding to TR causes a dissociation of corepressor and recruitment of
coactivator protein, which, in turn, recruits additional proteins such as RNA polymerase that are responsible for transcription of
downstream DNA into RNA and eventually protein.

EXTRACELLULAR RECEPTORS

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Example of extracellular receptor include:
 Coagulation factors.
 Antibodies
 Cytokines
 Complement C5a (activated).

COAGULATION FACTORS (ANTI-THROMBIN 3)

Coagulation factors are plasma proteins behaving like receptors. Anti-thrombin 3 are extracellular proteins which
inactivates some of the coagulation factors (eg active factor X). Anti-thrombin 3 behaves like a receptor, it has
heparin binding domain and an effector domain. Some drugs bind with coagulation factors in such a way that their
action is either prolonged or reduced. When heparin binds at the ligand binding domain, it results in enhanced ability
of anti-thrombin 3 to inactivate coagulation factors.

FORECES BETWEEN RECEPTOR AND LIGAND

 Van der Waal
 Hydrophobic interaction
 H+ bonds
 Ionic bond
 Covalent bond (strongest force)

Monoamines – amides derived from one amino acid

Amino acid amine
Tyrosine T3 and T4
Catecholamines [ Dopamine, Adrenaline, Noradrenaline]
Histidine Histamine
Tryptophan 5 -OH tryptamine

Monoamine Oxidase

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 Catechol ring

Dopamine showing catechol ring, ethylene group (with beta carbon) and the amine group

Catecholamine catabolism involves the removal of the two OH group of the catechol ring by catechol – O- methyl
transferase (COMT). The OH group at the beta carbon is removed by monoamine oxidase inhibitors (MAOI).

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EXTRACELLULAR SIGNALLING (SIGNAL TRANSDUCTION)

G-PROTEIN COUPLED RECEPTORS

Embedded within is a receptor – the G-protein coupled receptor. The receptor hqs 3 portions:
o Ligand binding domain.
o 7 transmembrane domains [receptor portion]
o Effector domain.
On the extracellular site is the signal/ligand binding domain. The receptor portion goes in and out of the membrane
7 times in a snake-like motion. The receptor is associated with a G-protein network which consists of 3 subunits –
heterotrimeric G-protein (). When the signal binds at the ligand binding domain, there is a conformational
change within the trimetric protein subunit of the G-protein. The  subunit is dissociated while the  and  subunits
remain close to the plasma membrane. The GDP on the  subunit is converted to GTP thereby creating a GTP-
bound  subunit that is now active. Active  subunit can act in a few ways:
 Gs [stimulate]
 Gi [inhibits]
 Gq

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The Gs activates adenylate cyclase whose role is to convert ATP into cAMP. The cAMP then activates protein
kinase A [PKA]. The PKA will have further downstream secondary messenger effects.
The Gi does the opposite, it inhibits adenylate cyclase thereby preventing the conversion of ATP to cAMP and
activation of protein kinase A.

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The Gq activates phospholipase C which activates the conversion of Phosphatidylinositol 4, 5-bisphosphate [PIP2]
to Inositol triphosphate or inositol [ IP3] and DAG each of which carry out unique effects.
IP3 causes a release of Ca2+ from the endoplasmic reticulum and DAG activates protein kinase C [PKC].
The combination of Ca2+ being released from the endoplasmic reticulum and protein kinase C being activated by
DAG would both have further downstream effect particularly Ca 2+ which would go on to activate a whole host of
enzymes and carry out secondary messenger functions.

A G-protein couple receptor can cause either:

 The activation of protein kinase A
 The inhibition of protein kinase A or
 The activation of both Ca2+ and protein kinase C.
Depending of what the intending effect is to the secondary messenger system, protein kinase A, Ca 2+ and protein
kinase C can go on to have further intracellular control.

The hormones under the control of the cAMP pathway include:

 FSH
 LH
 ACTH
 TSH
 CRH
 hCG
 ADH
 MSH
 PTH
 Calcitonin
 GHRH
 Glucagon
 Histamine (H2)

The hormones under the control of IP3 include:

 GnRH
 Oxytocin
 ADH
 TRH
 Histamine
 Angiotensin II
 Gastrin

RECEPTOR TYROSINE KINASE

Receptor tyrosine kinases are the largest class of signal transductors. They are very unique in that receptor tyrosine
kinases have inherent enzyme activity – although they are receptors, they are technically enzymes hence the name
receptor tyrosine kinase.
Growth factors or local signalling molecules will bind on top of the receptor tyrosine kinases. When this happens, it
forces two tyrosine receptors to move close to one another and link up in a process called dimerization to form a
dimer. The then dimer then undergoes a process called cross phosphorylation of the tyrosine residues – the tyrosine
kinase activity in each of these dimers cross phosphorylate each other ie they phosphorylate the tyrosine on the other
receptor tyrosine kinase.

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Cross phosphorylation results in the formation of SH2 domain. This is basically a binding site on top of receptor
tyrosine kinase where various enzymes and other molecules can bind to kick off complex signal transduction.
RAS is a low molecular weight GTP-binding protein(G-protein). Ras acts as a critical relay in signal transduction by
cycling between an active conformation state when bound to GTP, and an inactive state when bound to GDP – it
works as the on/off switch in the signaling of molecules leading to cell proliferation.

When RAS binds to the SH2 domain of receptor tyrosine kinase, the GDP is exchanged for GTP and RAS becomes
activated. Activated RAS will under this complex pathway:

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 RASGTP

MAP-Kinase-Kinase-Kinase RAF

MAP-Kinase-Kinase MEK

MAP-Kinase ERK

As you go down the pathway, there are activators in the form of serine threonine kinases in the MAP kinase
cascades, it drops one kinase as you go down the cascade.

Receptor tyrosine kinases controls:

 Insulin
 IGF-1

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  FGF
 PDGF
 EGF

Receptor Tyrosine Kinase [R3K)

RAS Three Kinases

cGMP PATHWAYS
Nitric oxide (NO) crosses the membrane and interacts with guanylate cyclase. Guanylate cyclase converts GTP into cGMP which
goes on to activate protein kinase G (PKG).
The endocrine hormones that are controlled in this pathway are:
 BNP
 ANP
 EDRF
The cGMP pathway has really profound effects on smooth muscles, so this pathway has a lot of effects on vasodilation.
Nitric oxide kicks off the cGMP pathway and it control the BNP, ANP and EDRF.
The signalling pathways that regulate the synthesis of cGMP in cells include hormonal regulation of transmembrane guanylate
cyclase such as the atrial natriuretic peptide receptor [ANP] and the activation of soluble forms of guanylate cyclase by nitric
oxide [NO].

The role of nitric oxide in stimulating soluble guanyl cyclase and promoting vascular smooth muscle relaxation.
NOS [Nitric Oxide Synthetase]
P [Phosphate group]
PKG [Protein kinase G]

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NEUROHYPOPHYSIS (Nervous)
The neurohypophysis (pars posterior) is a structure that is located at the base of the brain and is the posterior lobe of
the pituitary gland.

ADENOHYPOPHYSIS (Glandular)
The anterior pituitary (adenohypophysis) is a lobe of the gland that regulates several physiological processes
(including stress, growth, reproduction and lactation).

PARS NERVOSA
The pars nervosa is a neuroendocrine structure that, along with the anterior lobe, intermediate lobe, infundibular
stalk, makes up the pituitary gland. This structure lies within the Sella turcica, a saddle-shaped indentation in the
sphenoid bone that lies posterior to the nasopharynx.

PARS DISTALIS
This is the portion in which the majority of the hormone production occurs. It is the distal part of the pituitary and
forms the majority adenohypophysis.

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TRUE or FALSE?

• The Pars nervosa of the pituitary gland forms the anterior pituitary? F
[Pars nervosa is neurohypophysis]
• Oxytocin is released from the neurohypophysis T

HYPOTHALAMIC -PITUIATARY ANATOMY

HYPOTHALAMIC NUCLEI

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HORMONES OF THE NEUROHYPOHYSIS

Vasopressin/ADH Oxytocin
Stimulus Baro/Osmoreceptors Uterine contraction, Breast feeding
Synthesis Magnocellular cells of SON/PVN Hypothalamus
Pituitary cells Herring bodies in axon of Posterior Pituitary
End Organ Kidney/Vasculature/Diverse Brain/Uterus/ Breast/Diverse
Product Water balance & Vascular tone Lactation (Milk ejection)
Uterine contraction
Social behavior
etc

HYPOTHALAMIC NUCLEI

HORMONES OF THE ANTERIOR PITUITARY

Releasing H Pituitary Cells Pituitary H End Organ Product

TRH / Thyroid thyrotrope TSH Thyroid Thyroxine
CRH / Adrenal Corticotrope ACTH Adrenal Cortisol
GnRH / Gonads Gonadotrope LH and FSH Testis or Ovaries Testosterone /Estradiol
GHRH / Growth Somatotrope GH Liver IGF – 1
Dopamine (Inhibitor) Lactotrope Prolactin Mammary gland Milk (no feedback)

TRUE or FALSE?

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 • Sheehan’s syndrome differentially affects the anterior & posterior pituitary
• Sheehan’s is more likely to cause selective rather than pan-hypopituitarism

PITUITARY – THINK SHEEHAN’S SYNDROME

Sheehan’s syndrome is a postpartum hypopituitarism caused by necrosis of the pituitary gland due to sudden
hypovolaemia. It is usually the result of severe hypotension or shock caused by massive hemorrhage during or after
delivery.
The criteria for diagnosis of Sheehan’s syndrome includes a typical obstetric history of:

 Severe postpartum vaginal bleeding.

 Severe hypotension or shock for which blood transfusion or fluid replacement is necessary.
 Failure of postpartum lactation.
 Failure to resume regular menses after delivery.
 Partial or panhypopituitarism and
 Empty Sella on CT scan or MRI.
Sheehan’s syndrome refers to postpartum hypopituitarism as a result of pituitary necrosis occurring during severe
hypotension or shock secondary to massive bleeding during or just after deliver. Though first described by HL
Sheehan in 1837, it was known as Simmond’s disease until 1939 when Sheehan described the disease was due to
postpartum necrosis of the anterior pituitary following postpartum haemorrhage.
Adenohypophyseal ischaemic necrosis following hypoperfusion is the cause of Adenohypophyseal insufficiency.

The underlying process leading to Sheehan’s syndrome is the infarction of the physiologically enlarged pituitary
gland, particularly anterior lobe, secondary to the grossly decreased blood supply during intra-partum or postpartum
events.
Though vasospasm, autoimmunity, small sella size, and disseminated intravascular coagulation may also have a role
in the development of Sheehan’s syndrome, none has been conclusively proven.
The clinical presentation of Sheehan’s syndrome from longstanding non-specific features such as weakness, fatigue,
and anaemia to profound abrupt hypopituitary resulting in coma and death. The mean duration between postpartum
bleeding and the subsequent development of symptoms varies from 1 to 33 years.
Characteristic manifestations include failure to lactate or to resume menses, genital and axillary hair loss, asthenia
and weakness, fine wrinkles around the eyes and lips, signs of premature aging, dry skin, hypopigmentation and
other evidence of hypopituitarism.
Uncommonly, it can present acutely with circulatory collapse, severe hyponatraemia, diabetes insipidus,
hypoglycaemia, congestive cardiac failure or psychosis.
The extent of anterior pituitary involvement varies in different series. The main involvement was the secretion of
growth hormone [GH] and prolactin (90 – 100%), while deficiencies in cortisol secretion, gonadotropin and thyroid
stimulating hormone (TSH) ranged from 50 – 100%.
Lactation failure is a very common clinical feature and the lack of prolactin administration of thyrotropin releasing
hormone (TRH) has been suggested as procedure for screening of patients suspected to have SS.

Hyponatraemia is the most common electrolyte disturbance occurring in 33 – 69% of all cases. Hypothyroidism and
glucocorticoid deficiency by decreasing free water clearance independent of vasopressin cause hyponatraemia.
Syndrome of inappropriate ADH secretion (SIADH) and volume depletion are the other factors leading to
hyponatremia. Clinical diabetes insipidus is apparently an uncommon complication of postpartum pituitary necrosis
occurring in about 5% of all cases.

Haematological abnormalities are common and include:

 Normocytic normochromic anaemia.
 Pancytopenia.
 Acquired factor VIII and von Willebrand factor (aFVIII -VWF) deficiency.
Anaemia is well recognized as a feature of hypopituitarism.

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Many hormonal deficiencies, such as hypothyroidism, adrenal insufficiency and gonadal hormonal deficiency, can
explain normochromic anaemia in hypopituitarism. Pancytopenia as a result of an anterior hormone deficiency has
not been clearly investigated. It is a consequence of the loss of effect of pituitary hormones on metabolic reactions to
hematopoiesis, which is related to hypopituitarism.

The presence of anti-pituitary antibodies [APAs] has been demonstrated in some patients with SS, suggesting that an
autoimmune pituitary process could be involved in this syndrome. It is proposed that sequestered antigens due to
tissue necrosis could trigger autoimmunity and may cause delayed hypopituitarism in these patients.
The criteria for the diagnosis of SS are as follows:
o Typical obstetric history of intrapartum or postpartum bleeding.
o Hypotension or shock.
o Agalactia.
o Failure to resume regular menses after delivery.
o Hypopituitarism and
o Empty Sella on CT or MRI.

The diagnosis of Sheehan’s syndrome is based on the features of hormone deficiency, a suggest obstetric history,
and decreased basal hormones levels [free T3 and T4, TSH, cortisol, ACTH]. The diagnosis can be made reliably in
the presence of lactational failure, prolonged amenorrhea and hypoglycaemic crises.

The goal of therapy is to replace deficient hormones. The treatment is important not only to correct endocrine
abnormalities, but also to reduce mortality due to hypopituitarism. The treatment of SS is replacement of deficient
hormones. ACTH and TSH deficiencies should be replaced with glucocorticoids and thyroxin respectively.
Gonadotropin deficiency and hypogonadism should be treated with hormonal replacement therapy.

TRUE or FALSE?

• Sheehan’s syndrome differentially affects the anterior & posterior pituitary T

• Sheehan’s is more likely to cause selective rather than pan-hypopituitarism T

• Pituitary necrosis due to hypoperfusion (classically severe haemorrhage in childbirth)

• Results in selective ant. necrosis pit & occasionally panhypopituitarism
– Ant pit hypertrophy in pregnancy, low pressure system, no change in blood supply. Not same for
post pit
• Symptoms/conditions of panhypopituitarism (red = commonest in Sheehan’s):
– Lactation problems
– Amenorrhoea/infertility/libido (GH & LH/FSH)
– Depression, fatigue, central obesity (GH)
– Addison’s [Insufficient]
– Hypothyroidism
– Gonadal development/Growth retardation (paeds)
– DI

GROWTH HORMONE- SOMATOTROPIN – DWARFISM- GIGANTISM- ACROMEGALY

PITUITARY ADENOMA
Pituitary adenomas are tumors of the anterior pituitary. Most pituitary tumors are slow-growing and benign. They
are classified based on size or cell of origin. Pituitary adenoma can be described as microadenoma, macroadenoma,
and giant tumors based on size. Microadenoma is a tumor less than 10 mm, while macroadenoma describes a tumor
larger than 10mm. Giant pituitary tumors are bigger than 40 mm. There are functioning pituitary adenomas in which

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the cell type that composes them causes increased secretion of one or multiple hormones of the anterior pituitary.
Alternatively, there are nonfunctioning adenomas that do not secrete hormones, but they can potentially compress
the surrounding areas of the anterior pituitary leading to hormonal deficiencies. Patients with pituitary adenoma
need to be evaluated by a multidisciplinary team that should include endocrinology, ophthalmology and
neurosurgery.

AETIOLOGY
The pathogenesis of pituitary adenoma remains unknown. Most of the pituitary adenomas are sporadic.

 Non-function
 Prolactin-secreting
 Growth Hormone-secretary
 ACTH secreting
Genetic mutation is rarely a feature of pituitary adenoma.

EPIDEMIOLOGY

Pituitary adenomas are mostly found incidentally on imaging modalities obtained for other reasons. Given the
insidious nature of the pituitary adenomas, smaller size, and incidental diagnosis, it is challenging to accurately
estimate the prevalence of pituitary adenomas in the general population. The estimated prevalence of pituitary
adenomas is extrapolated from autopsy and radiological data.

HISTORY AND PHYSICAL

The presentation of pituitary adenoma depends on tumor size and functional status.
Pituitary microadenoma is usually an incidental finding on MRI head. Patients are asymptomatic unless the tumor is
hormonally active.
Pituitary macroadenoma presents with mass effects and potentially hormonal deficiency or hormonal excess.
Pituitary apoplexy is a sudden hemorrhage into pituitary adenoma. It is very rare. It presents with symptoms of a
mass effect that includes sudden headaches and vision changes along with hormonal deficiency.

Symptoms from Mass Effect:

 Visual impairment: Visual impairment is reported in approximated 40% to 60% of patients. Suprasellar
extension of the pituitary adenoma compresses the optic chiasm leading to visual field defects. Bitemporal
defect is the most prevalent pattern, followed by homonymous defects. The involvement of the oculomotor
nerve can lead to diplopia, while the fourth, fifth, and sixth cranial nerves may also be involved with
invasive tumors.
 Headache: Headache is commonly reported in pituitary adenoma; however, it is a non-specific symptom.
 Hormonal deficiency: One or more anterior pituitary hormonal deficiencies can be observed in patients
with pituitary macroadenoma.
Gonadotropin deficiency:

 Amenorrhea in females
 Erectile dysfunction in males
Growth Hormone deficiency adults

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  Fatigue
 Weight gain
Thyroid-stimulating hormone (TSH) deficiency

 Weight gain
 Fatigue
 Cold intolerance
 Constipation
ACTH deficiency

 Fatigue
 Arthralgia
 Weight loss
 Low blood pressure
 Dizziness
 Nausea & vomiting
 Abdominal pain

Functioning or secretary adenomas

The clinical presentation depends on the hormone secreted as described below:

PROLACTIN-SECRETING ADENOMA
Elevated prolactin suppresses the gonadotrophin levels leading to:
 Infertility
 Decrease libido, and
 Osteoporosis in both sexes.
 Amenorrhea and galactorrhea [females]
 Erectile dysfunction and gynecomastia [males]

GH SECRETING ADENOMA [ACROMEGALY]

Presentation includes:
 Headaches
 Vision changes
 Increase in ring or shoe size
 Arthritis
 Carpal tunnel syndrome and
 Excessive sweating.

Clinically patients have:

 Coarse facial features
 Frontal bossing
 Enlarged nose
 Prognathism
 Enlarged tongue and
 Skin tags.

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Other comorbidities:
 Hypertension
 Cardiomyopathy
 Obstructive sleep apnea
 Multiple colonic polys.

ACTH-SECRETING ADENOMA [CUSHING DISEASE]

Presents with:
 Weight gain
 Muscle weakness
 Mood disorders
 Easy bruising and
 Multiple fractures
Clinical features include:
o Round face
o Facial plethora
o Supra-clavicular fat
o Ecchymoses
o Purple striae on the abdominal area and armpit.

TSH SECRETING ADENOMA

Patients have symptoms of:
 Palpitations
 Arrhythmias
 Weight loss
 Tremors and Goitre.

EVALUATION
Most pituitary adenomas are detected incidentally on routine CT imaging. An MRI with gadolinium is necessary for
the distinction of a mass from an aneurysm and to assess for hemorrhage into the mass.
Additionally, screening for hypopituitarism and assessing for hypersecretion is warranted. The Endocrine Society
clinical practice guidelines recommend a complete biochemical assessment, even in asymptomatic patients. This
evaluation includes the measurement of various hormones such as:
 Prolactin
 TSH
 Free T4
 FSH
 IGF-1
 GH
 Estradiol
 Testosterone
 BMP and
 Fasting early morning cortisol.

PROLACTIN

39
The prolactin level usually correlates with the size of the adenoma. Serum prolactin level of less than 200 ng/ml is
present in microadenoma, due to the "stalk effect " in macroadenoma or medications. A serum prolactin level of
greater than 200 ng/ml suggests prolactin-secreting macroadenoma. Prolactin becomes elevated in:

 Pregnancy
 Breastfeeding
 Nipple stimulation
 Chest wall trauma
 Hypothyroidism
 Renal failure and
 Certain categories of medications:
o Antipsychotics
o Antidepressants
o Opiates
o Antiemetics.

 Pregnancy
Macroprolactin, also known as "big -prolactin," is the inactive form of prolactin. It is essential to diagnose
macroprolactin to avoid unnecessary medical treatment. The diagnosis of macroprolactin involves precipitation of
the serum with polyethylene glycol (PEG). The presence of free prolactin over 60% confirms prolactinoma.

IGF – 1/ GH
Serum IGF-1 is a screening test for the diagnosis of acromegaly and GH deficiency. Conditions like:
o Poorly controlled diabetes
o Malnutrition
o Sepsis
o Hypothyroidism
o Hepatic and renal failure

can impact the IGF – 1 and GH levels.

In patients with acromegaly, where the IGF-1 level is not found to be high or is equivocal, the serum GH level can
be assessed after a 75 gm oral glucose challenge test. A non-suppressed GH level of greater than 1 ng/dl with
hyperglycemia confirms acromegaly. In adults, isolated GH deficiency requires further evaluation with provocative
testing like Insulin-induced hypoglycemia test, glucagon stimulation test, or the newly developed macimorelin
stimulation test.

CORTISOL
Early morning fasting cortisol level can be useful in assessing the hypothalamic-pituitary-adrenal (HPA) axis
insufficiency. AM cortisol level of greater than 14 mcg/dl is suggestive of normal HPA axis. If morning cortisol is
equivocal or low, the clinician should obtain a cosyntropin stim test. Random cortisol level measurement does not
help in identifying patients with cortisol excess.

CUSHING DISEASE
The screening tests for Cushing disease include checking:
 Late-night salivary cortisol (around midnight).
 24-hour urine free cortisol, or

40
  Dexamethasone suppression test (DST).

Late-night salivary cortisol has a greater than 90% sensitivity and specificity if done accurately. DST includes
checking early morning cortisol after taking 1 mg of dexamethasone at 11:00 pm to midnight. A cortisol level of 1.8
mcg/dl or higher suggests hypercortisolemia. Urine free cortisol requires accurate 24-hour urine collection.
Interpretation of the screening test for cortisol excess should proceed cautiously as many factors like exogenous
steroids, depression, excess alcohol intake, and oral contraceptives can affect cortisol levels.

Once hypercortisolemia is confirmed biochemically, the next step is to find the etiology by checking ACTH.
Hypercortisolemia with elevated ACTH suggests a corticotroph adenoma.

INFERIOR PETROSAL SINUS SAMPLING [IPSS]

ACTH producing adenomas are frequently small, and an MRI of the head can be normal in 50% of the patients. In
the setting of normal MRI head or pituitary microadenoma less the 0.6 cm, inferior petrosal sinus sampling (IPSS) is
recommended to differentiate between ectopic vs. pituitary Cushing.
IPSS is an invasive procedure where catheters are inserted into the petrosal sinuses bilaterally. ACTH level
measurement takes place before and after stimulation with the corticotropin-releasing hormone (CRH). A threefold
increase in ACTH levels suggests a pituitary source.

TSH/Free T4
Low free T4 with normal or low TSH stipulates secondary (central) hypothyroidism. TSH-producing adenoma will
present with elevated T4 and T3 with inappropriately normal or elevated TSH.

Gonadotropin levels (LH/FSH)

Low estradiol or testosterone levels with normal or low LH/FSH levels suggest hypogonadotropic
hypogonadism. The sex hormones can not be interpreted accurately in females if they are on oral contraceptives.
Post-menopausal females will physiologically have elevated FSH levels.

TREATMENT / MANAGEMENT
The management of pituitary adenomas requires an endocrinologist and a neurosurgeon to work closely together and
develop an "individualized patient-centric" approach.
Treatment of Non-Functioning Adenomas
Transsphenoidal resection is recommended in patients with macroadenomas and the following scenarios:

 Visual field deficit due to tumor

 Other visual abnormalities as ophthalmoplegia
 Compression of the optic nerves or chiasm on imaging
 Pituitary apoplexy with visual disturbance
 Loss of endocrine function
 Significant growth of pituitary tumor over time
After surgery there is usually an improvement in visual symptoms and hormonal dysfunction in most patients.
Radiotherapy is a consideration in patients with persistent residual or recurrent tumor.
In nonfunctional adenomas that do not require surgical management, annual follow-up with endocrinology is
important to assess for tumoral growth and development of hypopituitarism. MRI of head is obtained annually for
three years and if stable, thereafter less frequently.

41
Treatment of Individual Functioning Tumors

 Prolactin-Secreting Adenoma: The goal of treatment is to restore gonadal function and decrease tumor
size. Observation with periodic monitoring of prolactin levels can be an option in patients who are
asymptomatic with microadenoma.
Medical Therapy
Dopamine agonists (DA) are the first-line treatment for prolactin-secreting tumors. The currently available DAs are
cabergoline and bromocriptine. Cabergoline is more than 90% effective in normalizing prolactin levels and
decreasing tumor size. The adverse effects of DA are dizziness due to postural hypotension, valvular heart
abnormalities, and the development of compulsive behavior or mood changes. DA could be discontinued after two
years of treatment if the MRI of head did not show a visible tumor. Monitoring serum prolactin levels annually is
needed in these patients as there is some risk of recurrence or growth after stopping DA.
Surgery
Transsphenoidal surgery is often reserved for prolactin-secreting tumors which are resistant to medical treatment,
patients who develop adverse effects to dopamine agonists and, in patients desiring pregnancy with tumor size of
more than one centimeter.
Radiation Therapy
Radiotherapy is seldom used in cases of aggressive prolactinomas, where frequent surgeries and medical therapy
have failed to control the size of the adenoma.

 GH Secreting adenoma: The goal is to decrease growth hormone levels to less than 1ug/L and get IGF-1
levels to the normal age-adjusted range.
Surgery: Trans-sphenoidal surgery is the first-line treatment for GH-secreting tumors. In the hands of an
experienced surgeon, normalization of IGF-1 is achieved in 80% to 90% of patients with microadenomas and 40%
to 60% of patients with macroadenomas.
Medical therapy: Medical treatment is considered in patients with persistently elevated IGF-1 and GH levels at
three months after surgery or in non-surgical candidates with invasive tumors. Somatostatin analogs (SSA) are the
first-line treatment for acromegaly. Current available SSAs are octreotide, lanreotide, and pasireotide. The adverse
effects of SSA include gallbladder sludge and stones, abdominal cramps, flatulence, diarrhea, and alopecia.
Pasireotide can lead to hyperglycemia in 50 to 70% of patients. DA, like cabergoline, is also used for mildly
elevated IGF-1 level post-surgery or as an adjunct therapy with SSA. If the GH remains elevated, pegvisomant, a
GH receptor blocker, can be used in combination with SSA or alone for the treatment of acromegaly.
Radiotherapy: Radiation treatment may be used as an adjunct in patients with elevated IGF-1 levels after surgery,
but it will take several years to be effective.

 ACTH secreting adenoma: The goal of treatment is to decrease cortisol levels rapidly and to reduce the
associated complications and mortality.
Surgery: Trans-sphenoidal surgery is the first-line treatment for Cushing's disease. The cure rate is 70% to 90 % in
the hands of an expert surgeon with initial and repeated surgeries.
Medical therapy: DA (cabergoline) and SSA (pasireotide, pasireotide LAR) are the drugs directed at the pituitary
to decrease ACTH secretion. Ketoconazole, metyrapone, mitotane, and etomidate also decrease adrenal cortisol
production. Ketoconazole can lead to liver toxicity and prolongation of the QT interval. Metyrapone is 50 to 60%
effective in reducing the cortisol level. Mitotane is an adrenolytic drug, mostly used in patients with adrenocortical
cancer. Etomidate is given intravenously in critically ill patients with severe hypercortisolemia as a bridge to work
on other treatment interventions. The glucocorticoid receptor blocker, Mifepristone, can be used in selected patients
with hypercortisolemia and diabetes.

42
Bilateral adrenalectomy can lead to an immediate cure of hypercortisolemia with resultant adrenal insufficiency
requiring lifelong treatment. Nelson syndrome, which is radiological pituitary tumor enlargement, can occur in 50 %
of patients after adrenalectomy.
Radiotherapy: Radiation treatment serves as an adjunct after surgery and medical therapy.

 TSH secreting adenoma: Trans-sphenoidal surgery is the initial preferred treatment option leading to a
cure in 50% to 90% of patients. It is crucial to control hyperthyroidism before surgery to avoid thyroid
storm. Presurgical euthyroidism is achieved by using anti-thyroidal medical therapy like methimazole or
SSA. Patients who are not cured by surgery can be treated with SSA alone to decrease TSH levels and
tumor size, or in combination with radiation treatment.

ACROMEGALY & PITUITARY

TRUE or FALSE?

• 80% of acromegaly is caused by pituitary adenoma T

• Acromegaly always causes gigantism F
• IGF-1 levels can help diagnose acromegaly.T

ACROMEGALY
• Syndrome of excessive growth hormone
• Commonest cause – pituitary adenoma (98%)
• Incidence 6-8/million cases in UK
• Spot Dx:
– Coarse & oily skin
– Soft tissue overgrowth (lips, tongue etc)
– Jaw & brow overgrowth
– Large hands and feet.

43
44
45
MECHANISMS OF HORMONAL CONTROL – GHRH, GH & IGF – 1

46
Growth Hormone (GH) is a protein hormone that has anabolic effects on tissues throughout the body. GH has two
types of effects:
 Direct effects
 Indirect effects
Direct Effects: GH stimulates lipolysis through its action on adipose cell GH receptors, thus increasing the
concentration of circulating fatty acids.

Indirect Effects: the majority of GH effects are mediated through insulin-like growth factor 1 [IGF-1], a hormone
secreted by the liver in response to circulating GH. IGF-1 promotes cell growth and development.
GH is released from the pituitary gland in a pulsatile fashion, particularly at night. Regulation of pituitary GH
secretion is complex:
GH secretion is promoted by the release of hypothalamic GHRH, but is inhibited by hypothalamic secretion of
somatostatin.
In addition, GH secretion is part of a negative feedback loop in which IGF-1 inhibits pituitary secretion of GH.
Overall, plasma GH concentration is usually very low, but is increased at:
 Time of physiological stress
 Hypoglycaemia
 Exercise
GH secretion is inhibited by:
 Insulin

47
  FFA

PATHOPHYSIOLOGY OF GROWTH HORMONE [GH]

The pathophysiology of growth hormone includes deficiency or excess of the hormone, with predictable effects on:
 Linear growth
 Organ growth
 Carbohydrate metabolism
 Lipid metabolism
GH Deficiency:
 Children
o Dwarfism
o Failure to grow
o Short status
o Mild obesity
o Delayed puberty

Causes of GH deficiency
 Defects at every step in the hypothalamic-anterior pituitary-target tissue axis
o  secretion of ACTH due to hypothalamic dysfunction.
o Primary deficiency of GH secretion from the anterior pituitary
o Failure to generate somatomedins in the liver
o Deficiency of GH or somatomedin receptors in target tissues [GH resistance].
 Treatment:
o Human GH replacement [children].

48
Somatomedins are a group of proteins produced predominantly by the liver when growth hormones act on target tissues.
Somatomedins inhibits the release of GH by acting directly on anterior pituitary and by stimulating the secretion of somatostatin
from the hypothalamus.

ACROMEGALY
GH excess causes acromegaly and is most often due to growth hormone-secreting pituitary adenoma. The
consequences of excess growth hormone differ, depending on whether the excess occurs before or after puberty.
Before puberty:
 Gigantism [ linear growth] due to intense hormonal stimulation at the epiphyseal plates.
After puberty:
  periosteal growth bone growth
  increased organ size
  Hand and foot size
 Enlargement of the tongue
 Coarsening if facial features
 Insulin resistance
 Glucose intolerance

49
Treatment:
 Somatostatin analogues [octretide] – inhibits GH secretion by the anterior pituitary.

 GH-MEDIATED INSULIN RESISTANCE

GH antagonizes insulin action via various molecular pathways. Chronic GH secretion suppresses the anti-lipolytic
action of insulin and increases FFA flux into the systemic circulation; thus, promoting lipotoxicity, which causes
pathophysiological problems, including insulin resistance.

Acromegaly is characterized by chronic overproduction of growth hormone [GH] that leads to insulin resistance,
glucose intolerance and, ultimately, diabetes. The main physiological role of growth hormone are the regulation of
postnatal growth and lipolysis. These actions are highly dependent on the nutritional state, which partitions the
metabolic actions of GH. GH is released from pituitary somatotroph cells in a pulsatile fashion that is tightly
controlled by hormones and nutrients. GH secretion is enhanced by:
 GHRH
 Fasting
 Stress
 Exercise
 Hypoglycemia and is
Suppressed by:
 Somatostatin
 Insulin
 Insulin-like growth factor (IGF-1)

50
  Glucose and
 Free fatty acids

GH excess in acromegaly results, with few exceptions, from a benign tumour of pituitary somatotroph cells and
leads to chronically increased GH concentrations, which do not respond to the classical physiological feed-back
inhibition. Therefore, acromegaly is characterized by a concomitant increase in both GH and IFG-1 production and
activity. The metabolic consequence of acromegaly is insulin resistance, which may progress to diabetes. The
underlying pathophysiological mechanisms are increased lipolysis, reduced peripheral glucose utilization and
enhanced gluconeogenesis.

51
HOW?

52
53
ACROMEGALY & PITUITARY
TRUE or FALSE?

• 80% of acromegaly is caused by pituitary adenoma T

• Acromegaly always causes gigantism F [ before puberty]
• IGF-1 levels can help diagnose acromegaly.

ACROMEGALY
• Syndrome of excessive growth hormone
• Commonest cause – pituitary adenoma (98%)
• Incidence 6-8/million cases in UK
• Spot Dx:
– Coarse & oily skin
– Soft tissue overgrowth (lips, tongue etc)
– Jaw & brow overgrowth
– Large hands and feet.

A 54-year-old male with acromegaly presents for trans-sphenoidal hypophysectomy.

a) What is acromegaly.
b) List the clinical features of acromegaly which are of relevance to the anaesthetist.
c) What other clinical presentations of a pituitary adenoma may be encountered?
d) What specific considerations, including surgical factors, may influence the conduct of anaesthesia in this
patient?

Clinical Features important to the Anaesthetist

 Skin and conn tissue
o Difficult cannulation
 Airway [large tongue]
o BMV & laryngoscopy considerations – full difficult intubation prep
o Goitre (25%) + Tracheal compression
o Sleep apnoea post operatively
o Respiratory drive & effect of opiates etc.
 Cardiac disease
o IHDx
o Hypertension
o CM
o Conduction problems
 Endocrine
o DM (25%)
o Hypothyroidism
o Hypoadrenalism

Clinical Presentation of Pituitary Adenomas:

 Mass effects
 Hormonal deficiencies
 Hormonal excess

54
  Pituitary apoplexy – sudden haemorrhage into the pituitary adenoma. It is very rare. It presents with
symptoms of mass effect that includes:
 Sudden headaches
 Visual changes +
 Hormonal deficiency.

Surgical factor:
Transsphenoidal – through the nose, therefore shared airway.
Position – supine with head tilt backward.

ADRENALS & STEROIDS

ANDRENAL GLANDS & HORMONES
TRUE/FALSE

 The adrenal glands consist of an inner medulla and outer cortex T

 The medulla produces mainly catecholamines T
 The cortex produces mainly catecholamines F
 The zona glomerulosa produces aldosterone T
 The zona fasciculata produces androgens F

 Tyrosine is the precursor for catecholamines T

 Epinephrine is the precursor of norepinephrine F
 Aldosterone causes sodium and water retention T
 Cortisol inhibits gluconeogenesis F
 The zona reticularis produces sex hormones T

Phaeochromocytoma

– Arises from the adrenal medulla T

– Is bilateral in 10% of patients T
– Causes paroxysms of hypotension F
– May present initially with symptoms of myocardial ischaemia T
– Can be diagnosed by measuring plasma norepinephrine T

Cushing’s disease
o Is caused by an adrenal adenoma F
o Causes progressive weight loss F
o May cause amenorrhea T
o May present with symptoms of diabetes mellitus T
o Is diagnosed using a dexamethasone suppression test T

55
Addison’s disease
 Is due to failure of the adrenal medulla F
 Is associated with increased pigmentation T
 Causes progressive weight loss T
 Causes low plasma ACTH levels F
 Will require treatment with increased steroids peri-operatively T

DEVEOPMENT
 The adrenal cortex and medulla have distinct embryological origins.
 The medullary portion consist of chromaffin cells derived from the ectodermal cells of the neural crest.
 Cortex is of mesodermal origin.

56
Foetus at 7 weeks. Transverse sections at level of the adrenals show developing gonads and adrenal cortex within urogenital
ridge. Migration of neural crest cells from sympathetic ganglion forms adrenal medulla.

ANATOMY OF ADRENAL GLANDS

THE ARTERIAL BLOOD SUPPLY TO EACH ADRENAL GLAND IS VIA 3 ADRENAL ARTERIES.
Very rich blood supply [3 arteries] for a tiny gland that weights a few grams

 The superior suprarenal artery – a branch of the inferior phrenic artery.

 The middle suprarenal artery – a branch of the aorta
 The inferior suprarenal artery – a branch of the renal artery.

THE VENOUS DRAINAGE IS DIFFERENT ON EITHER SIDE

o The right into the inferior vena cava
o The left into either the left renal or left inferior phrenic vein.

57
NERVE SUPPLY
 The adrenal medulla is a modified sympathetic ganglion made up of densely innervated granule containing cells and
constitutes about 30% of the mass of the adrenal gland.
 Approximately 90% of cells are adrenaline secreting cells while the others 10% are mainly the noradrenaline secreting
cells.

Neurotransmitters of the sympathetic nervous system are Ach[preganglionic], epinephrine [postganglionic].

The greater and lesser splanchnic nerves pass through the celiac ganglion, but do not make a synapse until they reach the adrenal
medulla. Here the nerve terminal releases acetylcholine at the surface of the chromaffin cells of the adrenal medulla. These cells
serve as postganglionic nerves cells, but instead of making a neural connection of their own, they secret epinephrine into the
blood[A].
The Ach then stimulate the production of epinephrine and norepinephrine. Therefore, the adrenal medulla is essentially the 1 st
part of the synaptic process.

58
However, the greater splanchnic nerve that goes to the kidney [B] does synapse at the celiac ganglion and therefore Ach is the
neurotransmitter there and the post synaptic nerve reaches the kidney. So when it comes to the renin-angiotensin system, it is
stimulated by the postganglionic nerve.

59
The adrenal glands are triangular organs closely related to the superior poles of the kidneys at the level of the T12
vertebral body. Each adrenal gland is surrounded by a protective fat pad and renal facia. The adrenal gland consists
of two distinct parts that differ in their embryological origins.

The outer adrenal cortex:

Makes up 70% of the adrenal gland’s weight. The adrenal cortex is derived from mesoderm and is composed of
three layers:

 Zona glomerulosa: the outermost layer – main site of aldosterone production.

o Displays occasional lipid droplets and a wealth of smooth ER.
o These cells manufacture, in response to ACTH and angiotensin II, aldosterone and a limited
quantity of deoxycorticosterone.

60
  Zona fasciculata: the middle layer – main site of glucocorticoid synthesis.
o Widest region of the cortex
o The large cells are arranged in longitudinal columns, are so well endowed by lipid droplets that in
histologic sections they resemble sponges – hence they are called spongiocytes.
o In response to ACTH, these cells secret the glucocorticoids cortisol and corticosterone.
 Zona reticularis:
o Thinnest and innermost layer.
o The cells resemble the spongiocytes of the zona fasciculata but with smaller lipid droplets.
o The parenchymal cells of this zone are arranged in networks of anastomosing cords and
manufacture androgens, predominantly:
 Dehydroepiandrosterone
 Androstenedione.
There are weak androgens that are converted to testosterone by the peripheral tissues.

Inner adrenal medulla.

The inner medulla is innervated by T5-T9 preganglionic sympathetic neurons; the adrenal medulla can be
considered to be a modified sympathetic ganglion.

ADRENOCORTICAL HORMONES
 All of the adrenocortical hormones are derived from cholesterol.
 Can be synthesized in the gland but is mostly taken up from the circulation.
 The mineralocorticoids and glucocorticoids are term C21 steroids because they have 21 carbon atoms in
their structure.
 The sex hormones are C19 steroids.

61
There are about 50 cytochrome p450 enzyme in the human body and it is not possible to survive for 1 hour without these
enzymes.
Cryptochrome P450 is very relevant to anaesthetic practice. They are heavily involved in the synthesis of adrenal hormones.

62
STEROID HORMONES
 Steroid hormones are relatively insoluble in plasma and must be carried by other molecules.
 Approximately 955 of plasma cortisol is bound to proteins; of which 80 -90% is bound to cortisol binding globulin
[CBG] and 10 – 15% to albumin.
 The remaining 5% is unbound and, therefore, free to cross cell membranes and bind to glucocorticoid and
mineralocorticoid receptors
 Affinity of CBG for synthetic corticosteroid is negligible apart from prednisolone, which has an affinity of about 505
of that of cortisol.

63
Classification of Hormones and their mechanism of action.

CYTOCHROME P450
 The P450 enzymes involved in steroid hormone biosynthesis are membrane bound protein associated with either the
mitochondrial membrane or the endoplasmic reticulum (microsomal).
 These enzymes are necessary for the detoxification of foreign chemicals and the metabolism of drugs.
 Very relevant to anaesthetic practice because a lot of the drugs we use are metabolized by the enzyme system.

Common metabolizing enzyme polymorphism Drugs affected

CYP2D6 Codeine
Tramadol
Methadone
Oxycodone
Hydrocodone
Ondansetron

CYP3A4 Midazolam / Alprazolam / Diazepam

Zolpidem / Fentanyl / Alfentanil / Sufentanil
Dexamethasone/ Methylprednisolone /
Granisetron

CYP2C9 Celecoxib
Naproxen

AMINE HORMONES STRUCTURES AND FUNCTIONS

 Made of 1 – 2 amino acids
 Receptors
o Membrane
o intracellular
 Small size, OH group
 Benzene ring
 Examples
o Thyroxine
o Adrenaline
o Noradrenaline

64
  Catecholamines have an extremely short half-life (< 2 minutes).
 Clearance from the blood involves uptake by both neuronal and non-neuronal tissues where they are either recycled or
degraded by either monoamide oxidase or catechol-O-methyltransferase (COMT).
 About 50% of the secreted catecholamines appear in the urine as free or conjugated Metanephrines and
normetanephrines and about 35% as vanillylmandelic acid (VMA).

AMINE HORMONE ACTIONS

ALPHA [] ADRENORECEPTOR

o These are subdivided into:
o  - 1 Receptor:
 Responsible for vascular smooth muscle contraction, i.e control the degree of vasocontsricion in the
skin, gut and kidneys.
 Stimulate glycogenolysis and gluconeogenesis
 Relaxes pregnant uterus.

o  -2:
 Responsible for platelet activation – increased adhesiveness
 Synaptic transmission
 Inhibits insulin release
 Stimulates glucagon release.

BETA [] ADRENORECEPTOR

They are subdivided into:
 - 1 Receptors:
 Increases the rate [positive chronotropic] and force of contraction [positive inotropic] of the heart.
  renin secretion

 - 2 Receptor:
o Smooth muscle relaxation i.e dilatation of bronchioles and blood vessels in skeletal muscles.
o Stimulate glycogenolysis and gluconeogenesis.
o  insulin secretion from beta cells of the pancreas.
o  renin secretion

AMINE HORMONES ACT THROUG SURFACE RECEPTORS

Once secreted, circulating epinephrine is free to associate with specific adrenergic receptors or adrenoceptors located on the
surface membranes of target cells. Numerous types of adrenoceptors exist and are generically grouped as α or β, each of which
has several subtypes (see Table 15-2). All adrenoceptors, isolated from a variety of tissues and species, are classic G protein–
coupled receptors. As indicated in Figure 47-5, the intracellular action of a specific catecholamine is determined by the
complement of receptors present on the surface of a specific cell. For example, when epinephrine binds to the β 1-adrenergic
receptor, it activates a Gα s protein, which stimulates adenylyl cyclase, promotes increases in [cAMP] i, and thus enhances the
activity of PKA (see Table 15-2). In contrast, when the same hormone binds to a cell displaying principally α 2 receptors, it
activates a Gαi protein, which inhibits adenylyl cyclase, diminishes [cAMP] i, and therefore reduces PKA activity. Thus, the
response of a specific tissue to adrenergic stimulation (whether through circulating epinephrine or through norepinephrine
released locally by sympathetic neurons) is determined by the receptor repertoire displayed by the cell. The same is true for DA;
the DA-1 (D1) receptor is coupled to Gαs and the DA-2 (D2) receptor is linked to Gαi.

65
Amine Hormones – Organization of Endocrine Control

Catecholamine receptors. The 1, 2 and D1 receptors all interact with Gs, which activates adenylate cyclase (AC) and raises
levels of cAMP. The -2 and D2 receptors interact with GI, which inhibits AC. Additionally, the -1 receptor interacts with
Gq, which activates phospholipase C (PLC), which in turn converts phosphoinositide in the cell membrane to inositol
triphosphate (IP3) and diacylglycerol (DAG). Protein kinase C activation causes proliferation and regulation of genes.
Dopamine also can interact with several GPCRs. The S1 receptors is coupled to Gs and the D2 receptor is linked to Gi.

Epinephrine has a greater affinity for β-adrenergic receptors than for α-adrenergic receptors, whereas norepinephrine acts
predominantly through α-adrenergic receptors. The various signal transduction systems linked to these receptors are discussed
in Chapter 3. β-Adrenergic stimulation occurs through the adenylyl cyclase system. The α 2-adrenergic receptor also usually acts
through adenylyl cyclase. However, α1-adrenergic stimulation is linked to Gα q, which activates a membrane-associated PLC that
liberates IP3 and DAG. IP3 can release Ca2+ from intracellular stores, and DAG directly enhances the activity of PKC. Combined,
these actions enhance the cellular activity of Ca 2+-dependent kinases, which produce a metabolic response that is characteristic of
the specific cell. The response to adrenergic agonists may be, for example, glycogenolysis in the liver or muscle (predominantly a
β effect), contraction (an α1 effect) or relaxation (a β2 effect) of vascular smooth muscle, a change in the inotropic or chronotropic
state of the heart (a β1 effect), or various other effects.

66
Sympathetic nervous system activity stimulates the chromaffin cells to release granules containing adrenaline (80%)
and noradrenaline (20%).

A mnemonic for remembering the order of these layers is:

GFR – Glomerulosa Fasciculata Reticularis
A mnemonic for remembering the hormones secreted by each layer is:
ACTH
A - Aldosterone
C - Cortisol

67
 T - Testosterone Hormone

PHAEOCHROMOCYTOMA
A 45-year-old male presents for laparoscopic resection of a phaeochromocytoma.

a) Describe the synthesis and metabolism of catecholamines (20%).

Describe the:
b) Presentation (20%)
c) Investigations (30%) and
d) Anaesthetic considerations (30%).
When planning to anaesthetize for phaeochromocytoma?

BIOSYNTHESIS OF CATECHOLAMINES
Structurally, catecholamines consist of catechol [a benzene ring with two hydroxyl groups] with an amine side
chain.

Catechol ring

Catecholamine
Catecholamines are derived from the amino acid tyrosine.
 Tyrosine is acquired from the diet or through the hydroxylation of phenylalanine in the liver.
 Tyrosine is taken up into the cytoplasm of chromaffin cells, where it is converted to L-3,4-dihydroxyphenylalanine (L-
DOPA). This is the rate limiting step of catecholamine biosynthesis.
 L-DOPA is converted into dopamine.
 Dopamine is converted into noradrenaline.
 Noradrenaline is converted into adrenaline by the enzyme phenylethanolamine N-methyl transferase (PNMT). This
enzyme is only present in the chromaffin cells of the adrenal medulla. Therefore, whilst noradrenaline may be
synthesized elsewhere (eg sympathetic nerve terminals), adrenaline can only be synthesized within the adrenal medulla.
 Noradrenaline and adrenaline are then packaged into granules, which also contain ATP, chromogranin A and opioid
peptides such as metenkephalin.

68
69
The catecholamine biosynthetic pathway in an adrenomedullary chromaffin cell or a pheochromocytoma cell. Norepinephrine
and epinephrine are stored in separate chromaffin storage vesicles.
LAT-L-type amino acid transporter; TH – tyrosine hydroxylase; L-DOPA- L-3,4-dihydroxyphenylalanine; AADC – aromatic L-
amino acid decarboxylase; DBH-dopamine -hydroxylase; PNMT – phenylethanolamine-N-methyltransferase; BH4-
tetrahydrobiopterin; 02 – molecular oxygen; VitB6-pyridoxalphosphate; VitC-ascorbate; VNMAT- vesicular monoamine
transporters; GR- glucocorticoid receptor.
Brown shadow above L-tyrosine – sympathetic fibre of splanchnic nerve.
 Dietary L-tyrosine is transported to sympathetic nerve terminal cytosol – adrenaline synthesis
 L-tyrosine is transported into the cytoplasm of adrenal chromaffin cells by the membrane L-type amino acid transporter
system (LAT1 and LAT2).
 Except for DBH, all the enzymes are localized in the cytoplasm of the chromaffin cells.

MECHANISM OF HORMONAL CONTROL – NEGATIVE FEEDBACK

CONTROL
Secretion of hormones from the adrenal cortex is under hypothalamic and pituitary control. The adrenal medulla is stimulated to
release catecholamines by activation of the sympathetic nervous system. Both controlling mechanisms are activated by stress.
Hyperkalemia and angiotensin II stimulate the release of aldosterone. Adrenocortical hormones cause feedback inhibition of their
upstream regulatory hormones. Cortisol also acts in a paracrine fashion to stimulate catecholamine release. Epinephrine and
norepinephrine act on the pituitary to stimulate the release of adrenocorticotropic hormone (ACTH). (CRH, corticotropin-
releasing hormone)

70
Whilst the hormones of the adrenal cortex are controlled by negative-feedback loops, the catecholamines of the adrenal medulla
are secreted in response to sympathetic nervous system activity; there is no negative feedback control of catecholamine secretion.
Secretion of catecholamines takes place as follows:
 In response to various stimuli:
o Exercise
o Trauma
o Pain
o Hypovolaemia
o Hypoglycaemia
o Hypothermia and

71
 o Anxiety

REGULATION OF AMINE HORMONES SECRETION

The human adrenal medulla secretes principally epinephrine (see Chapter 50). The final products are stored in vesicles
called chromaffin granules. Secretion of catecholamines by the adrenal medulla appears to be mediated entirely by stimulation
of the sympathetic division of the autonomic nervous system (see Chapter 14). Unlike the situation for many peptide hormones,
in which the circulating concentration of the hormone (e.g., TSH) negatively feeds back on secretion of the releasing hormone
(e.g., TRH), the amine hormones do not have such a hierarchic feedback system. Rather, the feedback of amine hormones is
indirect. The higher control center does not sense circulating levels of the amine hormones (e.g., epinephrine), but rather a
physiological end effect of that amine hormone (e.g., blood pressure; see Chapter 23). The sensor of the end effect may be a
peripheral receptor (e.g., stretch receptor) that communicates to the higher center (e.g., the CNS), and the efferent limb is the
sympathetic outflow that determines release of the amine.

72
Action potentials are generated in the pre-ganglionic sympathetic nerve that terminate on the chromaffin cells of the adrenal
medulla.

73
  Like other pre-ganglionic sympathetic neurons, acetylcholine (Ach) is released from the terminal bouton.
 Ach activates nicotinic receptors on the chromaffin cell membrane, increasing cell membrane Na + and K+ permeability,
which results in net depolarization.
 Membrane depolarization opens voltage-gated Ca2+ channels; the influx of Ca2+ into the chromaffin cells triggers
exocytosis of the catecholamine-containing granules, releasing adrenaline and noradrenaline into the circulation.

NB: catecholamine release from the adrenal medulla does not take place in isolation, it is part of a wider sympathetic nervous
response that include extensive noradrenaline release at sympathetic nerve terminals.

74
FIGURE 47-3 Hypothalamic-pituitary axis. The pituitary (or hypophysis) is actually two glands—an anterior pituitary and a
posterior pituitary (or neurohypophysis). Although in both cases the hypothalamus controls the secretion of hormones by the
pituitary, the mechanisms are very different. Anterior pituitary: Small-bodied neurons in the hypothalamus
secrete releasing and inhibitory factors into a rich, funnel-shaped plexus of capillaries that penetrates the median eminence and
surrounds the infundibular recess. The cell bodies of these neurons are in several nuclei that surround the third ventricle. These
include the arcuate nucleus, the paraventricular and ventromedial nuclei, and the medial preoptic and periventricular regions. The

75
capillaries (primary plexus), which are outside of the blood-brain barrier, coalesce into long portal veins that carry the releasing
and inhibitory factors down the pituitary stalk to the anterior pituitary. Other neurons secrete their releasing factors into a
capillary plexus that is much further down the pituitary stalk; short portal veins carry these releasing factors to the anterior
pituitary. There, the portal veins break up into the secondary capillary plexus of the anterior pituitary and deliver the releasing
and inhibitory factors to the “troph” cells that actually secrete the anterior pituitary hormones (GH, TSH, ACTH, LH, FSH, and
PRL) that enter the systemic bloodstream and distribute throughout the body. Posterior pituitary: Large neurons in the
paraventricular and supraoptic nuclei of the hypothalamus actually synthesize the hormones AVP and oxytocin (OT). These
hormones travel down the axons of the hypothalamic neurons to the posterior pituitary, where the nerve terminals relea se the
hormones, like neurotransmitters, into a rich plexus of vessels.

DISPOSITION & METABOLISM

 Most neutral CA are stored in vesicles. Leak out in to cytosol, or are released and undergo reuptake by pre-
synaptic or perivascular structures.
 Most CA recycled (whether leak or release), but some undergo metabolism by -- MAO.
 Only 10 – 20 % neuronally released CA reach the circulation.
 CA that escapes or is delivered i.v in to the plasma is mainly:
o Freely circulating (60%)
o Remainder protein bound (approx. 10%) or Hb bound in erythrocytes.
 25% of plasma CA clearance is by re-uptake & then metabolism by COMT.
 Clearance occurs predominantly in lungs and liver. Heart is also an important site of CA uptake.
 Biphasic plasma decay (5 mins – re-uptake; 1 month – plasma protein decay).
 CA filtered almost unchanged in urine (note urinary dopamine doesn’t reflect plasma dopamine due to
renal parenchymal L-dopa metabolism).

76
77
CATECHOLAMINE METABOLISM
o COMT – membrane-bound & soluble (cytosolic).
o MAO (A/B) – neuronal and mitochondrial.
o Metanephrines are the main metabolites from non-neuronal sources – importance in phaeochromocytoma
testing
The plasma half-life of catecholamine is very short: both adrenaline and noradrenaline have a plasma half-life of 2
minutes. Noradrenaline and adrenaline are both sequentially metabolized by catechol-O-methyltransferase (COMT)
and monoamine oxidase (MOA), two enzymes distributed widely throughout the body. Metanephrine is an
intermediate in this process, with vanillylmandelic acid produced after both enzymes have exerted their effects.
Phaeochromocytoma, a tumour of chromaffin cells associated with excessive secretion of catecholamines, may be
diagnosed through raised Metanephrine concentrations.

78
Neuronal, extraneuronal and adrenal pathways of metabolism for noradrenaline and adrenaline. NA, noradrenaline;
A, adrenaline; DHPG, dihydroxyphenylglycol; MN, metanephrine; NMN, normetanephrine; MHPG,
methoxyhydroxyphenylglycol; VMA, vanillylmandelic acid; MHPG-SO 4 , methoxyhydroxyphenylglycol sulphate;
NMN-SO 4 , normetanephrine sulphate; MN-SO 4 metanephrine sulphate; MAO, monoamine oxidase; COMT,
catechol-O-methyltransferase; ADH, alcohol dehydrogenase; SULT1A3, sulfotransferase type 1A3.

79
Model illustrating the regional pathways of norepinephrine and epinephrine metabolism. Most norepinephrine is
released and metabolized within sympathetic nerves, including up to a half produced in sympathetic nerves of
mesenteric organs. Sulfate conjugation of catecholamines and catecholamine metabolites, particularly MHPG,
occurs mainly in mesenteric organs, whereas production of VMA occurs mainly in the liver. These represent the
main metabolites excreted in urine.
SULT1A3 - sulfotransferase type 1A3
NE – norepinephrine
EPI - epinephrine
NMN – normetanephrine
MN – metanephrine
NMN-SO4 - normetanephrine sulfate
MN-SO4 - metanephrine sulfate
MHPG-SO4 - 3-methoxy-4-hydroxyphenylglycol sulfate.

PHEOCHROMOCYTOMA

80
Phaeochromocytoma (PCC) is a rare catecholamine-secreting tumour of adrenal origin. When it is extra-adrenal, it is
referred to as paraganglioma. It is a rare neuroendocrine catecholamine-secreting tumour originating from
chromaffin tissue. The term ‘pheochromocytoma’ refers to the colour the tumour cells get when stained with
chromaffin salts. (In Greek, phaios means dusky, chroma means colour, and cytoma means tumour). Yearly, 1 – 2
per 1,000 are diagnosed with PCC . PCC is the cause of hypertension in 1 in 500 adults. These tumours are usually
diagnosed by the 4th – 5th decade and are found equally in both genders. Hereditary pheochromocytoma usually
presents at a younger age.

ANATOMY & PHYSIOLOGY

The cells in chromaffin tissue produce and store catecholamines i.e.norepinephrine and epinephrine. Some tumors
may also produce dopamine. The clinical manifestations of PCC originate from excessive catecholamine secretion
by the tumor cell either continuously or intermittently.
The normal adrenal medulla secretes about 85% epinephrine and 15% norepinephrine, but norepinephrine is the
predominant catecholamine secreted by PCC.
Most PCC are intra-adrenal and solitary. As per the traditional "10 percent rule" for pheochromocytoma: 10% of
pheochromocytomas are familial, 10% are malignant, 10% are extra-adrenal, and 10% are in children. However, this
10 percent rule is oversimplified and incorrect as the prevalence of extra-adrenal tumors (paragangliomas) is as high
as 20%, and about 20 to 30% of these tumors are hereditary.
Familial syndromes associated with pheochromocytomas include multiple endocrine neoplasia type 2A and 2B,
neurofibromatosis (Von Recklinghausen disease), and Von Hippel-Lindau syndrome.

Presentation
The clinical manifestation of PCC originates from excessive catecholamine secretion by the tumour cell either
continuously or intermittently. The classical triad of symptoms in patient with PCC consists of:
 Episodic headaches
 Diaphoresis
 Tachycardia
Signs:
 High blood pressure – commonest (BP may be normal in 10 – 20% of patients).
 Hyperglycaemia
 Polyuria
 Polydipsia
 Tremor
 Orthostatic hypotension
 Visual blurring and
 Weight loss.

High blood pressure is caused by the release of noradrenaline and adrenaline from the tumour. The release of
catecholamine can be persistent or episodic; therefore, the patient may have constant hypertension or episodic
hypertension. Between 10 – 20% of patients may not have any clinical features, and the tumour is sometimes found
incidentally during a workup.

Investigation
PCC is suspected based on the clinical features and diagnosed by measuring the levels of:
 Epinephrine
 Norepinephrine
 Metabolites

81
 o Metanephrine
o Normetanephrine
o Vanillylmandelic acid
either in urine or blood. Measurement of 24-hour fractionated normetanephrine and catecholamines levels in
suspected patients is the best method to diagnose PCC.
Measurement of plasma fractionated Metanephrines is an alternative test, but 24-hours urine test are generally
considered superior to plasma tests for diagnosis because the tumour secrets catecholamines only intermittently, and
the catecholamines have a short half-life. Plasma-fractionated Metanephrine may be used as a first-line test for
children due to the difficulty in obtaining complete 24-hour urine.
 CT and MRI scan.
Patients with positive results should be further evaluated with imaging to confirm and localize the tumour. CT and
MRI are most commonly used due to their wide availability. MRI involves no radiation, and it can distinguish PCC
from other adrenal masses though it is expensive and more time-consuming. Computed tomography with or without
iodine 131-labeled meta-iodobenzylguanidine (MIBG) is very accurate in diagnosing as well as localizing the
tumour.
A provocative test with glucagon was used to confirm or exclude PCC in the past but it is not preferred due to low
sensitivity (<50%) and the risk of precipitation of severe hypertension.
 Suppression tests using clonidine or phentolamines are also sometimes used for diagnostic purposes.
Clonidine inhibits the release of catecholamines via a neurogenic mechanism. Clonidine does not affect the
catecholamines release by PCC.

Pre-operative Workup
Pre-operative preparation and optimization are essential to decrease peri-operative morbidity and mortality in
pheochromocytoma.

Roizen criteria:
 No in-hospital BP > 160/90 mmHg for 24 hours before surgery
 No orthostatic hypotension with blood pressure <90/45 mmHg
 No ST or T wave changes for 1 week before surgery.
 No more than 5 premature ventricular contractions per minutes.

Catecholamines (noradrenaline is the most common) released from the tumour cause vasoconstriction, and hence
patients with PCC usually have contracted intravascular volume despite being hypertensive. It is vital to optimize
intravascular volume to decrease peri-operative hemodynamic fluctuations. An alpha-adrenergic blocker is
administered starting 10 -14 days preoperatively to optimize blood pressure and ensure euvolaemia for volume for
volume expansion. Phenoxybenzamine is the most commonly used drug. It is an irreversible, nonspecific alpha-
adrenergic blocker. It is long-acting and has a half-life of approximately 24 hours.

Selective alpha-1-adrenergic blocking agents, prazosin, terazosin, and doxazosin may all be used to facilitate
preoperative α-blockade. Blockade of alpha-1 and alpha-2 leads to smooth muscle relaxation in arterioles and
venous capacitance vessels. Orthostatic hypotension and reflex tachycardia, especially in the setting of hypovolemia,
are potential side effects of the alpha blockade, particularly with long-acting phenoxybenzamine. Selective alpha-1-
adrenergic blocking agents cause less reflex tachycardia than non-selective alpha-blockers because the alpha-2
inhibitory activity is left intact.
The successful alpha blockade is reflected by normalizing blood pressure with mild orthostasis. The beta blockade
should never be initiated before the alpha blockade. They should be started only after an adequate length of the
alpha blockade is established; if not, a hypertensive crisis can occur due to unopposed alpha-receptor stimulation.
Alpha-methyl-para-tyrosine (metyrosine) inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine
synthesis. This can be used as an appropriate adjunct in malignant or unresectable tumors. Patients with long-
standing PCCs can develop severe cardiomyopathy. A detailed preoperative assessment by an experienced
anesthesiologist is required to evaluate cardiovascular status, adequacy of alpha and beta blockade, volume
resuscitation, and any other comorbidities.

82
Technique or Treatment
Surgical Approach
Minimally-invasive adrenalectomy via retroperitoneal or transperitoneal approach is the gold standard for
pheochromocytoma resection. A minimally invasive approach is preferred, as it leads to lower postoperative pain
scores, earlier ambulation, and faster recovery. This approach has shown a lowered incidence of postoperative
thromboembolic complications, reduced hospital stays, and is cost-effective. However, open procedures may be
needed for larger masses and extra-adrenal tumors.

Anaesthetic Management
Patients should be pre-medicated with anti-anxiety medication like midazolam. An arterial line is preferred before
induction as induction may result in hemodynamic lability. General anesthesia alone or with an epidural is used for
PCC resection. Epidural may be considered if open surgery is planned to provide adequate pain management in the
postoperative period. Good IV access with two peripheral lines is necessary. Intra-operative transesophageal
echocardiogram (TEE)/Pulmonary artery catheter may be considered in patients with severe cardiomyopathy to
guide fluid management/inotrope administration or to assess ventricular function.
Central venous access for vasopressor/inotrope administration may be placed in patients with poor LV function.
Propofol is the most commonly used agent for the induction of anesthesia if the patient has good LV function.
Patients with cardiomyopathy would need cardio-stable slow induction with divided doses of propofol or etomidate
or narcotic-based induction. Ketamine should be avoided because of its sympathomimetic properties. Smooth
induction of anesthesia with an optimal depth of anesthesia is the main goal to avoid hypertensive response during
laryngoscopy and endotracheal intubation.
Laryngoscopy and endotracheal intubation often cause hypertension and tachycardia, which could be exaggerated in
patients with PCC due to the release of catecholamines. Severe hypertension and tachycardia may result in
arrhythmias and myocardial ischemia. The elevation in blood pressure and heart rate associated with laryngoscopy
and intubation can be prevented or minimized by ensuring adequate depth of anesthesia.
Sevoflurane is the most commonly used inhalational agent for the maintenance of anesthesia for PCC resection as it
lacks the arrhythmogenic potential and has a favorable hemodynamic profile compared with other inhalational
agents. Desflurane can result in tachycardia and hypertension, especially when concentration is increased rapidly.
Sympathomimetic drugs (ketamine, ephedrine) and drugs causing histamine release (atracurium, morphine) should
be avoided. Metoclopramide is contra-indicated as it can induce hypertensive crisis and can also cause adrenergic
myocarditis with cardiogenic shock in patients with PCC.
It may be mediated by metoclopramide inhibiting dopaminergic suppression of presynaptic norepinephrine release.
It has also been found to directly stimulate the release of catecholamines in PCC. Glucagon can release
catecholamines in PCC, resulting in a hypertensive crisis.

Intraoperative Haemodynamic Management

Peritoneal insufflation during laparoscopic resection and tumor manipulation during surgery can cause an abrupt
release of catecholamine, resulting in severe hypertension and tachycardia. This hypertensive crisis may result in
myocardial ischemia or stroke.
Short and rapidly acting vasodilators like nitroprusside, nitroglycerine, or calcium channel blockers like nifedipine
and clevidipine are commonly used to control hypertension. Catecholamine excess can also result in life-threatening
coronary artery vasospasm. Calcium channel blockers are beneficial in controlling vasospasm. Clevidipine is a
newer dihydropyridine calcium channel antagonist used intravenously to reduce blood pressure. Intravenous
clevidipine has a rapid onset and short duration of action and can be easily titrated for predictable blood pressure

83
control. Phentolamine can be used to rapidly control hypertensive episodes. It is a short-acting non-selective alpha-1
and alpha-2 antagonist with a duration of action of 10 to 15 minutes.
In a patient with PCC, beta-blocker should only be considered after α-blocker administration. Or else, unopposed
catecholamine-induced α-agonism can trigger an acute hypertensive crisis and significantly raise afterload and
myocardial oxygen demand. Labetalol is not preferred due to its β-adrenergic antagonism, which can provoke
unpredictable, unopposed α-receptor agonism from circulating catecholamines resulting in hypertensive crisis.
Intravenous labetalol has an α:β receptor antagonism ratio of 1:7. Thus, it has a preference for β-receptor and the
potential for worsening hypertension. Labetalol may result in persistent hypotension and bradycardia following the
removal of the tumor. If pre-operative α-antagonism has been instituted, beta-blocker like esmolol or metoprolol
may be titrated to control heart rate.
Esmolol is a short-acting, competitive antagonist of beta-1-adrenergic receptors[33]. It is rapidly inactivated by red
cell esterases and has a half-life of 9 minutes. Due to the short half-life, esmolol is only administered intravenously.
For intra-operative hypertensive crisis and tachycardia, a loading dose of 500 to 1000 mcg/kg over 1 minute,
followed by an infusion of 50 mcg/kg per minute until the max dose of 200 mcg/kg per minute, can be used to
control blood pressure.
The depth of anesthesia can also be changed to optimize hemodynamic response. After the ligation of the blood
vessel of the tumor, a precipitous drop in blood pressure may occur. This is usually due to the sudden drop in
endogenous catecholamine levels in the setting of chronic downregulation of alpha-adrenergic receptors in patients
with PCC. Fluid bolus with vasoconstrictors like phenylephrine and noradrenaline are used to maintain blood
pressure. In refractory hypotension, vasopressin infusion ( 0.01 to 0.03 units/minute) has been used to maintain
blood pressure.
Vasopressin is particularly effective in managing hypotension in pheochromocytoma as vasopressin has no action on
peripheral adrenergic receptors for its effect. When all these vasoactive agents are not adequately effective,
methylene blue may be tried. Methylene blue inhibits nitric oxide synthase and guanylate cyclase and has been
found effective in managing refractory vasoplegic patients. Hemodynamically stable patients are extubated at the
end of surgery and transferred to the post-anesthesia care unit. However, patients requiring vasopressors to maintain
adequate blood pressure are transferred to the intensive care unit.

Complications
Following the excision of the tumor, hypotension may ensue. This hypotension is multifactorial. It may be due to the
downregulation of alpha-adrenergic receptors, hypovolemia, or residual effects of long-acting antihypertensive
medications like phenoxybenzamine. Up to half of the patients may be hypertensive for a few days after the tumor
resection.
Plasma catecholamine levels (norepinephrine) may not decrease to normal for a few days after the tumor resection.
Persistent hypertension may also signify a residual tumor. Hypoglycemia is another significant concern; blood sugar
should be checked regularly every 4 to 6 hours. As catecholamine inhibits insulin secretion, hence sudden decrease
in catecholamine level after the resection of a tumor can result in a rebound increase in insulin secretion.

Clinical Significance
Surgical resection of the tumor is the treatment of choice for PCC and has a success rate of more than 90%.
However, due to end organ damage resulting from excessive catecholamine and labile hemodynamics from
fluctuating catecholamine levels, it is one of the most complex and challenging tasks for anesthesiologists.

84
Adequate pre-op optimization is mandatory to decrease perioperative morbidity and mortality. Perioperative
management for PCC should be done by a multidisciplinary team, including an anesthesiologist, surgeon, and
endocrinologist. Pre-operative evaluation should focus on assessing end-organ damage due to elevated
catecholamine levels. These patients are at risk for catecholamine-induced cardiomyopathy and may present with
arrhythmias, myocardial ischemia, and reduced ventricular ejection fraction.
Pre-op preparation with alpha-adrenergic and beta blockade is recommended to control blood pressure and restore
intravascular volume. Despite optimization, the patient may have labile hemodynamics in the perioperative period.
General anesthesia is required for laparoscopic resection of PCC. Smooth induction with adequate depth of
anesthesia is the goal of anesthesia. Invasive blood monitoring is mandatory during surgery. An arterial line should
be placed before induction of anesthesia, which facilitates the early recognition and management of hemodynamic
changes.
Hemodynamic instability is the most common complication during surgery. Hypertension and tachycardia are
common during intubation and before the ligation of the tumor. Hypotension may be commonly seen after
ligation/removal of the tumor—close communication with the surgeon help in anticipation of events that might
cause hemodynamic fluctuation.

A 45-year-old male presents for laparoscopic resection of a phaeochromocytoma.

a) Describe the synthesis and metabolism of catecholamines (20%).

Describe the:
b) Presentation (20%)
c) Investigations (30%) and
d) Anaesthetic considerations (30%).
When planning to anaesthetize for phaeochromocytoma?

PHEOCHROMOCYTOMA
SYNTHESIS

85
PRESENTATION
The clinical manifestation of PCC originates from excessive catecholamine secretion by the tumour cell either
continuously or intermittently. The classical triad of symptoms in patient with PCC consists of:
 Episodic headaches
 Diaphoresis
 Tachycardia
Signs:
 High blood pressure – commonest (BP may be normal in 10 – 20% of patients).
 Hyperglycaemia
 Polyuria
 Polydipsia
 Tremor
 Orthostatic hypotension

86
  Visual blurring and
 Weight loss.

INVESTIGATION
Pheochromocytoma is suspected based on the clinical features and diagnosed by:
1. Measurement of 24-hour fractionated urinary Metanephrines and catecholamines.
2. Measurement of plasma fractionated Metanephrines (alternative/first line test).
3. CT & MRI Imaging [further evaluation to confirm and localize the tumor]

 MRI
o No radiation
o Can distinguish PCC from other adrenal masses.
o Expensive and time consuming
 CT scan  iodine 131-labeled meta-iodobenzylguanidine (MIBG).
o Very accurate in diagnosis and localization of tumor.

4. Provocative test with glucagon [used to confirm or exclude PCC in the past]

 Low sensitivity
 Risk of precipitation of severe hypertension.
5. Suppression test using clonidine or phentolamine.

 Clonidine:
o Inhibits the release of catecholamines via neurogenic mechanism
o Does not affect the catecholamine released by PCC.

ANAESTHETIC CONSIDERATION
o Premedication with anxiolytic like midazolam.
o Arterial line before induction [possible haemodynamic instability during induction]
o GA alone or GA + Epidural [Epidural for open surgery  adequate postop pain]
o Good IV access with 2 peripheral lines
o  Intraoperative TEE/Pulmonary Artery Cather [cardiomyopathy]  fluid mgt & inotrope / access
ventricular function
o Central venous access [ poor left ventricular function] vasopressors/inotropes
o Induction:
o Goal – smooth induction with optimal depth of anaesthesia to avoid hypertensive responses during
laryngoscopy and intubation.
o Agents:
 Propofol – good LV function
 Cardiostable slow induction:
 divided doses of propofol/etomidate/narcotic-based induction
 Ketamine is contraindicated.
o Maintenance:
o Inhalational agent:
 Sevoflurane
 Lacks arrhythmogenic potential
 Favorable hemodynamic profile.

87
 o Contraindication
 Desflurane (rapidly increased concentration)
 Tachycardia
 Hypertension
 Sympathomimetics
 Ketamine
 ephedrine
 Histamine release
 Atracurium
 Morphine
 Metoclopramide
 Induce hypertensive crises
 Cause adrenergic myocarditis with cardiogenic shock in PCC pts.

INTRA-OPERATIVE HEMODYNAMIC MGT

Severe hypertension and tachycardia

 Short and rapid acting vasodilators

o Nitroprusside
o nitroglycerine
 Calcium channel blockers
o Nifedipine
o Clevidipine

Life threatening severe coronary vasospasm due to catecholamine excess

 calcium channel blockers

o Clevidipine (IV)
 Rapid onset
 Short duration
Hypertensive Episodes

 phentolamine (1st line)

o short-acting [10 -15 minutes]
o non-selective -1 and -2 antagonist
 -blockers (titrated to control heart rate)
o Esmolol
o Metoprolol

Precipitous drop in blood pressure

 Reduce the depth of anaesthesia

 Fluid bolus
 Vasopressors
o Phenylephrine
o Noradrenaline
o Vasopressin infusion (refractory hypotension)
o Methylene blue [when all else fails].

88
ADDISON’S DISEASE AND ADRENAL CRISIS
A patient with newly diagnosed Addison’s disease presents for an emergency appendectomy.
a) Briefly describe the steps in steroid synthesis within the body (15 %).
b) How does Addison’s disease or adrenal insufficiency present? (20%).
c) How is it diagnosed? (15%).
d) What is the management of an adrenal crisis? (30%)
e) Outline, with reasons, your perioperative corticosteroid regimens in patients taking steroids at the time of
surgery (20%).

TRUE or FALSE

 the adrenal glands lie inferior to the kidney.

 The zona glomerulosa of the adrenal cortex is the deepest layer of the 3 cortical layers.
 There are 4 cortical layers in the adrenal cortex.
 Glucocorticoids are produced in the central layer of the adrenal cortex.

89
CHOLESTEROL TRANSFER TO ADRENALS
The adrenal cortex is a tissue of excess in terms of both cholesterol metabolism and cholesterol exchange with the
circulation. Exceptionally high levels of lipoprotein receptors in this highly vascularized tissue provide ready access
to dietary cholesterol, allowing the adrenocortical cells to maintain impressive stores of cytoplasmic cholesterol
ester (CE) droplets. Steroidogenic cholesterol in adrenal cells transfers to PBR and then StAR in the mitochondria
from the plasma membrane. Cholesterol is taken up from both LDL receptors and apoA/HDL receptors (SR-BI) in
caveolin-rich (Cav-rich) domains. Tightly packed among the CE droplets are specialized mitochondria, carrying in
their inner membranes high levels of the cytochrome P450scc (CYP11A1).

This enzyme carries out the so-called side chain cleavage reaction, consuming cholesterol to produce pregnenolone,
the precursor of cortisol and all other steroids. Glucocorticoid synthesis is tightly regulated at the level of cholesterol
metabolism, which responds to ACTH stimulation over a period of minutes and ceases equally quickly when this
hormone is removed. Remarkably, this dynamic process is modulated under most circumstances not by control of
the intrinsic enzymatic activity of P450scc, but rather by substrate availability. For this reason, cholesterol transport
within the mitochondrion has emerged as the key control point for steroidogenesis.

90
The adrenal cortex is not alone in requiring efficient and controlled delivery of cholesterol into mitochondria. Other
steroidogenic cells, including several cell types in the ovary, the Leydig cells of the testis, and a subset of
hippocampal neurons, also employ P450scc to produce pregnenolone and a variety of downstream steroid hormones
or neurosteroids. In vertebrates ranging from birds and fish to mammals, these various cell types all express a short-
lived mitochondrial import factor now called the steroidogenic acute regulatory protein (StAR), which mediates this
process.

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Lipid metabolism and the adrenal gland.
The liver is the principal site of apolipoprotein synthesis. One of the key apolipoproteins, ApoA1, comprises a large
fraction of high-density lipoprotein (HDL) particles. The hepatically derived lecithin-cholesterol acyltransferase
enzyme (LCAT) binds to ApoA1 on HDL and esterifies free cholesterol. Once this process is complete, the HDL
particle is mature and can be trafficked to peripheral tissues. Within the adrenal gland, cholesterol is offloaded, and
uptake occurs through the mitochondrial steroidogenic acute regulatory protein (StAR), which is the rate-limiting
step in the production of steroid hormones (A). In cirrhosis, this process is disrupted by decreased hepatic synthesis
of both ApoA1 and LCAT, leading to impaired formation of adequate mature HDL molecules to provide adequate
substrate for normal adrenal steroidogenesis. However, whether this leads to a clinically significant decrease in
cortisol production is unknown (B).

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STEROID BIOSYNTHESIS

STEPS INVOLVED IN STEROID SYNTHESIS WITHIN THE BODY

The 1st step in each pathway is catalyzed by cholesterol desmolase (CYP11A1). In this step the long side chain of
cholesterol is removed (ie, side chain cleavage) and cholesterol is converted to pregnenolone.

93
Cholesterol desmolase is the rate-limiting enzyme in the pathway, and is stimulated by ACTH.

94
MECHANISM OF HORMAL CONTROL – NEGATIVE FEEDBACK
95
96
97
Which one of the following reflect the clinical use of corticosteroids?
• Anti-emetic
• Foetal lung maturation
• Anti-inflammatory
• Immunosuppression
• Allergy
• Appetite stimulation
• All of the above

98
TRUE or FALSE: the side effects of long-term corticosteroid use are….
• Dysrhythmia?
• Diabetes mellitus?
• Hypotension?
• Hair loss?
• Adipose gain and striae?

A 35-year-old male patient with a history of asthma is scheduled for a laparotomy and bowel resection. He is taking
20mg of prednisolone daily. As this patient requires intravenous hydrocortisone during the peri-operative period,
which one of the following is equivalent to 20 mg prednisolone?

a) 100 mg of hydrocortisone
b) 80 mg of hydrocortisone
c) 75 mg of hydrocortisone
d) 90 mg of hydrocortisone
e) 50 mg of hydrocortisone

5mg of prednisolone is equivalent to 20 mg of hydrocortisone. Therefore, 20 mg of prednisolone is equivalent to

80mg of hydrocortisone.

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Relative potencies of steroid preparations

Steroid Potency
Dexamethasone 1
Methylprednisolone 4
Prednisolone 5
Hydrocortisone 20
Cortisone acetate 25

A 64-year-old male is listed for excision of a ganglion on the wrist. He suffers from rheumatoid arthritis and asthma.
He takes his salbutamol inhaler 200g t.d.s and prednisolone 15 mg once a day. He has been on these drugs for over
2 years. Which of the following is the most appropriate with regard to his peri-operative management?

a) Prednisolone 15 mg on the morning of surgery.

b) Hydrocortisone 100 mg at induction.
c) Hydrocortisone 50 mg at induction and 50 mg 6 hours postoperatively.
d) Prednisolone 15 mg on the morning of surgery and hydrocortisone 50 mg at induction.
e) Hydrocortisone 100 mg at induction and 50 mg 6 hours postoperatively.

Answer: A. Prednisolone 15 mg on the morning of surgery.

Those patients taking more than 10 mg of prednisolone a day need their routine pre-operative dose of steroid or
hydrocortisone 25 mg IV at induction for minor surgery. This patient is having minor surgery; routine pre-operative
steroid cover is sufficient.
During prolonged therapy with corticosteroids, adrenal medulla atrophy develops. Abrupt withdrawal can lead to
acute adrenal insufficiency. To compensate for diminished adrenocortical response caused by prolonged
corticosteroid treatment, significant intercurrent illness, trauma or surgical procedures, there should be a temporary
increase in the dose. Any patient taking more than 10 mg of prednisolone a day would require supplementary
hydrocortisone during the peri-operative period.
For minor surgery, the usual oral corticosteroid dose on the morning of the surgery or hydrocortisone 25 – 50 mg
intravenously at induction is sufficient. The usual oral corticosteroid dose is recommended after surgery.
For moderate or major surgery, the usual oral corticosteroid dose is given on the morning of surgery and
hydrocortisone 25 mg intravenously at induction, following hydrocortisone 25 mg three times a day by intravenous
injection for 24 hours after moderate surgery or for 48 – 72 hours after major surgery. The usual pre-operative oral
corticosteroid dose is recommended on stopping hydrocortisone injections.


EFFECTS OF PROLONGED USE OF STEROIDS

100
GC & FLUID & Na+ RETENTION

101
SELF-ENHANCEMENT BY GC

102
103
GC & OSTEOPOROSIS

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GC AND OTHER EFFECTS

• A cachectic patient presents to ED with severe refractory hypotension, hypoglycaemia & hyperkalaemia.
• The most likely explanation is:
– Conns syndrome?
– T4 renal tubular acidosis?
– Graves disease?
– Addison’s syndrome?

ADDISON DISEASE

105
A patient with newly diagnosed Addison’s disease presents for an emergency appendectomy.

a) Briefly describe the steps in steroid synthesis within the body (15 %).
b) How does Addison’s disease or adrenal insufficiency present? (20%).
c) How is it diagnosed? (15%).
d) What is the management of an adrenal crisis? (30%)
e) Outline, with reasons, your perioperative corticosteroid regimens in patients taking steroids at the time of
surgery (20%).

ADDISON DISEASE
Addison disease, or primary adrenocortical insufficiency, is commonly caused by autoimmune destruction of all the
zones of the adrenal cortex. In this disease, there is decreased synthesis of all adrenocortical hormones, resulting in
decreased circulating levels of cortisol, aldosterone, and adrenal androgens. The symptoms of Addison disease can
be predicted on the basis of the known physiological effects of these hormones. The loss of glucocorticoids
(cortisol) produces:
 Hypoglycaemia
 Anorexia
 Weight loss
 Nausea and vomiting and
 Weakness.
The loss of mineralocorticoids(aldosterone) produces:
 Hyperkalaemia
 Metabolic acidosis and
 Hypotension – due to decreased ECF volume.
In women, the loss of adrenal androgens, DHEA and androstenedione, results in:
 Decreased pubic and axillary hair and
 Decreased libido
Addison disease is also characterized by hyperpigmentation of the skin particularly of the:
 Elbow
 Knees
 Nail beds
 Nipples and areola and on
 Recent scars.
Hyperpigmentation is a result of increased levels of ACTH (which contains the -MSH fragment).
Hyperpigmentation therefore provides an important clue about the aetiology pf Addison disease: ACTH levels may
be high, not low, and the cause of the hypocortisolism must not be a primary defect in ACTH secretion from the
anterior pituitary. Rather, the hypocortisolism of Addison disease must be due to a primary defect in the adrenal
cortex itself (ie, primary adrenal insufficiency), with low levels of cortisol then causing an increase in ACTH
secretion by negative feedback. Treatment of Addison disease includes glucocorticoid and mineralocorticoid
replacement.

A 45-year-old woman is admitted to the hospital with a history of progressive weakness and weight loss, occasional
nausea, and darkening skin pigmentation. On physical examination, she is thin, has dark skin creases, and has
diminished axillary and pubic hair. Her blood pressure is 120/80 mmHg when supine and 106/50 mmHg when
standing. Her pulse rate is 100/minute when supine and 120/minute when standing. Laboratory studies yield the
following values:

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 Serum Urine
Na+ 120 mEq/l 
K+ 5.8 mEq/l 
HCO3- 120 mEg/l pH
Osmolarity 254 mOsm/l 450 mOsm/l
Arterial Blood gases are consistent with metabolic acidosis. Blood urea nitrogen (BUN) and serum creatinine are
increased. Her blood glucose concentration is low-normal, and she becomes hypoglycaemic upon fasting. Serum
levels of ACTH are elevated. An ACTH stimulation test shows a ‘’flat’’ cortisol response (ie, the adrenal cortex did
not respond to ACTH).
The woman is treated with cortisol, taken twice daily, early morning and late afternoon, and fludrocortisone, a
synthetic mineralocorticoid.

EXPLANATION OF CASE
The woman has primary adrenocortical insufficiency (Addison disease), in which all layers of the adrenal cortex are
destroyed. None of the adrenocortical hormones, glucocorticoids, mineralocorticoids, and adrenal androgens are
secreted in adequate amounts. Decreased blood levels of cortisol, via negative feedback mechanisms, then cause
increased secretion of ACTH by the anterior lobe of the pituitary. The woman’s abnormal serum and urine values,
orthostatic hypotension, hypoglycaemia, decreased body hair, and hyperpigmentation can be explained by decreased
circulating levels of adrenocortical steroids as follows:
The woman has increased serum K+ (hyperkalaemia) and metabolic acidosis. Simultaneously, urinary excretion of
K+ is decreased, and urine pH is increased. These disturbances of K + and acid-base balance are caused by the loss of
the adrenocortical hormone aldosterone. Normally, aldosterone stimulates K + and H+ secretion in the renal distal
tubule and collecting duct. Therefore, when there is a deficiency of aldosterone, the kidneys secrets inadequate
amounts of K+ and H+, elevating their respective blood levels and causing hyperkalaemia and metabolic acidosis.
(Accordingly, the excretion of K+ and H+ in urine is decreased).
When the woman moves from a supine to a standing position, her blood pressure decreases and her pulse rate
increases. Orthostatic hypotension the decrease in blood pressure upon standing, is explained by a deficiency of
aldosterone and a deficiency of cortisol. In addition to its effects on K + and H+ secretion, aldosterone stimulates
renal Na+ reabsorption. When aldosterone is deficient, there is inadequate renal Na + reabsorption, which results in
decreased body Na+ content, decreased ECF volume and blood volume, and decreased arterial blood pressure
(especially when standing). Lack of cortisol contributes to hypotension by reducing the vascular responsiveness to
catecholamines. The increased pulse rate upon standing reflects the response of the baroreceptor reflex to this
orthostatic decrease in blood pressure. A component of the baroreceptor reflex response is increased heart rate,
which attempts to restore blood pressure back to normal. The woman’s elevated BUN and serum creatinine reflect a
decreased GFR, which is consistent with decreased ECF volume (ie, prerenal azotemia).
The woman’s decreased serum Na + and serum osmolarity are secondary to the ECF volume contraction. When ECF
volume decreases by 10% or more, ADH secretion is stimulated. ADH then circulates to the kidney, stimulating
water reabsorption, as reflected in the hyperosmotic urine. The reabsorbed water is added to the body fluids, diluting
them, as reflected in the decreased Na + and osmolarity. ADH secreted under such hypovolaemic conditions is quite
appropriate for her volume status but inappropriate for her serum osmolarity.
Hypoglycaemia, nausea, weight loss, and weakness are caused by a deficiency of glucocorticoids. The decreased
body Na+ content and decreased ECF volume also contribute to weight loss because a large percentage of body
weight is water. Hyperpigmentation resulted from negative feedback on the anterior pituitary by the low circulating
cortisol levels. The decreased levels of cortisol stimulate secretion of ACTH, which contains the -MSH fragment.
When circulating levels of ACTH are elevated, as in Addison disease, the -MSH component os the molecule
produces darkening skin pigmentation.
The woman has decreased pubic and axillary hair from the loss of the adrenal androgens, DHEA and
androstenedione. (In females, adrenal androgens are the major source of androgens).

TREATMENT
Treatment of this patient consists of replacing the missing adrenocortical steroid hormones, which are necessary for
life. She is given a synthetic mineralocorticoid [fludrocortisone] and glucocorticoid[cortisol]. Cortisol is
administered twice daily, a large dose in early morning and a smaller dose in late afternoon, to simulate the normal
diurnal pattern of cortisol secretion.

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ADDISON’S DISEASE [PRIMARY ADRENAL INSUFFICIENTY/HYPOADRENALISM
Addison disease, also known as autoimmune adrenalitis, is an acquired primary adrenal insufficiency. Primary
adrenal insufficiency is termed Addison disease when an autoimmune process causes the condition and is a rare but
potentially life-threatening emergency condition. Addison disease results from the destruction of the bilateral
adrenal cortex, leading to decreased adrenocortical hormones, including cortisol, aldosterone, and androgens.
Addison disease's insidious course of action usually presents with glucocorticoid deficiency followed by
mineralocorticoid. However, the condition can also present acutely, often triggered by intercurrent illness. The
presentation of adrenal insufficiency depends on the rate and extent of adrenal function involvement. The most
common cause of primary adrenal insufficiency is Addison disease, associated with increased levels of 21-
hydroxylase antibodies.

Addison disease usually manifests as an insidious and gradual onset of nonspecific symptoms, often resulting in a
delayed diagnosis. The symptoms may worsen over a period, which makes early recognition difficult. A high
clinical suspicion should be maintained to avoid misdiagnosis. In many cases, the diagnosis is made only after the
patient presents with an acute adrenal crisis manifesting with hypotension, hyponatremia, hyperkalemia, and
hypoglycemia. The diagnosis is established by demonstrating low cortisol and aldosterone levels, high renin levels,
and a blunt cortisol response with ACTH stimulation. Addison crisis is a severe endocrine emergency; immediate
recognition and treatment are required. For stabilized patients diagnosed with Addison disease, life-long treatment
with hormonal replacement is needed. Maintenance therapy aims to provide a replacement to maintain a physiologic
glucocorticoid and mineralocorticoid level.

ETIOLOGY
Addison disease is caused by an inability of the adrenal cortices to produce adequate adrenocortical hormones. The
condition is classified as primary or secondary adrenal insufficiency.
Primary Adrenal Insufficiency
Any disease process that causes direct injury to the adrenal cortex can result in primary adrenal insufficiency (ie,
Addison disease), including autoimmune, infectious, hemorrhagic, pharmacologic, and infiltrative etiologies.
Autoimmune
Autoimmune destruction of the adrenal glands is the most common cause of Addison's disease. This destruction
occurs as antibodies develop against the adrenal cortex. Autoimmune destruction can be an isolated finding or type 1
and 2 autoimmune polyglandular endocrinopathies. Patients with autoimmune adrenal disease are more likely to
have polyglandular autoimmune syndromes.

 Type 1 autoimmune polyglandular syndrome is manifested by autoimmune polyendocrinopathy,

candidiasis, and ectodermal dysplasia. The classic triad consists of hypoparathyroidism, Addison disease,
and mucocutaneous candidiasis.
 Type 2 autoimmune polyglandular syndrome is associated with several conditions:
o Autoimmune thyroiditis (ie, Schmidt syndrome)
o Type 1 diabetes (ie, Carpenter syndrome)
o Autoimmune conditions (eg, pernicious anemia, vitiligo, or alopecia)
o Addison disease has been reported with celiac disease

Infections
Infectious etiologies include sepsis, tuberculosis, cytomegalovirus, and HIV. The prevalence of tuberculosis has
declined, but HIV has emerged as the most important cause of adrenal insufficiency associated with adrenal

108
necrosis. Other infectious causes include disseminated fungal infections, histoplasmosis, and syphilis.
Blastomycosis is another cause of Addison disease, particularly in South America.
Adrenal Hemorrhage
DIC, trauma, meningococcemia, and neoplastic processes can precipitate bilateral adrenal hemorrhages. An Adrenal
crisis due to meningococcemia is known as the Waterhouse-Friderichsen syndrome and is more common in children
and patients with asplenia.
Infiltration
Adrenal infiltration frequently occurs with hemochromatosis, amyloidosis, and metastases. Other causes include
sarcoidosis, lymphoma, and genetic disorders such as congenital adrenal hyperplasia and adrenal
leukodystrophy. Wolman disease is a rare inborn error of metabolism that presents with diarrhea,
hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Antiphospholipid antibody syndrome has
been identified as a cause of adrenal insufficiency.
Medications
Certain pharmacologic etiologies can lead to adrenal insufficiency by blocking cortisol synthesis. For instance,
ketoconazole directly inhibits adrenal enzymes, and etomidate can have a dose-dependent effect by selectively
inhibiting 11β-hydroxylase, decreasing deoxycortisol conversion to cortisol.
Secondary Adrenal Insufficiency
Secondary insufficiency occurs most commonly due to exogenous steroid administration, resulting in the
suppression of ACTH synthesis. Secondary adrenal insufficiency is a pituitary-dependent loss of ACTH secretion,
which reduces glucocorticoid production. However, mineralocorticoid secretion, including aldosterone, remains
relatively normal.[5] Secondary adrenal insufficiency is more common than primary insufficiency, with symptoms
usually occurring after the discontinuation of a steroid.

 Primary: autoimmune-mediated intrinsic adrenal gland dysfunction, which leads to cortisol and aldosterone
deficiency
 Secondary: chronic glucocorticoid administration resulting in hypothalamic-pituitary dysfunction and
cortisol deficiency alone.

EPIDEMIOLOGY
Addison's disease is rare, with an incidence of .6 per 100,000 of the population annually. The total number of people
affected by this condition at a given time ranges from 4 to 11 per 100,000 of the population. In adults, the typical
age of Addison disease presentation is 30 to 50 years and is more frequently seen in women. Risk factors for the
autoimmune type of Addison's disease, which is the most common type, include other autoimmune conditions:

 Type I diabetes
 Hypoparathyroidism
 Hypopituitarism
 Pernicious anemia
 Graves' disease
 Chronic thyroiditis
 Dermatis herpetiformis
 Vitiligo
 Myasthenia gravis

PATHOPHYSIOLOGY

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Adrenal failure in Addison disease results in decreased cortisol production initially followed by that of aldosterone,
both of which will eventually result in an elevation of adrenocorticotropic (ACTH) and melanocyte-stimulating
hormone (MSH) hormones due to the loss of negative feedback inhibition.

HISTORY & PHYSICAL

Addison disease usually manifests as an insidious and gradual onset of nonspecific symptoms, often resulting in a
delayed diagnosis. The symptoms may worsen over a period, which makes early recognition difficult. A high
clinical suspicion should be maintained to avoid misdiagnosis. In many cases, the diagnosis is made only after the
patient presents with an acute adrenal crisis manifesting with hypotension, hyponatremia, hyperkalemia, and
hypoglycemia. This may be precipitated by a stressful illness or triggering factors such as infection, trauma, surgery,
vomiting, or diarrhea. Significant stress or disease can unmask cortisol and mineralocorticoid deficiency.
Addison disease can occur at any age but most often presents during the second or third decades of life. The initial
presenting features include fatigue, generalized weakness, weight loss, nausea, vomiting, abdominal pain, dizziness,
tachycardia, and hypotension. Clinicians should also assess for wasting of subcutaneous tissue. There may
be declining health over several weeks or months. Due to its variable presentation, a high index of suspicion for
Addison disease is necessary when evaluating patients with nonspecific symptoms. These may include unexplained
fatigue, poor appetite, chronic abdominal pain, or weight loss. Addisonian crisis is manifested by severe
dehydration, confusion, refractory hypotension, and shock and is more likely to occur in primary adrenal
insufficiency than secondary adrenal insufficiency.
Physical evaluation should include an examination of the skin and mucous membranes for
hyperpigmentation. Hyperpigmentation of skin and mucous membranes, a hallmark of Addison disease, is usually
generalized and most prominent in sun-exposed and pressure areas. Specific sites should be carefully evaluated for
hyperpigmentation, including the palmar creases, gingival mucosa, lips, particularly the vermilion border, elbows,
knuckles, posterior neck, breast areola, nipples, and nail beds. Hyperpigmentation may appear as bronzing of the
skin or diffuse darkening or dark patches and occurs in almost all patients with Addison disease. However, there
have been few reports of patients with adrenal insufficiency without hyperpigmentation. This may delay the
diagnosis. Also, hyperpigmentation is not seen in secondary insufficiency because ACTH and MSH levels are
low. Elevated ACTH and melanocyte-stimulating hormone are causative factors and are believed to occur due to
ACTH binding to the melanocyte receptors responsible for pigmentation. Furthermore, multiple new nevi may
develop, and decreased or sparse axillary and pubic hair may occur in female patients. Vitiligo may also be
observed.

EVALUATION

Diagnostic Laboratory Studies

The diagnosis of Addison disease is established by demonstrating:

 Low cortisol and aldosterone levels.

 High renin levels and a
 Blunt cortisol response with ACTH stimulation.
The following is the recommended diagnostic approach for the evaluation of Addison disease.

 An inappropriately low cortisol level

 Assessing the adrenal cortex's functional capacity to synthesize cortisol and determine whether the cortisol
deficiency is related to a corticotropin (ACTH) deficiency will help to classify whether the adrenal
insufficiency is primary or secondary.
 Determining whether a treatable cause is present and performing further evaluation should be directed by
its underlying cause.

Cortisol Level

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Circadian rhythm of ACTH and cortisol secretion

A low random cortisol level is characteristically seen with Addison disease. Cortisol typically follows a diurnal
pattern with the highest level in the early morning; therefore, an early morning level should be obtained. However,
getting an early morning cortisol level in the emergency department (ED) is impractical. Furthermore, these
results are not readily available during an ED visit. A single serum cortisol level determination is insufficient to
assess adrenal function. However, a morning cortisol level >18 mcg/dL is a normal finding and may exclude an
Addison disease diagnosis, while a low cortisol level of <3 mcg/dL is sufficient to diagnose adrenal insufficiency.
The following is a summary of cortisol level interpretation.

Morning cortisol > 18 g/dl Normal

< 3 g/dl < 165 nmol/l Adrenal insufficiency

3 – 19 g/dl Equivocal [further evaluation]

ACTH Level and Corticotropin Stimulation Test [Synacthan test]

The ACTH level is markedly elevated in primary adrenal insufficiency. However, the level is not elevated or within
the reference range in patients with central adrenal insufficiency. In equivocal cases, the diagnosis is confirmed by
an ACTH (ie, cosyntropin) stimulation test, which causes rapid stimulation of cortisol and aldosterone secretion. An
ACTH stimulation test is a first-line diagnostic test for evaluating adrenal insufficiency. Furthermore, plasma
cortisol levels should be measured at 0 minutes and 30 to 60 minutes after the administration of ACTH.
Corticotropin-releasing hormone (CRH) stimulates ACTH release from the pituitary. In primary adrenal
insufficiency, a high ACTH level is present, which rises further after CRH stimulation; however, serum cortisol
secretion cannot be stimulated. Conversely, a low ACTH level is seen in secondary adrenal insufficiency, failing to
respond to CRH. The following is a summary of the interpretation of the ACTH stimulation test.

ACTH levels  Primary adrenal insufficiency

N/ Central adrenal insufficiency

Synacthan [ACTH stimulation]

Peak cortisol levels > 18 g/dl Normal response

< 18 g/dl or no response Adrenal insufficiency

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Aldosterone and Renin Level
Serum renin and aldosterone levels should be obtained to determine whether a mineralocorticoid deficiency is
present. Both cortisol and aldosterone are missing in primary adrenal insufficiency. A low aldosterone
concentration is present despite markedly increased plasma renin activity. In secondary adrenal insufficiency, the
aldosterone level will be normal. Increased plasma renin activity can be seen; this indicates that there is adrenal
cortex dysfunction. A high level occurs when there is a low level of serum aldosterone.

Comprehensive Metabolic Panel

Laboratory findings that are characteristic of Addison disease include hyponatremia, hyperkalemia, and
hypoglycemia. Hyponatremia is due to cortisol and aldosterone deficiency. Aldosterone deficiency causes sodium
wasting, and cortisol decreases antidiuretic hormone, leading to increased water absorption. Hypovolemia also
triggers ADH secretion. Hyperkalemia is secondary to low aldosterone levels, which causes natriuresis and
potassium retention. However, hyperkalemia does not occur in secondary disease; this helps to distinguish it from
primary adrenal insufficiency. Hypoglycemia is multifactorial, including decreased oral intake and lack of
glucocorticoids, which are essential for gluconeogenesis. Hypercalcemia may be present, which reflects extracellular
fluid loss.

Thyroid-stimulating Hormone
A slight elevation of thyroid stimulating hormone (TSH) level can occur in adrenal insufficiency due to decreased
cortisol levels and abnormal TSH circadian rhythm. If TSH elevation persists, clinicians should consider the
possibility of hypothyroidism.

Anti–21-hydroxylase Antibodies
Anti-adrenal antibodies (eg, 21-hydroxylase antibodies) are the markers of autoimmune destruction of the adrenal
gland. The 21-hydroxylase enzyme is essential for cortisol synthesis in the adrenal cortex and can help determine an
underlying cause in patients with clinical features of adrenal insufficiency. Anti-adrenal antibodies are also
necessary to evaluate other organ-specific autoimmune conditions.

Diagnostic Imaging Studies

A biochemical diagnosis of adrenal insufficiency should be made before obtaining imaging studies, as radiographic
findings are nonspecific. In patients with adrenal insufficiency, a chest radiograph may reveal a small heart, which
may be due to a decrease in the cardiac workload. In suspected cases of adrenal hemorrhage, an abdominal
computed tomography (CT) scan may provide helpful information in determining the cause. For example, bilateral
enlargement of the adrenal glands may be seen with adrenal hemorrhage. Additionally, adrenal gland calcification or
hemorrhage can be seen with tuberculosis.
Furthermore, a finding on imaging of small adrenal glands suggests autoimmune adrenal destruction. A magnetic
resonance imaging (MRI) of the hypothalamic-pituitary region should be obtained if ACTH is inappropriately low in
the presence of cortisol deficiency. A pituitary baseline profile should also be obtained.

Additional Diagnostic Studies

Additional studies should be directed to determine the underlying cause of adrenal insufficiency. A PPD test should
be performed to evaluate for tuberculosis. A serum very long-chain fatty acid profile should be obtained in

112
cases where adrenal leukodystrophy is suspected. Complete blood count (CBC) may reveal neutropenia,
lymphocytosis, and eosinophilia. In patients with hyperkalemia, electrocardiograms (ECG) may show tall and
peaked T waves. Histology examination is useful in investigating infiltrative causes of adrenal insufficiency. The
finding of caseating granulomas may suggest tuberculosis, whereas a non-caseating granuloma may be due to
sarcoidosis.

TREATMENT/MANAGEMENT

Early recognition is critical for the management of acute adrenal insufficiency. Addison crisis is a severe endocrine
emergency; immediate recognition and treatment are required. Addison crisis that is not promptly recognized and
treated can be fatal. The confirmatory laboratory evaluation should not delay the treatment. Blood samples should be
obtained for subsequent measurement of ACTH and cortisol levels. The elevation of ACTH with low cortisol is
diagnostic of a primary adrenal insufficiency. Cortisol in the ACTH stimulation test may be measured when initial
laboratory evaluation cannot establish the diagnosis. Plasma renin level is often elevated and indicates a
mineralocorticoid deficiency, accompanied by a low aldosterone level.

Acute Phase Therapy

The approach to patients with an adrenal crisis consists of the following components.

 Fluid resuscitation: to restore the intravascular volume with intravenous (IV) normal saline
 Dextrose: to correct hypoglycemia
 Correction of the hormone deficiency: both glucocorticoid and mineralocorticoid
Hydrocortisone should be immediately administered as the initial hormonal treatment. The recommended adult
regimen for adrenal crisis is hydrocortisone 100 mg intravenous (IV) bolus initially, followed by 50 to 100 mg IV
every 6 hours over 24 hours. In children, the dosage is 50 mg/m2 IV bolus with a maximum dose of 100 mg,
followed by 50 to 100 mg/m2. Since this dose has significant mineralocorticoid activity, other mineralocorticoids
(eg, fludrocortisone) are unnecessary during the acute phase. Dexamethasone 4 mg IV bolus can be considered in
the ED when emergent steroid administration is required, as dexamethasone is less likely to interfere with the serum
cortisol assays. Dexamethasone is long-acting and does not interfere with biochemical assays of endogenous
glucocorticoid production. Prednisone and dexamethasone have little or no mineralocorticoid activity. Initial fluid
replacement with a normal saline bolus followed by 5% glucose in isotonic saline is also recommended.
Hypoglycemia should be treated promptly.

Maintenance Phase Therapy

In patients with stabilized Addison disease, life-long treatment with hormonal replacement is required. Maintenance
therapy aims to provide a replacement to maintain a physiologic glucocorticoid and mineralocorticoid level. The
usual dosage regimens are as follows:

 Glucocorticoid
o Hydrocortisone 5 to 25 mg/day divided into 2 or 3 doses
o Prednisone 3 to 5 mg/day

Doses should be adjusted according to the clinical response and normalization of electrolyte abnormalities. To
minimize adverse effects, the dosage should be titrated to the lowest possible dose that controls symptoms; the
patient should also be ensured to be clinically well. A plasma renin level can also be used to adjust the doses. Serum
ACTH levels may vary significantly and cannot be used for dose adjustment. Clinicians should also consider a
patient's concurrent medications when deciding the glucocorticoid dose. For example, certain drugs, such as
rifampin, can increase hepatic glucocorticoid metabolism and may inactivate cortisol. Dexamethasone is not an
appropriate choice for maintenance treatment as the dose titration is challenging and increases the risk of the
Cushing effect.
Fludrocortisone should be administered at a sufficient dose to keep the plasma renin level in the reference range.
An elevated PRA indicates a higher dose of fludrocortisone is required. The mineralocorticoid dosage should be

113
tailored to address the degree of stress. Furthermore, identifying and treating underlying causes such as sepsis is
critical for an optimal outcome. The treatment of associated conditions should also be provided.

 Mineralocorticoid
o Fludrocortisone .05 to .2 mg daily
o Hydrocortisone (in children) 8 mg/m2/day orally initially, divided into 3 or 4 doses.

Treatment Considerations
 In patients with Addison disease, glucocorticoid secretion does not increase during stress. Therefore, in the
presence of fever, infection, or other illnesses, the hydrocortisone dose should be increased to compensate
for a possible stress response.
 Generally, a usual hydrocortisone stress dose is 2 to 3 times the daily maintenance dose.
 Patients taking rifampin require an increased dose of hydrocortisone, as rifampin increases the clearance of
hydrocortisone.
 Thyroid hormone can increase the hepatic clearance of cortisol, precipitating an adrenal crisis.
Glucocorticoid replacement can potentially normalize thyroid-stimulating hormone.
 In patients with concomitant diabetes insipidus, glucocorticoid therapy can aggravate diabetes insipidus.
Cortisol is required for free-water clearance, and cortisol deficiency may prevent polyuria.
 Pregnancy, particularly during the third trimester, increases corticosteroid requirements.

DIFFERENTIAL DIAGNOSIS
The differential diagnosis of adrenal crisis includes most other conditions that can cause shock. The differential
diagnosis of adrenal insufficiency is broad, including the following conditions.

 Sepsis: Many features of sepsis overlap with adrenal insufficiency. The presentation includes weakness,
fatigue, vomiting, hypotension, and shock. The primary adrenal insufficiency diagnosis is confirmed by
low cortisol response to ACTH stimulation test and low ACTH level.

 Shock: Any type of shock with a decreased serum cortisol level suggests adrenal insufficiency.

 Chronic fatigue syndrome: Chronic persisting or relapsing fatigue may mimic adrenal insufficiency.
However, laboratory evaluations such as cortisol level after corticotropin stimulation differentiate it from
adrenal insufficiency.

 Infectious mononucleosis: The presentation may be similar to fever, fatigue, and myalgias, which may
occur in both conditions. However, exudative pharyngitis is present in this condition. IgM antibodies to
viral capsid antigens are present.

 Hypothyroidism: As with adrenal insufficiency, fatigue may be present in hypothyroidism. However,

hypothyroidism is associated with weight gain. The cortisol level differentiates both conditions.

TOXICITY AND ADVERSE EFFECT MANAGEMENT

A delay in initiating the treatment can have severe consequences and may increase rates of morbidity and mortality.

PROGNOSIS
The treatment of Addison disease involves a life-long replacement of glucocorticoids and mineralocorticoids.
However, most patients live an active life. A strict balance is required to avoid over- or under-treatment with
glucocorticoids. Therefore, careful monitoring is needed. Over-treatment with glucocorticoids may result in obesity,
diabetes, and osteoporosis. Over-treatment with mineralocorticoids can cause hypertension.

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Up to 50% of patients with Addison disease may develop another autoimmune condition; therefore, continued
clinical monitoring is recommended. Thyroid hormone replacement before glucocorticoid administration may
precipitate an adrenal crisis in unrecognized patients due to increased cortisol clearance. Rapid recognition and
treatment are necessary in acute adrenal crisis.

COMPLICATIONS
Several complications can occur due to Addison disease or secondary to inappropriate treatment. Addison disease
can progress to an adrenal crisis if not recognized and promptly treated, resulting in hypotension, shock,
hypoglycemia, acute cardiovascular decompensation, and death. Patients with adrenal insufficiency are also at
higher risk of death due to infections, cancer, and cardiovascular causes. Delayed recognition and treatment of
hypoglycemia can cause serious consequences. A supraphysiologic glucocorticoid replacement can lead to the
development of Cushing syndrome. Growth suppression can occur in children. Premature ovarian failure or primary
ovarian insufficiency may develop in up to 10% of women with Addison disease.

ADDISON’S PRESENTATION

Clinical Biochemical
Weight loss hypoglycaemia
Lethargy hyperkalaemia
Low mood hyponatraemia
Anorexia hypocalcaemia
Sx of hypoglycaemia + Hypotension Refractory hypotension
Polydipsia + polyuria
Seizures
Pigmentation

DIAGNOSIS
 Perform short synacthan test
 Take sample of blood for cortisol then give ACTH (tetracosactide 250 g) and 30 mins and 60 min later
take sample. Diagnosis – if 1st cortisol low and increase or less than 550 nmol/l
 Early morning cortisol if <165nmol/l
 Early morning ACTH if > 22nmol/l
 Insulin tolerance test 0.1U/kg injected into fasted patient this results in hypoglycaemia <2.2mmol/l causes
release of ACTH and increased cortisol >500 nmol/l.

MANAGEMENT
 Supportive management
 Transfer to high dependency unit for invasive monitoring
 ABC
 Support ventilation as required.
 IV access and IV fluids resuscitation with central access for inotropes to maintain MAP and fluid balance.
 Replace electrolytes as required with care not to raise Na + level too quickly, max 1mmol per hour. Monitor
K+ levels and treat as required.
 May need dextrose to maintain blood glucose.
 Give IV hydrocortisone 200 mg plus 100 mg 6 hourly until taking oral ( 20 mg in am and 10 mg in the
evening) plus fludrocortisone 50 – 100 g/day

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PERI-OP STEROIDS & REPLACEMENT
Endogenous steroid is released normally in response to surgery depending on the magnitude of the surgery. Therapy
with glucocorticoids results in suppression of the HPA axis and therefore no or less endogenous release.
Depends dose of steroid and time taken last steroid and type of surgery (major):

 If <10 mg/day – No additional cover needed.

 If > 10 mg prednisolone or equivalent/day in the past 3 months + minor surgery:

o Give 25mg hydrocortisone on induction
o 100 mg/day for 24 hours
 Moderate use –
o Usual pre op dose +
o 25 mg hydrocortisone on induction +
o 100 mg/day for 24 hours.
 Major surgery –
o Usual pre-op steroids +
o 25 mg hydrocortisone on induction +
o 100 mg/day for 48 - 72 hours.

CONN’S DISEASE AND HYPERALDOSTERONISM

a) What is aldosterone? Describe the renin-aldosterone relationship (40%).
b) What are the causes of primary and secondary hyperaldosteronism? (20%).
c) How does hyperaldosteronism or Conn’s disease present? (20%).
d) Describe the biochemical abnormalities associated with Conn’s disease (10%).
e) How may it be diagnosed? (10%).

ALDOSTERONE
• Mineralocorticoid hormone
• Synthesised in ZG of adrenal medulla in response to action of ATII or [K+]
• ATII levels increase in response to renin release which occurs when macula densa senses less tubular
filtrate and sodium ( ATI release, ACE converts to ATII)
• Aldosterone acts on DCT & collecting ducts to increase Na+ resorption

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SECRETION, EFFECTS AND DEGRADATION OF ALDOSTERONE

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM[RAAS]
The renin–angiotensin−aldosterone system regulates sodium balance, fluid volume, and blood pressure (BP). Renin
is released by the kidneys in response to reduced perfusion (due to decreased plasma volume and BP). Renin then
stimulates angiotensinogen to convert angiotensin I to angiotensin II in the lungs. Angiotensin II causes
vasoconstriction and stimulates the secretion of aldosterone from the adrenal cortex. Aldosterone causes sodium
(and water) reabsorption, thus increasing fluid volume, BP, and renal perfusion. Angiotensin II and aldosterone
cause feedback inhibition of renin secretion. Renin is also inhibited by normalization of renal perfusion. (GFR,
glomerular filtration rate; RBF, renal blood flow)

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– Hyperkalemia causes increased aldosterone production, which increases the renal excretion of K +.

MECHANISM OF HORMONAL CONTROL – NEGAGIVE

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CAUSES OF HYPERALDOSTERONISM

PRIMARY SECONDARY
Adrenal adenoma Chronic activation of RAS system
Hyperplasia HF
Chronic liver disease & Ascites

PRESENTATION AND ELECTROLYTE ABNORMALITIES

 Rx resistant hypertension
 Electrolyte abnormalities
o Sometimes metabolic alkalosis
o Low K+

DIAGNOSINS
o Aldosterone to renin ratio (high) confirms primary hyperaldosteronism.
o MRI of adrenals may reveal adenoma
o Scanning with labelled precursors of aldosterone will differentiate between adenoma and hyperplasia.

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A 65-year-old female patient is admitted to the intensive care unit following a craniotomy and debulking of a
posterior fossa tumour. Her serum sodium is 120 mmol/l. Which of the following is the most important investigation
in establishing the diagnosis of cerebral salt wasting syndrome as a cause of hyponatraemia?

a) Total urinary sodium excretion.

b) Urinary sodium concentration
c) Serum osmolality
d) Fractional excretion of uric acid
e) Urinary osmolality

ANSWER: A. Total urinary sodium excretion.

The most common cause of hyponatraemia is the syndrome of inappropriate ADH secretion (SIADH). Cerebral salt wasting
syndrome (CSWS) also causes hyponatraemia, and is seen in patients with traumatic brain injury.
The urinary sodium concentration is elevated in both SIADH and cerebral salt wasting syndrome (> 40 mmol/l). However, total
urinary sodium excretion (urine sodium concentration x urine volume in 24 hours) is substantially higher than sodium intake in
cerebral salt wasting syndrome but generally equals sodium intake in SIADH. Therefore, the net sodium balance (intake minus
output) is negative in cerebral salt wasting syndrome.
Fractional excretion of uric acid (FEUA) is defined as the percentage of urate filtered by the glomeruli that is excreted in urine.
Patients with either cerebral salt wasting syndrome or SIADH can have hypouricaemia and elevated FEUA. However, after
correction of hyponatraemia, hypouricaemia and elevated FEUA may normalize in SIADH but persist in cerebral salt wasting
syndrome. Serum osmolality is reduced in both SIADH and CSWS. Urinary osmolality is increased in both of these conditions.
Excessive renal excretion of sodium leads to depletion of extracellular volume and reduced effective circulating volume. Reduced
circulating volume and reduced blood pressure activates baroreceptors which increases the secretion of antidiuretic hormone from
the posterior pituitary. This leads to water retention and restores the extracellular fluid volume.
Failure to distinguish CSWS from SIADH as the cause of hyponatraemia could lead to inappropriate therapy (ie fluid restriction).
This can exacerbate extracellular volume depletion and compromise cerebral perfusion.
The possible mechanism is that the injured brain may release natriuretic proteins that act directly on the renal tubules. In addition,
cerebral injury may increase sympathetic nervous system activity, elevating renal perfusion pressure and releasing dopamine.

THYROID & PARATHYROIDS

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Cross section of the neck at C4 showing site of injection of the cervical plexus blocks. deep, intermediate, and subcutaneous.
Note the investing layer of cervical fascia that putatively acts as a barrier to deep spread of s.c. injection. It is this anatomical
layer whose existence is questioned by the studies of Nash and colleagues.

Thyroid is a very vascular organ with one of the highest blood flow per gram tissue of any organ in the body. It is made up of
follicles – a single line of cells. When the thyroid is inactive the follicles are quite big and the cells are flat. As the thyroid gets
more active, the follicles shrink in size and the cells change shape and become cuboidal columnal.

Endocrine gland
o Maintains homeostasis
o Hormone – chemical substance produced in one tissue and conveyed in bloodstream to another site to
effect physiological activity.

TRUE or FALSE?

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 • T3 is the active hormone whereas rT3 is inactive T
• Chlorine is central to thyroid hormone metabolism F
• T3 and T4 are mainly bound to albumin & transthyretin (TTR) in the bloodstream F (T3 albumin, T4
thyroxine binding globulin]
• All thyroid binding proteins bind T4 at least 10x more strongly than T3
• [TBG] is much lower than [albumin] and [TTR]

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BINDING OF THYROID HORMONES IN THE CIRUCLATION
Thyroid hormones (T4 and T3) circulate in the blood-stream either bound to plasma proteins or free (unbound). Most
T4 and T3 circulates bound to thyroxine-binding globulin (TBG). Smaller amounts circulate bound to T4-binding
prealbumin and albumin. Still smaller amounts circulate in the free unbound, form. Because only free thyroid
hormones are physiologically active, the role of TBG is to provide a large reservoir of circulating thyroid hormones,
which can be released and added to the pool of free hormones.

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In a normal functioning thyroid, the pituitary gland produces TSH - when a healthy thyroid gets this message, it
produces two hormones - triiodothyronine (T3) and thyroxine (T4). T4 is converted to T3 on an as-needed basis to
regulate metabolic functions.

Your liver also converts T4 to rT3 (reverse T3) which is inactive and actually blocks the action of T3. This is part of
the body's normal process to keep your hormones in balance and get rid of unneeded T4. Normally about 40% of T4
is converted to T3 and 20% to rT3. However if the proportion of rT3 dominates then it can produce hypothyroid
symptoms, even though your thyroid function test results may appear normal.

ACTIVATION OF T4 IN TARGET TISSUE

As noted, the major secretory product of the thyroid gland is T 4, which is the less active form of thyroid hormone.
This problem is solved in the target tissues by the enzyme 5`-iodinase which converts T 4 to T3 by removing 1 atom
of I2 from the outer ring of the molecule.
The target tissue also converts a portion of the T 4 to reverse T3 (rT3) by removing 1 atom of I 2 from the inner ring of
the molecule; rT3 is inactive. Essentially, T4 serves as a precursor for T3, and the relative amounts of T4 converted to
T3 and rT3 determine how much active hormone is produced in the target tissue.
In starvation (fasting), target tissue 5`-iodinase plays an interesting role. Starvation inhibits 5`-iodinase in tissues
such as skeletal muscle, thus lowering O 2 consumption and basal metabolic rate (BMR) during periods of caloric

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deprivation. However, brain 5`-oidinase differs from the 5`-iodinase in other tissues and is therefore not inhibited in
starvation; in this way, brain levels of T3 are protected even during caloric deprivation.

MECHANISM OF HORMONAL CONROL – NEGATIVE FEEDBACK

CONTROL

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T3 EFFECTIVE rT3 ANTAGONISES T3
The clinical importance of TH transporters was established by the discovery of mutations in the MCT8 gene which
is located on the X chromosome, as a cause of psychomotor retardation accompanied by TH abnormality. Affected
males display a severe delay in motor and neurological development. Soon after the description of the first patient, it
was realized that the phenotype has similarities to the Allan-Herndon-Dudley syndrome (AHDS), the first X-linked
mental retardation syndrome described in 1944. Genetic analysis in these families revealed that MCT8 mutation are
the genetic basis of AHDS. To date, over 100 families have been reported with pathogenic mutations in MCT8.

Allan-Herndon-Dudley syndrome (AHDS) -also known as MCT8 deficiency – is a rare genetic disorder that affects
a child’s cognition, mobility and overall health. In individuals with AHDS, thyroid hormone is unable to enter cells
in the brain because of a defect in a thyroid hormone transporter called MCT8.

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Model of TH regulation at the cellular level. Transporters are required for uptake and release of T 4 and T3. MCT8 is prototypic for
cellular T3 and T4 transport. Three deiodinases are involved in activation or inactivation of TH. D1 is mainly involved in TH
regulation in serum and therefore is not shown in the figure. D2 and D3 are important for local TH regulation. D2 converts T4 to
bioactive T3, whereas D3 degrades T3 to 3, 3`-T2. Insertion of the selenocysteine into the deiodinases requires SBP2. Ultimately,
T3 binds to its nuclear receptor (TRs) and modulates gene expression of T3 target genes.

HYPOYHYROID
 Thyroiditis – autoimmune (Hashimoto)
 Iatrogenic
 Thyroid hormone resistance
 Euthyroid sick syndrome
 Congenital hypothyroid
 Others
o Iodine deficiency
o Drugs (amiodarone).
 Secondary hypothyroidism
o Pituitary disease
o Idiopathic TRH deficiency

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Clinical features – related to Anaesthesia
 Reduced BMR
 Hypothermia(elderly)
 Increased sensitivity to opioids and anaesthetic agents
 CVS
o HR
o  SV
o  CO
o Pericardial effusions
 RS
o Loose the ability to response to hypoxia and hypercarbia and so hypoventilate
o Maximum breathing capacity reduces
o Pleural effusions
 Skin
o Thick from deposit of polysaccharides below the skin - myxoderma

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 o Thickening of the vocal cords - stridor
 Haematology
o anaemia
 GIT
o Constipation

PRE-OP
 Look for symptoms and signs of hypothyroidism
 Patient should be euthyroid [levothyroxine]
 Triiodothyronine can be used in an emergency – ITU with full monitoring.
 Look for hoarse voice [vocal cord involvement]
 Look for goitre – difficult airway
 Investigation - FBC, U&E , ECG
 Imaging: CXR [thoracic inlet view/CT

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Untreated hypothyroid patient [ during pandemic]
 Care with premedication
 Blood loss poorly tolerated
 Respiratory response to hypoxia and hypercarbia reduced
 Opioids associated with prolonged respiratory depression and delayed recovery.
 Hyponatraemia –  free water excretion

HYPERTHRYOID
Causes
 Graves’ disease
 Thyroid nodule (toxic)
 Toxic nodule struma (Plummer’s disease)
 Hashitoxicosis
 Rare – choriocarcinoma
 Pituitary adenoma

Clinical Features
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  Due to excess T3 [Triiodothyronine] and T4[Thyroxine]
 General
o anxiety
 CVS
o Tachycardia/AF
o  CO  Heart failure particularly in the elderly.
o  -receptors in the heart thereby Increasing the sensitivity to catecholamine
 Respiratory
 GI
 Neurological
 Haematology
o Prone to thrombocytopenia

MALIGNANT
 Papillary – commonest, slow growing, spreads to lymph nodes glands in the neck.
 Follicular – next most common, slow growing – metastasizes to lung and bone
 Medullary – C cells, metastasizes
 Anaplastic – the worst of all, Rare aggressive tumour
 Lymphoma
 Secondary deposits

DRUGS USED IN THYROID DISEASE

 Thyroid hormone replacement -thyroxine
o Levothyroxine
Younger patients – 1.6 g/kg body weight  100 g per day.
Older patient/CVS disease – start at 25 – 50 g/day and titrate

o T3 rarely used outside emergency replacement.

 Thyrotoxicosis [Hyperthyroid]
o Radioactive iodine
o Carbimazole
 Avoid in pregnancy or any patient trying to get pregnant.
 Bone marrow suppression
o Propylthiouracil
 Bone marrow suppression – therefore check the full blood count constantly.
 Glomerulonephritis

o Beta blocker

ANAESTHESIA FOR THYROIDECTOMY

PREOP
 Must be euthyroid prior to surgery.
 Careful evaluation of the CVS - arrhythmias
 Airway assessment – Goitre [ location, size, signs of airway obstruction-stridor – dynamic or fixed stridor]
 Investigation
o FBC
o E&U
o Ca2+
o ECG
o Imaging – X-ray/CT scan? size, location, elective tracheostomy
o G and S
 ? Nasendoscopy – see the cords and how they move

Nasendoscopy:

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Is a diagnostic procedure that involves the examination of the nasal tube, throat, and larynx [voice box]? It collects
comprehensive photos or films of the structures using an endoscope, a specialized telescopic instrument that is guided through
the nasal channel until the bottom of the throat.
 Consider premed [increased dose] if anxious.
 Continue thyroid medication up till surgery.
 Intonation can be challenging
o Tracheal compression - smaller ETT, reenforced tube
o Tracheal deviation
 Care with securing ETT
 Eye protection [especially in patients with thyroid eye disease.]

INTRAOP
 Monitoring
o Standard AAGBI
o Laryngeal nerve monitoring – short-acting muscle relaxants

 Positioning
o Supine
o Head up tilt, sandbag, shoulder roll
o Arms by side
 Maintenance
o Choice of TIVA or modern volatile
 Fluid management
o Large bore cannula
o Maintenance fluid
 Analgesia
o Simple [100g fentanyl + Paracetamol]
o Short-acting opioids
o Local anaesthetic infiltration/cervical plexus block
 Antiemesis
o No cough/retching or vomiting

 Raise intrathoracic pressure at end [haemostasis] to release the vessels that were not tied during dissection
o Valsalva manoeuvre

POSTOP
 Smooth extubation
 Beware of laryngeal nerve damage – at the end of the case do laryngoscopy and see the patient breathing on the tube
[ both cords moving]. Nowadays, imaging can show if the laryngeal nerve is damaged as a result of surgery.
Dexamethasone is given in case the cords are swollen.
 Beware of tracheomalacia [rare] – in case of mild tracheomalacia, give facemask CPAP until the patient is fully awake.
If it is severe, you need to get the tube out very quickly and then tracheostomy.

Preoperative Risk factors tor tracheomalacia [50% reduction in tracheal lumen – prerequisite for diagnosis]
 Large Goitre > 5 years
 Pre-operative recurrent laryngeal nerve palsy.
 Significant tracheal narrowing and deviation
 Retrosternal extension
 Difficult tracheal intubation
 Thyroid cancer

TRACHEOMALACIA
Although definitive criteria are lacking, a cut off of a 50% reduction in tracheal lumen is usually considered a prerequisite for
diagnosis. This relies largely on dynamic imaging, either CT or MRI. However, in patients with extrinsic compression such as
those due to goiter, tracheomalacia may theoretically only become apparent following removal of their compressive agent.
Consequently, tracheomalacia may present unheralded as an emergency after thyroidectomy; hence historically, it has been
feared as a complication of thyroidectomy. Though a number of investigations have been mentioned in the literature, in a

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postoperative patient a high clinical suspicion and bronchoscopy can be used for effective diagnosis and treatment. The airway is
directly visualized during spontaneous respiration using a flexible bronchoscopy. The findings consist of the triad of:
 Loss of normal semicircular shape of tracheal lumen
 Forward ballooning of the posterior membranous wall and
 Anteroposterior narrowing of the traceal lumen.

The important point is recognition of tracheomalacia on the operating table before extubation. There is no single foolproof
criterion for confirming a diagnosis of tracheomalacia. However, for the intraoperative diagnosis of tracheomalacia, we have
taken one or more of the following criteria:
o Soft and floppy trachea on palpation by the surgeon at the end of thyroidectomy. However, because of splinting effect
of the endotracheal tube (ETT) in situ, it is difficult to appreciate a soft trachea. We therefore ask the anesthesiologist to
gradually withdraw the tube for a short distance and then feel the tracheal without the tube in site. This maneuver may
also help the surgeon recognize an obvious collapse of the tracheal wall.

o Obstruction to spontaneous respiration during gradual withdrawal of the ETT after thyroidectomy.

o Difficulty in negotiating the suction catheter beyond the ETT after gradual withdrawal.

o After closure of the wound, tracheomalacia can be suspected:

o If there is absence of peritubal leak on deflation of ETT cuff

o Volume pressure loop on ventilator or
o Development of respiratory stridor along with falling hemoglobin oxygen saturation (SpO2) on pulse
oximetry despite the administration of increasing FiO2.

The typical manifestation of postoperative tracheomalacia is acute respiratory distress following extubation not explained by any
other cause. This invariably necessitates prompt re-intubation or a tracheostomy, following which the distress is promptly
relieved. Anticipation of possible tracheomalacia helps in instituting preventive or prompt remedial measures.
We recommend treating postoperative tracheomalacia following thyroidectomy expectantly. Mild variants, which may not be
recognized postoperatively, may be managed with respiratory exercises. Mask ventilation using a CPAP mode may also be a
useful adjunct. The majority will respond to conservative management, consisting of humidified air, chest physical therapy, slow
and careful feedings to prevent aspiration, and control of infection and secretions with antibiotics.

Prolonged Intubation
Patients who are unable to maintain oxygen saturation with these measures may be managed with intubation for longer periods.
When extubation after about 2 weeks becomes a problem, we perform tracheostomy. The inflammatory response that sets in due
to the indwelling tracheostomy or endotracheal tube leads to a stiffening of the tracheal wall thereby preventing the expiratory
collapse. This is paradoxical since a long-standing tracheostomy tube can result in tracheomalacia because of pressure-related
degeneration of the tracheal cartilages.

Tracheostomy
We prefer to go for an intraoperative tracheostomy if there is definite softening of the trachea6,7 we think that it is better to do a
tracheostomy at the time of surgery, as it is easier to visualize the part of trachea most suitable for tracheostomy. Further, the
tracheal toilet as well as ventilator care, if needed, is easier in patients with tracheostomy than in those with the ETT kept in
place. Unlike prolonged intubation, tracheostomy results in fibrosis around a soft trachea resulting in early recovery from
tracheomalacia. We also did not encounter any cases of tracheal stenosis following tracheostomy for tracheomalacia. Most of the
tracheostomized patients had their tracheostomy tube removed after a week.

COMPLICATIONS OF THYROIDECTOMY
Intraoperative
 Bleeding
 Damage to RLN

Postop
 Bleeding
 Airway obstruction[bleeding/oedema]
 Thyroid storm

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  Hypocalcaemia
 Pneumothorax [because of closeness to the apices of the lungs]

Immediate
Longer term

POST THYROID BLEED

 AAGBI and others in 2021 produced guidelines SCOOP on post thyroid bleed; how to identify a thyroid bleed and
what to do about it.

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COMPLICATIONS OF SURGERY IN PATIENTS WITH THYROID DISEASE
 Hypothyroid
o Coma! – give T3
 Hyperthyroid
 Thyroid storm
 Pyrexia
 Confusion, restlessness and delirium’
 CVS
o Tachycardia
o AF
o High output cardiac failure
 flushing sweating abdominal pain
 dehydration, ketosis

Treatment of thyroid storm [Thyrotoxic crises]

 recognize and treat promptly.
 Senior help, alert ITU
 O2, ABCDE
 Rehydration, cooling, sedation with chlorpromazine – Paracetamol
 Beta blockers [Esmolol, propranolol, metoprolol]
 Antithyroid drugs:
o Thioamide [carbimazole]
o Lugol’s iodine
 May require intubation, sedation and ventilation

HYPERTHYROIDISM AND THYROIDECTOMY

A 45-year-old woman with Grave’s disease and palpable Goitre presents for elective thyroidectomy.
a) Describe the regulation of thyroid hormone synthesis and secretion (15%).
b) Name 4 drugs that may be used to treat thyrotoxicosis and briefly outline their mechanism of action (25%).
c) What are the main anaesthetic priorities in assessing a patient with thyrotoxicosis who is presenting for thyroid
surgery? (30%).
d) List the procedure specific complications that may present in the post-operative thyroidectomy patients (40%).

o Propranolol
o -Blocker
o Reduces T4  T3 in periphery.
o Carbimazole
o Converted to methimazole. Inhibits thyroid peroxidase, blocks iodine oxidation from iodide. Reduces T3/4
synthesis.
o Propylthiouracil
o Blocks iodination of tyrosine residues on TG. Inhibits T4  T3
o Iodine
o Inhibits T3 & T4 production, reduces thyroid vascularity.

Preoperative assessment:
  CT scan of the neck [size and position of any Goitre]/ X-ray of thoracic inlet
 ? Compression or invasion of structures surrounding the thyroid gland.
o Stridor – trachea
o Obstruction – superior vena cava
o Horner’s syndrome – sympathetic chain
o Hoarse voice – recurrent laryngeal nerve
 Anticipated difficult intubation
o Gaseous or awake fibreoptic technique
o Tracheostomy under local anaesthesia

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Intraoperatively:
 Electrophysiological testing of the recurrent laryngeal nerve may preclude the use of muscle relaxants following
induction; therefore, a remifentanil infusion is commonly used.

Procedure specific postoperative complications:

 Haemorrhage [trachea compression and rapid airway obstruction]
 Recurrent laryngeal nerve palsy
 Severe hypocalcaemia  laryngospasm if severe.
 tracheomalacia

Recurrent laryngeal nerve palsy may be due to surgical retraction or transection. it may be unilateral or bilateral.
Bilateral recurrent laryngeal nerve palsy results in complete adduction of the vocal cords and therefore complete
airway obstruction. Immediate reintubation is required and a tracheostomy may be necessary.
Tracheomalacia, characterized by flaccid tracheal cartilage that collapses on inspiration resulting in airway
obstruction. Patients who have long-standing or very large Goitre are at much greater risk of tracheomalacia. Prior to
extubation, it is useful to deflate the endotracheal tube cuff to check for air leak.

THYROID HORMONE [T3] RECEPTOR [T3R] ACTIVATION – THINK GRAVE’S

PATHOGENESIS OF GRAVE’S DISEASE

Transcriptional activation of thyroid hormones (T3) receptor [T3R] generally requires the binding of its high affinity
ligand.

Graves’s disease is caused by autoantibodies to the thyrotropin receptor (TRAb) that activated the receptor, thereby
stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing diffuse Goitre). The
presence of TRAb in serum and eye involvement on clinical examination immediately distinguishes the disorder
from other causes of hyperthyroidism.

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 HYPERTHRYODISM HYPOTHYROIDISM
SYMPTOMS SYMPTOMS
BMR BMR
Weight loss Weight gain
Negative nitrogen balance Positive nitrogen balance
 Heat production  Heat production
Sweating Cold sensitivity
 Cardiac Output  Cardiac Output
Dyspnea [shortness of breath] Hypoventilation
Tremor, muscle weakness Lethargy, mental slowness
Exophthalmos Drooping eyelids
Goitre Myxedema
Growth retardation [Perinatal]
Goitre
CAUSES CAUSES
Grave Dx [ thyroid stimulating Immunoglobulins] Hashimoto Thyroiditis [Autoimmune]
Thyroid neoplasm Surgery for hyperthyroidism
Excess TSH secretion Iodide deficiency
Exogenous T3 or T4 [factitious] Congenital [cretinism]
Decreased TRH or TSH
TSH LEVELS TSH LEVELS
[Feedback inhibition of T3 on the anterior lobe [-ve feedback – thyroid gland
[If defect is in anterior pituitary]  [ Hypothalamus or anterior pituitary
TREATMENT TREATMENT
Propylthiouracil [Peroxidase enzyme/ T3/T4 synthesis] Thyroid hormone replacement therapy
Thyroidectomy
131 -
I [destroys thyroid]
-Adrenergic blocking agent [Adjunct therapy]

HYPERTHYROIDISM AND THYROIDECTOMY

A 45-year-old woman with Grave’s disease and palpable Goitre presents for elective thyroidectomy.
e) Describe the regulation of thyroid hormone synthesis and secretion (15%).
f) Name 4 drugs that may be used to treat thyrotoxicosis and briefly outline their mechanism of action (25%).
g) What are the main anaesthetic priorities in assessing a patient with thyrotoxicosis who is presenting for
thyroid surgery? (30%).
h) List the procedure specific complications that may present in the post-operative thyroidectomy patients
(40%).

o Propranolol
o -Blocker
o Reduces T4  T3 in periphery.
o Carbimazole
o Converted to methimazole. Inhibits thyroid peroxidase, blocks iodine oxidation from iodide.
Reduces T3/4 synthesis.
o Propylthiouracil
o Blocks iodination of tyrosine residues on TG. Inhibits T4  T3
o Iodine
o Inhibits T3 & T4 production, reduces thyroid vascularity.

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Preoperative assessment:
  CT scan of the neck [size and position of any Goitre]/ X-ray of thoracic inlet
 ? Compression or invasion of structures surrounding the thyroid gland.
o Stridor – trachea
o Obstruction – superior vena cava
o Horner’s syndrome – sympathetic chain
o Hoarse voice – recurrent laryngeal nerve
 Anticipated difficult intubation
o Gaseous or awake fibreoptic technique
o Tracheostomy under local anaesthesia

Intraoperatively:
 Electrophysiological testing of the recurrent laryngeal nerve may preclude the use of muscle relaxants
following induction; therefore, a remifentanil infusion is commonly used.

Procedure specific postoperative complications:

 Haemorrhage [trachea compression and rapid airway obstruction]
 Recurrent laryngeal nerve palsy
 Severe hypocalcaemia  laryngospasm if severe.
 tracheomalacia

Recurrent laryngeal nerve palsy may be due to surgical retraction or transection. it may be unilateral or bilateral.
Bilateral recurrent laryngeal nerve palsy results in complete adduction of the vocal cords and therefore complete
airway obstruction. Immediate reintubation is required and a tracheostomy may be necessary.
Tracheomalacia, characterized by flaccid tracheal cartilage that collapses on inspiration resulting in airway
obstruction. Patients who have long-standing or very large Goitre are at much greater risk of tracheomalacia. Prior to
extubation, it is useful to deflate the endotracheal tube cuff to check for air leak.

A 29-year-old female has puffy skin, a hoarse voice and complains of an intolerance to cold. Her plasma thyroid
stimulating hormone (TSH) level is low and this increases significantly if she is given thyrotropin releasing hormone
(TRH). Which one of the following is the most likely diagnosis in this woman?
a) hypothyroidism due to a primary abnormality in the pituitary gland.
b) Hyperthyroidism due to a thyroid tumour
c) Hypothyroidism due to thyroid tumour.
d) Hyperthyroidism due to a primary abnormality in the hypothalamus
e) Hypothyroidism due to a primary abnormality in the hypothalamus.

Answer: E. Hypothyroidism due to a primary abnormality in the hypothalamus

The symptoms and signs of this woman suggest that she is suffering from hypothyroidism. TSH levels rising after
administration of TRH indicates that endogenous TRH production is deficient. TRH is produced by the
hypothalamus. Therefore, this patient has a primary abnormality in the hypothalamus. TSH is produced by the
anterior pituitary.

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PARATHYROIDS
 PTH:
 Stones
 Groans
 Moans
 Psychic overtones

Renal
 Renal stones
 Tubular dysfunction
 Polyuria
 Polydipsia
Skeletal
 Osteopenia
 Subcortical bone resorption
 Bone pain
 Pathological fractions
Nervous system
o Fatigue
o Loss of skeletal muscle strength and proximal musculatures
o Mood disturbances
Gastrointestinal
o Peptic ulcer disease
Cardiovascular
 Hypertension
 ECG changes
o Shortened QT interval and ST segments
o Cardiac conduction defects.

TRUE or FALSE?
• Ca2+ levels feedback to determine PTH release
• Mg2+ levels do not affect PTH release
• PTH directly affects the gut to enhance Ca2+ absorption
• Hypercalcaemia in cancer occurs due to tumour ADH secretion

MECHANISM OF HORMONAL CONTROL – NEGATIVE FEEDBACK CONTROL

149
PTH & BONE

150
151
PTH & VITAMIN D

152
EXOCRINE & ENDOCRINE PANCREAS

153
Endocrine and exocrine pancreas.

154
THE PANCREAS IS AN EXOCRINE AND ENDOCRINE ORGAN
The pancreas has key roles in the regulation of macronutrient digestion and hence metabolism/energy homeostasis
by releasing various digestive enzymes and pancreatic hormones. It is located behind the stomach within the left
upper abdominal cavity and is partitioned into head, body and tail.

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156
 The majority of this secretory organ consists of acinar—or exocrine—cells that secrete the pancreatic juice
containing digestive enzymes, such as amylase, pancreatic lipase and trypsinogen, into the ducts, that is, the main
pancreatic and the accessory pancreatic duct. In contrast, pancreatic hormones are released in an endocrine manner,
that is, direct secretion into the blood stream. The endocrine cells are clustered together, thereby forming the so-
called islets of Langerhans, which are small, island-like structures within the exocrine pancreatic tissue that account
for only 1–2% of the entire organ.

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There are five different cell types releasing various hormones from the endocrine system:

o -cells – glucagon (15 – 20%).

o -cells – insulin and amylin-C-peptide (65 – 80%)
o γ-cells – pancreatic polypeptide (PP) (3 – 5%)
o δ-cells – somatostatin (3 – 10%)
o ɛ-cells – ghrelin (<1%).

Each of the hormones has distinct functions. Glucagon increases blood glucose levels, whereas insulin decreases
them. Somatostatin inhibits both, glucagon and insulin release, whereas PP regulates the exocrine and endocrine
secretion activity of the pancreas. Altogether, these hormones regulate glucose homeostasis in vertebrates.

Through its various hormones, particularly glucagon and insulin, the pancreas maintains blood glucose levels within
a very narrow range of 4–6 mM. This preservation is accomplished by the opposing and balanced actions of
glucagon and insulin, referred to as glucose homeostasis. During sleep or in between meals, when blood glucose
levels are low, glucagon is released from α-cells to promote hepatic glycogenolysis. In addition, glucagon drives
hepatic and renal gluconeogenesis to increase endogenous blood glucose levels during prolonged fasting. In
contrast, insulin secretion from β-cells is stimulated by elevated exogenous glucose levels, such as those occurring
after a meal. After docking to its receptor on muscle and adipose tissue, insulin enables the insulin-dependent
uptake of glucose into these tissues and hence lowers blood glucose levels by removing the exogenous glucose from
the blood stream. Furthermore, insulin promotes glycogenesis, lipogenesis and the incorporation of amino acids into
proteins, thus, it is an anabolic hormone, in contrast to the catabolic activity of glucagon.

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Maintenance of blood glucose levels by glycogen and insulin. When blood glucose levels are low, the pancreas
secretes glucagon, which increases endogenous blood glucose levels through glycogenolysis. After a meal, when
exogenous blood glucose levels are high, insulin is released to trigger glucose uptake into insulin-dependent muscle
and adipose tissues as well as to promote glycogenesis.

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PANCREATIC REGULATION OF GLUCOSE HOMEOSTASIS
In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels.
This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly
from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas
represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon.

INSULIN SECRETION SIGNALING PATHWAY

Endocrine cells secrete their respective hormones in response to external signals, such as nutrient intake or stress,
via humoral, neural or hormonal signaling pathways. The underlying molecular process that translates the stimulus
into the actual hormone release is called stimulus-secretion coupling which is known as the stimulus-dependent
exocytosis of a particular substance, such as glucose-stimulated β-cell insulin release.

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In β-cells, the main stimulus for insulin release are elevated blood glucose levels following a meal. The circulating
blood glucose is taken up by the facilitative glucose transporter GLUT2 (SLC2A2), which is located on the surface
of the β-cells. Once inside the cell, glucose undergoes glycolysis, thereby generating adenosine triphosphate (ATP),
resulting in an increased ATP/ADP ratio. This altered ratio then leads to the closure of ATP-sensitive K +-channels
(KATP-channels). Under non-stimulated conditions, these channels are open to ensure the maintenance of the resting
potential by transporting positively charged K +-ions down their concentration gradient out of the cell. Upon closure,
the subsequent decrease in the magnitude of the outwardly directed K +-current elicits the depolarization of the
membrane, followed by the opening of voltage-dependent Ca+-channels (VDCCs).

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 The increase in intracellular calcium concentrations eventually triggers the fusion of insulin-containing granules
with the membrane and the subsequent release of their content.
The whole secretory process is biphasic with the first phase peaking around 5 minutes after the glucose stimulus
with the majority of insulin being released during this first phase. In the second, somewhat slower, phase, the
remaining insulin is secreted. Insulin is stored in large dense-core vesicles that are recruited to the proximity of the
plasma membrane following stimulation such that insulin is readily available.
The key molecules that mediate the fusion of the insulin-containing large dense-core vesicles are the:
 Synaptosomal-associated protein of 25 kDa (SNAP-25).
 Syntaxin-1 and
 Synaptobrevin 2 (or Vesicle-Associated Membrane Protein VAMP2),

all of which belong to the superfamily of the soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP)
receptor proteins (SNAREs).
Together with the Sec1/Munc18-like (SM) proteins they form the so-called SNARE complex. To initiate fusion,
synaptobrevin 2, a vesicle (v-)SNARE that is integrated into the vesicle's membrane, fuses with the target
(t-)SNAREs syntaxin-1 and SNAP-25, which are located in the target cell membrane, with mammalian
uncoordinated (munc)-18 playing a key regulatory role.

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163
Glucose-stimulated insulin release from a pancreatic -cell. Exogenous glucose is taken up by GLUT2 and
undergoes glycolysis inside the cell. Elevated adenosine triphosphate (ATP) levels alter the ATP/ADP ratio, which
in turn leads to the closure of ATP-sensitive K + channels. The subsequent membrane depolarization opens voltage-
dependent Ca2+ channels in response to increasing intracellular calcium levels, which eventually trigger insulin
secretion following vesicle fusion with the membrane.

The role of the brain in glucose homeostasis

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The interplay of the panaceas with the brain, liver, gut as well as adipose and muscle tissue. The pancreas interacts
with the brain, liver, gut and adipose and muscle tissue in a highly sophisticated network via various hormones,
neurotransmitters and cytokines. Brain-Derived Neurotrophic Factor [BNDF], Cholecystokinin [CCK], Glucose-
Dependent Insulinotropic peptide [GIP], Glucagon-like Peptide -1[ GLP-1], Gastrin-Releasing Peptide [GRP],
Interleukin – 6 [IL-6], Melanin concentrating Hormone [MCH], Neuropeptide Y [NPY], Pituitary Adenylate
cyclase-activating Polypeptide [PACAP], Pro-opiomelanocortin [POMC], Vasoactive Intestinal Peptide [VIP].

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-cell in Diabetes Mellitus

THE PANCREATIC GLUCOSTAT – HYPERGLYCAEMIA &

HYPOGLYCAEMIA

Pancreatic endocrine cells are regulated by intrinsic and paracrine signals in response to glucose. At basal glucose
levels pancreatic -cells (A, left) are electrically inactive, owing to their open ATP-sensitive K + (KATP) channels and
resultant hyperpolarized membrane potential, and thus do not secrete insulin.

In contrast, -cell in the presence of low glucose, (A right) are electrically active, due to a relatively elevated
ATP/ADP ratio (even at low glucose). This results in closure of most, but perhaps not all K ATP channels and a
depolarized membrane potential that allows action potential firing mediated by a combination of voltage-dependent
Na+, Ca2+(VDCC), and K+(Kv) channels. Entry of Ca2+ through VDCCs triggers the exocytosis of glucagon-
containing secretary granules.

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When plasma glucose is increased (B), glucose enters pancreatic islet cells through plasma membrane glucose
transporters (GLUT) where it is metabolized through glycolysis and mitochondrial oxidative metabolism. This
results in increase in intracellular ATP/ADP ratio (in the case of -cells, a further increase) and closure of K ATP
channels.

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In the case of β-cell (B, top left) this results in membrane depolarization and firing of action potentials that, in
combination with additional mitochondrial signals, results in the exocytosis of insulin-containing granules. In -
cells, further closure of KATP channels may further depolarize the membrane and lead to the depolarization-
dependent inactivation of Na+ channels and VDCCs.

Glucagon secretion is also inhibited by paracrine factors secreted from β-cells and pancreatic δ-cells. These signals
may interact with putative α-cell metabolic sensors (ie, PASK and AMPK) to produce the physiological suppression
of glucagon secretion.

INSULIN-GLUCAGON CROSS-TALK

Paracrine interactions between islet cells. Insulin secreted by β-cells acts as a prime hormone of glucose homeostasis
and inhibits glucagon secretion by -cells. Whereas glucagon activates insulin and somatostatin secretion,
somatostatin secreted by  cells and ghrelin by  cells inhibit insulin secretion.

DIABETES & DKA

A 65-year-old man with a 15-year history of diabetes mellitus is listed on the emergency list for aorto-bifemoral
grafting procedure following an unsuccessful series of debridement.

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 a) Briefly describe the pathophysiology of diabetes (10%).
b) What systemic complications of diabetes mellitus would you look for in preoperative assessment? (30%).
c) How would you assess for the presence of autonomic neuropathy? (10%)
d) List the classes of drugs that exist to treat diabetes mellitus (20%).
e) How would you manage this man’s glucose control preoperatively and intraoperatively? (30%).

DM PATHOPHYSIOLOGY
• Absolute or relative lack of insulin
– Type 1 (absolute; young, autoimmune/pancreatic resection or failure) vs Type 2 (relative; older,
obesity, drugs, pregnancy)
• Failure of insulin signalling triggers hyperglycaemia via gluconeogenesis
• Diagnosed:
– Symptoms of hyperglycaemia with:
– BM≥7mmol/L or ≥ 11.2mmol/L 2h post 75g OGTT
– HbA1C ≥ 6.5

SYSTEMIC SEQUELAE
• Hyperglycaemia  micro & macrovascular complications:
– Neuropathy (inc. autonomic)
– Retinopathy
• Microvascular dysfunction  neuronal hypoxia
• Microvascular dysfunction  same + retinal neovascularisn.
– Nephropathy
• Hyperfiltration, RAAS activation, microvascular dysfunction
– IHDx, CVA, PVDx
– Poor immunity, tendency to infections & slow wound healing
– Airway (ltd mouth opening)

DIABETES MELLITUS AND ANAESTHESIA

A 65-year-old man with a 15-year history of diabetes mellitus is listed on the emergency list for an aorto-bifemoral
grafting procedure following an unsuccessful series of debridement.
a) Briefly describe the pathophysiology of diabetes (10%).
b) What systemic complications of diabetes mellitus would you look for in preoperative assessment? (30%).
c) How would you assess for the presence of autonomic neuropathy? (10%)
d) List the classes of drugs that exist to treat diabetes mellitus (20%).
e) How would you manage this man’s glucose control preoperatively and intraoperatively? (30%).

DRUGS
o Insulin
o Biguanides / Metformin
o Sulphonylurea
o Meglitinides / Prandial glucose regulator/ Glinides
o Alpha-glucosidase inhibitors
o Thiazolidinedione / Glitazones
o DPP-4 inhibitors / Gliptins
o Incretin mimetics/GLP-1 analogues
o Amylin analogues

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DDP-4 inhibitors and GLP-1Ras: cardiovascular safety and benefits
Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors are commonly used treatments for
patients with type 2 diabetes mellitus (T2DM). Both anti-diabetic treatments function by playing key modulatory
roles in the incretin system.
Dipeptidyl peptidase 4 (DPP-4) inhibitors are a group of antihyperglycemic medications used to manage type 2
diabetes mellitus, which is a significant risk factor for coronary disease, heart failure, stroke, and many other
cardiovascular condition

Pharmacological treatment modalities such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl
peptidase-4 (DPP-4) inhibitors have become increasingly accepted as viable antidiabetic treatment options due to
their safety and favorable cardiovascular profiles

Molecular bases of incretin system

Synthesis and distribution of GLP-1

GLP-1, GLP-2, and glucose-dependent insulinotropic polypeptide (GIP) are the predominant gut-derived incretin
hormones that lead to postprandial insulin secretion in a glucose-dependent fashion. GLP-1 was originally identified
as a 37 amino acid (GLP-1 1–37) long peptide. However, subsequent studies identified that biologically active GLP-1
is cleaved to contain only 31 amino acids (GLP-1 7–37). It is also known that there is an isoform of GLP-1, which is
one amino acid shorter in both the full length (GLP-1 1–36) and its active form (GLP-17–36). The biologically active
forms of GLP-1 are rapidly degraded by DPP-4, resulting in the production of inactive forms of GLP-1 (GLP-1 9–
37 and GLP-19–36) [11].

GLP-1 is primarily produced by enteroendocrine L-cells that are dispersed throughout the small and large intestines.
Yet, GLP-1 is mainly localized to the distal small bowel and colon and is released following nutrient intake [ 12, 13]
and it has been shown that M1 and M2 muscarinic receptors may also be involved in the regulation of GLP-1 release
[14].

Molecular structure of DPP-4

DPP-4 has two domains and two subdomains: α/β hydrolase domain (Gln508-Pro766), β-propeller domain (Arg54-
Asn497), receptor binding subdomain, and a core subdomain. DPP-4 was first identified as CD26, and is a 110 kD
protein that can be found on the cell surface as a monomer, homodimer, or homotetramer. The homodimer form of
DPP-4 is the main catalytically active form. The proteolytically active DPP-4 homodimer is found in two forms: a
single-pass type II integral transmembrane protein and a soluble protein stripped of any membrane spanning regions
or intracellular regions. DPP-4 carries out its exopeptidase activity by cleaving proteins or peptides after
encountering a proline or alanine in the second position from the N-terminal end of the amino acid chain. Residues
630, 708, and 740 form the catalytic triad and are indispensable for its catalytic activity. Other functionally crucial
residues are 294 and 340–343 within the cysteine-rich domain, which function as adenosine deaminase (ADA)
binding domains. Therefore, the functional domains responsible for currently discovered function of DPP-4 are all
located in the extracellular portion and the functions of intracellular domain of DPP-4 remain elusive. The structures
of DPP-4 and GLP-1 are illustrated in Fig.

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Molecular basis of incretin axis: DPP-4 proteins consist of a short intracellular domain (6 amino acids), a
transmembrane domain, and a large extracellular domain. The extracellular domain is responsible for the enzymatic
cleavage of the substrates and binding to its ligands including fibronectin and ADA. DPP-4 inactivates GLP-1 by
removing N-terminal dipeptide His7Ala8 from active form of GLP-1, which results in the loss of its affinity to GLP-
1R. GLP-1R is a G-protein coupled receptor and its biding with active GLP-1 activates PI3K and PKA pathway by
increasing intracellular cAMP concentration. DPP-4 dipeptidyl peptidase-4, sDPP-4 soluble DPP-4, AA amino acid,
ADA adenosine deaminase, GLP-1 glucagon-like peptide-1, GLP-1R glucagon-like peptide-1 receptor, cAMP
cyclic adenosine monophosphate, PKA protein kinase A, PI3K phosphoinositide 3-kinase.

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173
THERAPY OF ENDOCRINE DISEASE: Amylin and calcitonin -physiology and pharmacology

Amylin, a beta cell hormone, has satiating properties and also delays gastric emptying and inhibits postprandial
glucagon secretion with the net result of reducing postprandial glucose excursions. Amylin acts through the six
amylin receptors, which share the core component with the calcitonin receptor. Calcitonin, derived from thyroid C
cells, is best known for its role in humane calcium metabolism, where it inhibits osteoclasts and reduces circulating
calcium.
However, calcitonin, particularly of salmon origin, has also been shown to affect insulin sensitivity, reduce the
gastric emptying rate and promote satiation. Preclinical trials with agents targeting the calcitonin receptor and the
amylin receptors, show improvements in several parameters of glucose metabolism including insulin sensitivity and
some of those agents are currently undergoing clinical trials.

PERIOPERATIVE DM MANAGEMENT

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DIABETIC KETOACIDOSIS
You are asked to review an 18-year-old male in the Emergency Department who has been found obtunded at home.
He is an insulin dependent diabetic with a history of poor control. Capillary blood glucose is 23.4 mmol/l.

a) Briefly describe the pathophysiology of diabetes ketoacidosis (DKA) – 20%

b) List the clinical and biochemical findings that confirm severe DKA? – 30%
c) Outline the management plan for severe DKA within the first hour. – 30%
d) What are the serious complications that can follow the management of DKA? – 20%.

DKA: TRUE or FALSE?

• Free fatty acids result from lipolysis?

• Ketone bodies only arise from proteolysis?
• The renal threshold for glycosuria is 18mmol/L
• Although BMs are high, human cells cannot utilise glucose in DKA

DKA PATHOPHYSIOLOGY

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Diabetic ketoacidosis (DKA) is a complex disordered metabolic state characterized by hyperglycaemia, ketonaemia,
and acidosis. DKA usually occurs as a consequence of absolute or relative insulin deficiency that is accompanied by
an increase in counter regulatory hormones (ie glucagon, cortisol, growth hormone, catecholamine). This type of
hormonal imbalance enhances hepatic gluconeogenesis and glycogenolysis resulting in severe hyperglycaemia.
Enhanced lipolysis increases serum free fatty acids that are then metabolized as an alternative energy source in the
process of ketogenesis. This results in accumulation of large quantities of ketone bodies and subsequent metabolic
acidosis. Ketones include:
 Acetone
 3-beta-hydroxybutyrate and
 Acetoacetate
The predominant ketone in the blood is 3-beta-hydroxybutyrate.
There are several mechanisms responsible for fluid depletion in DKA. These include:
 Osmotic diuresis due to hyperglycaemia
 Vomiting – commonly associated with DKA and eventually
 Inability to take in fluid due to diminished level of consciousness.
Electrolytes shift and depletion are in part related to the osmotic diuresis. Hyperkalaemia and hypokalaemia need
particular attention.

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Also increased glucagon, GH and Catecholamines.

DKA FINDINGS

BIOCHEMICAL CLINICAL
Partially compensated metabolic acidosis Lethargy/Confusion
High anion gap Tachypnoea (Kussmaul)
K+ / Nausea and vomiting
Vomiting/AKI/Acidosis Abdominal pain
Dilutional hyponatraemia Sympathetic activation
WCC 10 – 15 (without infection) Hypotension and dehydration
Ketone breath
Concurrent acute pathology if not due to missed doses

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 DKA COMPLICATIONS
• Fluid overload
– Cerebral oedema (esp. children)
– Pulmonary oedema
• Solutes
– Hypoglycaemia
– Hypo/hyperkalaemia
– Hypophosphataemia (usually self-limiting)

 Hypokalaemia and hyperkalaemia

 Hypoglycaemia
 Cerebral oedema
 Others
o Venous thromboembolic disease (particularly if CVP are used)
o Transient acute kidney injury (up to 50% of adults)
 Rare
o Pulmonary oedema
o  in pancreatic enzyme  acute pancreatitis
o Cardiomyopathy
o Rhabdomyolysis and
o Gastrointestinal bleeding

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Hypokalaemia & hyperkalaemia
Due to the dehydration, lack of insulin and metabolic acidosis, hyperkalaemia should be sought when DKA is
initially diagnosed. Hypokalaemia and hyperkalaemia are potentially life-threatening conditions during the
management of DKA. Because of the risk of acute pre-renal injury associated with severe dehydration, it is
recommended that no potassium be prescribed with the initial fluid resuscitation or if the serum potassium level
remains above 5.5 mmol/l. A normal or even elevated serum potassium concentration may be seen due to the
extracellular shift of potassium in acidotic conditions, and this very poorly reflects total potassium stores. However,
potassium will almost always fall as the DKA is treated with insulin and the UK survey showed that 67.1%
developed hypokalaemia (<4.0 mmol/l) at 24 hours after admission.

Thus, it is recommended that 0.9% sodium chloride solution with potassium 40 mmol/l (ready-mixed) is prescribed
as long as the serum potassium level is below 5.5 mmol/l and the person is passing urine. If the serum potassium
level falls below 3.5 mmol/l the potassium regimen needs review. Where the fluid balance permits, an increase in
the rate of the infusion of 0.9% sodium chloride solution with potassium 40 mmol/l is possible. Otherwise, all
aspects of its use must comply with local and national guidance.
In addition to inadequate replacement, the main driver for hypokalaemia is the use of insulin. Thus, when glucose
drops below 14 mmol/l, consider reducing the rate of intravenous insulin infusion to 0.05 units/kg/hr.
Trusts needs to ensure that they have local protocols in place which allow for the safe administration of concentrated
potassium solutions. This may require transfer to a level 2 or level 3 environment.

Hypoglycaemia (27.6% in UK national survey)

The blood glucose may fall very rapidly as ketoacidosis is corrected and a common mistake is to allow the blood
glucose to drop to hypoglycaemic levels. Severe hypoglycaemia (i.e requiring third party assistance) is also
associated with increased length of stay, cardiac arrhythmia, acute brain injury and death. The main driver for
hypoglycaemia in the use of insulin. Thus, in addition to commencing 10% dextrose to run alongside the 0.9%
sodium chloride solution, when glucose drops below 14 mmol/l, consider reducing the rate of intravenous insulin
infusion to 0.05 units/kg/hr.

Cerebral oedema
Cerebral oedema causing symptoms is relatively uncommon in adults, although my occur in those who are
physically slight or in younger adults. Asymptomatic cerebral oedema may be a common occurrence, and may exist
prior to treatment starting. The exact cause of this phenomenon is unknown. Reassuringly a large randomized
controlled trial of 0.9% sodium chloride solution vs 0.45% sodium chloride solution each given either rapidly or
slowly, showed no difference in the rates of developing neurological injury. It is thus possible that an idiosyncratic
response to the metabolic injury and subsequent treatment. However, any deterioration in Glasgow Coma Scale
score should prompt urgent treatment and imaging. If cerebral oedema is suspected, urgent treatment with mannitol
or hypertonic saline to induce osmotic fluid shifts should be started and not be delayed whilst awaiting imaging.

GLUCOSE CONTROL AND DIABETES

DR KEVIN KELLY

GLUCOSE HOMEOSTASIS

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INSULIN:
o Insulin is a peptide hormone produced by beta cells of the pancreatic islets; it is considered to be the main anabolic
hormone of the body.
o It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of glucose from the blood
into liver, fat and skeletal muscle cells.

GLUCAGON:
o Glucagon is a peptide hormone, produced by alpha cells of the pancreas. It raises concentration of glucose and fatty
acids in the bloodstream, and is considered to be the main catabolic hormone of the body.

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CLASSICATION:

 Diabetes mellitus is a disease caused by deficiency or diminished effectiveness of endogenous insulin.

 It is characterized by:
o Hyperglycaemia
o Deranged metabolism and
o Sequelae predominantly affecting the vasculature.
 Type 1 diabetes mellitus: results from the body’s failure to produce sufficient insulin.
 Type 2 diabetes mellitus: results from resistance to the insulin, often initially with normal or increased levels of
circulating insulin.
 Gestational diabetes affects about 4% of all pregnant women. It may precede development of type 2 (or rarely type 1)
diabetes.
 Maturity – onset diabetes of the young (MODY) includes several forms of diabetes with monogenetic defects of beta
cell function (impaired insulin secretion), usually manifesting as mild hyperglycaemia at a younger age and usually
inherited in an autosomal-dominant manner.

SECONDARY DIABETES
 Accounts for only 1 – 2% of patients with diabetes mellitus.
 Pancreatic disease:
o Cystic fibrosis
o Chronic pancreatitis
o Pancreatectomy
o Carcinoma of the pancreas.
 Endocrine:
o Cushing’s syndrome
o Acromegaly
o Thyrotoxicosis
o Phaeochromocytoma
o glucagonoma
 Drug induced:
o Thiazide diuretics
o Corticosteroids
o Atypical antipsychotics
o Antiretroviral protease inhibitors
 Congenital lipodystrophy
 Acanthosis nigricans- a skin pigmentation problem characterized by dark, velvety, and thick patches of skin usually
formed in the skin folds and creases.
 Genetic:
o Wolfram’s syndrome (which is also referred to as DIDMOAD: Diabetes Insipidus, Diabetes Mellitus, Optic
Atrophy and Deafness)
o Friedreich’s ataxia
o Dystrophia myotonica
o Haemochromatosis
o Glycogen storage diseases.

TYPE 1 DIABETES MELLITUS

 The development of type 1 diabetes mellitus is based on a combination of a genetic predisposition and an autoimmune
process that results in gradual destruction of the beta cells of the pancreas, leading to absolute insulin deficiency.
 There is usually a pre-diabetic phase where autoimmunity has already developed but with no clinical apparent insulin
dependency. Insulin autoantibodies can be detected in genetically predisposed individuals as early as 6 – 12 months of
age.
 Possible triggers for the process may include viruses, dietary factors, environmental toxins, and emotional or physical
stress.

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  Approximately 15% of those with diabetes have type 1 diabetes – usually juvenile-onset, but it may occur at any age. It
may be associated with other autoimmune diseases. It is characterized by insulin deficiency.
 There is 30 – 50% concordance in identical twins and a positive family history in 10% of people with type 1 diabetes.
Screening for the diagnosis of diabetes in first-degree relatives of patients with type 1 is therefore reasonable, keeping
in mind that the absolute risk is quite low.
 Associated with HLA DR3 AND DR4 and islet cell antibodies around the time of diagnosis.
 Patients always need insulin treatment are prone to ketoacidosis.
 Those most at-risk population for type 1 is Caucasian of northern European ancestry. Incidence is high in Scandinavian
people.

TYPE 2 DIABETES MELLITUS

o Approximately 85% of those with diabetes; they are usually older at presentation (usually > 30 years of age) but it is
increasingly diagnosed in children and adolescents.
o Type 2 diabetes is associated with excess body weight and physical inactivity.
o All racial groups are affected but there is increased prevalence in people of South Asian, African, Africa-Caribbean,
Polynesian, Middle Eastern and American-Indian ancestry.
o It is caused by impaired insulin secretion and insulin resistance and has a gradual onset.
o Those with type 2 diabetes may eventually need insulin treatment.
o The increasing prevalence of diabetes worldwide has led to a situation where approximately 360 million people had
diabetes in 2011, of whom more than 95% would have had type 2 diabetes. This number is estimated to increase to an
extra 52 million by 2030 and it is thought that about half of those will be unaware of their diagnosis.

RISK FACTORS FOR TYPE 2 DIABETES

o Obesity, especially central (truncal) obesity.
o Lack of physical activity.
o Ethnicity: People of:
o South Asian
o African
o African – Caribbean
o Polynesian
o Middle-Eastern and
o American – Indian descent are at greater risk of type 2 diabetes, compared with the white population.
o History of gestational diabetes.
o Impaired glucose tolerance
o Impaired fasting glucose
o Drug therapy:
o Combined use of a thiazide diuretic with beta blocker
o Low-fibre, high glycaemic index diet
o Metabolic syndrome
o Polycystic ovary syndrome
o Family history (2.4-fold increased risk for type 2 diabetes)
o Adults who had low birth weight for gestational age.
o Statins have been associated with a small, but statistically significant risk of new-onset diabetes. Patients with risk
factors for developing diabetes mellitus may be at higher risk. This risk is likely outweighed by the benefits of reducing
cardiovascular risk.
CLINICAL PRESENTATION
 Patients with all types of diabetes may present with:
o Polyuria.
o Polydipsia
o Lethargy
o Boils
o Pruritus vulvae or
o Frequent recurrent or prolonged infections.
 Patients with type 1 diabetes may also present with:
o Weight loss
o Dehydration

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 o Ketonuria and
o Hyperventilation.
o Presentation of type 1 diabetes tends to be acute with a short duration of symptoms.
 Presentation of type 1 diabetes tends to be acute with a short duration of symptoms.
 Presentation in patients with type 2 diabetes tends to be subacute with a longer duration of symptoms.
 Patients with diabetes may present with acute or chronic complications

DIAGNOSIS
 Diabetes is usually diagnosed by an HbA1c of 48 mmol/mol (6.5%) or more. If the use of HbA1c is inappropriate (eg,
people with end-stage chronic kidney disease), type 2 diabetes is diagnosed by a fasting plasma glucose level of 7.0
mmol/l or greater.

 In an asymptomatic person, the diagnosis of diabetes should never be based on a single abnormal HbA1c or fasting
plasma glucose level; at least one additional abnormal HbA1c or plasma glucose level is essential.

 In a symptomatic person (thirst, increased urination, recurrent infections, weight loss, drowsiness and coma), diabetes
can be diagnosed with more confidence on the basis of a single abnormal HbA1c or fasting plasma glucose level
(although a second test may be prudent).

 Severe hyperglycaemia in people with an acute infection, trauma, circulatory or other stress may be transitory and
should not be regarded as diagnostic of diabetes.

ACUTE COMPLICATIONS
o Diabetic ketoacidosis
o Hyperosmolar Hyperglycaemic State
o hypoglycaemia

CHRONIC COMPLICATIONS
 Cardiovascular disease:
o Stable angina
o Acute Coronary Syndrome
o Cerebrovascular Events and
o Peripheral Arterial Disease.
 Diabetic Nephropathy.
 Diabetic Retinopathy.
 Diabetic Neuropathy.
 Autonomic Neuropathy (? Reflux despite fasting)
 Frequent recurrent and persistent infections.

CLINICAL IMPACT

TYPE 1 DIABETES
o Many people with type 1 diabetes have good health but there is an increased risk of:
o Severe sight impairment
o End-stage kidney disease
o Cardiovascular disease and in some cases
o Early death.

TYPE 2 DIABETES
o 75% of people with type 2 diabetes will die of heart disease and 15% of stroke.
o The mortality rate from cardiovascular disease is up to 5 times higher in people with diabetes than in people without
diabetes.

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 o For every 1% increase in HbA1c level, the risk of death from a diabetes related cause increase by 21%.

MANAGEMENT
 Diabetes education: structured education and self-management (at diagnosis and regularly reviewed and reinforced) to
promote awareness.
 Diet and lifestyle: healthy diet, weight loss if the person is overweight, smoking cessation, regular physical exercise.
 Maximizing glucose control while minimizing adverse effects of treatment, such as hypoglycaemia.
 Reduction of other risk factors for complications of diabetes, including early detection and management of
hypertension, drug treatment to modify lipid levels and consideration of antiplatelet therapy with aspirin.
 Monitoring and early intervention for complications of diabetes, including cardiovascular disease, feet problems, eye
problems, kidney problems and neuropathy.

PHARMACOLOGICAL MANAGEMENT

INSULIN

SHORT-ACTING INSULIN
 Short-acting (soluble) insulin is usually injected 15 – 30 minutes before meals. Soluble insulin is also the most
appropriate form of insulin for use in diabetic emergencies – eg, diabetic ketoacidosis and at the time of surgery.

 When injected subcutaneously, soluble insulin has a rapid onset of action (30 – 60 minutes), a peak action between 2
and 4 hours, and a duration of action of up to 8 hours.

 When injected intravenously, soluble insulin has a very short half-life of only about 5 minutes and its effect disappears
within 30 minutes.

 The rapid-acting human insulin analogues (insulin Aspart, insulin Glulisine and insulin lispro) have a faster onset and
shorter duration of action than soluble insulin.

 Rapid-acting human insulin analogues can also be administered by subcutaneous infusion.

INTERMEDIATE-ACTING AND LONG-ACTING INSULINS

o Subcutaneous injections of intermediate-acting and long-acting insulins have an onset of action of approximately 1 – 2
hours, and a maximal effect at 4 – 12 hours and a duration of 16 – 42 hours. Some are given twice daily in conjunction
with short-acting (soluble) insulin; others are given once daily, particularly in elderly patients.
o Soluble insulin can be mixed with intermediate-acting and long-acting insulins (except insulin determir, insuline
glargine and insulin degludec) in the syringe but there may be some reduction of the initial effect of the soluble insulin,
especially when mixed with protamine-zinc insulin.

o Isophane insulin is a suspension of insulin with protamine and is particularly useful for initiation of twice-daily insulin
regimens.

o Insulin zinc suspension has a more prolonged duration of action. Protamine zinc insulin is usually given once daily
with short-acting (soluble) insulin. However, it binds with the soluble insulin when mixed in the same syringe and is
now rarely used.

o Insulin glargine and insulin determir are both long-acting human insulin analogues with a prolonged duration of action.
Insulin glargine is given once daily and insulin determir is given once or twice daily.

o Insulin degludec is a long-acting human insulin analogue for once daily subcutaneous administration.

CONTINOUS SUBCUTANEOUS INSULIN INFUSION [CSII] THERAPY, OR INSULIN

PUMP THERAPY

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  In CSII therapy, an adjustable basal infusion rate of insulin is given via an indwelling catheter, supplied from a syringe
reservoir worn underneath the patient clothing.

 The patient can then activate pre-meal boluses. Pumps can be disconnected for short periods (up to 1 hour) for activities
such as swimming.

 They can be pre-preprogrammed – for example, to compensate for nocturnal and early morning glucose fluctuations.
The rate of insulin absorption from pumps is more predictable than multiple subcutaneous injections.

 CSII therapy provides some advantages over multiple daily injections (MDIs) in type 1 diabetes, both for children and
adults.

 CSII therapy is particularly useful for patients with recurrent hypoglycaemia, unpredictable lives, delayed meals or pre-
breakfast hyperglycaemia.

 The insulin used in pumps may be soluble or fast-acting analogue.

OTHER DRUGS

METFORMIN
 Metformin is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose.
 Metformin may act via 3 mechanisms:
o Reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis.
o In muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilization.
o Delay of intestinal glucose absorption.
 It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.
 Caution in procedure with contrast

SULFONYLUREAS [GLICLAZIDE]
o Sulfonylureas are thought to act by enhancing pancreatic islet cell function.
o They are also though to act on the liver, stimulating the glycolytic pathway and inhibiting the production of glucose.
o They generally have a duration of action of 12 – 24 hours.
o They can cause hypoglycaemia.

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ACARBOSE
 Acarbose acts by inhibiting intestinal alpha glucosidases, which delays the absorption and digestion of sucrose and
starch.
 Acarbose is usually only used when other oral glucose-lowering medications cannot be used.
 The use of acarbose is limited by its gastrointestinal adverse effects but these do decrease with time.

RAPID-ACTING INSULIN SECRETAGOGUES – POSTPRANDIAL GLUCOSE

REGULATORS
 The two meglitinides licensed for use in the UK are repaglinide and nateglinide.
 They are relatively short-acting stimulators of insulin secretion (< 6 hours).
 They act by binding to various sites on pancreatic beta cells.
 Risks:
o hypoglycaemia

THIAZOLIDINEDIONES
 Thiazolidinediones (TDZs) or ‘Glitazones’ eg pioglitazone.
 Its mechanism of action is still subject to debate but is thought to act in a similar manner to metformin, increasing
hepatic sensitivity to insulin, and enhancing glucose clearance.
 Unlike metformin, it appears to have an effect on insulin-mediated glucose uptake at all insulin levels, making it
effective in patients with insulin resistance.
 Do not commence or continue a TDZ in patients who have heart failure, or who are at higher risk of fracture:

DIPEPTIDYLPEPTIDASE-4 INHIBITORS
o Linagliptin, saxagliptin, sitagliptin and vildagliptin inhibit dipeptidylpeptidase-4 to increase insulin secretion and lower
glucagon secretion.
o Hypersensitivity reactions may occur (anaphylaxis, angioedema and Stevens -Johnson syndrome).

GLUCAGON-LIKE PEPTIDE-1 MIMETICS

 Exenatide and liraglutide are both given by subcutaneous injection.
 There is once-daily treatment option.
 They activate the GLP-1 receptor to increase insulin secretion, suppress glucagon secretion and slow gastric emptying.
 Treatment is associated with the prevention of weight gain and possibly even with weight loss.

SODIUM-GLUCOSE CO-TRANSPORT 2 INHIBITORS

 Sodium-glucose co-transport 2 inhibitors (Canagliflozin, Dapagliflozin and Empaglifozin).
 SGLT-2 inhibitors reduce glucose reabsorption in the renal proximal convoluted tubule and increase urinary glucose
excretion.

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PERIOPERATIVE MANAGEMENT
 Diabetes affects 10 – 15% of the surgical population and patients with diabetes undergoing surgery have greater:
o Complication rates
o Mortality rates and
o Length of hospital stay.
 Their care is impacted by complication relating to diabetes, particularly cardiovascular.
 Most patients with diabetes have many years of experience of managing their own care.
 It is essential that communication amongst healthcare professionals and the patient is accurate and well informed at all
times.

PERIOPERATIVE MANAGEMENT GOALS

Modern management of the surgical patient with diabetes focuses on:
 Thorough pre-operative assessment and optimization of their diabetes (as defined by a HbA1c < 69 mmol/mol.
 Deciding if the patient can be managed by simple manipulation of pre-existing treatment during their stay.
 A short starvation period (maximum of 1 missed meal) rather than use of a variable-rate intravenous insulin infusion
(VRII).
 Safe use of VRII when it is the only option, for example:
o Emergency patients
o Patients expected NOT to return to a normal diet immediately postoperatively and
o Patients with poorly controlled diabetes.

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INSULIN – REFER THE AAGBI 2015 PUBLICATION ON PERIOPERATIVE MGT OF DIABETES
 Insulin
 Oral hypoglycaemics

VARIABLE RATE INTRAVENOUS INSULIN INFUSION (VRIII)

o Variable-rate intravenous insulin infusions are overused in the peri-operative setting.
o Their use is associated with:
o Hypoglycaemia
o Hyperglycaemia and ketosis on cessation and
o Hyponatraemia
o There seems to be a significant risk of hypoglycaemia in patients with a CBG of 4 – 6 mmol and on a VRIII

HYPOTHALAMUS AND THERMOREGULATION

TRUE or FALSE?

• Brown adipose tissue is only found in human neonates?

• Adipose thermogenesis is mediated by α1 adrenoceptors?
• Ambient temperature has no effect on cutaneous α1 adrenoceptor noradrenaline affinity?

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 AGE
PAEDIATRICS ELDERLY
No/poor shivering Decreased muscle mass
Behavioral control lost (neonates/infants) Decreased shiver reflex
Diminished evaporative heat loss ability Altered thermoregulatory thresholds
Altered AD: Volume ratio Slower composition variable (sarcopenic or obese)
BAT available

ENERGY BALANCE, METABOLISM, LACTATE …..to come

HOMEOSTASIS OF BODY MASS

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PHYSILOGICAL RESPONSES” EXCERCISE
• Acute responses (intensity dependent)
– Sympathetic response – anticipatory response (↑RR, ↑HR)
– VR↑ (skeletal & thoracic muscle pumps)
– Microvascular beds dilate (skeletal muscle, skin  ↓TPR), constrict elsewhere (splanchnic bed)
– So SV & CO↑
– Variable response BP. May increase (resistance training), may decrease slightly (aerobic exercise)
– PAP shouldn’t change significantly as CO is accommodated passively
• Chronic changes include improved
– exercise capacity due to changes in haematocrit (EPO)
– SV & HR response to exercise (changes in β-AR system)
– Better microvascular function (endothelian health)

THE RESPONSE OF THE CVS TO STRESS - HAEMORRHAGE

• Experimental response to haemorrhage slightly different to reality
• CVS response usually modified by pain and anxiety too, or in hospital by anaesthesia & drugs
• The response is graded – hence classes of haemorrhagic shock differ in HR, CRT, RR & MAP
• Compensation:
– Extent dependent on SNS state (age, “fitness”)
– Will eventually fail & MAP will start to decrease
– Can be maladaptive – tissue perfusion suffers in effort to preserve MAP & keep the organism’s
CNS perfused

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DISORDERS OF WEIGHT
ANOREXIA NERVOSA
A 21-year-old woman is listed for open reduction and internal fixation of her right ankle. She has a BMI of 16 kg/m 2
and a past medical history of anorexia nervosa.
a) Define anorexia nervosa.
b) Outline the physiological abnormalities that may be present in this patient and how they would affect her
anaesthetic management.

PHYSIOLOGICAL RESPONSE TO STARVATION

• Glycogen reserves depleted
• Fall in blood glucose  decrease in insulin levels
• Leptin decreases as fat mass falls
• Switch to lipolysis & proteolysis  fatty acid metabolism & ketone body dependence of organs (vs
glucose)
• Elimination of ketone bodies  natriuresis and diuresis
• BP decreases, HR decreases
• K+ levels drop, uric acid levels increase. Mg/Ca/PO4 stable

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 • ECG changes  R axis, T & QRS amplitude decrease. QT prolongation, TWI & ST depression in extreme
starvation

MULTISYSTEM!!

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ANAESTHESIA AND OBESITY
a) Describe the effect of obesity on the respiratory and cardiovascular systems.
b) How does this equal difficulty with anaesthetic management?
c) Describe the main principles of intraoperative management in bariatric surgery.
d) What are the main complications of restrictive and malabsorptive techniques?
e) How might you decide if the patient requires postoperative ICU/HDU postoperatively?
f) What are the main anaesthetic related recommendations of the NCEPOD report on bariatric surgery?

PHYSIOLOGICAL RESPONSES: OBESITY

• Resp – decreased FRC, CC, FEV1, faster desaturation time
• Increased SVR, BP, cardiomegaly
• Insulin resistance common
• MetAFLD &/or DM
• Pseudo-Cushings – unclear cause as cortisol levels usually normal

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 RESPIRATORY CARDIOVASCULAR
OSA HT & PHT
Polycythaemia & PHT IHDx
T2RF CM
Asthma type syndrome RVF & CCF
Reduced compliance Dysrhythmia
Reduced FRC Dyslipidaemia
Increased VO2 Sudden cardiac death
V/Q mismatch
Faster desaturation

IMPLICATIONS
• Pre-op
– Likely to need more cardiac Ix
• Airway
– Head up technique for BMV, laryngoscopy. ?RSI
– No LMAs
– Post-op resp. depression (short acting drugs intra-op)
• Ventilation
– PEEP, higher MAwP,
• Post-op
– Extubate sat up
– OSA & NIV

ANAESTHETIC PRINCIPLES
• Access & monitoring
• Table weight limit
• ?Induce on table – pt mobilises self
• Pre-O2 & diff intubn precautions
• Drugs – sux ABW, most others IBW
• Use short-acting intra-op drugs
• VTE prophylaxis

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WHAT ARE THE COMPLICATIONS OF RESTRICTIVE & MALABSORPTIVE
TECHNIQUES?

RESTRICTIVE
o Band slippage
o Pouch dilation
o Stomach prolapse
o Obstruction
o Dysphagia
o Reflux
o Band erosion
o Erosive oesophagitis
o Tubing disconnection and malfunction

MALABSORPTIVE
 Longer surgical procedure
 B12/Fe2+/Ca2+/Folate deficiency
 Dumping syndrome: Post-prandial abdominal and vasomotor symptoms.

HOW MIGHT YOU DECIDE IF THE PATIENT REQUIRES POSTOPERATIVE ICU/HDU

POSTOPERATIVELY?
 Montefione obesity Surgery Score (MOSS)
 Suggests need for HDU care if age > 40 or history of asthma/snoring.
 Other factors to consider:
o Gastric band surgery.
o Male
o BMI > 50
o OSA
o Significant co-morbidities
o Previous abdominal surgery.

WHAT ARE THE MAIN ANAESTHETIC RELATED RECOMMENDATIONS OF THE NCEPOD REPORT ON
BARIATRIC SURGERY?

In common with other types of specialist surgery, bariatric surgery is not for the occasional operator. The specialist
Association involved with bariatric surgery should provide guidance regarding the numbers of procedures which
both independent operators and institutions should achieve in order to optimize outcomes.

All patients must have access to the full range of specialist professionals appropriate for their needs in line with
NICE guidelines.

All bariatric patients should have an assessment of the predicted difficulty of intubation recorded.

All bariatric patients should attend a pre-assessment clinic, during which they should have access to a full range of
health professionals appropriate to their needs, including where required pre-admission assessment by an
anaesthetist.

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Synthesis of mineralocorticoids, glucocorticoids and androgens.

201
202
Secretion, effects and degradation of aldosterone

Amine hormones are made from tyrosine and tryptophan

Four major amine hormones are recognized. The adrenal medulla makes the catecholamine
hormones epinephrine and norepinephrine from the amino acid tyrosine (see Fig. 13-8C). These hormones are the principal
active amine hormones made by the endocrine system. In addition to acting as a hormone, norepinephrine also serves as a
neurotransmitter in the CNS (see p. 312) and in postganglionic sympathetic neurons (see pp. 342–343). Dopamine, which is also
synthesized from tyrosine, acts as a neurotransmitter in the CNS (see p. 313); it is synthesized in other tissues, but its functional
role outside the nervous system is not well clarified. Finally, the hormone serotonin is made from tryptophan (see Fig. 13-8B) by
endocrine cells that are located within the gut mucosa. Serotonin appears to act locally to regulate both motor and secretory
function in the gut, and also acts as a neurotransmitter in the CNS (see pp. 312–313).

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The human adrenal medulla secretes principally epinephrine (see pp. 1030–1033). The final products are stored in vesicles
called chromaffin granules. Secretion of catecholamines by the adrenal medulla appears to be mediated entirely by stimulation
of the sympathetic division of the autonomic nervous system (see p. 343). Unlike the situation for many peptide hormones, in
which the circulating concentration of the hormone (e.g., TSH) negatively feeds back on secretion of the releasing hormone (e.g.,
TRH), the amine hormones do not have such a hierarchic feedback system. Rather, the feedback of amine hormones is indirect.
The higher control center does not sense circulating levels of the amine hormones (e.g., epinephrine) but rather a physiological
end effect of that amine hormone (e.g., blood pressure; see pp. 534–536). The sensor of the end effect may be a peripheral
receptor (e.g., stretch receptor) that communicates to the higher center (e.g., the CNS), and the efferent limb is the sympathetic
outflow that determines release of the amine.

Serotonin (5-hydroxytryptamine, or 5-HT), in addition to being an important neurotransmitter in the CNS (see pp. 312–
313 and Fig. 13-7B), is a hormone made by neuroendocrine cells, principally located within the lining of the small intestine and
larger bronchi. Unlike the other hormones that we discuss in this chapter, serotonin is not made by a specific gland. Little is
known about feedback regulation or even regulation of secretion of this hormone. Serotonin arouses considerable clinical interest
because of the dramatic clinical presentation of patients with unusual tumors—called carcinoid tumors—of serotonin-secreting
cells. Individuals with these tumors frequently present with carcinoid syndrome, characterized by episodes of spontaneous
intense flushing in a typical pattern involving the head and neck and associated with diarrhea, bronchospasm, and occasionally
right-sided valvular heart disease. The primary tumors involved can occur within the intestinal tract, in the bronchial tree, or more
rarely at other sites.

Amine hormones act via surface receptors

Once secreted, circulating epinephrine is free to associate with specific adrenergic receptors, or adrenoceptors, located on the
surface membranes of target cells. Numerous types of adrenoceptors exist and are generically grouped as α or β, each of which
has several subtypes (see Table 14-2). Epinephrine has a greater affinity for β-adrenergic receptors than for α-adrenergic
receptors, whereas norepinephrine acts predominantly through α-adrenergic receptors. All adrenoceptors that have been isolated
from a variety of tissues and species are classic G protein–coupled receptors (GPCRs). β-adrenergic stimulation occurs through
the adenylyl cyclase system. The α 2 receptor also usually acts through adenylyl cyclase. However, α 1-adrenergic stimulation is
linked to Gαq, which activates a membrane-associated PLC that liberates IP 3 and DAG. IP3 can release Ca2+ from intracellular
stores, and DAG directly enhances the activity of PKC. Combined, these actions enhance the cellular activity of Ca 2+-dependent
kinases, which produce a metabolic response that is characteristic of the specific cell.

As indicated in Figure 47-5, the intracellular action of a specific catecholamine is determined by the complement of receptors
present on the surface of a specific cell. For example, when epinephrine binds to the β 1-adrenergic receptor, it activates a
Gαs protein, which stimulates adenylyl cyclase, promotes increases in [cAMP] i, and thus enhances the activity of PKA (see Table
14-2). In contrast, when the same hormone binds to a cell displaying principally α 2 receptors, it activates a Gαi protein, which
inhibits adenylyl cyclase, diminishes [cAMP] i, and therefore reduces PKA activity. Thus, the response of a specific cell to
adrenergic stimulation (whether via circulating epinephrine or via norepinephrine released locally by sympathetic neurons)
depends on the receptor repertoire displayed by the cell. As a result, the response to adrenergic agonists varies among tissues; for
example, glycogenolysis in the liver or muscle (predominantly a β effect), contraction (an α 1 effect) or relaxation (a β2 effect) in
vascular smooth muscle, or a change in the inotropic or chronotropic state of the heart (a β1 effect).

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FIGURE 47-5 Catecholamine receptors. The β1, β2, and D1 receptors all interact with Gαs, which activates adenylyl cyclase (AC)
and raises levels of cAMP. The α 2 and D2 receptors interact with Gαi, which inhibits AC. Additionally, the α 1 receptor interacts
with Gαq, which activates PLC, which in turn converts phosphoinositides in the cell membrane to IP3 and DAG.

Dopamine also can interact with several GPCRs. The D1 receptor is coupled to Gαs and the D2 receptor is linked to Gαi.

Steroid and Thyroid Hormones

Cholesterol is the precursor for the steroid hormones: cortisol, aldosterone, estradiol, progesterone, and testosterone

Members of the family of hormones called steroids share a common biochemical parentage: all are synthesized from cholesterol.
Only two tissues in the body possess the enzymatic apparatus to convert cholesterol to active hormones. The adrenal
cortex makes cortisol (the main glucocorticoid hormone), aldosterone (the principal mineralocorticoid in humans), and
androgens. The gonads make either estrogen and progesterone (ovary) or testosterone (testis). In each case, production of steroid
hormones is regulated by trophic hormones released from the pituitary. For aldosterone, the renin-angiotensin system also plays
an important regulatory role.

The pathways involved in steroid synthesis are summarized in Figure 47-6. Cells that produce steroid hormones can use, as a
starting material for hormone synthesis, the cholesterol that is circulating in the blood in association with low-density lipoprotein
(LDL; see p. 968). Alternatively, these cells can synthesize cholesterol de novo from acetate (see Fig. 46-16). In humans, LDL
cholesterol appears to furnish ~80% of the cholesterol used for steroid synthesis (see Fig. 47-6). An LDL particle contains both
free cholesterol and cholesteryl esters, in addition to phospholipids and protein. The cell takes up this LDL particle via the LDL
receptor and receptor-mediated endocytosis (see p. 42) into clathrin-coated vesicles. Lysosomal hydrolases then act on the
cholesteryl esters to release free cholesterol. The cholesterol nucleus, whether taken up or synthesized de novo, subsequently
undergoes a series of reactions that culminate in the formation of pregnenolone, the common precursor of all steroid hormones.
Via divergent pathways, pregnenolone is then further metabolized to the major steroid hormones: the mineralocorticoid
aldosterone (see Fig. 50-2), the glucocorticoid cortisol (see Fig. 50-2), the androgen testosterone (see Fig. 54-6), and the estrogen
estradiol (see Fig. 55-8).

FIGURE 47-6 Uptake of cholesterol and synthesis of steroid hormones from cholesterol. The cholesterol needed as the starting
material in the synthesis of steroid hormones comes from two sources. Approximately 80% is taken up as LDL particles via
receptor-mediated endocytosis. The cell synthesizes the remaining cholesterol de novo from acetyl coenzyme A (Acetyl CoA).
Apo B-100, apolipoprotein B-100; VLDL, very-low-density lipoprotein.

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Unlike the peptide and amine hormones considered above, steroid hormones are not stored in secretory vesicles before their
secretion (Table 47-4). For these hormones, synthesis and secretion are very closely linked temporally. Steroid-secreting cells are
capable of increasing the secretion of steroid hormones many-fold within several hours. The lack of a preformed storage pool of
steroid hormones does not appear to limit the effectiveness of these cells as an endocrine regulatory system. Furthermore, steroid
hormones, unlike peptide and amine hormones, mediate nearly all their actions on target tissues by regulating gene transcription.
As a result, the response of target tissues to steroids typically occurs over hours to days.

TABLE 47-4

Differences Between Steroid and Peptide/Amine Hormones

PROPERTY STEROID HORMONES PEPTIDE/AMINE HORMONES

Storage pools None Secretory vesicles
Interaction with cell Diffusion through cell Binding to receptor on cell membrane
membrane membrane
Receptor In cytoplasm or nucleus On cell membrane
Action Regulation of gene transcription Signal-transduction cascade(s) that affect a
(primarily) variety of cell processes
Response time Hours to days (primarily) Seconds to minutes
Like cholesterol itself, steroid hormones are poorly soluble in water. On their release into the circulation, some steroid hormones
associate with specific binding proteins (e.g., cortisol-binding globulin) that transport the steroid hormones through the
circulatory system to their target tissues. The presence of these binding proteins, whose concentration in the circulation can
change in response to a variety of physiological conditions, can complicate efforts to measure the amount of active steroid
hormone in the circulation.

Steroid hormones bind to intracellular receptors that regulate gene transcription

Steroid hormones appear to enter their target cell by simple diffusion across the plasma membrane (Fig. 47-7). Once within the
cell, steroid hormones are bound with high affinity (KD in the range of 1 nM) to receptor proteins located in the cytosol or the
nucleus. As detailed in Chapter 4, binding of steroid hormone to its receptor results in a change in the receptor conformation so
that the “active” receptor-hormone complex now binds with high affinity to specific DNA sequences called hormone response
elements (see p. 90) or steroid response elements (SREs), also called sterol regulatory elements. These sequences are within the
5′ region of target genes whose transcription is regulated by the specific steroid hormone–receptor complex. Termination of gene
regulation by the steroid hormone–receptor complex is not as well understood as initiation of the signal. The receptor protein
may be modified in a manner that permits dissociation of the hormone and DNA. The receptor itself could then be recycled and
the steroid molecule metabolized or otherwise cleared from the cell.

FIGURE 47-7 Action of steroid hormones. The activated steroid hormone receptor binds to specific stretches of DNA called
steroid response elements (SREs), which stimulates the transcription of appropriate genes. hsp, heat shock protein.

Steroid receptors are monomeric phosphoproteins with a molecular weight that is between 80 and 100 kDa. A remarkable
similarity is seen among receptors for the glucocorticoids, sex steroids, retinoic acid, the steroid-like vitamin 1,25-
dihydroxyvitamin D, and thyroid hormone. The genes encoding the receptors for these diverse hormones are considered part of a

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gene superfamily (see pp. 71–72). Each of these receptors has a similar modular construction with six domains (A through F).
The homology among receptors is especially striking for the C domain, particularly the C1 subdomain, which is the part of the
receptor molecule that is responsible for binding to DNA (see Fig. 3-14).

Steroid hormone receptors dimerize on binding to their target sites on DNA. Dimerization appears essential for the regulation of
gene transcription. Within the C1 DNA-binding domain of the steroid receptor monomer are two zinc fingers that are involved in
binding of the receptor to DNA (see p. 82). Even receptors with very different biological actions have a striking sequence
similarity in this domain of the receptor. Because the specificity with which genes are regulated by a specific steroid receptor
arises from the specificity of the DNA-binding domain, mutations in this region can greatly alter hormone function. For example,
substitution of two amino acids in the glucocorticoid receptor causes the mutated glucocorticoid receptor to bind to DNA to
which the estrogen receptor normally binds. In such a system, a glucocorticoid could have an estrogen-like effect.

The activated steroid receptor, binding as a dimer to SREs in the 5′ region of a gene, regulates the rate of transcription of that
gene. Each response element is identifiable as a consensus sequence of nucleotides, or a region of regulatory DNA in which the
nucleotide sequences are preserved through different cell types. The effect of gene regulation by activated steroid receptors
binding to an SRE is dramatically illustrated by the chick ovalbumin gene. Chicks that are not exposed to estrogen have
approximately four copies of the ovalbumin mRNA per cell in the oviduct. A 7-day course of estrogen treatment increases the
number of copies of message 10,000-fold! This increase in message is principally the result of an increased rate of gene
transcription. However, steroid hormones can also stabilize specific mRNA molecules and increase their half-life. N47-2

N47-2

Stabilization of mRNA by Estrogen

Contributed by Gene Barrett

For example, in frogs, estrogen increases the half-life of the mRNA for vitellogen (which is formed by Xenopus liver) from <20
hours to ~500 hours.

The 5′ flanking region of the gene typically has one or more SREs upstream of the TATA box, a nucleotide sequence rich in
adenine and thymine that is located near the starting point for transcription (see p. 78). The activated steroid hormone receptors
recognize these SREs from their specific consensus sequences. For example, one particular consensus sequence designates a site
as a glucocorticoid response element if the SRE is in a cell with a glucocorticoid receptor. This same consensus sequence in a
cell of the endometrium would be recognized by the activated progesterone receptor or, in the renal distal tubule, by the
activated mineralocorticoid receptor. The specificity of the response thus depends on the cell's expression of particular steroid
receptors, not simply the consensus sequence. For example, the renal distal tubule cell expresses relatively more
mineralocorticoid receptors than it does progesterone receptors when compared with the endometrium. As a result, changes in
plasma aldosterone regulate Na+ reabsorption in the kidney with greater sensitivity than does circulating progesterone. However,
very high levels of progesterone can, like aldosterone, promote salt reabsorption.

From the foregoing it should be apparent that the specificity of response of a tissue to steroid hormones depends on the
abundance of specific steroid receptors expressed within a cell. Because all somatic cells have the full complement of DNA with
genes possessing SREs, whether a cell responds to circulating estrogen (e.g., breast), androgen (e.g., prostate), or
mineralocorticoid (e.g., renal collecting duct) depends on the receptors present in the cell. This specificity raises the obvious, but
as yet unanswered, question of what regulates the expression of specific steroid receptors by specific tissues.

Within a given tissue, several factors control the concentration of steroid hormone receptors. In the cytosol of all steroid-
responsive tissues, steroid receptor levels usually drop dramatically immediately after exposure of the tissue to the agonist
hormone. This decrease in receptor level is the result of net movement of the agonist-receptor complex to the nucleus.
Eventually, the cytosolic receptors are repopulated. Depending on the tissue, this repopulation may involve new synthesis of
steroid hormone receptors or simply recycling of receptors from the nucleus after dissociation of the agonist from the receptor. In
addition, some steroids reduce the synthesis of their own receptor in target tissues. For example, progesterone reduces the
synthesis of progesterone receptor by the uterus, thus leading to an overall net reduction or downregulation of progesterone
receptor concentration in a target tissue. An interesting observation in this regard is that the genes for steroid receptor proteins
do not appear to have SREs in their 5′ flanking region. Thus, this regulation of receptor number probably involves trans-acting
transcriptional factors other than the steroid hormones themselves.

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Other factors that affect the concentration of steroid receptors in target tissues include the state of differentiation of the tissue, the
presence of other hormones that affect steroid receptor synthesis, and whether the steroid hormone has previously stimulated the
tissue. For example, estrogen receptor concentrations are low in an unstimulated uterus but rise dramatically in an estrogen-
primed uterus (receptor upregulation). Regulation of steroid receptor number is clearly one factor that alters overall tissue
sensitivity to these hormones (Box 47-3).

Box 47-3

Quantitation of Steroid Receptors in Patients with Cancer

The affinity of steroid molecules for their receptors can be studied in vitro in a manner analogous to that described for the
radioimmunoassay of peptide hormones (see Fig. 47-1). In a typical immunoassay, an antibody with high affinity for a hormone
or other compound binds to a radioactively labeled hormone or other molecule. A sample containing an unknown amount of the
compound to be measured is added to the antibody-labeled hormone mixture and displaces the radioisotope from the antibody in
proportion to the concentration of the unknown. The amount of unknown can be quantitated by comparison to the displacing
activity of known standards.

For quantitating steroid receptors, cell extracts containing an unknown amount of steroid receptors are incubated with increasing
concentrations of labeled steroid hormone. At each concentration, hormone that is bound by the receptor is separated from that
remaining free in the extract. The result is a saturation curve (Fig. 47-8A), provided the tissue extract has a finite number of
specific hormone receptors. This saturation curve can often be linearized by a simple arithmetic manipulation called a Scatchard
plot (see Fig. 47-8B). This analysis allows quantitation of the affinity of the receptor for the hormone and provides an estimate of
the number of receptors (actually, the concentration of receptors) for that particular hormone.

FIGURE 47-8 Quantitating receptor affinity and number of receptors. A, A plot of bound hormone (i.e., hormone-receptor
complex) on the y-axis versus free steroid concentration on the x-axis. In this example, we have assumed that the KD for hormone
binding is 3 nM and that the maximal bound-hormone concentration is 0.5 nM. B, This plot is a transformation of the data
in A. The colored points in the plot match the points of like color in A. Plotted on the y-axis is the ratio of [bound hormone] to
[free hormone]. Plotted on the x-axis is [bound hormone]. The slope of this relationship gives the −1/KD, where KD is the
dissociation constant (3 nM). The x-axis intercept gives the total number of receptors (0.5 nM).

The technique of quantitating receptor number has found an important application in determining the number of estrogen and
progesterone receptors present in breast cancer cells. The number of estrogen and progesterone receptors per milligram of breast
cancer tissue (obtained by biopsy of the breast or involved lymph node) is quantitated with radiolabeled estrogen (or
progesterone). For postmenopausal women with estrogen receptor–positive breast cancer (i.e., a tumor with a high level of
estrogen receptors), treatment with an antiestrogen (e.g., tamoxifen) is effective therapy. For premenopausal women, an
antiestrogen may be used as well, or the ovaries can be removed surgically. The woman might be given an aromatase inhibitor
that blocks estradiol synthesis or a long-acting gonadotropin-releasing hormone (GnRH) agonist, which paradoxically blocks
both LH and FSH production by the anterior pituitary and thereby reduces estradiol production and accomplishes a medical
oophorectomy. The continuous (as opposed to the normally pulsatile) administration of GnRH downregulates GnRH receptors in
the anterior pituitary (see Box 55-2).

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These therapies are not effective in patients with cancers that do not express significant numbers of estrogen receptors. The
presence of abundant estrogen and progesterone receptors in breast tumors correlates with a more favorable prognosis, possibly
because of the relatively advanced state of differentiation of the tumor, as well as the tumor's responsiveness to manipulation by
estrogen or progesterone therapy.

Thyroid hormones bind to intracellular receptors that regulate metabolic rate

In many respects, the thyroid gland and thyroid hormone are unique among the classic endocrine axes. In Chapter 49, we will see
that this uniqueness begins with the structure of the thyroid gland, which is composed of follicles. Each follicle is an epithelial
monolayer encircling a protein-rich fluid. The principal protein component of the follicular fluid is an extremely large protein,
thyroglobulin. Neither of the two thyroid hormones—T 4 nor T3—is free in the follicular fluid. Rather, these hormones are formed
by the iodination of tyrosine residues within the primary structure of the thyroglobulin molecule.

T4 and T3 remain part of the thyroglobulin molecule in the follicle lumen until thyroid secretion is stimulated. The entire
thyroglobulin molecule then undergoes endocytosis by the follicular cell and is degraded within the lysosomes of these cells.
Finally, the follicular cell releases the free T 4 and T3 into the circulation. Once secreted, T 4 is tightly bound to one of several
binding proteins. It is carried to its sites of action, which include nearly all the cells in the body. In the process of this transport,
the liver and other tissues take up some of the T4 and partially deiodinate it to T3; this T3 can then re-enter the circulation.

Both T3 and T4 enter target cells and bind to cytosolic and nuclear receptors. These receptors are similar to those for steroid
hormones (see pp. 71–72). T3 has higher affinity than T4 for the thyroid hormone receptor. Even though it accounts for only ~5%
of the circulating thyroid hormone, T3 is probably the main effector of thyroid hormone signaling. The activated thyroid hormone
receptor binds to thyroid hormone response elements in the 5′ region of responsive genes and regulates the transcription of
multiple target genes.

Thyroid hormone receptors are present in many tissues, including the heart, vascular smooth muscle, skeletal muscle, liver,
kidney, skin, and CNS. A major role for thyroid hormone is overall regulation of metabolic rate. Because T 4 affects multiple
tissues, individuals affected by disorders involving oversecretion or undersecretion of thyroid hormone manifest a host of varied
symptoms that reflect the involvement of multiple organ systems.

Steroid and thyroid hormones can also have nongenomic actions

A central dogma has been that all the diverse actions of steroid and thyroid hormones are due to genomic regulation. However,
the very rapid onset of some effects (occurring within 2 to 15 minutes) appear incompatible with a mechanism requiring new
protein synthesis. Such accumulating evidence suggests that steroid and thyroid hormones can bind to receptors that modulate the
activity of cytosolic proteins and thereby regulate their activity or behavior via a nongenomic action. An example is the binding
of extracellular estrogen or aldosterone to the GPCR called GPR30, also known as the G-protein estrogen receptor (GPER).
Receptor occupancy rapidly activates Gαs and then adenylyl cyclase (see p. 53), thereby raising [cAMP]i and stimulating PKA
(see p. 57). In addition, GPR30 indirectly activates the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase
(see pp. 68–70), and some of its downstream effectors, such as phosphatidylinositol 3-kinase (PI3K; see pp. 69–70) and
the mitogen-activated protein kinases (MAPKs; see pp. 68–69). Besides estrogen and aldosterone, other ligands of nuclear
receptors have nongenomic actions: thyroid hormones, testosterone, and glucocorticoids.

Medical Physiology, 3rd Edition

CHAPTER 48. Endocrine Regulation of Growth and Body Mass
Eugene J. Barrett

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