KIN 4043 - Therapeutic Case Study

Therapeutic Case Study
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Aetiology:
Elevated levels of cortisol hormone are mainly responsible for the occurrence of Cushing
syndrome. Cortisol is mainly produced by adrenal glands in the body. Cortisol performs
important functions in the body like regulation of blood pressure and normal functioning of
cardiovascular system. Cortisol is also helpful in responding to stress and metabolizing
carbohydrates, proteins and fats in the usable energy. However, elevated levels of cortisol,
disrupt these physiological processes and lead to development of Cushing syndrome. Cortisol
levels in MV might increase due to high levels of stress, malnutrition, depression and high
levels of emotional stress. Cortisol levels in a person can also increase due to athletic
training, alcoholism and panic disorders. High doses of anti-inflammatory medications like
corticosteroids might increase cortisol levels. Pituitary gland releases more
adrenocorticotropic (ACTH) hormone in pituitary gland tumor. This increase in the
adrenocorticotroic hormone is known as Cushing’s disease. Adrenal gland abnormality or
tumor might cuase Cushing’s syndrome. Even though70 – 80 % cases of the Cushing's
syndrome occur due to excessive secretion of ACTH from the pituitary adenomas, it is
evident that only 10 – 15 % pituitary adenomas secret excessive ACTH. Even though
approximately 10 % cases of the Cushing's syndrome occur due to excessive secretion of
cortisol from the adrenal adenomas, it is evident that only 6 % adrenal adenomas secret
excessive cortisol. However, exact aetiology of excessive secretion of ACTH from pituitary
adenomas and cortisol secretion from adrenal adenomas has not been well established.
Genetic studies established that mutation in the ubiquitin-specific protease 8 is responsible
for Cushing's disease 1,2.
Difference between Cushing’s syndrome and Cushing’s disease:
Tumor in the adrenal gland produces more amount of cortisol. This leads to the development
of Cushing’s syndrome. Cushing’s syndrome can also be developed due to tumor in the
pituitary gland. Cushing’s syndrome is the group of symptoms in which cortisol levels
remains elevated for the longer duration. Tumor in the pituitary gland produces more amount
of ACTH. This ACTH stimulates more secretion of cortisol from the adrenal gland. This type
of Cushing’s syndrome is called as Cushing’s disease. Tumors produced by ACTH can be
produced anywhere in the body and these are termed as ectopic tumors. Long term steroid
administration is one of the causes of Cushing’s syndrome. Cushing’s disease may occur due
to the endogenous factors like self-overproduction of cortisol by the body. Endogenous over-
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production of cortisol may occur due to pituitary tumor (Cushing’s disease), adrenal tumor
and ectopic tumors3.
Physiology:
Hypothalamus is the part of brain below which pituitary gland is present. Corticotropin-
releasing hormone (CRH) is secreted by paraventricular nucleus (PVN) of the hypothalamus.
CRH stimulates pituitary gland to secret ACTH. ACTH gets transported through blood and as
result adrenal gland gets stimulated to secret cortisol. Zona fasciculata is the region of cortex
of adrenal gland which is responsible for the secretion of cortisol. Corticosteroid hormones
are under the control of hypothalamus-pituitary-adrenal axis. Corticosteroids exhibit most
prominent metabolic activity during the postprandial period. During this period, these
hormones behave as contra-insular hormones. Hence, it provides substrates for oxidative
metabolism and stimulate lipolysis and proteolysis. This results in the release of fatty acids
and amino acids which induce glucose production by stimulating gluconeogenesis and
inhibiting glycogen synthesis. Elevated levels of cortisol are responsible for the negative
feedback which is responsible for the reduced secretion of ACTH4,5.
Pathophysiology:
In all types of etiologies of Cushing syndrome, there are raised levels of cortisol. Cortisol
secreting adenoma in the cortex of adrenal gland occurs in Cushing’s syndrome. This
adenoma of cortex of adrenal gland might be of primary hypercortisolism or hypercorticism
types. Cushing’s syndrome due to elevated levels of ACTH is known as ectopic Cushing
syndrome. Patients with severe hypercortisolism are associated with the phenotypes like
glucose intolerance, dyslipidaemia, metabolic bone disease, and abnormal weight gain. On
the other hand patients with mild or moderate hypercortisolism are rarely associated with
glucose intolerance, dyslipidaemia, metabolic bone disease, and abnormal weight gain.
Hence, it would be difficult to differentiate these patients from other patients with metabolic
syndrome. There is presentation of striae, supraclavicular fat pads, and proximal muscle
weakness in patients with increased hypercortisolism6. Elevated levels of corticosteroids
results in the augmented production of glucose at the level of liver and skeletal muscle. In
liver corticosteroids increase levels of glucose by stimulating gluconeogenesis and inhibiting
insulin sensitivity. Corticosteroids stimulate gluconeogenesis by acting on different genes
responsible for glucose metabolism. Corticosteroids reduce insulin sensitivity by exerting
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antagonistic effect on metabolic action of insulin which is most important hormone required
for suppression of glucose production7,8.
Corticosteroids decrease expression and phosphorylation of insulin receptor substrate (IRS)-
1, phosphatidylinositol-3kinase (PI3K) and protein kinase B (PKB/AKT). As a result, there is
decrease in migration of glucose transporter GLUT4 to the cell surface which results in the
reduction of glucose uptake. It also leads to decrease of glycogen synthase kinase (GSK)-3
phosphorylation and results in the decrease of glycogen synthesis. In skeletal muscles,
corticosteroids increase insulin resistance which results in the decreased glucose uptake and
prevention of glycogen synthesis. Corticosteroids exhibit effect on insulin resistance by
directly acting on the insulin receptor or alteration in the insulin function by altering lipid and
protein metabolism9,10.
Corticosteroids also play prominent role in the regulating adipose tissue differentiation,
distribution and metabolism. Corticosteroids can stimulate differentiation of pre-adipocytes in
adipocytes. Increased adipocytes are associated with raised body fat mass. Corticosteroid
specifically act on visceral fat and not on the peripheral fat. Hence, corticosteroids are
associated with central obesity in Cushing’s syndrome. Corticosteroids also play role in the
release of hormone like adipokine which is responsible for the development of insulin
resistance. Co-occurrence of insulin resistance and increased visceral fat can lead to the
development of metabolic syndrome which is associated with impairment in the glucose
metabolism. Metabolic syndrome comprises of visceral obesity, diabetes mellitus, and
dyslipidemia. Effect of corticosteroids on the pancreatic beta cells result in the decreased
insulin secretion. Corticosteroids exhibit effect on insulin secretion in dose dependent and
time dependent manner. Corticosteroid exhibit effect on different steps of insulin secretion
like glucose uptake, glucose utilization and calcium fluxes and exocytosis of granules
containing insulin. Glucose transporter GLUT2 and glucokinase expression gets reduced due
to corticosteroids11,12.
Corticosteroids can change AMP-activated protein kinase (AMPK) activity in tissue specific
manner. Suppression of AMPK is proportional to hypercortisolism. Due to tissue specific
activities, AMPK increases appetite, visceral obesity and dyslipidemia. Upon activation,
AMPK plays key role in glycolysis and fatty acid synthesis which produces ATP. Due to
hormone-sensitive lipase (HSL), there is increased level of lipids form adipose tissue which
lead to development of adipocytes. 11 β- hydroxysteroid dehydrogenase type 1 (11 βH SD1)
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