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METABOLIC > ENDOCRINOLOGY - ADRENAL > Flashcards

ENDOCRINOLOGY - ADRENAL Flashcards

1
Q

What is congenital adrenal hyperplasia?

A

A group of autosomal recessive metabolic disorders characterised by defects in certain genes which results in a partial or total lack of an enzyme involved in steroids genesis within the adrenal cortex which leads to large adrenal glands. (Low cortisol -> pituitary releases more ACTH -> continuous stimulation of adrenal gland -> adrenal gland hyperplasia)

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2
Q

Whats the most common enzyme deficiency in congenital adrenal hyperplasia?

A

21 hydroxylase deficiency

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3
Q

Whats the function of 21 hydroxylase?

A

Catalyses the conversion of progesterone to deoxycorticosterone in the mineralocorticoid synthesis pathway
And conversion of 17-hydroxyprogesterone to 11-deoxycortisol in the glucocorticoid pathway

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4
Q

Outline the pathology of 21 hydroxylase deficinecy?

A

It causes a cortisol and aldosterone deficiency

17 hydroxyprogesterone and 17 hydroxypregnenolone fail to be used in the cortisol pathways, they get shunted in the zona reticularis and will increase the androgen pathway

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5
Q

What symptoms does 21 hydprxylase deficiency cause?

A

masculization of females, early onset of puberty
vomiting, dehydration and hypotension
hypoglycaemia

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6
Q

Why does 21 hydrxylase deficiency cause masculization of females or early onset puberty?

A

The andorgen pathway is hyperstimulated

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7
Q

Why does 21 hydrxylase deficiency cause vomiting, dehydration and hypotension ?

A

Reduced mineralocorticoid pathway = low aldosterone = salt is not retained but instead enters urine = salt wasting

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8
Q

Why does 21 hydrxylase deficiency cause hypoglycaemia?

A

Reduced cortisol synthesis as glucocorticoid pathway cannot happen
Depleted cortisol increases insulin sensitivity

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9
Q

Other than 21 hydroxylase, what other enzyme deficiencies can cause congenital adrenal hyperplasia?

A

11 beta hydroxylase
17 alpha hydroxylase

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10
Q

Whats the function of 11 beta hydroxylase?

A

Converts deoxycorticosterone to corticosterone in the mineralocorticoid pathway
Converts 11 deoxycortisol to cortisol

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11
Q

Outline the pathology of 11 beta hydroxylase deficiency?

A

Mineralocorticoid and glucocorticoid pathways can’t happen = low aldosterone and low cortisol
17 hydroxypregnenolone and 17 hydroxyprogesterone are used in the androgen pathway instead
Different from 21 hydroxylase deficiency as there is a deoxycorticosterone excess (acts like a weak mineralocorticoid)

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12
Q

How does 11 beta hydroxylase deficiency present?

A

masculization of females, early onset of puberty
Hypertension
Hypoglycaemia

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13
Q

Why does 11 beta hydroxylase deficiency cause hypertension?

A

As there’s a build up of deoxycorticosterone which acts as a weak mineralocorticoid = retains salt and fluids

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14
Q

Whats the function of 17 alpha hydroxylase?

A

Converts pregnenolone and progesterone to 17 hydroxypregnenolone and 17 hydroxyprogesterone respectively

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15
Q

Whats the pathology of 17 alpha hydroxylase deficiency?

A

Low levels of 17 hydroxypregnenolone and 17 hydroxyprogesterone prevents androgen and glucocorticoid pathways happening = low cortisol and low dihydrotestosterone
This pregnenolone and progesterone are used for the mineralocorticoid pathway which causes raised corticosterone and 11-deoxycorticosterone
(Aldosterone levels may vary depending on RAAS)

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16
Q

How does 17-alpha hydroxylasew deficiency present?

A

Hypertension
ambiguous genitalia and undescended testes in males. In females it can cause a lack of secondary sex characteristics
Hypoglycaemia

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17
Q

How is congenital adrenal hyperplasia treated?

A

Exogenous glucocorticoids (hydrocortisone), mineralocorticoids (fludrocortisone), sex steroid replacement, antihypertensives
Atypical genitalia correction therapy

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18
Q

How can virilization in Congenital adrenal hyperplasia-affected girls be prevented?

A

Prenatal treatment with dexamethasone

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19
Q

Where is aldosterone produced? Whats its function?

A

Zona glomerulosa
Increase sodium, decrease potassium , increase blood volume

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20
Q

What stimulates aldosterone release?

A

Angiotensin 2

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21
Q

Outline aldosterone moa?

A

it stimulates Na+/K+ pumps on principal cells to drive K+ into cells and Na+ out of cells and into the blood
Aldosterone also stimulates the proton ATPase pumps in alpha intercalated pumps which causes more H+ to be excreted into the urine and HCO3- into the extracellular space = increasing pH

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22
Q

What are primary causes of hyperaldosteronism?

A

Idiopathic adrenal hyperplasia
Conn syndrome - adrenal adenoma
Familial hyperaldosteronism

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23
Q

What is conn syndrome?

A

Primary hyperaldosteronism

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24
Q

What are secondary causes of hyperaldosteronism?

A

excessive activation of the renin-angiotensin-aldosterone system (RAAS). This activation can be due to a renin-producing tumor, renal artery stenosis, or edematous disorders like left ventricular heart failure, pregnancy, cor pulmonale, or cirrhosis with ascites.

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25
What electrolyte changes does hyperaldosteronism cause?
Hypokalaemia, hypernatraemia Metabolic alkalosis
26
What symptoms does hyperaldosteronism cause?
Headaches flushing - from hypertension Constipation, weakness, heart rhythm changes - hyperkalaemia symptoms
27
How do we diagnose hyperaldosteronism?
plasma aldosterone/renin ratio Primary will show high aldosterone and low renin due to neg feedback Secondary will show high renin and high aldosterone high-resolution CT abdomen and adrenal vein sampling is used to differentiate between unilateral and bilateral sources of aldosterone excess if the CT is normal adrenal venous sampling (AVS) can be used to distinguish between unilateral adenoma and bilateral hyperplasia
28
How is hyperaldosteronism treated?
If adrenal adenoma -> surgery If B/L adrenocorticala hyperplasia ->Aldosterone antagonist e.g. spironolactone
29
Whats the difference between adrenal adenoma and adrenal carcinoma?
Adenomas are benign Carcinomas are malignant
30
What is Cushing syndrome?
A disorder where excess cortisol is in the blood - caused by prolonged exposure to elevated levels of either endogenous or exogenous glucocorticoids This has neg feedback so less CRH and ACTH produced which means zona fasciculata gets less stimulation to make cortisol - adrenal glands shrink
31
What is Cushing disease”
When a pituitary adenoma making excess ACTH
32
What are the functions of cortisol??
Increase gluconeogenesis, proteolysis and lipolysis in times of stress Increases sensitivity of peripheral blood vessels to catecholamines Dampens inflammatory and immune responses by decreasing the production and release of prostaglandins and interleukins and inhibiting T lymphocytes Influence on mood and memory?
33
What are the effects of the high cortisol in Cushing syndrome?
Severe muscle, bone and skin breakdown. High blood glucose so high insulin. High insulin activates lipoprotein lipase in adipocyte which causes accumulation of more fat cells. This leads to central obesity Individual is more susceptible to infections as immune system is dampened High cortisol amplifies the effects of catecholamines on blood vessels. It also can bind to mineralocorticoid receptors and trigger their effect = both increase bp Impairs normal brain function Inhibits GnRH which interferes with normal ovarian and testicular function
34
What are the causes of Cushing syndrome?
Long term steroid use Excess production of glucocorticoids e.g. Pituitary adenoma, ectopic production, adrenal adenoma, adrenal carcinoma
35
Whats the most common cause of ectopic production of ACTH?
Small cell lung cancer
36
What causes of Cushing syndrome are ACTH dependant? Why?
Cushing disease and ectopic sources of ACTH Both produce ACTH = stimulates more cortisol production (Therapeutic corticosteroid use and adrenal tumours are ACTH independent as they don’t rely on ACTH stimulation to produce cortisol)
37
What are the main symptoms of Cushing syndrome?
Weight gain - full moon face. Buffalo hump, central obesity Fatigue Depression Skin changes e.g. striae and ulcers Muscle wasting Thin arms and legs Easy bruising Diabetes Gonadal dysfunction/irregular menses Osteoporiss Psychological problems
38
How do we diagnose Cushing syndrome?
8 mg overnight dexamethasone suppression test is first line 24-hour urinary free cortisol late-night salivary cortisol 9am and midnight Plasma ACTH levels for localisation MRI of pituitary, CT of adrenals or site of suspected ectopic site
39
What are the 2 types of dexamethasone suppression test?
Low dose - helps in the initial diagnosis of Cushing syndrome, as a screening or a confirmatory test High dose - helps determine the cause
40
Why is dexamethasone the steroid of choice for evaluating the HPA axis?
Dexamethasone is a potent synthetic corticosteroid with high affinity for the glucocorticoid receptors and long duration of action. It possesses minimal mineralocorticoid activity and unlike other glucocorticoids, it does not interfere with cortisol measurement in the plasma, urine or saliva.
41
How do you carry out the dexamethasone suppression test?
Give dexamethasone at 10pm at night Measure cortisol and ACTH at 9am the next morning
42
What is the low dose dexamethasone suppression test?
Using 1mg dexamethasone This determines whether the pt has Cushing syndrome Normally dexamethasone would suppress CRH release and ACTH release = reduction in cortisol In Cushing syndrome you have high cortisol to begin with so the dexamethasone isnt enough to cause any suppression - body is used to higher levels of glucocorticoids
43
What is the high dose dexamethasone suppression test?
Using 8mg dexamethasone This determines the cause of Cushing syndrome In Cushing disease, this large dose of dexamethasone can suppress the anterior pituitary = reduced cortisol In adrenal tumours producing cortisol, this dexamethasone will block CRH and CTH but has no effect on adrenal gland = cortisol will remain high and ACTH is low In ectopic production of ACTH, dexamethasone has no effect on this area = cortisol remains high and ACTH is high
44
How do you treat Cushing syndrome?
Stop drugs causing it - slow withdrawal Surgical resection of tumours Adrenal steroid inhibitors e.g. ketoconazole or metyrapone
45
What is the moa of ketoconazole?
inhibition of adrenal 11 beta-hydroxylase and 17,20-lyase, and it, in some unknown way, prevents the expected rise in ACTH secretion
46
What is Addison’s disease?
Primary adrenal insufficiency where there is a reduction in cortisol and aldosterone
47
What are the main causes of Addison’s disease?
Autoimmune - most common uk Infections like TB - most common worldwide Waterhouse - friderichsen syndrome Metastatic carcinoma
48
What does it mean when the adrenal cortex is described as having a high functional reserve?
This means when there are sympotms, the majority of the adrenal cortex has been destroyed.
49
What is secondary adrenal insufficiency?
a result of inadequate ACTH stimulating the adrenal glands, resulting in low cortisol release. This is the result of loss or damage to the pituitary gland. This can be due to surgery to remove a pituitary tumour, infection, loss of blood flow or radiotherapy. There is also a condition called Sheehan’s syndrome where massive blood loss during childbirth leads to pituitary gland necrosis.
50
What is tertiary adrenal insufficiency?
the result of inadequate CRH release by the hypothalamus. This is usually the result of patients being on long term oral steroids (for more than 3 weeks) causing suppression of the hypothalamus. When the exogenous steroids are suddenly withdrawn the hypothalamus cannot respond fast enough and endogenous steroids are not adequately produced.
51
What are the symptoms of adrenal insufficiency?
Fatigue Nausea and vomiting Cramps/Abdominal pain Reduced libido or loss of secondary sex characteristics - mostly affects women (men have testes as major source of androgens)
52
What are the signs of adrenal insufficiency?
Bronze hyperpigmentation of skin Hypotension - Low aldosterone
53
Why does adrenal insufficiency cause bronze pigmentation of the skin?
Zona fasciculata damaged so cortisol levels falls = this results in low blood glucose during times of stress. This causes pituitary gland to become overactive so it produces proopiomelanocortin which is a precursor to both ACTH and melanocyte stimulating hormone (ACTH melanogenesis)
54
What is addisonian crisis?
the term used to describe an acute presentation of severe Addisons, where the absence of steroid hormones leads to a life threatening presentation. They present with: reduced consciousness, hypotension, hypoglycaemia, hyponatraemia, hyperkaemia It can be the first presentation of Addisons Disease or triggered by infection, trauma or other acute illness in someone with established Addisons. It can present in someone on long term steroids suddenly withdrawing those steroids.
55
How do you manage addisonian crisis?
Intensive monitoring if unwell Parenteral steroids (i.e. IV hydrocortisone 100mg stat then 100mg every 6 hours) IV fluid resuscitation Correct hypoglycaemia Careful monitoring of electrolytes and fluid balance
56
How is adrenal insufficiency diagnosed?
Electrolytes - hyponatraemia and hyperkalaemia Short synacthen test Check for adrenal autoantibodies CT adrenals or MRI pituitary depending on suspected cause
57
What is the short synacthen test?
The test involves giving synacthen, which is synthetic ACTH. The blood cortisol is measured at baseline, 30 and 60 minutes after administration. The synthetic ACTH will stimulate healthy adrenal glands to produce cortisol and the cortisol level should at least double. A failure of cortisol to rise (less than double the baseline) indicates primary adrenal insufficiency (Addison’s disease).
58
How is adrenal insufficiency managed?
Hydrocortisone Fludrocortisone Maybe androgen replacement? Patients are given a steroid card and an emergency ID tag to alert emergency services that they are dependent on steroids for life. Doses should not be missed as they are essential to life. Doses are doubled during an acute illness until they have recovered to match the normal steroid response to illness.
59
What is Waterhouse-friderichsen syndrome?
Blood vessels in adrenal gland rupture during a severe bacterial infection so the adrenals fill with blood. This results in acute adrenal insufficiency
60
What can cause Waterhouse-friderichsen syndrome?
severe infection- 80% of the time its caused by neissera meningitis Can also be caused by pseudomonas aeruginosa, haemophilus influenza, E.coli, staph aureus and neisseria gonorrhoea.
61
Outline the pathology of Waterhouse-friderichsen syndrome?
bacteria have endotoxins which damage endothelial cells of blood vessels which causes them to release procaogulant tissue factor which promotes blood clot formation and trigger DIC. Septic embolus gets lodged in the adrenal gland which causes bp to increase and rupturing the blood vessel. The DIC makes it hard to form clots so the blood pools in the adrenal gland. This increases local blood pressure which pinches shut the nearby blood vessels. This causes ischaemia and eventually necrosis of adrenal gland cells -> addisonian crisis Left untreated this is fatal
62
What are the symptoms of Waterhouse friderichsen syndrome?
Malaise, fever, chills, headache, vomiting Then signs of shock like hypotension and tachycardia Widespread petechial lesions which can develop into purpura (when caused by neisseria meningitidis) Eventually a loss of consciousness
63
How is Waterhouse-friderichsen syndrome diagnosed?
Short synacthen test Blood cultures Adrenal insufficiency signs e.g. hyponatraemia, hypoglycaemia, hyperkalaemia Increased D-Dimer, prolonged PT - signs of DIC Ultrasound showing blood in adrenals
64
How is Waterhouse-friderichsen syndrome treated?
Antibiotics Glucocorticoids for adrenal insufficiency Fluids, vasopressors and oxygen for shock Transfusions for DIC
65
How can waterhouse-friderichsen syndrome be prevented?
Routine vaccination against meningococcal disease
66
What is an adrenal incidentaloma?
an unsuspected tumor in one or both of your adrenal glands. This type of tumor is usually found by chance during an imaging test, such as an ultrasound or CT scan, for another condition.
67
What is a pheochromocytoma?
A rare adrenal gland tumour of a chromaffin cells
68
Where are chromaffin cells found within the adrenals gland?
In the medulla
69
Whats the function of chromaffin cells?
To secrete catecholamines
70
Where does pheochromocytoma affect?
Normally a singular adrenal gland but sometimes it can be both They can affect other areas of the body which contain catecholamines e.g. carotid arteries, bladder and abdominal aorta
71
What syndromes are pheochromocytomas associated with?
MEN2a and 2b Von hippel-lindau disease Neurofibromatosis
72
What is neurofibromatosis?
a group of genetic disorders that cause tumors to form on nerve tissue Mutation in NF1 which codes for neurofibromin
73
What foods can increase catecholamines release and why?
Wine Cheese Chocolate All contain tyramine
74
Whats the effect of pheochromocytoma?
Excess catecholamines release can lead to hypertension which can break small vessels in the heart, brain and eyes causing haemorrhage and ischaemia
75
What are the main symptoms/signs of pheochromocytoma?
Hypertension Anxiety Headaches Sweating Palpitations
76
How do you diagnosed pheochromocytoma?
Measuring catecholamines level in urine or blood Measuring catecholamines metabolites in urine e.g. metanephrine, normetanephrine, dopamine, and vanillylmandelic acid (VMA).
77
How do we treat pheochromocytomas?
Surgery can only be performed safely after the careful administration of alpha-blockers for at least two to three weeks prior to surgery.
78
What are MEN syndromes?
Multiple endocrine neoplasia Inherited disease that cause tumours to grow in the endocrine glands
79
What endocrine glands are affected in MEN syndromes?
Pituitary Thyroid Parathyroid Adrenal Pancreas
80
What hormones does the pituitary gland secrete?
TSH ACTH FSH LH Prolactin Oxytocin ADH Melanocyte stimulating hormone
81
What hormones does the thyroid gland secrete?
Thyroid hormones Calcitonin
82
What hormones does the parathyroid gland secrete?
Parathyroid hormones
83
What hormones does the adrenal gland secrete?
Epinephrine and norepinephrine Mineralocorticoids, glucocorticoids and adrenal androgens
84
What hormones does the pancreas secrete?
Insulin Glucagon Gastrin Vasoactive intestinal peptide
85
Whats the pathology behind MEN type 1?
MEN1 gene mutations on chromosome 11 - normally encodes menin protein Forms a tumour suppressor gene
86
Whats the pathology behind MEN type 2A and 2b?
Mutation of RET which is a protooncogene
87
Whats the genetic basis behind MEN syndromes?
Autosomal dominant
88
What are the most common tumours in MEN type 1?
Parathyroid tumours Pancreatic tumours Pituitary tumours
89
What happens in parathyroid tumours?
Increased production of PTH = increased bone breakdown = hypercalcaemia = calcium kidney stones
90
What are the 3 types of pancreatic tumours?
Gastrinoma Insulinoma Glucagonoma
91
What happens in gastrinoma?
Produces excess gastrin which increases HCL which can cause peptic ulcers, abdominal pain and vomiting
92
What happens in Insulinoma?
Production of excess insulin = hypoglycameia
93
What happens in Glucagonoma?
Production of excess glucagon = hyperglycaemia
94
Whats the most common pituitary adenoma?
Prolactinoma
95
Whats the consequence of prolactinomas?
Galactorrhoea in women and gynaecomastia in men
96
What can pituitary adenomas secrete?
Excess prolactin, GH, corticotrophin release hormone, TSH etc
97
What are the most common tumours in MEN2a?
Thyroid medullary cancer Parathyroid adenoma Pheochromocytoma
98
What are the most common tumours in MEN2b?
Thyroid medullary cancer Pheochromocytoma Multiple neuromas
99
What are multiple neuromas?
Tumours from nervous tissue of skin and mouth - typicall affects tongue, lips and roof of mouth
100
How are MEN syndromes diagnosed?
Genetic testing for MEN and RET mutations
101
How are MEN syndromes treated?
Tumours removed with surgery In MEN type 2, a thyroidectomy is performed to prevent thyroid medullary cancer. It may also be removed in family members too.
102
What is Nelson’s syndrome?
rapid enlargement of a pituitary corticotroph adenoma that occurs after a bilateral adrenalectomy This eliminates production of cortisol and the lack of cortisol's negative feedback can allow any pre-existing pituitary adenoma to grow unchecked. Continued growth can cause mass effects due to physical compression of brain tissue. Increased production of ACTH can result in increased melanocyte stimulating hormone which can result in hyperpigmentation. Monitoring of ACTH level and pituitary MRI are recommended 3-6 months after surgery and regularly thereafter.
103
What are the sick day rules for Addison’s diseasE?
Double the dose of glucocorticoids but keep the same dose of mineralocorticoids
104
Why does adrenal insufficiency commonly affect people with HIV?
Due to cytomegalovirus (CMV)-related necrotising adrenalitis - HIV increases risk of CMV infection
105
What test can be used to differentiate between true Cushing and pseudo-Cushing?
The insulin stress test
106
Work out the cause of these high-dose dexamethasone suppression test results… Cortisol not suppressed but ACTH suppressed
Cushing syndrome e.g. adrenal adenoma (the steroid suppresses the CRH and ACTh release but cannot affect the actual cortisol release from the tumour)
107
Work out the cause of these high-dose dexamethasone suppression test results… Cortisol suppressed and ACTH suppressed
Cushing disease - pituitary adenoma causing ACTH secretion The steroid can suppress CRH and ACTH so cortisol is not released
108
Work out the cause of these high-dose dexamethasone suppression test results… Cortisol not suppressed and ACTH not suppressed
Ectopic ACTH syndrome e.g. small cell lung cancer The steroid cannot suppress CRH or ACTH

METABOLIC (43 decks)

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