Endocrinology for Studs

ENDOCRINOLOGY

 Hyperprolactinemia : Excess production (Pituitary adenoma) or Disinhibition [decrease dopamine – dopamine antagonist (Phenothiazine, metoclopramide) – dopamine depleting agents (methyldopa, Reserpine) –
primary hypothyroidism (increase TRH-activated dopamine which overcome the normal dopamine inhibition)] Physiologic [pregnancy, breast feeding, stress]
Other [Sarcoidosis] – Microadenomas (amenorrhea, galactorrhea, decrease libido)

– Macroadenomas (visual field defect – heteronymous hemianopsia) – other important pathology [hypoestrogenism – osteoporosis]

˗ First step in management of Hyperprolactinemia  rule out Hypothyroidism (measure THS level)

˗ Diagnosis – Prolactin level › 1000 mIU/L suggest pituitary adenoma.

˗ Tx : Bromocriptine (dopamine agonist), surgery if doesn’t get help with drug.
Stop using dopamine antagonist/deplete drugs.

 Acromegaly : ↑↑ GH (gigantism in children) – pituitary adenoma – b/w 3rd
and 5th decade – c/o unable to wear wedding ring, increase in shoe size – entrapment neuropathy, osteoarthritis, hypertension, impaired glucose
tolerance, heart failure (late) – symptoms for an average of 9 yrs before diagnosis – Diagnosis: GH level remains › 1 μg/L after giving 100gm of glucose orally – Tx: Bromocriptine, Octreotide, surgery

 Laron Dwarfism : congenital absent of GH receptor - ↑ GH, ↓ IGF-1 & undetectable GH binding protein in blood

 Hypopituitarism : decrease level of one or more pituitary hormones (decrease in most pituitary hormones is referred as panhypopituitarism) – FSH & LH (most common), GH then TSH and lastly ACTH – Causes: Pituitary adenoma
Craniopharyngioma, meningioma, gliomas, Pituitary apoplexy (acute hemorrhage in preexisting pituitary adenoma - emergency), Sheehan syndrome (postpartum necrosis of pituitary due to loss of blood intrapartum), Infection, Autoimmune, Empty sella syndrome – amenorrhea, infertility, decrease libido, fatigue, inability to lactate (1st sign in Sheehan syndrome) - Tx: replacement of hormones. Cortisol and Thyroid hormones replacement is most important step in management during emergency. Treat underlying causes

 CT head – No pituitary + normal hormone level – Empty sella Syndrome

 Very small pituitary tumor on MRI, but no abnormality in hormones and absence of any symptoms, next step? – repeat MRI after 6-12 months

 Diabetes Insipidus : excessive thirst, polyuria (form dilute urine in the presence of Hypernatremia) – central (insufficient ADH) & Nephrogenic (unresponsiveness of kidney to ADH) – Diagnosis: (1) increase in Urine Osm after giving vasopressin – central DI. (2) increase Urine Osm after dehydration

– psychogenic – Tx: central DI – vasopressin (SC) / Desmopressin (intranasally, SC, orally), Chlorpropamide, Carbamazapine (increase ADH secretion) –
Nephrogenic DI – Amiloride (K+ sparing diuretics) – Mx of Hypotension in pt with DI – IV normal saline

 SIADH : cancers (small cell CA of lung), Drugs (Chlorpropamide, carbamazapine) – continuously form concentrated urine in the presence of hyponatremia – Tx: fluid restriction, Demeclocycline, Lithium

 * Diabetes Insipidus → elevated Serum Osmolarity
* Primary polydipsia (Psychogenic) → both serum & urine diluted

* SIADH → elevated urine osmolarity

 Conn’s Syndrome : Primary Hyperaldosteronism – adenoma of zona glomerulosa (adrenal gland) – hypertension (sodium retention), hypokalamia (muscle weakness) – plasma aldosterone to plasma rennin activity (>30 suggest
diagnosis) (Initial screening test) – Tx: resection [D/D: Renal artery stenosis – BUN:Cr >20:1, abd bruits, hypokalamia is less severe than Conn’s syndrome; If Hypokalamia in Conn’s is in 2.something range, hypokalamia in renal artery
stenosis is in 3.something range but less than 3.5; (3.5 – 5.0 normal range)]

· Patient with HTN & hypokalemia, next step? – plasma aldosterone and renin ratio
[Dx: Primary Hyperaldosteronism (Conn’s syndrome)]

 Hyperthyroidism : ↑↑ T3 & T4, ↓↓ TSH – heat intolerance, weight loss, diarrhea, tremor, arrhythmias; Exophthalmos & dermatopathies (only in Grave’s disease) – Grave’s disease - ↑ RAIU (radioactive iodine uptake), anti-TSH receptor antibodies. Toxic nodular goiter (single / multiple) - ↑ RAIU. de Quarian Thyroiditis – subacute granulomatous, giant cell - ↓ RAIU – painful (transient hyperthyroidism). Subacute lymphocytic Thyroiditis - ↓ RAIU – painless (transient hyperthyroidism). Ectopic thyroid tissue – struma ovarii – Tx:
antithyroid drugs (only PTU(propythiouracil) safe in pregnancy), radioactive iodine, subtotal thyroidectomy (only indicated in pregnancy in 2nd trimester) – Tx: subacute thyroiditis – NSAIDs & beta-blockers

 Tx of Grave’s disease in USA –> radioactive iodine ablation with concurrent administration of glucocorticoids to prevent worsening of ophthalmopathy

 Thyroid storm : First step Propranolol (to control symptoms) & PTU and then radio active iodine or surgery for permanent treatment [Radio active iodine aggravate hyperthyroidism initially so never give it before giving PTU]

 Tx of hyperthyroidism in pregnancy – PTU; if PTU fails, surgery

 Hypothyroidism : ↓↓ T3 & T4, ↑↑ TSH (primary) but normal / ↓ TSH (secondary / tertiary) – cold intolerance, weight gain, amenorrhea, carpal tunnel syndrome, slow deep tendon reflexes with prolonged relaxation phase, myxedema (prolonged hypothyroidism) – Hashimoto Thyroiditis : antimicrosomal antibody, anti-thyroglobulin antibody, lymphocytic infiltration – associated with lymphoma in thyroid gland – Tx: levothyroxine(T4), in secondary & tertiary first give hydrocortisone then replace thyroid hormone. – Calcium and Iron preparation decrease absorption of levothyroxine –

Estrogen increase metabolism of levothyroxine therefore it is important to increase dose of levothyroxine in patient taking HRT – important side effect: AF and osteoporosis

 Congenital Hypothyroidism: apathy, weakness, hypotonia, large tongue, abdominal bloating and umbilical hernia – MCC of congenital hypothyroidism in USA – thyroid dysgenesis – Neonatal screening for Hypothyroidism: total T4 and TSH; If T4 is low and TSH is >20 U/L, next step? – repeat free T4 and TSH on a regular blood draw to confirm diagnosis

 Asymptomatic Hypothyroidism: look for Anti-thyroid antibodies, abnormal lipid profile or menstrual abnormality – If any out of three present, start treatment (levothyroxine)

 Myxedema : results from the accumulation of increased amounts of hyaluronic acid and chondroitin sulfate in the dermis in both lesional and normal skin – can be seen in both hypothyroidism and hyperthyroidism – jelly like infiltration in
subcutaneous tissue, eye puffiness, non-pitting edema, drowsiness, lethargy and coma (in severe cases) – Tx: intravenous steroids, levothyroxine

 Reidle Thyroiditis : intense fibrosis of thyroid gland and surrounding structure

 Papillary CA : most common thyroid CA – h/o radiation exposure – Tx: surgery (small), radiation (large tumor)

 Follicular CA : elderly – spread hematogenously – Tx: near total Thyroidectomy + post-op- radiation

 Medullary CA : parafollicular cell of thyroid gland - ↑↑↑ Calcitonin – association with MEN type-2b – more malignant then follicular – Tx: Thyroidectomy

 Anaplastic CA : elderly – highly malignant with rapid and painful enlargement of thyroid gland – poor prognosis

 Patient with Thyroidectomy due to CA should receive thyroxine life long. Check than 0.35, increase dose of thyroxine

 Thyroid nodule : measure TSH (first step); If TSH normal, next step? – FNAC; If TSH decreased, next step? – Radioisotope scan; If hot nodule (increase uptake of radioisotope), next step? – Observation

 Most common cause (MCC) of thyroid nodule – benign colloid nodule

 2nd MCC of thyroid nodule – follicular adenoma

 Parathyroid Hormone : It stimulates Osteoclast & 1-α-hydroxylase (increase production of active form of Vit-D → 1-25-(OH)2-D) – increase Ca+2 level by bone resorption (osteoclast) & by absorption of Ca+2 from gut and kidney (Vit-D)

 Vit - D : increase absorption of both Ca+2 & Phosphorus (PO4) from intestine + increase absorption of Ca+2 and decrease absorption of PO4 from kidney

 Magnesium : cofactor for adenylate cyclase – cAMP is require for PTH
activation – therefore hypomagnesemia can cause hypocalcemia
(hypomagnesemia is the most common pathologic cause of hypocalcemia in the hospital - Cause of refractory hypokalemia in alcoholics → Hypomegnesemia)
 Calcitonin : inhibit bone resorption
 Primary Hypo- / Hyperparathyroidism : plasma calcium & phosphate
levels are changing in opposite direction EXCEPT CRF which causes secondary hyperparathyroidism but in CRF there is hypocalcemia & hyperparathyroidism (moves in opposite direction)

 Pseudohypoparathyroidism – resistance to PTH on its target tissue. High PTH and High phosphorus [true Hypoparathyroidism has high phosphorus and low
PTH; calcium is low in both]
 Secondary Hyperparathyroidism : Increase PTH, decrease Ca+2 level
& its excretion and decrease PO4 level & normal/increase its excretion
 Secondary Hypoparathyroidism : Decrease PTH, increase Ca+2 level
& its excretion and increase PO4 level & normal/decrease its excretion.
 Hypercalcemia : primary hyperparathyroidism (one gland hyperplasia), PTHlike
substance secretion from CA, Immobilization for prolong time [can cause excessive bone resorption], Sarcoidosis – Osteitis fibrosa cystica, lytic lesions on x-rays – serum Ca+2 level more than 10.2 mg/dl – Tx: oral rehydration with 2-3
L/day is very effective in chronic form. Sever Hypercalcemia (›15 mg/dl) is an emergency – IV normal saline (first step), Loop diuretics, IV Pamidronate.

 Calcium level above 7 in patient with low albumin level (Normal – 4 g/dl) usually doesn’t require any intervention

 Hungry bone syndrome : hypocalcemia after surgical removal of a hyperactive parathyroid gland.

 Hypocalcemia : tetany, muscle cramps / spasm, Chvostek sign (percussion of Facial N. leads to contraction of facial muscles), Trousseau’s sign (inflation of BP cuff on the arm of patient above SBP for more than 3 mins leads to flexion of metacarpophalangeal joints and extension of interphalangeal joint), QTprolongation on EKG – always check for albumin level (1 gm/dl drop in albumin → calcium level drop by 0.8 mg/dl) – Tx: for acute condition – IV calcium gluconate, for chronic condition (low Ca & low PO4 – Vit-D deficiency)
– oral calcium 2-4 gm/day, Vit-D; If associated hyperphosphatemia (eg. CRF) – dietary phosphate restriction, phosphate binders.

 Pathogenesis of DM : Nonenzymatic glycosylation (glucose + AA) →
↑vessel permeability to protein and ↑athrogenesis; Osmotic damage → Aldolase reductase (glucose → sorbitol) → sorbitol draws water into tissues causing damage
(eg. retinopathy); Diabetic microangiopathy → ↑synthesis of type-IV collagen in
basement membrane & mesangium

˗ Tight blood sugar control decrease the risk of development of microvascular complication (retinopathy, nephropathy, neuropathy)
˗ ACE inhibitors has shown to reduce insulin resistance

 Diagnosis of DM : symptomatic patient (polyuria, Ploydipsia, polyphagia) with random blood glucose level › 200 mg/dl or fasting blood glucose › 126 mg/dl on two occasion or blood glucose › 200 mg/dl at 2 hrs and on at least one of
the earlier samples.
 HbA1c : used to follow compliance of the treatment and glucose control in
patient with diabetes.

 Somogyi effect : rebound hyperglycemia in the morning because of counter regulatory hormone release after an episode of hypoglycemia in the middle of night.
 Dawn Phenomenon : early morning rise in plasma glucose requiring increased amount of insulin to maintain euglycemia. [dawn goes up]
 Insulinoma : increase in both plasma insulin and C peptide
 Exogenous insulin administration : very high insulin level but low C peptide

 Sulfonylureas : increase in both plasma insulin and C peptide, plasma/urine
sulfonylurea (+) – Tx of refractory hypoglycemia due to sulfonylureas overdose –
Octreotide
 Management of Diabetic Ketoacidosis:
1. IV Normal saline + IV regular insulin
2. correction of electrolyte imbalance (especially K+)
(D 5% in 0.45% saline with potassium after glucose level reaches 200-250
mg/dl)
3. Treatment of precipitating factor.
˗ Important point to remember in Tx of DKA: Start regular insulin subcutaneously
30-60 mins before stopping IV insulin
˗ Cause of hyperkalemia in DKA – extracellular shift of K+
 Tx of Hyperosmolar Hyperglycemia: Hydration and Insulin. Hydration
[hyponatremia / hypovolemic shock – 0.9% NaCl (Normal saline); Hypernatremia
– 0.45% NaCl (half normal saline)]
 Tx of Alcoholic Ketoacidosis – Hydration (IV fluids containing Dextrose) and
Thiamine
· Type-II Diabetic patient with low bicarbonate, normal blood sugar – order ABG
& lactic acid level – Dx: Metabolic acidosis due to Metformin
 Somatostaninoma – diabetes (inhibits insulin release), gall stones (inhibits gall
bladder motility) and Malabsorption (inhibit release of pancreatic enzymes) – Dx:
measure fasting somatostatin level (>160 pg/ml is very suggestive)
 Best screening and diagnostic test for diabetic neuropathy – nerve conduction
studies (show axonal pattern of nerve damage)
 Primary Hypercortisolism (Adrenal Tumor) - ↑ cortisol, ↓ ACTH
 Pituitary Cushing (Cushing’s disease) - ↑ cortisol, ↑ ACTH. High dose
Dexamethasone test - ↓cortisol, ↓ ACTH by 50%
 Ectopic ACTH secretion - ↑ cortisol, ↑ ACTH. High dose Dexamethasone test –
No suppression of ACTH
 Patient with sign & symptoms of Cushing – low dose overnight
Dexamethasone suppression test (best initial test) – if abnormal then order 24
hrs urine-free cortisol – if abnormal (Cushing Syndrome) – then order high dose
Dexamethasone test – if no suppression of ACTH then order ACTH level – if
high ACTH level (Ectopic ACTH secretion – CT chest will be the next step) – if
low ACTH level (Adrenal neoplasia) – then order Urinary 17KS, DHEA-S &
Abdominal CT – if high level of these hormones and greater than 4 cm mass on
CT (Adrenal CA) – if low level of these hormones and less than 4 cm mass on CT
(Adrenal hyperplasia)

 If low dose overnight dexamethasone test is normal, Cushing is ruled out
 If 24-hrs urine-free cortisol test is normal, no Cushing
 Young patient with HTN, diabetes, osteoporosis and hypokalamia should screen
for Cushing’s syndrome (order dexamethasone suppression test)
 Patient with central hypothyroidism [low normal TSH and low T4], next step? –
rule out adrenal insufficiency (order cosyntropin stimulation test)
 Tx of acute adrenal insufficiency – IV Dexamethasone (long acting)
 Short-term use of glucocorticoids (less than 3 wks) even in high dose can be
discontinued rapidly without causing significant adrenal insufficiency

· Bitemporal hemianopsia and tanned skin (hyperpigmentation) following adrenalectomy for Cushing’s disease – Nelson’s syndrome

 17 α Hydroxylase Deficiency : ↓ cortisol and androgen but ↑ 11-deoxycorticosterone (weak mineralocorticoid due to which retention of sodium occur and hypertension develop)

 21 β Hydroxylase Deficiency : ↓ cortisol and mineralocorticoid but ↑ androgens

 11 β Hydroxylase Deficiency : ↓ cortisol but ↑ androgens and
mineralocorticoid

 Increase ACTH in all of 3 enzymes deficiency (above)

 Male ambiguous genitalia (male pseudohermaphrodite) – 17 α-Hydroxylase

 Female ambiguous genitalia (female pseudohermaphrodite) – 21 & 11 β-Hydroxylase

 Female Hypogonadism – 17 α Hydroxylase
 Precocious puberty in male – 21 & 11 β Hydroxylase
 Dx of 21-Hydroxylase deficiency is confirmed by documenting elevated 17-alpha
hydroxyprogesterone (not 17-alpha hydroxypregnenolone)
 MEN 1 (Wermer) – Pancreas (ZE syndrome), Pituitary, Hyperparathyroidism (3P)

 MEN 2a (Sipple) – Hyperparathyroidism, Pheochromocytoma, Medullary CA of Thyroid

 MEN 2b (3) – Pheochromocytoma, Medullary CA of Thyroid, mucosal neuroma (lips/tongue)

 Presence of Y chromosome – germinal tissue differentiate in to Testes

 hCG + LH → leyding cells → testosterone → wallfian duct (epididymis, ductus deference, ejaculatory duct) → 5 α reductase convert testosterone in dihydrotestosteron (DHT) which induce urogenital sinus & genital tubercle to form penis, prostate & scrotum

 Sertoli cells → secrete MIF (mullerian inhibiting factor) which inhibit paramesonephric duct (uterus, uterine tubes, cervix & upper part of vagina)

 If MIF absent – uterus (paramesonephric duct structure) develop with normal
male structure
 If Testosterone absent – wallfian duct regress (male internal structure not
develop)
 If 5 α reductase absent – DHT not formed. Therefore male external structures
not develop but female external structures develop.
 Absence of Y chromosome – germinal tissue differentiate in to Ovaries. Wallfian
(mesonephric duct) regress and female genitalia develop

Testicular Feminization –> androgen receptor insensitivity, Mullerian duct structure develop in the presence of testes. (No effect of testosterone & DHT)

Disorders of the Pituitary Gland

Sheehan syndrome > loss of blood intrapartum > postpartum
necrosis of pituitary

ANTERIOR PITUITARY

1. Pituitary Tumors

Pituitary Adenomas

Nelson's syndrome: pitutary adenoma following bilateral adrenalectomy

Craniopharyngiomas

Meningiomas/Metastatic Tumors

2. Hypopituitarism

Acromegaly

Hyperprolactinemia

Causes:

Drugs: methyldopa, haloperidol

Clinical:

Women: amenorrhea, galactorrhea, infertility

Men: impotence

POSTERIOR PITUITARY

1. Diabetes Insipidus

Decreased production or ineffective action of ADH

2. Syndrome of Inappropriate Secretion of ADH (SIADH)

Thyroid

HYPERTHYROIDISM

Graves Disease

Autoantibody to TSH receptor stimulates gland

Thyroid storm > Tx: First step Propranolol (to control symptoms)

Hashimoto Thyroiditis > lymphocytic infiltration

HYPOTHYROIDISM

'Myxedematous Madness': the title of a paper I read in medical school that brought to my attention the psychiatric aspect of thyroid disease

'I was so young and unafraid then - thought I could rule the world, thought I knew everything, thought I had all the solutions, all the answers. I was so young, so innocent, so unprepared.'

Thyroid Cancer

Papillary - most common

Follicular - second most comon ,more aggressive than papillary

Medullary -

Anaplastic - most aggressive - rapidly fatal within weeks

Diabetes Mellitus

Word coined by Aretaeus (81–133 CE) of Cappadocia [Greek diabaínein: "passing through", a reference to one of the diabetes major symptoms of excessive urine discharge - In 1675 Thomas Willis added mellitus (Greek mel, "honey") when he noted that a diabetic's urine and blood has a sweet taste]

Type I

Link to genetic loci HLA DR3 and DR4

Type II

100% concordance in identical twins

Diabetic Ketoacidosis

KETOacidosis -> incresed ketones

'Juicy Fruit' breath

Treatment: IVF + insulin, treat infection if present

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Tuesday, February 23, 2010