2. Endocrinology

“It is not stress that kills Addison, it is the absence of reaction to it.”

2.1 Disorders of the Anterior Pituitary Gland (Adenohypophysis)

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Abbreviations: GHRH, growth hormone releasing hormone; GH, growth hormone; IGF-1, insulinlike growth factor-1; Prl, prolactin; ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.

Hormone secreted by anterior pituitary gland

Pituitary adenoma producing the hormone in excess is called the following



Lactotroph adenoma

Galactorrhea/amenorrhea syndrome

Growth hormone

Somatotroph adenoma


Adrenocorticotrophic hormone

Corticotroph adenoma

Cushing’s disease

Thyroid-stimulating hormone

Thyrotroph adenoma

Secondary hyperthyroidism


GTA, my favorite video-game (Grand Theft Auto)

2.1.1 Common Features of All Pituitary Adenomas

  • As pituitary gland is near to the optic chiasm, pituitary adenomas cause compressive visual field defects, which primarily involve the temporal fields causing bitemporal hemianopsia

    1 Think of a person always hitting the car on the side, but not on the front or the back of the car.

  • Large adenoma can compress surrounding pituitary tissue, causing pressure atrophy and hypopituitarism. This leads to sequential loss of anterior pituitary hormones. Growth hormone (GH) and gonadotrophin-releasing hormones (GnRHs) are affected earlier in the disease course, followed by thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH).

  • • Children commonly present with stunted growth due to early development of GH deficiency.

  • In adults, deficiency of GnRHs (luteinizing hormone [LH] and follicle-stimulating hormone [FSH] deficiency) is more problematic. Men commonly present with impotence and women with amenorrhea.

  • An adenoma can be functioning (secreting a hormone in excess, as above) or nonfunctioning.

  • A large functioning pituitary adenoma can present with signs of excess of one of the pituitary hormones and deficiency of other pituitary hormones. For example, a large somatotroph adenoma can present with acromegaly and central hypothyroidism/ hypocortisolemia.

2.1.2 Prolactinoma (Lactotroph Adenoma)

Background: Benign tumor that autonomously secretes prolactin hormone. It is the most common tumor of the pituitary gland.

Pathophysiology/presentation: Excessive secretion of prolactin stimulates mammary glands and also decreases GnRH secretion, causing hypogonadism (decreased LH/FSH production) and the following clinical effects


  • Galactorrhea

  • Development of low estrogen/progesterone state and its complications, such as osteoporosis, oligomenorrhea/amenorrhea, etc.


  • Loss of libido and impotence

  • Gynecomastia +/- galactorrhea

Presentation scenarios

  • CCS: 40-year-old female presents with milky breast discharge and oligomenorrhea.

  • CCS: 55-year-old male presents with decreased libido and impotence. Physical exam reveals visual defects primarily involving bitemporal visual fields.

Work-up: First SIM is to check serum prolactin level and rule out the following conditions that can increase prolactin secretion.


Order qualitative beta-human chorionic gonadotropin test


Check TSH level

Medication side effect

Dopamine directly inhibits prolactin secretion. So, medication that either block dopamine receptors (e.g., metoclopramide, typical antipsychotics) or deplete dopamine (α-methyldopa) can increase prolactin secretion

If the above conditions are ruled out and serum prolactin level is high, NSIDx is MRI of the pituitary gland.

2 If a mass is seen in the pituitary area, also evaluate for hypersecretion of other pituitary hormones.


Treatment is indicated in any degree of hypogonadism (e.g., amenorrhea) or in patients with bothersome galactorrhea.

3 In postmenopausal women with no visual defects, regular monitoring with MRI and prolactin levels may be done.

  • Treatment of choice is pharmacologic. Use cabergoline, which has fewer side effects than bromocriptine. (Dopamine agonist decrease prolactin hormone secretion and shrink tumor size.)

  • Surgical treatment (removal of adenoma) is done when patients fail to respond to medical management. Note that even in patients with significant neurologic symptoms, medical treatment should be tried first.

  • Radiotherapy is considered when medical and surgical treatments fail.

Clinical Case Scenarios

A 35-year-old male presents with gynecomastia and decreased libido. He also gives hx of longstanding issues with constipation and cold intolerance. Exam reveals mild decrease in bitemporal visual acuity. He is found to have low TSH and high serum prolactin level. MRI shows pituitary enlargement.

  1. What is the likely dx?

  2. What will be the dx if the patient had elevated TSH instead, along with high serum prolactin level? (Low-yield question; a little bit harder to answer).

2.1.3 Acromegaly and Gigantism

Etiology: Excess GH (Growth Hormone) secretion occurs most commonly from a tumor in the pituitary gland. Other rare causes are ectopic GH or GH-releasing hormone secretion from cancers.


When excess GH secretion occurs in:

It results in:


Gigantism: occurs when growth plates have not fused


Acromegaly: occurs when the growth plates have already fused.

  • Presents with bony and soft tissue overgrowth—enlargement of hands and feet, coarsening of facial features, thickening of skin folds, and enlargement of mandible (protruded jaws)

  • Most of the internal organs are also enlarged

  • Other associated findings are hypertension (HTN), impaired glucose tolerance, diabetes mellitus, entrapment neuropathy (e.g., carpal tunnel syndrome), and osteoarthritis

  • Most common cause of death is cardiovascular disease


  • First SIDx: measure insulin-like growth factor-1 (IGF-1) level aka somatomedin. Somatomedin (IGF-1) is a substance secreted by liver in response to GH. This is a great surrogate marker for GH level.

  • If IGF-1 level is elevated, NSIDx is glucose suppression test. GH levels are measured before and after patient ingests 100 g of glucose. Normally, glucose load should suppress GH secretion. Nonsuppressible GH level confirms diagnosis of autonomous GH secretion.

  • NSIDx is brain MRI to locate the tumor.


  • Treatment of choice is surgical (transsphenoidal resection of pituitary adenoma).

  • Medical treatment is indicated in patients who are at high risk for surgery or when surgical therapy fails. Use somatostatin analogues (octreotide or lanreotide) +/- cabergoline, a dopamine agonist (both inhibit GH release). If still not controlled, use pegvisomant—a somatomedin antagonist that blocks somatomedin (GH) receptors.

  • Radiotherapy is considered when medical and surgical treatments fail.

In a nutshell

Management steps for various pituitary adenomas

Pituitary adenoma

Tests to be performed in the following order

Treatment (given in order of preference)


Thyroid-stimulating hormone, pregnancy test, and serum prolactin level1 → MRI brain

Medical therapy → surgery → radiotherapy


Insulin–like growth factor-1 levels1 → oral glucose load test → MRI brain

Surgery → medical therapy → radiotherapy

In all endocrinology cases, when excess hormone secretion is suspected, first step in management is to check the hormone level. Imaging studies are done only after laboratory confirmation of high hormone levels.

Cushing’s disease will be discussed in adrenal section of this chapter.

2.1.4 Hypopituitarism

Pathophysiology: Various pathologic processes can involve the pituitary gland and cause hypopituitarism—autoimmune, infectious, trauma, tumor compression, metastasis, infiltrative (sarcoidosis and hemochromatosis), postsurgical removal of pituitary adenoma, etc. Additional causative scenarios include the following.

Pituitary gland can be affected by

Which may occur in the following situations

Ischemic necrosis

Postpartum pituitary necrosis aka Sheehan’s syndrome: CCS – patient with hx of severe postpartum bleeding now presents with inability to lactate


Postpartum pituitary hypophysitis (autoimmune destruction of pituitary gland)

Pressure atrophy


4 Craniopharyngioma

• It is a benign tumor, derived from embryonic tissue (Rathke’s pouch), which occurs most commonly in children but can present in any age group (even in people in 50-60s).

• It can present similarly to a nonfunctioning pituitary adenoma with features of pressure atrophy and visual deficits.

• Central nervous system imaging may reveal calcified mass around pituitary fossa or just above it.

• Treatment is surgical removal.

or pituitary macroadenoma: patients usually have bitemporal visual field defects

Hormone involved

Clinical features of deficiency

NSIDx (Next step in dx)


  • Females: decreased libido, oligomenorrhea/ amenorrhea and anovulation (infertility)

  • Males: impotence, decreased libido, loss of hair, etc.

Serum LH & FSH


  • Children: delayed height development

  • Adults: nonspecific symptoms, such as fatigue and reduced muscle mass

NSIDx is IGF-1 level

  • If low, dx is made.

  • If equivocal, NSIDx is to do provocative testing- measure serum growth hormone after administration of any of the following-

    • Arginine+growth hormone releasing hormone (GHRH), or

    • Arginine+L-DOPA, or

    • glucagon injection, or

    • macimorelin, a ghrelin agonista


Features of hypothyroidism



Fatigue, decreased appetite, weight loss, etc.

Serum cortisol, ACTH, and cosyntropinb stimulation test

a Insulin-induced hypoglycemia was used as a provocative method in the past, but it can be a very uncomfortable experience for the patient, so it is no longer used.

b Cosyntropin is a recombinant ACTH.

Abbreviations: ACTH, adrenocorticotropic hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GnRH, gonadotropin-releasing hormone; IGF-1, insulin–like growth factor-1; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.


Hormone replacement. Replace cortisol before replacing thyroid hormone. If thyroid hormone is replaced before cortisol, this will increase the requirements for cortisone and precipitate a hypoadrenal crisis.

2.1.5 Pituitary Apoplexy

Background: Patients with large pituitary adenoma can develop pituitary apoplexy, an acute clinical syndrome caused by either hemorrhage and/or infarction of the pituitary gland.

Presentation: Hemorrhagic form usually presents with sudden severe headache (“thunderclap” headache) +/- signs of meningism. Look for rapidly worsening visual deficits (due to pressure on optic chiasm).

This may be followed by symptoms due to essential hormone deficiency. Predominant feature is hypotension due to acute adrenal insufficiency.

Management: It is a medical emergency. NSIM is IV fluids and IV hydrocortisone.

2.1.6 Posterior Pituitary Lobe (aka Neurohypophysis)

  • Posterior pituitary secretes antidiuretic hormone (ADH aka vasopressin) and oxytocin.

    5 Oxytocin hormone is discussed further in Obstetrics chapter. ADH will be discussed in this chapter.

  • ADH promotes reabsorption of free water from the kidneys and maintains serum sodium concentration and plasma osmolarity.

  • Increased ADH secretion leads to increased total body water resulting in decreased serum Na+ concentration.


2.2 Disorders of Sodium Hemostasis and Antidiuretic Hormone of Posterior Pituitary Gland

2.2.1 Diabetes Insipidus

Pathophysiology: Diabetes insipidus (DI) is either due to deficiency of ADH or resistance to ADH effect. This results in excretion of excessive amount of diluted urine by kidneys, resulting in loss of free water. The resulting polyuria is usually accompanied with compensatory polydipsia.

Central DI is due to absolute ADH deficiency

Various pathologic processes that can affect the posterior pituitary and cause central DI are: autoimmune, infectious, trauma, tumor compression, metastasis, infiltrative (sarcoidosis and hemochromatosis), postsurgical removal of pituitary adenoma, etc.

7 Similar in etiology to hypopituitarism above

Nephrogenic DI is due to kidneys’ resistance to ADH

The causes of nephrogenic DI can be many: medications (e.g. lithium, amphotericin B), sarcoidosis, amyloidosis, polycystic kidney disease, hypercalcemia, hypokalemia, etc.

Presentation: Usually patients with polyuria have intact thirst mechanism, so if they lose 20 L of water, they will drink 20 L of water continuously replenishing the free water loss. In situations where thirst mechanism is impaired (sedatives, altered mental state) or if there is a problem with access to water (long car ride, incarceration), patients can become acutely ill, dehydrated, and may develop acute hypernatremia.

8 Clinical features of hypo/ and hypernatremia are somewhat similar: headache, lethargy, coma, and eventually seizures can develop.

Differential diagnosis of diabetes insipidus

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Work-up: NSIDx is serial measurements of urinary and plasma osmolarity (after water deprivation, followed by ADH administration) as shown below.

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Fig. 2.3
1,2 Exogenous ADH will not have effect, as ADH is already working at maximum after water deprivation.
3 In psychogenic or drug-induced polydipsia the concentrating ability of kidneys gets impaired. It may take days, after normalizing water intake, for the concentrating ability of kidneys to come back to normal.
4 To differentiate nephrogenic DI from central DI, administer desmopressin (an ADH analogue). More than 50% increase in urine osmolarity after desmopressin indicates ADH deficiency (central DI).

Table representation of the graph above

Plasma osmolarity

Urine osmolarity

What happens to urine osmolarity after giving desmopressin




No change

Psychogenic or drug-induced polydipsiaa


No change

Nephrogenic DI

Central DI

aIn psychogenic/drug-induced polydipsia, both plasma osmolarity and urine osmolarity is low.

bLow urine osmolarity despite high plasma osmolarity points towards DI.

Abbreviation: DI, diabetes insipidus.

Management of central/nephrogenic DI:

  • Address the underlying cause.

  • First step in treatment is to decrease solute intake (low salt and protein diet). This decreases polyuria. (In DI, the kidneys lose the ability to concentrate urine. With fixed urine osmolarity, urine output is primarily determined by amount of solute intake and solute content in urine.)

  • Second step is to use hydrochlorothiazide (HCTZ) in patients with persistent polyuria. (Diuretics induce a state of partial volume depletion, which increases proximal sodium and water absorption, leading to less delivery of water to distal ADH-sensitive areas.)

  • Desmopressin is used for central DI, if decreased solute/protein intake and/or HCTZ treatment fails to control polyuria, or if symptoms are severe.

  • Nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., indomethacin), which increase renal concentrating ability, can also be used as an adjunct.

  • For lithium-induced DI, amiloride is the drug of choice.

In a nutshell

Likely cause of polyuria + polydipsia in various settings

Polyuria + polydipsia +…. ↓

Likely diagnosis (dx)


Uncontrolled diabetes mellitus (glucose-induced diuresis)

Fatigue + muscle weakness

Hypokalemia-induced nephrogenic DI

Constipation+ abdominal pain

Hypercalcemia-induced nephrogenic DI


Diabetes insipidus or psychogenic/drug-induced polydipsia

2.2.2 Hypernatremia


  • Free water loss due to diabetes insipidus.

  • Hypotonic fluid loss without water replacement

    9 Absence of water replacement typically occurs in patients with advanced age, dementia, and mental retardation, because these patients have decreased or diminished thirst response mechanism.

  • Fluid loss from skin, due to burns or excessive sweating (fever, vigorous exercise, hot weather, etc.).

  • Fluid loss from gastrointestinal tract, due to osmotic diarrhea (e.g., lactulose ingestion) and diarrhea in infants. (Note: In adults, diarrheal fluid is isotonic.)

  • Fluid loss from kidneys, due to osmotic diuresis (e.g., diabetic ketoacidosis [DKA], hyperosmolar nonketotic coma [HONK], or drugs such as mannitol).


  • First step is to look for coexistent volume depletion.

  • If blood pressure is low (systolic BP ≤ 90 mmHg) and/or heart rate is high (> 90-100 beats per minute), 1st SIM is IV normal saline.

  • If euvolemic, use IV hypotonic fluids such as 5% dextrose solution in water or if coexistent mild volume depletion is present, use 5% dextrose half normal saline.

  • The rate of correction of chronic hypernatremia should not exceed > 10 to 12 mEq/L per day, otherwise cerebral edema may develop. For acute hypernatremia of less than 48 hours’ duration, more aggressive correction can be done (1-2 mEq/L correction per hour).

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2.2.3 Hyponatremia

First step is to find out if serum sodium is truly low: Is it true or is it pseudohyponatremia?

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aDo direct lab measurement of osmolarity, which might be different from calculated plasma osmolarity.

10 FYI: Calculated plasma osmolarity = 2 × serum Na+ (if BUN and glucose have normal values).

bIn true hyponatremia, measured plasma osmolarity should be low.

cHypertriglyceridemia and hyperproteinemia can cause a decrease in measured serum Na+ level (pseudohyponatremia) with no change in directly measured plasma osmolarity. This is an artefactual issue.

dHigh serum glucose level decreases measured serum Na+ level (pseudohyponatremia) and increases plasma osmolarity.

11In hyperglycemia, for every 100 mg/dL rise in blood glucose above 100 mg/ dL, measured serum Na+ decreases by 1.6 mEq/L.

For example, electrolyte panel shows glucose level of 804 mg/dL and serum Na+ of 125 mEq/L. Corrected true serum Na+ = 7 × 1.6 + 125 = 136.2 mEq/L.

Explanation: 7 is because glucose is elevated 700 mg/dL above 100 mg/dL in this case. Note: This situation is very common in DKA or HONK patients.

True Hyponatremia

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Hypervolemic Hyponatremia

12 In hypervolemic and hypovolemic states there is a compensatory increase in aldosterone and ADH secretion. Aldosterone reabsorbs isotonic fluid, but ADH reabsorbs hypotonic fluid (water). It is due to ADH that hyponatremia occurs.

In these conditions, development of hyponatremia is a poor prognostic sign. Level of hyponatremia parallels the severity of the underlying condition. Treatment includes restriction of sodium/ water intake and diuretics.

Hypovolemic Hyponatremia

13 Look for clues such as dry mouth, elevated heart rate, low BP, orthostatic hypotension, Creatinine elevation, elevated bicarbonate, etc. that suggest hypovolemia

Measure urine Na+ level to differentiate renal fluid loss from extrarenal fluid loss (if source of fluid loss is not clinically evident).

Urinary Na+ > 20 mmol/L= renal fluid loss

  • Diuretics (prescribed or surreptitiously ingested): thiazide-like diuretics are common perpetrators (e.g., HCTZ, metolazone)

    14 Patients with hx of hyponatremia should not be on thiazide-like diuretics.

  • Salt-losing nephropathies, for example, Fanconi syndrome, or acute tubular necrosis (diuretic phase)

Urinary Na+ < 20 mmol/L = extrarenal fluid loss

Patients develop hyponatremia due to compensatory increase in ADH/ aldosterone secretion generally with increased free water intake

  • GI losses (diarrhea, vomiting, etc.)

  • Skin losses (burns, toxic epidermal necrolysis, etc.)

  • Addison’s disease (loss of aldosterone and cortisol hormone)

Euvolemic hyponatremia

Urine Na+ > 20 and/ or urine osmolarity > 300

Despite hyponatremia and low serum osmolarity, kidneys are still inappropriately concentrating urine

  • MCC is syndrome of inappropriate secretion of ADH (SIADH)

  • Hypothyroidism (mechanism not completely understood)

Urine Na+ < 20 and/ or urine osmolarity < 300

  • Psychogenic polydipsia: hx of drinking > 15-20 L of water per day

  • Beer potomania is due to significant intake of beer. Beer is poor in solutes and sodium, but high in calories, thus it suppresses hunger and reduces intake of other foods (and solute)

  • Tea and toast diet: some patients (particularly elderly) who have poor social support may resort to eating only simple foods like breads, crackers and water, which do not need to be cooked, but have very low salt content

Management of true hyponatremia

Severity (normal serum Na+ is 135-145 mEq/L)

NSIM along with free water restriction and treatment of underlying cause ↓

130-135 mEq/L

Free water restriction only

121 to < 130 mEq/L with mild symptoms (mild confusion, fatigue, gait disturbance, nausea, vomiting, etc.)

Directed toward underlying etiology:

  • If hypovolemic—normal saline

  • In SIADH—salt tablets (1st step), +/- loop diuretics (induces ADH resistance) +/- vaptansa

  • In hypervolemic states—diuretics (such as Lasix), +/- vaptansa

120 mEq/L and/or severe symptoms (e.g., severe confusion, coma, seizures, respiratory arrest)

Hypertonic salineb +/- desmopressin to prevent rapid correction of sodiurmc

aVasopressin receptor antagonist (tolvaptan, conivaptan, mozavaptan, etc.) can be used adjunctively in SIADH and hypervolemic states.

bHypertonic saline is also indicated in acute symptomatic hyponatremia that develops within 24 hours (even if symptoms are only mild).

cRate of sodium correction should not be faster than 0.5-1 mEq/L per hour. Rapid overcorrection may result in central pontine myelinolysis (osmotic demyelination), which usually presents with focal neurological deficits like the ones seen in pontine hemorrhage or infarction (severe cases might present with quadriplegic locked-in-syndrome). (See Chapter 10, Neurology for further details).


Remember the numbers 120 and 130 for degree of hyponatremia.

2.2.4 Syndrome of Inappropriate Secretion of ADH

Etiology: SIADH can be caused by multiple processes, such as trauma, infection, malignancy (especially in lung or brain, e.g., lung injury, head injury, pneumonia, encephalitis, small cell cancer) and medications.MRS-1 Important association to remember is small-cell lung cancer.

Pathophysiology Excessive ADH secretion leads to excessive free water reabsorption and hyponatremia.

Treatment: Its treatment is directed toward underlying condition and also depends upon the severity of hyponatremia and symptoms (see table for management of true hyponatremia). Demeclocycline (ADH receptor blocker) is not commonly used nowadays because of increased risk of nephrotoxicity and high cost.


MRS-1 Drugs that can stimulate secretion of ADH (Tip: most of the drugs start with “C”)






vinCristine and vinblastine.





Antidepressants SSRIs (Citalopram, sertraline, etc.), Tricyclic antidepressants

In a nutshell

How to find out the cause of hyponatremia?

First step is to look at volume status

Urine Na+ (mmol/L)

Urine osmolarity



< 20


Extrarenal fluid loss

> 20

Renal fluid loss


> 20


Syndrome of inappropriate antidiuretic hormone secretion

< 20


Psychogenic polydipsia, beer potomania, or tea and toast diet

Clinical Case Scenarios

3. A 45-year-old female has serum sodium of 112 mEq/L and altered mental status. What is the NSIM?

2.3 Disorders of Calcium Hemostasis and Parathyroid Gland

2.3.1 Basics of Calcium (Ca2+) Metabolism

  • Total serum calcium = bound calcium + free calcium.

  • Bound form: Calcium is a positively charged ion which binds to albumin and other negatively charged compounds (e.g., citrate, PO4 , SO4 ).

  • Free form is the one that is biologically active and closely regulated by parathyroid hormone (PTH).

  • The two hormones that regulate calcium are PTH and Vitamin D.


Vitamin D

  • Secreted by the parathyroid glands and works on kidneys and bones

Requires hydroxylation in liver and kidney to become biologically active

  • Signals osteoblasts to activate osteoclasts. Osteoclasts then start dissolving bone, thereby decreasing bone density and in the process release more calcium and phosphorus into the blood

  • Signals the kidneys to increase reabsorption of Ca2+ and excretion of PO4

Signals the intestinal epithelial cells to increase


Vitamin D

Final effect is ↑ Ca2+ and decreased PO4 1

Final effect is ↑ Ca2+ and ↑ PO4 1

If calcium and phosphorus are in opposite directions, think PTH related and if they are both in same direction, think vitamin D related.

Patients with hypoalbuminemia (due to liver cirrhosis, protein-losing enteropathy, malnutrition, etc.) can have the following issue with calcium mechanics:

– Decreased total calcium but normal free Ca2+ level. These patients are asymptomatic.

Standard chem-7 or basal metabolic profile (BMP) tests measure total calcium. Hence if serum albumin is low, the calcium needs to be corrected with the help of a formula using serum albumin. We don’t need to know this formula for boards.

A case of masked hypercalcemia:

I had once taken care of a patient, who didn’t have a primary care doctor, who presented with fatigue. Complete metabolic profile revealed high normal calcium level and very low serum albumin. Corrected calcium value was found to be more than 14. She ended up having a diagnosis of severe acute hypercalcemia due to parathyroid adenoma. Hypoalbuminemia was probably a result of severe malnutrition due to hypercalcemia associated gastrointestinal symptoms.

2.3.2 Disorders of Calcium Metabolism

For the tables below, cover the diagnosis column (right most column) and try to explain mechanism of calcium disorder. Again, let us reiterate an important point—If calcium and phosphorus are in opposite directions, think PTH related; if they are both in same direction, think vitamin D related.





Vitamin D



↑ /or high Na

N or lowb

NSIDx is 24-hour urinary calcium.

  • Elevated urinary Ca2+ = primary hyperparathyroidism (parathyroid adenoma or hyperplasia)

  • Low urinary Ca2+ = familial hypocalciuric hypercalcemia (discussed later in section of primary hyperparathyroidism)



N or lowb

PTH-related peptide (PTHrP) secreted from cancer cells (squamous cell cancer of lung, breast cancer, etc.). This peptide works just like PTHc.


  • Overproduction of calcitriol (vitamin D) from lymphomas or Granulomas (e.g., in sarcoidosis or generalized granulomatous infection) (glucocorticoids are effective in this form of hypercalcemia)

  • Excessive vitamin D intake

N or ↑



Consider causes that increase bone resorption—prolonged immobilityd, multiple myeloma, hyperthyroidism. (Look for elevated alkaline phosphatase)

aIn hypercalcemia, PTH should be low if feedback mechanism is intact.

bDue to negative feedback from hypercalcemia.

c Hypercalcemia of malignancy can be due to PTHrP secretion (typically by squamous cell carcinoma) or due to cytokines secreted by osteoclastic metastatic cells (multiple myeloma is a classic example). Cancers at times can cause both types (e.g. breast cancers).

dPatients who have high bone turnover rate (e.g., Paget’s disease or in children), immobilization can lead to development of significant hypercalcemia (Hypercalcemia of Immobilization).

Abbreviation: PTH, parathyroid hormone

Hypocalcemic disorders




Vitamin D





Primary hypoparathyroidism (Etiology: DiGeorge syndrome, thyroidectomy complication, parathyroidectomy, polyglandular autoimmune syndrome, etc.)




Chronic renal failurea









Vitamin D deficiency (osteomalacia in adults and ricketsc in children)




N or

Vitamin D resistant ricketsd

aIn renal failure, there are two primary mechanisms: (1) retention of PO4 2 (which chelates calcium), (2) decrease in vitamin D production.

bLooks like it is a PTH-related disorder with calcium and phosphorus in opposite direction. Calcium is low even though PTH is high. So, PTH must not be working at all. Dx is pseudohypoparathyroidism, where there is a defect in PTH receptor, so even if PTH is present, it does not exert its effect.

cFor rickets, look for frontal bossing, bowed legs, and enlargement of costochondral junction.

dPrimary pathology is defect in vitamin D receptors, so even though vitamin D level is normal or high there is lack of effect.

e ↑ = secondary hyperparathyroidism (Elevated alkaline phosphatase is present in all cases except in pseudohypoparathyroidism.)

Clinical Case Scenarios




Vitamin D


A pediatric patient presents with frontal bossing, bowed legs, and enlargement of costochondral junction.





Hereditary hypophosphatemic ricketsa

An old patient’s x-ray shows diffuse thinning of bone.






aHeritable disorder in which the primary problem is significant phoshaturia (phosphate wasting).

In a nutshell

Miscellaneous info on calcium-related disorders:

  • Hydrochlorothiazide can cause mild serum hypercalcemia by increasing urinary calcium reabsorption. This hypocalciuric effect is helpful in prevention of stone formation in hypercalciuric recurrent calcium phosphate stones.

  • Differences in clinical features of hyper-/hypocalcemia



  • Decreases neuromuscular conduction and signaling pathways

  • Increases neuromuscular conduction

  • Constipation, fatigue, lethargy, muscle weakness, cardiac arrhythmias, etc.

  • Blunts ADH signaling pathway which may lead to nephrogenic diabetes insipidus (polyuria, polydipsia)

  • Muscle cramps, paresthesia, tetany, cardiac arrhythmias, etc.

Abbreviation: PTH, parathyroid hormone.

Hypercalcemia Clinical features

  • Gastrointestinal: constipation, abdominal pain, pancreatitis, etc.

  • Renal: polyuria/polydipsia.

  • Neurological symptoms depending upon severity: difficulty concentration → fatigue, weakness → altered mental status → seizures, coma.

  • cardiac: arrhythmias can also occur.

Normal serum calcium is ≤ 10.2 mg/dL


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aFurosemide (Lasix) is not routinely indicated in management of hypercalcemia. If patients develop volume overload with IV normal saline, it can be judiciously used.

b Bisphosphonates decrease osteoclastic activity. As opposed to calcitonin, it takes at least few days for the hypocalcemic effect to kick in, but it is more sustained. It is contraindicated in severe renal failure.

Bisphosphonates are also indicated in patients with symptoms related to bone resorption, for example, patient with acute back pain due to metastatic osteolytic lesion.

Denosumab is an alternative treatment of persistent hypercalcemia of malignancy refractory to bisphosphonates.

cIV calcitonin is mostly recommended in patients with serum Ca2+ > 14. It decreases calcium levels faster than bisphosphonates do, but its efficacy is reduced after 48 hours. In severely hypercalcemic patients, hemodialysis can be done as a treatment of last resort.

Primary Hyperparathyroidism

Etiology: MCC is parathyroid adenoma. Other causes include parathyroid hyperplasia/ malignancy.

Presentation: hypercalcemia.

Workup: After detecting elevated calcium levels, NSIDx is to check serum PTH level.

15 If PTH is low or low-normal, NSIDx- check PTHrP, vit D levels (1,25 and 25-OH forms).

If elevated or upper side of normal range, NSIDx is 24-hour urinary calcium measurement. If 24-hour urinary calcium is elevated the dx is primary hyperparathyroidism.

16 If 24-hour urinary calcium is low, the dx is Familial hypocalciuric hypercalcemia: High calcium, via calcium-sensing receptors should generally decrease PTH secretion from parathyroid glands and increase calcium excretion from kidneys.

In this rare disorder, calcium-sensing receptors in the parathyroid gland and kidneys are defective. These patients have high normal or high PTH level and low 24-hour urinary calcium excretion, despite high serum calcium. Genetic testing is confirmatory.

Management of Primary Hyperparathyroidism

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a Symptomatic hypercalcemia is an obvious indication. In asymptomatic patients, the following are indications for surgery:

Young patients < 50 years of age with no comorbidities, who have low risk for surgery

Pregnant patients

Calcium phosphate renal stones, nephrocalcinosis or 24-hour urinary calcium > 400 mg/day

Serum calcium level of 1 mg/dL or more above the upper limit of normal


Reduced renal function (eGFR < 60 mL/minute)

bOther options are CT or MRI scan of parathyroid gland. Localization of tumor is not necessary in patients undergoing nonsurgical management.

cA potential complication of removal of parathyroid adenoma is hungry bone syndrome. (7 to 10 days after surgery with precipitous decline in PTH levels, bones can go into a rapid remineralization phase with increased uptake of calcium and phosphates, resulting in serum hypocalcemia and hypophosphatemia. This is usually self-remitting and transient.)

dCinacalcet decreases PTH secretion by activating calcium-sensing receptors in parathyroid glands (it acts by “mimicking” calcium).

The MCC (most common cause) of hypercalcemia in nonhospital outpatient setting is primary hyperparathyroidism.

The MCC of hypercalcemia in hospital setting is malignancy. ”

Hypocalcemia Additional etiologies of hypocalcemia


Underlying mechanism

Multiple units of blood transfusion

Citrate (a negatively charged ion), which is used as an anticoagulant in blood bags, binds with free Ca2+ causing hypocalcemia

Acute hypoxemia (e.g., pulmonary embolus) or panic disorder with increased respiratory rate

Respiratory alkalosis: in alkalosis, there is depletion of positively charged ions (e.g., H+ion) and abundance of negatively charged ions (e.g., HCO3 ). Hence, Serum albumin becomes more negatively charged, and more free Ca2+ binds with albumin, decreasing the free calcium level

Patient is an alcoholic or is malnourished

Hypomagnesemia inhibits PTH secretion

Nephrotic syndrome

This is due to loss of cholecalciferol (vitamin D)-binding protein in urine

Presentation: Acute hypocalcemia leads to generalized neuromuscular and cardiac hyperexcitability.

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Management: Treatment of acute hypocalcemia is with IV calcium gluconate or calcium chloride. Maintenance is with oral calcium.


Potassium-calciummagnesium and QT interval always go in opposite directions. If potassium, magnesium or calcium is low, QT interval is prolonged.

2.4 Thyroid Hormone

Thyroid hormone controls the basal metabolic rate and Na+–K+–ATPase pump in all our cells.

In hyperthyroidism, everything is fast

In hypothyroidism, everything is slow

Weight loss despite increased appetite (due to increased basal metabolic rate)

Weight gain despite decreased appetite (due to decreased basal metabolic rate)

Heat intolerance due to increased basal metabolic rate and increased intrinsic heat production (even minimal external heat makes patients uncomfortable)

Cold intolerance



Diarrhea due to increased GI motility


Increased deep tendon reflexes

Slow deep tendon reflexes, slow speech and movement

Excessive production and expression of β1 adrenergic receptors leads to increased β1 adrenergic activity = sweating, tachycardia, anxiety, and tremors
The drug of choice to control these symptoms is β blockers

Additional features: sparse hair, croaky voice, puffy looking face, and myxedema

Note: Both hypo- and hyperthyroidism can cause proximal muscle myopathy.

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Dec 11, 2021 | Posted by in ENDOCRINOLOGY | Comments Off on 2. Endocrinology

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