Articles Resources Directory Glossary RVU Calculator Login
Buy Now

Endocrinology IM Board Review

General Endocrine Principles

  •  Endocrine glands secrete hormones directly into the bloodstream to act on distant organs (unlike exocrine glands, which use ducts).
  •  Hormone levels are largely controlled by negative feedback loops: e.g. the hypothalamus and pituitary adjust their output based on circulating hormone levels from target glands.
  •  Many hormones are organized in axes (hypothalamus → pituitary → target gland). Higher levels in the axis stimulate the next step, and end-hormones feed back to inhibit earlier steps to maintain balance.
  •  There are different classes of hormones: peptide hormones (e.g. insulin, ACTH) which act on cell-surface receptors, and steroid hormones (e.g. cortisol, thyroid hormone) which cross cell membranes to act on intracellular receptors.
  •  Endocrine disorders often reflect over- or under-production of hormones. The clinical effects depend on which hormone is affected and whether levels are too high or too low.

Pituitary Gland

  •  The pituitary gland (“master gland”) is located at the base of the brain in the sella turcica. It has two parts with distinct functions: anterior pituitary and posterior pituitary.
  •  The anterior pituitary (adenohypophysis) produces key hormones that regulate other endocrine glands: TSH, ACTH, FSH, LH, GH, and prolactin. The anterior pituitary is controlled by the hypothalamus via releasing hormones.
  •  The posterior pituitary (neurohypophysis) stores and releases ADH (antidiuretic hormone) and oxytocin. These hormones are made in the hypothalamus and travel to the posterior pituitary for release. ADH regulates water balance (kidney water reabsorption) and oxytocin triggers uterine contractions and milk release.
  •  ADH disorders: Deficient ADH causes diabetes insipidus (excessive dilute urination and thirst), whereas excessive ADH (e.g. in SIADH) causes water retention and hyponatremia (low sodium).
  •  Pituitary tumors (adenomas) are a common pituitary issue. They can be functional (secreting excess hormones) or non-functional. A large tumor can cause mass effect (headaches, vision changes like bitemporal hemianopsia by optic chiasm compression) and hypopituitarism by compressing normal pituitary tissue.

Hormone Testing

  •  Always obtain biochemical confirmation of an endocrine disorder before proceeding to imaging studies. Hormone blood tests are crucial to confirm disease (to avoid mistaking incidental imaging findings for pathology).
  •  It’s important to measure both the pituitary (trophic) hormone and the target gland hormone together. This helps determine if a disorder is primary (problem in the target gland) or secondary (problem in the pituitary/hypothalamus).
  • Use dynamic tests to assess endocrine function when baseline levels are inconclusive. If you suspect an overactive hormone condition, perform a suppression test (tries to shut down hormone production). If you suspect an underactive condition, perform a stimulation test (tries to provoke hormone production).
    •  Suppression test: Used for suspected hormone excess. Example: low-dose dexamethasone suppression test for Cushing’s syndrome (cortisol excess) – in Cushing’s, cortisol fails to suppress normally. Another example: oral glucose tolerance test to check if growth hormone will suppress (it should suppress in normal individuals; failure to suppress suggests acromegaly).
    •  Stimulation test: Used for suspected hormone deficiency. Example: ACTH (cosyntropin) stimulation test in adrenal insufficiency – in primary Addison’s disease the adrenal glands won’t produce cortisol in response. Another example: water deprivation test in diabetes insipidus (to see if dehydration triggers ADH effect and concentrates urine; failure to concentrate suggests DI).
  •  Hormone levels can fluctuate (pulsatile secretion, circadian rhythms) and can be affected by factors like binding proteins or illness. Interpret tests in the context of the patient’s clinical picture. In some cases, multiple measurements or specialized tests are needed for accurate diagnosis.

Endocrine Terminology (Primary vs Secondary vs Tertiary)

  • Primary endocrine disorder: A problem originating in the target endocrine gland itself. The gland fails or overproduces hormone. Example: primary hypothyroidism (thyroid gland failure) → low thyroid hormone, but high TSH from the pituitary (because the pituitary is responding appropriately to the low hormone by increasing TSH).
  • Secondary endocrine disorder: A problem at the level of the pituitary gland (the gland that controls the target organ). The pituitary’s output is abnormal, affecting the target gland’s function. Example: secondary hypothyroidism (pituitary isn’t secreting TSH) → low TSH leads to low thyroid hormone; the thyroid is normal but under-stimulated.
  •  Tertiary endocrine disorder: A problem at the level of the hypothalamus (which produces releasing hormones that act on the pituitary). This is less common clinically. For instance, tertiary adrenal insufficiency could be due to lack of CRH from the hypothalamus (often seen in chronic steroid use leading to suppressed hypothalamic function).
  •  The term “central” is often used to denote hypothalamic/pituitary causes (secondary/tertiary) as opposed to primary. For example, central diabetes insipidus = ADH deficiency due to a pituitary/hypothalamus issue, versus nephrogenic diabetes insipidus (a kidney issue).
  •  By comparing levels of pituitary hormones and target hormones, you can distinguish primary vs central causes. Example: Low cortisol with high ACTH = primary adrenal failure (Addison’s); low cortisol with low ACTH = secondary (pituitary) adrenal insufficiency.

Diabetes Insipidus

  •  Diabetes insipidus (DI) is an endocrine disorder characterized by the inability to concentrate urine, leading to excessive urination (polyuria) and intense thirst (polydipsia). It results from problems with ADH (antidiuretic hormone) signaling.
  •  Central DI: Caused by insufficient ADH production or release from the pituitary (common causes: head trauma, neurosurgery, tumors, or idiopathic).
  •  Nephrogenic DI: Caused by kidneys not responding to ADH (due to renal disease or drugs like lithium). In nephrogenic DI, ADH levels are normal or high, but the kidneys can’t respond.
  •  Key symptoms of DI include very large volumes of dilute urine and dehydration if fluid intake is not maintained. Patients often crave ice water. Unlike diabetes mellitus, there is no excess blood sugar in DI (urine is bland, hence “insipidus”).
  •  Diagnosis: Water deprivation test is the classic diagnostic tool. In this test, water intake is withheld to see if the patient’s urine will concentrate. In DI, the urine remains abnormally dilute despite dehydration. Giving desmopressin (synthetic ADH) after water deprivation will differentiate the types: in central DI, desmopressin will concentrate the urine (because it replaces the missing ADH); in nephrogenic DI, desmopressin will have minimal effect (kidneys still can’t respond).
  •  Treatment: For central DI, desmopressin is the treatment of choice (replaces ADH and reduces urine output). For nephrogenic DI, treat the underlying cause if possible (e.g. stop offending drugs), and measures like a low-salt/protein diet, thiazide diuretics or NSAIDs can help reduce urine volume.

Prolactinoma

  •  A prolactinoma is a benign pituitary adenoma that secretes excessive prolactin. It is the most common type of functional pituitary tumor.
  •  Elevated prolactin (hyperprolactinemia) causes symptoms primarily by suppressing GnRH, leading to low sex hormones. In women, prolactinoma often causes galactorrhea (milky nipple discharge not related to breastfeeding) and amenorrhea (loss of menstrual periods). Women may also have infertility. In men, it can cause low libido, erectile dysfunction, and sometimes breast enlargement (gynecomastia); men often present later, as they lack the early menstrual clues.
  •  Large prolactinomas (macroadenomas) can produce mass effect symptoms. Patients may experience headaches and bitemporal hemianopsia (loss of peripheral vision) due to the tumor pressing on the optic chiasm. Compression of normal pituitary tissue can also cause hypopituitarism (leading to fatigue, adrenal insufficiency, hypothyroidism, etc., due to loss of other hormones).
  •  Diagnosis: Very high blood prolactin levels suggest prolactinoma (after ruling out other causes of high prolactin such as medications or hypothyroidism). An MRI of the brain/pituitary confirms the presence of a pituitary tumor.
  •  Treatment: First-line treatment is medical therapy with dopamine agonists such as bromocriptine or cabergoline. Dopamine inhibits prolactin release, so these drugs shrink the tumor and restore normal prolactin levels, often improving symptoms. Surgery (transsphenoidal resection) is usually reserved for cases that fail medical therapy or have significant compression of nearby structures.

Acromegaly

  •  Acromegaly is caused by excessive growth hormone (GH) secretion in adults, usually from a GH-secreting pituitary adenoma (a type of pituitary tumor). If the condition occurs in children or adolescents before growth plates close, it causes gigantism (excessive linear growth).
  •  Symptoms and signs develop gradually. Patients have enlargement of the hands and feet (ring or shoe size increases), coarse facial features (enlarged jaw, nose, frontal bones), spaced-out teeth (due to jaw growth), and soft tissue swelling (for example, enlarged tongue and deep voice from larynx enlargement). They often suffer from joint pain (arthralgias) and excessive sweating. Organ enlargement (organomegaly), including the heart (which can lead to hypertension and heart failure), can occur in long-standing cases.
  •  Metabolic effects: GH antagonizes insulin, so acromegaly can cause insulin resistance or diabetes mellitus (GH is diabetogenic). Patients may have symptoms of high blood sugar or even be diagnosed with type 2 diabetes due to chronic GH excess.
  •  Diagnosis: The best initial test is an insulin-like growth factor 1 (IGF-1) level, which will be elevated (IGF-1 is produced by the liver under GH stimulation and levels are more constant than GH levels). The definitive test is a GH suppression test: normally, an oral glucose load should suppress GH release, but in acromegaly, GH levels remain high despite glucose. MRI imaging of the pituitary is then used to locate and assess the size of the adenoma.
  •  Treatment: The primary treatment is transsphenoidal surgical removal of the pituitary tumor. If surgery cannot remove all tumor or is contraindicated, medical therapy is used: somatostatin analogs (octreotide or lanreotide) can suppress GH release, and a GH receptor antagonist (pegvisomant) can block effects of GH. Radiation therapy is another option if needed. Successful treatment leads to improved symptoms and decreases the risk of complications (like cardiovascular disease).

Pituitary Apoplexy

  •  Pituitary apoplexy is a sudden hemorrhage or infarction of the pituitary gland, typically occurring in a pre-existing pituitary adenoma. It results in an abrupt loss of pituitary function and neurosurgical emergency.
  •  Presentation: Patients often present with a sudden, severe headache (often described as the “worst headache of my life”), visual disturbances (such as double vision or acute loss of peripheral vision) due to pressure on the optic chiasm or cranial nerves, and signs of acute hormonal deficiencies. Hypotension, collapse, and acute adrenal insufficiency can occur because the pituitary suddenly stops producing ACTH (leading to cortisol deficiency). There may also be nausea, vomiting, and altered mental status if intracranial pressure increases.
  •  On examination, ophthalmoplegia (eye movement palsies) may be seen if the hemorrhage compresses the cranial nerves in the cavernous sinus (affecting CN III, IV, VI). If not recognized and treated, it can lead to permanent vision loss and chronic hypopituitarism.
  •  Management: This is a medical emergency. Immediate high-dose glucocorticoid therapy (IV hydrocortisone) is given to treat life-threatening cortisol deficiency. Prompt neurosurgical decompression (transsphenoidal surgery) may be required to relieve pressure and remove the hemorrhagic tumor. Supportive care in an ICU is often needed.
  •  Long-term, patients may require lifelong hormone replacement if pituitary function does not recover (e.g. thyroid hormone, sex steroids, cortisol, depending on which axes are affected). Early treatment significantly improves outcomes in pituitary apoplexy.

Thyroid Disorders

  • Hypothyroidism: A condition of thyroid hormone deficiency resulting in a slowed metabolic state.
    •  Causes: The most common cause in iodine-sufficient areas is Hashimoto thyroiditis (autoimmune destruction of the thyroid). Other causes include iodine deficiency (in regions lacking iodine), thyroid surgery or radioiodine treatment, certain medications, or congenital thyroid dysgenesis.
    •  Symptoms: Everything “slows down.” Patients experience fatigue, weight gain despite poor appetite, cold intolerance, dry skin and hair loss, constipation, and slowed heart rate (bradycardia). They may have memory impairment or depression. Physical exam can show a goiter (if thyroid is enlarged, as in Hashimoto’s early stage) or an atrophic thyroid (late-stage Hashimoto’s). Severe prolonged hypothyroidism can lead to myxedema — puffiness of the face and tissues due to mucopolysaccharide deposition (myxedema coma is a life-threatening extreme form of hypothyroidism).
    •  Lab findings: Low free T4 (and T3) levels. In primary hypothyroidism, TSH is high (the pituitary is trying to stimulate the thyroid). In secondary (pituitary) hypothyroidism, TSH is low or normal (and other pituitary hormone deficiencies may be present).
    •  Treatment: Thyroid hormone replacement with levothyroxine (synthetic T4) is the standard. Doses are adjusted until TSH (or T4 levels in secondary cases) normalize. Improvement in symptoms occurs over weeks to months once proper levels are restored.
  •  Hyperthyroidism (Thyrotoxicosis): A condition of excess thyroid hormones resulting in an accelerated metabolic state.
    •  Causes: The most common cause is Graves’ disease (autoimmune hyperthyroidism where antibodies stimulate the TSH receptor, causing diffuse thyroid overactivity). Other causes include toxic multinodular goiter or toxic adenoma (autonomous thyroid nodules producing hormone), early phase of subacute thyroiditis (transient release of thyroid hormone), and rare TSH-secreting pituitary adenomas (secondary hyperthyroidism). Overconsumption of thyroid hormone (factitious hyperthyroidism) is another cause.
    •  Symptoms: Everything “speeds up.” Patients have weight loss despite increased appetite, heat intolerance (feel overly warm), sweating, nervousness, irritability, insomnia, tremors, and a rapid heartbeat (tachycardia) or heart palpitations (can lead to atrial fibrillation in some cases). They may have frequent bowel movements or diarrhea.
    •  Signs: The thyroid gland is often enlarged (goiter). In Graves’ disease specifically, unique features can be present: exophthalmos (bulging eyes) and pretibial myxedema (thickened skin over the shins), caused by autoimmune tissue reactions. Hand tremor and hyperreflexia can be noted on exam.
    •  Lab findings: High free T4 (and T3). In primary hyperthyroidism (like Graves’ or toxic nodules), TSH is suppressed (very low) due to negative feedback. In the rare case of secondary hyperthyroidism (TSH-secreting pituitary tumor), TSH will be high along with high T4/T3.
    •  Treatment: Management aims to reduce thyroid hormone levels and alleviate symptoms. Beta-blockers (e.g. propranolol) are often used first to control adrenergic symptoms like tremor and palpitations. Antithyroid medications such as methimazole (or propylthiouracil, PTU, in certain cases like pregnancy) are used to reduce hormone synthesis. Definitive treatment can be achieved with radioactive iodine ablation (which destroys overactive thyroid tissue) or surgical thyroidectomy, especially if a large goiter or suspicion of cancer. Graves’ ophthalmopathy may require additional therapies (steroids or orbital decompression) if severe.

Euthyroid Sick Syndrome

  •  Euthyroid Sick Syndrome, or non-thyroidal illness syndrome, refers to abnormal thyroid function tests seen in patients with a serious illness, despite a clinically normal thyroid. The body transiently adjusts hormone levels during illness.
  •  Typical pattern: Low T3 is most common (called “low T3 syndrome” – due to reduced conversion of T4 to T3 in peripheral tissues during illness). T4 may be low or normal, and TSH is usually normal or slightly low. In severe or prolonged illness, T4 can also drop (low T3 and T4, with low or normal TSH).
  •  Patients with euthyroid sick syndrome do not usually have obvious symptoms of thyroid disease – the abnormal labs are due to the illness’s effects on hormone metabolism. For example, a hospitalized patient with sepsis might have low T3/T4 but these will normalize after recovery.
  •  Clinical approach: Recognize this pattern so as not to misdiagnose hypothyroidism. Thyroid hormone treatment is not indicated in euthyroid sick syndrome. The correct approach is to treat the underlying illness and re-check thyroid function once the patient has recovered. Only if thyroid labs remain abnormal after recovery should primary thyroid disease be considered.

Thyroid Nodules

  •  Thyroid nodules are lumps or growths in the thyroid gland. They are very common and often asymptomatic, discovered on exam or incidentally on imaging. The main concern with a nodule is whether it might be thyroid cancer (though most nodules are benign).
  •  Initial evaluation: Check a TSH level and perform a thyroid ultrasound. TSH helps guide further testing: if TSH is low, the nodule might be producing thyroid hormone (a “hot” nodule). If TSH is normal or high, or if there are high-risk features, further workup is needed.
  •  If TSH is suppressed (low), a radioactive iodine uptake scan is often done. A nodule that takes up radioiodine (“hot nodule”) and produces hormone is usually benign (autonomous adenoma or toxic nodule). A nodule that does not take up iodine (“cold nodule”) could be hypo-functioning and has a higher risk of being malignant.
  •  Ultrasound is the best imaging to characterize thyroid nodules. Features that raise suspicion for malignancy include: microcalcifications, irregular or blurred margins, taller-than-wide shape on imaging, solid composition (as opposed to cystic), and increased blood flow. The size of the nodule is also important (greater than 1–1.5 cm, especially if solid, often warrants further evaluation).
  •  Fine-needle aspiration (FNA) biopsy is the definitive step to evaluate thyroid nodules for cancer. Indications for FNA include nodules above a certain size threshold (typically >1 cm if suspicious ultrasound features, or >1.5-2 cm if no suspicious features) or any nodule with significantly suspicious ultrasound characteristics regardless of size. The FNA is a minimally invasive procedure to obtain cells for cytology.
  •  The vast majority of thyroid nodules are benign (e.g. colloid nodules or benign follicular adenomas). If cancer is present, the most common thyroid cancer is papillary carcinoma, which has an excellent prognosis. Other types (follicular, medullary, anaplastic thyroid carcinoma) are less common. Management of a malignant nodule generally involves surgical removal of the thyroid (partial or total thyroidectomy) often followed by radioactive iodine for certain types.

Adrenal Disorders

  •   Cushing’s Syndrome: Refers to the clinical state of excess cortisol exposure.
    •  Etiologies: Can be exogenous (due to taking glucocorticoid medications long-term, which is the most common overall cause) or endogenous. Endogenous Cushing’s can be ACTH-dependent or ACTH-independent. Cushing’s disease is a specific term for an ACTH-secreting pituitary adenoma causing cortisol excess (an ACTH-dependent Cushing’s). Other causes include an adrenal cortisol-producing tumor (ACTH-independent) or ectopic ACTH production (e.g. small cell lung carcinoma making ACTH).
    •  Clinical features: Cortisol excess causes weight gain (especially central obesity; thin limbs with fat concentrated in abdomen), a round “moon face,” and a “buffalo hump” (fat pad on upper back/neck). Skin changes are common: purple striae on the abdomen (due to skin thinning and stretching), easy bruising, and slow wound healing. Patients develop hypertension, high blood sugar (cortisol induces insulin resistance, sometimes causing diabetes), and muscle weakness (from muscle protein breakdown). Osteoporosis can occur with chronic cortisol excess. There are often psychological effects (mood swings, depression or euphoria). Women may have menstrual irregularities and signs of androgen excess (cortisol excess often comes with some androgen excess from adrenals).
    •  Diagnosis: If Cushing’s is suspected, screening tests are done to confirm cortisol excess. Common tests: low-dose dexamethasone suppression test (normally dexamethasone suppresses cortisol production via feedback; in Cushing’s syndrome, cortisol remains inappropriately high), 24-hour urinary free cortisol (elevated in Cushing’s), or late-night salivary cortisol (cortisol fails to drop at night). Once confirmed, an ACTH level is checked to classify the cause: low ACTH points to an adrenal source (tumor), while high ACTH indicates an ACTH-dependent cause (pituitary or ectopic). High-dose dexamethasone suppression can further differentiate pituitary vs ectopic ACTH: a pituitary adenoma’s cortisol production may partially suppress on high-dose (because some feedback sensitivity remains), whereas an ectopic ACTH source will not suppress.
    •  Treatment: Depends on the cause. For exogenous steroid use, gradually taper off the steroids if feasible. For Cushing’s disease (pituitary adenoma), transsphenoidal surgery to remove the tumor is first-line. Adrenal tumors might require adrenalectomy. If surgery is not possible or as a bridge, medications can block cortisol production (ketoconazole, metyrapone, etc.). Patients require careful management and often need hormone replacement temporarily after tumor removal until the remaining normal axis recovers.
  • Addison’s Disease: Refers to primary adrenal insufficiency, where the adrenal cortex is destroyed or not functioning, leading to deficient production of cortisol (and often aldosterone).
    •  Causes: In developed countries, most commonly autoimmune adrenalitis (the body’s immune system attacks the adrenal cortex). Worldwide, tuberculosis of the adrenals is a leading cause. Other causes include metastatic cancer to adrenal glands, adrenal hemorrhage (e.g. Waterhouse-Friderichsen syndrome in meningococcemia), or genetic conditions. Secondary adrenal insufficiency (not called Addison’s) is due to pituitary ACTH deficiency (often from chronic steroid use causing suppression, or pituitary disease).
    •  Symptoms: Often vague and gradual. Fatigue, weakness, weight loss, and GI symptoms like nausea, vomiting, or abdominal pain are common. Patients may have dizziness or fainting from hypotension (low blood pressure). In primary Addison’s, lack of aldosterone leads to salt craving and electrolyte imbalances (low sodium, high potassium). Hyperpigmentation of the skin (diffuse tanning or darkening, especially in skin creases, scars, or gums) is a classic sign in primary Addison’s – this happens because high ACTH levels (from loss of feedback) stimulate melanocytes (ACTH shares a precursor with MSH). In secondary adrenal insufficiency, hyperpigmentation is absent (low ACTH) and aldosterone is usually normal (since aldosterone is regulated mainly by the kidney’s renin-angiotensin system).
    •  Diagnosis: Low morning cortisol level with high ACTH confirms primary adrenal insufficiency (Addison’s). An ACTH stimulation test (cosyntropin test) is often used: synthetic ACTH is given – in Addison’s disease the adrenal glands cannot produce cortisol, so cortisol remains low. In secondary adrenal insufficiency, ACTH will be low and cortisol low (and on ACTH stimulation test, cortisol may rise somewhat if adrenals are still intact but just under-stimulated chronically). Electrolytes show hyponatremia and hyperkalemia in primary Addison’s due to aldosterone deficiency.
    •  Treatment: Lifelong hormone replacement is required. Glucocorticoid replacement (usually oral hydrocortisone or prednisone) to replace cortisol, and mineralocorticoid replacement (fludrocortisone) to replace aldosterone in primary adrenal insufficiency. Patients are taught to increase their steroid doses during stress or illness (to mimic the normal stress response) – failing to do so can precipitate an adrenal crisis.
    •  Adrenal Crisis: This is an acute, life-threatening exacerbation of adrenal insufficiency, often triggered by stress (infection, trauma) or by sudden withdrawal of steroids. It presents with severe weakness, confusion, vomiting, abdominal pain, high fever, and shock (very low blood pressure). It requires emergency treatment with IV fluids and high-dose IV hydrocortisone. Prevention involves ensuring adequate steroid dosing during stress and patient education.
  • Primary Hyperaldosteronism (Conn Syndrome): An adrenal disorder where the adrenal cortex (zona glomerulosa) produces too much aldosterone independent of normal regulation.
    •  Cause: Often due to an aldosterone-producing adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia.
    •  Effects: Excess aldosterone causes the kidneys to retain sodium and water (leading to hypertension) and excrete potassium (leading to hypokalemia). Patients may have high blood pressure that is difficult to control and symptoms of low potassium such as muscle weakness, cramps, or even arrhythmias. They often have metabolic alkalosis (due to hydrogen ion loss alongside potassium).
    •  Diagnosis: High aldosterone levels with low renin (renin is suppressed due to feedback from hypertension/volume expansion). An aldosterone-renin ratio test is a screening tool. Confirmatory tests (like saline infusion test or fludrocortisone suppression test) show inappropriate aldosterone secretion despite measures that should suppress it. Adrenal CT scan can localize an adenoma vs hyperplasia.
    •  Treatment: For a single adenoma, surgical removal (adrenalectomy) can cure the hypertension and abnormalities. If bilateral hyperplasia or surgery not an option, medical therapy with aldosterone antagonists (spironolactone or eplerenone) is used to block aldosterone’s effects. Managing blood pressure and potassium is key.
  • Pheochromocytoma: A tumor of the adrenal medulla (or extra-adrenal paraganglia) that secretes catecholamines (epinephrine and norepinephrine), leading to episodic symptoms. Although technically a tumor of the medulla (part of the sympathetic nervous system), it’s often discussed with adrenal disorders.
    •  Features: Classic triad of episodes of headache, sweating, and tachycardia (fast heart rate) with hypertension. Blood pressure spikes can be severe and intermittent. Patients often appear pale during episodes (vasoconstriction). Triggers for episodes can include stress, certain foods (tyramine-containing like aged cheese or wine), or positional changes, but they may occur spontaneously.
    •  Diagnosis: Elevated levels of catecholamine breakdown products in the urine or blood confirm excess catecholamines (for example, high metanephrines or vanillylmandelic acid (VMA) levels). Imaging (CT/MRI of adrenal glands) is used to locate the tumor. Pheochromocytomas are associated with certain genetic conditions (MEN 2, VHL, NF1), so those might be considered.
    •  Treatment: The tumor needs to be removed surgically, but proper medical preparation is critical. Patients are treated with alpha-adrenergic blockade (typically phenoxybenzamine, a non-selective alpha blocker) for 7-14 days prior to surgery to control blood pressure and prevent intraoperative hypertensive crises. After adequate alpha blockade, beta blockers are often added to control heart rate (but never start beta blocker before alpha blockade, as unopposed alpha stimulation could worsen BP). Then surgical resection (adrenalectomy) is performed. With successful removal, hypertension and symptoms often resolve, but lifelong follow-up is needed as these tumors can recur or be part of hereditary syndromes.

 

 

 

Adrenal Insufficiency (Addison’s Disease)

  •  Etiologies: Primary adrenal insufficiency (Addison’s) is most often autoimmune (in developed countries), with adrenal destruction leading to loss of cortisol, aldosterone, and adrenal androgens. Other causes include infections (TB, HIV, fungal), hemorrhage/infarction (e.g. Waterhouse-Friderichsen syndrome in meningococcemia causing adrenal hemorrhage), or drugs (e.g. ketoconazole suppressing adrenal function). Secondary adrenal insufficiency results from pituitary or hypothalamic disease (tumor, infarction, Sheehan syndrome) or chronic exogenous steroid use leading to HPA axis suppression (most common cause of secondary AI).
  •  Clinical Features: Addison’s disease typically presents with fatigue, weakness, weight loss, hypotension (especially orthostatic), and hyperpigmentation of skin/mucosa (due to high ACTH levels stimulating melanocytes). Patients often have hyponatremia and hyperkalemia from aldosterone deficiency (salt-wasting causing cravings for salt). Primary AI can also cause GI symptoms (abdominal pain, nausea), sugar craving (due to glucocorticoid deficiency causing hypoglycemia), and vitiligo (associated autoimmune skin depigmentation). In secondary adrenal insufficiency (pituitary ACTH deficiency), there is no hyperpigmentation (low ACTH) and no hyperkalemia (aldosterone is typically normal because RAAS intact); hypotension and hyponatremia may be milder than in primary.
  •  Diagnosis: Initial evaluation is an 8 AM plasma cortisol level. A very low morning cortisol (e.g. < 3 µg/dL) is strongly suggestive of AI, while a cortisol > 18 µg/dL essentially rules it out. If cortisol is low or indeterminate, perform an ACTH (cosyntropin) stimulation test: synthetic ACTH is given IV, and cortisol is measured at 30 and 60 minutes. Failure of cortisol to rise significantly (peak cortisol remains < 18 µg/dL) confirms adrenal insufficiency. Measure plasma ACTH concurrently to differentiate causes: in primary Addison’s, ACTH is elevated (often > 50–60 pg/mL due to loss of feedback), whereas in secondary AI, ACTH is low or inappropriately normal. Additional findings in primary AI include high plasma renin (due to low aldosterone) and the presence of adrenal autoantibodies (in autoimmune Addison’s). Tip: Always consider adrenal insufficiency in refractory hypotension or unexplained hypoglycemia; cosyntropin test is the diagnostic gold standard.
  •  Management: Glucocorticoid replacement is lifesaving – typically oral hydrocortisone (physiologic split doses) or prednisone. Mineralocorticoid replacement with fludrocortisone is required in primary AI (to replace aldosterone) but not in secondary AI (intact RAAS). Educate patients to increase steroid doses during stress (illness, surgery) to prevent crisis. DHEA supplementation can be considered in women with low energy or mood despite cortisol replacement (adrenal androgens are low in Addison’s). Monitor treatment by clinical symptoms and ACTH levels (in primary AI, ACTH should decline toward normal with adequate steroid dosing).
  •  Adrenal Crisis: An acute adrenal crisis is a life-threatening emergency precipitated by stress (infection, surgery) in an Addisonian patient or sudden steroid withdrawal. It presents with shock (hypotension, tachycardia), severe weakness, abdominal pain, vomiting, fever, and confusion. Treat immediately – do not wait for labs: administer IV hydrocortisone (100 mg bolus, then q6h), aggressive IV fluids (support blood pressure and volume), correct hypoglycemia and electrolyte imbalances. Identify and treat the precipitating cause (e.g. infection) and provide stress-dose steroids during acute illness. Clinical pearl: In an undifferentiated shock, if adrenal crisis is suspected, give IV dexamethasone (won’t interfere with cortisol assay) while awaiting diagnostic confirmation.

 Cushing’s Syndrome (Hypercortisolism)

  • Causes: Cushing’s syndrome refers to the clinical effects of excess cortisol. The most common cause overall is exogenous glucocorticoid therapy (iatrogenic Cushing’s). Endogenous causes include Cushing’s disease (an ACTH-secreting pituitary adenoma – the most common endogenous cause), ectopic ACTH production (e.g. small cell lung carcinoma, bronchial carcinoid), and cortisol-secreting adrenal tumors (adenoma or carcinoma).
  • Clinical Features: Classic features are central obesity (weight gain with thin extremities), “moon facies” (rounded face), buffalo hump (fat pad on upper back), and purple striae (wide violaceous stretch marks, especially on abdomen, due to collagen breakdown and thinning skin). Patients often have proximal muscle weakness (difficulty climbing stairs or rising from a chair), easy bruising, hirsutism (excess hair) and acne (from androgen co-secretion), osteoporosis (from bone resorption), hypertension, and hyperglycemia (can cause insulin resistance or new-onset diabetes). Neuropsychiatric symptoms (mood changes, insomnia) are also common.
  • Diagnosis (Screening): If Cushing’s is suspected (e.g. by physical stigmata or unexplained rapid weight gain with hypertension and diabetes), perform an initial screening test for hypercortisolism. Accepted screening tests (need at least one abnormal) include:
    •  Low-dose dexamethasone suppression test: administer 1 mg dexamethasone at night (11 PM) and measure serum cortisol the next morning (~8 AM). In normal individuals, cortisol is suppressed to < 5 µg/dL; failure to suppress (morning cortisol remains elevated > 5 µg/dL) indicates Cushing’s syndrome.
    •  24-hour urinary free cortisol (will be high in Cushing’s; requires collection over 24h).
    •  Late-night salivary cortisol (will be elevated in Cushing’s due to loss of normal diurnal drop at night).
  • Diagnosis (Differentiation): Once hypercortisolism is confirmed by screening, measure plasma ACTH to classify:
    •  If ACTH is low (suppressed), this suggests an ACTH-independent Cushing’s (likely an adrenal tumor producing cortisol autonomously or exogenous steroid use). Proceed to adrenal imaging (CT/MRI) to locate adrenal lesion.
    •  If ACTH is normal or high, it is ACTH-dependent Cushing’s (either pituitary or ectopic ACTH). To distinguish pituitary vs ectopic source, use a high-dose dexamethasone suppression test: give high-dose (8 mg) dexamethasone overnight or 2 mg every 6 hours for 48h, and then measure cortisol. Pituitary Cushing’s disease will typically show significant suppression of cortisol (because pituitary adenoma retains some feedback sensitivity), often >50% reduction in cortisol or drop in urinary cortisol, whereas ectopic ACTH (e.g. from a tumor) will not suppress (cortisol stays high). Additionally, pituitary MRI can identify an adenoma, and an ectopic source may be sought with imaging (CT chest/abdomen for lung or other tumors). CRH stimulation test is another tool: pituitary ACTH tumors usually increase ACTH/cortisol with CRH, whereas ectopic sources do not respond.
  • Management: The definitive treatment is to remove the source of excess cortisol. For Cushing’s disease (pituitary adenoma), first-line treatment is transsphenoidal surgical resection of the adenoma. For an adrenal adenoma or carcinoma, adrenalectomy is indicated. Ectopic ACTH-producing tumors should be resected if possible (e.g. small cell lung cancer usually treated medically, but other tumors like carcinoid can be removed). Patients on exogenous steroids should have their dose tapered gradually if clinically feasible to allow recovery of the HPA axis. In cases where surgery is not possible or while awaiting effect, medical therapy to block cortisol can be used (e.g. ketoconazole or metyrapone to inhibit adrenal cortisol synthesis; or mifepristone – a glucocorticoid receptor blocker – in refractory cases). Post-surgery, patients may require temporary stress-dose steroids and gradual steroid taper until normal cortisol production returns. Pearl: Long-term uncontrolled Cushing’s leads to serious morbidity (cardiovascular disease, infections, etc.), so prompt diagnosis and management improve outcomes.

 

Primary Hyperaldosteronism (Conn’s Syndrome)

  •  Overview: Primary hyperaldosteronism is autonomous overproduction of aldosterone by the adrenal glands, leading to hypertension and hypokalemia. It is most commonly caused by an aldosterone-producing adrenal adenoma (Conn’s syndrome) or bilateral adrenal hyperplasia. (Rarely, an adrenal carcinoma or genetic familial hyperaldosteronism is the cause.) Secondary hyperaldosteronism, by contrast, is due to increased renin from extra-adrenal causes (e.g. renal artery stenosis, diuretic use, heart failure, cirrhosis) leading to high renin and high aldosterone.
  •  Clinical Clues: Suspect primary hyperaldosteronism in a patient with refractory hypertension (especially at a young age or requiring multiple drugs) or hypertension with unexplained hypokalemia. Symptoms of hypokalemia may include muscle weakness, cramps, or even periodic paralysis, but many patients are normokalemic. Metabolic alkalosis is often present (due to H+ loss in exchange for Na+). Patients usually lack significant edema due to aldosterone escape (renal tubules compensate to avoid massive fluid retention), but mild hypernatremia can occur.
  •  Screening and Diagnosis: The best initial test is the plasma aldosterone-to-renin ratio (ARR). This should be done after correcting any hypokalemia (as low K suppresses aldosterone). A high ARR (e.g. ARR > 20–30) with an elevated plasma aldosterone (for example, aldosterone level > 15 ng/dL) suggests primary hyperaldosteronism. In primary hyperaldo, aldosterone is high and renin is low (due to feedback suppression); in secondary causes, both aldo and renin are high. If screening is positive, confirmatory testing is required: common confirmatory tests include salt suppression tests such as oral high-salt diet or IV saline loading – normally, high salt intake should suppress aldosterone, but in primary hyperaldo, aldosterone remains inappropriately elevated. For example, failure to suppress aldosterone (e.g. 24-hour urine aldosterone > 12 µg on high salt diet, or plasma aldosterone > 10 ng/dL after saline infusion) confirms the diagnosis. Once confirmed, localize the source: adrenal CT imaging is performed to look for an adenoma vs bilateral enlargement. Often adrenal vein sampling is done (especially in patients >35) to distinguish unilateral adenoma (one side with high aldosterone output) from bilateral adrenal hyperplasia, since small tumors might not be obvious on imaging.
  •  Treatment: For a unilateral aldosterone-producing adenoma, surgical removal (adrenalectomy) can be curative (along with perioperative blood pressure management). If surgery is not an option or the cause is bilateral adrenal hyperplasia, medical therapy is used: aldosterone antagonists like spironolactone (a potassium-sparing diuretic) are first-line. Eplerenone is an alternative selective aldosterone blocker with fewer side effects (less gynecomastia) if spironolactone is not tolerated. Treating hyperaldosteronism can significantly improve blood pressure control and reduce cardiovascular risk. Clinical pearl: Primary hyperaldo should be suspected in hypertensive patients with low plasma renin activity and unexplained hypokalemia (though K can be normal in ~30% cases). Also, consider screening in hypertensive patients with adrenal incidentalomas or those with hypertension and a family history of early strokes.

 

Pheochromocytoma

  •  Overview: Pheochromocytomas are catecholamine-secreting tumors arising from chromaffin cells of the adrenal medulla (often unilateral). Extra-adrenal catecholamine-secreting tumors (in paraganglia) are called paragangliomas. Although rare, pheochromocytoma is an important cause of secondary hypertension and can be lethal if unrecognized. Remember the associations: they can occur as part of MEN 2A/2B syndromes (with medullary thyroid carcinoma and hyperparathyroidism in MEN2A), and other genetic syndromes (VHL, NF1). Classically, pheos follow the “10% rule”: ~10% are bilateral, 10% are extra-adrenal, 10% are malignant, and 10% familial (though in reality, familial cases are >20%).
  •  Clinical Features: Pheochromocytoma classically presents with episodic symptoms: episodes of paroxysmal hypertension (though some have sustained HTN), severe headaches, sweating, and tachycardia/palpitations. This triad (headache, sweating, tachycardia) with hypertension should prompt evaluation for pheo. Patients may also experience tremor, anxiety, pallor, chest pain, or abdominal pain during attacks. Episodes can be precipitated by stress, exercise, bending, or certain foods (e.g. tyramine) or medications that trigger catecholamine release.
  •  Diagnosis: The best initial test is to measure catecholamine metabolites. Plasma free metanephrines (highly sensitive) can be drawn — if elevated (especially >3x normal), it strongly suggests pheochromocytoma. Alternatively, a 24-hour urine collection for metanephrines and catecholamines can be done (useful if pre-test probability is moderate or to confirm plasma results). If biochemical testing is positive, locate the tumor with imaging: typically an MRI or CT scan of the abdomen (adrenal glands) is done. If those are normal and suspicion remains, consider imaging for extra-adrenal paragangliomas (e.g. MIBG scintigraphy or DOTATATE PET for occult tumors). In certain cases, a clonidine suppression test may help differentiate true pheo from other causes of high catecholamines (clonidine will not suppress catecholamine levels in pheochromocytoma).
  •  Management: The definitive treatment is surgical resection of the tumor, but proper pre-operative management is critical to prevent catecholamine surge during surgery. Alpha-adrenergic blockade is the first step: patients are started on a long-acting alpha blocker such as phenoxybenzamine (non-selective α-blocker) or a selective α1-blocker (e.g. doxazosin) for at least 7-14 days pre-op. Achieve adequate α-blockade indicated by mild orthostatic hypotension and controlled blood pressure. After alpha blockade, beta-blockade is added if needed to control tachycardia (typically a few days before surgery, e.g. start propranolol or metoprolol) – never start a beta-blocker first (unopposed alpha stimulation could precipitate a hypertensive crisis). During surgery, have IV phentolamine (short-acting α-blocker) ready for blood pressure spikes. Post-operative, watch for hypotension (due to catecholamine drop) or hypoglycemia (due to high insulin levels after tumor removal). In metastatic or inoperable cases, medical management with alpha/beta blockers is used, and MIBG therapy or other targeted therapies may be considered. Pearl: Remember to screen for pheochromocytoma in patients with resistant hypertension with typical paroxysmal symptoms or in familial syndrome carriers. Also, avoid provoking hypertensive crises – if a pheo is known or suspected, never palpate aggressively or biopsy the adrenal mass before biochemical testing (risk of catecholamine surge).

 

Lipid Disorders (Hyperlipidemia Management)

  •   Screening & Risk Stratification: Lipid management for boards focuses on atherosclerotic cardiovascular disease (ASCVD) prevention. Adults should have a fasting lipid panel checked; guidelines emphasize treating based on risk categories rather than exact LDL targets. Four major patient groups benefit from statin therapy:
    1. Secondary prevention (Clinical ASCVD): Patients with established ASCVD (history of MI, angina, stroke/TIA, peripheral arterial disease, etc.) should be on a high-intensity statin (unless contraindicated) to reduce risk of recurrence.
    2. Severe hypercholesterolemia (LDL ≥ 190 mg/dL****):** These patients (often with familial hypercholesterolemia) get high-intensity statin therapy, regardless of other risk factors.
    3. Diabetes (age 40–75, LDL 70–189): All diabetics in this age range should at least be on a moderate-intensity statin. If the diabetic patient has additional risk factors or is >50 years old, consider high-intensity statin to further reduce risk.
    4. Primary prevention (no ASCVD, no diabetes, LDL 70–189): Use the 10-year ASCVD risk calculator. If 10-year risk ≥ 7.5%, initiate moderate-intensity statin (borderline cases 5–7.4% consider risk enhancers; if ≥ 20% risk, high-intensity is reasonable). Risk enhancers include family history of premature ASCVD, high-risk conditions (CKD, HIV, etc.), or biomarkers (e.g. Lp(a), high coronary calcium score).
  • Statin Intensity: High-intensity statins (e.g. atorvastatin 40-80 mg, rosuvastatin 20-40 mg) can lower LDL by ≥50%. Moderate-intensity statins (e.g. atorva 10-20, rosuva 5-10, simvastatin 20-40) lower LDL by ~30-50%. Know the common side effects: statins can cause hepatotoxicity (monitor LFTs; mild ALT rise is okay, but >3x ULN consider holding) and myopathy (muscle pain or weakness; rare rhabdomyolysis especially when combined with fibrates or certain medications). If a patient develops intolerable muscle aches on one statin, you can trial a different statin or lower dose; true statin intolerance may necessitate alternative therapies. Pearl: Statins are contraindicated in acute liver disease and pregnancy. For boards, remember that statins also provide plaque stabilization and mortality benefit beyond just lowering LDL.
  • Non-Statin Therapies: If LDL remains high despite maximally tolerated statin (especially in very high-risk patients like ASCVD + risk factors, or LDL still ≥ 70 on therapy), consider adding ezetimibe (which reduces cholesterol absorption in the gut) as a second-line. In familial hypercholesterolemia or very high-risk patients not at goal, PCSK9 inhibitors (injectable monoclonal antibodies like alirocumab or evolocumab) can further dramatically lower LDL. Other agents: Bile acid sequestrants (cholestyramine, colesevelam) lower LDL modestly but can cause GI side effects and increase triglycerides; niacin (vitamin B3) raises HDL and lowers TG modestly but is limited by flushing (preventable with aspirin) and risk of gout & hepatotoxicity; fibrates (e.g. fenofibrate, gemfibrozil) are primarily to lower triglycerides and raise HDL, used especially when TG are very high.
  • Hypertriglyceridemia: Mild-moderate TG elevation often accompanies metabolic syndrome. However, severe hypertriglyceridemia (TG > 500 mg/dL, and especially > 1000 mg/dL) poses a risk for acute pancreatitis. Management of very high TG includes lifestyle changes (low-fat diet, no alcohol, weight loss, better glycemic control in diabetics) and medications like fibrates (first-line) or high-dose omega-3 fish oils. Once TG are reduced (<500), focus can shift to LDL management if needed. In pancreatitis risk, reducing TG is the priority.
  • Clinical Clues: Tendon xanthomas (for example, on the Achilles tendon or extensor tendons of hands) or xanthelasma (yellow plaques on eyelids) are signs of longstanding high LDL, often familial hypercholesterolemia. Eruptive xanthomas (clusters of small red-yellow papules on elbows, knees, buttocks) indicate extremely high triglycerides. Pancreatitis in a patient with TG >1000 is a known complication. For exam purposes, if you see those clues, think of the corresponding lipid disorder. Always address secondary causes of dyslipidemia as well: hypothyroidism, uncontrolled diabetes (increases TG), nephrotic syndrome, cholestatic liver disease, alcohol use, and certain medications can all influence lipid levels.

 

Reproductive Endocrinology

  • Amenorrhea Workup: Amenorrhea is the absence of menstrual periods. Primary amenorrhea is when a girl has no menses by age 15 (with normal secondary sexual development) or by 13 (with no pubertal signs). Secondary amenorrhea is cessation of menses for >3 months in a woman who previously had regular cycles (or >6 months if cycles were irregular). The first step in any amenorrhea is to rule out pregnancy – always check a β-hCG test. If pregnancy is negative, evaluate for other causes: check TSH (hypothyroidism can cause menstrual irregularity) and prolactin level (hyperprolactinemia suppresses GnRH). If prolactin is elevated, address that (see below). If TSH and prolactin are normal, further workup depends on clinical context. Consider ovarian failure vs hypothalamic-pituitary causes vs outflow tract problems:
    •  If there are signs of estrogen deficiency (hot flashes, vaginal dryness) or the patient is age >40, suspect ovarian failure (menopause or premature ovarian insufficiency). In ovarian failure, FSH is elevated (loss of negative feedback). Autoimmune ovarian failure or chemotherapy are common causes of premature ovarian insufficiency.
    •  If there is a history of uterine instrumentation (like D&C) or infection, consider an outflow tract problem such as Asherman syndrome (intrauterine adhesions) – the uterus cannot shed lining.
    •  A useful tool is the progestin withdrawal test: give a course of progesterone (e.g. medroxyprogesterone for 10 days) then stop – if the endometrium has been primed by estrogen, withdrawal will cause bleeding. A positive withdrawal bleed indicates the patient has adequate estrogen (and an intact uterus) but is likely not ovulating (anovulation, seen in conditions like PCOS). No bleed after progesterone suggests either low estrogen levels (hypogonadism) or an outflow tract issue (uterine scarring or cervical stenosis).
    •  For primary amenorrhea with lack of secondary sexual characteristics, think of delayed puberty etiologies: hypergonadotropic hypogonadism (e.g. Turner syndrome – XO karyotype, ovarian streaks, high FSH) vs hypogonadotropic hypogonadism (e.g. Kallmann syndrome – GnRH deficiency with anosmia, low FSH/LH).
  • Polycystic Ovary Syndrome (PCOS): PCOS is a common cause of oligo-ovulation and hyperandrogenism in women of reproductive age. Diagnosis is clinical, often using Rotterdam criteria (need 2 of 3: irregular cycles (oligo- or amenorrhea due to anovulation), clinical or biochemical hyperandrogenism (hirsutism, acne, elevated testosterone/DHEA), and polycystic ovaries on ultrasound). Patients typically present with menstrual irregularities, hirsutism (excess hair on face/chest), acne, and often obesity and insulin resistance (acanthosis nigricans may be present). Lab findings can include an elevated LH:FSH ratio (often 2:1 or 3:1, though not in all cases), elevated androgens (testosterone, androstenedione), and ultrasound showing multiple small ovarian follicles. Management: First-line is lifestyle modification (diet, exercise, weight loss) which can restore ovulation. For menstrual regulation and hirsutism, combined oral contraceptive pills are a mainstay (provide estrogen/progestin to regulate cycles and reduce androgen levels). For hyperandrogenic symptoms, add spironolactone (an anti-androgen) to help with hirsutism (ensure contraception, as spironolactone is teratogenic). If fertility is desired, ovulation can be induced with medications like clomiphene citrate or letrozole (aromatase inhibitor) after weight loss; metformin is also used to improve insulin sensitivity and can help restore ovulation in some patients (metformin is particularly useful if there is glucose intolerance). PCOS patients should be screened and managed for metabolic complications: they have higher risk of type 2 diabetes (do an OGTT or fasting glucose), dyslipidemia, and endometrial hyperplasia (due to unopposed estrogen from anovulation – protect the endometrium with cyclic progestin or OCPs to prevent endometrial cancer). Pearl: In a young woman with irregular periods, obesity, and facial hair, PCOS is likely – but always rule out other causes of hyperandrogenism (e.g. check serum 17-OH progesterone to exclude late-onset congenital adrenal hyperplasia, and DHEA-S to exclude an adrenal tumor if virilization is extreme).
  • Hyperprolactinemia: Elevated prolactin can cause hypogonadism by suppressing GnRH. In women, it often presents as amenorrhea and galactorrhea (milky nipple discharge); in men, as low libido, erectile dysfunction, infertility, and sometimes gynecomastia. Common causes of hyperprolactinemia include prolactinoma (pituitary lactotroph adenoma), medications (especially antipsychotics like risperidone, metoclopramide, SSRIs, etc.), hypothyroidism (high TRH in primary hypothyroid stimulates prolactin release), and chest wall or spinal cord injury. Workup: check prolactin level – a very high level (e.g. > 200 ng/mL) strongly suggests a prolactinoma. Always check TSH as well, since hypothyroidism must be corrected if present. If prolactin is high without an obvious medication cause or hypothyroid, get a pituitary MRI to look for an adenoma. Treatment of prolactinoma: first-line is medical therapy with dopamine agonists – cabergoline or bromocriptine – which often shrink the tumor and normalize prolactin (cabergoline is preferred due to better efficacy and tolerance). Indications for surgery (transsphenoidal resection) include intolerant or refractory to medical therapy, very large tumors with vision loss (bitemporal hemianopsia from optic chiasm compression), or apoplexy. For medication-induced hyperprolactinemia, discontinuing or switching the offending drug is ideal if possible. Pearl: In a patient with amenorrhea and galactorrhea, always think of checking a pregnancy test (since pregnancy itself causes high prolactin) and then serum prolactin. Also remember that mild prolactin elevations (~30-100) can be from meds or hypothyroid, whereas levels >200 are usually a prolactinoma.
  • Male Hypogonadism: In men, hypogonadism presents with fatigue, decreased muscle mass, low libido, erectile dysfunction, and sometimes gynecomastia. Causes are divided into primary (testicular) vs secondary (pituitary/hypothalamic). In primary hypogonadism, the testes fail to produce testosterone, so testosterone is low but FSH/LH are high (hypergonadotropic). Causes include Klinefelter syndrome (47,XXY – testicular fibrosis, small firm testes, tall stature, gynecomastia), damage from radiation or chemotherapy, mumps orchitis, testicular torsion or trauma, and hemochromatosis (iron deposition in testes). In secondary hypogonadism, there is insufficient gonadotropin (LH/FSH) from the pituitary or hypothalamus (hypogonadotropic hypogonadism), so testosterone is low with low/normal LH/FSH. Causes include pituitary tumors (e.g. a large non-functioning adenoma compressing gonadotropes), hyperprolactinemia (prolactin inhibits GnRH), chronic steroid or opioid use, chronic illnesses, obesity (elevated estrogen from adipose can suppress axis), and genetic GnRH deficiency (e.g. Kallmann syndrome, associated with anosmia). Evaluation: check a morning total testosterone level (normal ~300–800 ng/dL; if < 300 ng/dL on two separate mornings, it’s low). Then check LH/FSH to differentiate primary vs secondary. Additional tests: serum prolactin (for pituitary tumor), iron studies (hemochromatosis), and pituitary MRI if central cause suspected (especially if there are other pituitary hormone deficiencies or visual field defects). Treatment: For men who do not desire fertility, testosterone replacement therapy (e.g. transdermal or intramuscular testosterone) can improve symptoms – but it’s contraindicated in prostate cancer and used cautiously in older men (monitor PSA, hematocrit as testosterone can cause erythrocytosis). If fertility is desired and it’s a secondary hypogonadism issue, treatments like gonadotropin injections or pulsatile GnRH can be used to induce spermatogenesis, or treat the underlying cause (e.g. remove tumor, treat hyperprolactinemia). Pearl: Always evaluate for reversible causes (like medications or hyperprolactinemia) before starting long-term testosterone. In Klinefelter syndrome, aside from testosterone therapy, patients may need fertility counseling (usually infertile) and screening for associated issues (breast cancer risk is slightly elevated, so some recommend monitoring for gynecomastia changes).

 

Diabetes Mellitus

  • Type 1 vs Type 2: Diabetes is a group of disorders characterized by chronic hyperglycemia. Type 1 DM is an autoimmune destruction of pancreatic beta-cells leading to absolute insulin deficiency. It often presents in childhood or young adulthood with polyuria, polydipsia, weight loss, and DKA as a common initial presentation. Type 1 patients are usually lean and prone to ketosis; they require insulin for survival and often have other autoimmune diseases (thyroid, celiac, etc.). Type 2 DM is caused by insulin resistance and relative insulin secretory defect. It typically occurs in adults (though now also adolescents) with risk factors like obesity, sedentary lifestyle, and genetic predisposition. Type 2 often presents with gradual symptoms or is discovered on screening; DKA is uncommon at diagnosis (but HHS can occur). These patients often have metabolic syndrome (central obesity, hypertension, dyslipidemia). Insulin levels may be high early on (compensatory) but diminish over time as beta-cell function declines. LADA (latent autoimmune diabetes in adults) is essentially type 1 presenting later in life, often initially misdiagnosed as type 2.
  • Diagnostic Criteria: Diabetes is diagnosed by any of the following (on two separate occasions if asymptomatic):
    •  Fasting plasma glucose ≥ 126 mg/dL**** (after an 8-hour fast).
    •  **Hemoglobin A1c ≥ 6.5%****.
    •  Oral glucose tolerance test (75g OGTT): 2-hour glucose ≥ 200 mg/dL.
    •  Random plasma glucose ≥ 200 mg/dL with classic hyperglycemia symptoms (polyuria, polydipsia, unexplained weight loss) – this can be diagnostic with just one occurrence if symptomatic.

    A result in the diabetic range should be confirmed on a separate day if the patient is asymptomatic. Pre-diabetes is indicated by an A1c of 5.7–6.4%, fasting glucose 100–125 mg/dL (impaired fasting glucose), or 2-hr OGTT 140–199 mg/dL (impaired glucose tolerance). Normal is A1c ~5.6% or below, fasting <100. Pearl: Screening for diabetes is recommended for all adults ≥ 35 (ADA 2023; used to be 45) or any adult with BMI ≥ 25 (≥23 in Asians) plus an additional risk factor (like hypertension, dyslipidemia, family history, or gestational diabetes history). Early identification of pre-diabetes allows intervention with lifestyle changes to prevent progression.

  • Management Overview: The foundation of diabetes management is lifestyle modification – diet (carbohydrate-controlled, heart-healthy diet) and regular exercise (at least 150 min/week) which can dramatically improve glycemic control and weight. For Type 1 DM, insulin replacement is required (multiple daily injections or insulin pump); there is no role for oral agents. For Type 2 DM, first-line pharmacotherapy is metformin (unless contraindicated). Metformin (a biguanide) decreases hepatic gluconeogenesis and improves insulin sensitivity – it aids weight loss or is weight neutral, does not cause hypoglycemia, and has proven cardiovascular benefits. It is contraindicated in significant renal impairment (eGFR <30) or advanced heart failure due to risk of lactic acidosis. If glycemic targets are not met with metformin and lifestyle, additional medications are added based on patient factors. The ADA recommends a patient-centered approach: consider ASCVD, heart failure, chronic kidney disease, need for weight loss, risk of hypoglycemia, and cost when choosing second-line agents. Targets: Generally aim for HbA1c < 7% in most nonpregnant adults to reduce microvascular complications. A stricter goal (6.5%) may be used in younger healthy patients, whereas a looser goal (≤8%) is reasonable in older patients or those with comorbidities to avoid hypoglycemia. Blood pressure control (< 130/80 mmHg in diabetics, per ACC/AHA) and statin therapy are also crucial parts of diabetes care (because of high cardiovascular risk).
  •  Diabetes Medications: Apart from metformin, there are several classes:
    •  Sulfonylureas (e.g. glipizide, glyburide): Increase pancreatic insulin secretion. They are effective at lowering glucose but can cause hypoglycemia (especially glyburide) and weight gain. Used as add-on or if metformin not tolerated; inexpensive but risk of sulfa allergy.
    •  Thiazolidinediones (TZDs, e.g. pioglitazone, rosiglitazone): Improve insulin sensitivity in peripheral tissues via PPAR-γ activation. They take weeks to work. Side effects: weight gain, edema (can precipitate heart failure – avoid in NYHA class III/IV HF), and risk of osteoporosis and fractures; pioglitazone may have a slight risk of bladder cancer with long-term use.
    •  GLP-1 receptor agonists (e.g. liraglutide, semaglutide, exenatide): Injectable (some new oral forms of semaglutide exist) analogues of incretin hormone GLP-1. They increase glucose-dependent insulin secretion, slow gastric emptying, and promote satiety. Benefits: significant weight loss and reduction in cardiovascular events (especially liraglutide, semaglutide) – great choice in diabetics who are obese or have ASCVD. They do not usually cause hypoglycemia by themselves. Side effects: GI upset (nausea/vomiting common initially), and risk of pancreatitis. Contraindicated in patients with a history of medullary thyroid carcinoma or MEN2 (risk of C-cell hyperplasia in rodents).
    •  DPP-4 inhibitors (e.g. sitagliptin, linagliptin): Oral meds that prevent breakdown of endogenous incretins (like GLP-1), leading to increased insulin release and decreased glucagon. They are weight-neutral and generally well-tolerated (very low hypoglycemia risk), but their efficacy in lowering A1c is modest. Few side effects, though rare cases of pancreatitis or joint pain have been reported.
    •  SGLT2 inhibitors (e.g. empagliflozin, canagliflozin, dapagliflozin): Oral meds that inhibit sodium-glucose co-transporter in the kidney, causing glycosuria and lowering blood glucose. They also cause a modest weight loss and blood pressure reduction. Crucially, they have been shown to improve cardiovascular outcomes and reduce progression of CKD and heart failure hospitalizations (empagliflozin, dapagliflozin in particular). They do not cause hypoglycemia by themselves. Side effects: increased risk of UTIs and genital yeast infections (from glucosuria), can cause dehydration (osmotic diuresis), euglycemic DKA (rare), and caution in advanced kidney disease (less effective when GFR low). Canagliflozin has a slight risk of amputations and fractures in some studies.
    •  Insulin therapy: Required for all Type 1 and often necessary in Type 2 as beta-cell function declines or if glucose is very high (A1c >10% or glucose >300, initial insulin can be used). Insulin regimens include basal-bolus (long-acting basal insulin once daily like glargine or detemir, plus rapid-acting analogs like lispro/aspart before meals for prandial coverage) which most closely mimics physiologic insulin, or twice-daily mixed insulin regimens (e.g. NPH + regular). In Type 2, sometimes a single long-acting basal insulin at night is added to oral meds for control. Key side effect of insulin is hypoglycemia (especially if mismatch of timing or dose with meals or exercise) and weight gain. Patients must be educated on signs of hypoglycemia and how to treat it (glucose tablets, glucagon kit if severe). Pearl: When starting insulin drip for DKA or when tight control is needed, remember to monitor and replete potassium, as insulin drives K+ into cells.
  • Acute Complications – DKA vs HHS: Diabetic ketoacidosis (DKA) usually occurs in Type 1 (or advanced insulin-deficient type 2) from severe insulin deficiency often triggered by infection, infarction, non-adherence, or new-onset type 1. It is characterized by hyperglycemia (usually > 250 mg/dL but often <600), ketosis (ketones in blood/urine), and anion gap metabolic acidosis (arterial pH < 7.3, high anion gap due to ketones). Clinical features: polyuria, polydipsia, dehydration, abdominal pain, nausea/vomiting, Kussmaul respirations (deep rapid breathing to blow off CO₂), and fruity odor to breath (acetone). Total body potassium is depleted even if serum K appears normal or high (shift out of cells due to acidosis and lack of insulin). Hyperosmolar hyperglycemic state (HHS) typically occurs in Type 2 older patients; here some insulin is present so ketosis is minimal, but extreme hyperglycemia develops (often > 600 mg/dL, with serum osmolarity >320 mOsm/kg) leading to severe dehydration and altered mental status (confusion, even coma). pH is usually >7.3 (no significant acidosis). Both are medical emergencies. Management: for DKA – vigorous IV fluids (start with isotonic saline), IV insulin drip (regular insulin infusion) and careful electrolyte management. Replace potassium if low or normal – insulin will drive K into cells and can cause life-threatening hypokalemia, so make sure K is >3.3 mEq/L before starting insulin; add K+ to IV fluids if K is not high. Typically, even if K is normal, total body K is depleted, so repletion is needed as acidosis corrects. Monitor fingerstick glucoses and anion gap; add dextrose to IV fluids once glucose ~200 to prevent hypoglycemia until gap closes. Treat any precipitating cause (e.g. antibiotics for infection). For HHS, the principles are similar: aggressive IV fluids (often these patients are ~9L depleted), IV insulin (though lower doses may suffice than DKA), and electrolyte monitoring; careful because these patients are often older with comorbidities – avoid dropping glucose too fast (can cause cerebral edema). Pearl: In DKA, resolution is defined not by normalization of glucose but by closure of the anion gap (indicating ketone clearance); the patient should be transitioned to subcutaneous insulin when gap is closed and they can eat, with overlap of insulin drip and SQ insulin to prevent relapse.
  • Chronic Complications: Chronic hyperglycemia leads to microvascular and macrovascular complications. Microvascular complications include diabetic retinopathy (leading cause of blindness; nonproliferative changes like microaneurysms and exudates, progressing to proliferative neovascularization – require annual dilated eye exams; treat advanced disease with laser photocoagulation or anti-VEGF injections), diabetic nephropathy (leading cause of ESRD; characterized by proteinuria, initially microalbuminuria >30 mg/day progressing to overt proteinuria – screen annually with urine albumin/Cr ratio; treat with ACE inhibitors or ARBs if any albuminuria, as they reduce intraglomerular pressure and slow progression), and diabetic neuropathy (peripheral neuropathy causing stocking-glove sensory loss, pain, paresthesias – predisposes to foot ulcers; also autonomic neuropathy causing gastroparesis, orthostatic hypotension, erectile dysfunction). Macrovascular complications include accelerated atherosclerosis leading to coronary artery disease (MI risk), stroke, and peripheral artery disease. Managing diabetes intensively reduces microvascular complications significantly (as shown in DCCT and UKPDS trials), whereas macrovascular risk reduction also relies heavily on controlling blood pressure and lipids. Aspirin is indicated for secondary prevention in diabetics with known ASCVD (and some experts recommend it for primary prevention in older high-risk diabetics, though guidelines vary). Foot care is crucial: diabetics should have at least yearly foot exams (checking for sensation with a monofilament, pulses) and patient education on daily foot inspection and proper footwear to prevent ulcers. Good glycemic control (near-normal A1c without severe hypoglycemia) from diagnosis can prevent or delay these complications. Remember that ACE inhibitors or ARBs are recommended if the patient has hypertension with diabetes, especially if any proteinuria, as they are renal-protective. Statin therapy is recommended for essentially all diabetics over 40 (as noted in lipid section) to mitigate CV risk.
 

 

Type 2 Diabetes Medication Strategy

  •  Lifestyle modification + Metformin is the initial therapy for most patients with type 2 diabetes (T2DM). Diet, weight loss, and exercise improve glycemic control and should be continued alongside medications. Metformin (unless contraindicated) is first-line due to its efficacy, low cost, weight neutrality, and low risk of hypoglycemia.
  • Add a second agent if hemoglobin A1c remains above target after ~3 months of metformin and lifestyle. The choice of a second-line medication is individualized based on comorbidities and patient factors:
    •  Atherosclerotic CV disease (ASCVD): Prefer GLP-1 agonist (e.g. liraglutide) or SGLT2 inhibitor (e.g. empagliflozin) for proven cardiovascular benefit.
    •  Heart failure or CKD: Favor SGLT2 inhibitors (e.g. empagliflozin, dapagliflozin) which reduce heart failure hospitalizations and slow renal progression.
    •  Need to minimize hypoglycemia: Use agents like DPP-4 inhibitors, GLP-1 agonists, or SGLT2 inhibitors (avoid sulfonylureas and high-dose insulin).
    •  Need to minimize weight gain/promote weight loss: Choose GLP-1 agonists or SGLT2 inhibitors (associated with weight loss). Avoid TZDs and sulfonylureas which cause weight gain.
    •  Cost concerns: Older drugs like sulfonylureas or TZDs (thiazolidinediones) are cheaper options, though they have more side effects (hypoglycemia for sulfonylureas; edema for TZDs).
  •  Escalate therapy if needed: If dual therapy doesn’t achieve glycemic goals, progress to triple therapy (e.g. metformin + two other classes). Avoid using overlapping mechanism drugs together (e.g. DPP-4 inhibitor + GLP-1 agonist is not beneficial). Ultimately, insulin therapy may be required for glycemic control if oral/injectable agents are insufficient.
  •  Insulin as initial therapy: If A1c is very high (≥10% or blood glucose >300 mg/dL) or if patient is symptomatic (weight loss, polyuria, polydipsia) or has severe hyperglycemia at diagnosis, consider starting insulin early ± metformin. Once glucose is controlled, they can sometimes transition to oral agents.

 

Metformin: Use, Risks, and Benefits

  •  First-line agent: Metformin (a biguanide) is the preferred initial pharmacologic treatment for T2DM barring contraindications. It reduces hepatic gluconeogenesis and improves peripheral insulin sensitivity. Expected A1c reduction is ~1–2%.
  •  Benefits: Weight-neutral (often slight weight loss), and no hypoglycemia as monotherapy. It has cardiovascular benefits (metformin showed reduced risk of CV events in some patients) and is low-cost. It can be used in pre-diabetes to prevent progression (especially in younger obese patients).
  •  GI side effects are common: nausea, diarrhea, abdominal cramping – usually improved by slow titration and taking with food. Vitamin B₁₂ deficiency can occur with long-term use (periodically monitor B₁₂ levels if neuropathy or anemia develops).
  •  Lactic acidosis (rare but serious): Metformin can cause lactic acidosis in susceptible patients by impairing hepatic lactate uptake. Risk is highest in the setting of renal insufficiency or any condition causing poor tissue perfusion or hypoxia. Contraindications: eGFR <30 mL/min (renal failure) – do not use metformin. Use caution or dose-reduce if eGFR 30–45. Also avoid in significant hepatic impairment, unstable heart failure, or sepsis/shock due to elevated lactic acidosis risk. Temporarily hold metformin before IV contrast studies or surgery (to reduce risk of acidosis).

 

Hypoglycemia and Diagnostic Workup

  • Definition and symptoms: Clinically significant hypoglycemia is typically glucose <55–60 mg/dL (3.0 mmol/L), though symptoms can begin at higher levels. Whipple’s triad defines true hypoglycemia: (1) symptoms of hypoglycemia (tremor, sweating, palpitations, confusion, seizures), (2) a low plasma glucose at that time, and (3) relief of symptoms when glucose is raised. Common causes include diabetes medications (insulin, sulfonylureas), critical illnesses, hormone deficiencies, or endogenous hyperinsulinism.
  • Initial evaluation: If a patient without diabetes presents with fasting hypoglycemia, check a plasma insulin, C-peptide, and beta-hydroxybutyrate level during the hypoglycemic episode. Also screen for oral hypoglycemic agents in the blood or urine if surreptitious use is suspected. An 72-hour supervised fast in the hospital is the gold-standard diagnostic test for fasting hypoglycemia (in suspected insulinoma or factitious hypoglycemia) – the patient is observed until they become hypoglycemic and labs are drawn.
  • Endogenous vs exogenous insulin: Distinguish causes by insulin and C-peptide levels:
    •  Insulinoma (pancreatic β-cell tumor): High insulin and high C-peptide during hypoglycemia (inappropriate insulin secretion). Proinsulin levels are often elevated as well. Sulfonylurea screen will be negative. Insulinomas are a cause of fasting hypoglycemia and often cause weight gain; treatment is surgical resection.
    •  Exogenous insulin administration: High insulin level with low C-peptide (and low proinsulin) – exogenous insulin suppresses endogenous C-peptide. This suggests factitious (surreptitious) use of insulin (often in medical personnel or those seeking attention).
    •  Sulfonylurea-induced hypoglycemia: High insulin and high C-peptide (since the pancreas is stimulated), but the sulfonylurea screen is positive in blood or urine. This can mimic insulinoma, so always check for sulfonylurea if insulin and C-peptide are elevated.
  • Other causes: If insulin is appropriately low during hypoglycemia, consider non-insulin etiologies: adrenal insufficiency (cortisol deficiency), severe liver failure (impaired gluconeogenesis), alcohol (impairs gluconeogenesis), or critical illness (sepsis). Reactive (postprandial) hypoglycemia can occur after gastric bypass surgery or in early type 2 diabetes.
  • Management of hypoglycemia: If the patient is conscious with mild symptoms, give oral fast-acting carbohydrates (glucose tablets or juice). If severe or unconscious, administer IV dextrose (50% dextrose ampule) or IM glucagon (if IV access is not available). Patients on insulin should be educated on recognition and treatment of hypoglycemia. In recurrent hyperinsulinism (like insulinoma), medications such as diazoxide (which inhibits insulin release) or octreotide can be used if not surgical. Always address the underlying cause (e.g., adjust diabetes regimen if iatrogenic).

 

DPP-4, GLP-1, SGLT2: Mechanisms, Indications, and Risks

  • DPP-4 Inhibitors (e.g. sitagliptin, saxagliptin, linagliptin): Mechanism: Inhibit dipeptidyl peptidase-4, the enzyme that degrades incretin hormones (GLP-1/GIP), thereby prolonging their action. This increases glucose-dependent insulin release and decreases glucagon. Indication: Add-on therapy in T2DM for additional A1c reduction (~0.5-1%) without weight gain; useful if aiming to avoid hypoglycemia. Well tolerated and weight-neutral. Risks/Side effects: Generally mild; can cause nasopharyngitis or URIs, headache. Rarely, associated with acute pancreatitis. Saxagliptin (and possibly alogliptin) has been linked to increased risk of heart failure hospitalizations in some studies – use with caution in patients with HF. No hypoglycemia when used alone. Dose adjustments needed in renal impairment (except linagliptin).
  •  GLP-1 Receptor Agonists (e.g. exenatide, liraglutide, dulaglutide, semaglutide): Mechanism: Analogues of glucagon-like peptide-1 that bind GLP-1 receptors, enhancing glucose-dependent insulin secretion, suppressing glucagon, slowing gastric emptying, and increasing satiety. Indications: T2DM patients, especially those who benefit from weight loss (GLP-1 RAs can lead to significant weight reduction). Certain GLP-1 RAs (liraglutide, semaglutide) have demonstrated cardiovascular risk reduction in patients with diabetes and ASCVD. Often used when metformin alone is inadequate, or as an alternative in metformin-intolerant patients. Risks/Side effects: Gastrointestinal side effects are common – nausea, vomiting, early satiety – usually improve over time. Risk of acute pancreatitis has been observed (caution if history of pancreatitis). They carry a black-box warning for medullary thyroid carcinoma risk (seen in rodent studies); contraindicated in patients with a personal or family history of MEN2 or medullary thyroid cancer. Generally low risk of hypoglycemia (because action is glucose-dependent). Given via subcutaneous injection (except oral semaglutide).
  •  SGLT2 Inhibitors (e.g. canagliflozin, empagliflozin, dapagliflozin): Mechanism: Inhibit the sodium-glucose cotransporter-2 in the proximal renal tubules, reducing glucose reabsorption and increasing urinary glucose excretion. Result is lower blood glucose and a mild osmotic diuresis. Indications: Add-on therapy in T2DM, particularly beneficial in patients with heart failure or CKD – these drugs reduce progression of diabetic kidney disease and lower heart failure events. Also cause modest weight loss and blood pressure reduction. Empagliflozin, canagliflozin, and dapagliflozin have shown reduced cardiovascular events in high-risk patients. Risks/Side effects: Increased glycosuria leads to genitourinary infections (vaginal yeast infections, UTIs) and can cause dehydration (leading to hypotension or dizziness). Euglycemic DKA is a rare but serious complication – diabetic ketoacidosis with only mildly elevated blood glucose, particularly in insulin-dependent patients or perioperatively. Canagliflozin has been associated with higher risk of toe amputations and bone fractures in some trials (use caution in patients with peripheral arterial disease or osteoporosis). All SGLT2 inhibitors carry a small risk of Fournier’s gangrene (necrotizing fasciitis of the perineum). Avoid or dose-reduce if renal impairment (ineffective when GFR is low and risk of side effects higher). No significant hypoglycemia risk by themselves.

 

Insulin: Inpatient and Outpatient Regimens

  •  Outpatient insulin management: In T2DM, insulin is often added when oral agents no longer maintain glycemic control (especially if A1c is very high or patient is symptomatic). A common starting regimen is basal insulin (long-acting insulin like glargine or detemir once daily, or NPH twice daily) added to oral meds. Typical starting dose is ~0.1–0.2 units/kg at bedtime (or a fixed 10 units) and titrated every few days based on fasting glucose. If A1c remains above target despite basal insulin (especially if postprandial sugars are high), add prandial (mealtime) insulin with rapid-acting analogs (lispro, aspart, glulisine) before meals – this is the basal-bolus regimen. An alternative for simplicity is using premixed insulin (e.g. 70/30 NPH/regular or analog mixes) twice daily, though this sacrifices some control for fewer injections. Patients with Type 1 diabetes lack endogenous insulin and require a basal-bolus insulin regimen from diagnosis (total daily insulin ~0.5 units/kg split roughly half basal, half rapid divided among meals). Insulin therapy is associated with weight gain and risk of hypoglycemia, so dose adjustments are made cautiously. Educate patients on insulin administration (proper injection technique, rotating sites to avoid lipodystrophy, and signs of hypoglycemia).
  •  Inpatient insulin regimen: Hospitalized diabetic patients (especially type 1 or insulin-treated type 2) are managed with insulin rather than oral agents. If the patient is eating, use a basal + prandial + correction insulin regimen: a long-acting basal insulin to cover baseline needs, nutritional insulin (short/rapid-acting) with meals, and correctional insulin (sliding scale) for high glucose values. If the patient is NPO, hold prandial doses and use basal insulin plus correction sliding scale as needed. Avoid using sliding-scale insulin alone as the sole regimen except in very short-term situations, as it leads to uncontrolled glucose fluctuations. IV insulin infusion is used in critical care settings or for conditions like DKA, HHS, or perioperative glycemic control in ICU – it allows rapid titration (insulin drip with hourly glucose checks). In hospitalized patients, maintain glucose roughly between 140–180 mg/dL for most critically ill and noncritically ill patients (this target balance avoids both severe hyperglycemia and hypoglycemia). Tighter control (<140) has not shown outcome benefit and increases hypoglycemia risk, so it’s generally avoided in the acute care setting.

 

A1C and Blood Pressure Targets

  •  Hemoglobin A1c goals: For nonpregnant adults with diabetes, an A1c <7% is the general target to reduce microvascular complications (retinopathy, nephropathy). However, goals should be individualized. Stringent control (<6.5%) may be chosen for younger patients with long life expectancy, no cardiovascular disease, and low risk of hypoglycemia – provided it can be achieved safely. Less stringent goals (<8% or even up to 8.5%) are appropriate for older patients, or those with advanced complications, multiple comorbidities, or a history of severe hypoglycemia – in whom tight control risks may outweigh benefits. Always consider patient-specific factors: the key is to balance glycemic benefits with risk of hypoglycemia. Hemoglobin A1c reflects approximately 3-month average glucose levels; remember conditions that affect red blood cell turnover (anemia, hemolysis, recent transfusion, CKD) can make A1c less reliable. In such cases, use fructosamine or frequent fingerstick/CGM readings to assess control.
  •  Blood pressure targets in diabetes: Tight blood pressure control is crucial in diabetics to prevent cardiovascular and kidney complications. Current guidelines generally recommend a BP <140/90 mmHg at minimum for patients with diabetes. ACE inhibitors or ARBs are first-line for hypertension in diabetes (especially if albuminuria) due to renal protective effects. Many experts and the ADA advise aiming for <130/80 in diabetics who can tolerate it, particularly if they have high cardiovascular risk, as lower BP further reduces stroke risk and nephropathy progression. However, use clinical judgment: in frail or elderly patients, overly aggressive BP lowering can cause dizziness or falls. So the consensus is <140/90 for all, with an optimal target of ~130/80 if achievable without undue side effects.

 

Bariatric Surgery Criteria and Outcomes

  •  Indications (BMI criteria): Bariatric surgery is considered for patients with severe obesity, especially if comorbidities are present. BMI ≥40 kg/m² is an indication even without comorbid conditions. BMI ≥35 with at least one serious obesity-related comorbidity (such as T2DM, hypertension, obstructive sleep apnea, non-alcoholic fatty liver disease, etc.) is also an indication. Some guidelines also consider BMI 30–34.9 with difficult-to-control diabetes or metabolic syndrome for certain procedures, but the classic board criteria are ≥35 with comorbidity or ≥40 regardless of comorbidity. Candidates should have attempted lifestyle weight-loss interventions and be psychologically ready for surgery and the necessary post-op lifestyle changes.
  •  Types of surgery: Common bariatric procedures include Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy, and adjustable gastric banding (less common now). RYGB and sleeve are most commonly performed; RYGB is both restrictive and mildly malabsorptive, while the sleeve is primarily restrictive. Biliopancreatic diversion with duodenal switch is a more malabsorptive procedure used in super-obesity.
  •  Outcomes and benefits: Bariatric surgery is the most effective treatment for morbid obesity – patients typically achieve significant and sustained weight loss (often 25–35% of body weight lost, depending on procedure). Type 2 diabetes often markedly improves or even remits after surgery: many patients have normalization of blood glucose and A1c within weeks post-op (especially with gastric bypass, due to hormonal changes like increased GLP-1). Surgery also improves or resolves hypertension, dyslipidemia, and obstructive sleep apnea in many cases. There is evidence of reduced long-term mortality and lower incidence of myocardial infarction, stroke, and cancer in post-bariatric patients compared to those who remain morbidly obese.
  •  Risks and considerations: As with any major surgery, there are perioperative risks (bleeding, infection, pulmonary embolism). Long-term, RYGB can cause nutritional deficiencies (iron, B12, calcium, fat-soluble vitamins) due to altered absorption – patients require lifelong vitamin/mineral supplements and monitoring. Dumping syndrome can occur after gastric bypass (rapid gastric emptying causing tachycardia, cramping, diarrhea after high-sugar meals). Gallstones often develop with rapid weight loss (sometimes prophylactic ursodiol is given or the gallbladder is removed during bypass). Patients must adhere to dietary restrictions and follow-up; psychological support is important. Overall, for qualified patients, the benefits on morbidity and mortality generally outweigh the risks.

 

Hypercalcemia and Hypocalcemia: Workup and Management

  •  Hypercalcemia:
    • Clinical features: "Stones, bones, groans, moans, and psychiatric overtones." Patients may develop kidney stones (calcium stones), bone pain (from bone resorption), abdominal groans (nausea, constipation, pancreatitis), psychic moans (confusion, depression), and polyuria/polydipsia (causing dehydration). On EKG, look for a short QT interval.
    •  Workup – check PTH level: The parathyroid hormone (PTH) level guides the differential diagnosis:
      •  High or normal PTH in the setting of high Ca²⁺: PTH-dependent hypercalcemia. The most common cause is primary hyperparathyroidism (usually a parathyroid adenoma), especially in outpatient settings. Other causes: lithium therapy (raises PTH set-point), tertiary hyperparathyroidism (in dialysis patients with long-standing secondary hyperpara), or Familial Hypocalciuric Hypercalcemia (FHH) – a benign AD condition due to a Ca-sensing receptor mutation; PTH is mildly high-normal and patients have lifelong mildly elevated Ca with low urinary calcium excretion (distinguish from primary HPT).
      •  Low (suppressed) PTH: PTH-independent hypercalcemia. Here, suspect malignancy as the top cause (especially in hospitalized patients). Malignancy can cause high calcium via PTHrP secretion (e.g. squamous cell lung cancer, renal carcinoma, breast cancer mets – PTHrP will be elevated), or via bone metastases producing cytokines (as in breast/prostate) or vitamin D production (some lymphomas or granulomatous diseases increase 1,25-D). Other causes of PTH-independent hypercalcemia: excess vitamin D intake or granulomatous diseases (sarcoidosis, TB) raising calcitriol, thyrotoxicosis (increases bone turnover), vitamin A toxicity, immobilization (especially in teens or Paget disease due to rapid bone turnover and lack of weight-bearing), and thiazide diuretics (cause increased renal Ca reabsorption; usually mild Ca elevation). Measure PTHrP level if malignancy is suspected and 25-OH vitamin D (and 1,25-D if granuloma suspected).
    • Management: Depends on severity. Mild hypercalcemia (Ca < 12 mg/dL) without symptoms usually just needs hydration and treating the cause (no urgent therapy). Moderate (Ca ~12–14) may warrant treatment if symptomatic. Severe hypercalcemia (Ca ≥ 14 or severe symptoms): Aggressive IV saline is the first step (expands volume and increases calcium excretion). Add IV calcitonin for quick temporary reduction (works within hours by inhibiting osteoclasts and promoting calciuresis). For longer-term control, give IV bisphosphonates (like zoledronic acid or pamidronate) – these reduce bone resorption but take 2-3 days to act, lasting weeks. In hypercalcemia due to vitamin D or granulomatous disease, use glucocorticoids (e.g. prednisone) to reduce GI calcium absorption and vitamin D activation. In severe, refractory cases or renal failure, dialysis with a low-calcium dialysate can be used to remove calcium. Primary hyperparathyroidism: definitive treatment is parathyroidectomy if criteria met (symptomatic, Ca significantly high >1 mg/dL above normal, osteoporosis, kidney stones, or patient <50 years old). Otherwise, if mild, can be managed medically (stay hydrated, avoid thiazides, monitor bone density; cinacalcet can be used to lower Ca by tricking the Ca-sensing receptor).
  •  Hypocalcemia:
    • Clinical features: Causes neuromuscular irritability – perioral numbness, tingling in fingertips, muscle cramps. Tetany (involuntary muscle contractions) can occur, leading to Chvostek’s sign (facial twitch when tapping the facial nerve) and Trousseau’s sign (carpal spasm when inflating a BP cuff on the arm). Severe hypocalcemia can cause seizures or laryngospasm. EKG may show a prolonged QT interval.
    •  Workup: Again, check PTH level in the context of low calcium:
      •  High PTH (appropriate response, i.e. secondary hyperparathyroidism): The parathyroid gland is working to correct the low Ca. Causes include vitamin D deficiency (most common: due to inadequate diet, lack of sun, malabsorption, or chronic kidney disease with decreased 1,25-D production), chronic kidney disease (CKD) (phosphate retention and low calcitriol cause hypocalcemia – part of renal osteodystrophy), and pseudohypoparathyroidism (rare genetic end-organ resistance to PTH; PTH is high but calcium remains low). Other causes: pancreatitis (acute pancreatitis causes calcium precipitation in the pancreas), tumor lysis syndrome (phosphate binds Ca), hypomagnesemia (low Mg causes PTH resistance and decreases PTH secretion). In vitamin D deficiency, 25-OH vitamin D is low; in CKD, 1,25-D is low and phosphate is high.
      •  Low or inappropriately normal PTH: This indicates hypoparathyroidism (primary). Causes: post-surgical (most common – accidental removal or damage to parathyroids during thyroid or neck surgery), autoimmune destruction of parathyroids, infiltrative diseases (hemochromatosis, Wilson’s), or congenital absence (DiGeorge syndrome). Also, severe hypomagnesemia can cause low PTH levels (reversible when Mg is corrected).
      •  Also consider artifact: pseudohypocalcemia from low albumin – total serum calcium is low, but ionized calcium is normal (no symptoms). Corrected calcium = measured Ca + 0.8*(4 - albumin). Always check albumin or ionized Ca to confirm true hypocalcemia.
    • Management: For acute severe hypocalcemia (e.g. Ca <7.0 mg/dL with severe tetany, seizures, arrhythmia), give IV calcium (usually calcium gluconate via slow infusion, or calcium chloride in central line) and monitor ECG. For less severe cases or chronic hypocalcemia, give oral calcium supplements (1-2 grams elemental Ca daily) plus vitamin D. Vitamin D supplementation could be calcitriol (1,25-D) if the patient has hypoparathyroidism or CKD (because they can’t activate vitamin D), or high-dose ergocalciferol/cholecalciferol if vit D deficient. In hypoparathyroidism (low PTH), treatment consists of oral calcium and calcitriol lifelong; thiazide diuretics can help reduce urinary calcium loss. Magnesium should be checked and repleted if low, as low Mg exacerbates hypocalcemia. Treat underlying causes when possible (e.g. thyroidectomy patients may recover some parathyroid function over time; vitamin D deficiency needs repletion, etc.).

 

MEN Syndromes: MEN1, MEN2A, MEN2B

  • MEN 1 (Wermer syndrome): An autosomal dominant syndrome caused by mutation of the MEN1 tumor suppressor gene (menin). It is characterized by 3 P’s – tumors of the Parathyroid, Pancreatic endocrine tumors, and Pituitary:
    •  Parathyroid: Primary hyperparathyroidism from multiple parathyroid adenomas or hyperplasia (causing hypercalcemia, kidney stones). Often the first manifestation (appears in young adulthood).
    •  Pancreatic endocrine tumors: often Gastrinomas (Zollinger-Ellison syndrome with recurrent peptic ulcers) or Insulinomas (causing hypoglycemia). Other islet cell tumors may occur (VIPomas causing secretory diarrhea, Glucagonomas causing diabetes & rash). These can be life-threatening and are a major cause of morbidity in MEN1.
    •  Pituitary: usually a pituitary adenoma (most commonly prolactinoma, causing galactorrhea/amenorrhea in women or hypogonadism in men; or less commonly GH-secreting acromegaly, or ACTH-secreting Cushing disease).
    •  Clinical note: Menin gene is on chromosome 11. MEN1 patients often require surveillance for these tumors. Treatment is directed at each tumor (parathyroidectomy for hyperpara, surgical or medical therapy for endocrine pancreatic tumors, pituitary adenoma resection or bromocriptine if prolactinoma, etc.).
  • MEN 2A (Sipple syndrome): An autosomal dominant syndrome caused by mutations in the RET proto-oncogene (a receptor tyrosine kinase). Components are 2 P’s + 1 M: Parathyroid, Pheochromocytoma, Medullary thyroid carcinoma:
    •  Medullary thyroid carcinoma (MTC): nearly all MEN2 patients develop MTC, a calcitonin-secreting malignancy of the thyroid C cells. It can be aggressive; thus, identified carriers of RET mutation require prophylactic thyroidectomy, often in childhood (especially in MEN2B, but also in 2A typically by age 5 or early adolescence).
    •  Pheochromocytoma: adrenal medullary tumor in ~50% of MEN2A, secreting catecholamines (causing episodic headaches, sweating, tachycardia, hypertension). Patients need to be screened (plasma metanephrines) and treated if present (alpha-blockade then adrenalectomy) – especially important before thyroid surgery to avoid a catecholamine crisis.
    •  Parathyroid hyperplasia: about 15–20% of MEN2A patients develop hyperparathyroidism (much less frequent than in MEN1). Leads to hypercalcemia symptoms; may require parathyroidectomy if significant.
    •  Clinical note: The RET mutation in MEN2A is also associated with cutaneous lichen amyloidosis in some kindreds. Management centers on early thyroidectomy and vigilant screening for pheo and hyperpara.
  • MEN 2B: Also caused by RET gene mutations (often a different codon than 2A). Previously called MEN3, it has 1 P + 3 M’s: Pheochromocytoma, Medullary thyroid carcinoma, Mucosal neuromas, Marfanoid body habitus:
    •  Medullary thyroid carcinoma: occurs in 100% of MEN2B, often early in life and more aggressive than in 2A. Prophylactic thyroidectomy in infancy (within first year of life) is recommended once diagnosed by genetic testing.
    •  Pheochromocytoma: as in MEN2A, can develop and must be screened for and treated.
    •  Mucosal neuromas: benign neuroma lesions on the tongue, lips, and lining of the mouth, and also GI tract. On exam, patients have bumpy, enlarged lips or tongue due to these neuromas. This is a distinctive feature of MEN2B.
    •  Marfanoid habitus: Many MEN2B patients have a Marfan-like body habitus – tall, long limbs, high-arched palate, hyperflexible joints. They do not actually have lens or aortic issues like true Marfan syndrome, but the body shape is similar.
    •  Clinical note: Unlike 2A, MEN2B does not cause parathyroid disease. Neuromas on the tongue or eyelids, along with marfanoid features, in a young patient with thyroid carcinoma signs is a classic presentation. Management is early thyroidectomy and monitoring for pheos.

 

Osteomalacia and Paget’s Disease

  •  Osteomalacia: A bone disorder in adults caused by defective mineralization of osteoid, usually due to severe vitamin D deficiency (the adult counterpart of rickets in children). Causes include malabsorption (e.g. celiac, bariatric surgery), lack of sunlight, poor diet, chronic kidney or liver disease (impaired vitamin D activation), and certain medications (like anticonvulsants that increase vitamin D catabolism). Lab findings: low 25-OH vitamin D level, hypocalcemia, hypophosphatemia, and elevated PTH (secondary hyperparathyroidism in response to low Ca). Alkaline phosphatase is elevated (increased osteoblast activity trying to mineralize bone). Symptoms include diffuse bone and muscle pain, weakness (difficulty walking, waddling gait), and bone tenderness. Fractures or pseudofractures (Looser’s zones, which are incomplete fractures with poorly mineralized edges) are characteristic on x-ray. In children (rickets), findings include bone deformities like bowed legs, rachitic rosary (costochondral junction swelling), and growth plate widening. Treatment: replenish vitamin D and calcium. High-dose oral vitamin D2/D3 is given, along with calcium supplementation; phosphate supplements if needed. Treat underlying malabsorption or renal disease as possible. With proper repletion, labs normalize and bone gradually remineralizes.
  •  Paget’s disease of bone (Osteitis Deformans): A chronic disorder of mosaic disorganized bone remodeling in focal areas of the skeleton. Excessive osteoclast activity followed by chaotic osteoblast activity leads to structurally weak, enlarged, and misshapen bones. Usually affects older adults and is often asymptomatic (discovered by elevated alkaline phosphatase or an incidental x-ray). When symptoms occur, they include bone pain and skeletal deformities: enlarged skull (hat no longer fits), frontal bossing, hearing loss (due to cranial bone involvement compressing the auditory nerve), and bowing of legs or asymmetric enlargement of long bones. Labs: Very high alkaline phosphatase (from high bone turnover) is typical; calcium and phosphate are normal (unless the patient is immobilized or has co-existing calcium issues). Radiology: X-rays show mixed lytic and sclerotic lesions; skull may have a “cotton wool” appearance from irregular bone thickening; long bones can show cortical thickening and bowing. Complications: High-output cardiac failure can occur in extensive disease (due to increased vascularity of bone). There is a small risk (<1%) of osteosarcoma or other sarcoma developing in an affected bone (presenting as sudden severe pain in a Pagetic bone). Treatment: If patients are symptomatic or have active disease in high-risk locations (skull, spine, weight-bearing bones), treat with bisphosphonates (e.g. high-dose alendronate or IV zoledronic acid) which are very effective in reducing bone turnover and ALP levels. Calcitonin is a second-line therapy. Pain can be managed with NSAIDs. Monitor alkaline phosphatase as a marker of disease activity. Paget’s disease is often tested – remember the combination of an older patient with an isolated very high ALP, bone pain, and hearing loss; the correct management is a bisphosphonate.