One-sentence version: the hypothalamus controls the pituitary two different ways — by blood to the anterior lobe, and by nerve to the posterior lobe — and that difference explains everything the posterior pituitary does and does not do.

The hypothalamus sits at the base of the brain, connected to the pituitary by the infundibulum (pituitary stalk). It contains special neurosecretory cells that synthesise and secrete the hormones below.

Hypothalamic releasing and inhibitory hormones:

• TRH — thyrotropin-releasing hormone
• CRH — corticotropin-releasing hormone
• GnRH — gonadotropin-releasing hormone
• GHRH — growth hormone-releasing hormone, and hypothalamic somatostatin, which inhibits it
• PRH and PIH — prolactin-releasing and prolactin-inhibiting hormone
• Substance P

What the anterior pituitary then releases, and onto what:

• Growth hormone (GH) — growth, cell reproduction and regeneration
• Prolactin (PRL) — milk production
• TSH — stimulates the thyroid to produce thyroid hormones
• ACTH — stimulates the adrenal cortex to release cortisol
• FSH — egg production in females, sperm production in males
• LH — triggers ovulation; stimulates testosterone production

The feedback rule, worked through one axis:

1. CRH is released from the HYPOTHALAMUS
2. CRH stimulates the ANTERIOR PITUITARY to release ACTH
3. ACTH stimulates the ADRENAL CORTEX to release CORTISOL
4. CORTISOL exerts NEGATIVE FEEDBACK on BOTH the hypothalamus and the anterior pituitary, reducing CRH and ACTH — which prevents overactivation of the stress response

The two central rows are the traps. In central hypothyroidism a normal TSH sits beside a low T4 — the pituitary is failing to respond, so the number that should have risen did not. In central hyperthyroidism a TSH-secreting pituitary adenoma keeps TSH normal or high while thyroid hormone climbs.

Where autoimmunity splits — this is the single diagram worth memorising:

• Genes and environment generate autoimmunity to the thyroid gland
• CELLULAR autoimmunity → thyroid gland DESTRUCTION → Hashimoto thyroiditis → HYPOTHYROIDISM
• ANTIBODY-MEDIATED autoimmunity → thyroid gland STIMULATION → Graves disease → HYPERTHYROIDISM

Same trigger, two immune mechanisms, opposite diseases. The majority of primary thyroid diseases are idiopathic and caused by autoimmune mechanisms.

Hyperthyroidism — causes:

• Primary: Graves disease (most common), toxic multinodular goiter, solitary toxic adenoma
• Central (secondary): less common — TSH-secreting pituitary adenomas
• Terminology: thyrotoxicosis is any cause of increased thyroid hormone — including ingestion of excessive amounts of thyroid hormone medication. Hyperthyroidism is the form in which the excess is secreted from the thyroid gland.

Graves mechanism: self-reactive T lymphocytes sensitise against thyroid antigens and activate B lymphocytes to produce thyroid-stimulating immunoglobulins (TSI). These bind to and activate the TSH receptor, producing unregulated synthesis of T3 and T4 and enlargement of the gland (thyromegaly). The hormones accelerate metabolic processes — weight loss, increased appetite, heat intolerance, palpitations, tremors, anxiety, and exophthalmos.

Hypothyroidism — causes:

• Primary (the majority of cases): autoimmune thyroiditis — chronic lymphocytic (Hashimoto) thyroiditis; iatrogenic loss of thyroid tissue after surgery, radioactive treatment, or head and neck radiation; medications — lithium and amiodarone; endemic iodine deficiency, relatively rare in the United States because of iodised salt and fortified foods
• Central (secondary): pituitary failure to synthesise adequate TSH, or lack of TRH. Pituitary tumors — or the consequences of treating them — are the most common cause; also traumatic brain injury, subarachnoid haemorrhage, pituitary infarction
• Hypothalamic dysfunction results in low TH, low TSH and low TRH

Of all thyroid disorders, primary hypothyroidism is the commonest — somewhere between 4% and 7% of people in the United States, and more of them women than men.

Subclinical hypothyroidism, which the week 6 deck treats as its own topic:

• Elevated serum thyrotropin (TSH) with a normal free T4 within the population reference range
• Caused by autoimmune thyroid disease in the majority of cases
• Ranges 3% to 15% of the total population; higher with increasing age, female sex, and suboptimal iodine status
• The mechanism is compensatory: the gland cannot make enough hormone, so the pituitary raises TSH to flog it
• A thyrotropin level of 10 mIU/L distinguishes mild from more severe subclinical hypothyroidism; approximately 75% of patients have a level below 10
• Progression to overt hypothyroidism is common over time

Where the hormones come from — the numbers the deck gives:

• T4 is produced exclusively by the thyroid gland
• Of the hormone the gland secretes, 80% is T4 and 20% is T3
• Of circulating T3, only 10% comes from the gland; 90% is derived from peripheral conversion of T4 to T3

HYPOthyroidism:

• Hormone replacement therapy with levothyroxine is the treatment of choice — and it is the treatment of choice for both primary and central thyroid disorders
• That is the whole of it. Replace what the gland cannot make.

HYPERthyroidism — treatment is directed at controlling excessive thyroid hormone production, secretion or action:

• Antithyroid drug therapy — the deck names methimazole and propylthiouracil
• Radioactive iodine therapy — absorbed only by thyroid tissue, causing death of those cells. Its selectivity is the point: the isotope goes where iodine goes.
• Surgery — removal of nodules, or of part or all of the thyroid gland

Where each option sits. Antithyroid drugs suppress production without destroying tissue and can be stopped. Radioactive iodine and surgery are definitive and largely irreversible. The trade-off between reversibility and durability is the decision.

One-sentence version: Hashimoto disease — chronic lymphocytic thyroiditis — is gradual, inflammatory, autoimmune destruction of thyroid tissue, and it is the most common cause of primary hypothyroidism in the United States.

The mechanism:

• Infiltration of the thyroid with autoreactive T lymphocytes
• Antithyroid antibodies — antithyroid peroxidase and antithyroglobulin antibodies
• Natural killer cells
• Together these induce inflammation, glandular apoptosis and tissue destruction

Several genetic risk factors feed into it, and it tends to appear beside other autoimmune disease — the chapter lists Hashimoto thyroiditis together with pernicious anemia and idiopathic hypoparathyroidism as the autoimmune company Addison disease keeps.

Two arms run in parallel, and they produce apparently contradictory findings:

1. AUTOIMMUNITY → CELLULAR DESTRUCTION of the thyroid gland → GOITER
2. DESTRUCTION → DECREASED T3 AND T4 → the PITUITARY RAISES TSH → HYPOTHYROIDISM: myxedema, slow metabolic rate, decreased cardiac output, weight gain, lethargy, cold intolerance, decreased mental acuity

How autoimmune thyroid disease is confirmed — the deck is specific that diagnosis is determined by elevated antithyroid antibody titres:

• Anti-thyroglobulin antibodies
• Antimicrosomal / anti-thyroid peroxidase antibodies (TPOAb)
• TSH receptor antibodies (TSHRAb)

Where Hashimoto sits in the framework: it is the named example of primary hypothyroidism — the thyroid is being stimulated properly but cannot produce enough hormone, because the gland itself is the problem. Contrast secondary, where the pituitary is not stimulating a healthy thyroid.

The mechanism behind every finding below: increased metabolic rate, plus increased tissue sensitivity to stimulation by the sympathetic nervous system — thyroid hormone increases β-adrenergic receptor sensitivity. The patient looks like someone on too much adrenaline because, at the receptor, they are.

A worked physical exam from the week 6 case: HR 112 bpm, BP 138/84, temperature 99.8°F; anxious and fidgety; neck — diffusely enlarged, non-tender thyroid with bruit; eyes — bilateral exophthalmos and lid lag; skin — warm and moist; neuro — fine tremor in the hands. Alongside 12 lb of unintentional weight loss, heat intolerance, palpitations and difficulty sleeping.

Why TSH is the marker you follow. In primary disease the pituitary is intact and is reacting to how much thyroid hormone reaches it. That makes TSH a sensitive readout of whether the replacement dose is right — more sensitive than the patient's description of how they feel, and quicker to move than T4.

Reading a treated patient:

• TSH still ELEVATED on levothyroxine → UNDER-replaced. The pituitary is still calling for more hormone.
• TSH now SUPPRESSED on levothyroxine → OVER-replaced. The patient has been made iatrogenically thyrotoxic — the same lab pattern as primary hyperthyroidism.
• TSH normalised → the replacement is matched to the person's requirement.
• TSH rising after treatment for HYPERthyroidism → the expected complication. Excessive ablation of the gland leads to hypothyroidism, and a rising TSH is how it is caught.

A worked lab set from the week 6 Graves case, with the reference ranges as the deck gives them:

• TSH <0.01 mIU/L (normal 0.4–4.0) — suppressed
• Free T4 3.2 ng/dL (normal 0.8–1.8) — elevated
• T3 280 ng/dL (normal 80–180) — elevated, often disproportionately so in Graves
• TSI positive (normally negative) — the most specific marker; confirms Graves
• Anti-TPO mildly elevated — an autoimmune marker; more commonly associated with Hashimoto but present in Graves too, so it supports autoimmunity without naming the disease

One-sentence version: type 1 diabetes is a primary β-cell defect — autoimmune destruction of the insulin-producing β cells of the pancreatic islets, producing absolute insulin deficiency.

The sequence:

1. GENETIC SUSCEPTIBILITY plus ENVIRONMENTAL FACTORS
2. A GRADUAL PROCESS OF AUTOIMMUNE DESTRUCTION of the β cells in genetically susceptible individuals
3. INSULIN DEFICIENCY — absent or nearly absent insulin production
4. IMBALANCED GLUCOSE REGULATION
5. METABOLIC CONSEQUENCES — the symptoms below, and susceptibility to diabetic ketoacidosis

A non-autoimmune (idiopathic) form also exists, and its cause is unknown. The autoimmune route is the common theory, not the only one.

Epidemiology:

• 5% to 10% of all diabetes cases; prevalence rate 0.17%
• The most common pediatric chronic disease — approximately 187,000 US children under 20, and the incidence is increasing
• 10% to 13% of newly diagnosed individuals have a first-degree relative with type 1; 50% concordance in twins
• Rare during the first 9 months of life; peak onset at 11 to 13 years, slightly earlier for girls; rare in adults older than 30
• Generally normal weight or underweight — a contrast with type 2, where obesity is common

Presentation is RAPID — polyuria, polydipsia, weight loss — with increased susceptibility to diabetic ketoacidosis. Type 2 is gradual. That difference in tempo is diagnostic in itself.

Treatment:

• Exogenous insulin therapy — non-negotiable, because there is no endogenous insulin
• Carbohydrate counting and meal planning
• Regular blood glucose monitoring; continuous glucose monitoring
• Diabetes education and self-management, including education on hypoglycemia management

One caveat the textbook adds: although most individuals with type 1 are of normal or decreased weight, an increasing number have both type 1 diabetes and the clinical manifestations of metabolic syndrome — obesity, dyslipidemia, hypertension — and are at high risk for heart disease and stroke.

The four criteria — any ONE of these:

1. HbA1c ≥ 6.5% (measured in a DCCT-referenced assay)
2. FASTING PLASMA GLUCOSE ≥ 126 mg/dL — fasting defined as no caloric intake for at least 8 hours
3. 2-HOUR PLASMA GLUCOSE ≥ 200 mg/dL during an oral glucose tolerance test
4. RANDOM PLASMA GLUCOSE ≥ 200 mg/dL — but ONLY in an individual with classic symptoms of hyperglycemia or a hyperglycemic crisis

What separates the two types:

• Type 1: autoantibodies are PRESENT — anti-islet cell antibodies and anti-glutamic acid decarboxylase (GAD) antibodies; the deck also names ICA
• Type 2: autoantibodies are ABSENT

Presentation differs even where the symptoms overlap. Type 1: rapid onset of polyuria, polydipsia and weight loss, with susceptibility to DKA. Type 2: gradual onset of polyuria, polydipsia and fatigue, with increased risk of complications — cardiovascular disease, neuropathy, nephropathy — often already present at diagnosis because the disease was silent for years.

HYPERCORTISOLISM — terminology first, because the two names are not synonyms:

• Cushing SYNDROME — the clinical manifestations resulting from chronic exposure to excess cortisol, regardless of cause
• Cushing DISEASE — excess endogenous secretion of ACTH specifically

A Cushing-like syndrome may also develop as a side effect of long-term pharmacologic administration of glucocorticoids — a cause with no tumor to find, and the only one on this card that is prescribed rather than acquired.

HYPOCORTISOLISM:

• Two routes in: too little ACTH reaching the adrenals to stimulate them, or adrenals that cannot make and release their hormones in the first place
• Sometimes only part of the cortex is affected, so only cortisol, or only aldosterone, or only the adrenal androgens is lost

Addison disease is primary adrenal insufficiency. It is relatively rare, occurs most often between 30 and 60 years, and in the United States is most commonly caused by autoimmune destruction of adrenal cortical cells. Chronic infections affecting the adrenal — tuberculosis — account for the majority of cases in underdeveloped countries. It is characterised by inadequate corticosteroid AND mineralocorticoid synthesis with ELEVATED serum ACTH — the loss of negative feedback. It is associated with other autoimmune disease, especially Hashimoto thyroiditis, pernicious anemia and idiopathic hypoparathyroidism.

Laboratory in Addison disease: serum and urine cortisol are depressed and ACTH levels are increased. Blood urea nitrogen may rise from dehydration; serum glucose is low; eosinophil and lymphocyte counts are often elevated; hyperkalemia is seen and may cause mild alkalosis. The ACTH stimulation test is used to evaluate serum cortisol levels. Treatment is lifetime glucocorticoid and mineralocorticoid replacement, with dietary modification — at least 150 mEq of sodium per day, increased with excessive sweating or diarrhea — and additional cortisol during acute stressors such as infection, surgery or trauma.

Weight gain is the most common feature, and it results from accumulation of adipose tissue in the trunk, facial and cervical areas — described as truncal (central) obesity, moon face and buffalo hump.

The skin findings deserve their own mechanism, because they are the visual signature:

• Loss of collagen → thin, weakened integumentary tissue through which capillaries are more visible, and which is easily stretched by adipose deposits → the characteristic purple striae on the trunk
• Loss of collagenous support around small vessels → they rupture easily → easy bruising, even with minor trauma
• Thin, atrophied skin is easily damaged → skin breaks and ulcerations
• Bronze or brownish hyperpigmentation of skin, mucous membranes and hair occurs when ACTH levels are very high — the same MSH-precursor mechanism as in Addison disease

Glucose intolerance, specifically: two things cause it — cortisol makes tissues insulin-resistant, and it drives the liver to manufacture more glucose and stock more glycogen. The deck flags this as the association to know.

In children, cortisol interferes with the action of growth hormone in long bones — so a child presenting with short stature may be experiencing growth retardation from Cushing syndrome rather than growth hormone deficiency.

Laboratory and diagnosis:

• Routine labs may reveal hyperglycemia, glycosuria, hypokalemia and metabolic alkalosis
• Confirmatory tests: serum and urinary cortisol levels, serum ACTH levels, dexamethasone suppression testing
• Late-evening salivary cortisol is used as a screening test
• Tumors are diagnosed using imaging procedures

Treatment is specific to the cause — surgery, medication, radiation — and differentiating pituitary from ectopic from adrenal causes is essential. Without treatment, individuals with Cushing syndrome have a high risk of overwhelming infection and significant complications from generalised arteriosclerosis and hypertensive disease.

Virilism in females with ACTH-dependent disease — increased hair growth especially facial, acne, oligomenorrhea — follows the raised adrenal androgens. Voice changes, hairline recession and clitoral hypertrophy are rare unless an adrenal carcinoma is involved.

Start with what PTH does, because both diseases are this list turned up or down:

• Bone — stimulates osteoclasts, releasing calcium from bone into the bloodstream
• Kidney — increases renal calcium reabsorption, so less calcium is excreted; and enhances renal phosphate EXCRETION
• Intestine — promotes activation of vitamin D (calcitriol), which enhances calcium absorption from the gut

So PTH raises calcium and lowers phosphate. Hypercalcemia with hypophosphatemia is the hallmark of primary hyperparathyroidism; hypocalcemia with hyperphosphatemia is the hallmark of hypoparathyroidism.

HYPERPARATHYROIDISM — greater than normal PTH secretion with associated hypercalcemia:

• PRIMARY — inappropriate excess secretion by one or more glands, not under the usual feedback control. 80% to 85% parathyroid adenoma, 10%–15% hyperplasia, approximately 1% parathyroid carcinoma; genetic causes include multiple endocrine neoplasia. Calcium rises from increased bone resorption and GI absorption but fails to inhibit PTH secretion. Some individuals maintain normal calcium despite elevated PTH and are diagnosed only when they develop osteoporosis.
• SECONDARY — a compensatory response to chronic hypocalcemia, commonly from decreased activation of vitamin D in renal failure. PTH is elevated but not enough to achieve normal calcium, because activated vitamin D is insufficient. Other causes: dietary vitamin D or calcium deficiency, decreased intestinal absorption, and drugs — phenytoin, phenobarbital, laxatives — that accelerate vitamin D metabolism or decrease calcium absorption.
• TERTIARY — develops after any long-standing period of hypocalcemia — chronic dialysis, renal transplantation, GI malabsorption. Parathyroid chief cell hyperplasia leads to excessive PTH and may cause hypercalcemia. The gland that was compensating has become autonomous.

Why primary hyperparathyroidism makes stones — three variables that must all be present:

1. HYPERCALCIURIA — the tubules must filter large amounts of calcium
2. ABNORMALLY ALKALINE URINE
3. HYPERPHOSPHATURIA — from PTH-enhanced renal phosphate excretion, which also produces the hypophosphatemia

Together these predispose to calcium stones, particularly in the renal pelvis or collecting ducts, which may be associated with infection and impaired renal function. Chronic hypercalcemia is also associated with mild insulin resistance.

Symptoms of hypercalcemia, by system:

• Renal — renal colic, nephrolithiasis, recurrent urinary tract infections, renal failure; polyuria and polydipsia from a direct effect on the tubule decreasing responsiveness to ADH
• Bone — osteoporosis, pathologic fractures, kyphosis of the dorsal spine, compression fractures of the vertebral bodies; bone pain
• GI — anorexia, nausea and vomiting from central stimulation of the vomiting centre; constipation from decreased peristalsis; abdominal pain and peptic ulcer disease from hypercalcemia-stimulated hypergastrinemia; pancreatitis
• Neuromuscular — muscle weakness, myalgia, fatigue
• Neuropsychiatric — impaired memory, confusion, depression, anxiety, psychosis; headache
• Cardiovascular — hypertension

HYPOPARATHYROIDISM — abnormally low PTH:

• Most commonly caused by damage to the parathyroid glands during THYROID surgery, because of the anatomic proximity of the glands to the thyroid
• Hypomagnesemia inhibits PTH secretion — and this is reversible: when serum magnesium returns to normal, PTH secretion returns to normal. Causes include chronic alcoholism, malnutrition, malabsorption, increased renal clearance from aminoglycosides or certain chemotherapeutic agents, and prolonged magnesium-deficient parenteral nutrition.
• Genetic syndromes — familial hypoparathyroidism and DiGeorge syndrome
• Pseudohypoparathyroidism — an inherited defect in tissue RESPONSIVENESS to PTH, producing hypocalcemia despite normal to elevated PTH levels

The mechanism when PTH is absent:

1. IMPAIRED RESORPTION OF CALCIUM from bone and the renal tubules → HYPOCALCEMIA
2. INCREASED RENAL REABSORPTION OF PHOSPHATE → HYPERPHOSPHATEMIA
3. HYPERPHOSPHATEMIA FURTHER LOWERS CALCIUM by inhibiting the activation of vitamin D, thereby lowering GI calcium absorption — a second hit on the same ion

Manifestations of hypocalcemia:

• Muscle spasms, which can progress to TETANY; tingling, numbness and paresthesia; twitching; seizures
• Chvostek's sign and Trousseau's sign — clinical tests for neuromuscular irritability
• Prolonged QT interval on ECG
• Dry skin and loss of body and scalp hair
• Irreversible complications: teeth that fail to develop properly; nails with horizontal ridging; cataracts; calcium deposited in the basal ganglia, which can bring a parkinsonian syndrome with it; and skeletal deformity — shortened digits, and long bones that bow

Treatment:

• Hyperparathyroidism — parathyroidectomy for primary disease: removal of the solitary adenoma, or complete removal of three glands and partial removal of the fourth in hyperplasia. Calcimimetics increase parathyroid calcium receptor sensitivity and so lower PTH. Observation is recommended for asymptomatic individuals with mild hypercalcemia, who are advised to avoid dehydration and limit dietary calcium. Secondary disease in chronic renal disease: calcium replacement, dietary phosphate restriction and phosphate binders, vitamin D replacement, sometimes dialysis.
• Hypoparathyroidism — the goal is to maintain normal calcium and phosphorus. Acutely: parenteral calcium, which corrects serum calcium within minutes. Chronically: pharmacologic doses of cholecalciferol (vitamin D3) and oral calcium, with active vitamin D analogs; magnesium supplementation if hypomagnesemia is present. Recombinant human PTH replacement is safe and effective.

The rule that separates primary from secondary: if the serum calcium concentration is LOW despite elevated PTH, secondary hyperparathyroidism is likely — and evaluation of renal function may reveal chronic renal disease. Primary disease drives calcium up; secondary disease is chasing a calcium that will not come up.

Imaging and additional studies:

• Imaging procedures to localise adenomas before surgery
• Parathyroid scintigraphy — detects abnormal parathyroid glands
• Bone densitometry — assesses bone mineral density, which matters because some individuals with primary disease keep a normal calcium and are diagnosed only when osteoporosis appears
• Urine tests — increased urinary calcium excretion

Why the workup includes the kidney and vitamin D at all: secondary hyperparathyroidism is commonly associated with decreased activation of vitamin D in renal failure. Checking renal function and 25-hydroxyvitamin D is what distinguishes a gland that is malfunctioning from a gland that is responding correctly to a problem elsewhere.

Management follows the distinction. Observation for asymptomatic mild hypercalcemia. Surgical removal for more severe primary disease. For secondary disease, correct the underlying cause — calcium replacement, dietary phosphate restriction and phosphate binders, vitamin D replacement, dialysis in severe cases.