ENDOCRINE Flashcards

Question

Leptin

Answer 1

↓ Levels during: * Starvation * Sleep deprivation ↑ Levels in: * Obesity (due to leptin resistance) * Fed state Source: * Adipose tissue Effects: * ↓ Appetite (long term) * ↓ Neuropeptide Y release Leptin gene mutation causes obesity.

Answer 2

Regulation: * Protein-rich chyme Source: * L cells of the small and large intestine Effects: * ↓ Appetite (short term) * ↓ Gastric emptying

Answer 3

Regulation: * Glucose (cosecreted with insulin) Source: * β cells of the pancreas Effects: * ↓ Appetite (short term) * ↓ Gastric emptying * ↓ Glucagon release

Answer 4

FSH LH ACTH TSH CRH hCG ADH (V2- receptor) MSH PTH Calcitonin Histamine (H2-receptor) Glucagon GHRH

Answer 5

BNP ANP EDRF (NO)

Answer 6

GnRH ADH (V1-receptor) TRH Oxytocin Gastrin Angiotensin II Histamine (H1-receptor)

Answer 7

Progesterone Estrogen Testosterone Cortisol Aldosterone T3/T4 Vitamin D

Answer 8

IGF-1 FGF PDGF EGF Insulin TGF-β **MAP kinase pathway**

Answer 9

G-CSF Erythropoietin Thrombopoietin Prolactin Immunomodulators (eg, cytokines IL-2, IL-6, IFN) GH **JAK/STAT pathway** Think acidophils and cytokines GET a JAKed PIG

Answer 10

* A hormone produced by adipose tissue. * Modulates insulin sensitivity, enhances fatty acid breakdown and has anti-inflammatory effects. * Inversely related to adiposity.

Answer 11

↓ leptin ↑ ghrelin and insulin

Answer 12

Increased pituitary ADH secretion 1. CNS conditions * Stroke * Trauma, bleeding (subarachnoid hemorrhage) * Infection * Following neurosurgery (e.g., transsphenoidal pituitary surgery) * Psychosis 2. Chronic disease * Pulmonary (pneumonia, COPD) * HIV * Acute intermittent porphyria 3. Drugs * Anticonvulsants (e.g., carbamazepine, valproate) * Antidepressants * SSRIs (e.g., sertraline) * MAO inhibitors * TCAs (e.g., amitriptyline) * Antineoplastic agents * Mitotic inhibitors (e.g., vincristine) * Alkylating agents (e.g., cyclophosphamide, cisplatin) * Antipsychotics (e.g., haloperidol) * Analgesics (e.g., NSAIDS, opioids) * Illicit substances (e.g., MDMA) Paraneoplastic ectopic ADH production 1. Small cell lung carcinoma 2. Head and neck cancer 3. Extrapulmonary small cell carcinoma 4. Olfactory neuroblastoma Nephrogenic SIADH * Mutation of vasopressin-2 receptor gene (gain of function mutation causes constitutive receptor activation)

Answer 13

Most common form → caused by insufficient or absent hypothalamic synthesis or secretion of antidiuretic hormone (ADH) from the posterior pituitary Types: 1. 1. Primary (∼ ⅓ of cases) * Most cases are idiopathic. * The hereditary form is rare. * Autoimmune etiology of primary CDI has been suggested 2. Secondary (∼ ⅔ of cases) * Brain tumors (especially craniopharyngioma) and cerebral metastasis (most common → lung cancer and leukemia/lymphoma) * Neurosurgery → usually after the removal of large adenomas * Traumatic brain injury, pituitary bleeding, subarachnoid hemorrhage * Pituitary ischemia (e.g., Sheehan syndrome, ischemic stroke) * Infection (e.g., meningitis)

Answer 14

Rare → caused by defective ADH receptors in the distal tubules and collecting ducts Types: 1. Hereditary (mutation in ADH receptor) → very rare 2. Acquired * Adverse effect of medications (lithium, demeclocycline) * Hypokalemia, hypercalcemia (both lower responsiveness to ADH and sodium reabsorption) * Renal disease (e.g., autosomal dominant polycystic kidney disease, renal amyloidosis) * Pregnancy (due to transient ADH resistance in the 2nd half of pregnancy; called gestational diabetes insipidus)

Answer 15

* Psychiatric diseases (e.g. schizophrenia, obsessive-compulsive disorder) * Lesions in the hypothalamic thirst center

Answer 16

1. Intrasellar/parasellar masses (compress the pituitary gland and cause hypopituitarism) * Nonsecretory pituitary macroadenomas (≥ 10 mm in diameter) are the most common cause of hypopituitarism among adults (microadenomas (\< 10 mm) are usually too small to cause hypopituitarism) * Less common → meningiomas, craniopharyngiomas, internal carotid artery aneurysms, Rathke cleft cyst (a benign, intrasellar/suprasellar cyst that arises from the remnants of the Rathke pouch) (the sella turcica, which contains the pituitary gland, is surrounded laterally by the cavernous sinus (which contains the internal carotid artery), superiorly by the diaphragma sellae (a fold of dural matter), and inferiorly by the sphenoid sinus and Rathke pouch) 2. Pituitary apoplexy * Infarction of the pituitary gland as a result of ischemia and/or hemorrhage * Most commonly occurs in patients with a preexisting pituitary adenoma * Primarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressure arterial system and is, therefore, vulnerable to ischemia and infarction (in contrast, the posterior pituitary gland is thought to receive its blood supply from a higher-pressure arterial system. Accordingly, the posterior pituitary gland hormones, including antidiuretic hormone and oxytocin, are not typically affected in patients with pituitary apoplexy) * Sheehan syndrome → postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage. * During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia. * Blood loss during delivery/postpartum hemorrhage → hypovolemia → vasospasm of hypophyseal vessels → ischemia of the pituitary gland → empty sella turcica on imaging 3. Traumatic brain injury (especially around the skull base)

Answer 17

1. Infiltration of the pituitary and/or hypothalamus * Hemochromatosis * Sarcoidosis * Lymphocytic histiocytosis (infiltration of plasma cells and other lymphocytes leading to autoimmune destruction of the pituitary gland; usually seen during late pregnancy or in the postpartum period) * Langerhans cell histiocytosis * Infections → meningitis, TB, tertiary syphilis, toxoplasmosis, fungi (e.g., histoplasmosis) 2. Empty sella syndrome 3. Congenital deficiency of hypothalamic hormones * GnRH deficiency (Kallmann syndrome) * Prader-Willi syndrome

Answer 18

These procedures are performed to treat pituitary tumors 1. Hypophysectomy 2. Pituitary irradiation

Answer 19

* Infarction of the pituitary gland as a result of ischemia and/or hemorrhage * Most commonly occurs in patients with a preexisting pituitary adenoma * Primarily affects the anterior pituitary gland because it receives its blood supply from a relatively low-pressure arterial system and is, therefore, vulnerable to ischemia and infarction (in contrast, the posterior pituitary gland is thought to receive its blood supply from a higher-pressure arterial system. Accordingly, the posterior pituitary gland hormones, including antidiuretic hormone and oxytocin, are not typically affected in patients with pituitary apoplexy) * Sheehan syndrome → postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage. * Manifests with acute onset of: 1. Severe headache 2. Hypopituitarism 3. Bilateral hemianopia, diplopia (due to damage to CN III) 4. Sudden hypotension, possibly shock

Answer 20

* Postpartum necrosis of the pituitary gland. Usually occurs following postpartum hemorrhage, but can also occur even without clinical evidence of hemorrhage. * During pregnancy, hypertrophy of prolactin-producing regions increases the size of the pituitary gland, making it very sensitive to ischemia. * Blood loss during delivery/postpartum hemorrhage → hypovolemia → vasospasm of hypophyseal vessels → ischemia of the pituitary gland → empty sella turcica on imaging

Answer 21

Tumor mass effects * Headache, vision loss (bitemporal hemianopsia), cranial nerve palsies * ♀ → Oligomenorrhea, secondary amenorrhea, galactorrhea, vaginal atrophy * ♂ → Erectile dysfunction, decreased libido, ↓ testicular volume Soft tissue effects * Doughy skin texture, hyperhidrosis (caused by enlarged sweat glands) * Deepeninf the voice, macroglossia with fissures, obstructive sleep apnea (caused by enlargement of larynx and pharynxg o in addition to macroglossia) Skeletal effects * Coarsening of facial features slowly progressing with age → enlarged nose, forehead, and jaw (macrognathia) with diastema (enlarged gap between the top incisors) * Widened hands, fingers, and feet * Painful arthropathy (ankles, knees, hips, spine) Consider acromegaly in patients who report having had to increase hat, shoe, glove, and ring sizes in the past!

Answer 22

Hormone analysis 1. Serum IGF-1 concentration → the best single test (interpretation based on age-adapted IGF-1 levels, which are highest during puberty and decrease with age. Due to its half-life of several hours and constant secretion (as opposed to GH), a single test is already conclusive) * Elevated IGF-1 level → acromegaly suspected; conduct - oral glucose tolerance test (OGTT). * Normal IGF-1 level → acromegaly ruled out 2. Oral glucose tolerance test (OGTT) with baseline GH and measure GH after 2 hours → the most specific test (food intake elevates blood sugar levels, which leads to a physiological decrease in GH secretion. In patients with acromegaly, this regulatory mechanism has no effect on ectopic production of GH. Accordingly, acromegaly can be ruled out if GH is suppressed following a glucose load) * If GH suppressed → acromegaly ruled out * If GH not suppressed → confirmed acromegaly; conduct pituitary MRI to determine the source of excess GH Pituitary MRI Imaging modality of choice * Usually shows a visible mass → confirmed GH-secreting pituitary adenoma * If normal → screen for an extrapituitary cause (e.g., CT scan of the chest and abdomen, measure GHRH)

Answer 23

* Transsphenoidal adenomectomy is the method of choice for treating acromegaly. * In patients with inoperable tumors or unsuccessful surgery, medication and radiotherapy are indicated to reduce tumor size and limit the effects of GH and IGF-1 (adequate treatment may improve the prognosis by partially reversing and preventing complications of GH and IGF-1 (e.g., reduced soft tissue swelling improves sleep apnea)) Surgery * Transsphenoidal adenomectomy (preferred method) * Surgical debulking (in patients with parasellar disease and inoperable tumors) Medication * Somatostatin analogs (e.g., octreotide, lanreotide) (may reduce GH secretion and tumor size. However, not all pituitary adenomas respond) * Dopamine agonists (e.g., cabergoline) → reduce tumor size and GH secretion * GH receptor antagonists (e.g., pegvisomant) (bind to GH receptors without activating these, thereby inhibiting the effects of GH. However, tumor size is not decreased by receptor antagonists) Radiotherapy

Answer 24

Complications lead to increased mortality. * Cardiovascular complications → the main cause of death 1. Hypertension (∼ 30% of cases) (the exact cause of hypertension in patients with acromegaly is unknown. Hypertrophy and cardiomyopathy are partially attributable to direct cell proliferation, and partially to hypertension) 2. Left ventricular hypertrophy and cardiomyopathy 3. Arrhythmia 4. Valvular disease Impaired glucose tolerance and diabetes mellitus (up to 50% of cases) * Colorectal polyps and cancer * Thyroid enlargement and cancer (despite the thyroid being enlarged, thyroid hormone levels are usually normal) * Carpal tunnel syndrome (edematous swelling of the synovial tendon sheaths and local proliferation of connective tissue) * Cerebral aneurysm * Hypopituitarism * Psychological impairment (↓ quality of life, anxiety, ↓ self-esteem)

Answer 25

1. 1. Sporadic (∼ 85% of cases) * Thyroid hypoplasia, dysplasia, or ectopy * Thyroid aplasia (athyroidism) * Transplacental transmission of maternal antithyroid antibodies Iodine deficiency 2. Hereditary (∼ 15% of cases) * Dyshormonogenetic goiter → defects in thyroid hormone synthesis (most commonly in thyroid peroxidase) lead to thyroid hyperplasia and goiter. * Peripheral resistance to thyroid hormones

Answer 26

* Primary hypothyroidism → insufficient thyroid hormone production 1. Hashimoto thyroiditis * The most common cause of hypothyroidism in iodine-sufficient regions * Associated with other autoimmune diseases (e.g., vitiligo, pernicious anemia, type 1 diabetes mellitus, and systemic lupus erythematosus) 2. Postpartum thyroiditis (subacute lymphocytic thyroiditis) 3. De Quervain thyroiditis (subacute granulomatous thyroiditis) → often subsequent to a flu-like illness 4. Iatrogenic → e.g., post thyroidectomy, radioiodine therapy, antithyroid medication (e.g., amiodarone, lithium) 5. Nutritional (insufficient intake of iodine) → the most common cause of hypothyroidism worldwide, particularly in iodine-deficient regions 6. Riedel thyroiditis → occurs in IgG4-related systemic disease 7. Wolff-Chaikoff effect * Secondary hypothyroidism → pituitary disorders (e.g., pituitary adenoma) → TSH deficiency * Tertiary hypothyroidism → hypothalamic disorders → TRH deficiency

Answer 27

* Generalized decrease in the basal metabolic rate → decreased oxygen and substrate consumption, leading to: 1. CNS → apathy, slowed cognition 2. Skin and appendages → skin dryness, alopecia 3. Lipid profile → ↑ low-density lipoproteins, ↑ triglycerides 4. Cold intolerance * Decreased sympathetic activity leads to: 1. Decreased sweating 2. Cold skin (due to decreased blood flow) 3. Constipation (due to decreased gastrointestinal motility) 4. Bradycardia * Decreased transcription of sarcolemmal genes (e.g., calcium ATPases) → decreased cardiac output, myopathy * Hyperprolactinemia → ↑ prolactin production is stimulated by TRH → suppression of LH, FSH, GnRH, and testosterone and stimulation of breast tissue growth * Myxedema → due to accumulation of glycosaminoglycans and hyaluronic acid within the reticular layer of the dermis * Complex protein mucopolysaccharides bind water → nonpitting edema * Initially, edema is pretibial, but as the condition progresses it can generalize, resulting in a range of symptoms

Answer 28

* Symptoms related to decreased metabolic rate 1. Fatigue, decreased physical activity 2. Cold intolerance 3. Decreased sweating 4. Hair loss, brittle nails, and cold, dry skin 5. Weight gain (despite poor appetite) 6. Constipation 7. Bradycardia * Hypothyroid myopathy (can manifest with elevated serum creatinine kinase levels), myalgia, stiffness, cramps * Woltman sign → a delayed relaxation of the deep tendon reflexes, which is commonly seen in patients with hypothyroidism, but can also be associated with advanced age, pregnancy, and diabetes mellitus. * Entrapment syndromes (e.g., carpal tunnel syndrome) * Symptoms related to generalized myxedema * Doughy skin texture, puffy appearance * Myxedematous heart disease (dilated cardiomyopathy, bradycardia, dyspnea) * Hoarse voice, difficulty articulating words * Pretibial and periorbital edema * Myxedema coma * Symptoms of hyperprolactinemia * Abnormal menstrual cycle (esp. secondary amenorrhea or menorrhagia) * Galactorrhea (lactation in individuals (both men and women) who are not breastfeeding) * Decreased libido, erectile dysfunction, delayed ejaculation, and infertility in men * Further symptoms * Impaired cognition (concentration, memory), somnolence, depression (especially in elderly individuals) * Hypertension (hypothyroidism can increase peripheral vascular resistance and therefore elevate blood pressure, especially in hypertensive patients) * Goiter (in Hashimoto thyroiditis) or atrophic thyroid (in atrophic thyroiditis) * Older patients may not have typical symptoms of hypothyroidism. Instead, they may appear to have dementia or depression.

Answer 29

* Children with congenital hypothyroidism may have general signs and symptoms of hypothyroidism in addition to those typical in neonates. Postpartum 1. Umbilical hernia 2. Prolonged neonatal jaundice 3. Hypotonia 4. Decreased activity, poor feeding, and adipsia (absence of thirst, even in the case of dehydration) 5. Hoarse cry, macroglossia * Congenital iodine deficiency syndrome → a complication of congenital hypothyroidism that manifests leads to an impaired development of the brain and skeleton, resulting in skeletal abnormalities (e.g., short stature and delayed fontanelle closure) and intellectual disabilities Most children with congenital hypothyroidism do not have symptoms at the time of birth because the placenta supplies the fetus with maternal thyroid hormone. For this reason, neonatal screening is vital even if children are asymptomatic. Irreversible intellectual disabilities can be avoided through early initiation of adequate therapy!

Answer 30

* Etiology → occurs in severe illness or severe physical stress (most common in intensive care patients) * Normal thyroid function → no symptoms of hyperthyroidism or hypothyroidism * Cytokines (e.g., interleukin 6) cause various changes in levels of circulating TSH and thyroid hormones. * Altered deiodinase enzyme activity * ↓ Conversion of T4 to T3 * ↑ Conversion of T4 to reverse T3 (rT3) by thyroxine 5-monodeiodinase * ↓ Thyroid binding globulin * Clinical features → specific to underlying nonthyroidal illness * Laboratory * Low T3 syndrome → decrease in both total and FT3 levels, normal FT4 and TSH, and increased reverse T3 * Low T3 low T4 syndrome → FT4 levels may be low in prolonged courses of illness (indicates a poor prognosis) * Treatment * Treat underlying illness * Thyroid hormone replacement is usually not recommended because thyroid function is normal (there is not conclusive evidence that thyroid hormone substitution is beneficial to patients with ESS)

Answer 31

* Insufficient end-organ sensitivity to thyroid hormones * Etiology → deficits in thyroid hormone metabolism, transport, or receptor interaction as a result of genetic mutations * Clinical features → symptoms of both hypothyroidism and hyperthyroidism are possible. * Laboratory → Persistently elevated FT4 and FT3 and absent TSH suppression is typical. * Therapy → No causative therapy is available.

Answer 32

**Increased dosage necessary** 1. Estrogen 2. SERM (increase thyroxin-binding globulin (TBG) in the serum) 3. Bile acid-binding resins 4. Omeprazole 5. Calcium carbonate (reduces gastrointestinal absorption of thyroid hormone) 6. Phenytoin 7. Carbamazepine (increases metabolism of thyroid hormones) 8. Propranolol (reduces conversion of T4 to T3) **Reduced dosage necessary** → glucocorticoids (decrease TBG in the serum)

Answer 33

* Extremely rare condition caused by the decompensation of an existing thyroid hormone deficiency and can be triggered by infections, surgery, and trauma. * Potentially life-threatening condition and, if left untreated, is fatal in ∼ 40% of cases. * Clinical presentation * Cardinal symptoms → impaired mental status, hypothermia, and concurrent myxedema * Hypoventilation with hypercapnia * Hypotension (possibly shock) and bradycardia * Diagnosis * TSH and T4 (to evaluate thyroid function) * Cortisol (to exclude concomitant adrenal insufficiency) * Hypoglycemia and hyponatremia (their presence can be due to hypothyroidism alone or also due concomitant adrenal insufficiency) * ↑ CK and LDH * ECG → low-voltage QRS complexes, flattened or inverted T waves * CSF analysis → slightly ↑ CSF protein * Treatment: * IV combination of levothyroxine and liothyronine plus IV hydrocortisone (until concomitant adrenal insufficiency is ruled out) * Patients should be treated and monitored in an ICU.

Answer 34

* Painless goiter * Early-stage → rubbery and symmetrically enlarged * Late-stage → normal-sized or small if extensive fibrosis has occurred Iodine uptake on scintigraphy → patchy and irregular * Pathology findings: * Lymphocytic infiltration with germinal centers and oncocytic-metaplastic cells (Hurthle cells)

Answer 35

* Diffuse and firm painless goiter Iodine uptake on scintigraphy → reduced * Pathology findings: * Lymphocytic infiltration and disrupted thyroid follicles with occasional germinal center formation

Answer 36

* Associated with HLA-B35 * Painful, diffuse and firm goiter * Increase thyroglobulin * Decrease blood flow on thyroid ultrasound * ↑ ESR * Iodine uptake on scintigraphy → reduced * Pathology findings: * Multinucleated giant cells and granuloma formation

Answer 37

* Painless diffuse or nodular goiter * Iodine uptake on scintigraphy → absent or patchy * Pathology findings: * Depend on the cause

Answer 38

* Painless, slowly growing and stone-hard goiter * Iodine uptake on scintigraphy → normal or reduced * Pathology findings: * Dense and white fibrotic tissue, macrophages, eosinophils

Answer 39

* Hyperfunctioning tissue takes up large amounts of radioactive iodine * The rest of the glandular tissue is suppressed and does not take up the RAI

Answer 40

* Non-functioning nodules do not take up any radioactive iodine and appear "cold”, but the surrounding normal thyroid tissue takes up radioactive iodine and appears "warm"

Answer 41

* Changes to morphology → diffuse enlargement or nodules * Increased perfusion → either diffuse (Graves disease, toxic adenoma) or nodular (toxic MNG) * Decreased perfusion → destructive causes of hyperthyroidism (e.g., subacute thyroiditis or postpartum destructive thyroiditis) * Hypoechoic areas in acute thyroiditis and malignancy

Answer 42

* Iatrogenic * Thyroid surgery (manipulation of the thyroid causes the release of thyroid hormones. Pretreatment with beta blockers, antithyroid drugs, and potassium iodide has drastically decreased the incidence of thyroid storm in patients undergoing surgery) * Radioactive iodine ablation (RAIA) * Exogenous iodine from contrast media or amiodarone * Discontinuation of antithyroid medication (most commonly discontinuation of medication in Graves disease) * Stress-related catecholamine surge (worsens the preexisting hyperadrenergic state of hyperthyroidism) * Nonthyroidal surgery * Anesthesia induction * Labor * Intercurrent illness, e.g., sepsis, myocardial infarction, diabetic ketoacidosis

Answer 43

* Hyperpyrexia with profuse sweating * Tachycardia (\> 140/minute) and (possibly severe) arrhythmia (e.g., atrial fibrillation), hypertension with wide pulse pressure, congestive cardiac failure (the cardiovascular system is often most severely affected) * Hypotension/shock secondary to high output heart failure or hypovolemia as a result of GI and insensible losses * Symptoms of thyrotoxicosis * Abdominal pain * Severe nausea, vomiting, diarrhea, possibly jaundice * Severe agitation and anxiety, delirium and psychoses, seizures, coma (neuropsychiatric symptoms are seen in most cases of thyroid storm)

Answer 44

* Inhibition of thyroid hormone synthesis * First line → propylthiouracil (generally preferred over methimazole for the initial treatment of thyroid storm because it additionally inhibits peripheral conversion of T4 to T3) * Alternative → methimazole * Inhibition of thyroid hormone release (through the Wolff-Chaikoff effect) 1. First line → iodine solutions given at least 1 hour after antithyroid drugs (to avoid exacerbation of thyroid storm due to increased iodine uptake) * Potassium iodide solution * Lugol solution 2. In patients with iodine allergy or iodine-induced thyrotoxicosis, lithium can be used. * Inhibition of peripheral conversion of T4 to T3 1. Propranolol (inhibition of peripheral T4 hormone conversion is a secondary effect or propranolol in addition to beta blockade) 2. Glucocorticoids → can also treat concurrent adrenal insufficiency (relative adrenal insufficiency can occur during thyroid storm because of hypermetabolism and accelerated turnover of cortisol; cortisol levels are thus inappropriately low or normal compared to other situations with significant stress) * First line → hydrocortisone * Alternative → dexamethasone

Answer 45

* Painless diffuse and smooth goiter * Thyroid function tests → ↓/Undetectable TSH, ↑ T3/T4 * Antibodies → ↑ TRAbs, anti-TPO antibody, and anti-Tg * Iodine uptake on scintigraphy → diffuse * Pathologic findings: * Diffuse hyperplasia and hypertrophy of follicular cells

Answer 46

* Painless multi nodular goiter * Thyroid function tests → ↓ TSH, ↑ T3/T4 Antibodies → absent * Iodine uptake on scintigraphy → multiple focal areas of increased uptake * Pathologic findings: * Patches of enlarged follicular cells distended with colloid and flattened epithelium

Answer 47

* Painless diffuse and firm goiter * ↑ ESR * Thyroid function tests: * Thyrotoxic phase → ↓ TSH, ↑ T3/T4, and ↑ thyroglobulin * Hypothyroid phase → ↑ TSH and ↓ T3/T4 * Antibodies → Anti-TPO antibody * Iodine uptake on scintigraphy → reduced * Pathologic findings: * Absence of germinal follicles, lymphocytic infiltration on histology

Answer 48

* Painless goiter * Thyroid function tests → ↓ TSH, ↑ T3/T4 * Antibodies → possible ↑ TRAb in patients with Graves disease * Iodine uptake on scintigraphy → reduced * Pathologic findings: * Depends on underlying thyroid disorder

Answer 49

* Follicular adenoma is the most common type of thyroid adenoma * Clinical features * Often presents as a slow-growing solitary nodule * Patients are typically euthyroid. * In rare cases, patients can manifest with clinical features of hyperthyroidism (∼ 1% of follicular adenomas develop into toxic adenomas) * Diagnostics * Follicular adenoma is a histopathological diagnosis. * Cytology alone cannot distinguish between adenoma and carcinoma. * Thyroid function tests → TSH is typically normal. * Thyroid ultrasound → may show sonographic signs of malignancy or appear benign * FNAC * Follicular neoplasm or follicular lesion of undetermined significance * Cannot distinguish between follicular adenoma and carcinoma * Confirmatory test * Surgical excision (e.g., hemithyroidectomy) with histologic analysis * Findings → normal follicular structure with no tumor invasion into the surrounding tissues (e.g., capsule, blood vessels) * Treatment * Thyroid surgery is always indicated, both for definitive diagnosis and treatment. * Initial surgical excision shows no evidence of cancer → no further treatment required * If follicular cancer is identified on histopathology → completion thyroidectomy and adjuvant treatment of thyroid cancer as needed

Answer 50

* Third most common cause of hyperthyroidism * Gain-of-function mutations of TSH receptor gene in a single precursor cell → autonomous functioning of the thyroid follicular cells of a single nodule → focal hyperplasia of thyroid follicular cells → toxic adenoma * The autonomous thyroid nodule overproduces thyroid hormones → hyperthyroidism → decrease in pituitary TSH secretion → suppression of hormone production in the rest of the gland * Clinical features * Palpable, usually painless nodule in otherwise normal gland * Symptoms of thyrotoxicosis * Diagnostics * Thyroid function tests → ↑ T3 and ↓ TSH * Thyroid ultrasound → sonographic signs of a benign thyroid nodule; in some cases, increased perfusion * Thyroid scintigraphy → solitary, hot nodule; suppression of rest of the gland * FNAC → indicated not as a confirmatory test for toxic adenoma but to identify malignancy in suspicious nodules * Treatment 1. Initial management → treatment of hyperthyroidism * Beta blockers for symptom control * Antithyroid drugs to achieve euthyroidism 2. Definitive treatment options * Hemithyroidectomy or isthmusectomy for a solitary toxic adenoma * Radioactive iodine ablation (RAIA) * Less invasive therapy (e.g., ethanol ablation, radiofrequency ablation, laser ablation) may be considered in patients who are neither candidates for surgery nor RAIA

Answer 51

* Age → often \> 60 years * Second most common cause of hyperthyroidism * Develops in 10% of patients with a long-standing nodular goiter * More prevalent in iodine-deficient regions * Chronic iodine deficiency/thyroid dysfunction → decreased hormone production → increased hypothalamic TRH secretion → persistent TSH stimulation of the thyroid gland → hyperplasia of thyroid nodules, some more active than others → multinodular goiter (nontoxic MNG) * Multiple somatic mutations of TSH receptor occur in long-standing goiters (\> 60% of cases) → autonomous functioning of some nodules (toxic MNG) → hyperthyroidism (due to ↑ release of both T3 and T4) * Clinical features * Painless goiter with multiple palpable nodules * Symptoms of thyrotoxicosis * Diagnostics * Thyroid function tests → ↑ T3 and ↓ TSH * Thyroid ultrasound → multiple nodules within the thyroid parenchyma; increased perfusion * Thyroid scintigraphy → increased radioiodine uptake by multiple hyperfunctioning (hot) nodules; decreased uptake (suppression) by the rest of the gland and intervening parenchyma; hypofunctioning or cold nodules may also be present in the multinodular gland. * FNAC → not routinely required * Histopathology of resected tissue → patches of enlarged follicular cells distended with colloid and with flattened epithelium * Treatment * Initial management → treatment of hyperthyroidism 1. Beta blockers for symptom control 2. Antithyroid drugs to achieve euthyroidism * Definitive treatment options 1. Total thyroidectomy or near-total thyroidectomy 2. Radioactive iodine ablation

Answer 52

* Simple cysts are exclusively fluid-filled nodules lined by benign epithelial cells. * Complex cysts are partly solid and partly cystic and carry a 5–10% risk of malignancy. Malignancy risk is higher in cysts with a \> 50% solid component. * Most commonly due to cystic degeneration of thyroid tissue or involution of an adenoma * Clinical features * Palpable thyroid nodule * Hemorrhage into a cyst → pain and rapid enlargement of the nodule * A large cyst or extensive hemorrhage can cause compression symptoms (e.g., hoarseness, dysphagia). * Diagnostics * Thyroid function tests → typically normal * Thyroid ultrasound → cystic components appear anechoic; may be mixed with solid components * FNAC * Purely cystic nodule → diagnostic FNAC not recommended * Partly cystic nodule → low risk pattern (eccentric solid component) → FNAC if size is ≥ 1.5 cm; very low risk pattern → consider FNAC if size is ≥ 2 cm. * Treatment * Benign cysts * Asymptomatic cysts → observation * Large or symptomatic cysts (or patient preference) 1. Aspiration with/without ethanol ablation 2. Surgery may be considered if aspiration is not effective

Answer 53

- Associated with MEN2 (RET gene mutations) or familial medullary carcinoma

Answer 54

- Associated with RET/PTC rearrangements and BRAF mutations - Ionizing Radiation (particularly during childhood) Incidence of thyroid cancer (especially papillary) increased after the atomic bombing of Hiroshima and Nagasaki, as well as after the Chernobyl disaster.

Answer 55

- Associated with PAX8-PPAR-γ rearrangement and RAS mutation

Answer 56

- Associated with TP53 mutation

Answer 57

- Large, polygonal epithelial cell with eosinophilic granular cytoplasm as a result of numerous altered mitochondria - Nonspecific -Observed in Hashimoto thyroiditis, Graves disease, previously-irradiated thyroid glands, and in Hurthle cell adenoma (no vascular or capsular invasion; no metastasis) - They are also found in the parathyroid glands, salivary glands, and kidneys

Answer 58

- Solid or mostly solid hypoechoic nodule(s) (echogenicity of the nodule is evaluated relative to the adjacent strap muscles. Approximately 90% of thyroid cancers are solid (i.e., not cystic and not spongiform). Purely cystic or spongiform lesions are typically benign) - Irregular margins (irregular margins can be infiltrative, lobulated, or spiculated) - Microcalcifications within nodules - Nodules that are taller than wide (signifying growth unrestricted by anatomic planes) - Extrathyroidal growth

Answer 59

- Thyroglobulin (Tg) → precursor of thyroid hormones; produced exclusively by the thyroid gland - Indicated after total thyroidectomy or radioactive iodine ablation (RAIA) therapy (Tg levels should be undetectable after a successful total thyroidectomy or RAIA) - Baseline (pretreatment) levels are not routinely indicated.

Answer 60

- Thyroglobulin (Tg) → precursor of thyroid hormones; produced exclusively by the thyroid gland - Indicated after total thyroidectomy or radioactive iodine ablation (RAIA) therapy (Tg levels should be undetectable after a successful total thyroidectomy or RAIA) - Baseline (pretreatment) levels are not routinely indicated.

Answer 61

1. Calcitonin → hormone secreted by parafollicular cells, which is the tissue of origin of medullary carcinoma - Indicated preoperatively if FNAC is suspicious for medullary carcinoma (supportive diagnostic marker) - Used to monitor response to therapy 2. Carcinoembryonic antigen (CEA) → nonspecific marker, used in combination with calcitonin to monitor response to therapy

Answer 62

- Empty-appearing large oval nuclei with central clearing Occurrence 1. Papillary thyroid carcinomas 2. Autoimmune thyroiditis (e.g., Hashimoto disease, Grave disease)

Answer 63

- Longitudinal invaginations of nuclear bilayer Occurrence: 1. Papillary thyroid carcinomas

Answer 64

1. “Orphan Annie” Eyes Nuclei - Empty-appearing large oval nuclei with central clearing 2. Nuclear Grooves - Longitudinal invaginations of nuclear bilayer 3. Psammoma bodies - Concentric lamellar calcifications - Seen in diseases associated with calcific degeneration

Answer 65

- Ovoid cells of C cell origin and therefore without follicle development - Amyloid in the stroma (stains with Congo red)

Answer 66

- Uniform follicles (absence of follicles and nuclear atypia are associated with poor prognosis) - Vascular and/or capsular invasion (to distinguish follicular adenoma, in which there is no invasion of the thyroid capsule)

Answer 67

- Undifferentiated giant cell (i.e., osteoclast-like cell) - Areas of necrosis and hemorrhage

Answer 68

1. Well-differentiated thyroid cancer Total thyroidectomy (with neck dissection as needed) 2. Poorly-differentiated thyroid cancer - Total thyroidectomy + neck dissection ± radiation therapy and/or systemic chemotherapy as needed (RAIA and TSH suppression therapy is not required in the management of medullary carcinoma as it does not arise from thyroid follicular cells. Thyroid hormone replacement will be required after total thyroidectomy.)

Answer 69

- Postoperative → most commonly occurs as the result of accidental injury to parathyroids (or their blood supply) during thyroidectomy, parathyroidectomy, or radical neck dissection - Autoimmune → second most common cause - Nonautoimmune destruction 1. Infiltration of parathyroid gland - Wilson disease - Hemochromatosis - Granulomas - Metastases 2. Radiation-induced destruction 3. Gram-negative sepsis 4. Toxic shock syndrome 5. HIV infection - Congenital 1. Parathyroid gland aplasia or hypoplasia (DiGeorge syndrome) 2. PTH gene mutation 3. Autosomal dominant hypocalcemia (mutation of calcium-sensing receptors that causes these receptors to be active even at normal calcium levels. These receptors then bind calcium, decreasing levels of free serum calcium.)

Answer 70

- Acute manifestations 1. Symptoms of hypocalcemia, such as tetany - Chronic manifestations 1. Extrapyramidal disorders (secondary to basal ganglia calcifications) - Parkinsonism - Dystonia - Hemiballismus - Choreoathetosis - Oculogyric crises - Dementia 2. Ocular disease - Cataracts - Keratoconjunctivitis 3. Skeletal manifestations - Increased bone mineral density - Osteosclerosis 4. Dental abnormalities - Dental hypoplasia - Failure of tooth eruption - Defective root formation 5. Cutaneous manifestations - Dry, puffy, coarse skin

Answer 71

- Chvostek sign - Trousseau sign Laboratory tests - Hypocalcemia with low or inappropriately normal PTH - Hyperphosphatemia - Normal 25-hydroxyvitamin D (25[OH]D) - Normal or low 1,25-dihydroxyvitamin D (1,25[OH]2D) → low concentration of PTH cannot stimulate renal production of 1,25[OH]2D - Normal magnesium - Normal creatinine

Answer 72

- End-organ (i.e., bones and kidneys) resistance to parathyroid hormone (PTH) despite sufficient PTH synthesis due to a defective Gs protein α subunit - Autosomal dominant - Inherited from the mother (GNAS gene imprinting) - Mutations in GNAS1 → impaired encoding of α subunit → missing activation of adenylate cyclase when PTH binds to Gs → resistance to PTH in kidney and bone tissue Clinical features 1. Albright hereditary osteodystrophy (AHO) - Round face - Short stature - Obesity - Brachydactyly of the 4th and 5th fingers - Intellectual disability - Subcutaneous ossifications 2. Symptoms related to low calcium and high phosphate levels - Seizures - Numbness, tetany - Cataracts - Dental problems Diagnostics Persistent hypocalcemia despite ↑ PTH levels ↑ Phosphate levels

Answer 73

- Extremely rare condition that mimics PHP1A but without end-organ resistance to PTH - Autosomal dominant - Defective Gs protein α subunit is inherited from the father (GNAS gene imprinting). - The normal allele from the mother allows for maintaining the responsiveness of the kidneys to PTH. Clinical features: - Albright hereditary osteodystrophy (individuals affected by pseudopseudohypoparathyroidism show the clinical features of AHO, but do not experience symptoms related to low calcium and high phosphate levels, unlike in PHP1A) Diagnostics: Normal calcium, PTH, and phosphate

Answer 74

- Round face - Short stature - Obesity - Brachydactyly of the 4th and 5th fingers - Intellectual disability - Subcutaneous ossifications

Answer 75

Mutation of calcium-sensing receptors that causes these receptors to be active even at normal calcium levels. These receptors then bind calcium, decreasing levels of free serum calcium

Answer 76

Hypercalcemia results from abnormally active parathyroid glands.

Answer 77

Hypocalcemia results in reactive overproduction of PTH.

Answer 78

Hypercalcemia results from untreated sHPT, with continuously elevated PTH levels.

Answer 79

1. Parathyroid gland adenoma (∼ 85%) → benign tumor of the parathyroid glands 2. Hyperplasia and multiple adenomas (∼ 15%) 3. In rare cases, carcinomas (∼ 0.5%) or idiopathic 4. MEN type 1 or 2 5. Lithium

Answer 80

1. Chronic kidney disease (most frequent cause) 2. Malnutrition 3. Vitamin D deficiency (e.g., reduced exposure to sunlight, nutritional deficiency, liver cirrhosis) 4. Cholestasis (bile is necessary for the absorption of fat in the intestines. Vitamin D3 is a fat-soluble agent and requires bile to be absorbed)

Answer 81

Caused by persistent secondary hyperparathyroidism In longstanding secondary hyperparathyroidism, the parathyroid glands may become severely enlarged and continue to be overactive, even if the original stimulus (e.g., hypocalcemia) is no longer present.

Answer 82

* Genetic defects in the β cell function * Different forms of autosomal dominant inherited diabetes mellitus that manifest before the age of 25 years and are not associated with obesity or autoantibodies * 6 subtypes, the most common being MODY II and MODY III * Caused by genetic defects in the glucokinase gene and hepatocyte nuclear factor-1-α, respectively * In contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite stable hyperglycemia and chronically elevated HbA1C levels * All other subtypes require medical treatment, either with insulin or sulfonylureas

Answer 83

- Variety of metabolic effects on the body, primarily contributing to the generation of energy reserves and glycemic control. - Carbohydrate metabolism → insulin is the only hormone in the body that lowers the blood glucose level (stimulates glucose uptake into cells and glycogen production; inhibits glycogenolysis and gluconeogenesis) - Protein metabolism → stimulates protein synthesis (muscles). Stimulates amino acid uptake into cells; inhibits proteolysis - Lipid metabolism → maintains a fat depot and has an antiketogenic effect (stimulates fatty acid uptake into cells and lipogenesis; inhibits lipolysis and the β-oxidation of free fatty acids in the liver) - Electrolyte regulation → stimulates intracellular potassium accumulation (directly stimulates Na+/K+ ATPase and promotes intracellular alkalosis, reduces phosphate levels (glucose binds to phosphate in the cell), and stimulates magnesium uptake into cells). Increase Na retention in kidneys

Answer 84

Two major mechanisms: 1. Peripheral insulin resistance - Numerous genetic and environmental factors -- Central obesity → increased plasma levels of free fatty acids → impaired insulin-dependent glucose uptake into hepatocytes, myocytes, and adipocytes (the absence of the insulin-dependent inhibition of hepatic glycogenolysis and gluconeogenesis further promotes hyperglycemia) -- Increased serine kinase activity in liver, fat and skeletal muscle cells → phosphorylation of insulin receptor substrate (IRS)-1 → decreased affinity of IRS-1 for PI3K → decreased expression of GLUT4 channels → decreased cellular glucose uptake 2. Pancreatic β cell dysfunction - Accumulation of pro-amylin (islet amyloid polypeptide) in the pancreas → decreased endogenous insulin production. - Peripheral insulin resistance creates a huge demand for glucose lowering hormones, resulting in increased production of pro-insulin and pro-amylin. The pancreatic proteolytic enzymes that convert pro-insulin and pro-amylin into insulin and amylin are not able to keep up with the high levels of secretion, which leads to the accumulation of pro-amylin. - The exact mechanism by which pro-amylin aggregates decrease insulin production is not completely understood. - Initially, insulin resistance is compensated by increased insulin and amylin secretion (postprandial hypoglycemia may occur due to reactively elevated insulin secretion, stimulating rapid glucose uptake into cells (regulatory hyperinsulinemia)) - Over the course of the disease, insulin resistance progresses, while insulin secretion capacity declines. - After a period of impaired glucose tolerance with isolated postprandial hyperglycemia, diabetes manifests with fasting hyperglycemia.

Answer 85

- A single random blood glucose level ≥ 200 mg/dL is sufficient for diagnosis - Fasting plasma glucose (FPG) in mg/dL (mmol/L) ≥ 126 (≥ 7.0) - 2-hour glucose value after oral glucose tolerance test (OGTT) in mg/dL (mmol/L) ≥ 200 (≥ 11.1) - Hemoglobin A1C (HbA1c or A1C) in % ≥ 6.5 Additional tests 1. Specific autoantibodies for diabetes mellitus type 1 - Anti-GAD antibodies - Anti-tyrosine phosphatase-related islet antigen (IA-2) - Islet cell surface antibody (ICSA; against ganglioside) (Anti-GAD and Anti-IA-2 are positive in \> 90% of cases) 2. C-peptide - ↓ C-peptide levels indicate an absolute insulin deficiency → type 1 diabetes - ↑ C-peptide levels may indicate insulin resistance and hyperinsulinemia → type 2 diabetes 3. Urine analysis - Microalbuminuria → an early sign of diabetic nephropathy (over the course of the disease, the level of albuminuria correlates with the risk of cardiovascular and renal complications) - Glucosuria → Testing urine for glucose does not suffice to establish the diagnosis of diabetes mellitus. The renal threshold for glucose is reached if the blood glucose level exceeds 150–180 mg/dL (8.3–10 mmol/L). Higher blood glucose levels lead to urinary glucose excretion. In some conditions, glucosuria may occur despite normoglycemia (e.g., tubulointerstitial nephritis, physiological in pregnancy). In addition, the renal threshold may be increased in diabetic kidney disease; glucosuria may be absent despite hyperglycemia as a result. Therefore, it is important to measure fasting glucose levels. - Ketone bodies (usually accompanied by glucosuria) → positive in acute metabolic decompensation in diabetes mellitus (diabetic ketoacidosis)

Answer 86

- Rare neuroendocrine tumor of the pancreas that secretes glucagon. In \> 50% of cases, metastasis is present at diagnosis. Clinical Findings: - Nonspecific symptoms, weight loss (80%), necrolytic migratory erythema (70%), impaired glucose tolerance or diabetes mellitus (75–95%), chronic diarrhea (30%), deep vein thrombosis, and depression Diagnostics: Requires a high index of suspicion to make the diagnosis ↑ glucagon, ↑ blood glucose levels, normocytic normochromic anemia (90%) Imaging (CT) → locate the tumor Treatment - Glycemic control - Octreotide (somatostatin) - Pancreatic resection

Answer 87

- A cutaneous paraneoplastic syndrome that is mainly associated with pancreatic tumors secreting glucagon, but also hepatitis B, C, and bronchial carcinoma - Occurrence of multiple areas of centrifugally spreading erythema, located predominantly on the face, perineum, and lower extremities (nutritional deficiencies (e.g., decreased amino acid levels) are thought to be the underlying pathomechanism for the development of the erythema. On the other hand, zinc deficiency may result in similar skin lesions) - Develop into painful and pruritic crusty patches with central areas of bronze-colored induration - Tend to resolve and reappear in a different location - Skin biopsy shows epidermal necrosis

Answer 88

- Rare neuroendocrine tumor of δ-cell (D-cell) origin that is usually located in the pancreas or gastrointestinal tract and secretes somatostatin. Clinical findings: - Abdominal pain - Weight loss - Classic triad 1. Glucose intolerance (due to inhibition of insulin secretion) 2. Cholelithiasis (due to inhibition of cholecystokinin-induced gallbladder contraction) 3. Steatorrhea (due to inhibition of exocrine pancreatic function) - Achlorhydria (due to inhibition of gastrin-induced proton secretion) Diagnostics: - ↑ somatostatin, ↑ blood glucose levels Imaging → locate the tumor Treatment: - Octreotide → inhibition of somatostatin secretion - Pancreatic resection → curative if no metastases are present - Chemotherapy

Answer 89

1. Physical activity → decreases insulin by 1–2 units per 20–30 minutes activity 2. Illness, stress, and changes in diet - Increase in insulin demand → many illnesses are associated with elevated blood glucose levels due to an acute stress reaction. The subsequent increase in insulin demand cannot be met by patients with insulin deficiency. A higher insulin dose is required. - Decrease in insulin demand → vomiting and diarrhea lead to decreased glucose uptake, increasing the risk of hypoglycemia. 3. Surgery → ⅓–½ of the usual daily requirement with frequent monitoring

Answer 90

Macrovascular disease - More common in patients with type 2 diabetes - The major determinants are metabolic risk factors, which include obesity, dyslipidemia, and arterial hypertension. Hyperglycemia may be less related to the development of macrovascular disease. - Manifestations 1. Coronary heart disease (CHD) 2. Cerebrovascular disease 3. Peripheral artery disease (PAD) 4. Mönckeberg arteriosclerosis (medial calcific sclerosis = variant of PAD). PAD diagnostic tools are unreliable in patients with Mönckeberg's arteriosclerosis Microvascular disease - Onset → typically arises 5–10 years after onset of disease - Chronic hyperglycemia is the primary factor influencing the development of microvascular disease; results in glycation of proteins and lipids with subsequent impaired protein and cell membrane function and tissue damage - Manifestations 1. Diabetic nephropathy 2. Diabetic retinopathy 3. Diabetic neuropathy 4. Diabetic foot Diabetic cardiomyopathy Diabetic fatty liver disease Hyporeninemic hypoaldosteronism Limited joint mobility (formerly known as diabetic cheiroarthropathy) (tight waxy skin, and stiffness of the small joints of the hand; prayer sign (inability to approximate the palms due to flexion contractures of the PIP and MCP joints)) Sialadenosis Increased risk of infection (Poor perfusion of tissue (macrovascular/microvascular disease) and a weak immune system may lead to a higher risk of infection. In addition, growth of bacteria and fungi (e.g., Candida albicans) occurs, likely due to hyperglycemia. Certain infections occur almost exclusively in diabetics (e.g., otitis externa maligna due to Pseudomonas aeruginosa)) Necrobiosis lipoidica Mucormycosis (zygomycosis)

Answer 91

* Major cause of end stage renal disease (ESRD) * Seen in patients with diabetes for \> 10 years (usually develops after 5 years with diabetes mellitus; however, patients with type 2 diabetes may present with renal damage at diagnosis. Many patients with type 2 diabetes have additional risk factors for kidney disease (e.g., hypertension)) * Chronic hyperglycemia → glycation (also called non-enzymatic glycosylation or NEG) of the basement membrane (protein glycation) → increased permeability and thickening of the basement membrane and stiffening of the efferent arteriole → hyperfiltration (increase in GFR) → increase in intraglomerular pressure (mechanism behind hyperfiltration is not fully understood; dilation of the afferent arterioles plays an important role) → progressive glomerular hypertrophy, increase in renal size, and glomerular scarring (glomerulosclerosis) → worsening of filtration capacity Three major histological changes can be seen on LM (chronic hyperglycemia, hyperlipidemia, elevated levels of growth hormones, and intraglomerular hypertension are responsible for these changes) 1. Mesangial expansion 2. Glomerular basement membrane thickening 3. Glomerulosclerosis (later stages) * Diffuse hyalinization (most common) * Pathognomonic nodular glomerulosclerosis (Kimmelstiel-Wilson nodules) [glomerular capillary hypertension and hyperfiltration → increase in mesangial matrix → eosinophilic hyaline material in the area of glomerular capillary loops; can progressively consume the entire glomerulus → hypofiltration (↓ GFR)] Clinical features: * Often asymptomatic; patients may complain of foamy urine * Progressive diabetic kidney disease with signs of renal failure and risk of uremia (e.g., uremic polyneuropathy) * Arterial hypertension * Urine analysis → proteinuria. Initially moderately increased albuminuria (microalbuminuria); eventually significantly increased albuminuria (macroproteinuria) → nephrotic syndrome may develop. Prevention and management 1. Stringent glycemic control (may delay the progression of microalbuminuria or partially reverse diabetic nephropathy) 2. Antihypertensive treatment → ACE inhibitors OR angiotensin-receptor blockers are the first-line antihypertensive drugs in patients with diabetes (prevent the progression of albuminuria and may protect against renal tubulointerstitial fibrosis) * Second line agents to be added to ACE inhibitors or ARBs to further control hypertension include diuretics or calcium channel blockers 3. Dietary modification → daily salt intake \< 5–6 g/day; phosphorus and potassium intake restriction in advanced nephropathy; protein restriction (proteinuria (albuminuria) in diabetic nephropathy may be improved and the progression of renal insufficiency delayed by reducing protein consumption (max. 0.8–1 g/kg/day))

Answer 92

* After 15 years with disease, approx. 90% of type 1 diabetic patients and approx. 25% of type 2 diabetic patients develop diabetic retinopathy. * The most common cause of visual impairment and blindness in patients aged 25–74 years in the US * Asymptomatic until very late stages of disease 1. Visual impairment 2. Progression to blindness Ophthalmological findings and classification of diabetic retinopathy 1. Nonproliferative retinopathy (mild, moderate, severe) → accounts for most cases of diabetic retinopathy * Findings → intraretinal microvascular abnormalities (IRMA), including microaneurysms; caliber changes in venous vessels; intraretinal hemorrhage; hard exudates (lipid deposits in the retina), retinal edema, and cotton-wool spots (fluffy white patches on the retina; axoplasmic congestion due to retinal ischemia) * Visual loss, most commonly due to macular edema 2. Proliferative retinopathy * Findings → preretinal neovascularization is the hallmark of PDR (primarily arising from the optic disc and retinal vessels), fibrovascular proliferation (neovascularization and abnormal growth of connective tissue into the retina. Fibrosis may lead to traction retinal detachment), vitreous hemorrhage, traction retinal detachment (due to fibrosis of the vitreous body), rubeosis iridis (neovascularization of the iris; risk of hemorrhage and congestion of the trabecular meshwork) → secondary glaucoma. Additionally, findings of nonproliferative retinopathy are usually present. * Visual loss may be due to vitreous hemorrhage, retinal detachment, or neovascular glaucoma. 3. Macular edema * Findings → clinically significant retinal thickening and edema involving the macula, hard exudates, macular ischemia (avascular region in the area of the fovea due to capillary occlusion) * May occur in all stages of NPDR and PDR Treatment 1. Nonproliferative retinopathy * Laser treatment → focal photocoagulation * Intravitreal anti-vascular endothelial growth factor (VEGF) injection 2. Proliferative retinopathy and severe nonproliferative retinopathy * Laser treatment → panretinal photocoagulation over the course of numerous appointments (destruction of ischemic areas of the retina prevents further neovascularization by reducing the production of VEGF by ischemic tissue). Risks associated with laser treatment → night vision impairment, visual field loss, further fibrosis of the vitreous body with risk of retinal detachment * Vitrectomy in case of traction retinal detachment and vitreal hemorrhage 3. Macular edema * VEGF inhibitors * Focal photocoagulation

Answer 93

* Distal symmetric polyneuropathy * Chronic hyperglycemia causes glycation of axon proteins with subsequent development of progressive sensomotoric neuropathy; typically affects multiple peripheral nerves * Most common form of polyneuropathy in Western countries. Clinical features 1. Early → progressive symmetric loss of sensation in the distal lower extremities (loss of vibration sense may be tested with a tuning fork) * A "stocking-glove" sensory loss pattern with proximal progression is typical * Dysesthesia (burning feet) may occur * A similar sensory loss pattern may occur in the upper extremities. 2. Late → pain at rest and at night (painful diabetic neuropathy), but also decreased pain perception, motor weakness, and areflexia Special types: * Mononeuropathy 1. Cranial mononeuropathy (cranial nerve III is most commonly involved → diabetic third nerve palsy presents with eye pain, diplopia, ptosis, and an inability to adduct the eye (pupils are spared!); mononeuropathy of the cranial nerves VI and IV may also occur) 2. Peripheral mononeuropathy (the median, ulnar, and common peroneal nerves are often affected) 3. Mononeuropathy multiplex → asymmetric neuropathy, affecting the multiple peripheral and cranial nerves 4. Diabetic truncal neuropathy (involvement of intercostal nerves results in truncal pain) 5. Diabetic lumbosacral plexopathy (severe deep thigh pain as well as weakness and atrophy of thigh and hip muscles) Screening * Tuning fork → decreased vibration sense * Monofilament test → decreased pressure sense * Pinprick (pain assessment) or temperature assessment → decreased sensation Treatment 1. Optimal glycemic control (can prevent the onset and progression of diabetic neuropathy. However, once established, glycemic control cannot reverse diabetic neuropathy) 2. Pain management * Anticonvulsants → pregabalin (most effective; usually first-choice), gabapentin, and sodium valproate * Antidepressants 1. Tricyclic antidepressants → amitriptyline 2. SNRI → duloxetine, venlafaxine 3. Miscellaneous → lidocaine patch, capsaicin spray, isosorbide dinitrate spray 4. Opioids → dextromethorphan, morphine sulfate, tramadol, and oxycodone

Answer 94

1. Lack of or insufficient insulin replacement therapy * Undiagnosed, untreated diabetes mellitus * Treatment failure in known diabetics → insulin pump failure, forgotten insulin injection, noncompliance with insulin therapy 2. Increased insulin demand * Stress → infections, surgery, trauma, myocardial infarction * Drugs → glucocorticoid therapy, cocaine use, alcohol abuse * Hypovolemia resulting from diabetic ketoacidosis (DKA) can lead to acute kidney injury (AKI) due to decreased renal blood flow. Hypovolemic shock may also develop. * Intracellular potassium deficit (as a result of hyperglycemic hyperosmolality, potassium shifts along with water from inside cells to the extracellular space and is lost in the urine). Insulin normally promotes cellular potassium uptake but is absent in DKA, compounding the problem. A total body potassium deficit develops in the body, although serum potassium may be normal or even paradoxically elevated. * Insulin deficiency → hyperosmolality → K+ shift out of cells + lack of insulin to promote K+ uptake → intracellular K+depleted → total body K+ deficit despite normal or even elevated serum K+ - There is a total body potassium deficit. This becomes important during treatment, when insulin replacement leads to rapid potassium uptake by depleted cells and patients may require potassium replacement.

Answer 95

* Primarily affects patients with type 2 diabetes * The pathophysiology of HHS is similar to that of DKA. However, in HHS, there are still small amounts of insulin being secreted by the pancreas, and this is sufficient to prevent DKA by suppressing lipolysis and, in turn, ketogenesis (for this reason, HHS typically occurs in patients with type 2 diabetes, as the condition involves a relative insulin deficiency, rather than the absolute insulin deficiency of type 1 diabetes. However, DKA can also occur in the advanced stages of type 2 diabetes, when beta cell function has declined so much that insulin levels are negligible)

Answer 96

* Rapid onset (\< 24 h) in contrast to HHS 1. Polyuria 2. Polydipsia 3. Recent weight loss 4. Nausea and vomiting (vomiting expels gastric acid, shifting the acid-base balance of the body) 5. Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse 6. Altered mental status 7. Lethargy 8. Coma 9. Other neurological exam abnormalities, e.g., blurred vision and weakness 10. Abdominal pain (the state of ketoacidosis leads to irritation of the peritoneum. This can cause diffuse abdominal tenderness on palpation with guarding, possibly even to the extent that an acute abdominal pathology is suspected) 11. Fruity odor on the breath (from exhaled acetone) 12. Hyperventilation → long, deep breaths (Kussmaul respirations) (respiratory compensation for the state of metabolic acidosis)

Answer 97

1. Hyperglycemia 2. High anion gap metabolic acidosis 3. Ketonuria/ketonemia 4. Pregnancy and SGLT2-inhibitors can cause euglycemic DKA (i.e., high anion gap metabolic acidosis with normal or near-normal glucose). 5. Urine ketones → standard urine dipstick assays detect acetoacetate and acetone but not beta-hydroxybutyrate. 6. Serum beta-hydroxybutyrate (is the most common ketone produced in DKA. Serum measurement is more sensitive than urine ketone measurement and can also be used to monitor the response to therapy) 7. Hyponatremia is common, due to hypovolemic hyponatremia and hypertonic hyponatremia 8. Potassium → normal or elevated (despite a total body deficit) 9. Magnesium levels are typically low (due to osmotic diuresis) 10. Phosphorus levels may be falsely elevated despite a total body deficit. 11. BUN and creatinine are often elevated (↑ BUN and creatinine suggest AKI, which in hyperglycemic crisis is often due to osmotic diuresis and dehydration and typically responds to fluid resuscitation. Persistently elevated BUN and creatinine despite fluid resuscitation should prompt further investigation) 12. Leukocytosis may be present even in the absence of infection in patients with hyperglycemic crisis. 13. Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Answer 98

* IV access with two large-bore peripheral IV lines * Fluid resuscitation → initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium * Electrolyte repletion (especially potassium) * Short-acting insulin (regular insulin) therapy (administration of insulin is essential in halting lipolysis and ketoacidosis in patients with DKA; halting ketone formation is far more important than rapidly decreasing the serum glucose level) * IV bicarbonate (only in severe metabolic acidosis) * Identify and treat the underlying cause. * Consider admission to the ICU. * Potassium levels must be ≥ 3.3 mEq/L before insulin therapy is initiated. If potassium level is \< 3.3 mEq/L, potassium should be repleted and rechecked prior to giving any insulin (insulin causes an intracellular shift of K+, which can cause life-threatening hypokalemia)

Answer 99

* Characterized by symptoms of marked dehydration (and loss of electrolytes) due to the predominating hyperglycemia and osmotic diuresis. * Symptoms typically begin more slowly and progress insidiously. 1. Polyuria 2. Polydipsia 3. Recent weight loss 4. Nausea and vomiting (vomiting expels gastric acid, shifting the acid-base balance of the body) 5. Signs of volume depletion (i.e., dry mucous membranes, decreased skin turgor), hypotension, circulatory collapse 6. Altered mental status 7. Lethargy 8. Coma 9. Other neurological exam abnormalities, e.g., blurred vision and weakness

Answer 100

1. Hyperglycemia 2. Hyperosmolality 3. Dehydration without ketonuria 4. Hyponatremia is common due to hypovolemic hyponatremia and hypertonic hyponatremia 5. BUN and creatinine are often elevated (↑ BUN and creatinine suggest AKI, which in hyperglycemic crisis is often due to osmotic diuresis and dehydration and typically responds to fluid resuscitation. Persistently elevated BUN and creatinine despite fluid resuscitation should prompt further investigation) 6. Leukocytosis may be present even in the absence of infection in patients with hyperglycemic crisis. Infection, myocardial infarction, and pancreatitis should be ruled out in all patients presenting with a hyperglycemic crisis.

Answer 101

* IV access with two large-bore peripheral IV lines * Fluid resuscitation → initially with isotonic saline (0.9% NaCl), then 0.45% or 0.9% depending on corrected serum sodium * Electrolyte repletion (especially potassium) * Short-acting insulin (regular insulin) therapy * Consider admission to the ICU.

Answer 102

* Paraneoplastic syndrome → ↑ ACTH secretion → bilateral adrenal gland hyperplasia Carcinomas include: 1. Small cell lung cancer 2. Renal cell carcinoma 3. Pancreatic or bronchial carcinoid tumors 4. Pheochromocytoma 5. Medullary thyroid carcinoma

Answer 103

1. Skin * Thin, easily bruisable skin with ecchymoses * Stretch marks (classically purple abdominal striae) * Hirsutism * Acne * If secondary hypercortisolism → often hyperpigmentation (darkening of the skin due to an overproduction of melanin), especially in areas that are not normally exposed to the sun (e.g., palm creases, oral cavity). Caused by excessive ACTH production because melanocyte-stimulating hormone (MSH) is cleaved from the same precursor as ACTH called proopiomelanocortin (POMC). Not a feature of primary hypercortisolism * Delayed wound healing * Flushing of the face 2. Neuropsychological → lethargy, depression, sleep disturbance, psychosis 3. Musculoskeletal * Osteopenia, osteoporosis, pathological fractures, avascular necrosis of the femoral head (due to inhibition of calcitriol synthesis by cortisol) * Muscle atrophy/weakness (catabolic effect on protein metabolism results in muscle atrophy and weakness. Proximal muscles are more commonly affected) 4. Endocrine and metabolic * Insulin resistance → hyperglycemia → mild polyuria in the case of severe hyperglycemia - Dyslipidemia (increased cortisol → increased lipolysis) * Weight gain characterized by central obesity, moon facies, and a buffalo hump (these symptoms result from the relocation of body fat from the body periphery to the body center) * ♂ → Decreased libido * ♀ → Decreased libido, virilization, and/or irregular menstrual cycles (e.g., amenorrhea) (hypercortisolism results in inhibition of gonadotropin release) * Growth delay (in children) 5. Other features * Secondary hypertension (∼ 90% of cases) (caused by the following pathophysiological effects → 1. Mineralocorticoid effect of cortisol (increased water and sodium retention with increased potassium excretion); 2. Enhanced sympathetic activity; 3. Amplified response to catecholamines; 4. Secretion of prehormones with mineralocorticoid effect; 5. Activation of the renin-angiotensin-aldosterone system (RAAS)) * Increased susceptibility to infections (due to immunosuppression) * Peptic ulcer disease * Cataracts (prolonged hypercortisolism is typically associated with posterior subcapsular cataracts)

Answer 104

1. Hypernatremia, hypokalemia, metabolic alkalosis (11β-hydroxysteroid dehydrogenase converts cortisol to cortisone (which has lesser mineralocorticoid activity). The enzyme also prevents the binding of cortisol to the renal mineralocorticoid receptor. When cortisol levels surge (as occurs with ectopic ACTH production) the enzyme 11β-hydroxysteroid dehydrogenase becomes saturated. As a result, cortisol that is not inactivated is free to bind to mineralocorticoid receptors causing ↑ water and sodium retention, ↑ K+ excretion, and ↑ H+ excretion) 2. Hyperglycemia → due to stimulation of gluconeogenesis enzymes (e.g., glucose-6-phosphatase) and inhibition of glucose uptake in peripheral tissue 3. Hyperlipidemia (hypercholesterolemia and hypertriglyceridemia) 4. Leukocytosis (predominantly neutrophilic), eosinopenia (hypercortisolism causes the demargination of neutrophils from the endothelial lining of vessels. Therefore, no left shift is seen. The presence of a left shift along with leucocytosis may signify an infection)

Answer 105

* Post adrenalectomy syndrome * Etiology → bilateral adrenalectomy in patients with a previously undiscovered pituitary adenoma (bilateral adrenalectomy is no longer commonly performed as a treatment for Cushing syndrome) * Bilateral adrenalectomy → no endogenous cortisol production → no negative feedback from cortisol on hypothalamus → increased CRH production → uncontrolled enlargement of preexisting ACTH-secreting pituitary adenoma → increased secretion of ACTH and MSH → symptoms of pituitary adenoma and ↑ MSH Clinical Features * Headaches, bitemporal hemianopia (mass effect), cutaneous hyperpigmentation Diagnostics * High levels of beta-MSH and ACTH * Pituitary adenoma on MRI confirms the diagnosis. Treatment: * Surgery (e.g., transsphenoidal resection) and/or pituitary radiation therapy (e.g, in the case of tumor residues after surgery)

Answer 106

* Caused by abrupt destruction of the adrenal gland (acute adrenal insufficiency; e.g., due to massive adrenal hemorrhage) or by its gradual progressive destruction or atrophy (chronic adrenal insufficiency; e.g., due to autoimmune conditions, infection). 1. Autoimmune adrenalitis * Most common cause in the US (∼ 80–90% of all cases of primary adrenal insufficiency) * Associated with other autoimmune endocrinopathies 2. Infectious adrenalitis * Tuberculosis → most common cause worldwide, but rare in the US * CMV disease in immunosuppressed states (especially AIDS) * Histoplasmosis 3. Adrenal hemorrhage * Sepsis (especially meningococcal sepsis (endotoxic shock) → hemorrhagic necrosis (Waterhouse-Friderichsen syndrome)) * Disseminated intravascular coagulation (DIC) * Anticoagulation (especially heparin (heparin-induced thrombocytopenia)) * Venous thromboembolism, especially in antiphospholipid syndrome (APS). Recurrent thromboses are a typical manifestation of APS. * Adrenal tumor (most commonly pheochromocytoma) → intratumoral bleeding * Short-term steroid usage * Trauma (mostly blunt trauma, can also occur postoperatively) * In neonates → birth trauma, difficult labor (e.g., breech delivery, forceps/vacuum delivery, prolonged labor), maternal diabetes 4. Infiltration of the adrenal glands * Tumors (adrenocortical tumors, lymphomas, metastatic carcinoma) * Amyloidosis * Hemochromatosis 5. Adrenalectomy 6. Impaired activity of enzymes that are responsible for cortisol synthesis * Cortisol synthesis inhibitors (e.g., rifampin, fluconazole, phenytoin, ketoconazole) → drug-induced adrenal insufficiency * 21β-hydroxylase deficiency 7. Vitamin B5 deficiency (vitamin B5 increases production of glucocorticoids and other adrenal hormones. In vitamin B5 deficiency, adrenal function is impaired)

Answer 107

* Caused by conditions that decrease ACTH production (impaired hypothalamic-pituitary-adrenal axis). 1. Sudden discontinuation of chronic glucocorticoid therapy or stress (e.g., infection, trauma, surgery) during prolonged glucocorticoid therapy * Prolonged iatrogenic suppression of the hypothalamic-pituitary-adrenal axis due to long-term cortisol therapy → ↓ CRH/ACTH release (negative feedback) → ↓ endogenous cortisol * Impaired endogenous cortisol production in addition to discontinuation of steroid treatment, decrease in dosage, or increase in requirement (e.g., stress) → acute glucocorticoid deficiency 2. Hypopituitarism → ↓ ACTH → ↓ endogenous cortisol

Answer 108

* Caused by conditions that decrease CRH production. 1. The most common cause is sudden discontinuation of chronic glucocorticoid therapy. 2. Rarer causes include hypothalamic dysfunction (e.g., due to trauma, mass, hemorrhage, or anorexia) → ↓ CRH → ↓ ACTH → ↓ cortisol release

Answer 109

* Acute, severe glucocorticoid deficiency that requires immediate emergency treatment. Precipitating factors 1. Stress in patients with underlying adrenal insufficiency e.g.: * Gastrointestinal illness (most common) * Other infections * Perioperative period * Physical stress or pain * Psychological stress 2. Sudden discontinuation of glucocorticoids after prolonged glucocorticoid therapy 3. Bilateral adrenal hemorrhage or infarction (e.g., Waterhouse-Friderichsen syndrome) 4. Pituitary apoplexy Signs and symptoms 1. Hypotension, shock 2. Impaired consciousness, coma 3. Fever 4. Vomiting, diarrhea 5. Severe abdominal pain (which can resemble peritonitis) 6. Consider adrenal crisis in patients with severe hypotension refractory to fluid resuscitation and/or vasopressors. Diagnosis 1. Hyponatremia 2. Hyperkalemia 3. Hypocalcemia 4. Hypoglycemia 5. Normal anion gap metabolic acidosis Management 1. Adrenal crisis can be life-threatening, so treatment with high doses of hydrocortisone should be started immediately, without waiting for diagnostic confirmation of hypocortisolism * Hydrocortisone (preferred) * Prednisolone (alternative if hydrocortisone is unavailable) * Dexamethasone (least preferred alternative if hydrocortisone is unavailable) (has no mineralocorticoid activity and requires concurrent substitution with fludrocortisone) 2. Consider adding mineralocorticoid replacement, e.g., fludrocortisone (off-label) for the following: * Patients receiving glucocorticoids other than hydrocortisone * Patients with septic shock 3. Fluid resuscitation 4. Hypoglycemia → IV dextrose, e.g., 50% dextrose 5. Identify and treat underlying causes (e.g., sepsis). 6. Consider higher-level monitoring, e.g., intensive care

Answer 110

- Caused by autonomous overproduction of aldosterone in the zona glomerulosa of one or both adrenal glands - Most commonly due to the following conditions: 1. Bilateral idiopathic hyperplasia of the adrenal glands (∼ 60%) (often manifests with only mild symptoms and normokalemia) 2. Aldosterone-producing adrenal adenoma (Conn syndrome) or aldosteronoma (∼ 30%) (usually manifests with marked hypokalemia and more severe symptoms than idiopathic hyperplasia of the adrenal glands) 3. Less common causes include: - Unilateral hyperplasia of one adrenal gland - Familial hyperaldosteronism - Aldosterone-secreting carcinomas of the adrenal cortex - Ectopic aldosterone-producing tumors (e.g., in the kidneys, ovaries)

Answer 111

* Cause → unclear * Genetic associations → chromosomal abnormalities, especially deletions (found in ∼ 50% of neuroblastomas) 1. Deletions of 1p, 11q, and 14q chromosomosomal regions (deletion of the short arm of chromosome 1 (1p deletion) is the most common chromosomal alteration associated with neuroblastomas. The tumor suppressor gene KIF1B is present in this region) 2. Amplification and overexpression of oncogene MYCN (N-myc) (in approx. 25% of patients with neuroblastomas, the MYCN oncogene on chromosome 2p is replicated 50–100 times. These copies remain as extrachromosomal DNA (double minutes) or can be integrated into a chromosome, and result in overexpression of the growth-promoting transcription factor MYCN. The cause of this amplification is not completely understood) * Risk factors 1. Maternal → gestational diabetes, opiates, folate deficiency 2. Congenital syndromes → Turner syndrome, neurofibromatosis, Hirschsprung's disease, Beckwith-Wiedemann syndrome 3. Familial

Answer 112

Pheochromocytoma; neuroblastoma

Answer 113

General Symptoms 1. Failure to thrive or weight loss 2. Fever 3. Nausea, vomiting, loss of appetite 4. Hypertension (generally caused by renal artery compression) Location of primary tumor 1. Abdomen (in \> 60% of cases) * Palpable, firm, irregular abdominal mass that may cross the midline (in contrast to Wilms tumor, which is smooth and usually does not cross the midline) * Abdominal distension and pain * Hepatomegaly * Constipation 2. Chest (in ∼ 20% of cases) → particularly paravertebral ganglia * Spinal cord compression → back pain, weakness, numbness, ataxia, loss of bowel or bladder control * Scoliosis * Dyspnea, cough * Inspiratory stridor 3. Neck * Horner syndrome * Symptoms due to spinal cord compressions Location of metastases 1. Orbit of the eye * Periorbital ecchymoses (“raccoon eyes”) (bleeding in the tissue surrounding the orbit of the eye) * Proptosis 2. Bones * Bone pain * Anemia (bone marrow suppression) 3. Skin * Subcutaneous nodules Paraneoplastic syndromes 1. Chronic diarrhea → electrolyte imbalances (neuroblastomas may secrete vasoactive intestinal peptide (VIP)) 2. Opsoclonus-myoclonus-ataxia → a paraneoplastic syndrome of unclear etiology characterized by rapid and multi-directional eye movements, rhythmic jerks of the limbs, and ataxia (dancing eyes dancing feet syndrome) (at least 50% of children with opsoclonus-myoclonus have an underlying neuroblastoma). Believed to be an autoantibody response to CNS antigens 3. Possibly hypertension, tachycardia, palpitations, sweating, flushing (due to tumor catecholamine secretion) (hypertension is more commonly seen in pheochromocytoma)

Answer 114

* ↑ Catecholamine metabolites homovanillic acid (HVA) and vanillylmandelic acid (VMA) in 24-hour urine Blood * ↑ Catecholamine metabolites (HVA/VMA) * ↑ Lactate dehydrogenase (LDH), ferritin, neuron-specific enolase (NSE) * Anemia suggests bone marrow suppression by tumor metastases Imaging → to identify the primary site * Abdominal ultrasound * CT or MRI (depending on the presumable site of the lesion) Scintigraphy * MIBG scan → Uptake scan of metaiodobenzylguanidine (MIBG) combined with a radioactive iodine tracer (MIBG is similar in structure to norepinephrine, so it is taken up by sympathetic nerve cells, including neuroblastoma or pheochromocytoma tumor cells, throughout the body. Certain radioactive iodine tracers have a therapeutic use) Biopsy 1. Image-guided needle aspiration of the tumor or biopsy at the time of surgical tumor resection * Evaluation for MYCN gene amplification * Evaluation for DNA ploidy 2. Bilateral bone marrow biopsy of iliac crests Pathology 1. Homer Wright rosettes → halo-like clusters of neuroblast cells surrounding a central pale area containing neuropil (associated with tumors of neuronal origin such as neuroblastoma, medulloblastoma, primitive neuroectodermal tumors, and pineoblastoma) 2. Small round blue cells with hyperchromatic nuclei 3. Bombesin and NSE positive (tumor marker for neuroblastoma, small cell carcinoma of the lung, pancreatic cancer, and gastric cancer)

Answer 115

* The majority of pheochromocytomas are benign, unilateral, catecholamine-producing tumors, that rarely produce other hormones such as EPO. * Tumors arise from chromaffin cells, which are derived from the neural crest. Localization * ∼ 90% adrenal medulla (physiologically activated by acetylcholine) (adrenal medulla is considered a modified sympathetic ganglion, which is innervated by sympathetic preganglionic neurons) * ∼ 10% extra-adrenal in the sympathetic ganglia (also referred to as catecholamine-secreting paragangliomas) * ∼ 10% at multiple locations 25% of pheochromocytomas are hereditary (germline mutations): 1. Multiple endocrine neoplasia type 2 (MEN 2A, MEN 2B) 2. Neurofibromatosis type 1 (NF1) 3. Von Hippel-Lindau disease (VHL)

Answer 116

* Autosomal Dominant * Mutation of the MEN1 gene (located on chromosome 11) → altered expression of menin protein Principal Manifestation: 1. Primary hyperparathyroidism (parathyroid adenoma) Further Manifestations: 1. Endocrine pancreatic tumors * Gastrinoma (most common) * Insulinoma * VIPoma * Glucagonoma (rare) 2. Pituitary adenoma → most commonly prolactinoma 3. Carcinoid tumors (∼ 10–15% of cases) 4. Nonendocrine tumors (e.g. angiofibromas, collagenomas, meningiomas) Management: 1. Parathyroidectomy 2. Excision of pancreatic tumor 3. Transsphenoidal surgery for excision of pituitary adenoma

Answer 117

* Autosomal Dominant * Altered expression of the RET proto-oncogene → elevated tyrosine kinase activity Principal Manifestation: 1. Medullary thyroid carcinoma Further Manifestations: 1. Pheochromocytoma (∼ 40% of cases) 2. Primary hyperparathyroidism (∼ 20–30% of cases) Management: 1. Thyroidectomy including cervical lymph nodes * Pheochromocytoma should first be ruled out (e.g., by measuring urine metanephrines) or treated before undergoing surgery (intraoperative catecholamines released from a pheochromocytoma could otherwise lead to hemodynamic instability during the procedure) 2. If pheochromocytoma → adrenalectomy 3. If hyperparathyroidism → parathyroidectomy

Answer 118

* Autosomal Dominant * Altered expression of the RET proto-oncogene → elevated tyrosine kinase activity Principal Manifestation: 1. Medullary thyroid carcinoma Further Manifestations: 1. Pheochromocytoma (∼ 40% of cases) 2. Multiple neurinomas → mucosal neuromas (e.g., lips, tongue), intestinal ganglioneuromatosis) (polypoid growth from proliferating ganglion and Schwann cells) 3. Marfanoid habitus Management: 1. Thyroidectomy including cervical lymph nodes * Pheochromocytoma should first be ruled out (e.g., by measuring urine metanephrines) or treated before undergoing surgery (intraoperative catecholamines released from a pheochromocytoma could otherwise lead to hemodynamic instability during the procedure) 2. If pheochromocytoma → adrenalectomy 3. If hyperparathyroidism → parathyroidectomy

Answer 119

Wermer syndrome

Answer 120

Sipple syndrome

Answer 121

* Neuroendocrine tumors that arise from amine precursor uptake and decarboxylation (APUD) cells. * ⅓ are Multiple * ⅓ are associated with another Malignancy * ⅓ Metastasize Secretory Products: * Carcinoid tumors can synthesize different hormones (most commonly serotonin). * Serotonin is degraded via the following mechanisms: 1. First-pass metabolism in the liver 2. Monoamine oxidases in the lung * Serotonin can reach systemic circulation under the following conditions: 1. Intestinal carcinoid tumors with liver metastases (these tumors are usually asymptomatic because of the first-pass metabolism of the hormones in the liver. After the tumor has metastasized to the liver, first-pass metabolism is impaired) 2. Extraintestinal carcinoid tumors (these tumors are more likely to be symptomatic due to the lack of first-pass metabolism) * ↑ Serotonin in systemic circulation can lead to: 1. Carcinoid syndrome 2. Carcinoid heart disease 3. Pellagra due to increased serotonin metabolism * Carcinoid syndrome 1. Diarrhea and abdominal cramps 2. Cutaneous flushing (lasts up to 30 minutes and causes reddening of the face, neck, and chest. May be accompanied by a burning sensation). Possible triggers → alcohol consumption, food intake, stress. In severe cases, may be accompanied by tachycardia and fluctuating blood pressure 3. Dyspnea, wheezing (asthma-like attacks) 4. Palpitations 5. Possible weight loss despite normal appetite * Carcinoid heart disease (liver metastases of the carcinoid tumor produce serotonin which travels to the right heart via the inferior vena cava. This way, serotonin leads to endocardial fibrosis of the right heart) * Endocardial fibrosis that especially affects the right heart (left heart is better protected because of hormone inactivation in the lungs) * Tricuspid insufficiency and/or pulmonary stenosis * Symptoms of right-sided heart failure * Causes late complications in 20–70% of metastatic carcinoids * Other symptoms → abdominal pain (may be due to local tumor growth and/or fibrosis of the mesenteric vessels) Biopsy * Histology → prominent rosettes composed of numerous small monomorphic cells with salt-and-pepper chromatin * Immunohistochemistry → immunostaining with synaptophysin, chromogranin A, and neuron-specific enolase (NSE) to confirm neuroendocrine origin

Answer 122

* Neuroendocrine tumor that secretes excess VIP (vasoactive intestinal polypeptide) * Associated with MEN1 syndrome (5% of cases) * Excess VIP → ↑ relaxation of gastric and intestinal smooth muscles and cAMP activity (similar to cholera toxin) → secretory diarrhea and inhibition of gastric acid production * VIP also stimulates vasodilation, bone resorption, and glycogenolysis * Tumor location → the primary tumor is most frequently found in the pancreas (however, it arises from APUD cells rather than α or β pancreatic islet cells) Clinical Features * WDHA syndrome (watery diarrhea, hypokalemia, achlorhydria) → tea-colored watery diarrhea (\> 700 mL/day) → dehydration * Weight loss * Abdominal pain, nausea, vomiting * Achlorhydria → ↓ iron and B12 absorption → anemia Diagnostics * ↑ Serum VIP concentration (\> 75 pg/mL) * Hypokalemia * Hypercalcemia (manifests in almost 50% of all patients. The mechanism behind this is not yet understood) * Hyperglycemia * Gastric achlorhydria or hypochlorhydria (measured via nasogastric tube) * CT scan to localize the primary tumor Treatment * Tumor resection * Octreotide (inhibits VIP secretion)