Endocrine Pathology

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jknell
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Endocrine Pathology
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2013-03-19 01:37:11
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Renal pathology and pharmocology
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  1. Cushing's syndrome
    Causes, findings
    ↑ cortisol

    Exogenous (iatrogenic) steroids is #1 cause; ↓ ACTH

    • Endogenous causes:
    • 1. Cushing's disease (70%): ACTH secretion from pituitary adenoma; ↑ ACTH
    • 2. Ectopic ACTH (15%): nonpituitary tissue making ACTH (e.g. small cell lung cancer, bronchial carcinoids); ↑ ACTH
    • 3. Adrenal (15%): adenoma, carcinoma, nodular adrenal hyperplasia; ↓ ACTH

    • Presentation:
    • -hypertension
    • -weight gain, moon facies, truncal obesisty, buffalo hump
    • -hyperglycemia (insulin resistance)
    • -skin changes (thinning, striae)
    • -osteoporosis
    • -amenorrhea
    • -immune suppression
  2. Dexamethasone suppression test
    • "Dex" is an exogenous steroid that provides negative feedback to the pituitary to ↓ ACTH secretion
  3. Hyperaldosteronism
    Conn syndrome
    • Primary: adrenal hyperplasia or aldo-secreting adrenal adenoma (Conn's syndrome)
    • Presentation:
    • -hypertension
    • -hyhpokalemia
    • -metabolic alkalosis
    • -low plasma renin
    • -bilateral or unilateral

    • Treatment:
    • -surgery to remove the tumor
    • -spironolactone (aldosterone antagonist)

    • Secondary: Renal perception of low ECV → overactive renin-angiotensin system
    • -high plasma renin
    • Causes:
    • -Renal artery stenosis
    • -chronic renal failure
    • -CHF
    • -cirrhosis
    • -nephrotic syndrome
  4. Addison's disease
    • Chronic 1° adrenal insufficiency due to adrenal atrophy or destruction by disease (autoimmune, TB, metastasis)
    • ·Deficiency of aldosterone and cortisol

    • Sx:
    • -hypotension (hyponatremic volume contraction)
    • -hyperkalemia
    • -acidosis
    • -skin hyperpigmentation (due to MSH, by-product of ↑ACTH)

    *Characterized by Adrenal Atrophy and Absence of hormone production; involves All 3 cortical divisions (spares medulla)

    **Distinguish from 2° adrenal insufficiency(↓ pituitary ACTH production), which has no skin hyperpigmentation and no hyperkalemia
  5. Waterhouse-Friderichsen syndrome
    • Acute 1° adrenal insufficiency due to adrenal hemorrhage
    • Associated with:
    • Neisseria meningitidis septicemia
    • - DIC
    • - Endotoxic shock
  6. Pheochromocytoma
    • Most common tumor of adrenal medulla in adults
    • -Derived from chromaffin cells (neural crest)

    • -Most secrete epinephrine, NE, and dopamine → episodic hypertension
    • - ↑ Urinary VMA (breakdown product of NE, EPI)
    • - ↑ Plasma catecholamines
    • - Associated with neurofibromatosis type 1MEN types 2A and 2B

    • Treatment:
    • -Surgical removal only after effective α- and β-blockade:
    •     - Irreversible α-antagonist (phenoxybenzamine) given first to avoid hypertensive crisis
    •     - β-blockers given to slow heart rate


    • *Episodic hyperadrenergic symptoms (5 P's):
    • -Pressure (elevated BP)
    • -Pain (headache)
    • -Perspiration
    • -Palpitations (tachycardia)
    • -Pallor

    • *Rule of 10's:
    • -10% malignant
    • -10% bilateral
    • -10% extra-adrenal
    • -10% calcify
    • -10% in kids
  7. Catecholamine synthesis and breakdown
  8. Neuroblastoma
    • Most common tumor of the adrenal medulla in children
    • Can occur anywhere along the sympathetic chain
    • ↑ Urine homovanillic acid (HVA) (breakdown product of DA)
    • Less likely to develop hypertension
    • Overexpression of N-myc oncogene is associated with rapid tumor progression
  9. Thyroglossal duct cyst
    • Cystic dilation of thyroglossal duct remnant
    • **thyroid develops at base of tongue and travels along the thyroglossal duct to the anterior neck
    • Duct normally involutes
    • Presentationanterior neck mass
  10. Lingual thyroid
    • Persistence of thyroid tissue at the base of tongue
    • Presentation: base of tongue mass
  11. Hypothyroidism (aka myxedema)
    signs/sx, lab findings
    Decreased metabolic rate, decreases SNS activity

    • Sx:
    • -Myxedema- accumulation of glycosaminoglycans in the skin and soft tissue
    • -Cold intolerance (↓ heat production)
    • -Weight gain, ↓ appetite
    • -Hypoactive, lethargy, fatigue, weakness
    • -Constipation
    • -↓ reflexes
    • -Myxedema (facial/periorbital)
    • -Dry, cool skin; coarse, brittle hair
    • -Bradycardia, dyspnea on exertion
    • -slowing of mental activity
    • -Muscle weakness
    • -Bradycardia w/decreased CO →SOB and fatigue
    • -Oligomenorrhea
    • -Hypercholesterolemia
    • -Constipation

    • Labs:
    • -↑ TSH (sensitive for 1° hypothyroidism)
    • -↓ free T4
  12. Hyperthyroidism
    signs/sx, labs
    Increased basal metabolic rate, increased SNS activity

    • Sx:
    • -Heat intolerance (↑ heat production)
    • -Weight loss, ↑ appetite
    • -Hyperactivity
    • -Tachycardia
    • -Diarrhea, malabsorption
    • -↑ reflexes
    • -Pretibial myxedema (Grave's disease)
    • -Warm, moist skin; fine hair
    • -Chest pain, palpitations, arrhythmias, ↑ β-adrenergic receptors
    • -Oligomenorrhea
    • -bone resoprtion with hypercalcemia (risk for osteoporosis)
    • -Hypercholesterolemia
    • -Hyperglycemia (gluconeogenesis and glycogenolysis)

    • Labs:
    • -↓ TSH (if 1°)
    • -↑ free or total T4
    • -↑ free or total T3
  13. Hypothyroidism
    causes
    • Hashimoto's thyroiditis
    • Cretinism
    • Subacute thyroiditis (de Quervain's)
    • Riedel's thyroiditis
    • Other causes (drugs [lithium], surgical removal or radioablation)
  14. Hashimoto's thyroiditis
    • -Most common cause of hypothyroidism
    • -Autoimmune destruction/disorder (thyroid peroxidase, antithyroglobulin antibodies)
    • -Associated with HLA-DR5
    • -↑ risk of non-Hodgkin's lymphoma

    • Histology: Hürthle cells (eosinophilic metaplasia of cells that line follicles), lymphocytic infiltrate with germinal centers
    • →increased risk for B-cell (marginal zone) lymphoma


    Findings: moderately enlarged, nontender thyroid

    *May be hyperthyroid early in course (thyrotoxicosis during follicular rupture)
  15. Cretinism
    • Severe fetal hypothyroidism
    • -Endemic cretinism where endemic goiter is prevalent (lack of dietary iodine)
    • -Sporadic cretinism is caused by defect in T4 formation or developmental failure in thyroid formation
    • -dyshormonogenetic goiter: congenital defect in thyroid hormone production: most commonly involves thyroid peroxidase

    • Sx: 
    • -mental retardation
    • -short stature with skeletal abnormalities
    • -coarse facial features
    • -enlarged tongue
    • -umbilical hernias

    • Findings*5 P's
    • -Pot-bellied
    • -Pale
    • -Puffy-faced child
    • -Protruding umbilicus
    • -Protuberant tongue
  16. Subacute thyroiditis
    (de Quervain's)
    Self-limited hypothyroidism often following a flu-like illness

    Histology: granulomatous inflammation

    Findings: ↑ ESR, jaw pain, early inflammation, very tender thyroid


    *may be hyperthyroid early in course
  17. Riedel's fibrosing thyroiditis
    Chronic inflammation with extensive fibrosis of the thyroid gland (hypothyroid)

    Findings: fixed, hard (rock-like), and painless/nontender goiter, often in young females

    *Considered a manifestation of IgG4-related systemic disease
  18. Other causes of hypothyroidism
    • Congenital hypothyroidism
    • iodine deficiency
    • goitrogens
    • Wolff-Chaikoff effects
    • painless thyroiditis
  19. Hyperthyroidism
    • Toxic multinodular goider
    • Graves' disease
    • Thyroid storm
  20. Multinodular goider
    • Enlarged thyroid gland with multiple nodules
    • Cause: relative iodine deficiency
    • Usually nontoxic (euthyroid)
  21. Toxic multinodular goiter
    • Focal patches of hyperfunctioning follicular cells working independently of TSH due to mutation in TSH receptor
    • ↑ release of T3 and T4
    • Hot nodules are rarely malignant
    • Jod-Basedow phenomenon: thyrotoxicosis if a pt with iodine deficiency goiter is made iodine replete
  22. Graves' disease
    • Autoimmune (IgG) hyperthyroidism with thyroid-stimulating immunoglobulins (TSI)
    • Opthalmopathy (proptosis, EOM swelling)
    • Pretibial myxedema
    • ↑ in connective tissue deposition
    • Diffuse goiter
    • Often presents during stress (childbirth); often in women of child-bearing age
    • Histology: irregular follicles with scalloped colloid and chronic inflammation
    • Tx:β-blockers, thioamide (blocks peroxidase), and radioiodine ablation
  23. Thyroid storm
    • Stress-induced catecholamine surge leading to death by arrhythmia
    • -other sx: hyperthermia, vomiting with hypovolemic shock
    • Serious complication of Graves' or other hyperthyroid disorders
    • May see ↑ ALP due to ↑ bone turnover
    • Tx: propylthiouracil (PTU), β blockers, and steroids
  24. PTU
    tx of thyroid storm
    • Propylthiouracil (PTU)
    • inhibits peroxidase-mediated oxidation, organification, and coupling steps of thyroid hormone synthesis as well as peripheral conversion of T4 to T3
  25. Thyroid neoplasia
    • Follicular adenoma: benign, usually non-functional
    • Papillary carcinoma: most common type of thyroid cancer (80%)
    • Follicular carcinoma
    • Medullary carcinoma
    • Anaplastic carcinoma
  26. Thyroid cancer
    • Papillary carcinoma: most common
    • -Excellent prognosis
    • -Histology: empty-appearing nuclei (Orphan Annie's eyes); psammoma bodies, nuclear grooves
    • -
    • -↑ risk with childhood irradiation

    • Follicular carcinoma: invasion through the fibrous capsule
    • -good prognosis
    • -uniform follicles
    • -Mets generally occur hematogenously

    • Medullary carcinoma:
    • -from parafollicular "C cells"
    • -produce calcitonin → hypocalcemia
    • -Histology: calcitonin deposits within tumor as sheets of amyloid in stroma
    • -Associated with MEN types 2A and 2B

    • Undifferentiated/anaplastic:
    • -older patients
    • -very poor prognosis

    • Lymphoma:
    • -associated with Hashimoto's thyroiditis
  27. Hyperparathyroidism
    Primary
    Disorder of the parathyroid gland itself; usually a parathyroid adeonma; sporadic hyperplasia and parathyroid carcinoma are less common

    Parathyroid adenoma: benign neoplasm, most often asymptomatic hypercalcemia

    • -Hypercalcemia
    • -Hypercalciuria (renal stones)
    • -Hypophosphatemia
    • -↑ PTH
    • -↑ alkaline phosphatase
    • -↑ cAMP in urine

    • Sx: often asymptomatic, or may present with weakness and constipation ("groans")
    • -CNS disturbances
    • Osteitis fibrosa cystica - cystic bone spaces filled with brown fibrous tissue (bone pain)

    "Stones, bones, and groans"
  28. Hyperparathyroidism
    Secondary
    • 2° hyperplasi due to ↓ gut Ca2+ absorption and ↑ phosphate
    • -Most often in chronic renal failure (hypo-VitD → decrease Ca absorption; decreased phosphate excretion → decreased free calcium)

    • Labs:
    • -Hypocalcemia
    • -hyperphosphatemia in chronic renal failure (hypophosphatemia in most other causes)
    • -↑ alkaline phosphatase
    • -↑ PTH

    Renal osteodystrophy: bone lesions due to 2° or 3° hyperparathyroidism due, in turn, to renal disease
  29. Hyperparathyroidism
    Tertiary
    • Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease
    • ↑↑PTH
    • ↑Ca2+
  30. Hypoparathyroidism
    causes, findings
    • Causes:
    • -Accidental surgical excision
    • -Autoimmune destruction
    • -DiGeorge syndrome (failure to develop 3rd, 4th pharyngeal pouch)

    • Findingssx due to low serum calcium
    • -hypocalcemia
    • -numbness and tingling
    • -tetany
    • -Chvostek's sign: tapping of facial nerve → contraction of facial muscles
    • -Trousseau's sign: occlusion of brachial artery with BP cuff → capal spasm
  31. Pseudohypoparathyroidism
    Albright's hereditary osteodystrophy
    End-organ ressitance to PTH

    • Labs:
    • -hypocalcemia
    • -Increased PTH

    • Autosomal dominant form: kidney unresponsiveness to PTH; defect in Gs leading to increased cAMP
    • -Hypocalcemia
    • -Shortened 4th/5th digits
    • -Short stature
  32. PTH and calcium pathologies
  33. Pituitary adenoma
    prolactinoma
    Benign tumor of anterior pituitary cells:

    • Functional vs. non-functional:
    • -hormone producing
    • -mass effect

    • Most commonly prolactinoma
    • Findings:
    • -amenorrhea
    • -galactorrhea
    • -low libido
    • -infertility (↓GnRH)
    • -headache

    *Can impinge on optic chiasm → bitemporal hemianopia

    • Treatment:
    • -dopamine agonists (bromocriptine or cabergoline) for prolactinomas
    • -surgical resection
  34. Pituitary adenoma
    Growth hormone cell adenoma
    • Gigantism in children
    • Acromegaly in adults:
    • -enlarged bones of hands, feet, and jaw
    • -growth of visceral organs → dysfunction (cardiac failure)
    • -Enlarged tongue

    • Presentation:
    • -Secondary diabetes mellitus (GH induces liver gluconeogenesis)

    Diagnosed by elevated GH and insulin growth factor-1 (IGF-1), lack of GH suppression by oral glucose

    • Tx:
    • -octreotide (somatostatin analog)
    • -GH receptor antagonists
    • -Surgery
  35. ACTH cell adenoma
    Secrete ACTH leading to Cushing syndrome
  36. Acromegaly
    findings, diagnosis, treatment
    Excess GH in adults. Typically caused by pituitary adenoma

    • Findings:
    • -large tongue with deep furrows
    • -deep voice
    • -large hands and feet
    • -coarse facial features
    • -impaired glucose tolerance (insulin resistance)

    • Diagnosis:
    • -↑ serum IGF-1
    • -Failure to suppress serum GH following oral glucose tolerance test
    • -pituitary mass seen on brain MRI

    • Tx:
    • -Resection followed by somatostatin analog if not cured

    *↑GH in children → gigantism (↑ linear bone growth)
  37. Diabetes insipidus
    findings, diagnosis, treatment
    Characterized by intense thirst and polyuria together with an inability to concentrate urine owing to a lack of ADH or lack or renal response to ADH

    • Central DI: lack of ADH → hypothalamic or posterior pituitary pathology
    • -pituitary tumor
    • -trauma
    • -surgery
    • -histiocytosis X
    • Sx:
    • -polyuria, polydipsia
    • -hypernatremia, high serum osmolality
    • -Low urine osmolality
    • Dx: fails water deprivation test (fails to increase urine osmolality)

    • Nephrogenic DI: lack of renal response to ADH
    • -Hereditary
    • -2° to hypercalcemia, lithium, demeclocycline [ADH antagonist]
    • sx: same as central
    • Dx: same
    • Tx: does not respond to desmopressin (synthetic ADH)

    • Findings:
    • -Urine specific gravity <1.006
    • -Serum osmolality >290mOsm/L

    • Diagnosis:
    • -Water deprivation test: Uosm doesn't ↑
    • -response to desmopressin (synthetic ADH) distinguishes central DI from nephrogenic DI

    • Tx:
    • -Adequate fluid intake
    • -Central: intranasal desmopressin
    • -Nephrogenic: HCTZ, indomethacin, or amiloride
  38. Syndrome of inappropriate antidiuretic hormone
    SIADH
    • Sx:
    • -Excessive ADH secretion and water retention
    • -Hyponatremia with continued urinary Na+ excretion → neuronal swelling and cerebral edema
    • -Mental status changes, seizures
    • -Uosm > Posm (low serum osmolality)
    • -Body responds with ↓ aldosterone (hyponatremia) to maintain near-normal volume status
    • -Very low sodium levels can lead to seizures
    • **Must correct slowly

    • Causes:
    • -Ectopic ADH (small cell lung cancer)
    • -CNS disorders/head trauma
    • -Pulmonary disease
    • -Drugs (e.g. cyclophosphamide)

    • Treatment:
    • -fluid restriction
    • -IV saline
    • -Conivaptan, tolvaptan, demeclocycline
  39. Hypopituitarism
    • Undersecretion of pituitary hormones due to:
    • -Nonsecreting pituitary adenoma (adults), craniopharyngioma (children)
    • -Pituitary apoplexy (bleeding into an adenoma)
    • -Sheehan's syndrome (ischemic infarct of pituitary following postpartum bleeding; usually presents with failure to lactate, loss of pubic hair, fatigue)
    • -Empty sella syndrome (atrophy or compression of pituitary, often idiopathic, common in obese women)
    • -Brain injury, hemorrhage
    • -Radiation

    Sx don't arise till >75% of pituitary parenchyma is lost

    • Treatment:
    • -Substitution therapy (corticosteroids, thyroxine, sex steroids, human growth hormone)
  40. Diabetes melitus
    Chronic manifestations
    • Nonenzymatic glycosylation:
    • 1. Small vessel disease (diffuse thickening of basement membrane)
    • -retinopathy (hemorrhage, exudates, microaneurysms, vessel proliferation)
    • -glaucoma
    • -nephropathy (nodular sclerosis, progressive proteinuria, chronic renal failure, arteriosclerosis leading to HTN, Kimmelstiel-Wilson nodules)

    • 2. Large vessel atherosclerosis
    • -CAD
    • -Peripheral vascular occlusive disease
    • -Gangrene → limb loss
    • -Cerebrovascular disease

    • Osmotic damage (sorbitol accumulation in organs with aldose reductase):
    • -Neuropathy (motor, sensory, and autonomic degeneration)
    • -Cataracts
  41. Diabetes melitus
    Acute manifestations
    • Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmoalr coma (type 2), unopposed secretion of GH and epinephrine (exacerbating hyperglycemia)
  42. Diabetes Melitus
    tests
    • Fasting serum glucose >126
    • Random blood glucose >200
    • Oral glucose tolerance test (OGTT): 2hr>200
    • HbA1C (reflects average blood glucose over prior 3 months)
  43. Diabetes melitus
    Type 1
    • 1° defect: Autoimmune destruction of β cells
    • Insulin always needed
    • Presents: <30 years of age
    • NOT associated with obesity
    • Relatively weak genetic predisposition (50% concordance in twins)
    • Polygenic
    • HLA associations: HLA-DR3 and 4
    • Severe glucose inolerance
    • High sensitivity to insulin
    • Ketoacidosis: common
    • β cell number ↓
    • Serum insulin level ↓
    • Classic sx (poyluria, polydipsia, polyphagia, weight loss): common
    • Histology: Islet leukocytic infiltarte
  44. Diabetes melitus
    Type 2
    • 1° defect: ↑ resistance to insulin, progressive pancreatic β cell failure
    • Insulin needed sometimes
    • Presents: >40 years of age
    • Associated with obesity
    • Strong genetic predisposition (90% concordance in twins)
    • Polygenic
    • No HLA associations
    • Mild to moderate glucose inolerance
    • Low sensitivity to insulin
    • Ketoacidosis: rare
    • β cell number is variable (with amyloid deposits)
    • Serum insulin level is variable
    • Classic sx (poyluria, polydipsia, polyphagia, weight loss): Sometimes
    • Histology: Islet amyloid (AIAPP) deposits)
  45. Diabetic ketoacidosis (DKA)
    Pathophysiology
    • Significant complication of diabetes (usually type 1)
    • -Usually due to ↑ insulin requirement from ↑ stress (e.g. infection)
    • -Excess fat breakdown and ↑ ketogenesis from ↑ free fatty acids, which are then made into ketone bodies (β-hydroxybutryate > acetoacetate)

    Labs: hyperglycemia, anion gap metabolic acidosis, hyperkalemia

    Presents: Kussmaul respirations, dehydration, nauseea, vomiting, mental status change, fruity smelling breath (acetone)
  46. Diabetic ketoacidosis (DKA)
    signs/sx, labs, complications, tx
    • Signs/Sx:
    • -Kussmaul respirations
    • -Naus/vom, abdominal pain
    • -psychosis/delirium
    • -dehydration
    • -Fruity breath odor (exhaled acetone)

    • Labs:
    • -Hyperglycemia
    • -↑ H+, ↓ HCO3- (anion gap metabolic acidosis), ↑ blood ketone levels
    • -leukocytosis
    • -Hyperkalemia, but depleted intracellular K+ due to transcellular shift from ↓ insulin

    • Complications: Life-threatening mucormycosis, 
    • -Rhizopus infection,
    • -cerebral edema,
    • -cardiac arrhythmias,
    • -heart failure

    • Treatment:
    • -IV fluids, IV insulin and K+ (to replete intracellular stores)
    • -glucose if necessary to prevent hypoglycemia
  47. Pancreatic endocrine neoplasms
    • 1. Tumor of islet cells - MEN1
    • 2. Insulinomas: increased insulin, increased C-peptide
    • 3. Gastrinomas (zollinger-Ellison)
    • 4. Somatostatinomas: achlorhydria and cholelithiasis with steatorrhea
    • 5. VIPomas: watery diarrhea, hypokalemia, achlorhydria
  48. Carcinoid syndrome
    • Rare syndrome caused by carcinoid tumors (neuroendocrine cells), especially metastatic small bowel tumors (secrete high levels of 5-HT)
    • -NOT seen in tumors limited to GI tract (first past metabolism of 5-HT in liver)
    • Sx:
    • -recurrent diarrhea,
    • -cutaneous flushing,
    • -asthmatic wheezing,
    • -right sided valvular disease
    • -↑ 5-HIAA in urine
    • -niacin deficiency

    Tx: somatostatin analog (e.g. octreotide)

    • Rule of 1/3s:
    • -1/3 metastasize
    • -1/3 present with 2nd malignancy
    • -1/3 multiple

    *most common tumor of appendix
  49. Zollinger-Ellison syndrome
    • Gastrin-secreting tumor of pancreas or duodenum
    • Stomach shows rugal thickening with acid hypersecretion
    • Causes recurrent ulcers
    • May be assocaited with MEN type 1
  50. Multiple endocrine neoplasias
    (MEN)
    • MEN 1 (Wermer's syndrome) - 3P's (Pituitary, Parathyroid, Pancreas)
    • MEN 2A (Sipple's syndrome) - 2P's (Parathyroid, Pheochromocytoma)
    • MEN 2B - 1P (Pheochrommocytoma)
    • **All MEN syndromes have autosomal dominant inheritance
  51. MEN 1 (Wermer's syndrome)
    • Parathyroid tumors
    • Pituitary tumors (prolactin or GH)
    • Pancreatic endocrine tumors: ZE syndrome, insulinomas, VIPomas, glucagonomas (rare)
    • Commonly present with kidney stones and stomach ulcers
  52. MEN 2A (Sipple's syndrome)
    • Medullary thyroid carcinoma (secretes calcitonin)
    • Pheochromocytoma
    • Parathyroid tumors
    • *Associated with ret gene mutation
  53. MEN 2B
    • Medullary thyroid carcinoma (secretes calcitonin)
    • Pheochromocytoma
    • Oral/intestinal ganglioneuromatosis (associated with marfanoid habitus)
    • *Associated with ret gene mutation
  54. Congenital adrenal hyperplasia (CAH)
    Excessive sex steroids with hyperplasia of both adrenal galnds

    • 21-hydroxylase deficiency is the most common
    • Sx:
    • -Salt wasting with hyponatremia, hyperkalemia, and hypovolemia (lack of aldosterone)
    • -Life-threatening hypotension due to lack of cortisol (vascular tone)
    • -Clitoral enlargement or precocious puberty (excess androgens)

    • 11-hydroxylase deficiency:
    • -Increased sex steroids
    • -Decreased cortisol
    • -Increased mineralocorticoid (weak)
    • -Same as 21hydroxylase deficiency without salt wasting

    • 17-hydroxylase deficiency:
    • -Increased Mineralocorticoid
    • -Decreased Cortisol
    • -Decreased sex steroids

  55. Diabetes drugs
    strategies for DM1/2; Rx classes (mechanisms)
    • -DM 1: low-sugar diet, insulin replacement
    • -DM 2: dietary modification and exercise for wieght loss; oral hypoglycemics and insulin replacements

    • Drug classes:
    • -Insulin: short/rapid-acting, long acting
    • -Biguanides: Metformin (mechanism unknown; ↓gluconeogenesis, ↑ glycolysis, ↑ peripheral glucose uptake)
    • -Sulfonylureas: Glipizide (mechanism: close K+ channels in β-cell membrane → depolarizes cell membrane → triggering insulin release via ↑ Ca2+ influx)
    • -Glitazones/thiazolidinediones: "-glitazones" (↑ insulin sensitivity)
    • -α-glucoside inhibitors: Acarbose (inhibit intestinal brush-border α-glucosidases)
    • -Amylin analogs: Pramlintide (↓ glucagon)
    • -GLP-1 analogs: Exenatide (↑ insulin, ↓ glucagon release)
    • -DPP-4 inhibitors: linagliptin (↑ insulin, ↓ glucagon release)
  56. Insulin
    Mechanism, clinical use, toxicities
    • Lispro (rapid-acting)
    • Aspart (rapid-acting)
    • Glulisine (rapid-acting)
    • Regular (short-acting)
    • NPH (intermediate)
    • Glargine (long-acting)
    • Detemir (long acting)

    • Action: bind insulin receptor (tyrosine kinase activity)
    • -Liver: ↑ glucose stored as glycogen
    • -Muscle: ↑ glycogen and protein synthesis, K+ uptake
    • -Fat: aids TG storage

    Clinical use: Type 1 DM, type 2 DM, gestational diabetes, life-threatening hyperkalemia, and stress-induced hyperglycemia

    Toxicity: hypoglycemia, very rarely hypersensitivity reaction
  57. Biguanides
    Mechanism, clinical use, toxicities
    Metformine

    • ActionExact mechanism unknown
    • -↓ gluconeogenesis
    • -↑ glycolysis
    • -↑ peripheral glucose uptake (insulin sensitivity)

    • Clinical use: oral
    • -First line therapy in DM2
    • -Can be used in pts without islet function

    • Toxicities: GI upset
    • -Lactic acidosis (*contraindicated in renal failure)
  58. Sulfonylureas
    Mechanism, clinical use, toxicities
    • Fist generation: Tolbutamide, chlorpropamide
    • Second generation: Glyburide, glimepiride, glipizide

    • Mechanism:
    • -Close K+ channel in β-cell membrane, so cell depolarizes
    • -leads to ↑Ca2+influx which triggers release of insulin

    • Clinical use: stimulates release of endogenous insulin in type 2 DM
    • -Require some islet cell function, useless in DM1

    • Toxicities:
    • -First gen: disulfiram-like effects
    • -Second gen: hypoglycemia
  59. Glitazones/thiazolidinediones
    Mechanism, clinical use, toxicities
    Pioglitazone, Rosiglitazone

    • Mechanism:
    • -↑ insulin sensitivity in peripheral tissue
    • -binds to PPAR-γ nuclear transcription regulator

    • Clinical use
    • -Used as monotherapy in type 2 DM, or in combination

    • Toxicities:
    • -Weight gain
    • -Edema
    • -Hepatotoxicity
    • -Heart failure
  60. α-glucosidase inhibitors
    Mechanism, clinical use, toxicities
    Acarbose, Miglitol

    • Mechanism:
    • -Inhibit intestinal brush-border α-glucosidases
    • -Delayed sugar hydrolysis and glucose absorption → ↓ postprandial hyperglycemia

    Clinical use: Monotherapy in type 2 DM, or combination

    Toxicities: GI disturbances
  61. Amylin analogs
    Mechanism, clinical use, toxicities
    Pramlintide

    Mechanism:↓ glucagon

    Clinical use: type 1 or 2 DM

    • Toxicities:
    • -Hypoglycemia
    • -Nausea
    • -Diarrhea
  62. GLP-1 analogs
    Mechanism, clinical use, toxicities
    Exenatide, Liraglutide

    • Mechanism:
    • ↑ insulin, ↓ glucagon release

    Clinical use: Type 2 DM

    Toxicities:

    • -Naus/Vom
    • -pancreatitis
  63. DPP-4 inhibitors
    Mechanism, clinical use, toxicities
    Linagliptin, saxagliptin, sitagliptin

    • Mechanism:
    • -↑ insulin, ↓ glucagon release

    Clinical use: Type 2 DM

    Toxicities: mild urinary or respiratory infections
  64. Propylthiouracil, methimazole
    Mechanism, clinical use, toxicities
    • Mechanism:
    • -Block peroxidase, inhibiting organification of iodide and coupling of thyroid hormone synthesis
    • -Propylthiouracil also blocks 5'-deiodinase, decreasing peripheral conversion of T4 to T3

    Clinical use: Hyperthyroidism

    • Toxicity:
    • -Skin rash
    • -agranulocytosis (rare)
    • -aplastic anemia
    • -hepatotoxicity (propylthiouracil)
    • -Methimazole is a possible teratogen
  65. Levothyroxine, triiodothyronine
    Mechanism, clinical use, toxicities
    • Mechanism: Thyroxine replacement
    • Clinical use: hypothyroidism, myxedema
    • Toxicity: Tachycardia, heat intolerance, tremors, arrhythmias
  66. Hypothalamic/pituitary drugs
    Drug and clinical use
    • GH → GH deficiency, Turner syndrome
    • Somatostatin (octreotide) → Acromegaly, carcinoid, gastrinoma, glucagonoma, esophageal varices
    • Oxytocin → Stimulates labor, uterine contraction, milk let-down; controls uterine hemorrhage
    • ADH (desmporessin) → Pituitary (central) DI
  67. Demeclocycline
    Mechanism, clinical use, toxicity
    • Mechanism: ADH antagonist (member of the tetracycline family)
    • Clinical use: SIADH
    • Toxicity: Nephrogenic DI, photosensitivity, abnormalities of bone and teeth
  68. Glucocorticoids
    Hydrocortisone, prednisone, triamcinolone, dexamethasone, beclomethasone
    Mechanism, clinical use, toxicity
    • Mechanism: ↓ production of leukotrienes and PGs by inhibiting phospholipase A2 and expression of COX-2
    • Clinical use: Addison's disease, inflammation, immune suppression, asthma
    • Toxicity: Iatrogenic Cushing's syndrome → buffalo hump, moon facies, truncal obesity, muscle wasting, thin skin, easy bruising, osteoporosis, adrenocortical atrophy, peptic ulcers, diabetes (if chronic). Adrenal insufficiency when stopping drug abruptly after chronic use

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