Biochemistry Diseases (Chapters 27-52)



Biochemistry Diseases (Chapters 27-37)

▪ Respiratory Distress Syndrome (RDS) – Premature babies can have low lecithin: sphingomyelin ratio of ~1.5 (normal >2.0) that results in insufficient surfactant and causes decreased lung development and severe difficulty breathing.

▪ Multiple Sclerosis – Loss of plasmologen (also sphingomyelin) from myelin causes demyelination. Plasmologen is a product of peroxosome glycerol ether phospholipids synthesis.

▪ Cholera – V. cholerae binds to GM1 receptors. The toxin maintains adenylyl cyclase activity, thus elevated cAMP, which causes oversecretion of chloride into intestinal lumen. Acts by inactivating αS subunit’s GTPase activity via Ribosylation.

▪ Fabry’s Disease – Defect in (-galactosidase A. Build up of ceramide trihexoside leads to skin rash and renal failure.

▪ Gaucher’s Disease – Defect in glucocerebrosidase. Build up of glucocerebroside leads to hepato/splenomegaly, long bone erosion, and mental retardation.

▪ Krabbe’s Disease – Defect in (-galactosidase. Build up of galactocerebroside leads to a lack of sphingomyelin and mental retardation.

▪ Niemann-Pick A & B – Defect in sphingomyelinase. Buildup of sphingomyelin leads to hepato/splenomegaly and mental retardation.

▪ Sandhoff’s Disease – Defect in both Hexosaminidase A & B. Build up of both GM2 and globoside lead to mental retardation, cherry red macula, rapid progression and early death.

▪ Tay-Sachs Disease – Defect in Hexosaminidase A. Buildup of GM2 leads to cherry red macula, blindness, mental retardation.

▪ Tropical Sprue – bacterial infection that leads to severely decreased lipid absorption.

▪ Celiac Sprue – Autoimmune reaction to dietary gluten that leads to decreased lipid absorption.

▪ Cholesterol Gallstones – Low bile salt/ cholesterol ratio favors cholesterol precipitation and stones. High ratio is unfavorable to stone formation. Statins reduce risk of stones by lowering cholesterol. Oral bile acids lower risk by increasing bile salts. Cholestyramine increases risk of stones by lowering bile salts more than cholesterol.

▪ Niemann-Pick C Disease – Defect in NPC-1 transporter that leads to elevated free cholesterol in lysosome/ late endosome. Trouble trafficking free cholesterol to the golgi, ER, plasma membrane, etc. Leads to hepato/splenomegaly and decreasing neurologic and motor functions.

▪ Wolman Disease – Defect in acid cholesterol ester dehydratase (ACEH) in lysosome / late endosome that leads to elevated cholesterol ester in the endosome. Lipids accumulate and is fatal near age 1 year due to organomegaly and necrosis of the adrenal cortex.

▪ Abetalipoproteinemia (Hypolipidemia)– defect in Apolipoprotein Beta (48 or 100) or TAG Transfer Protein (TTP) that results in faulty chylomicron or VLDL formation. Treat patient by feeding only small and medium chain fatty acids that enter portal blood directly.

▪ Tangier’s Disases (Hypolipidemia)– Defect in cholesterol efflux regulatory protein (CERP) that leads no removal of cholesterol esters by HDL. No treatment.

▪ Type I Hyperlipidemia – Defect in ApoCII or Lipoprotein Lipase that leads to increased chylomicrons, VLDL, and TAGs. If condition improves with blood transfusion, then ACII defect, if no improvement, then LPL Defect.

▪ Type II Hyperlipidemia (Familial Hypercholesterolemia) – Defect in LDL receptor in tissues that leads to large increases in circulating LDL.

▪ Type III Hyperlipidemia – Defect in ApoE or its receptor that leads to elevated HDL, Chylomicron remnants and elevated cholesterol and TAGs.

▪ Type IV Hyperlipidemia – Hepatic overproduction of VLDL due to obesity, Diabetes Mellitus that leads to elevated serum LDL.

▪ Diabetic Ketoacidosis (DKA) – Condition due to overproduction of ketones that leads to metabolic acidosis. Ketones normally promote insulin release to limit lipolysis, but relative or absolute insulin deficiency leads to ketone overproduction. Acetone is a product of the spontaneous breakdown of aceotacetate that gives the breath of a DKA patient a fruity smell.

Biochemistry Diseases (Chapters 38-52)

▪ Pertussis Toxin – Ribosylation of cys-residue on αI subunit that prevents the inhibition of adenylyl cyclase via GI and leads to overproduction of cAMP. B. pertussis generates its toxin in the lungs due to elevated temperatures.

▪ Vitamin A Deficiency – causes developmental defects of the CNS, craniofacial and cardiac structures. Night vision is defective, and its loss may be first sign of the diseases. Loss of keratinzation of epithelia and reduction in mucous secretions. Chronic eye dryness and lung and GI diseases more prominent.

▪ Hypervitaminosis A – Excess vitamin A increases unbound circulating retinol, which is toxic. Retinol’s elevation increases retinoic acid via mass action that may cause teratogenic effects in pregnancy, dermatitis and organomegaly.

▪ Type I Diabetes Mellitus (Insulin Dependent DM) – autoimmune destruction of pancreatic β-cells leads to a lack of insulin secretion. A viral infection in early childhood may increase the risk of DMI. Patients require insulin replacement therapy to prevent DKA, coma, and death. DM symptoms require 85% of β-cells to be lost.

▪ Type II Diabetes Mellitus (Non-insulin Dependent DM) – peripheral resistance to insulin and suppression of glucose stimulated release occurs as a result. Insulin resistance may cause β-cells to be overtaxed by producing insulin continuously, resulting in sluggish insulin release in response to glucose. Insulin resistance due to:

o Down regulation of Insulin receptor (decreased expression, or increased internalization)

o Antibodies to receptor (rare)

o Poor responsiveness in tissues due to decreased effectiveness or loss of post-receptor components of signal transduction pathway (IRS,PLC,SHC)

▪ Nephrogenic Diabetes Insipidus (NI) – Renal system does not respond to ADH/Vasopressin due to V2 receptor defect or post-receptor defects (aquaporin II Channel mutation). Dehydration, increases in plasma osmolarity.

▪ Neurogenic Diabestes Insipidus (NI) – Decreased secretion of ADH/Vasopressin from posterior pituitary due to mutations in Pre-pro-vasopressin or a block in axonal transport. Dehydration, increases in plasma osmolarity.

▪ Panhypopituitarism – complete deficiency of all anterior pituitary hormones. Leads to dwarfism, adrenal insufficiency, hypothyroid, hypoglycemia. Treat with GH, cortisone, synthetic thyroid hormone.

▪ Isolated GH Deficiency – selective lack of GH. Hypoglycemia does not lead to GH secretion, as expected in normal individual. Leads to dwarfism. Treat with human GH.

▪ Laron-Type Dwarfism – Defect in GH receptor or signal factors that results in IGF-1 deficiency. Patients are resistant to hGH therapy. Defective GH receptors leads to hypoglycemia, elevated TAGs in adipose tissue. Treat with synthetic IGF-1.

▪ African Pigmy Dwarfism – Defect in post-receptor components of IGF-receptor, therefore no treatment with IGF-1.

▪ Giantism – Excess GH release prior to epiphyseal closure that leads to tall stature, accelerated long bone growth.

▪ Acromegaly – Excess GH release after epiphyseal closure that leads to overgrowth of the extremities and short bones of the face. May be due to tumor, or inactive GTPase of αs that leads to GH synthesis and release constantly.

▪ Hyperthyroidism (Thyrotoxicosis) – Overproduction of T3/T4. Most commonly caused by Graves Disease.

▪ Graves Disease – autoimmune production of thyroid stimulating IgG (TSI). TSI activates the TSH receptor that causes uncontrolled production of T3/T4. Leads to exophthalmos, optic nerve degradation, and periodic paralysis. Treat by blocking hormone production with anti-thyroid drug or ablate thyroid with radioactive Iodine.

▪ Hypothyroidism – Insufficient amounts of free T3/T4 due to thyroid failure or disease of the pituitary or hypothalamus. Basal metabolic rate is decreased and leads to obesity, bradycardia, myxedema.

▪ Cretinism – intrauterine or neonatal hypothyroidism that leads to congential defects and mental retardation. Treat with synthetic thyroid hormone.

▪ Goiter – enlargement of the thyroid gland. Causes include:

o Elevated TSH due to decreased T4 levels (overcompensation). Patient is hypothyroid.

o Iodine deficiency leads to decreased T4 production, therefore elevated TSH. Patient is hypothyroid.

o Defects in thyroid enzymes, that result in decreased T4 release (I- pump, peroxidase, deiodinase). Patient is hypothyroid.

o Hashimoto’s Thyroiditis – autoimmune destruction of the thyroid. Patient is hypothyroid.

o TSH/TRH producing tumor. Patient is hyperthyroid.

o Graves Disease. Patient is hyperthyroid.

▪ Humoral Hypercalcemia of Malignancy (HHM) – non-bone metastasis of cancer causes release of PTH related protein that is embryologically active, but in CA, it binds PTH receptor and elicits PTH effect without feedback control of calcium. Leads to hypercalcemia and hypophosphatemia.

▪ Pseudohypoparathyroidism (PsHP) – defective Gs protein causes target cell resistenc to PTH and other Gs coupled protein responses (TSH, T4, GH). Leads to hypocalcemia and hyperphosphatemia. PTH infusion does not elicit a response of elevated phosphate in urine and no cAMP in urine, no elevation of serum calcium.

▪ Nutritional Rickets / Osteomalacia – Dietary deficiency of vitamin D along with insufficient exposure to sunlight, thus reduced endogenous vit. D synthesis. Reduced calcium phosphate levels lead to weak, rubbery bones. Rickets in children, osteomalacia.

▪ Renal Rickets / Osteodystrophy – rickets due to destruction of renal tissue that leads to insufficient 1,25(OH)2D3. Due to loss of renal 1-Hydroxylase reaction. Elevated 25-OH D3 serum levels.

▪ Hereditary Hypocalcemic Vitamin D resistant Rickets (HVDRR)

▪ Hypocalcemic Vitamin D resistant Rickets (HVDRR)

o Type I – Inherited defect in 1-OHase that leads to decreases 1,25(OH)2D3 production. Treat with exogenous 1,25(OH)2D3.

o Type II – End organ resistance to 1,25(OH)2D3 due to defect in receptor. Defect in DNA binding domain or hormone binding domain.

▪ Congential Adrenal Hyperplasia – Underproduction of cortisol leads to elevated ACTH that leads to hyperplasia.

o Excess ACTH due to low cortisol – defects in all proteins/enzymes associated with ZF, or to the GC receptor (loss of feedback).

o 17α-OHsteroids ok , but no cortisol in ZR leads to androgen production and virilization

o Excess DOC due to 11β and 17αOHase defects suppress aldosterone and causes hypertension.

o Defect of StAR prevents all steroid hormone synthesis and leads to sexual infantilism.

o GC receptor defect causes overstimulation of ZF/ZR leading to excessive DOC and cortisol (ineffective).

o MC receptor defect leads to overproduction of aldosterone but no effect in ZF/ZF.

▪ Hypercortisolism (Cushing’s Disease) – Elevated serum cortisol levels. Generally due to ACTH secreting tumors.

▪ Type I pseudohypoaldosteronism – aldosterone resistance.

o Defective aldosterone receptor (Autosomal Dominant).

o Downstream diminished response to aldosterone in sodium channel (Autosomal Recessive).

▪ Primary Hyperaldosteronism (Conn’s Disease) – Adenoma that secretes aldosterone, resulting in elevated sodium, HTN, and hypokalemia.

▪ Inherited Pseudohyperaldosteronism (Liddle Syndrome) – Defect in sodium channel that causes overreaction to aldosterone, therefore elevated sodium, decreased renin secretion and decreased aldosterone.

▪ Acquired pseudohyperaldosteronism (Licorice) – Licorice induces decreased cortisol degradation, elevated serum cortisol binds the mineralocorticoid receptors and increases sodium retention.

▪ Benign Prostatic Hyperplasia – DHT results in uncontrolled proliferation of prostate cells. 5α-Reductase-2 inhibitors lower DHT (flutamide).

▪ 17α-OHase Defect – no testosterone or DHT, therefore high LH levels. XY Male have female external genitalia lack wolffian structures.

▪ 5α-Reductase-2 Defect – Testosterone ok, but no DHT. Normal LH levels due to normal testosterone. XY male has wolffian structures with female external genitalia. Testosterone surge in puberty begins gender conversion/ virilization.

▪ Androgen Insensitivity Syndrome (AIS) – Androgen receptor defect therefore elevated testosterone and DHT with female external genitalia and lack wolffian structures.

▪ Prolactinoma – benign pituitary tumor of lactotrophic origin that excessively secrete prolactin.

o Females – Supress GnRH release, therefore low LH/FSH and amenorrhea. Galactorrhea occurs (milk let down) due to elevated PRL from tumor-lactogenic effect. Treat with bromocryptine.

o Males – Mammotrophic effect and decreased testosterone due to suppression of GnRH/LH/FSH.

▪ Obesity / DMII gene mutations:

o MC4-R defect prevents α-MSH satiety effect, therefore overeat

o β3 adrenergic receptor and Gs defect lead to decreased cAMP and decreased hormone sensitive lipase activity and decreased fat burn

o Leptin defect causes obesity (no control), DMII

o Leptin receptor causes obesity, decreased TSH, T3, LH/GnRH, GH, IGF-1

o PPARγ Defect promotes insulin resistance due to decreased resistin inhibition

o Uncoupling protein defect causes a decreased ability to freely burn fat to generate heat.

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