Clinical Cases and Correlations Flashcards
GP6D Deficiency
Causes
Most common genetic enzyme deficiency & most common cause of acute hemolysis
Occurs when:
- individual expresses < 50-60% of normal G6PD levels
AND
- body is subject to oxidative stress (H202) via infections, oxidant drugs (sulfa, bactrim), and fava beans
G6PD
Worldwide distribution
common in places where malaria is pandemic
hypothesized as an evolutionary adaptation against malaria due to increased destruction of plasmodium infected RBCs
G6PD
Cause of RBC destruction
Rise in H202 due to sub-optimal levels of NADPH
Oxidative damage to plasma membrane and hemoglobin in RBCs
Aggregated hemoglobin forms Heinz Bodies
Macrophages may engulf part of the membrane, causing characteristic “bite cells”
ETOH Hypoglycemia
2 Pathways
- in cytosol:
- ETOH oxidized in rxns via alcohol dehydrogenase and aldehyde dehydrogenase
- NADH (cyto) is produced in both rxns - In smooth ER:
- ETOH metabolized to acetaldehyde, feeds to aldehyde dehydrogenase rxn in cytosol, increasing NADH (cyto)
ETOH Hypoglycemia
Effects
Liver gluconeogenesis begins and become source of glucose in starvation states
High NADH levels drive rxns toward production of lactate and malate in cytosol.
Pyruvate and OAA are missing, so gluconeogenesis can’t happen.
Effect of Cyanide poisining
irreversibly binds to Fe3+ in ETC complex IV
Nitrates are the antidote, convert Fe2+ to Fe3+ which can bait cyanide before it reaches tissue
O2 is also administered
CO poisoning
CO binds to Fe2+ in complex IV, but less tightly than Cyanide.
Also binds to Fe2+ in hemoglobin, displacing O2
Niacin and Lipolysis
Pharmacologic levels of niacin inhibit lipolysis
Reduces production of VLDL and LDL
Ketogenesis and Diabetes
continued low I/G ratio leads to very active ketogenesis
Populations: untreated DM I, neonates consuming milk, adults on atkins diet
Ketonemia can occur, which can lead to DKA
Acetone, fruity odor in breath, sign of DKA
Fructokinase deficiency
benign condition
Fructose accumulates in the urine
Aldolase B deficiency
Fructose Poisoning
Mechanism:
1. hepatic accumulation of F1P due to metabolic block
- F1P is osmotically active, leading to liver damage and failure.
- Pi is tied up to make F1P, so Pi levels are decreased leading to decreased glycogenolysis and hypoglycemia
- Decreased Pi results in decreased ATP synth
THERAPY:
avoid dietary fructose and sucrose
Gal-1-P Uridyltransferase Deficiency
(Classic Galactosemia)
Mechanism
- metabolic block results in hepatic accumulation of Gal-1-P. Osmotic activity results in liver damage
- Galactose accumulates in liver and other tissues
- Galactose in the cell is converted to Galactitol by aldose reductase
Gal-1-P Uridyltransferase Deficiency
(Classic Galactosemia)
Presentation
- Galactosemia
- Galactosuria
- Liver damage due to increased Gal-1-P and galactitol
- Extrahepatic tissue damage
- Cataracts, kidney and nerve damage
Gal-1-P Uridyltransferase Deficiency
(Classic Galactosemia)
Therapy
Remove all dietary galactose including lactose containing foods and galactose containing compounds
Hypercholesterolemia (high LDL) drugs:
Statins
- Competitive inhibitors, similar to HMG-CoA, inhibit cholesterol synthesis
- Ex: lovastatin, simvastatin, atorvastatin
Mechanism:
1. Inhibition of HMG-CoA Reductase lowers cytosolic cholesterol
- LDL receptor synthesis is increased
- LDL mediated endocytosis is increased
- Decreased serum LDL
Hypercholesterolemia (high LDL) drugs:
Resins, Bile Acid Sequestrants
- Charged resin to form ionic bonds with bile acids. Insoluble complex excreted in feces
- Less bile acid/salt reabsorbed, more excreted.
Ex: cholestyramine, colestipol, colesevelam
Mechanism:
-Since more bile acids/salts are excreted, de novo synthesis using cholesterol as substrate needs to start in order to make up the difference.
-Increased use of cholesterol to produce more bile acids leads to lower cytosolic
cholesterol.
- As a result, LDL-receptor synthesis is increased.
- LDL-mediated endocytosis is increased.
- HMG-CoA reductase activity is also increased.
- This leads to decreased serum LDL-cholesterol
Hypercholesterolemia (high LDL) drugs:
Cholesterol absorption inhibitors
- Bind to protein cruicial for absorption in enterocytes and hepatocytes
- Cholesterol absorption inhibited
Ex: ezetimibe
Mechanism:
- Decreased absorption lowers cytosolic cholesterol
- LDL receptor synthesis is increased
- LDL endocytosis increased
- HMG-CoA reductase increased
- decreased serum LDL
Hypercholesterolemia (high LDL) drugs:
Combo Therapy
Commonly Statins/Ezetimibe or Statins/Cholestyramine
Familial Hypercholesterolemia
Presentation
Xanthomata- tumerous masses in subepithelial tissue of skin and tendons
Corneal Arcus
Atherosclerosis
Familial Hypercholesterolemia
Lipid profile
extremely high LDL with normal TAGs
Familial Hypercholesterolemia
Mechanism
defective LDL receptor leads to impaired serum LDL endocytosis
Serum LDL increases
Cytosolic cholesterol is lower, resulting in HMG-CoA Reductase activity and de novo synthesis
Cholesterol Gallstones/Cholelithiasis
Risk factors
- Fat (in men and women with either obesity or rapid weight loss)
- Female
- Forty (in women)
-Fertile (due to higher levels of estrogen, which increases cholesterol secretion into
bile)
-Fibrates (and other drugs that inhibit cholesterol 7-alpha-hydroxylase)
Cholesterol Gallstones/Cholelithiasis
Causes
imbalance of free cholesterol and phospholipids/bile solvent secreted by liver
3 Factors:
1. increase in cholesterol secretion into bile
- Decrease in level of bile salts/phospholipids
- delayred/incomplete gallbladder emptying
Cholesterol Gallstones/Cholelithiasis
Treatment
-Typically, surgical removal of the gallbladder (laparoscopic cholecystectomy) is
the treatment of choice.
-For patients unable to go through surgery, administration of exogenous
ursodeoxycholic acid (ursodiol, a bile acid) is used to supplement the body’s supply
of bile acids, resulting in a gradual (months to years) dissolution of the gallstones.
Familial Chylomicronemia
Problem Consequence Lipid Profile Presentation Therapy
Problem: deficiency of LPL or apo C-II
Consequence: TAG in CM cannot be hydrolized
Lipid profile: Elevated fasting CM w/ high TAGs
- Serum is turbid/milky
- VLDL not elevated
Presentation:
- Eruptive Xanthomata after meal
- Pancreatitis
Therapy:
- consumption of medium and short chain TAGs
- Fat soluble vitamin supplementation
Abetalipoproteinemia
CM Retention Disease
Problem: loss of function in MTP gene due to mutation
Consequence: TAGs not transferred to CM and VLDLs, cannot be assembled
Lipid Profile: CM, VLDL, LDL absent, hypolipidemia
Presentation:
- Failure to thrive
- Dietary fat accumulation in enterocytes
- Steatorrhea
- neuro deficits
Therapy:
-Low fat, calorie rich diet w/ vitamin supplementation
familial combined hyperlipidemia type IIb
Causes Consequences Lipid Profile Clinical Presentation Therapy
1o cause: overproduction of apo B-100
2o cause: obesity, metabolic syndrome, insulin resistance
Consequence: excessive VLDL production
Lipid Profile: decreased HDL, elevated VLDL and LDL
Presentation:
- Few manifestations
- High risk of premature CVD
Therapy:
- combo therapy of niacin and statins, resins
- diet and lifestyle
familial disbetalipoproteinemia type III
Causes
Lipid Profile
Clinical Presentation
Therapy
1o: poor apo E2 binding to Apo E receptor due to polymorphism of apo E gene
2o: high fat, DM, obesity, ETOH, hypothyroidism, estrogen deficiency
Lipid profile: elevated IDL and CM remnants
Presentation:
- Turboeruptive xanthomata
- palmar striated xanthomata
- high risk of CVD PAD
Therapy:
-combo therapy niacin, fibriates and statins,resins
Tangier disease (alpha-lipoprotein deficiency)
Causes Consequences Lipid Profile Clinical Presentation Therapy
Cause: ABCA1 def.
Consequence: cholesterol accumulation in tissue, nascent HDL degradation, impaired transfer of Apo E and Apo C-II
Lipid Profile: low HDL and LDL
Presentation:
- enlarged orange tonsils
- MI
- Clouding cornea
- peripheral neuropathy
Treatment:
NONE
Niacin
Lower TAGs: inhibits HSL and lipolysis decreasing VLDL and LDL production
Increase serum HDL: decreases Apo A-I breakdown, extending HDL life
Fibrates
Lower TAGs: activate LPL, VLDL clearance in creased. Secretion of nascent VLDL decreased
Increase serum HDL: increase Apo A-I expression
