Clinical (excluding Diabetes) Flashcards
ADH1B*1 polymorphism
less active isoform of ADH1
homo ADH1B1/1B1 polymorphism
risk to develop Wernicke-Korsakoff syndrome
Wernicke-Korsakoff syndrome
neuropsychiatric syndrome commonly associated with alcoholism and thiamine deficiency
how thiamine deficiency is produced (4 ways) in
homo ADH1B1/1B1 polymorphism
- alcoholics –> poor diet
- due to slower metabolism of EtOH, elevated [EtOH] persist….active transport by intestinal enterocytes is decreased by EtOH (decrease thiamine uptake)
- hepatic damage decreases formation of the active thiamine pyrophosphate cofactor (TPP)
- utilization of the active thiamine cofactor becomes impaired…Mg2+ is critical to thiamine utilization in tissues…Mg2+ is usually deficient in alcoholics
which cells are very sensitive to thiamine deficiency
neural (glial) cells
why you get neuro shit with W-K syndrome
ADH1B2/1B2 polymorphism
increases activity –> resulting in an increased acetaldehyde build up –> toxic if ALDH2 cannot keep up
homo ALDH22/22 polymorphism
increases Km for acetaldehyde and decreases Vmax
essentially inactivates ALDH
popular in Asian populations
ALDH2 inhibitor (Antabuse)
used to treat alcoholism
inhibits ALDH2 and get build up of acetaldehyde = nausea
dangerous if alcoholic continues to drink booze on it
acetaldehyde toxicity in liver
proteins
initially it forms adducts with numerous compounds in cell
will bind to amino acids –> (-) protein synthesis
will bind to alpha and beta tubulin –> (-) cellular processes like transport and secretion
results in (-) synthesis and secretion of important blood proteins like albumin and coagulation factors
acetaldehyde toxicity in liver on glutathione
causes functional impairment of peptide glutathione
important antioxidant….becomes oxidized while reducing ROSs
forms adduct with acetaldehyde and becomes impaired
….then lipids react with these ROS and form lipid peroxides –> carcinogenic or can cause hemolysis
also…
mitochondria function lowers –> (-) ALDH –> (+) acetaldehyde –> viscious cycle
acute metabolic changes in VLDL secretion vs. chronic changes
in response to EtOH metabolism
acute –> increase due to increase TG synthesis
chronic –> decrease once liver function lowers permanently
stages of hepatic damage
- acute short live biochemical effects –> reversible
- initially liver becomes enlarged, full of fat, and cross linked with collagen fibers (fibrosis)
- up to certain point the liver can compensate and reverse this - chronic EtOH comsumption –> irreversible
- laennec cirrhosis –> damage from acetaldehyde and ROS begins to compromise the hepatic function and liver begins to shrink and lose normal lobular shape
cirrhosis
- (-) gluconeogenesis
- (-) levels of important plasma proteins, like albumin and coagulation factors
- (-) VLDL secretion
- cytochrome p450 synthesis decreases and functional glutathione is affected
- -> drug and EtOH metabolism is impaired - (-) making bile acids from cholesterol (p450 enzymes)
- urea cycle lowers when mitochondria functions lowers –> hyperammonia
- lowered bilirubin conjugation –> juandice (hepatocellular jaundice)
liver fibrosis
collagen type I and fibronectin
Kupffer cells activated by hepatic damage…can also produce acetaldehyde themselves
then activate stellate cells through the secretion of growth factors (cytokines)
stellate change from lipid filled, vitamin A storage cells –> to one that proliferates, loses vitamin A and secrete fibrous material
and produce E.C. metalloproteases that digest normal matrix and replacing it with new fibrous material
ALT blood test
> 10x = acute viral hepatitis
<4x = chronic alcohol hepatitis
used to monitor treatment of a liver disease patient to see if treatment is working…
if AST increases –> switch treatment
