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Biochemistry of Boozin'

absorption iz stomach (25%)
metabolized to acetaldehyde by stomach and LI
rate limiting enzyme: gastric alcohol dehydrogenase
men have more of it than women, per pound body wt
metabolism of ethanol-->acetaldehyde-->acetate
one NAD+-->NADH with each of above oxidation rxns
drinking binge w/o food intake-->high NADH relative to NAD
and of course you remember that NADH is made from niacin, vitamin B3
alcohol abuse is the most common cause of thiamine deficiency, B1


high NADH/NAD+ causes:
*pyruvate-->lactate-->lactic acidosis (bad)
*depression of the TCA cycle (less pyruvate-->acetyl CoA, so less ATP production)
*inhibition of gluconeogenesis (from all 3 top sources: alanine, lactate, glycerol)
-->depletion of glycogen stores-->hypoglycemia (bad)
*promotes: dihydroxyacetone phosphate-->glycerol-3-phosphate
*promotes: acetoacetate-->beta-hydroxybutyrate

ACIDOSIS
increased lactic acid
increased beta-hydroxybutyric acid
increased anion gap

HIGH ACETYL COA
*used to synthesize fatty acids-->TGs-->fatty liver, high cholesterol, etc
*used to synthesize ketoacids (beta hydroxybutyric)

LONGTERM EFFECTS
*G3P combines with fatty acids-->triacylgylerols (triglycerides) which accumulate in liver
*fat in liver blocks protein synthesis-->can't make & secrete VLDL-->fatty liver disease (bad)

HIGH CALORIE
energy gained by oxidizing alcohol to CO2 & H2O: 7kcal/gram ATP
(carbs make 4, fats 9, prots 4)
no nutrition with these calories: empty

ALCOHOL RAMPS UP THE LIVER
induces phase I the cytochrome P-450 system
-->increase in need for enzymes for alcohol metabolism-->increased gene transcription of these genes-->more enzymes-->tolerance

THE LAW
legal blood limit for driving is 80-188 mg/dL

FATTY CHANGE IN THE LIVER (mechanisms)
A:
metabolism of alcohol-->increased glycerol-3-phosphate
G3P is an intermediate of glycolysis and substrate for TG synthesis
NADH promotes conversion of dihydroxyacetone phosphate-->glycerol-3-phosphate
B:
acetyl coenzyme A is end product of alcohol metabolism
also used for fatty acid synthesis
C:
decreased beta-oxidation of fatty acids
(due to alcohol, hypoxia, and also by the way diptheria toxin)
D:
increased mobilization of fatty acids from adipose tissue
(dt alc & starvation)
E:
decreased synthesis of apolipoprotein B-100-->increased CCl4 and decreased prot intake
F:
decreased hepatic release of VLDL-->increased CCl4 and decreased prot intake

SYSTEMIC EFFECTS
CV: dilated cardiomyopathy dt B1 def, HTN dt incr catecholamines
CNS: depressant esp of cortex and limbic sys, Wernicke's (confusion, ataxia, nystagmus), cerebellar atrophy dt loss of purkinje cells, cerebral atrophy dt loss of neurons, central pontine myelinolysis dt rapid IV fluid correction of hyponatremia
GI: oropharyngeal & upper to mid-esoph CA (SCC), acute hemorrhagic gastritis, Mallory Weiss & Boerhaave's syndrome, esophageal varices, pancreatitis (acute & chronic)
General: fetal alcohol syndrome (mental retardation, microcephaly, ASD)
GU: testicular atrophy dt decr test, decr spermatogenesis, incr risk of spont abort
Hematopoietic: folate def (decr resorption in jejunum)-->macrocytic anemia
Integument: porphyria cutanea tarda (photosensitive bullous lesions)
MS: rhabdomyolysis
PNS: neuropathies dt thiamine def

LAB FINDINGS WITH ALCOHOL ABUSE
hyperuricemia (lactic & beta-hydroxybutyric compete w/ uric for proximal tubule excretion)
hypertriglyceridemia (dt incr G3P)
serum aspartate aminotransferase (AST) greater than alanine aminotransferase (w/ liver dz)
increased serum gamma-glutamyltransferase (GGT) dt alc induction of SER hyperplasia


FROM ED AT http://www.pathguy.com/meltdown.txt

Alcohol: Your lecturer thinks he's being fair when he says that the
harm caused by alcohol exceeds, by an order of magnitude, the harm from
the illegal drugs. Yet most people who drink alcohol sensibly appear
to take no harm and perhaps even derive some healthy pleasure. Noah
needed a drink when... and made an "ass" of himself, the "butt" of his
son's joke. Proof: Double the percentage of ethanol. Nobody knows the
chemistry of drunkenness. The liver metabolizes alcohol first to
acetaldehyde (via alcohol dehydrogenase), then to acetic acid, and
ultimately to carbon dioxide and water. Problem drinkers lose their
dendritic spines; "each drink kills x-number of brain cells" is
rubbish. Each beer or shot raises a normal-size dude's blood alcohol
level by 20 mg/dL; "legally drunk" is maybe 100 mg/dL but you're
impaired below this. You metabolize alcohol at a rate of 15 mg/dL/hr,
using basically zero-order kinetics; faster if you're a practiced
drunkards.

Health problems of heavy drinkers: (1) alcoholic hepatitis and hepatic
cirrhosis; (2) brain damage (loss of dendritic spines, Wernicke,
Korsakoff, cerebellar atrophy); (3) pancreatitis (acute and the painful
chronic form); (4) cancer of esophagus, throat, and larynx; (5) GI
bleeding from ulcers, varices, gastritis; (6) fetal alcohol syndrome
(variable; look for flat philtrum, epicanthic folds, growth and mental
retardation); (7) neuropathy (numb fingers); (8) cardiomyopathy (rare);
(9) rhabdomyolysis (seldom dramatic, but probably contributes to long-
term wasting); (10) hangover, tremulousness, seizures, delirium tremens
on withdrawal ("pink elephants on parade", etc.); (11) losing job,
family, friends; (12) oh, and by the way, it probably has a slight
favorable effect on HDL and coronary atherosclerosis. Gee whiz.

"I've been asked if I ever get the
DT's. I don't know. It's hard to tell
where Hollywood ends and the DT's begin."

-- W.C. Fields

CIRRHOSIS notes from Nutrition Siebert 2010
characterized by altered storage of micronutrients
monitor for weight changes-->mm wasting
appetite, taste changes
watch for N/V
issues with swallowing, chewing
renal insufficiency, edema/ascites-->early satiety, needs small frequent meals
GI bleeds-->change in BMs
infections

energy needs vary but are generally higher than normal
130-140% if appear normal
150-175% if ascites, infection of malabsorption
carbs: needs small frequent meals to avoid probs dt altered epi/cortisol, insulin/glucagon levels

protein intake needs to be managed
.8g prot/kg body wt/day for nonalcoholic hep
if alcoholic needs 1.5g prot/kg/day

nutrition for cirrhosis
oral or liquid form best
prob def in A-Z and fat sol vits
may need water soluble forms of fat sol vits
increased PTT: give IV or IM vitamin K x 3 days and recheck
B vits: esp B1 Thiamin (100mg/qd for a limited time)
see Krauss table 31-4

more prone to cholestatis dz:
primary biliary cirrhosis (AI destrx of small and med intrahepatic bile ducts)
look for high chol, support bile flow
primary sclerosing cholangitis
fibrosing of extrahepatic bile ducts (do not give Cu or Mn bc is excreted in bile and may incrase cholestatis live dz)

NUTRITION IN ASCITES
sodium restriction
diuretic therapy
restrict what to 2g/day or less? sodium? I think so
glucose alerations common in 2/3 of cirrhosis pts
watch for fat malabsorption (stool) and
tx with long/medium chain fa's (milk fat, palm and coconut oil)
don't give bile
SAM-e 900mg qd (break down scar tissue, improve fx, helps with glutathione rdctn & cholestasis)
BCAA 5gm qd (improves prot processing in some pts)
Phosphatidylcholine 900mg qd (breaks down scar tissue, improves function)

HERBS FOR CIRRHOSIS
silmarin 400-600mg DD
schisandra 100 mg bid
astragalus 4-7 gms powder qd
thymus extracts 200mg tid

SSL PATHOLOGY NOTES ON ALCOHOL
antimetabolite for folic acid, magnesium, B vitamins esp B6 and B12
liver damage: alcoholic steatosis can lead to alcoholic hepatitis
body's attempts to repair results in alcoholic cirrhosis

NERVOUS SYSTEM EFFECTS
Wernicke syndrome: thiamind def, balance and gain affects, EOM muscles of the eye, ataxia, confusion, nystagmus, opthalmoplegia (degrees of)
Korsakoff syndrome: toxicity and thiamine def, irritable, combative, retrograde amnesia-->confabulation (story changes)
cerebellar degeneration: balance off
peripheral neuropathy: thiamine def (all b's) affects lower limbs bilaterally

CARDIOVASCULAR
cardiomyopathy (dilated is often B1 df) -->CHD
HTN: vasopressor

GI TRACT
gastritis, nausea, vomiting
pancreatitis: autodigestion of pancreas

SKELETAL MUSCLE
rhabdomyolysis, painful, leads to kidney failure

REPRODUCTIVE
testicular atrophy
spontaneous abortions

FETAL ALCOHOL SYNDROME
growth retardation, intellectual impairment, learning disabilities, developmental delays, speech impairment, hearing impairment, behavioral problems (impulse management), change in facial features
may occur with as little as 1 drink/day
10-12,000 cases/year in US
1-4.8 per 1000 live births

features
flattening of mid face, short upturned nose
small eyes, prominent epicanthal folds
no filtrume, thin upper lip, small jaw

"effect"
lesser affect but still alcohol was in system
estimated to be 2x as common as FAS

FROM BIOCHEM 1 NOTES
PATHOPHYSIOLOGY OF ACUTE ALCOHOL INTOXICATION
Ethanol CH3OH is metabolized in the liver in 3 steps
1) formation of acetaldehyde by cytosolic alcohol dehydrogenase
2) Formation of acetate by mitochondrial aldehyde dehydrogenase
3) Acetate is converted by acetyl CoA by other tissues
Ethanol metabolism in other tissues: Oxidized by liver detox mechanisms
Lots of NADH is produced
NADs are used in liver, none are left to move pyruvate to oxidation-->lactic acidosis
Liver is too busy to break up glycogen, hence blood sugar isn’t maintained by glycogen breakdown
Ehtanol contains 7kcal/gram stored energy (more than sugar, less than fat)
Coma mb caused by increased fluidity of cell membranes, incr permeability, decr cerebral fx
Ethanol protects vs methanol poisoning via competitive inhibition of enzyme
Ethanol causes production of acetaldehyde which is highly reactive, joins proteins including microtubules, may decrease transport of clotting factors and albumin into circulation
Native Americans and East Asians don’t process EtOH as well because they have an atypical enzyme which leads to near zero mitochondrial enzyme activity. They oxidize acetaldehyde by a cytosolic version of the enzyme with low affinityincr acetaldehyde (CH3CHO) which can’t go to acetatemore damaging consequences

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