Term
How is alcohol normally metabolized by the human body?
What are the major enzyme systems? |
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Definition
Metabolism takes place in hepatocyte with 2 enzymes (ADH and ALDH), ultimately reducing ethanol to acetate, which can enter the TCA cycle or produce Fatty Acids.
1) cytosolic Alcohol DH (ethanol to acetaldehyde)
- requires NAD and Zn++
- 80% of hepatic metabolism
- low Km (active under physiological conditions)
**CYP2E1 can be induced to serve the same function as ADH, using NADP as a co-enzyme**
2) mitochondrial Acetaldehyde DH (acetaldehyde to acetate)
- requires NAD and Zn++ as well
- Inhibited by disulfiram (Antabase)
- low activity in asians and slower than ADH (hangovers!) |
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Term
| What organs other than the liver have ADH, and are therefore able to perform some ethanol metabolism? |
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Definition
Gastric "first pass"
- Males>females
- Nonalcoholics> alcoholics
- Younger > older men
- Decreased by H2 blockers. |
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Term
| What are the major effects of alcohol on each primary segment of the GI tract? |
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Definition
1) Liver
- Structural (ballooning hepatocytes, lipid peroxidation/ROS, Fibrosis/cirrhosis
- Metabolic (excess NADH, drug clearance and protein secretion)
2) Pancreas
- chronic pancreatitis, fibrosis, loss of exocrine and/or endocrine function
3) Stomach
- Mucosal injury, gastritis, ulcer bleeding, secretion
4) Esophagus
- Reflux, Varices, Mallory-Weiss tears from vomiting (lower)
5) Small bowel/colon
- Malabsorption; diarrhea, villus flattening. |
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Term
| How does alcohol consumption affect the brain, adrenals and immune system? |
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Definition
ALSO a gondal toxin
1) Immune system:
- lowered resistance
- depressed production of PMNs
- depressed NKCs
- Abs vs. acetaldehyde adducts
2) Adrenals: alcohol is a stressor
- increased glucocorticoids
3) Brain:“If you drink, your brain will shrink”.
- Hepatic encephalopathy
- Withdrawal syndromes
- Wernicke’s encephalopathy (thiamine def) |
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Term
| Why is alcohol considered to have a low "biological value"? |
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Definition
1) Bomb Calorimetry 7.1 kcal/g
2) Low Biologic Value “Empty Calories
-oxidation w/o phosphorylation
- Cyp2E1 induction “wastes” energy
-ADH metabolism “wastes” energy
-mitochondrial damage ↓ energy utilization |
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Term
| How can alcohol cause liver disease? |
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Definition
Produces structural and metabolic changes.
1) Structurally
- Ballooning hepatocytes with lipid peroxidation (ROS), mega-mitochondria (oxygen demand) leading to fibrosis and cirrhosis.
2) Metabolically
- Loss of redox homeostasis
- Altered drug and xenobiotic clearance
- Sex hormone alterations (especially male) with "feminization"
- Decreased protein secretion (clotting factors!) |
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Term
| What components do alcoholic beverages contain? |
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Definition
Consumption increases basal metabolic rate (BMR) with diet-induced thermogenesis
1) Water
2) Ethanol
3) CHO (varied) |
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Term
How does ethanol alter digestion/absorption in each of the following GI locations?
1) Salivary gland
2) Esophagus
3) Stomach
4) Intestine
5) Bile system |
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Definition
1) Fibrosis and decreased salivary flow
2) Decreased peristalsis and LES pressure (reflux and stricture formation)
3) Acute gastritis and decreased emptying
4) Decreased motility and AA absorption
5) Decreased intraluminal BA with increased bacterial conjugation (more secondary BA contributes to steatorrhea and pigmented gallstones). |
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Term
| How does alcohol influence water-soluble vitamin metabolism? |
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Definition
DEFICIENCY IN: Thiamine (B1), Riboflavin (B2), Pyridoxine (B6), Folic Acid, B12 and Vitamin C
1) Thiamine deficiency
- Wernicke-Korsakoff, beriberi heart disease and polyneuropathy.
- replete it parenterally, then orally
2) B12 deficiency is relatively uncommon because of large stores, but can result in pancreatic insufficiency |
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Term
| How does alcohol influence fat-soluble vitamin metabolism? |
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Definition
Vision issues, osteoporosis, bleeding
ADKE
1) Vitamin A deficiency
- Seen in chronic ingesteion
2) Vitamin D
- 25 hydroxylation in kidney, bone and placenta remains intact, but Vitamin D3 stores (cholecalciferol) are depleted
- Alcoholics get decreased bone density and increased fractures.
3) Vitamin K
- Results from fat malabsorption (pancreatic insufficiency or biliary obstruction)
- Decreased clotting factors (BLEEDING)
4) Vitamin E deficiency is rare in alcoholics |
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Term
| How does alcohol influence CHO and Uric acid metabolism? |
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Definition
1) CHO (too much sugar when you drink and too little after!)
- Hyperglycemia with intake because of ethanol-induced insulin resistance
- Hypoglycemia during fasting because alcohol metabolism interferes with glucose metabolism
- Depression of intestinal dissacharidases
2) Uric acid (gouty arthritis)
- Decreased urinary excretion of UA secondary to elevated serum lactate generated because of increased NADH (from ADH) |
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Term
| How does Alcohol produce Fatty liver, hyperlipidemia and ketoacidosis? |
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Definition
Effects on lipid metabolism
Hyperlipidemia (TG>>cholesterol) with increased VLDL (type IV mostly), chylomicrons and some HDL. |
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Term
| What is the basic "repletion strategy" for alcoholics? |
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Definition
1) B1 (thiamine) 50mg (parenteral, then oral)
2) Riboflavin (MVI)
3) Pyridoxine (MVI)
4) Folic acid (hospital diet)
5) Vitamin A (2000-3000 mg in case of documented deficiency)
6) Zinc 220 mg daily (night blindness unresponsive to vitamin A)
7) Magnesium for symptomatic patients with low serum levels or refractory hypocalcemia.
8) Iron (only if documented deficiency) |
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Term
| Why are women more susceptible to liver disease from alcohol? |
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Definition
1) Increased volume of distribution
2) Increased gut permeability to endotoxin |
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Term
| What is the basic pathophysiology of liver injury from alcohol ingestion? |
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Definition
Direct toxin and activates Kupffer cells and stellate cells.
1) Direct toxin to hepatocyte and alters lipid metabolism (peroxidation with ROS)
2) Increases gut permeability to endotoxin, which activates Kupffer's cells to produce inflammatory mediators that both injure hepatocytes and stimulate stellate cells
- Stellate cells cause fibrosis and architectural distortion. |
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Term
| How does alcohol alter hepatocyte metabolism? |
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Definition
1) Steatosis
- Shunting of substrates to lipid biosynthesis due to excess NADH
- Impaired assembly/excretion of lipoproteins
- Increased peripheral fat catabolism
2) Induction of cytochrome p450
3) Free radical generation
4) Direct effect on microtubular and mitochrondrial function
5) Acetaldehyde leads to lipid peroxidation
6) Induced immunologic attack on hepatocytes because of altered antigens |
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Term
| What is the typical sequence of events in alcoholic liver disease progression? |
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Definition
1) Chronic alcohol abuse almost always causes Steatosis
2) 20-40% of steatosis becomes fibrosis and 8-20% of those become cirrhotic
3) 3-10% of cirrhosis cases progress to HCC |
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Term
| What is the pathophysiological basis of the progression for Steatohepatitis to Perivenular fibrosis? |
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Definition
Tissue injury and Stellate cell activation
1) Stellate cells transform into myofibroblasts that proliferate, secrete collagen and alter ECM
2) Fibrotic changes alter sinusoidal hemodynamics and can cause shunting of blood from portal tracts to central veins, rendering some hepatocytes hypoxic.
3) Hypoxic changes, oxidative stress and persistent regeneration can lead to micro-nodular cirrhosis, which can be changed to macro-nodular if alcohol is ceased.
4) Cirrhosis may progress to HCC! |
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Term
| What diagnostic tests are important in evaluating alcoholic liver disease? |
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Definition
1) AST>ALT and GGTP elevated MUCH greater than ALP when compared to biliary tract diseases
2) Biopsy used to secure diagnosis, rule out other causes of liver injury and stage extent of fibrosis. |
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