Liver and Alcohol Flashcards
Normal Alcohol Metabolism
- Ethanol –> acetylaldehyde
- Alcohol Dehydrogenase (ADH) in cytosol
- Requires NAD (niacin) and zinc
- Low Km so high affinity
- Many polymorphisms - variation in metabolism among ppl
- Acetylaldehyde –> acetate (can then enter TCA cycle or make FAs)
- Aldehyde dehydrogenase (ALDH) in mitochondria
- Requires NAD (niacin) and zinc
- Somewhat slower than ADH (so remaining acetylaldehyde - hangover)
MEOS
Microsomal ethanol oxidizing system
- Alternate Pathway (used if exceed capacity of ADH - AKA in alcoholics) - MEOS
- Ethanol –> acetylaldehyde by CYP2E1
- High Km (low affinity) so induced at high alcohol conc / chronic exposure
- Requires NADP (niacin)
- Other substrates - acetone, acetaminophen, CCl4
4 Acute Effects
- Fatty liver changes (steatosis)
- Acute gastritis
- CNS depression
- Resp arrest if very high levels
Chronic Effects on Liver, Pancreas, Esophagus, Stomach, Intestines
- Liver - ballooning hepatocytes, membrane lipid peroxidation (from free radicals), megamitochondria, proliferation of microsomal membranes, fibrosis, cirrhosis
- ** Depletion of NAD –> accumulation of fat and metabolic acidosis
- Pancreas - pancreatitis, fibrosis, lose endocrine/ exocrine function
- Stomach - mucosal injury, bleeding, dec emptying, stimulates secretion
- Esophagus - reflux, varices, upper squamous cell carcinoma, Mallory Weiss from vomiting
- SI/Colon - malabsorption, diarrhea, villi flattening, loss of dissacharides
Chronic Effects on Liver Function (7)
- Dec drug and toxin clearance
- Dec glutathione for conjugation
- Accumulate NADPH+ so lose redox ablity
- Acetate –> FAs –> steatosis
- Dec protein production such as clotting factors
- Zone 3 - dec urea cycle - inc ammonia
- Altered sex hormone homeostasis - gynecomastia, spider angioma, palmar erythema
5 Systemic Effects
- Dec immune function (lower resistance and depression)
- Hepatic encephalopathy, Wernicke encephalopathy (dec thiamin)
- Korsakoff’s psychosis
- Inc adrenal secretion (stressor)
- Gonads - dec testosterone in men, dec ovulation/prog in women
Fetal Alcohol Syndrome
Can result in short stature, mental retardation, behavior problems, neuro def, delayed puberty in child
Progression (+ what influences progression)
- Chronic alcohol abuse –> steatosis in 95% –> fibrosis in 20-40% –> cirrhosis in 10-20% –> HCC in 3-10%
- Dep on environment (amount of intake, binge, high content like liquor, high fat diet and obesity)
- Dep on genetics (MZ twin studies, Hispanics most affected, women have higher vol of distribution, gut permeability, metabolic polymorphisms)
What causes fatty liver?
- Excess NADH –> shunt substrates to lipid biosynthesis
- Impaired assembly/ excretion of lipoproteins
- Inc peripheral fat catabolism
Results of CYP Induction (7)
accelerated drug metabolism
enhanced testosterone/retinoid degradation
energy wasting
inc free radical production
glutathione depletion
lipid peroxidation
activation of carcinogens
Direct Effects of Acetylaldehyde (5)
- Covalently binds proteins
- Impairs mitochondria and microtubules
- Inhibits DNA repair
- Lipid peroxidation
- Stimulates immune attack on hepatocytes b/c now altered antigen
What causes fibrosis?
- Kuppfer cells activated –> produce inflammatory cells and cytokines –> activate Stellate cells –> fibrogenic –> fibrosis
- TNF-alpha, IL-1, IL-6
Gut Alterations
- Alcohol –> loosens tight junctions, inc mucin production, recruitment of inflammatory cells in gut wall
- Changes in gut microbiome which then inc translocation of bacteria from gut to liver via portal circulation –> LPS and other components then activate Kuppfer cells
4 Stages of Histopathology
1- Fatty Liver - micro or macro steatosis (most common in zone 3 - perivenular)
2- Alcoholic Hepatitis (steatohepatitis) - actual tissue injury and inflammation
- Hepatocyte swelling/balloon degeneration, Mallory’s hyaline, patches of neutrophils and maybe lymphocytes and ceroid-containing macrophages
3- Perivenular Fibrosis - stellate cells lay down collagen and alter ECM in zone 3
- Can lead to hemodynamic changes; cannot exchange blood from sinusoids to hepatocytes so shunt blood from portal tracts --> central vein
- Shunting can cause hypoxia of some hepatocytes which inhibits ability to regenerate
4- Cirrhosis - form portal-central and central-central bridging (micro-nodular cirrhosis)
- If stop alcohol intake now … can reverse some fibrosis (micro-nodular –> macro-nodular)
Micronutrient Deficiencies
- Water-Soluble Vit
- Thiamine - Wernike-Korsakoff, BeriBeri,
- Riboflavin
- Pyridoxine
- Folic Acid
- Vit B12 - uncommon b/c large body stores
- Vit C - Fat-Soluble Vit
- Vit A - less is absorbed and less stored in liver/ more liver degradation of Vit A
- Vit D - malabsorption, dec intake and less sunlight; leads to dec bone density
- Vit K - from fat malabsorption
- Vit E - rare but may see neuro problems - Water/ Na - retention; wt gain, ascites, edema, pleural effusions
- Mg - alcohol inc Mg excretion so lower amounts; also use Mg if refractive hypocalcemia
- Iron - can be iron def or iron overload
- Zinc - dry skin, growth retardation, poor appetite, lethargy, disordered taste, hypogonadism; supplement can also help w/ night blindness not responsive to Vit A
- Copper - excessive copper (hepatotoxic)
