Alcoholic liver disease

Question 1

Risk factors for developing ALD

Answer 1

• Genetics, male gender
• Amount of alcohol, type of alcohol, binge drinking
• Presence of other liver diseases, concurrent medicine (acetaminophen)
• > 3 drinks/day for men and >2 drinks/day for women for 10 yrs puts at risk for alcoholic liver disease

Question 2

Alcohol metabolism

Answer 2

• Most of it is broken down by ADH to acetaldehyde, then to acetate by ALDH, both of these reactions produce NADH
• Etoh can also be broken down to acetaldehyde by CYP2E1, which is responsible for metabolizing acetaminophen
• Liver damage begins near the central vein, where O2 levels are lowest and CYP2E1 levels are highest

Question 3

Pathogenesis of ALD

Answer 3

• Oxidative stress: increased production of ROS, esp in mito (from inflammation, CYP activity, endotoxin-induced cytokine release, decreased glutathione)
• Etoh causes release of LPS from gut bacteria which reaches the liver and causes kupffer cells to release cytokines (TNFa)
• ER stress
• Hypoxia (centrilobular hepatocytes first)
• Acetaldehyde toxicity
• Co-factors: diabetes/obesity, viral hepatitis, nutrition, other drugs
• Overall there is stimulation of apoptosis due to ROS generation and inflammation, and altered gene expression after heavy drinking

Question 4

Clinical aspects of ALD

Answer 4

• PE will generally be benign unless advanced liver disease, then see non-specific compensated cirrhotic findings: hepatomegaly (or small liver), splenomegaly, parotid gland enlargement, gynecomastia, palmar erythema, spider angiomata, asterixis, muscle wasting, jaundice/scleral icterus, Dupuytren’s contracture (fingers), abdominal wall collaterals
• Stages of ALD: fatty liver, fibrosis, alcoholic cirrhosis (alcoholic hepatitis can occur anywhere along the progression)
• Extrahepatic manifestations: wenicke-korsakoff (due to thiamine def) seen as ataxia, psychosis, visual disturbances
• Can also see BM suppression (direct effect of etoh)

Question 5

Lab Dx

Answer 5

• Liver panel may be nl in early ALD
• Can see elevation in AST, ALT, bilirubin
• AST/ALT is 1.5-3 (2), but overall values usually <300
• If values excess 300 think acetaminophen
• AST is higher b/c its found in cytoplasm and mito, ALT in mito only
• AST/ALT may be low b/c they require vit B6 and many alcoholics are B6 def
• Decreased protein, albumin
• Prolonged PT/INR

Question 6

Alcoholic fatty liver

Answer 6

• Earliest stage of injury, hepatocytes contain macrovesicular fat droplets
• Fatty liver not specific to ALD (diabetes, obesity), most pts ASx
• Condition can reverse w/ abstinence
• Production of NADH from etoh metabolism stimulates cells to produce TAGs/FAs and reduces beta-ox of stored TAGs/FAs
• Some pts have a more severe reaction, in which they can get jaundiced at this stage
• This is foamy fat degeneration (micro vesicular), due to more severe mito damage
• Pts usually exhibit high D bili, alk phos, and AST can be very high (up to 1000) in FFD
• This is occasionally fatal but most pts recover

Question 7

Alcoholic hepatitis

Answer 7

• Only a subset of ALD pts get it, most are chronic heavy drinkers w/ CLD (but don’t necessarily have cirrhosis)
• Often the pt will stop drinking a little before onset, b/c of feeling sick (Sxs develop in subacute manner)
• PE: fever, jaundice, tender hepatomegaly, bruit over liver, portal HTN complications in absence of cirrhosis
• Labs: AST/ALT >1.5 (2) w/ both generally <300, elevated WBC, prolonged INR, elevated bili, elevated Cr (bad prognosis)
• Can be fatal, esp in first 2-3 wks when Sxs are worst
• Mortality ranges depending on severity (btwn 25-50%)
• Many ways to classify severity of alcoholic hepatitis

Question 8

Pathology of alcoholic hepatitis

Answer 8

• Neutrophil infiltration of liver parenchyma
• Parenchyma shows ballooning degeneration of hepatocytes w/ intracellular hyaline deposits (mallory bodies)
• Ballooning may look like foamy fatty liver, and there may also be macrovessiclar fat or underlying cirrhosis
• There may be perisinusoidal and centrilobular fibrosis
• Histologically it can appear like NASH, but NASH is more insidious and indolent, w/ alcoholic hepatitis being more acute
• Also, NASH AST/ALT is 1.5)

Question 9

Rx of alcoholic hepatitis

Answer 9

• Manage withdrawal (takes 1 wks) and intoxication
• Rx complications of portal HTN
• Nutrition and replacement of vitamins, etc (most pts are malnourished)
• Management of metabolic derangements (thiamine, glc, folate, electrolytes)
• Corticosteroids to halt inflammatory process, w/ encephalopathy being biggest indicator to initiate steroids
• Steroids contraindicated in GI bleed or infection
• Should see improvement in serum bili after 1 wk of steroids
• TNFa inhibitor may be used, but steroids are best

Question 10

Alcoholic cirrhosis

Answer 10

• Increases risk of liver disease related death, HCC, pts need liver Tx
• 6 mo period of abstinence is recommended before liver Tx
• Many pts get to alcoholic cirrhosis w/o overt alcoholic hepatitis, but there is probably a subclinical hepatitis that contributed to cirrhosis development
• PE findings: see above
• Labs: low albumin, prolonged INR
• Caffeine consumption may reduce risk of alcoholic cirrhosis
• Things that exacerbate development of alcoholic cirrhosis: obesity (NASH), HCV