* Alcohol intake of g/day for men and g/day for women for 10 years.

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1 ALCOHOLIC LIVER DISEASE (ALD) Thuy Anh Le MD Mentor: Dr. Mario Chojkier 8/10/2010 EPIDEMIOLOGY Costs of alcohol abuse are ~$185 billion/year related to lost productivity and MVA. Etoh accounts for 40% deaths from cirrhosis and >30% cases of HCC in US Accounts for 50,000 deaths annually ALD develops in female after shorter duration of drinking and lower daily alcohol intake than men. Risk factors: amount of etoh ingested (not linear relationship with dev of liver dz), drinking beer or spirits more likely associated with liver dz than wine, genetic factors (MZ twins 2x likely to drink as dizygotic twins), polymorphisms of genes involved in etoh metabolism Table of alcohol content of beverages: Daily intake needed to exceed threshold for ALD Beverage Alcohol Service Size Amount of Men Women Content Etoh Beer 5% 12ox 13.85g 3-6cans cans Wine 12% 4 oz 10.7g 4-8 glasses 2-4glasses Fortified 20% 4oz 17.8g 2-4 glasses 1-2 glasses Wine Hard liquor 40% 1.5oz 13.4g 3-6drinks drinks * Alcohol intake of g/day for men and g/day for women for 10 years. SPECTRUM OF DISEASE Chronic etoh can lead to liver diseases ranging from mild fatty infiltration to cirrhosis and HCC Fatty liver: o Fat accumulation in liver cells seen in 90% of heavy drinkers though reversible with abstinence of 4-6weeks, 10% of those who continue to drink heavily develop cirrhosis w/in 5 years. o Mixed micro- and macrovesicular steatosis is more likely to develop cirrhosis than macrovesicular pattern alone. o More than steatosis alone is development of necroinflammation, with or w/o fat infiltration, and fibrosis occurring in 10-35% of heavy drinkers. Alcoholic hepatitis: ranges from mild to severe, life-threatening injury occurring 10-35% of hospitalized alcoholics. o Pts have high short-term mortality o Is a precursor of cirrhosis with associated long-term risk of cirrhosis 9x higher than patients with fatty liver alone. o Increases portal hypertension dramatically leading to increased related complications pressure returns to baseline ~6 weeks.

2 Cirrhosis o Fine mesh-like pattern of cirrhosis with prominent involvement of central vein developing in 8-20% of heavy drinkers (micronodular cirrhosis). o Overtime, lesion evolves to broad bands of fibrosis that separate large nodules of liver tissue (macronodular cirrhosis). HCC develops in this setting. PATHOGENESIS: there are many proposed mechanisms of alcohol injury to the liver Ethanol metabolism: Ethanol (ADH and CYP2E1) Acetaldehyde (Aldehyde Dehydrogenase) Acetate o Ethanol is metabolized by 3 major systems in liver: alcohol dehydrogenase (AHD) (the main enzyme system metabolizing etoh at low concentration), cytochrome P450 2E1 (CYP2E1) (works at high ethanol concentration), and catalase. o Acetaldehyde may have etiologic role in ALD by altering proteins or small molecules that are important in normal biologic processes and can be directly be toxic to cells. Modified molecules may stimulate the host-immune response and cause autoimmune-like reactions. Both human and animal models of ALD have found antibodies to these modified proteins. Acetaldehyde can impair mitochondrial transport system and sensitize hepatocytes to TNF-mediated killing. Acetaldehyde can induce collagen production so variable metabolism of alcohol may impact fibrogenesis. Oxidative stress: etoh consumption lead to increased CYP2E1 activity leaks electron to initiate oxidative stress reactive oxygen and nitrogen species. However, CYP2E1 is not the sole or dominant factor, but may involve nonparenchymal cells and infiltrating inflammatory cells. Oxidative stress can mediate liver injury by direct cell injury and cell signaling. Mitochondrial dysfunction: Glutathione, imported from cytosol, protects mitochondria against oxidative stress. In ALD, transport of glutathione is impaired mitochondrial injury and cell death. Impaired Proteasome Function: the proteasome removes irregular and damaged proteins generated by mutations, translational errors, or oxidative stress. Animal studies show chronic etoh feeding decrease proteolytic activity abnormal protein accumulation. Mallory bodies may be accumulated proteins that are not degraded hepatocytes death release cytokines IL-8 and IL-18 neutrophil recruitment and liver inflammation. Fibrosis: o Cytokines TGF-B, PDGF and connective tissue GF activation of kinase RSK in stellate cell becomes myofibroblast-like and produces collagen. o Drs. Chojkier and Buck are developing a dominant negative inhibitory peptide that blocks the development of liver fibrosis and helps reverse fibrosis. DIAGNOSIS History: anorexia, n/v, weakness, jaundice, weight loss, abdominal pain, fever, and diarrhea, screening for etoh abuse (CAGE)

3 PEx: o Hepatomegaly: present in 75% of pts with fatty liver and alcoholic hepatitis. Liver decreases in size as dz progresses o Hepatic tenderness, audible bruit over liver, spider angiomata, splenomegaly, and peripheral edema. o Jaundice and ascites found in 60% pts, more frequently in severe dz o HE and fever o Decompensated cirrhotics: muscle wasting, ascites, spider angiomata, palmar erythema, Dupuytren s contractures, some can have enlarged parotid and lacrimal glands, and Muercke s lines (white nails) Laboratory Laboratory Test Mild Dz Moderate Dz Severe Dz Hematocrit value (%) MCV (um^3) WBC count (per mm^3) Serum AST level (U/L) Serum ALT level (U/L) Serum alk phos (U/L) Serum bilirubin level (mg/dl) Prolong PT(s) Serum albumin Data from Mendenhall CL. Alcoholic hepatitis. Clin Gastro 1981; 10: Histopathology: liver biopsy is rarely needed to establish diagnosis used to clarify the diagnosis in atypical presentation or determine severity o Centrilobular and perivenular fatty infiltrate seen in pp drinking >60g etoh/day o Etoh hepatitis: ballooning degeneration of hepatocytes, alcoholic hyaline (Mallory or Mallory-Denk bodies) and PMNs infiltration. o Varying degree of fibrosis o Etoh cirrhosis: typically micronodular or mixed micro- and macronodular. In coexisting alcoholic hepatitis, alcoholic hyaline is seen and sclerosing hyaline necrosis and mod-severe fatty infiltration common. o Etoh cirrhosis abstained from alcohol for long time: gradual transformation to macronodular cirrhosis. DIFFERENTIAL DIAGNOSIS NAFLD: histologically indistinguishable from ALD. H/o daily etoh <20g/day supports NALFD. Often asymptomatic and have peripheral insulin resistance, obesity, HTN, and HL. Hereditary hemochromatosis: difficult to distinguish from ALD and secondary iron overload b/c pts can have elevated serum iron, ferritin and hepatic iron levels. 20% of end-stage etoh cirrhosis have sig hepatic siderosis, and 15-40% of pts with hereditary hemochromatosis consume >80g/day etoh. o Overlapping features of hepatomegaly, testicular atrophy, cardiomyopathy, and glucose intolerance.

4 o Test for HFE gene few pts with ALD and iron overload are homozygous for C282Y or heterozygous for C282Y and H63D HFE genes. Amiodarone hepatotoxicity: have similar histologic features of etoh hepatitis w/ or w/o cirrhosis but clinical setting should help distinguish. Budd-Chiari Syndrome: may look similar to ALD d/t rapid clinical deterioration, marked hepatomegaly, caudate lobe hypertrophy, and failure to visualize HV on Dopplers. o Venography to assess for patent hepatic veins o Liver biopsy. Sudden deterioration in a stable, well-compensated ALD pt should prompt thoughts of: o Tylenol hepatotoxicity: AST typically >1000 U/L, and Tylenol levels not helpful for diagnosis or management since liver injury typically has occurred. o Acute viral illness: important to vaccinate pts with etoh cirrhosis to hep A/B o HCC: tumor invasion of vessels can cause bleeding, abrupt HE PREDICTORS OF PROGNOSIS: HCV infection concurrent with ALD: liver dz is more severe, advanced dz occurs at younger age, and survival is shorter. Etoh and HCV acts synergistically in development of HCC. Obesity: risk of liver dz is 2-3x higher in drinkers who are obese than in drinkers with normal BMI and is an independent risk factor for both alcoholic hepatitis and cirrhosis Smoking: shown to accelerate progression of fibrosis in pts with ALD. Continued etoh associated with persistent and worsening disease Histology: Presence of inflammatory cells (esp. neutrophils), perivenular fibrosis and mixed pattern of macrovesicular and microvesicular fat are associated with worse prognosis. Laboratory: Leukocytosis due to hepatitis (not infection) parallels hepatic tissue neutrophilic infiltration 10-20% with persistent leukocytosis progress to subfulminant hepatic failure. Steatosis <20% or reversed or alternating blood flow in portal trunk and/or intrahepatic portal branches by Doppler u/s are independent predictors of poor survival. Indices of prognosis o Maddrey s Discriminant function = (4.6x [ PT control PT] + (serum bilirubin). DF > 32 assoc with high short term mortality. W/o steroids, 1 month mortality was 35% in absence of encephalopathy, 45% if HE present. (Imperiale 1990) o MELD score of 21 is 75% sens and 75% spec for 90-day mortality. Serial MELD with change in score 2 points in 1 st week hospitalization independently predicts in-hospital mortality. TREATMENT 1. Abstinence: beneficial effects on survival even in pts with decompensated cirrhosis. Reducing but not stopping also improves projected survival in pts with ALD. Regular meetings with RN or other health professionals more effective than intense counseling by alcohol treatment specialists. a. Use of Baclofen -- Addolorato et al: 10/03-11/06 84 alcohol-dependent pt with liver cirrhosis referred to Institute of Internal Medicine, Rome, Italy were randomized to oral baclofen (5mg tid x 3days, then 10mg tid x 12 weeks) versus

5 placebo. Primary outcome was proportion of pts achieving and maintaining alcohol abstinence by assessing at outpt visit on basis of pt s self-evaluation and family member interview, measure blood and/or urine etoh content; f/u of 4 weeks. Relapsed defined as etoh intake of >4 drinks/day or overall consumption of >14dirnks/week, intention to treat analysis. Results 30/40 (71%) baclofen group achieve and maintained abstinence compared with 12/42 (29%) of placebo. Cumulative abstinence duration was 2x higher in pts allocated baclofen than in those assigned placebo (62.8 days versus 30.8 days, p0.001). No hepatic side effects. 2. Nutritional support: obesity (7.1kcal/g of etoh) and malnutrition (associated with complications of infections, HE, ascites, and variceal bleeding). a. Levels of folate, B6, thiamine, vit A, and trace elements including selenium, zinc, copper and magnesium are often severely reduced in pts with ALD thought 2/2 i. Anorexia induced by proinflammatory cytokines like TNF and leptin ii. Intestinal fat and protein malabsorption iii. Catabolic state that promotes gluconeogenesis from skeletal and visceral proteins. b. Cabre et al randomized trial comparing inpatients AH (80% cirrhotics) to prednisone 40mg qday or liver-specific formula of 2000 calories/day through feeding tube x 28 days, f/u 1 year or until death 1 month mortality rates similar in both group (25% in steroid versus 31% in enteral feeding group but death in TEN occurred sig earlier (median 23 days steroid groups versus 7 days TEN); 1 year mortality rate was 37% steroid group versus 8% TEN group mainly due to enteral feeding having reduced infectious complications. Note that 7/10 f/u deaths in the steroid-treated groups occur first 1.5 months. c. No study on benefits of TPN. No documented complications of precipitating HE or stimulating bleeding for EV by tube feeding. Most pt can tolerate standard enteral products, only pts with overt HE require liver-specific products rich in branched-chain amino acids. d. Outpt studies Hirsch et al show pts in outpt liver clinic taking enteral nutritional support containing 1000kcal and 34g of protein had sig improve protein intake and fewer hospitalizations. 3. Anti-inflammatory and anticytokines drugs: a. Glucocorticoids: i. Ramond et al: double-blind RCT with 61 pts with bx-proved alcoholic hepatitis and either spontaneous HE (n=19) or DF >32; 57 pts had cirrhosis on biopsy. Primary endpoint was death within 2 months. By day 66 after randomization, 16/29 (55%) pts in placebo versus 4/32 (12.5%) p = Survival advantage for prednisone persisted after stratification by center and presence of HE and after adjustment for prognostic factors in hazards model. Survival benefit for up to 1 year but not 2 years after treatment. 1. No major complications - included only pts with severe dz. Excluded pt with GIB requiring transfusions, active infection, or e/o HRS.

6 ii. Should not be used in mild alcoholic hepatitis. In severe cases prednisone 40mg qday x 28 days, f/b 20mg qday x 7days, and 10mg qday x 7days may be beneficial. Response to steroids can be determined in 7 days (by reduction in serum bilirubin). Discontinue treatment at this time if no response achieved iii. A consensus statement from the American Association for the Study of Liver Diseases and the American College of Gastroenterology (updated in 2009) 1. Patients with mild to moderate alcoholic hepatitis (defined as a Maddrey score of <32) without hepatic encephalopathy and with improvement in serum bilirubin or decline in the Maddrey score during the first week of hospitalization should be monitored closely. Such patients will likely not require nor benefit from specific medical interventions other than nutritional support and abstinence. 2. Patients with severe disease (defined as a Maddrey score of 32 with or without hepatic encephalopathy) who do not have contraindications to glucocorticoids should be considered for a four-week course of prednisolone (40 mg/day, typically stopped or followed by a taper over two to four weeks or depending upon the clinical situation). Prednisolone is preferred to prednisone because the latter requires conversion to prednisolone (the active form) in the liver, a process that may be impaired in alcoholic hepatitis. b. Pentoxifylline: i. Thought to work to directly or indirectly inhibit TNF which reduces cytokine/chemokine inflammatory pathway but other pathways may be possible i.e. scavenger of superoxide. ii. Akriviadis et al: Prospective, randomized double-blind clinical trial with 101 pts all having DF >32 49 pt had pentoxifylline 400mg tid and 52 pt had placebo (vitamin B12) x 4 weeks. Primary endpoints were (1) effect of PTX on short-term survival and (2) progression to HRS. 12/49 (24.5%) on pentoxifylline versus 24/52 (46%) placebo died during index hospitalization (p=0.037). HRS was caused of death in 6 (50%) and 22 (91.7%) pts respectively. Variables independently associated with survival include age, creatinine level of randomization, and tx with PTX). 4. Antioxidants a. S-adenosylmethionine: SAM may be act as an antioxidant, maintain mitochondrial function, decreasing TNF levels. i. Multicenter clinical study administering SAM 1200mg qday sig reduced mortality rate and need for liver transplantation in Child s A and B cirrhosis. b. Silymarin: active ingredient in milk-thistle shown to be protective against various hepatotoxicities including carbon tetrachloride, Tylenol, iron overload, and poisonous mushrooms in animal models. No well-conducted human clinical trials but has become the most popular form of alternative medicine therapy for liver disease.

7 c. Vitamin E: has hepatoprotective effects in experimental liver injury. It can also block the process of collagen production occurring in response to oxidative stress. However, large randomized study of supplementation in ALD did not show sig benefit. d. Combination: inconsistent study results lead to conclusion that antioxidants should not be the sole therapy for alcoholic hepatitis; unclear whether they are helpful as adjunctive treatment. 5. Other medical therapies of no proven benefit: a. Colchicine: VA Cooperative Study of colchicines therapy in pts with etoh cirrhosis showed no beneficial effects on overall or liver-related mortality. b. Propylthiouracil: thought to treat the hypermetabolic state in chronic alcohol fed animals that may lead to relative hypoxia in centrilobular area but Cochrane review of 6 randomized trials of 700pts showed no beneficial effect. c. Anabolic steroids: are thought to decrease fatty infiltration, but no benefit in Cochrane review d. Ursodeoxycholic acid: 1 large multicenter controlled clinical trial found no beneficial effects. e. Polyenylphosphatigylcholine (aka lecithin) extract from soybeans shown to prevent septal fibrosis and cirrhosis in alcohol-fed baboons but human studies showed no positive effects. Sources: 1. Sleisenger and Fordtran s Gastrointestinal and Liver Disease. Ninth Edition Textbook. 2. O Shea et al. Alcoholic liver disease. Amer J of Gastro Jan;105: Addolorato et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomized, double-blind controlled study. Lancet Dec 8;379(9630): Cabre et al. Short- and Long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology Jul;32(1): Ramond et al. A randomized trial of prednisolone in patients with severe alcoholic hepatitis. NEJM Feb 20; 326(8): Akriviadis et al. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology Dec;119(6):