Hospital Medicine

Alcoholic hepatitis

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Alcoholic hepatitis

I. What every physician needs to know.

Alcoholic hepatitis is an acute reaction to prolonged excessive alcohol consumption. Mild forms of the syndrome improve without intervention, but when severe there is nearly a 50% 1 month mortality without treatment. Histologically, alcoholic hepatitis is characterized by swollen hepatocytes that contain Mallory bodies (alcoholic hyaline), a neutrophilic infiltrate, and fibrosis between the hepatocyte and the endothelial cell. The pathophysiology includes direct and indirect toxicity from ethanol, oxidative stress, impaired gut barrier function, and immune dysregulation.

Alcoholic liver disease has a spectrum of pathologic findings, including fatty liver disease, alcoholic hepatitis and eventually cirrhosis. Alcoholic hepatitis increases the risk of progression to cirrhosis, and is frequently seen with cirrhosis on liver biopsy.

II. Diagnostic Confirmation: Are you sure your patient has alcoholic hepatitis?

  • Acute jaundice with cholestatic liver findings in the setting of prolonged heavy alcohol use

  • Imaging confirming no biliary obstruction

  • Alcohol intake may have ceased or decreased in the preceding weeks when the patient first became ill

A. History Part I: Pattern Recognition:

Key symptoms of alcoholic hepatitis

  • Jaundice

  • Hepatomegaly

  • Right upper quadrant (RUQ) tenderness/mild pain (due to swelling of the liver capsule)

  • Ascites

  • Anorexia

  • Nausea

  • Encephalopathy

  • Fever

  • Ecchymoses

  • Hepatic bruit

  • Associated with: hepatorenal syndrome, gastrointestinal (GI) bleeding

B. History Part 2: Prevalence:

Alcoholic hepatitis has 20% prevalence among individuals with alcoholism.

  • Older age (typical age is 40-60 years old)

  • Female gender (although more men have alcoholic hepatitis due to the increased risk of alcohol abuse among men

  • Amount of alcohol (often greater than 100g/day) (standard drink in the United States = 14g)

  • Viral hepatitis

  • Obesity

  • Genetic polymorphisms

C. History Part 3: Competing diagnoses that can mimic alcoholic hepatitis.

  • Obstructive biliary processes, including hepatic abscess, Budd-Chiari syndrome, Mirizzi syndrome, pancreatic cancer, hepatocellular carcinoma, and cholangiocarcinoma.

  • Liver processes, such as chronic viral hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, hemochromatosis, Wilson's disease, autoimmune hepatitis, non-alcoholic steatohepatitis, alpha-1-antitrypsin deficiency, and drug-induced liver disease

  • Elevated iron studies due to increased alcohol intake and acute liver injury can mimic hemochromatosis.

D. Physical Examination Findings.

  • Jaundice

  • Hepatomegaly

  • RUQ tenderness/mild pain (due to swelling of the liver capsule)

  • Ascites

  • Hepatic bruit

  • Encephalopathy

  • Fever

  • Ecchymoses

E. What diagnostic tests should be performed?

N/A

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • Liver panel (total bilirubin, direct bilirubin, aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase)

  • - Elevated total and direct bilirubin

  • - Elevated AST/ALT (ratio often greater than 2, AST rarely greater than 400). If transaminases greater than1000, think of other etiologies.

  • - Mild elevation in alkaline phosphatase

  • Albumin (frequent hypoalbuminemia)

  • Prothrombin time/international normalized ratio (INR) (frequent coagulopathy)

  • Complete blood count (CBC) with differential (frequent leukocytosis with neutrophilia, often occult GI bleeding)

  • Chemistry 7 (frequent hyponatremia, risk of acute renal failure 2/2 hepatorenal syndrome, frequent acid/base abnormalities such as metabolic acidosis with renal failure or respiratory alkalosis due to liver failure)

  • Magnesium (rule out hypomagnesium with alcohol abuse)

  • If febrile, rule out infection:

  • - Blood cultures

  • - Urinalysis / urine culture to rule-out urinary tract infection

  • - Diagnostic paracentesis (if ascites is present) – to rule-out spontaneous bacterial peritonitis

  • Tests for specific liver diseases (if there is uncertainty in the diagnosis)

  • Liver biopsy - only when the diagnosis is uncertain, or if considering liver transplantation. Transjugular route preferred to decrease the bleeding risk.

Tests used to predict mortality and whether or not to treat:

  • Maddrey's discriminant function (DF) = [4.6 x (prothrombin time - control prothrombin time)] + serum bilirubin

  • - (Prothrombin time is in seconds. Bilirubin is in milligrams per deciliter.)

  • - If DF greater than or equal to 32, consider initiating prednisolone

  • - If DF greater than or equal to 32, mortality is 46.1% at 1 month

  • Model for end-stage liver disease (MELD) = 9.57 x log creatinine (in milligrams per deciliter) + 3.78 x log bilirubin (in milligrams per deciliter) + 11.20 x log INR + 6.43

  • - Increased MELD score portends a worse prognosis

  • - A MELD = 21 is associated with a 90 day mortality of 20%

  • Other scores are also used including Glasgow score, Child-Pugh score, age-bilirubin-INR-creatinine (ABIC) score

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

  • RUQ ultrasound with doppler.

  • Chest x-ray to rule out pneumonia (given fevers), and evaluate for sympathetic right sided pleural effusion.

  • Computed tomography (CT) head scan without contrast - (if mental status changes) to rule out subdural (or central nervous system (CNS) pathology otherwise) given increased fall risk with alcohol use and/or encephalopathy.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

  • Ammonia level (level does not correlate with presence or severity of hepatic encephalopathy)

  • Ceruloplasmin is unreliable (low levels seen in liver diseases besides Wilson's disease, including alcohol induced liver disease)

III. Default Management.

N/A

A. Immediate management.

Treating alcohol hepatitis

- If Maddrey's discriminant function is greater than or equal to 32 (may alternatively use MELD score or Glasgow score), consider use of prednisolone and hepatology consultation.

  • Prednisolone 40mg per os (PO) daily for 28 days (and stopped or tapered over the next 2 months). Historically this has been the drug of choice for alcoholic hepatitis. Recent data favors use of prednisolone over pentoxifylline when not contraindicated.

  • - Avoid in the setting of upper GI bleed and active infection.

  • - Prednisolone is used primarily (instead of prednisone) because prednisone requires conversion to prednisolone in the liver.

  • - Lille score used to determine if prednisolone should be discontinued after 7 days of treatment due to insufficient response.

Lille Score = 3.19 - 0.101 x age in years + 0.147 x albumin in g/L on day 0 + 0.0165 x change in bilirubin in micromoles/L from day 0 to 7 - 0.206 x renal insufficiency (rated as 0 if absent and 1 if present) - 0.0065 x bilirubin in micromoles/L on day 0 - 0.0096 x prothrombin time in seconds.

A Lille score greater than 0.45 indicates a patient has not benefited from corticosteroids.

  • Pentoxifylline 400mg PO three times daily for 28 days (up to 3 months). A recent meta-analysis of 22 studies suggested pentoxifylline reduces short term mortality but was limited by poor-quality evidence.

  • - Renal dosing (CrCl < 30): 400 mg PO daily for 28 days (up to 3 months)

Additional therapies under study: N-acetylcysteine, granulocyte colony stimulating factor, metadoxine, enteral nutrition, early liver transplantation, and combination therapies.

Treating alcohol withdrawal

  • Use short acting (e.g. lorazepam or oxazepam) rather than long acting (e.g. diazepam or chlordiazepoxide) benzodiazepines to lessen risk of over-sedation

  • A symptom-triggered approach, such as one based on the Clinical Institute Withdrawal Assessment for Alcohol Scale (CIWA-Ar), is preferred in order to minimize the cumulative benzodiazepine exposure and shorten hospital stay

Treating malnutrition (and risk of Wernicke-Korsakoff)

  • Regular oral diet (consider nutrition consult +/- enteral feeding if malnourished)

  • Thiamine 100mg daily (at least)

  • Folate 1mg daily (at least)

  • Multivitamin

Treating encephalopathy

  • Lactulose (titrate to 4 stools/day)

  • Rifaximin (if still encephalopathic with 4 stools/day on lactulose, and/or incontinence with lactulose)

Treating hepatorenal syndrome

  • Octreotide

  • Midodrine

  • Albumin intravenous (IV) (especially in the setting of spontaneous bacterial peritonitis)

Treating upper gastrointestinal bleed

  • Proton pump inhibitor

  • Octreotide

  • Emergent endoscopy

Treating lower gastrointestinal bleed

  • Sigmoidoscopy/colonoscopy

Treating coagulopathy

  • Vitamin K 5mg PO daily for 3 days (will treat concomitant nutritional deficiency of vitamin K)

B. Physical Examination Tips to Guide Management.

  • Evaluate for jaundice (evaluate for scleral icterus, skin and sublingual jaundice).

  • Do a thorough abdominal exam, evaluating for hepatomegaly and/or splenomegaly, hepatic bruit, RUQ tenderness suggesting swelling of liver capsule, ascites.

  • Evaluate for encephalopathy, looking for sleep/wake cycle changes, asterixis, lack of orientation, history from family regarding confusion.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

Every day:

  • CBC +/- differential - evaluate for occult bleeding, infection

  • Chemistry 7 (frequent hyponatremia, risk of acute renal failure 2/2 hepatorenal syndrome, acid/base changes

  • Magnesium and phosphorus – monitor for re-feeding syndrome daily with resumption of full enteral nutrition

Every day or every other day:

  • Liver panel (total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase)

Every few days:

  • Albumin (frequent hypoalbuminemia)

  • Prothrombin time/INR

D. Long-term management.

  • Treatment of alcohol (+/- drug) abuse/addiction

  • Evaluation for liver transplantation if fulminant liver failure and/or cirrhosis

E. Common Pitfalls and Side-Effects of Management

  • Stop prednisolone if upper GI bleeding or infection

  • Maximum dose of acetaminophen in 24 hours is 2000mg

IV. Management with Co-Morbidities

N/A

A. Renal Insufficiency.

Avoid non-steroidal anti-inflammatory drugs (NSAIDS) and angiotensin-converting enzyme inhibitors (ACE-inhibitors).

(See the chapter "Hepatorenal syndrome")

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure

Check echo to evaluate for cardiomyopathy due to alcohol. Avoid ACE-inhibitors, as they may increase the risk of hepatorenal syndrome.

D. Coronary Artery Disease or Peripheral Vascular Disease

Caution with aspirin if risk of bleeding.

E. Diabetes or other Endocrine issues

Follow for hypoglycemia if fulminant hepatic liver failure.

F. Malignancy

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc.)

Consider converting prednisone to prednisolone. If the patient is on chronic steroids at baseline, pentoxifylline could be used if treatment of the alcoholic hepatitis is necessary. Ultimately there is no evidence to guide management in the setting of baseline chronic steroids.

No change in standard management with human immunodeficiency virus (HIV).

H. Primary Lung Disease (COPD, Asthma, ILD)

No change in standard management.

I. Gastrointestinal or Nutrition Issues

  • In the setting of coagulopathy, treat with vitamin K 5mg PO daily for 3 days due to frequent vitamin K deficiency due to malnutrition, although coagulopathy is usually mainly due to liver failure.

  • Check vitamin B12 and folate levels in patients with macrocytosis.

  • Regular oral diet (consider enteral feeding if malnourished or unable to eat by mouth)

J. Hematologic or Coagulation Issues

In the setting of coagulopathy, treat with vitamin K 5mg PO daily for 3 days due to frequent vitamin K deficiency due to malnutrition, although coagulopathy is usually mainly due to liver failure.

K. Dementia or Psychiatric Illness/Treatment

Check vitamin B12 levels. Consider CNS imaging due to trauma risk with alcohol abuse/addiction.

V. Transitions of Care

A. Sign-out considerations While Hospitalized.

  • Avoid sleep agents (zolpidem, diphenhydramine) that could worsen encephalopathy; use trazadone 25mg-50mg PO before bedtime if necessary

  • Avoid benzodiazepines (unless for alcohol withdrawal) due to risk of encephalopathy

  • Caution with narcotics due to risk of worsening encephalopathy

  • Avoid NSAIDS due to risk of hepatorenal syndrome

  • Avoid ACE-inhibitors for hypertension due to risk of hepatorenal syndrome

  • Maximum dose of acetaminophen in 24 hours is 2000mg

B. Anticipated Length of Stay.

Length of stay is expected to be less than 7 days if mild and more than 7 or longer if severe.

C. When is the Patient Ready for Discharge.

The patient is ready to be discharged when liver tests and coagulation factors are stable, kidney function is normal or stable, and there is no evidence of GI bleeding, dropping hemoglobin (Hgb)/hematocrit (Hct) and no encephalopathy.

D. Arranging for Clinic Follow-up

N/A

1. When should clinic follow up be arranged and with whom.

Follow-up should be arranged with a primary care physician and a hepatologist - to investigate liver transplantation if necessary.

2. What tests should be conducted prior to discharge to enable best clinic first visit.

None

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit.

  • Liver panel (total bilirubin, direct bilirubin, AST, ALT, alkaline phosphatase)

  • Albumin

  • Prothrombin time/INR

  • CBC with differential

  • Chemistry 7

E. Placement Considerations.

  • Alcohol (and/or drug) rehabilitation

  • Short term skilled nursing home and/or rehab if debilitated

  • Hospice depending on prognosis and patient wishes

F. Prognosis and Patient Counseling.

When alcoholic hepatitis is severe there is nearly a 50% 1 month mortality without treatment. Abstinence improves survival.

VI. Patient Safety and Quality Measures

A. Core Indicator Standards and Documentation.

None

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Avoid deep vein thrombosis prophylaxis if GI bleeding.

VII. What's the evidence?

Akriviadis, E, Botla, R, Briggs, W, Han, S, Reynold, T, Shakil, O. "Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial". Gastroenterology. vol. 119. 2000. pp. 1637-1648.

Cauza, E, Maier-Dobersberger, T, Polli, C, Kaserer, K, Kramer, L, Ferenci, P. "Screening for Wilson's disease in patients with liver diseases by serum ceruloplasmin". J Hepatol. vol. 27. 1997. pp. 358-362.

Cohen, S, Ahn, J. "Review article: the diagnosis and management of alcoholic hepatitis". Aliment Pharmacol Ther. vol. 30. 2009. pp. 3-13.

de Alwis, N, Day, C. "Genetics of alcoholic liver disease and non-alcoholic fatty liver disease". Seminars in Liver Disease. vol. 27. 2007. pp. 44-54.

Dunn, W, Jamil, L, Brown, L, Wiesner, R, Kim, W, Menon, N, Malinchoc, M, Kamath, P, Shah, V. "MELD accurately predicts mortality in patients with alcoholic hepatitis". Hepatology. vol. 41. 2005. pp. 353-358.

Krishna, B, Gangopadhyay, S, Dutta, D, Das Baksi, S, Pani, A, Ghosh, P. "Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial". World J Gastroenterol. vol. 15. 2009. pp. 1613-1619.

Louvet, A, Diaz, E, Dharancy, S, Coevoet, H, Texier, F, Thevenot, T, Deltenre, P, Canva, V, Plane, C, Mathurin, P. "Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids". J Hepatol. vol. 48. 2008. pp. 465-470.

Louvet, A, Naveau, S, Abdelnour, M. "The Lille Model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids". Hepatology. vol. 45. 2007. pp. 1348-1354.

Lucey, M, Mathurin, P, Morgan, T. "Alcoholic Hepatitis". N Engl J Med. vol. 360. 2009. pp. 2758-2769.

Mathurin, P, Mendenhall, C, Carithers, R. "Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH". J Hepatol. vol. 36. 2002. pp. 480-487.

Mendenhall, C, Seeff, L, Diehl, A. "Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance". Hepatology. vol. 14. 1991. pp. 581-589.

Naveau, S, Giraud, V, Borotto, E, Aubert, A, Capron, F, Chaput, J-C. "Excess weight risk factor for alcoholic liver disease". Hepatology. vol. 25. 1997. pp. 108-111.

Park, SH, Kim, DJ, Kim, YS. "Pentoxifylline vs. corticosteroid to treat severe alcoholic hepatitis: a randomised, non-inferiority, open trial". J Hepatol. vol. 61. 2014. pp. 792-8.

Singh, S, Murad, MH, Chandar, AK. "Comparative effectiveness of pharmacological interventions for severe alcoholic hepatitis: a systemic review and network meta-analysis". Gastroenterology. vol. 149. 2015. pp. 958-70.

Stewart, S, Jones, D, Day, C. "Alcoholic liver disease: new insights into mechanisms and preventative strategies". Trends in Molecular Medicine. vol. 7. 2001. pp. 408-413.

Teli, M, Day, C, Burt, A, Bennett, M, James, O. "Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver". Lancet. vol. 346. 1995. pp. 987-990.

Thursz, MR, Richardson, P, Allison, M. "Prednisolone or pentoxifylline for alcoholic hepatitis". N Engl J Med. vol. 372. 2015. pp. 1619-28.

Whitfield, J, Zhu, G, Heath, A, Powell, L, Martin, N. "Effects of alcohol consumption on indices of iron stores and of iron stores on alcohol intake markers". Alcohol Clin. Exp. Res.. vol. 25. 2001. pp. 1037-1045.

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