Alcoholic Hepatitis

Alexander Kuo, M.D. Associate Professor of Medicine Director, Hepatology and Liver Transplantation UC San Diego

Disclosures

•  None

Learning Objectives

•  Spectrum of alcoholic liver disease •  Definition of acute alcoholic hepatitis •  Clinical presentation and treatment of AH •  Future therapeutic targets for AH •  Liver transplant for AH

Alcohol Use in the United States

•  In 2013, 86.8% of people 18 or over reported alcohol use at some point in their lifetime

•  70.7% reported they drank in the last year •  56.4% reported they drank in the last month

Substance Abuse and Mental Health Services Administration (SAMHSA). 2013 National Survey on Drug Use and Health (NSDUH)

Drinking Levels

•  Moderate alcohol use –  1 drink per day for women –  2 drinks per day for men

•  Binge drinking –  5 or more drinks in one occasion at least 1 time in the last month

•  Heavy drinking –  5 or more drinks in one occasion at least 5 days in the last

month

Alcohol Use Disorder (AUD)

•  DSM-4 –  Alcohol abuse –  Alcohol dependence

•  DSM-5 (May 2013) –  Alcohol Abuse Disorder

(AUD) •  Mild (2-3 symptoms) •  Moderate (4-5

symptoms) •  Severe (6 or more

symptoms)

Alcohol Use Disorder (AUD)

•  7.2% of people 18 and older had an AUD in 2012 = 17 million adults –  11.2 million men –  5.7 million women

•  855,00 adolescents (age 12-17) had an AUD in 2012 •  88,000 alcohol related deaths annually •  31% of all driving fatalities involve alcohol (10,076

deaths in 2013)

Substance Abuse and Mental Health Services Administration (SAMHSA). 2013 National Survey on Drug Use and Health (NSDUH) Substance Abuse and Mental Health Services Administration (SAMHSA). 2013 National Survey on Drug Use and Health (NSDUH)

Indications for liver transplantation in the U.S.

Orman et al. J Gastro Hep 2013.

Spectrum of Alcoholic Liver Disease

Alcoholic Hepatitis

•  Liver inflammation caused by excessive alcohol intake •  Diagnosed with liver biopsy showing ballooned

hepatocytes, Mallory hyaline, lobular inflammation, and peri-sinusoidal fibrosis

•  Mild clinical presentation –  elevation in aminotransferases that normalizes with sobriety

•  Severe clinical presentation –  Jaundice –  Ascites –  Encephalopathy –  Coagulopathy –  30-day mortality 30-50%

Case

•  40 year old woman is admitted with new onset jaundice, abdominal distention, and lower extremity edema

•  Labs show bilirubin 28, PT 22, INR 2.7, AST 250, ALT 70, WBC 12, Creatinine 1.0

•  MELD score 30 •  Discriminant Function score of 72 (>32 is severe)

–  DF=4.6 x(PT-lab control PT) +bilirubin •  “I only drink 2-3 glasses of wine a night.”

What is “one drink”? = 12 grams etoh

http://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/what-standard-drink

Case

•  Perform diagnostic paracentesis which rules out infection (spontaneous bacterial peritonitis)

•  UA, urine CXR, blood cx, and CXR all negative for infection

•  Transjugular liver biopsy performed

Case

•  Dietician is consulted. Tube feeds are started. •  Prednisolone 40 mg daily started •  HD #7 the bilirubin remains 28 •  Creatinine begins to rise, pentoxifylline 400 mg tid

started to reduce the chance for hepatorenal syndrome •  HD #10 creatinine 2.5, urine output falls to <600 cc daily •  HD #12 creatinine 3.9, anuric, SOB from large ascites,

pleural effusion, and mild pulmonary edema •  Renal consulted for dialysis but renal feels HD would be

futile •  Pleur-X catheter placed, patient discharged to hospice

and dies 2 days after discharge

What else could we have done?

Current Therapies for Alcoholic Hepatitis

•  Prednisolone 40 mg daily x28 days •  Pentoxifylline 400 mg tid x28 days •  IV NAC x7 days + steroids

STOPAH Trial

Thursz et al. NEJM April 2015.

•  1103 pts with severe AH randomized to prednisolone, pentoxifylline, both or neither

N-acetylcystine+steroids vs Steroids for AH

•  174 pts with severe AH randomized to NAC+prednisolone vs prednisolone only

Nguyen-Khac et al. NEJM Nov 2011.

Gzabo. Gastro 2015.

Gzabo. Gastro 2015.

Alcohol Liver Injury

Wheeler. Alcohol Red Health 2003.

Possible Future Therapeutic Targets

•  Alter the gut microbiome –  Probiotics –  Fecal transplantation?

•  Decrease gut permeability –  Zinc therapy –  Upregulate tight junctions

•  Decrease LPS-induced inflammation –  Anti-LPS antibodies –  TLR4 antagonists

Role for Liver Transplantation in AH

•  In pts with severe alcoholic hepatitis (DF>32) with no response to steroids, 6 month mortality is ~70%

•  6 month sobriety is a poor predictor for alcohol recidivism •  Better predictors are social support and psychiatric co-

morbidities •  Pts with alcoholic hepatitis have not been widely

considered for transplant due to lack of >6 months sobriety despite liver transplant being a established therapy

•  Possible barriers to wider use of LT include fear of recidivism, donor organ shortage, social/ethical considerations

Louvet et al. Hepatology 2007.

Liver Transplant for Alcoholic Hepatitis

•  7 centers in France performed early LT for pts with severe AH

•  Severe AH (DF>32) with non-response to steroids •  First decompensating event •  Good support •  Pts agree to lifelong alcohol abstinence •  All team members (hepatogists, nurses, surgeons, SW,

psychologist, residents, fellow) had to agree to list

Mathurin et al. NEJM 2011.

Liver Transplant for Alcoholic Hepatitis

•  26 pts transplanted for AH •  Represented 2.9% of all transplant performed between

2006-2010 at these 7 centers •  1 year survival in LT recipients vs controls with AH was

77% vs 23% •  3 pts resumed drinking

–  1 at 720 day –  1 at 750 days –  1 at 1140 days

Mathurin et al. NEJM 2011.

Survey of Liver Transplant Programs in U.S.

•  45 of 110 liver transplant centers responded to a survey emailed to program directors

•  12 of 45 centers (27%) reported listing pts with alcoholic hepatitis

•  Of 3,290 transplants performed, 45 were done for AH (1.37%)

•  6 month, 1 year and 5 year survival was 93%, 93%, and 87%

•  Alcohol recidivism rate was 17% (compared to 15-20% for pts transplanted for alcoholic cirrhosis)

Hasanin et al. Liver Transpl Jul 2015.

Summary

•  Alcoholic hepatitis is an acute presentation of alcoholic liver disease

•  In pts with severe AH (DF>32) who do not respond to steroids, 6 month mortality is ~70%

•  Treatment options focus on nutrition and steroids •  Liver transplant is an effective treatment for severe AH

–  Currently offered in <30% of transplant programs in the U.S. –  Outcomes are outstanding –  Alcohol recidivism rates are no different compared to pts

transplanted for alcoholic cirrhosis

•  Future therapies for AH may include altering the gut microbiome and preventing “leaky gut”

Thank you!