Management of Alcoholic Hepatitis

Transcription

1 Management of Alcoholic Hepatitis Richard K. Sterling, MD, MSc, FACP, FACG, FAASLD, AGAF VCU Hepatology Professor of Medicine Chief, Section of Hepatology Program Director, Transplant Hepatology Virginia Commonwealth University Richmond, VA

2 Conflicts of Interest in the last 12 months Advisory Board Merck, Bayer, AbbVie, Gilead, ViiV Baxter, Pfizer Research support Roche/Genentech, Merck, AbbVie, Gilead, Abbott Speaker None Stock/Financial interest None

3 Objectives Definitions Pathophysiology Presentation Therapy

4 Steatohepatitis H&E stain 20X Masson s trichrome Steatohepatitis Hepatocyte ballooning (large arrow) Mallory bodies (small arrow) Macrovesicular fat (dashed arrow) Perisinusoidal fibrosis (chicken wire)

5 Alcohol metabolism Alcoholic Steatohepatitis EtOH Stomach ADH- gender ethnicity Small bowel Acetate ALDH Mitochondria Acetaldehyde Liver toxicity ADH NADH NAD LIVER Microsomal ethanol Oxidizing system (MEOS) - CYP 2E1 - Inducible by chronic alcohol

6 Dose Duration Female Gender Ethnicity Other factors Obesity Iron Overload Factors Associated with Liver Injury Viral hepatitis (HCV, HBV) Genetic (PNPLA3 G allele) Tobacco use Coffee (protective) MODIFIERS Oxidative stress Cholestasis Recruitment of inflammatory cells Lipotoxicity

7 Alcohol Threshold Men 80 grams (6-pack/day) Women grams (4 drinks/day) 12 oz beer 4 oz drink Glass of wine grams/drink Type of alcohol may not matter (Beer/spirits >> wine)

8 Natural History of Alcoholic Hepatitis Normal liver Reverse can Takes wks-mo 80% Stop Alcohol (>40-60g/day) (90-100%) for several weeks Steatosis 20% progress 50% reverse Steatohepatitis 20-40% progress, 5-15% with abstinence Fibrosis ~10-20% of alcoholics Cirrhosis

9 Alcoholic Liver Disease: Natural History Alcoholic hepatitis: Women more likely to develop cirrhosis Those with clinically severe hepatitis more likely to progress to cirrhosis Perivenular lesions, degree of necrosis predictors of development of cirrhosis Acute mortality 10-20% (related to severity, complications and renal failure) 50-80% if DF > 32 SIRS (increased HR, RR, WBC, ans fever) predictive

10 Alcoholic Liver Disease Clinical Features Symptoms/signs of intoxication Symptoms/signs of withdrawal Hepatomegaly Jaundice Features of chronic liver disease Spiders, dupuytren contractures Extrahepatic manifestations: pancreatitis, neurologic disease, etc Fevers Leukocytosis (leukemoid reaction), elevated MCV, bilirubin >3 mg/dl AST : ALT > 1.5, but rarely > if alcohol alone If AST and ALT > 400, think acetaminophen Hemolysis: Zieve s syndrome or Burr cell anemia

11 ASH vs. NASH Alcohol-Non-Alcohol Index (ANI) BMI, MCV, AST/ALT ratio, gender Favors alcohol Lower BMI Higher MCV AST/ALT > 1 Male

12 Acute Alcoholic Liver Disease Management Management of intoxication Management of withdrawal (CIWAS) Nutrition (key and often overlooked) Kcal/kg/d g protein/kg/d Management of metabolic derangements: electrolytes: Mg, PO 4, K, Zn thiamine, glucose, folate vitamin K R/O infection (blood and urine culture, CXR, r/o SBP, C diff if diarrhea) Assessing severity Determining if treatment indicated

13 Assessing Severity Discriminant function (DF) = 4.6 x (PT-control) + bilirubin (mg) MELD PT/INR Creatinine Total bilirubin Both MELD and DF have similar sensitivity (75-85%) while MELD has higher specificity SIRS: Need 2 or more HR>100, Temp <36 or > 38C, RR >12, WBC >12,000 or <4000

14 R/o competing diagnosis Viral hepatitis: acute hepatitis A, B, C and E Autoimmune hepatitis: ANA, smooth muscle, IgG Drug induced: Antibiotics, herbals, Androgens Vascular/tumor: Budd Chiari, HCC Ischemic: shock, cocaine

15 Treatment of Alcoholic Hepatitis is now questioned (STOPAH Trial) 1103 pts with AH, DF > 32 and no contraindications 1:1:1:1 Prednisolone (40mg/d), PTX 400mg tid, Prednisolone/PTX, or neither Primary end point: 28 day mortality Similar among all groups (14%/19%/13%/17%*) No differences at 90 d and 1 yr outcomes SAE in 13% with pred vs. 7% not on pred (p=.002) However, MLR found steroids helped (OR 0.6; p=0.015) Meta-analysis showed 46% reduction in 28d mortality * Since the outcome in no tx group was lower than expected (35%), hard to believe Thursz et al. NEJM 2015:372:

16 DB-RCT adults 65 centers DF>32 Steroids or Pentoxyfilline for AH 28 day mortality Infection Pred 14% vs No Pred 7% % 1 yr: 37% Multivariable analysis OR 0.61 ( ) Steroids 28-day mortality by 39% (no difference in 90 day or 1 yr mortality)

17 Steroids or Pentoxyfilline for AH

18 Management of Acute Alcoholic Hepatitis Make the Diagnosis/Establish Severity Low Risk DF <32 & no HE, MELD <20 Decrease in bilirubin or Decrease in MELD by 2 points in first week Supportive Care Close follow up Treat withdrawal Modified from O Shea et al. Hepatology 2010;51: AGA Guidelines Mitchell et al. CGH 2017;15:5-12 ACG 2018 High Risk DF 32 (+ HE), MELD > 20 + SIRS Nutritional Assessment/Intervention Check for electrolyte disturbance, r/o infection (blood/urine/ascites), r/o HBV, HCV liver US w/ Doppler Glucose/Thiamine, Consider Nasoenteric Feeding Consider TJ liver biopsy to establish diagnosis Steroids +/- NAC Lille Score day 7 If contraindications to steroids (TB, HBV, infection, GI bleeding) Pentoxifylline

19 When to stop Steroids Lille Score at Day 7 Louvet, et al. Hepatology pts with severe alc hep tx with steroids. Lille Score: * (age in yrs) * (albumin day 0 in g/l) * (evolution in bilirubin level in um) * (renal insufficiency) * (bilirubin day 0 in um) * (prothrombin time in sec). The AUROC curve of the Lille model was 0.89, higher than the Child-Pugh (0.62) or Maddrey scores (0.66), both P < Ideal cutoff of 0.45 showed a marked decrease in 6-month survival as compared with others: 25% 3.8% versus 85% 2.5%, P < ) and was able to identify approximately 75% of the observed deaths Kaplan-Meier survival analysis according to 0.45 cutoff

20 Predictors of Alcohol Relapse* Lack of insight of the problem Lack of stable relationship Lack of family support (spouse > other) Less than 6 months sobriety (minimum 3 months) Depression of other psychologic disorder Family history of alcohol abuse Rustad JK Psychometrics 2015;56:21-35 DEW MA Liver Transpl 2008; 14: * After liver transplant

21 Liver transplantation for severe AH Early liver transplantation Steroid non-responders First liver disease related event Non-response by Lille score 0.45 Patient selection Absolute consensus of medical and transplant support staff No co-morbidities Social integration Supportive family Psychiatric evaluation Mathurin P NEJM 2011

22 Liver transplantation for severe alcoholic hepatitis

23 Summary on Treatment for Alcoholic Hepatitis Indications for steroids +/- NAC or PTX (AGA Guidelines 2017) DF > 32 or MELD > 20 Encephalopathy (seems to be the group that benefits most) Contraindications for steroids Sepsis, GI bleeding (must r/o before starting steroids) If contraindications, treat and reassess If contraindications, consider Pentoxifylline (400 mg tid) Seems to be a safe alternative, especially if steroids contraindicated (infection, bleeding) Not helpful if steroids fail Calculate Lille score after 7 days (if <0.45, continue) Liver transplantation not an option in most centers, but need to check with your referral center

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