ALCOHOLIC HEPATITIS

January 3, 2019 & January 10, 2019

Sonia Lin, MD

Standard Drink

National Institute on Alcohol Abuse and Alcoholism. https://www.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/what-

standard-drink

Screening for Alcohol Abuse

• CAGE

• 4 questions

• Less effective at recognizing less severe drinking disorders

• AUDIT

• 10 questions

• High sensitivity and specificity

• AUDIT-c

• 3 questions

• Initial screening test for diagnosis alcohol use disorder

• Identifies at-risk drinkers (binge drinkers)

Fiellin DA, et al. Screening for alcohol problems in primary care: a systematic review. Arch Intern Med 2000;160(13):1977-89.

AUDIT

Alcohol-Induced Liver Disease

Mueller S, Seitz HK, Rausch V. Non-invasive diagnosis of alcoholic liver disease. World J Gastroenterol 2014;20(40):14626-41.

Case

A 28-year-old woman complains of severe right upper

quadrant pain and jaundice. She has a low-grade

temperature of 100.1°F. On exam, she is icteric, but alert

and oriented with no asterixis. She has a severely tender,

enlarged liver. Her labs include AST = 250 U/L, ALT = 112

U/L, total bilirubin = 25 mg/dL, alkaline phosphatase = 230

U/L, albumin = 3.0 g/L, creatinine = 1.4 mg/dL, WBC =

18,000 mcL with a leftward shift, PT = 26 seconds, and INR

= 2.2.

What is your differential diagnosis for this patient?

Differential diagnosis:

• Choledocholithiasis

• Cholangitis

• Acute hepatitis*

• Pancreatitis

• Spontaneous bacterial peritonitis

• Appendicitis

• Infiltrative process of the liver → capsular swelling

• DILI

• Wilson’s Disease

• Autoimmune liver disease

What signs, symptoms, and laboratory values would

increase the likelihood of alcoholic hepatitis over other

diagnoses on your list?

History

• Between 40 – 60 yo

• History of heavy alcohol use (100 gm/day) x > 20 years

• Recently increased alcohol consumption

• Alcohol cessation weeks prior to presentation

• Stop drinking because they feel ill

Clinical Presentation

Clinical syndrome of jaundice + liver failure

Signs:

• Rapid onset of jaundice

• Fever

• Anorexia

• Ascites

• Proximal muscle loss

• Encephalopathy

• RUQ/epigastric abdominal pain

Physical Exam

• Hepatomegaly

• Fatty liver + swelling of hepatocytes

• Tender liver

• Hepatic bruit

• Sarcopenia

• Ascites

Laboratory Findings

• Moderate elevations of AST & ALT

• Typically < 300 U/L, rarely > 500 U/L

• AST:ALT ratio ≥ 2

• ↑ serum bilirubin (> 5 mg/dL)

• ↑ GGT

• Leukocytosis (neutrophil predominant)

• ↑ INR

Case cont.

The ER admits her to you with a working diagnosis of

choledocholithiasis. An ultrasound demonstrates a large

liver, no gallstones or dilation of bile ducts, and minimal

ascites. On exam, you hear a bruit over the right costal

margin and you note alcohol on her breath.

How would you approach treatment in this patient?

Diagnostic Approach

MUST rule out:

• Viral hepatitis

• Biliary obstruction

• Budd-Chiari

• Infection (SIRS)

• DILI

Obtain:

• Viral hepatitis panel

• Abdominal US + dopplers

Clinical presentation + liver dysfunction + exclusion of

acute liver disease

Liver Biopsy

Not required to make a diagnosis

• Obtain if there is doubt over a diagnosis

Pathologic features:

• Mallory-Denk bodies

• Hepatocellular ballooning

• Micro/macro steatosis

• Infiltration of neutrophils

Risk Factors for Mortality

• Older age

• Acute renal failure

• ↑ bilirubin

• ↑ INR

• ↑ WBC

• Alcohol consumption > 120 g/day

• Presence of infection or SIRS

• Hepatic encephalopathy

• Upper GI bleed

Prognostic Scoring Systems

Calculators for determining severity:

• Maddrey’s Discriminant Function (MDF)

• Glasgow Alcoholic Hepatitis Score (GAHS)

• MELD Score

Consider therapy in patients with:

• MDF ≥ 32

• Hepatic encephalopathy

• MELD > 11

• GAHS > 8

Maddrey’s Discriminant Function

DF = 4.6 x (patient’s PT – control PT) + Tbili

DF < 32 = mild-moderate

• Lower short term mortality (<10% at 1-3 months)

DF ≥ 32 = severe

• High short term mortality (25-45% in 1 month)

• Benefit from treatment

Maddrey WC, Boitnett JK, et al. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology 1978;75:193-9.

Glasgow Alcoholic Hepatitis Score

Glasgow score ≥ 9 = severe

• Benefit from treatment

variable 1 point 2 points 3 points

Age (years) < 50 ≥ 50

WBC (x109 L) < 15 ≥ 15

Urea (mg/dL) < 14 ≥ 14

INR < 1.5 1.5 - 2 > 2

Bilirubin (mg/dL) < 7.3 7.3 – 14.6 > 14.6

Forrest EH, Morris AJ, et al. The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids. Gut

2007;56:1743-6.

MELD Score

MELD Score

2002 Sheth et al.

• MELD score > 11 or ascites + total bili > 8 mg/dL associated

with a 30-day mortality of 21%

2005 Dunn et al.

• MELD score ≥ 21 associated with a 90-day mortality of 20%

2005 Srikureja et al.

• Change of MELD score ≥ 2 points in the first week

independently predicts in-hospital mortality

Sheth M, Riggs M, Patel T. Utility of the Mayo End-Stage Liver Disease (MELD) score in assessing prognosis of patients with alcoholic

hepatitis. BMC Gastroenterol 2002;2.

Dunn W, Jamil LH, Brown LS< et al. MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology 2005;41:353-8.

Srikureja W, Kyulo NL, Runyon BA, Hu KQ. MELD score is a better prognostic model than Child-Turcotte-Pugh score or Discriminant

Function score in patients with alcoholic hepatitis. J Hepatol 2005;42:700-706.

Assessing Disease Severity

√ Maddrey’s Discriminant Function (MDF)

√ Serial calculations of the MELD Score

Case

Her labs include AST = 250 U/L, ALT = 112 U/L, total

bilirubin = 25 mg/dL, alkaline phosphatase = 230 U/L,

albumin = 3.0 g/L, creatinine = 1.4 mg/dL, WBC = 18,000

mcL with a leftward shift, PT = 26 seconds, and INR = 2.2.

Maddrey’s DF: 4.6 x (patient’s PT – control PT) + Tbili

Patient’s MDF = 80

What is this patient’s prognosis?

Prognosis

Mortality is high without treatment

Carithers R, et al. Methylprednisolone therapy in patients with severe alcoholic hepatitis. Ann Int Med 1989;110:685-90.

Akriviadis E, et al. Pentoxifylline improves short-term survival in severe alcoholic hepatitis. Gastroenterology 2000;119:1637-48.

Methylprednisolone Placebo P-value

28-day mortality 6% 35% p = 0.006

Pentoxifylline Placebo P-value

28-day mortality 24.5% 46.1% p = 0.04

Treatment

• Abstinence

• Nutritional support

• Therapy for ascites and hepatic encephalopathy

• Corticosteroids

• Pentoxifylline

• N-acetylcysteine

• Anti-TNF-α therapy

Pathogenesis of Alcoholic Liver Disease

Kawaratani H, et al. The effect of inflammatory cytokines in alcoholic liver disease. Mediators Inflamm 2013;2013:495156.

Corticosteroids

Reduces levels of pro-inflammatory cytokines

1984 Mendenhall et al.• no benefit of steroids over placebo

1989 Reynolds et al., Daures et al., Imperiale et al. • improvement in survival

1995 Christensen et al. • no difference in survival

2002 Mathurin et al. • significant increase in short-term survival

2008 Rambaldi et al. • mortality benefit in patients with hepatic encephalopathy and/or MDF ≥

32

2015 Thursz et al. (STOPAH study)• improvement in 28-day mortality (trend, no significance), but not

medium or long-term outcome

2015 Singh et al.• meta-analysis, reduces short-term mortality by 46%

Corticosteroids

Mild-moderate AH (MDF < 32, no hepatic encephalopathy)

• No benefit from specific medical intervention other than

nutritional support and abstinence

Severe AH (MDF ≥ 32, hepatic encephalopathy)

• Prednisolone 40 mg/day x 28 days

Corticosteroids

Pentoxifylline

Phosphodiesterase inhibitor

• Modulates TNF-α transcription

2000 Akriviades et al. • reduced short-term mortality

2009 Whitfeld et al. • no conclusion can be drawn

2014 Parker et al. • possible survival benefit

2015 Thursz et al. (STOPAH study)• no survival benefit

2015 Singh et al.• Low quality evidence, decreases short-term mortality by 30%

Pentoxifylline

Mild-moderate AH (MDF < 32, no hepatic encephalopathy)

• No benefit from specific medical intervention other than

nutritional support and abstinence

Severe AH (MDF ≥ 32, hepatic encephalopathy)

• Pentoxifylline 400 mg PO TID x 4 weeks if contraindication

to steroid therapy• Early renal failure

• Active infection

** WANING evidence for efficacy of pentoxifylline

Pentoxifylline

Prednisolone + Pentoxifylline?

Randomized, double-blind, placebo-control, multi-center

No evidence to support dual therapyMathurin P, et al. Prednisolone with vs without pentoxifylline and survival of patients with severe alcoholic hepatitis. JAMA 2013;310:1033-

41.

Prednisolone +

pentoxifylline

Prednisolone +

placebo

6-month mortality 30.1% 30.8%

Hepatorenal syndrome 8.4% 15.3%

N-acetylcysteine

Antioxidant

• Decreases free-radicals in hepatocytes

• Reconstitutes glutathione in the liver

• Represses TNF-α expression

Prednisolone +

NAC

Prednisolone +

placebo

P-value

6-month mortality 27% 38% p = 0.07

3-month mortality 22% 34% p = 0.06

1-month mortality 8% 24% p = 0.006

Infection rate 19% 42% p = 0.001

Hepatorenal syndrome 9% 22% p = 0.02

Nguyen-Khac E, et al. Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med 2011;365:1781-9.

Anti-TNF-α Therapy

Infliximab

• Monoclonal chimeric anti-TNF antibody

• 2004 Naveau S, et al. randomized control trial*• Prednisolone + infliximab vs prednisolone + placebo

• Significant excess of severe infections

Etanercept

• Fusion protein of ligand-binding TNF to Fc of IgG1

• 2008 Boetticher NC, et al. randomized control trial• Etanercept vs placebo

• Significantly higher mortality rate at 6 months

** Use of these agents should be confined to clinical trials!

Porter C, et al. Certolizumab Pegol Does Not Bind the Neonatal Fc Receptor (FcRn): Consequences for FcRn-Mediated In Vitro

Transcytosis and Ex Vivo Human Placental Transfer. J Reprod Immunol. 2016;116:7-12.

Case cont.

After admitting the patient and ruling her out for an acute infection, you decide to start her on prednisolone. She receives counseling on alcohol cessation and is discharged two days later. One week later, she returns to your clinic. She feels fatigued and slightly nauseous, but denies any confusion. She says she is taking her medicine and abstaining from alcohol. On exam, she now has moderate abdominal distension, with shifting dullness, but no asterixis. Her repeat labs are as follows: total bilirubin = 10 mg/dL, AST = 105 U/L, ALT = 49 U/L, and creatinine = 1.4 mg/dL.

Is this patient’s hepatitis responding to the steroids? Should you continue the prednisolone?

Lille Model

Prognostic model incorporating 6 variables

• Predicts 6-month survival and response to steroids

Risk stratifies patients receiving steroids for 7 days

• Lille score ≥ 0.45: 6-month survival was 25% • “Non-responders”

• Stop prednisolone

• Lille score < 0.45: 5-month survival was 85%• “Responders”

If the patient does not respond to therapy, is there a

role for orthotopic liver transplantation?

Transplant?

Early liver transplantation is attractive

…but controversial.

Mathurin P, et al. Early liver transplantation for sever alcoholic hepatitis. N Engl J Med 2011;365:1790-1800.

Singal AK, et al. ACG Clinical Guideline: Alcoholic Liver Disease. Am J Gastroentrol 2018

Question 1

A 38-year-old woman is hospitalized for new-onset confusion and jaundice. She noticed a yellowish discoloration of the eyes 4 days before admission. Six weeks ago she developed sinus infection symptoms that were treated with amoxicillin-clavulanate. She has no history of liver disease. She does not drink alcohol or use illicit drugs or herbal supplements. She is now taking no medications.

On physical examination, temperature is 37.2 °C (99.0 °F), blood pressure is 118/82 mm Hg, pulse rate is 72/min, and respiration rate is 20/min; BMI is 27. She appears ill and is disoriented to time and date. Asterixis, scleral icterus, and jaundice are noted. Examination is negative for spider angiomata, palmar erythema, muscle wasting, and rash. The liver edge is palpable 2 cm below the costal margin. The spleen is not palpable.

Serologic studies for hepatitis A IgM, hepatitis B surface antigen,

hepatitis B core IgM, Epstein-Barr virus, cytomegalovirus IgM,

antinuclear antibody, anti–smooth muscle antibody, and

ceruloplasmin are all negative. The serum acetaminophen level is

0 µg/mL. A pregnancy test is negative.

Laboratory Studies

INR 1.9 (normal 0.8 – 1.2)

Prothrombin time 28s

ALT 199 U/L

AST 398 U/L

Total bilirubin 9.5 mg/dL

Creatinine 1.2 mg/dL

In addition to evaluation for liver transplantation, which of

the following is the most appropriate treatment?

A. Intravenous acyclovir

B. Intravenous glucocorticoids

C. Intravenous N-acetylcysteine

D. Oral pentoxyfylline

Question 2

A 47-year-old woman is evaluated in the emergency department after family members found her unresponsive and hyperventilating at home. She is admitted to the ICU, and intubation, ventilation, and supportive fluids are initiated. She has a history of alcohol-related medical problems and depression, and her family reports that she has consumed at least 50 g/d of alcohol for the past 2 months. History also includes appendectomy. Family history is negative for liver disease. Her only medication is varenicline (week 5).

On physical examination, the patient is intubated, ventilated, and sedated. Temperature is 38.5 °C (101.3 °F), blood pressure is 90/50 mm Hg, and sinus tachycardia is evident, with a pulse rate of 150/min. Jaundice, abdominal distention, absent bowel sounds, and an enlarged, tender liver with rounded edge are noted. There is 1+ bilateral peripheral edema. The nasogastric tube is draining green fluid with coffee-ground specks.

An abdominal radiograph shows distended loops of bowel with no

air-fluid levels.

Laboratory Studies

Hematocrit 24%

Leukocyte count 22,000/μL

Prothrombin time 23 s

ALT 410 U/L

AST 875 U/L

Total bilirubin 0.88 mg/dL

Which of the following medications is most likely to reduce

this patient’s 28-day mortality risk?

A. Pentoxifylline

B. Pentoxifylline and prednisolone

C. Prednisolone

D. Propranolol

Question 3

A 45-year-old man is admitted to the hospital for new-onset

right upper quadrant pain, ascites, fever, and anorexia. His

medical history is notable for hypertension and alcoholism.

His only medication is hydrochlorothiazide.

On physical examination, temperature is 38.1 °C (100.6

°F), blood pressure is 110/50 mm Hg, pulse rate is 92/min,

and respiration rate is 16/min. BMI is 24. Spider angiomata

are noted on the chest and neck. The liver edge is palpable

and tender. There is abdominal distention with flank

dullness to percussion.

The Maddrey discriminant function score is 36. Ultrasound

discloses coarsened hepatic echotexture, splenomegaly,

and a moderate to large amount of ascites. Diagnostic

paracentesis reveals spontaneous bacterial peritonitis, and

intravenous ceftriaxone is administered. Upper endoscopy

is notable for small esophageal varices without red wale

signs and no evidence of recent bleeding.

Laboratory Studies

Alkaline phosphatase 210 units/L

ALT 60 U/L

AST 125 U/L

Total bilirubin 6.5 mg/dL

Creatinine 1.8 mg/dL

In addition to continuing ceftriaxone and starting albumin,

which of the following is the most appropriate treatment?

A. Etanercept

B. Infliximab

C. Pentoxifylline

D. Prednisolone

Question 4

A 50-year-old man is evaluated during a routine visit for alcoholic cirrhosis. He has a 3-month history of hepatic encephalopathy, characterized by forgetfulness and personality changes, that is well controlled with lactulose. He has not consumed alcohol in the last 2 years. One year ago he developed ascites that required diuretics. At that time a screening upper endoscopy revealed no varices. His current medications are lactulose, spironolactone, and furosemide.

On physical examination, he is alert and in no distress. He is oriented but has mild psychomotor slowing. Vital signs are normal. Scleral icterus, temporal muscle wasting, and spider angiomata are noted. Neurologic examination reveals mild asterixis. On the Mini-Mental State Examination, he scores 28 out of 30, failing to recall one out of three objects and missing the day of the week.

Laboratory Studies

Hematocrit 33% AST 45 U/L

Platelet count 75,000/uL Total bilirubin 4 mg/dL

INR 1.4 Creatinine 1.3 mg/dL

Albumin 2.9 g/dL Electrolytes Normal

ALT 32 U/L

Which of the following is the most appropriate

management?

A. Add nadolol

B. Begin a low-protein diet

C. Continue medical treatment without changes

D. Refer for liver transplantation