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3/20/2018
1
Alcoholic Hepatitis: Current Challenges and
Future Directions Nikolaos T. Pyrsopoulos, MD, PhD, MBA
Professor and Chief,
Division of Gastroenterology and Hepatology
Medical Director Liver Transplantation
Rutgers- New Jersey Medical School
University Hospital
Outline
Disease Spectrum
Risk Factors
Clinical Presentation
Diagnosis
Prognostic Factors
Treatment
• May well be the oldest form of liver injury: fermented beverages were present as early as 10,000 BC.
Approximately 2/3 of adult Americans drink some alcohol.
Alcoholic liver disease encompasses a spectrum of injury from simple steatosis to frank cirrhosis.
Excessive alcohol consumption is the thirdleading preventable cause of death in the United States.
Total recorded alcohol per capita consumption (15+), in liters of pure alcohol
Making sense of the terminology of alcohol
Standard drink: NIAAA (National Institute on Alcohol Abuse and Alcoholism) a standard drink is any drink that contains 10 grams
of pure alcohol or 0.6 fluid ounces of pure alcohol
1 standard drink is equivalent to 1 unit
1 unit = 10 grams of alcohol
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What is a Standard DrinkBeverage Strength
by VolumeSize (volume)
Amount Standard Drinks
Low Alcohol Beer
2-3% 375 ml (1can)
10 grams 1
Regular Beer 4-5% 375 ml (1 can)
14-15 grams 1.5
Red or White Table Wine
10-14% 750 ml (1 bottle)
60-80 grams 6-8
Fortified wine (port or sherry)
18% 60 ml 10 grams 1
Spirits (gin or whiskey)
38-48% 30 ml (nip)
10 grams 1
Safe parameters for alcohol ingestion:
14 units per week in women, app 2 units/day
21 units per week in men, app 3 units/day
Prevalence and Natural History
Factors that affect the development of liver injury:
a) dose, duration, and type of alcohol
b) drinking patterns,
c) sex and ethnicity,
d) associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis and genetic factors
Prevalence and Natural History drink excessively and develop physical tolerance and
withdrawal: alcohol dependence
harmful use of alcohol defined by the development of negative social and
health consequences of drinking like unemployment, loss of family, organ damage, accidental injury, or death: alcohol abusers and problem drinkers
Prevalence and Natural History
The risk of cirrhosis consumption of more than 30 grams of alcohol per day (3 units/day), the highest risk is associated with consumption of more than 120 grams per day (12 units/day)
Point prevalence of cirrhosis is 1% in persons drinking 30 to 60 grams of alcohol a day (3-6 units) and up to 5.7% in those consuming 120 grams daily (12 units)
Histology
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Assessing Illness Severity
Maddrey’s Discriminant Function
MELD
Glasgow Alcoholic Hepatitis Score
ECBL
Lille model
Disease Spectrum of ALD
Normal Liver
If abstinent for 4-6 weeks 90-100% if drink more than 6 units daily
Alcoholic Hepatitis
Fatty liver
Cirrhosis
30% if continues to drink at least 4 units daily5-15% if abstinent10-35%
40% ?
Disease Spectrum of ALD
Spectrum varies from simple steatosis to cirrhosis
3 main histological stages:
fatty liver or simple steatosis
acute alcoholic hepatitis
hepatic fibrosis or cirrhosis
Disease Spectrum: Alcoholic Hepatitis (AH)
AH: True prevalence is unknown, but histologic studies of patients with ALD (alcoholic liver disease) suggest that AH may be present in as many as 10-35% of hospitalized alcoholic patients
Likelihood that AH will progress to permanent damage is increased among those who continue to abuse alcohol, amount of alcohol is unknown that leads to cirrhosis
Up to 40% of patients with severe alcoholic hepatitis die within 6 months after the onset of the clinical syndrome, appropriate diagnosis and treatment are essential
Can you get alcoholic hepatitis if you don’t have fatty liver?
Disease Spectrum: Fibrosis/Cirrhosis
Fibrosis starts in the perivenular area and is influenced by the amount of alcohol ingested
Perivenular fibrosis and deposition of fibronectin occurs in 40-60% of patients who ingest more than 60-80 grams/daily (6-8 units) for an average of 25 years
Perivenular sclerosis has been identified as a significant and independent risk factor for the progression of alcoholic liver injury to fibrosis or cirrhosis
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Clinical Presentation of Alcoholic Hepatitis
Clinical Presentation of Alcoholic Hepatitis (AH): cardinal sign is the rapid onset of jaundice
Other common signs and symptoms include:fevers, ascites, and proximal muscle loss
Patients with severe alcoholic hepatitis may have encephalopathy
Liver may be enlarged and tender
Within several weeks after discontinuation of alcohol intake, jaundice and fever may resolve, but ascites and hepatic encephalopathy may persist for months to years
Either continued jaundice or the onset of renal failure signifies a poor prognosis
Physical Exam Findings in Alcoholic Liver Disease (ALD)
No single physical finding or constellation of findings is 100% specific or sensitive for ALD
Some features may carry independent prognostic information, with the presence of specific features associated with an increased risk of mortality over one year. These include HE, presence of visible veins across the anterior abdominal wall, edema, ascites, spider nevi, and weakness.
Several centers have mentioned the presence of a hepatic bruit, but the sensitivity and specificity of this finding is uncertain
Jaundice associated with alcoholic liver
diseaseCaput medusae Portal HTN
Esophageal Varices Normal Gastro esophageal junction
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Diagnosis
Elevated AST and ALT ( rarely > 300 IU/ml) AST/ALT > 2:1 (> 80% pts) Increased GGT (70-90% pts) -independent of liver disease Leukocytosis with neutrophilia Increased MCV (80-100% pts) –due to ETOH induced
marrow toxicity, B12/folate deficiency Elevated creatinine-ominous sign (HRS) Carbohydrate deficient transferrin Elevated IgA levels Hyperbilirubinemia, coagulopathy, TCP
When to do a Liver Biopsy in ALD?
To confirm diagnosis
Exclude other causes of liver disease including primary or concomitant
Assess extent of liver damage
Ethanol induced cirrhosis
Macronodular (nodules >3cm in diameter), Brown, Non-fatty, Shrunken (<1 kg)
Alcoholic hepatitis
“Mallory bodies” Frank Burr Mallory (1862-1941)
American pathologist at the Boston City Hospital and Professor of Pathology at Harvard Medical School, after whom the Mallory body is named.
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Prognosis
Maddrey’s Discriminant Function (mDF)Model of End Stage Liver Disease (MELD)Glasgow Alcoholic Hepatitis Score (GAHS)
Prognostic Factors: MDF
Maddrey’s Discriminant Function (MDF), a disease-specific prognostic score is used to stratify a patient’s severity of illness.
Initial formula was derived in the context of clinical trials of alcoholic hepatitis, and later modified.
modified DF=4.6 (patient’s PTT-control PTT) + total bilirubin
Score of greater than 32, highest risk of dying, with a one month mortality as high as 30-50%. If also with hepatic encephalopathy, risk for death went even higher
Score of less than 32 : 17% mortality
Prognostic Tools: MELD MELD score, poor prognosis if greater than 11, but some
sources greater than 18.
If calculated MELD again one week into the hospital course and there has been a greater than 2 point change from the admission MELD, this been shown to independently predict in hospital mortality.
90 day mortality of a MELD score of 21 was found to be 20%
Prognostic Tools:Glasgow Alcoholic Hepatitis Score (GAHS)
Age (years) <50 + 1, >50 +2
WBC <15 +1, >15 +2
Urea <5 +1, >5 +2
PT ratio or INR <1.5 +1, >1.5-2.0 +2, >2 +3
Bilirubin <125 +1, 125-250 +2, >250 +3
Score of 9 or more identifies patients most at risk of death, a score of 9 or more can be used either on day 1 (admission day) or day 6-9.
The Lille score model
3.19–0.101×Age (years) +0.147×Albumin on day 0 (g/L) +0.0165×Evolution in bilirubin level (μmol/L) −0.206×Renal insufficiency −0.0065× Bilirubin on day 0 (μmol/L) −0.0096× PT (seconds) (www.lillemodel.com)
Lille score ≥ 0.45 predicts 75% mortality within 6 months in patients who have received corticosteroid therapy.
Analysis of Prognostic ToolsmDF MELD GAHS
Pros Simple
Does not require a liver biopsy
Simple
Does not require a liver biopsy
Predicts mortality at 90 days
Simple
Does not require a liver biopsy
Predicts mortality at 28/84 days when measured at days 1 and 7
Cons Doesn’t give a mortality prediction
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Upcoming Prognostic Tool
Degree of portal hypertension may be a sensitive marker of liver injury,
new proposed scoring system includes measurements of a marker of portal hypertension with asymmetric dimethylarginine and its stereoisomer to predict outcomes, sensitivity 73%, specificity of 83%, still in the works
AASLD Guidelines
Treatment
Abstinence
Corticosteroids
Pentoxyfylline
Anticytokine Therapy
Antioxidants
Nutritional Supplementation
Other agents: PTU, Colchicine, anabolic steroids
Main ongoing studies of targeted treatment for alcoholic hepatitis and alcoholic cirrhosis
Louvet, A. & Mathurin, P. (2015) Alcoholic liver disease: mechanisms of injury and targeted treatmentNat. Rev. Gastroenterol. Hepatol. doi:10.1038.nrgastro.2015.35
Treatment Strategy
After an episode of AH, no safe amount of alcohol consumption which can be recommended as AH can persist or redevelop
Need for therapy is less urgent in patients with AH who have a low risk of complications as estimated by a MDF score of <32 or GAHS score of <9. Particularly true in patients with improving bilirubin during hospitalization
Treatment: Abstinence
Abstinence: most therapeutic intervention for patients with ALD, improvement can be relatively rapid and in 66% of patients abstaining from alcohol, significant improvement was observed in 3 months
In those patients who achieve abstinence, naltrexone or acamprosate may be considered in combination with counseling to decrease the likelihood of relapse in patients with alcohol dependence/abuse
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Treatment: Steroids
Rationale for treatment:
Suppresses immune response through the mechanism of inhibiting transcription factors such as activator protein 1 (AP-1) and NF-k B
Suppresses inflammatory response by inhibiting cytokine synthesis
Treatment: Facts about Steroids
Use has been controversial
Most common steroids: prednisolone 40 mg po daily
Indications for treatment: MDF>32 in the absence of sepsis, hepatorenal syndrome, chronic hepatitis B, GI bleeding
Lack of efficacy can be determine by calculating the Lille score after 7 days of treatment
Lille score greater than 0.45 indicates a lack of response to steroids and predicts a 6 month survival rate of less than 25%.
Alcoholic hepatitis is unresponsive to steroid treatment in approximately 40% of patients: in this subgroup, pentoxyfylline has not been identified as effective
Overview of Steroids for Alcoholic Hepatitis
Benefits of Steroids Problems
Anti-inflammatory Systemic Sepsis
Reduces cytokines Tissue Viability
Prevents tissue injury Diabetogenic
Anabolic issues Inhibits liver regeneration
Short term gain No long term survival benefit
STOPAH TrialPrednisolone or Pentoxifylline for Alcoholic
Hepatitis
Treatment: Anticytokine Therapy
Cytokines implicated in ALD: IL-6, IL-10, TNF-alpha
Treatment: Infliximab and Etanercept
Type of drug:
Infiximab: monoclonal chimeric anti-TNF antibody
Etanercept: a fusion protein containing the ligand-binding portion of the human TNF receptor fused to the Fc portion of Human IgG1
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ELADELAD
Liver transplantation 2018
Clinical and biochemical suspicion of alcoholic hepatitis
Severity stratification(Maddrey’s discriminate function, MELD, ABIO, Child, Glasgow scores
Consider (transjugular if low platelet count) liver biopsy for confirmation
Intermediate and high risk Low risk
No or controlled infection Nutritional assessmentStandard supportive care
Severe Infection
Corticosteroids(Prednisone 40 mg)
Pentoxifyline(400mg three times daily for 4 weeks
Stop CorticosteroidsConsider for MARSConsider for clinical trials
4 weeks of corticosteroidsFollowed by a 2 week taper off
Lille score model at 7days<0.45>0.45
Easy Does it and smooth on the pedal!