ALCOHOLIC HEPATITIS · Carithers R, et al. Methylprednisolone therapy in patients with severe...
Transcript of ALCOHOLIC HEPATITIS · Carithers R, et al. Methylprednisolone therapy in patients with severe...
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