VIRAL HEPATITIS. Definitions. Acute Liver Disease (Hepatitis A &E, Alcoholic hepatitis, DILI and ALF) Acute Viral Hepatitis Symptoms

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1 Acute Liver Disease (Hepatitis A &E, Alcoholic hepatitis, DILI and ALF) Definitions AST and ALT Markers of hepatocellular injury Ryan M. Ford, MD Assistant Professor of Medicine Director of Viral Hepatitis Transplant Hepatology Emory Transplant Center July 23, 2016 Markers of liver function: albumin, bilirubin, prothrombin time Causes of Elevated Aminotransferases Aminotransferase levels < 350 U/mL - Alcoholic hepatitis, non-alcoholic fatty liver disease, chronic viral hepatitis (hepatitis B and C), drug-induced injury High levels (greater than 1,000 U/ml) - Acetaminophen toxicity, ischemic hepatitis, acute viral hepatitis, drug induced, reactivated hepatitis B VIRAL HEPATITIS Acute Viral Hepatitis Symptoms Major Types of Viral Hepatitis Variable Incubation Period PRODROME Anorexia Nausea & Vomiting Headache Malaise Arthralgias/myalgias Cough Fatigue 1-2 weeks JAUNDICE (Icteric Phase) Dark urine Pale stool RUQ pain Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Systemic viruses that may also affect the liver (Herpes simplex virus, Epstein-Barr virus, Cytomegalovirus, Adenovirus, Yellow Fever) 5 1

2 Hepatitis A Hepatitis A Prevalence (2005) RNA virus Incubation period days (28 days) May be contagious up to 7 days following jaundice Fecal-oral route of transmission (food or water) Risk factors: poor hygiene; overcrowding; institutions; endemic countries; food outbreaks No risk for chronic infection or cirrhosis Treatment is supportive 7 RISK FACTORS ASSOCIATED WITH HEPATITIS A, , UNITED STATES Unknown 46% Other Contact 8% Source: NNDSS/VHSP Contact of daycare child/employee 6% Sexual or Household Contact 14% Food- or waterborne outbreak 4% International travel 5% Men who have sex with men 10% Injection drug use 6% Child/employee in day-care 2% Hepatitis E RNA virus Fecal-oral transmission (rare person to person) Incubation period days (40 days) First documented in 1955 after outbreak in New Delhi, India Acute infection may be fatal, especially in pregnant women (10-20% case fatality rate) No chronic infection 10 Maternal and fetal outcomes in pregnant women with acute hepatitis E in India DRUG INDUCED LIVER INJURY (DILI) Patra Ann Intern Med 2007;147(1):

3 DILI--Scope and Incidence Over 1000 medications/herbal products implicated 30% of acute hepatitis 10% of hepatology consultations 10% of adverse drug events 50% of new cases of jaundice Leading cause of acute liver failure in the US Most frequent reason for medication withdrawal from the market DILI In 2001 FDA +AASLD jointly stated: ALT > 3x ULN + Tbili > 2x ULN is clinically significant liver disease Sgro C, et al. Hepatology. 2002;36: Shapiro MA, Lewis JH. Clin Liv Dis. 2007;11: Friis H, Andreasen PB. J Intern Med. 1992;232:133-8 Pillan PI. N Z Med J. 1996; 109: Larrey D. Semin Liv Dis. 2002;22: DILI: Mechanisms of Injury Direct hepatotoxins ( Predictable ) - Metabolites - Acetaminophen (NAPQI) Idiosyncratic Hepatotoxins Unpredictable damage Usually occurs within therapeutic dose range Variable latency (few days to one year) Idiosyncratic hepatotoxins ( Unpredictable ) Hypersensitivity Induction of autoimmune hepatitis Hy s Law - Severity/Prognosis Drug-induced liver disease + Elevated ALT (> 3X ULN) + Jaundice (bili > 2X ULN) = Ominous prognosis 10 50% mortality DILI NIH-Sponsored Registry: Analysis of 1 st 300 patients enrolled (non-acetaminophen) Causative Agents 73% - single prescribed medication 9% - dietary supplement 18% - multiple agents > 100 agents identified % antimicrobials - CNS agents - NSAIDs - Herbal supplements Zimmerman HJ. Hepatoxicity Chalasani N, et al. Gastroenterology.2008;135:

4 Herbal Supplements and DILI 9% of all DILI in US, 19-63% in Asian countries Increasing existence of multiingredient products commercially available. Single- and Multiple-Ingredient Agents Associated with DILI Types of herbal products implicated in DILI Dietary Supplement Health and Education Act of 1994 allowed manufacturers to market supplements without FDA approval or proof of efficacy Concerns with standardization and contamination Seeff Gastro 2015 Trends in liver injury from herbal products Seeff Gastro 2015 ALCOHOLIC LIVER DISEASE Steatosis steatohepatitis cirrhosis Steatosis Occurs within days of heavy alcohol use Generally asymptomatic Reversed with abstinence Advanced disease requires prolonged alcohol abuse Progression to steatohepatitis requires cytokines, oxidative stress, toxic metabolic products of ETOH Occurs in 15-20% Acute Alcoholic Hepatitis Prognostic Formulas Fever with leukocytosis and bandemia AST:ALT ratio of 2:1; enzymes rarely above 350 Elevated bilirubin Prolonged INR Elevated serum creatinine May require a liver biopsy for diagnosis Maddrey Discriminant Function MELD score ABIC (Age, bilirubin, INR, creatinine) Lille Score Glasgow score 4

5 Maddrey Discriminant Function 4.6 x (PT-control PT) + serum bilirubin (mg/dl) >32 indicates poor short term mortality Treatment Abstinence* Nutritional support* Medications (for severe cases?) Steroids? Pentoxifylline? Steroids plus pentoxifylline? NAC plus steroids? STOPAH Trial Thursz et al (NEJM April 2015) Over 1,000 patients with AAH Odds ratio for 28 day mortality with prednisolone alone was 0.72 (p=0.06) No apparent benefit with adding pentoxifylline 11% infection rate (13% in steroid group) ACUTE LIVER FAILURE Acute Liver Failure Approximately 2000 cases per year in US Often affects young people and has high morbidity and mortality (<15% survival if untreated) ALF--Definition Severe acute liver disease Evidence of coagulopathy (INR 1.5) PLUS Altered mental status < 8 weeks duration in a patient WITHOUT preexisting cirrhosis 5

6 ALF: Etiology Indeterminate CAUSE Drug-Induced Budd-Chiari Autoimmune HBV Acetaminophen Drug Hepatitis B Indeterminate HELLP Wilson s Acetaminophen Shock Other Hepatitis A Autoimmune Wilson s Pregnancy Budd-Chiari Malignancies Acute Liver Failure Study Group (308 patients): Lee WM, et al. Hepatology. 2008;47: HSV Renal Failure EFFECT Coma/ Cerebral Edema ACUTE LIVER FAILURE Bleeding Respiratory Failure Coagulopathy Shock HAV Infection Lee WM, AASLD 2008 Acetaminophen Hepatotoxicity Most common cause of ALF in US and Europe Either intended suicidal overdose or therapeutic misadventure Acetaminophen in the US 100,000 Poison Control Center calls annually 56,000 ED visits 2600 hospitalizations 42% of ALF, 48% were unintentional overdoses 450 annual deaths Acetaminophen Hepatotoxicity Risk Factors for Acetaminophen- Associated Liver Toxicity Dose-related toxin usually > 10 gm/day Very high liver enzymes (>3,500 U/L) Risk Factor Age Blood Level Chronic Excessive Alcohol Fasting Concomitant Medication Time of presentation Take Home Children are relatively resistant Dose, time since ingestion, gastric emptying, best indicator Lowers threshold and worsens prognosis Lowers threshold Lowers threshold (isoniazid, phenytoin, zidovudine) The later the worse 6

7 Acetaminophen < 4g/day Inter-individual variability and influence of other factors causes heterogeneity of fatal doses > g/day 2-6g/day with heavy alcohol Chalermrat Clin Liv Dis 2013 Acetaminophen Overdose - Management Activated charcoal if within 4 hours of ingestion N-Acetylcysteine Supportive care Chalermrat Clin Liv Dis 2013 Acetaminophen Overdose N- Acetylcysteine FHF: King s College Criteria PPV 88% NPV 65% NAC PPV 80% NPV 65% Chalermrat Clin Liv Dis

8 Management of Acute Liver Failure Make the diagnosis!! Acute hepatic disease with coagulopathy and encephalopathy ALF: Management Transfer to transplant center for immediate evaluation Monitor in ICU Treat underlying cause, if known Multidisciplinary approach Case #1 48 year old white female with a history of hypothyroidism presents to the ER with a 3 week history of right upper quadrant pain, fatigue, and jaundice. She has a history of recurrent UTIs treated with antibiotics. Her total bilirubin is 10 mg/dl, the ALT and AST are > 1000 U/L and her antinuclear antibody is positive with a titer of 1:160. Which of the following antibiotics may be responsible? A) Amoxicillin B) Levofloxacin C) Trimethoprim/Sulfamethoxazole D) Nitrofurantoin Case #2 A 22 year old female is brought to the local emergency room after taking an entire bottle of acetaminophen when her boyfriend broke up with her. She is slightly confused during the examination and her lab tests show an ALT of 10,000 U, bilirubin of 8, and an INR of 4.4. What is the next best step in management? A) Immediate IV steroids B) IV NAC and urgent transfer to a transplant center C) Admit to the local ICU for further observation and supportive care D) Place an NG tube and give charcoal 8