Fulminant Hepatic Failure- Acute Hepatitis B AM Report 07/07/09 Amy Auerbach

Fulminant Hepatic Failure Rapid development of severe acute liver injury with impaired synthetic function and encephalopathy In a patient who previously had a normal liver or had well-compensated disease

Etiology of Fulminant Hepatic Failure Toxins: Most common cause- Acetaminophen is the most common toxin; augmentin second most likely toxin Viral: Most common viral cause are the hepatitis viruses (hepatitis B more commonly progresses to FHF than hepatitis A) EBV, CMV, HSV, Varicella also potential etiologies Vascular: Portal vein thrombosis, Budd-Chiari syndrome, veno-occlusive disease, ischemic hepatitis Metabolic: Wilson’s disease, acute fatty liver of pregnancy, Reye’s syndrome Other: Autoimmune hepatitis, malignant infiltration of the liver, sepsis

Complications Encephalopathy Cerebral edema Hypoglycemia Metabolic acidosis Sepsis Coagulopathy Multiorgan Failure

Treatment Acetaminophen toxicity: NAC (NAC now used in non- acetaminophen related cases of fulminant hepatic failure as well) Herpes: Acyclovir Autoimmune: Steroids Budd-Chiari- Heparin/TIPS Supportive Care: Lactulose, stress ulcer prophylaxis, FFP if actively bleeding, antibiotics for infections Transplantation in all etiologies EXCEPT for infiltrating cancer (breast, melanoma, lymphoma)

Criteria for Transplantation

Hepatitis B Infection- Epidemiology Perinatal transmission most common in high prevalence areas Horizontal transmission (in early childhood) accounts for most cases in intermediate prevalence areas (minor breaks in skin or mucous membranes) Unprotected sexual intercourse and IVDA in adults accounts for most of spread in low prevalence areas Progression to chronic hepatitis B is much more common with perinatal transmission

Acute Hepatitis 70% of patients with acute hepatitis B have subclinical or anicteric hepatitis 30% develop icteric hepatitis .5-1% develop fulminant hepatic failure: believed to be secondary to massive immune- mediated lysis of infected hepatocytes

Acute Hepatitis B Incubation period lasts 1-4 months May develop anorexia, jaundice, nausea, RUQ discomfort Symptoms and jaundice typically resolve after 1-3 months Lab testing reveals elevations in ALT and AST up to 1000-2000 IU/L

Outcome after Acute Hepatitis B Traces of HBV often detectable in blood by PCR many years after clinical recovery Persistent histologic abnormalities may be present many years after serologic recovery Latent infection can maintain the T cell response for decades following clinical recovery

Hepatitis B Serologies HBsAg: Hepatitis B surface antigen- appears 1-10 weeks after an acute exposure to HBV - Usually becomes undetectable after four to six months - Persistence of HBsAg for more than six months implies chronic infection Anti-HBsAg- follows dissapearance of HBsAg - Typically persists for life and confers long term immunity - May not be detectable until after a window period of several weeks to months during

Hepatitis B Serologies IgM anti-HBc: IgM antibodies against hepatitis B core antigen: allow serologic diagnosis to be made during the “window period” and can help differentiate between acute and chronic infection Anti-HBc: hepatitis B core antigen- intracellular antigen expressed in infected hepatocytes: can help differentiate between immunized patients and patients who have cleared infection

Hepatitis B Serologies HBeAg: Hepatitis B e antigen- secretory protein processed from the precore protein Considered to be a marker of HBV replication and infectivity HBeAg to anti-HBe seroconversion occurs early in patients with acute infection- prior to HBsAg to anti-HBs seroconversion

Typical levels of alanine aminotransferase (ALT), HBV DNA, hepatitis B s and e antigens (HBsAg and HBeAg), and anti-HBc, anti-HBe, and anti-HBs antibodies are shown in acute self-limited HBV infection (Panel A) and in infections that become chronic (Panel B). The intensity of the responses, as a function of time after infection, is indicated schematically. HBV DNA may persist for many years after the resolution of acute self-limited infection.42

Chronic Hepatitis B May have stigmata of chronic liver disease: jaundice, splenomegaly, ascites, peripheral edema Mild elevation in serum AST/ALT Progression of cirrhosis is possible Extrahepatic manifestations: polyarteritis nodosa and glomerular disease

Replicative Phase: Immune Tolerance and Clearance High levels of HBV replication: presence of HBeAg and high levels of HBV DNA No evidence of active liver disease Immune tolerance usually lasts 10-30 years- in this time there is a very low rate of spontaneous HBeAg clearance Immune clearance occurs during second and third decades in patients with perinatally acquired HBV infection

Inactive Carrier State HBeAg negative and anti-Hbe positive These patients can still have significant histologic inflammation and/or fibrosis

Complications of Chronic Hepatitis B Cirrhosis HCC: surveillance for HCC recommended for chronic HBV carriers Reactivation following seroconversion: patients who receive immunosuppressive therapy (can also occur spontaneously) Vaccinate against hepatitis A and caution re: alcohol, acetaminophen use

Treatment Adult course is typically self-limiting In fulminant hepatic failure, lamivudine most commonly used (L-nucleoside agent) Patients with compensated cirrhosis and detectable level of HBV DNA are candidates to prevent progression Threshold for treating HBeAg-positive chronic HBV infection is lower than for HBeAg negative infection

Back to our case… Multiple reports of HBV reactivation in patients undergoing chemotherapy: risk is greatest upon withdrawal of treatment Risk is greatest for patients who are: HBsAg positive, male gender, use of corticosteroids, use of rituximab Other risk factors for reactivation: - HIV infection, superinfection with other hepatitis viruses, interferon therapy, corticosteroids, immunosuppressive therapy

Can reactivation be prevented? Mutliple studies have suggested a benefit from prophylactic use of antiviral treatments in patients at risk for HBV reactivation Anti-viral most commonly used is lamivudine Started before chemotherapy and maintained at least six months after withdrawal of chemotherapy

Take Home Points Acetaminophen toxicity is the most common cause of fulminant hepatic failure Hepatitis B is the most common viral cause of fulminant hepatic failure Anti-HepBc can help you tell the difference between an immunized patient and a patient who is “naturally” immune (positive in the patient who was exposed to infection) IgM Anti-HBc is most useful during the “window period” Prophylactic lamivudine can be used in setting of immunosuppression and chronic hepatitis B

References Uptodate.com Dienstag, Jules. Hepatitis B Virus Infection. NEJM Volm 359:1486- 1500 Lau GK et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology, 2003; 125:1742-1749