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

2. 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

3. 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

4. Complications Encephalopathy Cerebral edema Hypoglycemia
Metabolic acidosis
Sepsis
Coagulopathy
Multiorgan Failure

5. 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)

6. Criteria for Transplantation

7. 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

9. 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

10. 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 IU/L

11. 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

12. Hepatitis B Serologies
HBsAg: Hepatitis B surface antigen- appears 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

14. 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

16. 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

17. 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

18. 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

19. 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 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

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

21. 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

22. 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

23. 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

24. 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

25. 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

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