ACUTE EXACERBATION OF CHRONIC HEPATITIS B INFECTION

Soewignjo Soemohardjo and Stephanus Gunawan

Biomedika Hospital
Mataram
Abstract :

Acute exacerbation in patients with chronic hepatitis occurred if there is symptom of acute hepatitis accompanied by elevation of transminase more than 5 times of normal upper limit. It is often misdiagnosed as acute hepatitis especially in those with negative history of hepatitis in the past or had never been examined for hepatitis marker in the past.
There are two kinds of acute exacerbation occurred in chronic hepatitis. The first one is exacerbation in the immunomoclearance phase. And the second one occurred after inactive carrier phase or reactivation phase. The exacerbation occured in reactivation phase often called reactivation. There is no definite term for exacerbation in the immunoclearance phase . Many terms are used for it : acute flare, acute exacerbation etc.The exacebation in imuno clearance occurred in the HBeAg positive patient, while reactivation occurred HBeAg negative patient in patient with HBeAg negative chronic hepatitis B. To differentiate the two different exacerbation we propose acute flare for exacercabtion in the immnotolerance phase. While for the second exacerbation we retain the term of Reactivation.
Acute exacerbation of Chronic Hepatitis B can occur spontaneously, but it can occurs as the result of some triggers such as superinfection with other hepatitis virus suc as Hepatitis A, C or E. Reactivation may be happened in them case of treatment with potent immunosuppreives or cytotatic that usually occurred after the stop of the agent.
Repeated attack of flare or reactivation is common in the same patient, and the more frequent attacks occurred the more rapid it induced liver cirhosis. Because exacerbation of chronic hepatitis B is accompanied by the increase of viral replication anti viral agent as nucleoside analog is often beneficial for the patient, and it should be always considered as an option in the management of acute exacerbation of chronic hepatitis B. The Quantitative HBV DNA examination is important for the diagnoses of flare or reactivation.

INTRODUCTION

Hepatitis B is a to the non hepatopathic agent. The liver tissue abnormality is caused by immune response to the virus To understand acute exacerbation of chronic hepatitis B infection one should remember the diagram by Schalm (see fig 1)
This picture show four important phases of chronic hepatitis B natural history (1) The first phase is immune tolerance phase where there is almost no host immune response creating a condition that called the asymptomatic HBsAg carrier where the virus replicates freely but no hepatic tissue damage and no clinical illness. This immunotolerance phase may last for many years especially those infected perinatally. In infection occurring in adults this phase is much shorter because the immune system is more mature (2) In the second phase called immune clearance phase the immune response of the host begin increasing enable lysis of infected liver cellss and the decrease of viral load. the third phase called inactive phase or the immune controlled phase where immune response already succeeded to clear the virus .The fourth phase is reactivation phase or immune escape phase where reactivation can ocur.

New Picture

DIAGNOSIS AND CLINICAL PICTURE

Acute exacerbation in patients with chronic hepatitis B occurred if there is symptom of acute hepatitis accompanied by elevation of transaminase more than 5 times of normal upper limit (3,4). It is often misdiagnosed as acute hepatitis especially in those with negative history of hepatitis in the past or had never been examined for hepatitis B marker in the past. The clinical presentation of acute exacerbation of chronic hepatitis B infection is depending on the underlying hepatic condition whether it is mild such in asymptomatic carrier or it is severe as in severe chronic hepatitis B or in patient with cirrhosis (2,3). So the clical picture ranging from asymtomatic to severe liver decompensation and even mortatlity.
The quantitative HBV DNA examination is important for the diagnosis of flare or reactivation but in both condition the HBV DNA titer is high. So we will not be able to differentiate the two conditions only by the DNA levels. Many studies showed that DNA titer in acute flare is higher compared with that of reactivation.(1)
The reactivation and flare can be differentiated by testing for HBeAg and anti HBe in reactivation HBeAg is negative and anti HBe is positive, while and flare HBeAg as positive in anti HBe negative and should be remembered that reactivation the DNA sequencing will shows precore mutation.

TERMINOLOGY

There are two kinds of acute exacerbation occurred in chronic hepatitis. The first one is exacerbation in the immunoclearance phase. And the second one occurred after inactive carrier phase or in reactivation phase. The exacerbation occured in reactivation phase is often called reactivation (1) There is no definite term for exacerbation in the immunoclearance phase. Many terms are used interchangeably for it : acute flare, acute exacerbation, relapse etc (2,3,5,6,7) The exacerbation in immuno clearance occurred in the HBeAg positive patient, while reactivation occurred in HBeAg negative patient in patient with HBeAg negative chronic hepatitis B. To differentiate the two different exacerbation we proposed the term acute flare for exacercabtion in the immunotolerance phase. While for the second exacerbation it is better we retain the term of reactivation. The term of reactivation is suitable for the exacerbation in the HBeAg negative chronic hepatitis because it reflect the reactivation of a process that thought to be already inactive
In HBV DNA sequecing patient with acute flare shows wild HBV pattern, whila HBV DNA sequencing in the case of reactvation show pre core mutation. Thisd phenomena can be used to differentiate between the two conditions,

PATHOGENESIS

Acute exacerbation of Chronic Hepatitis B can occur spontaneously with unknown trigger, but it can occurs as the result of some clear triggers such as superinfection with other hepatitis virus such as Hepatitis A, C or E or other virus that affect liver such as Dengue virus. Reactivation may happened in the case of treatment with potent immunosuppresives or cytostatic that usually occurred after stopping the agent.(8,9)
The pathogenesis of spontaneous exacerbation of chronic hepatitis is not clear. It is already known that Hepatitis B virus is not cytopathic by itself. Thus the clinical condition depend much on the immune response directed against the virus. In asymptomatic patient the immune response is minimal, and for some unclear reason there can be a sudden increase of the immune response that trigger the cytolitic process aiming to infected cells (7,10) In the case of superinfection with other hepatitis virus it is thought that the increase of replication of the second virus hepatitis suppressed HBV replication. When the second hepatitis virus recedes its replication of the HBV replication rebound causing the acute exacerbation (11)
In the case of the reactivation of chronic Hepatitis B due to the administration of strong immunosuppressive or cytostatic the mechanism is more clear. Strong immunosuppression weakened immune response and it caused increased viral load. When the immunosupression is stopped suddenly the immune response rebound considerably and it lead to augmented cytolysis induced necrosis of the infected cell (8,9). Repeated attack of flare or reactivation is common in the same patient, and the more frequent attacks occurred the more rapid it induced liver cirrhosis on the patient (13) The repeated attack of exacerbation often run subclinically with transaminse that does not rise too high, making the diagnosis of reactivation difficult to make. And this condition often blurred the clinical condition.In the reactivation the excacerbation occur despite negativity of HBeAg and positivity of anti HBe, because the virus can not synthesize HBeAg, in the other hand the host cell produce antibody to HBeAg because on the T cell level HBeAg is similar to HBcAg.

TREATMENT

Because exacerbation of chronic hepatitis B is accompanied by the increase of viral replication anti viral agent is a rational treatment (3). Many reports showed the good result of antiviral treatment in severe exacerbation (12) and it should be always considered as an option in the management of acute exacerbation of chronic hepatitis B. If the underlying liver disease is severe there considerable risk of liver decompensation. And in those cases nucleoside analog is of a great help to prevent fatality (4,13) But there are some controversies wether nucleoside analog is the best agent to treat all case of acute exacerbation of hepatitis B infection. In the case where transaminase level is more that 10 times normal upper limit the administration of nucleoside can result in dramatic result. But in those case the viral load will decrease substantially an spontaneously within 3 months. But one must think whether the patient still survive while waiting for 3 months .(3,4,14)
Until now most experts thought that nucleoside analog is a rational treatment for acute exacerbation of chronic hepatitis B infection especially those due to immunosuppressive (1.2,14) but we should calculate the risk and benefit of antiviral agent in all cases of Acute exacerbation of Chronic Hepatitis B infection, remembering that spontaneous decrease of viral load is possible. (14)

REFFERENCES
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10. Kohrt HE, Ouyang DL, Keeffe EB. “Lamivudine prophylaxis for chemotherapy-induced reactivation ofchronic hepatitis B virus infection”. Aliment Pharmacol Ther, 2006 ;24(7):1003-1016.
11. Perillo RP. “acute flares in chronic hepatitis B: the natural an unnatural history of an immunologically mediated liver disease”. Gastroenterology 2001;120: 1009-1022.
12. Pungpapong S, Kim WR, Petericha J. “Natural History of HBV Infection: An Update for Clinician”. Mayo Clinic Proceeding 2007; 82:967-975.
13. Tsang SWC, Chan HLY, Leung NWY, Chau TN, Lai ST, Chan FKL, Sung JJY. “Lamivudine treatment for fulminant hepatic failure due to acute exacerbation of chronic hepatitis B infection:. Alimentary Pharmacology & Therapeutics 2008;15:1737-1744.
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