乙肝急性发作的处理

REVIEW ARTICLE Management of acute hepatitis B and reactivation of hepatitis B Ankur Jindal, Manoj Kumar and Shiv K. Sarin Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India Keywords Acute hepatitis B – Chronic hepatitis B – Hepatitis B reactivation – Antiviral drugs – Fulminant hepatitis – Hepatitis flare Abbreviations ACLR, acute-on-chronic liver failure; ALF, acute liver failure; AVH-B, acute hepatitis B; CHB, chronic hepatitis B; ESR1, oestrogen receptor alpha; GCSF, granulocyte-colony stimulating factor; HAV, hepatitis A virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis delta virus; HEV, hepatitis E virus; HIV, human immunodeficiency virus; NNRTI, non-nucleoside reverse transcriptase inhibitors; WHV woodchuck hepatitis virus. Correspondence Dr S K Sarin, MD, DM, Senior Professor, Hepatology, Institute of Liver & Biliary Sciences (ILBS), New Delhi, India Tel: +91 11 4630 0000 Fax: +91 11 2612 3504 e-mail: shivsarin@gmail.com DOI:10.1111/liv.12081 Abstract The natural course of hepatitis B virus infection and the resulting hepatic injury is determined by the degree of virus replication and the intensity of host immune response. Upon exposure to hepatitis B virus (HBV), individu- als with a vigorous and broad immune response develop acute self-limited infection, which may result in acute hepatitis. However, with stringent test- ing for HBV and universal precautions, acute HBV is rather rare. Reactiva- tion of HBV most often presents as acute hepatitis B (AVH-B) and clinically, it is difficult to differentiate AVH-B from reactivation of chronic hepatitis B (CHB) and it requires a high index of suspicion. In the presence of high HBV DNA (>2 9 104 IU/ml) underlying liver disease should be investigated by liver biopsy, endoscopy and/or imaging. The degree of liver failure often depends on the severity of acute insult and the stage of underlying chronic liver disease. Mutations in the HBV genome, immunosuppressive therapy and viral or drug induced injury are common causes of reactivation. As most patients with AVH-B resolve the infection spontaneously, antiviral therapy is not indicated in them. However, the use of a potent oral nucleoside(tide) analogue is necessary as soon as possible in patients with CHB reactivation. Liver transplantation should be considered in patients who develop liver fail- ure secondary to severe acute exacerbation. If this is not feasible, supportive therapy with the addition of granulocyte colony stimulating factor (GCSF) therapy could be beneficial. Hepatitis B virus (HBV) infection is the tenth leading cause of death worldwide (1). Almost 30% of the world population has been exposed to HBV and an estimated 400 million of these are chronically infected (2). The natural course of HBV infection is determined by the interplay between viral replication and the host immune response. Upon exposure to HBV, individuals with a vigorous and broad immune response to the virus develop an acute self-limited infection, which may result in acute hepatitis. An aberrant response can lead to fulminant hepatitis. Individuals who do not have a broad and vigorous immune response do not clear the virus, but develop persistent chronic hepatitis B virus. The virus persists in the body even after sero- logical recovery from acute hepatitis B; therefore, indi- viduals who have been exposed to HBV are at risk for reactivation [flare or exacerbation] of hepatitis when an immune imbalance occurs (3). The severity of the flare depends on the state of underlying liver disease. As patients with severe acute exacerbation of chronic hepatitis B may not have underlying cirrhosis, they may recover to relatively normal liver function in con- trast to those with end-stage cirrhosis. It is therefore important to recognize this clinical presentation of chronic hepatitis B. Although there is no consensus definition of reactiva- tion [flare or exacerbation] of hepatitis B is character- ized by sudden elevation of serum ALT levels. It usually refers to an abrupt increase in serum ALT to >5– 10 times the upper limit of normal or >3 times the baseline level (4). Reactivation of hepatitis in chronic HBV-infected patients is common and may be caused by a number of factors (Table 1). Reactivation of hepa- titis B virus (HBV) replication is a sudden increase or reappearance of serum HBV DNA in a patient with chronic or past HBV infection (5). This review will focus on management of acute hepa- titis B and reactivation of hepatitis B (flare or exacerba- tion) spontaneous or that owing to superimposed hepatotropic viruses. Acute hepatitis B During acute hepatitis B, manifestations range from subclinical or anicteric hepatitis to icteric and, in some cases, fulminant hepatitis. Liver International (2013) © 2012 John Wiley & Sons A/S164 Liver International ISSN 1478-3223 Approximately 70% of patients with acute hepatitis B have subclinical or anicteric hepatitis. The average incu- bation period is 75 days (range 40–140 days). The onset of hepatitis B is typically insidious, with nonspecific symptoms of malaise, poor appetite, nausea and pain in the right upper quadrant. During the icteric phase, fati- gue and anorexia usually worsen. Jaundice can last from a few days to several months, but usually 2–3 weeks. Itching and pale stools may occur. The convalescent phase begins with the resolution of jaundice. The physical signs of typical acute hepatitis B may include variable degrees of jaundice, mild and slightly tender hepatomegaly and mild enlargement of spleen and lymph nodes. Pathogenesis An incubation phase lasting weeks or months with increasing and finally very high viraemia, but without clinical or biochemical signs of liver damage shows that replication and persistance of HBV is not cytopathic per se. Analysis of the hepatocellular expression patterns in acutely HBV-infected chimpanzees showed that no host response to viral replication occurred during the incu- bation phase. HBV infection is a ‘stealth virus’ infection that does not stimulate the innate immune system, which recognizes pathogen-associated molecular pat- terns (6). In contrast, later during infection, most of the effector molecules associated with the adaptive cellular immune response are induced, followed by HBV anti- bodies. HBV elimination starts several weeks before the onset of the disease with T-cell-dependent noncytolytic mechanisms, but later cytolytic immune responses fol- low and generate the symptoms of acute hepatitis (7). During acute disease, high numbers of cytolytic CD8 (+) cells are present in the liver and they react with a multitude of HBV epitopes and eliminate the virus by destroying infected cells. The increased level of arginase in patients with acute hepatitis B suppresses the func- tions of activated CD8 (+) T cells. This mechanism might limit the amount of liver damage caused by acti- vated CD8 (+) T cells in patients with acute HBV infec- tion (8). A recent study compared the intrahepatic transcrip- tional profiles of neonatal woodchucks with self-limiting woodchuck hepatitis virus (WHV) infection to wood- chucks progressing to persistent WHV infection. Instead of early-acute stage (8 weeks) gene expression, a mid- acute phase (14 weeks) expression was seen and resolu- tion was associated with induction of a prominent cytotoxic T cell signature (9). The CD4(+) Foxp3(+) regulatory T cells (Tregs) mit- igate immunomediated liver damage by down-regulat- ing the antiviral activity of effector T cells but do not influence development of HBV-specific CD8 T cells or development of memory T cells. They may contribute to conservation of tissue integrity and organ function at the cost of prolonging virus clearance (10). We have shown that CD4 + Tregs were more abun- dant and there was a higher expression of CCR1, CCR3, CCR4, CCR5 and CCR8 in patients with AVH-B. Effec- tor T cells with a potential role in necro-inflammation accumulate during the acute infeciton and subsequent down-regulation occurs by T regulatory cells, favouring viral persistence during chronic infection (11). High disease activity usually leads to clinical and serological resolution. However, even after serological resolution, small amounts of cccDNA persist in the liver for years, decades and possibly for life. T-cell immunity suppresses viral replication originating from these cccDNA copies to very low levels (12). Anti-HBs is formed during convalescence and later stage may enhance opsonization of HBsAg and block de novo infection of hepatocytes by released HBV. In contrast to the other HBV antibodies, anti-HBc induction is par- tially T-cell independent. This explains the presence of anti-HBc even in those patients who do not build up an efficient immune response. Serological resolution is defined by disappearance of HBsAg, which may take months after onset. Diagnosis The main differential diagnosis of HBsAg-positive acute hepatitis is reactivation of hepatitis in CHB virus patients. Laboratory testing during the acute phase of acute hepatitis B reveals elevated alanine and aspartate amino- transferase levels (ALT and AST). Values up to 1000– 2000 IU/l are seen during the acute phase with ALT higher than AST. Serum alkaline phosphatase and lactic dehydrogenase are usually only mildly elevated (less than three-fold). Bilirubin is variably increased, in both direct and indirect fractions. Serum bilirubin concentra- tions may be normal in patients with anicteric hepatitis. Serum albumin decreases especially in protracted severe Table 1. Causes of reactivation [flare or exacerabation] of hepatitis in chronic hepatitis B virus infected patients Reactivation (flare or exacerbation) of hepatitis B Caused by immunosuppressive medications Cancer chemotherapy Antirejection drugs Corticosteroids Caused by antiviral therapy Interferon Nucleoside analogues Corticosteroid withdrawal Caused by superimposed infections with other hepatotropic viruses Hepatitis A/E virus Hepatitis C virus Hepatitis delta virus Caused by interaction with HIV infection Reactivated hepatitis Effect of immune reconstitution therapy Liver International (2013) © 2012 John Wiley & Sons A/S 165 Jindal et al. Acute hepatitis B hepatitis. The prothrombin time can increase and is the most reliable marker of severity and prognosis. In patients who recover, normalization of serum amin- otransferases usually occurs within 1–4 months. Persis- tently elevated serum ALT for more than 6 months may indicate progression to chronic hepatitis. Various au- toantibodies can appear during acute hepatitis B, most smooth muscle. The diagnosis of acute hepatitis B is based on the detection of HBsAg and IgM anti-HBc. During the ini- tial phase, markers of HBV replication, HBeAg and HBV DNA, are present. Resolution of infection is accompanied by the disappearance of HBV DNA, HBeAg to anti-HBe seroconversion and then HBsAg to anti-HBs seroconversion. As acute hepatitis B resolves, anti-HBe appears after anti-HBc, but before anti-HBs. It usually disappears earlier than anti-HBs. Patients rarely present during the window period when HBsAg has become negative, but anti-HBs is not yet positive. In this setting, which is more common in patients with fulminant hepatitis B with rapid clearance, IgM anti-HBc is the sole marker of acute HBV infection. During acute infection, HBsAg concentrations rise exponentially for weeks to months from undetectable to typical final concentrations of 10 000–100 000 ng/ml with 2–4 days of doubling time (13). If acute HBV is resolved, HBsAg decreases with an initial half-life of 8 days until it has been disappeared completely from serum after weeks to months. In about 25% of cases of acute resolving hepatitis B, HBsAg disappears much fas- ter, so that samples taken in the late acute phase may be HBsAg negative (14). A decrease in HBsAg concentra- tions by more than 50% within the first 4 weeks indicates resolving acute infection in >95% of cases (15). Hence, quantitative analysis of highly concentrated HBsAg is an excellent prognostic marker, indicating progression to chronicity if the values remain stable or increase. Anti-HBc immunoglobulin [IgM anti-HBc] may be useful in two situations: (a) to distinguish acute hepati- tis caused by HBV from a hepatitis of different aetiology in a patient with chronic HBV infection; and (b) to identify acute hepatitis in some hepatitis B patients, par- ticularly those with fulminant hepatitis B or HDV coin- fection, where HBsAg may have been eliminated very rapidly. Predominant TH1 immune response in AVH-B favours cell-mediating viral clearance, whereas TH2 mediated immune response in CHB favours antibody production. HBV antigens elicit immune mediated liver injury in a dose-dependent manner; therefore, low viral antigen load and subsequent resolution of infection in AVH-B compared to persistent viral antigenaemia in CHB leads to significantly increased production of HBV-specific antibodies (anti-HBe and anti-HBc) in CHB or exacerbation compared to AVH-B (16, 17). Tests should be quantitative because anti-HBc IgM is also positive in chronic hepatitis B and during convales- cence. Levels >600 Paul–Ehrlich units/mL or IgM anti- HBc (>1:1000) suggest an acute HBV infection with high inflammatory activity (18, 19). In all other situa- tions, concentrations are lower or undetectable. In one Greek study (20), low molecular weight (7–8S) IgM anti-HBc was observed more frequently in HDV super- infection and was related to low mortality. On the other hand, 19S IgM anti-HBc was observed more frequently in spontaneous reactivation of chronic hepatitis B and was related to a high mortality. Outcome of acute hepatitis B Fulminant hepatitis B is an atypical course for acute hepa- titis B infection, occurring in less than 1% of icteric cases. Typically, in fulminant disease, HBV DNA and HBeAg become undetectable as hepatic failure supervenes. The reasons that HBV has a fulminant course in some patients are not well-understood. A case-control trial evaluated risk factors for a fulminant course in an outbreak among injec- tion drug users. Compared with control patients, case patients were more likely to have used acetaminophen during their illness (P = 0.08), used more alcohol and methamphetamine, and lost more weight in the six months before illness. Furthermore, all nine isolates were genotype D (21).” A more comprehensive study by the US Acute Liver Failure Study Group comparing 34 patients with HBV- related acute liver failure with a cohort of 530 patients with chronic HBV infection showed a higher prevalence of genotype D in the acute liver failure group (32% vs. 16%) even after matching for race and HBeAg status (22). These results indicate that HBV genotypes may play a role in the outcome of acute infection. Profile and pattern of HBV mutations and their relevance Precore and core promoter variants have been described in association with fulminant hepatitis (23, 24). It has been suggested that these variants result in a fulminant course because of enhanced HBV replication or a more aggressive immune response (25). The mechanism by which precore variants cause fulminant hepatitis in the new host, but an inactive liver disease in the original host remains unclear. In a recent report from Japan, higher HBV DNA lev- els, subgenotypes B1/Bj, A1762T/G1764A, G1896A, G1899A and A2339G mutations were significantly more frequent in fulminant hepatitis B than in nonfulminant AVH-B. In multivariate analysis, G1896A mutations, serum HBV DNA (>5.23 log copies/ml) and total biliru- bin (>10.35 mg/ml) were independently associated with a fulminant outcome by AVH-B (26). Subgenotypes B1/ Bj HBV(HBV/B1) are known to frequently cause ALF in Japan. T1961V/C1962D mutations, which lead to S21 substitution in the core protein were found frequently in fulminant hepatitis B and may play important roles in the development of fulminant hepatitis B (27). Because of the increased use of lamivudine (28), AVH-B caused by lamivudine-resistant strains is being Liver International (2013) © 2012 John Wiley & Sons A/S166 Acute hepatitis B Jindal et al. described. In one study from China, lamivudine-resis- tant mutations identified using direct PCR sequencing were found in 11 of the 234 (4.7%) AVH-B patients. Two patients infected with viruses with lamivudine- resistant mutations developed severe acute hepatitis, whereas one patient developed CHB (29). Traces of HBV are often detectable in the blood using PCR for many years after a clinical recovery of acute hepatitis, despite the presence of serum antibodies and HBV-specific cytotoxic T cells, which can be present at high levels. Persistent histological abnormalities (includ- ing fibrosis and mild inflammation) were present as many as 10 years in another series in nine patients with a complete serological recovery after acute infection (30). These observations suggest that eradication of HBV rarely occurs after recovery from acute HBV infection and that latent infection can maintain the T cell response for decades following clinical recovery, thus keeping the virus under control. Immunosuppression in these patients can lead to reactivation of the virus. The rate of progression from acute to chronic hepati- tis B is mainly determined by the age at infection. The rate is approximately 90 per cent for a perinatally acquired infection, 20–50 per cent for infections between the age of 1 and 5 years old and less than 5 per cent for an adult-acquired infection. Treatment Treatment for acute HBV is mainly supportive. In addi- tion, appropriate measures should be taken to prevent infection in exposed contacts. The decision to hospital- ize patients should be individualized. Patients who have coagulopathy, are deeply jaundiced, or are encephalo- pathic should be hospitalized. Hospitalization may also be considered in patients who are older, have significant co-morbidities, or cannot tolerate oral intake. There is no consensus on whether patients should be treated with non-nucleoside reverse transcriptase inhibi- tors (NNRTI) therapy because few studies have addressed the benefits of antiviral therapy during acute infection (31–35) (Table 2). As virus-specific antibody- producing B cells are enriched early after acute viral infection, the host immune system needs to be exposed to viral antigen during the early phase to induce pro- duction of neutralizing antibodies. Therefore, giving antiviral therapy early may inhibit the production of neutralizing antibodies to some extent. Nevertheless, it has also been reported that anti-HBs does not develop in 10% of untreated patients with AVH-B and long- term follow-up of these patients would help define the risk of reactivation of hepatitis B virus (HBV) in patients treated with antiviral therapy (36). Thus, antiviral therapy is not indicated in the most patients with acute hepatitis B, but may be indicated in certain subgroups of patients: (i) Patients with fulmin- ant hepatitis B; (ii) Severe AVH-B: Individuals who ful- fil any two of the following criteria: (a) hepatic encephalopathy; (b) serum bilirubin >10.0 mg/dl; and (c) international normalized ratio (INR) >1.6, especially if it is increasing; (iii) A protracted course (such as persistent symptoms or marked jaundice (bilirubin >10 mg/dl) for more than 4 weeks after presentation); and (iv) Those who are immunocompromised, have concomitant infection with hepatitis C or D virus, or have pre-existing liver disease. These indications outline the limitations of differenti- ating AVH-B from reactivation of CHB. Interferon should be avoided because of the increased risk of hepa- tic necro-inflammation. Tenofovir, telbivudine and entecavir are acceptable options given as monotherapy because the treatment duration may be short. Treatment can be stopped when the patient’s clinical condition improves and