Natural History of the Disease

Exposure to HBV may result in asymptomatic, acute icteric, or, in some instances, fulminant hepatitis (0.1-0.5%). Approximately 5% of adults and 95% of peri-natally infected young children become persistently infected. The outcome depends on the age of the patient and genetic factors determining the efficiency of the host immune response. Genetic factors influencing outcome (in more than one study) include polymorphisms of the MHC class II glycoproteins, which influence presentation of viral peptides during induction of the cellular immune response, and mannin-binding lectins, which bind to mannose-termi-nated carbohydrate residues such as those present on the C-terminus of the Pre-S2 region of the middle envelope protein facilitating phagocytosis. The risk of chronicity in children decreases with increasing age. A small proportion of carriers each year may become HBsAg negative (0.05-2%, depending on age of infection), thus leading to resolution of the hepatitis.

Acute HBV Infection

The incubation period following exposure is 3-6 months. In the week before icterus appears, some patients develop a serum sickness-like syndrome including arthralgia, fever, and urticaria. The clinical picture varies from asymptomatic anicteric infection to protracted icterus and, in some patients (<1%), liver failure (fulminant hepatitis). The acute infection is self-limiting and most patients recover within 1-2 months after the onset of icterus.

Chronic HBV Infection

This is defined as persistent viremia of more than 6 months duration and accompanied by hepatic inflammation. The latter is based on histological examination of liver biopsy material that is followed by assigning of scores for necroinflammatory activity (out of 18) and stage of fibrosis (out of 6), which are used to decide whether a patient needs therapy.

Course of Chronic Infection

Chronic HBV infection is quite variable and is typically characterized by four phases. These phases are the immune tolerant, the immune clearance, the nonreplicative (immune-controlled low-level infection), and the reactivation phase that may be seen in some patients, particularly in Southern Europe and the Far East (Figure 6). During the immune-tolerant phase, the patient is HBsAg- and HBeAg-positive with high levels of HBV-DNA, but with near-normal or minimally elevated alanine aminotransferase (ALT) levels. Children infected at birth or soon after are more likely to go through this phase, which may last for 2-3 decades. During the immune clearance phase more commonly seen in those infected in adult life, HBeAg and HBV-DNA levels decrease, ALT levels increase, and necroinflammatory changes are seen in liver biopsies. Loss of HBeAg may be accompanied by an ALT flare, culminating in seroconversion to anti-HBe and entry to the nonreplicative phase when the infection is under

Natural History Disease Diagram

Figure 6 Diagram of the natural history of chronic HBV infection showing the immune tolerant, immune clearance, nonreplicative, and reactivation phases. Reproduced from Karayiannis P, Carman WF, and Thomas HC (2005) Molecular variations in the core promoter, precore and core regions of hepatitis B virus, and their clinical significance. In: Thomas HC, Lemon S, and Zuckerman AJ (eds.) Viral Hepatitis 3rd edn., pp. 242-262. London: Blackwell, with permission from Blackwell Publishing.

Figure 6 Diagram of the natural history of chronic HBV infection showing the immune tolerant, immune clearance, nonreplicative, and reactivation phases. Reproduced from Karayiannis P, Carman WF, and Thomas HC (2005) Molecular variations in the core promoter, precore and core regions of hepatitis B virus, and their clinical significance. In: Thomas HC, Lemon S, and Zuckerman AJ (eds.) Viral Hepatitis 3rd edn., pp. 242-262. London: Blackwell, with permission from Blackwell Publishing.

immune control. Viral DNA integration into the host genome may take place during chronic infection and persist during the nonreplicative (low replicative) phase. During this phase, plasma HBV-DNA may or may not be detectable, while ALT levels return to normal. This serological profile characterizes the 'inactive carrier state', which is maintained thereafter. Some patients, however, for reasons that still remain unknown, show disease reactivation accompanied by ALT rises and return of viremia. Such patients may exhibit fluctuations in ALT levels with occasional severe exacerbations. Continued necroinflammatory activity may lead to fibrosis, and faster development of cirrhosis and HCC.

Mutant Viruses and Chronic Infection

Anti-HBe-positive patients in the reactivated phase of the disease are also referred to as the HBeAg-negative vire-mic group. Genomic analyses has revealed that such patients carry natural mutants ofthe virus that have either reduced levels (core promoter variants) or complete abrogation of HBeAg (precore variants) production. These variants are selected at the time of, or soon after, serocon-version, and become dominant during the reactivation phase. The most common precore mutation is the G1896A substitution, which creates a premature stop codon in the precursor protein from which HBeAg is elaborated. This mutation affects the stem of the e encap-sidation signal, but leads to stronger base pairing with the A1896 change in genotypes with a T at position 1858 of the precore region, such as B, C, D, and E. The double mutation affecting the core promoter region (A1762T, G1764A) is thought to result in decreased transcription of the precore mRNA, with a knockon effect on HBeAg production, while pgRNA production remains the same or is even upregulated. It is now apparent that additional mutations in this region may contribute to this phenotype.

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