Hepatitis B is a viral infection that primarily targets the liver. Understanding its pathophysiology involves examining how the disease develops and progresses within the body, from initial viral entry to long-term changes in liver tissue. This infection affects millions worldwide and can lead to serious health complications.
The Hepatitis B Virus and Its Lifecycle
The Hepatitis B virus (HBV) is a small, partially double-stranded DNA virus belonging to the Hepadnaviridae family. Its structure includes an outer lipid envelope containing Hepatitis B surface antigen (HBsAg) and an inner nucleocapsid, which encloses the viral DNA genome along with a viral polymerase enzyme.
HBV primarily enters the human body through contact with infected bodily fluids, such as blood, semen, vaginal fluids, and saliva. Once inside, the virus specifically targets liver cells, known as hepatocytes. The infectious HBV particle binds to receptors on the surface of hepatocytes, facilitating its entry into the cell’s cytoplasm through endocytosis.
Following entry, the viral DNA is transported to the hepatocyte nucleus, where it forms a stable, covalently closed circular DNA (cccDNA). This cccDNA acts as a template for the transcription of viral RNA, including pre-genomic RNA (pgRNA). The pgRNA is then reverse-transcribed by the viral polymerase back into partially double-stranded DNA within newly formed nucleocapsids, which are subsequently enveloped and released as new viral particles. Viral components like HBsAg and Hepatitis B e-antigen (HBeAg) are produced during this replication process and can be detected in the blood, serving as indicators of active infection.
Immune System Response to HBV
The body’s immune system recognizes the presence of HBV, initiating both innate and adaptive immune responses to combat the infection. In the early stages of infection, innate immunity, involving cells like natural killer (NK) cells, attempts to limit initial viral spread by producing antiviral cytokines such as interferon-alpha. However, HBV has mechanisms to evade detection by the host innate immune system.
As the infection progresses, the adaptive immune response becomes crucial, involving T lymphocytes and B lymphocytes. Cytotoxic T lymphocytes (CTLs) play a central role by recognizing and targeting HBV-infected hepatocytes. These CTLs clear infected cells through cell-killing mechanisms, helping to reduce the viral load. B cells contribute by producing antibodies, such as the Hepatitis B surface antibody (anti-HBs), which neutralize free viral particles and can prevent future infections.
The outcome of an HBV infection largely depends on the effectiveness of this immune response. An effective and robust immune response, typically seen in acute infections in adults, can lead to viral clearance and recovery. Conversely, an ineffective or tolerant immune response, common in individuals infected at birth or in early childhood, results in persistent viral presence and chronic infection.
Mechanisms of Liver Injury
The persistent immune response against HBV-infected hepatocytes, particularly in chronic infection, leads to significant damage within the liver. This ongoing immune attack results in chronic inflammation, a condition known as hepatitis. Repeated cycles of inflammation, hepatocyte death, and subsequent regeneration contribute to the progression of liver disease.
As liver cells are continuously damaged and replaced, the body’s wound-healing process is activated, leading to the accumulation of scar tissue, a process termed fibrosis. This scarring initially occurs around the edges of the liver lobules, the smallest functional units of the liver. With continued inflammation, the fibrosis progresses, extending beyond the lobules and forming bridges of scar tissue between them.
Eventually, extensive scarring throughout the liver can lead to cirrhosis, a severe condition where the liver becomes hardened and nodular, significantly impairing its function.
While HBV itself is not considered directly cytopathic, the sustained immune attack on infected cells is the primary driver of this progressive liver injury.
Clinical Progression and Disease Outcomes
The clinical progression of Hepatitis B infection can vary significantly, often starting with an acute phase that may be asymptomatic or present with general symptoms like fatigue and abdominal pain. While many adults clear the virus spontaneously during this acute phase, a notable percentage, particularly those infected early in life, will develop chronic infection, defined by the persistence of Hepatitis B surface antigen (HBsAg) for more than six months.
Individuals with chronic HBV can experience distinct clinical states, reflecting the dynamic interplay between the virus and the host immune system. The “immune-tolerant” phase is characterized by high viral replication but minimal liver inflammation, often lasting for decades. This can transition into an “immune-active” phase, where the immune system begins to recognize and attack infected liver cells, leading to elevated liver enzyme levels and ongoing liver damage.
Successful immune activity can lead to an “inactive carrier” state, marked by lower viral levels and reduced liver inflammation. However, some individuals may experience viral “reactivation,” where the virus becomes active again, potentially leading to renewed liver damage. The accumulated liver damage from chronic inflammation, fibrosis, and cirrhosis can result in severe complications, including liver failure and hepatocellular carcinoma (liver cancer).