Hepatitis B natural history

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: João André Alves Silva, M.D. [2]

Overview

The course of hepatitis B may be extremely variable. Hepatitis B has different clinical manifestations depending on the patient’s age at infection, immune status, and the stage at which the disease is recognized. During the incubation period patients may experience flu-like symptoms, such as nausea, vomiting, and headaches. A person infected with hepatitis B virus may recover completely, become an asymptomatic carrier of the virus, develop chronic disease, or develop fulminant hepatitis. In acute hepatitis B, the incubation period may range from 45 to 120 days, depending on the amount of virus in the inoculum, host factors, and mode of transmission. These patients may experience the following symptoms: fatigue, nausea, vomiting, anorexia, abdominal discomfort, and jaundice. In most cases, no special diet or treatment are necessary. The risk of developing chronic hepatitis decreases with age, with infants having the highest risk. Chronic hepatitis may progress to: cirrhosis, liver failure, or hepatocellular carcinoma. In most cases the prognosis of acute hepatitis is good, with symptoms lasting 2 to 3 weeks. However, in infants and immunocompromised persons, the risk of developing chronic disease is increased.

Natural History

During the incubation phase of the disease, patients may feel unwell with possible nausea, vomiting, diarrhea, anorexia, and headaches. Patients may then become jaundiced, although low grade fever and loss of appetite may improve. Sometimes HBV infection produces neither jaundice nor other obvious symptoms.

Patients with asymptomatic HBV may become silent carriers of the virus, and constitute a reservoir for further transmission to others.

Patients infected with hepatitis B may:

• Recover completely from their acute HBV infection
• Not clear the virus (5-10%), becoming asymptomatic carriers
• Develop chronic hepatitis, which may become complicated by cirrhosis and/or liver cancer
• Develop fulminant hepatitis and die

In general, the frequency of clinical disease increases with age, whereas the likelihood of being a carrier decreases.

Acute Hepatitis B

• The acute form of the disease often resolves spontaneously after a 4-8 week illness. Most patients recover without significant consequences, and without recurrence. However, a favorable prognosis is not certain, especially in the elderly who can develop fulminating, fatal cases of acute hepatic necrosis. Young children rarely develop acute clinical disease, but many of those infected before the age of seven will become chronic carriers.

Incubation Period

• Usually ranges from 45 to 120 days (average of 60 to 90 days), based on:

• Amount of virus in the inoculum (a larger initial dose of virus is associated with a shorter incubation period)
• Mode of transmission
• Host factors

Preicteric or Prodromal Phase

• Period between initial symptoms and onset of jaundice
• Usually lasts from 3 to 10 days
• Nonspecific; characterized by insidious onset of:

• Fatigue
• Anorexia
• Abdominal discomfort
• Nausea
• Vomiting
• Arthralgias
• Rash
• Fever may be absent or mild

Icteric Phase

• The icteric phase is variable, but usually begins within 10 days of symptom onset and lasts from l to 3 weeks.
• The icteric phase is characterized by:

• Jaundice (clinically apparent when the total bilirubin level exceeds 20 to 40 mg/l)
• Yellowish discoloration of the mucous membranes, conjunctivae, and sclerae
• Dark urine
• Acholic stools
• Hepatic tenderness
• Hepatomegaly
• Splenomegaly (less common)

Convalescence Phase

• About 4-12 weeks thereafter, jaundice disappears and the illness resolves with the development of natural and protective antibodies (anti-HBs) in about 95% of adults.
• Malaise and fatigue may persist for weeks or months, while jaundice, anorexia, and other symptoms disappear.
• In most cases, no special treatment or diet is required, and patients need not be confined to bed. However, a small percentage of patients die from acute HBV infection.

Chronic Hepatitis B

• Although most adult patients recover completely from an acute episode of hepatitis B, in a significant proportion—5 to 10%—the virus persists in the body. This figure is much higher in children: 70 to 90% of infants infected in their first few years of life become chronic carriers of HBV.

• Chronic hepatitis generally develops over many years.

• The risk of chronic HBV infection decreases with age. As many as 90% of infants who acquire HBV infection from their mothers at birth become chronically infected. Of children who become infected with HBV between 1 year and 5 years of age, 30% to 50% become chronically infected. By adulthood, the risk of acquiring chronic HBV infection is approximately 5%.

• Three phases of viral replication occur during the course of HBV infection, especially in patients with chronic hepatitis B:

• High replicative phase - In this phase, HBsAg, HBeAg, and HBV DNA are present and detectable in the sera. Aminotransferase levels may increase, and moderate inflammatory activity is histologically apparent. The risk of evolving to cirrhosis is high.

• Low replicative phase - This phase is associated with the loss of HBeAg and a decrease or loss of the HBV DNA concentrations, with the appearance of anti-HBe. Histologically, a decrease in inflammatory activity is evident. Serologic changes, like the loss of HBV DNA and HBeAg, are referred to as seroconversion.

• Nonreplicative phase - Markers of viral replication are either absent or below detection level and inflammation is diminished. However, if cirrhosis has already developed, it persists indefinitely.

• Chronic infection is responsible for most HBV-related morbidity and mortality, including:

• Cirrhosis
• Liver failure
• Hepatocellular carcinoma

• Up to 20% of the chronic persistent hepatitis cases progress to cirrhosis. In cirrhosis, liver cells die and are progressively replaced with fibrotic tissue, leading to nodule formation. The internal structure of the liver is deranged, leading to the obstruction of blood flow and a decrease in liver function. This damage is caused by recurrent immune responses stimulated by the presence of the virus. Because liver inflammation can be totally asymptomatic, progression of inflammation to cirrhosis can occur without the knowledge of the patient.

Complications

While most acute HBV infections in adults result in complete recovery, fulminant hepatitis occurs in between 1 and 2% of acutely infected patients. Approximately 200 to 300 Americans die of fulminant disease each year. Although the consequences of acute HBV infection can be severe, most of the serious complications associated with HBV infection are the result of chronic disease. Approximately 25% of carriers develop serious liver disease such as chronic hepatitis, cirrhosis, or primary hepatocellular carcinoma.

Common complications of hepatitis include:

• Fulminant hepatitis
• Chronic hepatitis
• Cirrhosis
• Hepatocellular carcinoma

Hepatocellular Carcinoma

• Hepatitis B is often associated with hepatocellular carcinoma.
• More than 85% of examined hepatocellular tumours harbor integrated HBV DNA, often multiple copies per cell. The viral DNA integrants are usually highly rearranged, with deletions, inversions, and sequence reiterations all commonly observed. Most of these rearrangements ablate viral gene expression, but the integrations alter the host DNA.

• Every cell in the tumor contains an identical complement of HBV insertions. This implies that the integration event(s) preceded the clonal expansion of the cells.
• There is no similarity in the pattern of integration between different tumors, and variation is seen in both the integration site(s) and in the number of copies or partial copies of the viral genome.

Associated Disorders

Hepatitis B infection is associated with several disorders characterized by immune complex deposition. These include polyarteritis nodosa, membranous nephropathy, and Gianotti-Crosti syndrome.

Polyarthritis Nodosa

• One form of polyarthritis nodosa (PAN) is the hepatitis B virus-associated polyarthritis nodosa (HBV-PAN). Its occurence is attributed to the deposition of auto-immune complexes with excess antigen in tissues such as the kidneys, joints, and GI tract. It can be characterized by:

• Renal involvement
• Renal vasculitis
• Rare relapses, never occurring after viral replication has stopped and seroconversion has occurred.

• Clinically, it may present with high fever, anemia, leucocytosis, arthralgia, arthritis, renal disease, hypertension, heart disease, gastrointestinal disease, skin manifestations, and neurologic abnormalities. The disorder has a highly variable prognosis with mortality rates reaching 40% within 3 years without appropriate therapy. The diagnosis may be established by angiography.
• GI tract involvement represents the greatest cause of death
• Vaccination and blood safety have decreased the incidence of HBV-PAN

Membranous glomerulonephritis

HBV-associated membranous glomerulonephritis is more common in children than in adults, where spontaneous remission is seen in up to 60% of patients within 1 year. Spontaneous resolution of HBV-related membranous nephropathy is not a common finding among adults, especially in patients living in endemic regions. These patients often develop complications related to overt nephrotic syndrome. Remission of membranous nephropathy is associated with clearance of the HBeAg from the serum.

Papular acrodermatitis of childhood (Gianotti-Crosti syndrome)

Gianotti-Crosti syndrome is a distinctive disease of childhood. Patients present with skin lesions, lentil-sized, flat, erythematous, and papular eruptions localized to the face and extremities and lasting 15 to 20 days. The disease is accompanied by generalized lymphadenopathy and hepatomegaly. It is associated with acute anicteric hepatitis B of ayw subtype.

Prognosis

• Acute hepatitis often lasts for 2-3 weeks. The liver usually returns to normal within 4-6 months in most infected patients.

• Almost all newborns and about 50% of children who are infected with hepatitis B develop chronic hepatitis. More than 95% of people who become infected as adults or older children will stage a full recovery and develop protective immunity to the virus. 30% for younger children, and about 5% of newborns that acquire the infection from their mother at birth will clear the infection.
• This population has a 40% lifetime risk of death from cirrhosis or hepatocellular carcinoma.

• People who have chronic hepatitis B can transmit the infection. They are considered carriers of the disease, even if they do not have any symptoms.

• In developing countries, most people with liver cancer die within months of diagnosis. In high-income countries, surgery and chemotherapy can prolong life for up to a few years.

• Hepatitis D (HDV) can occur only with a concomitant hepatitis B infection. Co-infection with hepatitis D increases the risk of liver cirrhosis and HCC.