Hepatitis B

Hepatitis B virus (HBV) is a common viral infection worldwide and can be transmitted sexually, parenterally, or perinatally. After an incubation period of 1–6 months, most patients present with an asymptomatic or mild inflammation of the liver, which usually resolves spontaneously within a few weeks or months. However, 5% of all adult patients and 90% of infants born to a hepatitis B-positive mother develop chronic hepatitis. Chronically infected individuals may be either asymptomatic carriers or exhibit ongoing hepatic inflammation with an increased risk of liver cirrhosis and hepatocellular carcinoma. Serologic testing, which is decisive for diagnosing HBV, initially involves measurement of HBs antigen. An increase in serum anti‑HBs (also known as seroconversion) is a sign of recovery or successful immunization. Chronic hepatitis is indicated by persistently elevated HBs antigen levels, as well as high HBV DNA and transaminase levels in cases of persistent liver inflammation. Treatment of acute hepatitis B consists of supportive measures. In the case of fulminant hepatitis, liver transplantation may be necessary. For chronic hepatitis B, pegylated interferon alpha and nucleoside/nucleotide analogs (e.g., tenofovir) are used to reduce viral replication and infectivity. Prophylactic immunization with a recombinant vaccine is recommended for all age groups. Other preventative measures include post-exposure prophylaxis for newborns of hepatitis B-positive mothers and unvaccinated individuals with recent exposure to those who are hepatitis B-positive.

• More than 248 million people worldwide are chronically infected.
• ∼ 600,000 deaths annually from HBV-related liver disease
• High prevalence in Asia, Africa, and the Amazon basin
• United States
  • In 2014, there were 20,000 new hepatitis B infections and ∼ 2 million people with chronic hepatitis B.
  • Acute hepatitis B has declined by ∼ 82% after the introduction of the hepatitis B vaccine in 1991.

References:^[1][2][3][4]

Epidemiological data refers to the US, unless otherwise specified.

Virus

• Hepatitis B virus (HBV: DNA virus, hepadnavirus)

Transmission

The frequency and patterns of transmission vary worldwide.

1. Sexual
2. Parenteral
   • Needlestick injury
   • Contaminated instruments and shared needles
   • Contaminated blood products
3. Perinatal

High-risk groups for HBV infection

• IV drug users
• Individuals whose close contacts have chronic HBV infection
• Infants of HBV-positive mothers
• Professions with exposure to human blood and/or seminal/vaginal fluids
• Individuals with multiple sex partners or sex partners of HBV-positive people
• Patients undergoing hemodialysis; organ or blood transfusion recipients
• Hepatitis C virus (HCV) or HIV-positive individuals

Individuals whose medical history indicates a high risk for HBV infection should be tested!

References:^[5][6][7][8]

Acute infection

Hepatocytes infected by the hepatitis B virus express viral peptides on their surfaces → lymphocytes recognize HBV-derived peptides and become activated (CD8+ cytotoxic T cells) → lymphocytes attack liver cells (cellular immune response) → hepatic inflammation with destruction of hepatocytes

• Replication cycle
  1. After entering the host cell's nucleus, the viral polymerase completes the positive strand of the virus' partially double-stranded relaxed circular DNA (rcDNA).
  2. The rcDNA is converted to covalently closed circular DNA (cccDNA) primarily by host enzymes in a process that is not entirely understood.
  3. The cccDNA is then transcribed into viral mRNA by host RNA polymerase.
  4. The viral mRNA leaves the nucleus and is translated into HBV core proteins and reverse transcriptase in the cytoplasm.
  5. Viral mRNA and reverse transcriptase are packaged into a capsid, where viral mRNA is then reverse-transcribed into viral rcDNA.
  6. New viral DNA genomes are enveloped and leave the cell as progeny virions.

Chronic infection

If clearance of the virus fails

• Persistent hepatic inflammation with necrosis, mitosis, and regeneration processes → cirrhosis, cellular dysplasia → HCC
• Integration of HBV DNA into the host genome → altered expression of endogenous genes, chromosomal instability → HCC

References:^{[9][10][11][12]}

Incubation period

• 1–6 months

Acute infection

Acute HBV infections are defined as infections that were acquired in the past 6 months.

• Serum sickness-like syndrome can develop during the prodromal (preicteric) period; : rash, polyarthritis, fever
• Subclinical hepatitis (70% of cases)
• Symptomatic hepatitis (30% of cases; see also acute viral hepatitis)
  • Fever, skin rash, arthralgias, myalgias, fatigue
  • Nausea
  • Jaundice
  • Right upper quadrant pain
  • Symptoms usually resolve after 1–3 months
• Fulminant hepatitis (∼ 0.5% of cases)
• Most adults will clear infection

Recovery rates in adults are very good, with less than 5% of cases progressing to chronic infections. In contrast, the risk of developing chronic hepatitis is considerably higher in infants infected perinatally (90%) and young children (20–50%)!

Chronic infection

Chronic HBV infections are defined as infections persisting for more than 6 months with detection of HBsAg and possibly symptoms of liver damage.

• Most patients are inactive, non-contagious carriers.
• Potential reactivation of chronic inactive hepatitis: may be asymptomatic , imitate acute hepatitis, or result in hepatic failure
• Cirrhosis, stigmata of chronic liver disease (25% of cases)
• Extrahepatic manifestations (10–20% of cases)
  • Polyarteritis nodosa
  • Membranous glomerulonephritis

References:^{[13][7][14][15][16]}

Diagnostically relevant virus antigens, DNA, and antibodies

HBV antigen/DNA		Description	Corresponding antibodies
HBsAg	Hepatitis B surface antigen	Protein on the surface of HBV; first evidence of infection	Anti-HBs Indicates immunity to HBV due to vaccination or resolved infection Usually appears 1–3 months after infection.
HBcAg	Hepatitis B core antigen	Protein of the nucleocapsid	Anti‑HBc Anti-HBC IgM indicates recent infection with HBV (≤ 6 months) Anti-HBc IgG indicates resolved or chronic infections
HBeAg	Hepatitis B envelope antigen	Protein secreted by the virus that indicates viral replication and infectivity	Anti‑HBe Indicates long-term clearance of HBV
HBV DNA		DNA of HBV

Hepatitis B serology

		HBsAg	Anti-HBs	HbeAg	Anti-HBe	Anti-HBc	HBV DNA	Transaminases
Acute infection		↑	∅	↑	∅	↑ IgM	∅–↑	↑ (ALT > AST)
“Window period”		∅	∅	∅	∅–↑	↑ IgM first, then IgG	∅–↑	↑ (ALT > AST)
Resolved prior infection		∅	↑	∅	↑	↑ IgG	∅	∅
Virus persistence (chronic infection)	Active chronic infection	↑	∅	↑	∅	↑ IgG	HBV DNA > 2000 IU/mL	Normal or ↑
	Inactive chronic infection	↑	∅	∅	↑	↑ IgG	HBV DNA ≤ 2000 IU/mL	Normal
Vaccination		∅	↑	∅	∅	∅	∅	∅

• Testing algorithm
  • Screening: HBsAg (detectable 1–5 months after infection) and anti‑HBc IgM
  • If HBsAg is positive → measure HBeAg and HBV DNA; ;
  • Seroconversion of HBsAg to anti‑HBs indicates acute hepatitis resolution.

Additional tests

• Laboratory studies
  • Transaminases (AST, ALT)
    • Acute hepatitis: ↑ with AST/ALT ratio of < 1 (> 1 in fulminant infection)
    • Chronic hepatitis: variable values (usually < 100 U/L;; in active infection > 100 U/L) with AST/ALT ratio of ≥ 1
  • ↑ γ‑GT, bilirubin, GLDH, and/or AP
  • In cirrhosis: ↓ albumin, CHE
• Abdominal ultrasound
  • Acute hepatitis
    • ↑ Brightness of portal vein radicle walls
    • ↓ Echogenicity of the liver
  • Chronic hepatitis
    • ↓ Brightness and number of portal vein radicle walls
    • ↑ Liver echogenicity
• Liver biopsy (see “Pathology” below)
• Test of common coinfections (e.g., hepatitis C/D, syphilis, HIV)

Seroconversion of HBsAg to anti‑HBs indicates immune clearance of HBV!

HBeAg indicates Infectivity due to viral Existence(/persistence)!
References:^{[17][3][10][15][16][18][19][20][21]}

Acute viral hepatitis

• Eosinophilic single-cell necrosis (Councilman body)
• Kupffer cell proliferation
• Bridging necrosis

Chronic viral hepatitis

• Formation of lymphoid follicles and mononuclear infiltrates
• Piecemeal necrosis: periportal liver cell necrosis with lymphocytic infiltration; ; indicates chronic active hepatitis and poor prognosis
• Fibrous septa
• Ground glass hepatocytes
  • Definition: Hepatocytes with swollen transparent cytoplasm due to hyperplasia of the endoplasmic reticulum.
  • Only in hepatitis B
  • Result from an increased production of viral membrane particles (HBsAg)

Ground glass hepatocytes are only present in HBV, while piecemeal necrosis, fibrous septa, and periportal infiltrates also occur in other types of chronic hepatitis!

References:^{[22][23][24][25][26]}

Diff:

References:^{[22][23][24][25][26]}

Differential diagnosis of viral hepatitis
Pathogen	Viral family	Transmission route	Incubation period (days)	Symptoms/Signs	Serological diagnosis	Treatment	Prevention	Complications
Hepatitis A virus (HAV)	Picornavirus Non-enveloped virus Positive sense, single-stranded, linear RNA	Fecal-oral	15–50	Acute hepatitis: fever, malaise, loss of appetite, nausea, abdominal pain, jaundice, ↑ AST/ALT Children < 6 years often have no symptoms	Anti-HAV IgM	Supportive	Food and water hygiene Immunization	Full recovery within ∼ 3 months Does not become chronic
Hepatitis B virus (HBV)	Hepadnavirus Enveloped virus Partially double-stranded, circular DNA	Parenteral, sexual, perinatal	30–180	Often asymptomatic Serum sickness-like reaction in prodrome phase Acute hepatitis (see above) Stigmata of cirrhosis in chronic cases	HBsAg Anti-HBc HBeAg	Acute: supportive Chronic: interferon-α or tenofovir	Safe sex; screening of blood products; use of sterile instruments and needles HBV vaccination, post-exposure prophylaxis	Fulminant hepatitis Chronic disease (possibly cirrhosis, HCC)
Hepatitis C virus (HCV)	Flavivirus Enveloped virus Positive sense, single-stranded, linear RNA	Parenteral (rarely sexual or perinatal)	14–180	Often asymptomatic Acute hepatitis (see above) Stigmata of cirrhosis in chronic cases	Anti-HCV IgM HCV RNA	Acute: interferon-α or peginterferon-α Chronic: interferon-α plus ribavirin or DAAs (cure possible) Liver transplantation	Use of sterile instruments and needles; safe sex No vaccination for HCV available	Chronic disease (possibly cirrhosis, HCC)
Hepatitis D virus (HDV)	Deltavirus Enveloped virus Negative sense, single-stranded, circular RNA	Always coinfection with HBV HDV is a defective virus that requires the HBsAg for entry into hepatocytes Parenteral (rarely sexual, perinatal)	Coinfection: 45–160 Superinfection: 14–56	Acute hepatitis (see above) Superinfection: worse prognosis (fulminant hepatic failure)	HDV-RNA Anti-HDV IgM	Peginterferon-α	Prevention of HBV infection (see “Prevention” below)	Fulminant hepatitis High risk of severe chronic liver disease
Hepatitis E virus (HEV)	Hepevirus Non-enveloped virus Positive sense, single-stranded, linear RNA	Fecal-oral	15–64	Similar to hepatitis A, often milder course	Anti-HEV IgM	Acute: supportive	Food and water hygiene	Fulminant hepatitis High mortality rate in pregnant women

Hepatitis viruses A and E usually only cause AcutE hepatitis!
References:^{[5][27][28][29][30][10][31][32][33]}

The differential diagnoses listed here are not exhaustive.

Acute hepatitis B

• Supportive care
• For treatment of acute liver failure, see “Complications” below

Chronic hepatitis B

• Antiviral treatment
  • Indication: chronic active hepatitis B (see “Diagnostics” above) with evidence of liver inflammation (ALT ≥ 2 times upper limit) or cirrhosis
  • Goals
    • Reduce HBV DNA below detectable levels
    • Seroconversion of HBeAg to anti‑HBe
    • Reverse liver disease
  • Nucleoside/nucleotide analogs : indicated for patients with both decompensated and compensated liver disease and nonresponders to interferon treatment
    • Tenofovir is commonly the drug of choice
    • Entecavir
  • Pegylated interferon alfa (PEG-IFN-a) : especially in younger patients with compensated liver disease
    • Regimen is shorter than nucleoside/nucleotide analogs
    • Contraindications
      • Decompensated cirrhosis
      • Psychiatric conditions
      • Pregnancy
      • Autoimmune conditions
      • Leukopenia or thrombocytopenia
  • Coinfection with HDV is best treated with PEG-IFN-a.
• Surgical treatment
  • Liver transplantation
    • In cases of end-stage liver disease due to HBV
    • In cases of fulminant hepatic failure (emergent transplantation)

References:^[10][34]

Hepatitis D virus infection

• Epidemiology: 5% of all chronically infected HBV patients are carriers of the hepatitis D virus.
• Pathogen: Hepatitis D virus (HDV)
  • Incomplete viral particle resembling a viroid
  • Defective single-stranded RNA virus
  • Utilizes the HBsAg coat of HBV for propagation
• Transmission: sexual, parenteral, perinatal (only possible in combination with HBV )
• Course
  • Coinfection: more severe acute hepatitis, but 90% rate of convalescence
  • Superinfection of a chronic HBsAg carrier: ↑ risk of liver cirrhosis
  • In rare cases, fulminant hepatitis

Acute liver failure

• Definition: rapidly worsening liver function resulting in coagulopathy and hepatic encephalopathy
  • Fulminant liver failure: onset of hepatic encephalopathy; within 8 weeks of initial symptoms (e.g., jaundice)
  • Subacute liver failure: onset within ≤ 26 weeks
• Etiology
  • Drugs/toxins
    • Acetaminophen toxicity (most common)
    • Phenytoin, halothane, isoniazid
    • Amanita phalloides
    • Aflatoxin
    • Further risk factors: alcohol, cocaine
  • Viral hepatitis: hepatitis A, B, E, or B + D, CMV
  • Vascular disorders: Budd-Chiari syndrome, ischemic hepatitis
  • Pregnancy-related: HELLP syndrome, acute fatty liver of pregnancy
  • Others: autoimmune hepatitis, Wilson's disease
• Clinical features
  • Jaundice
  • Signs of hepatic encephalopathy: altered mental state, asterixis
  • Symptoms of cerebral edema: nausea, vomiting, confusion
• Diagnostics
  • Laboratory findings: ↑ PT with INR ≥ 1.5, often ↑↑ ALT and AST, ↑ bilirubin level, and platelet count ≤ 150,000/mm³
  • Further diagnostics: depending on the suspected underlying cause
    • Viral serologies
    • Toxicology screening (e.g., acetaminophen level)
    • Autoimmune hepatitis serology
    • RUQ abdominal ultrasound
• Treatment
  • Early transfer to a liver transplant center
  • Intravenous N-acetylcysteine
  • Address/prevent complications: e.g., cerebral edema, encephalopathy, coagulopathy, renal failure, and infection
  • Address underlying cause: e.g., antiviral treatment for hepatitis B, steroids for autoimmune hepatitis, or delivery for HELLP syndrome
  • Liver transplantation is the only therapeutic option for patients without sufficient regeneration of hepatocytes.
• Prognosis: The mortality rate without liver transplantation ranges from 30% (acetaminophen toxicity) to 80% (non-acetaminophen-related liver failure).

Long-term complications of hepatitis B

• Liver cirrhosis
• Hepatocellular carcinoma (HCC)
• Reactivation of previous HBV infection due to immunosuppression

References:^{[5][35][36][37][38][39]}

We list the most important complications. The selection is not exhaustive.

• Pre-exposure vaccination: recommended for all unvaccinated individuals (see immunization schedule)
• Post-exposure prophylaxis (PEP) for hepatitis B
  • Goal: prevention of HBV infection
  • Indication: exposure to HBV (e.g., percutaneous, ocular, mucosal)
  • Administration
    • Documented vaccine responder with HBsIgG ≥ 10 mIU/mL: no intervention needed
    • Documented non-responder : Administer two doses of hepatitis B immune globulin (HBIG) separated by 1 month
    • Unvaccinated individuals or incompletely vaccinated: simultaneous administration of hepatitis B immune globulin (HBIG) and hepatitis B vaccine (see also perinatal hepatitis B) and completion of original vaccination series
    • Vaccinated with 3 doses of hepatitis B vaccine but postvaccination anti-HBs status is unknown or anti-HBs <10 mIU/mL:
      • 1 dose of HBIG and
        • Administration of 3 consecutive doses of the hepatitis B vaccine and retest of anti-HBs level or alternatively
        • Administration of 1 dose of the vaccine and retest for anti-HBs in 1-2 months and if needed 2 additional doses and then retest anti-HBs level.

References:^[40][41]

Perinatal hepatitis B

Whereas maternal hepatitis B; infections rarely cause fetal complications during pregnancy, the risk of perinatal transmission is high, especially if the maternal viral load is increased. If an infant becomes infected, the risk of developing chronic hepatitis is 90%.

• Maternal screening for HBsAg should be performed on all women at the first prenatal visit.
• Management for HBsAg-positive mothers
  • In mild disease and/or low HBV DNA levels, therapy may be delayed until after birth
  • In severe disease; (e.g., cirrhosis) and/or high HBV DNA, therapy with nucleoside/nucleotide analogs (especially tenofovir) is commonly recommended
  • Delivery: spontaneous vaginal delivery possible
• Newborn immunization: within 12 hours of birth (first dose of hepatitis B vaccine series plus 1 dose of HBIG)
• Breastfeeding: allowed as long as passive‑active postexposure prophylaxis was given
• Infected newborns:
  • Usually asymptomatic, but up to 90% risk developing chronic infection and significant risk of cirrhosis and progression to hepatocellular carcinoma if left untreated
  • Serum studies:
    • Normal or only slightly elevated transaminases
    • High viral replication rate

Interferon therapy is contraindicated during pregnancy!
References:^[42]