Viral Hepatitis

No Results

No Results

processing….

Hepatitis, a general term referring to inflammation of the liver, may result from various causes, both infectious (ie, viral, bacterial, fungal, and parasitic organisms) and noninfectious (eg, alcohol, drugs, autoimmune diseases, and metabolic diseases); this article focuses on viral hepatitis, which accounts for more than 50% of cases of acute hepatitis in the United States, primarily in the emergency department setting.

In the United States, viral hepatitis is most commonly caused by hepatitis A virus (HAV), hepatitis B virus (HBV), and hepatitis C virus (HCV). These three viruses can all result in acute disease with symptoms of nausea, abdominal pain, fatigue, malaise, and jaundice. ^[1] Additionally, acute infection with HBV and HCV can lead to chronic infection. Patients who are chronically infected may go on to develop cirrhosis and hepatocellular carcinoma (HCC). ^[1] Furthermore, chronic hepatitis carriers remain infectious and may transmit the disease for many years. ^[2]

Other hepatotropic viruses known to cause hepatitis include hepatitis D virus (HDV) and hepatitis E virus (HEV). However, the term hepatotropic is itself a misnomer. Infections with hepatitis viruses, especially HBV and HBC, have been associated with a wide variety of extrahepatic manifestations. Infrequent causes of viral hepatitis include adenovirus, cytomegalovirus (CMV), Epstein-Barr virus (EBV) and, rarely, herpes simplex virus (HSV). Other pathogens (eg, virus SEN-V) may account for additional cases of non-A/non-E hepatitis.

The term viral hepatitis can describe either a clinical illness or the histologic findings associated with the disease. Acute infection with a hepatitis virus may result in conditions ranging from subclinical disease to self-limited symptomatic disease to fulminant hepatic failure. Adults with acute hepatitis A or B are usually symptomatic. Persons with acute hepatitis C may be either symptomatic or asymptomatic (ie, subclinical).

Typical symptoms of acute hepatitis are fatigue, anorexia, nausea, and vomiting. Very high aminotransferase values (>1000 U/L) and hyperbilirubinemia are often observed. Severe cases of acute hepatitis may progress rapidly to acute liver failure, marked by poor hepatic synthetic function. This is often defined as a prothrombin time (PT) of 16 seconds or an international normalized ratio (INR) of 1.5 in the absence of previous liver disease.

Fulminant hepatic failure (FHF) is defined as acute liver failure that is complicated by hepatic encephalopathy. In contrast to the encephalopathy associated with cirrhosis, the encephalopathy of FHF is attributed to increased permeability of the blood-brain barrier and to impaired osmoregulation in the brain, which leads to brain-cell swelling. The resulting brain edema is a potentially fatal complication of fulminant hepatic failure.

FHF may occur in as many as 1% of cases of acute hepatitis due to hepatitis A or B. Hepatitis E is a common cause in Asia; whether hepatitis C is a cause remains controversial. Although FHF may resolve, more than half of all cases result in death unless liver transplantation is performed in time.

Providing that acute viral hepatitis does not progress to FHF, many cases resolve over a period of days, weeks, or months. Acute HBV infection is generally considered resolved once an individual has developed antibodies to the hepatitis B surface antigen (anti-HBs) and has cleared hepatitis B surface antigen (HBsAg) from their serum. ^[3]  Alternatively, acute viral hepatitis may evolve into chronic hepatitis. HBV infection is considered to have progressed to chronic infection when HBsAg, hepatitis B e antigen (HBeAg), and high titers of hepatitis B viral DNA are found to persist in the serum for longer than 6 months. ^{[3, 4, 5]}  Hepatitis C infection is considered to have progressed to chronic infection when HCV RNA persists in the blood for longer than 6 months. ^{[6, 7]}  Hepatitis A and hepatitis E never progress to chronic hepatitis, either clinically or histologically.

The likelihood of progressing to chronic hepatitis B infection varies with the age at the time of infection. Chronic hepatitis B infection develops in up to 90% of individuals infected as neonates; however only 1-5% of individuals infected with HBV as adults develop chronic hepatitis B infection. ^[3] Chronic hepatitis C infection develops in 75-85% of patients infected with hepatitis C. ^[6] Individuals infected with HCV at a younger age are less likely to develop chronic hepatitis C infection. ^[6] Some patients with chronic hepatitis remain asymptomatic for their entire lives. Other patients report fatigue (ranging from mild to severe) and dyspepsia.

Individuals with chronic hepatitis B or hepatitis C infection may go on to develop cirrhosis, with histologic changes of severe fibrosis and nodular regeneration. In their study of serologic markers in patients with cirrhosis and hepatocellular carcinoma, Perz et al estimated that 57% of cirrhosis and 78% of hepatocellular carcinoma worldwide was attributable to chronic infection with either hepatitis B or C. ^[8]

Although some patients with cirrhosis are asymptomatic, others develop life-threatening complications. The clinical illnesses of chronic hepatitis and cirrhosis may take months, years, or decades to evolve.

The incubation period of hepatitis A virus (HAV) is 15-45 days (average, 4 weeks). The virus is excreted in stool during the first few weeks of infection, before the onset of symptoms. Young children who are infected with HAV usually remain asymptomatic. Acute hepatitis A is more severe and has higher mortality in adults than in children. The explanation for this is unknown.

Typical cases of acute HAV infection are marked by several weeks of malaise, anorexia, nausea, vomiting, and elevated aminotransferase levels. Jaundice develops in more severe cases. Some patients experience a cholestatic hepatitis, marked by the development of an elevated alkaline phosphatase (ALP) level, in contrast to the classic picture of elevated aminotransferase levels. Other patients may experience several relapses during the course of a year. Less than 1% of cases result in fulminant hepatic failure (FHF). HAV infection does not persist and does not lead to chronic hepatitis.

Hepatitis B virus (HBV) may be directly cytopathic to hepatocytes. However, immune system–mediated cytotoxicity plays a predominant role in causing liver damage. The immune assault is driven by human leukocyte antigen (HLA) class I–restricted CD8 cytotoxic T lymphocytes that recognize hepatitis B core antigen (HBcAg) and hepatitis B e antigen (HBeAg) on the cell membranes of infected hepatocytes.

Acute infection

The incubation period of HBV infection is 40-150 days (average, approximately 12 weeks). As with acute HAV infection, the clinical illness associated with acute HBV infection may range from mild disease to a disease as severe as FHF (< 1% of patients). After acute hepatitis resolves, 95% of adult patients and 5-10% of infected infants ultimately develop antibodies against hepatitis B surface antigen (HBsAg)—that is, anti-HBs—clear HBsAg (and HBV virions), and fully recover. About 5% of adult patients, 90% of infected infants, and 30-50% of children infected at age 1-5 years develop chronic infection. ^[9]

Some patients, particularly individuals who are infected as neonates or as young children, have elevated serum levels of HBV DNA and a positive blood test for the presence of HBeAg but have normal alanine aminotransferase (ALT) levels and show minimal histologic evidence of liver damage. These individuals are in the so-called “immune-tolerant phase” of disease. ^{[10, 11]}  Years later, some but not all of these individuals may enter the  “immune-active phase” of disease, in which the HBV DNA may remain elevated as the liver experiences active inflammation and fibrosis. An elevated ALT level is also noted during this period. Typically, the immune-active phase ends with the loss of HBeAg and the development of antibodies to HBeAg (anti-HBe). ^{[10, 11]}

Individuals who seroconvert from an HBeAg-positive state to an HBeAg-negative state may enter the “inactive carrier state” (previously known as the “healthy carrier state”). Such individuals are asymptomatic, have normal liver chemistry test results, and have normal or minimally abnormal liver biopsy results. Blood test evidence of HBV replication should be nonexistent or minimal, with a serum HBV DNA level in the range of 0 to 2000 IU/mL. ^{[10, 12]}

Inactive carriers remain infectious to others through parenteral or sexual transmission. Inactive carriers may ultimately develop anti-HBs and clear the virus. However, some inactive carriers develop chronic hepatitis, as determined by liver chemistry results, liver biopsy findings, and HBV DNA levels. Inactive carriers remain at risk for hepatocellular carcinoma (HCC), although the risk is low. At this point, no effective antiviral therapies are available for patients in an inactive carrier state.

Other patients who seroconvert may enter the “reactivation phase” of disease. These individuals remain HBeAg-negative but have serum HBV DNA levels higher than 2000 IU/mL and show evidence of active liver inflammation. These patients are said to have HBeAg-negative chronic hepatitis. ^[10]

Chronic infection

The 10-30% of HBsAg carriers who develop chronic hepatitis are often symptomatic. Fatigue is the most common symptom of chronic hepatitis B. Acute disease flares occasionally occur, with symptoms and signs similar to those of acute hepatitis. Extrahepatic manifestations of the disease (eg, polyarteritis nodosa, cryoglobulinemia, and glomerulonephritis) may develop. Chronic hepatitis B patients have abnormal liver chemistry results, blood test evidence of active HBV replication, and inflammatory or fibrotic activity on liver biopsy specimens (see the images below).

Patients with chronic hepatitis may be considered either HBeAg-positive or HBeAg-negative. In North America and Northern Europe, about 80% of chronic hepatitis B cases are HBeAg positive and 20% HBeAg negative. In Mediterranean countries and in some parts of Asia, 30-50% of cases are HBeAg positive and 50-80% HBeAg negative.

Patients with HBeAg-positive chronic hepatitis have signs of active viral replication, with an HBV DNA level greater than 2 × 10⁴ IU/mL. ^{[10, 12]} HBV DNA levels may be as high as 10¹¹ IU/mL.

Patients with HBeAg-negative chronic hepatitis were presumably infected with wild-type virus at some point. Over time, they acquired a mutation in either the precore or the core promoter region of the viral genome. In such patients with a precore mutant state, HBV continues to replicate, but HBeAg is not produced. Patients with a core mutant state appear to have downregulated HBeAg production. ^[13]

The vast majority of patients with HBeAg-negative chronic hepatitis B have a serum HBV DNA level greater than 2000 IU/mL. Typically, HBeAg-negative patients have lower HBV DNA levels than HBeAg-positive patients do. Commonly, the HBV DNA level is no higher than 2 × 10⁴ IU/mL. ^{[10, 12]}

HBV and HCC

An approximately 8-20% of untreated adults with chronic hepatitis B go on to develop cirrhosis within 5 years; of these individuals, 20% annually develop hepatic decompensation and 2-5% annually develop HCC (see the image below). ^{[5, 9]} ​ Globally, an estimated 30% of cases of cirrhosis and 45% of cases of HCC are attributed to HBV. ^[5] The incidence of HCC parallels the incidence of HBV infection in various countries around the world. Worldwide, up to 1 million cases of HCC are diagnosed each year. Most appear to be related to HBV infection.

In HBV-induced cirrhosis, as in cirrhosis due to other causes, hepatic inflammation and regeneration appear to stimulate mutational events and carcinogenesis. However, in HBV infection, in contrast to other liver diseases, the presence of cirrhosis is not a prerequisite for the development of HCC. The integration of HBV into the hepatocyte genome may lead to the activation of oncogenes or the inhibition of tumor suppressor genes. As an example, mutations or deletions of the p53 and RB tumor suppressor genes are seen in many cases of HCC. ^[14]

Multiple studies have demonstrated an association between elevated serum HBV DNA levels and an increased risk for the development of HCC. ^[15] Conversely, successful suppression of HBV infection by antiviral therapy can decrease the risk of developing HCC. ^{[16, 17]}

HCC is a treatable and potentially curable disease, whether the treatment entails tumor ablation (eg, with percutaneous injection of ethanol into the tumor), liver resection, or liver transplantation. The American Association for the Study of Liver Diseases (AASLD) and the World Health Organization (WHO) recommend screening for HBV-infected individuals who are at high risk for HCC, including men older than 40 years, individuals with HBV-induced cirrhosis, and persons with a family history of HCC. ^{[4, 5, 12]}

For these patients, ultrasonography of the liver and alpha-fetoprotein (AFP) testing every 6 months are recommended. No specific recommendations have been made for patients at low risk for HCC. Some clinicians recommend that low-risk patients (including inactive carriers) undergo only AFP and liver chemistry testing every 6 months. Other clinicians’ practice is to screen all chronic hepatitis B patients with ultrasonography and AFP testing every 6 months, with inactive carriers undergoing liver chemistry and AFP testing every 6 months; however, this is controversial.

HCV has a viral incubation period of approximately 8 weeks. Most cases of acute HCV infection are asymptomatic. Even when it is symptomatic, acute HCV infection tends to follow a mild course, with aminotransferase levels rarely higher than 1000 U/L. Whether acute HCV infection is a cause of FHF remains controversial.

Approximately 15-45% of patients acutely infected with HCV lose virologic markers for HCV. Thus, about 55-85% of newly infected patients remain viremic and may develop chronic liver disease. ^[18] In chronic hepatitis C, patients may or may not be symptomatic, with fatigue being the predominant reported symptom. Aminotransferase levels may range from reference values (< 40 U/L) to values as high as 300 U/L. However, no clear-cut association exists between aminotransferase levels and symptoms or risk of disease progression.

An estimated 15-30% of patients with chronic hepatitis C experience progression to cirrhosis. ^[18] This process may take decades. All patients who are newly diagnosed with well-compensated cirrhosis must be counseled regarding their risk of developing symptoms of liver failure (ie, decompensated cirrhosis). Only 30% of patients with well-compensated cirrhosis are anticipated to decompensate over a 10-year follow-up period.

Patients with HCV-induced cirrhosis are also at increased risk for the development of HCC (see the image below), especially in the setting of HBV coinfection. In the United States, HCC arises in 1-5% of patients with HCV-induced cirrhosis each year. ^[19] Accordingly, routine screening (eg, ultrasonography and AFP testing every 6 months) is recommended in patients with HCV-induced cirrhosis to rule out the development of HCC. ^{[7, 20]}  Nearly 20,000 deaths each year are attributable to HCV as an underlying or contributing cause of death. ^[19]

Simultaneous introduction of HBV and HDV into a patient results in the same clinical picture as acute infection with HBV alone. The resulting acute hepatitis may be mild or severe. Similarly, the risk of developing chronic HBV and HDV infection after acute exposure to both viruses is the same as the rate of developing chronic HBV infection after acute exposure to HBV (approximately 5% in adults ^[5] ). However, chronic HBV and HDV disease tends to progress more rapidly to cirrhosis than chronic HBV infection alone does. ^[5]  

Introduction of HDV into an individual already infected with HBV may have dramatic consequences. Superinfection may give HBsAg-positive patients the appearance of a sudden worsening or flare of hepatitis B. HDV superinfection may result in FHF. ^[5]

HEV has an incubation period of 2-10 weeks. ^[21] Acute HEV infection is generally less severe than acute HBV infection and is characterized by fluctuating aminotransferase levels. However, pregnant women, especially when infected during the third trimester, have a greater than 25% risk of mortality associated with acute HEV infection. ^[22] In a number of cases, FHF caused by HEV has necessitated liver transplantation.

Traditionally, HEV was not believed to cause chronic liver disease. However, several reports have described chronic hepatitis due to HEV in organ transplant recipients. ^[23] Liver histology revealed dense lymphocytic portal infiltrates with interface hepatitis, similar to the findings seen with hepatitis C infection. Some cases have progressed to cirrhosis. ^{[24, 25]}

Hepatitis viruses A, B, C, D (HAV, HBV, HCV, HDV [which requires coexisting HBV infection]), and E (HEV) cause the majority of clinical cases of viral hepatitis. Whether hepatitis G virus (HGV) is pathogenic in humans remains unclear. HAV, HBV, HCV, and HDV are the only hepatitis viruses endemic to the United States; HAV, HBV, and HCV are responsible for more than 90% of US cases of acute viral hepatitis. Whereas HAV and HBV are the most common causes of acute hepatitis in the United States, HCV is the most common cause of chronic hepatitis. ^[26]

The following are typical patterns by which hepatitis viruses are transmitted, with + symbols indicating the frequency of transmission (ie, more + symbols indicate increased frequency).

Fecal-oral transmission frequency is as follows:

HAV (+++)

HEV (+++)

Parenteral transmission frequency is as follows:

HBV (+++)

HCV (+++)

HDV (++)

HGV (++)

HAV (+)

Sexual transmission frequency is as follows:

HBV (+++)

HDV (++)

HCV (+)

Perinatal transmission frequency is as follows:

HBV (+++)

HCV (+)

HDV (+)

Sporadic (unknown) transmission frequency is as follows:

HBV (+)

HCV (+)

HAV (see the image below), a member of the Picornaviridae family, is an RNA virus with a size of 7.5 kb and a diameter of 27 nm. It has one serotype but multiple genotypes. Classic findings of acute HAV infection include a mononuclear cell infiltrate, interface hepatitis, focal hepatocyte dropout, ballooning degeneration, and acidophilic (Councilman-like) bodies. HAV is present in the highest concentration in the feces of infected individuals; the greatest fecal viral load tends to occur near the end of the HAV incubation period.

Most commonly, the virus spreads from person to person via the fecal-oral route. Contaminated water and food, including shellfish collected from sewage-contaminated water, have also resulted in epidemics of HAV infection. The virus may also be spread through sexual (anal-oral) contact. ^[27]  Transmission by blood transfusion is rare. Maternal-neonatal transmission has not been established.

Although HAV infection occurs throughout the world, the risk is highest in developing countries, areas of low socioeconomic status, and regions without sufficient sanitation. Higher infection rates also exist in settings where fecal-oral spread is likely, such as daycare centers. ^[28]

Other groups at high risk for HAV infection include international travelers, users of injection and noninjection drugs, and men who have sex with men. ^[27] International travel is the most frequently identified risk factor reported by case patients in the United States. ^[29] Close contacts of infected individuals are also at risk. ^[27] The secondary infection rate for hepatitis A virus in household contacts of patients with acute HAV infection is around 20%. Thus, secondary infection plays a significant role in the maintenance of HAV outbreaks.

HBV, a member of the Hepadnaviridae family, is a 3.2-kb partially doubled-stranded DNA virus. The positive strand is incomplete. The complete negative strand has four overlapping genes, as follows:

Gene S codes for hepatitis B surface antigen (HBsAg), a viral surface polypeptide

Gene C codes for hepatitis B core antigen (HBcAg), the nucleocapsid protein; it also codes for hepatitis B e antigen (HBeAg), whose function is unknown

Gene P codes for a DNA polymerase that has reverse transcriptase activity

Gene X codes for the X protein that has transcription-regulating activity

The viral core particle consists of a nucleocapsid, HBcAg, which surrounds HBV DNA, and DNA polymerase. The nucleocapsid is coated with HBsAg. The intact HBV virion is known as the Dane particle. Dane particles and spheres and tubules containing only HBsAg are found in the blood of infected patients. In contrast, HBcAg is not detected in the circulation. It can be identified by immunohistochemical staining of infected liver tissue.

HBV is known to have eight genotypic variants (genotypes A-H). Although preliminary studies suggest that particular HBV genotypes may predict the virus’s response to therapy or may be associated with more aggressive disease, it would be premature to incorporate HBV genotype testing into clinical practice on a routine basis.

HBV is readily detected in serum, and it is seen at very low levels in semen, vaginal mucus, saliva, and tears. The virus is not detected in urine, stool, or sweat. HBV can survive storage at –20°C (–4°F) and heating at 60°C (140°F) for 4 hours. It is inactivated by heating at 100°C (212°F) for 10 minutes or by washing with sodium hypochlorite (bleach).

The major reservoir of HBV in the United States consists of the 850,000 to 2.2 million people with chronic HBV infection. ^[26] In this group, those with HBeAg in their serum tend to have higher viral titers and thus greater infectivity.

HBV is transmitted both parenterally and sexually, most often by mucous membrane exposure or percutaneous exposure to infectious body fluids. Saliva, serum, and semen all have been determined to be infectious. ^{[26, 30]} Percutaneous exposures leading to the transmission of HBV include transfusion of blood or blood products, injection drug use with shared needles, hemodialysis, and needlesticks (or other wounds caused by sharp implements) in healthcare workers. ^{[26, 30]}

Globally and in the United States, perinatal transmission is one of the major modes of HBV transmission. The greatest risk of perinatal transmission occurs in infants of HBeAg-positive women. By age 6 months, these children have a 70-90% risk of infection, and of those who become infected, about 90% will go on to develop chronic infection with HBV. ^[9]

For infants born to HBeAg-negative women, the risk of infection is approximately 10-40%, with a chronic infection rate of 40-70%. Even if transmission does not occur in the perinatal period, these children are still at significant risk for the development of infection during early childhood.

Groups at high risk for HBV infection include intravenous (IV) drug users, persons born in endemic areas, and men who have sex with men. ^{[26, 30]}  Others at risk include healthcare workers exposed to infected blood or bodily fluids, recipients of multiple blood transfusions, patients undergoing hemodialysis, heterosexual persons with multiple partners or a history of sexually transmitted disease, institutionalized persons (eg, prisoners), and household contacts or sexual partners of HBV carriers. ^{[26, 30]}

HCV, a member of the Flaviviridae family, is a 9.4-kb RNA virus with a diameter of 55 nm. It has one serotype, but at least six major genotypes and more than 80 subtypes are described, with as little as 55% genetic sequence homology. Genotype 1b is the genotype most commonly seen in the United States, Europe, Japan, and Taiwan. Genotypes 1b and 1a (also common in the United States) are less responsive to interferon (IFN) therapy than other HCV genotypes are. The wide genetic variability of HCV hampers the efforts of scientists to design an effective anti-HCV vaccine.

HCV can be transmitted parenterally, perinatally, and sexually. Transmission occurs by percutaneous exposure to infected blood and plasma. ^{[18, 26]} The virus is transmitted most reliably through transfusion of infected blood or blood products, transplantation of organs from infected donors, and sharing of contaminated needles among IV drug users. ^{[18, 26]} Transmission by sexual activity and household contact occurs less frequently. Perinatal transmission occurs but is uncommon.

Genetic variations and HCV clearance

Genetic polymorphisms involving the IL28B gene have been found to affect the odds that HCV can be cleared in a given patient. The IL28B gene encodes IFN lambda-3. A single nucleotide polymorphism 3 kb upstream of the IL28B gene was associated with patients’ ability to clear HCV spontaneously.

In a study, about 53% of patients with the favorable C/C genotype and 23% of patients with the less favorable T/T genotype spontaneously cleared the virus. ^[31] Of the patients who were chronically infected with HCV, those with the C/C genotype were more likely to see viral eradication after treatment with pegylated IFN (Peg-IFN) plus ribavirin. ^[32]  In the same study, the C/C genotype was more common in persons of European ancestry than in those of African ancestry. In contrast, the T/T genotype was more common in persons of African ancestry. ^[31] These observations may help to explain why black individuals typically exhibit lower sustained virologic response (SVR) rates than white persons when treated with Peg-IFN plus ribavirin.

HDV, the single species in the Deltavirus genus, is a 1.7-kb single-stranded RNA virus. The viral particle is 36 nm in diameter and contains hepatitis D antigen (HDAg) and the RNA strand. It uses HBsAg as its envelope protein; thus, HBV coinfection is necessary for the packaging and release of HDV virions from infected hepatocytes.

Modes of transmission for HDV are similar to those for HBV. HDV is transmitted by exposure to infected blood and blood products. It can be transmitted percutaneously and sexually. ^[33] Perinatal transmission is rare.

HEV, the single species in the Hepevirus genus, is a 7.5-kb single-stranded RNA virus that is 32-34 nm in diameter. It is transmitted primarily via the fecal-oral route, with fecally contaminated water providing the most common means of transmission. ^{[21, 34]} Person-to-person transmission is rare, though maternal-neonatal transmission does occur. ^[34] Zoonotic spread is possible because some nonhuman primates (cows, pigs and wild boar, sheep, goats, rodents, deer) are susceptible to the disease. ^{[21, 35]}

Hepatitis G virus (HGV) (also known as human pegivirus [HPgV]) is similar to viruses in the Flaviviridae family, which includes HCV. ^[36]  (It is an RNA virus within the Pegivirus A species of the Flaviviridae family. ^[36] ) The HGV genome codes for 2900 amino acids. ^[34] The virus has 95% homology (at the amino acid level) with hepatitis GB virus C (HGBV-C) and 26% homology (at the amino acid level) with HCV.

Approximately 750 million people worldwide have HPgV viremia, with an estimated 1.5-2.5 billion people currently infected or with evidence of prior infection. ^[36] It can be transmitted through blood and blood products. ^[34] HGV coinfection is observed in 6% of chronic HBV infections and in 10% of chronic HCV infections. ^[34] About 75% of HPgV infections clear within 2 years of infection, and 25% persist. ^[36] HGV is associated with acute and chronic liver disease, but it has not been clearly implicated as an etiologic agent of hepatitis.

Other known viruses (eg, cytomegalovirus [CMV], Epstein-Barr virus [EBV], herpes simplex virus [HSV], and varicella-zoster virus [VZV]) may also cause inflammation of the liver, but they do not primarily target the liver.

The Centers for Disease Control and Prevention (CDC) conducts national surveillance for acute and chronic hepatitis infection. Data on chronic infections is limited because not all states report this information: For the year 2014, the CDC received reports on chronic hepatitis B virus (HBV) infection from 40 states and on chronic hepatitis C infection from 37 states. ^[9]  Additionally, the numbers of reported cases for acute and chronic hepatitis infection likely underestimate the true incidence of disease because most cases are asymptomatic.

Beginning in 2011, the CDC incorporated a new method for estimating the number of cases of hepatitis infection to better account for underreporting. ^[9]  In 2014, there were 1239 cases of hepatitis A virus (HAV) reported, ^[9]  which was significantly less than the 2979 cases of acute HAV infection reported in 2007. ^[1] Between 2011 and 2013, however, the number of reported hepatitis A cases increased, including a large hepatitis A outbreak in 2013 due to imported pomegranate seeds. ^{[9, 29]}  After adjusting for underreporting and under ascertainment, the CDC estimates that the actual number of new hepatitis A cases in 2014 was 2500. ^[9]

For HBV infection, rates of reported acute infections have been declining since 1990. ^[9] There were 2791 cases of acute infection in 2014, ^[9] as compared to 4519 cases of acute HBV infection reported in 2007. ^[1]  With correction for asymptomatic cases and underreporting, the true number of cases of acute hepatitis B infection in 2014 was estimated at 18,100. ^[9]  The incidence of childhood HBV infection is not well established, because more than 90% of such infections in children are asymptomatic.

The CDC estimates that approximately 850,000 to 2.2 million people in the U.S are chronically infected with HBV. ^{[9, 26]}  Over 70% of these infections occurred in foreign-born individuals, and over half of the chronic infections occurred in individuals identifying as Asian/Pacific Islanders. ^[9]

The annual number of reported cases of acute hepatitis C  increased steadily between 2010 and 2014. ^[9] There were  2194 case of acute hepatitis C infection reported in 2014; after adjusting for underreporting, the CDC estimates that there were 30,500 new infections in 2014. ^[19]  Approximately 2.7-3.9 million people In the United States have chronic hepatitis C. ^[19]

Globally, viral hepatitis was the seventh leading cause of death in 2013, up from the 10th leading cause in 1990. ^[37] Worldwide, HAV is responsible for an estimated 1.4 million infections annually. ^[38]  About 2 billion people in the world have evidence of past or current HBV infection, with 240 million chronic carriers of HBsAg. ^[5]  HBV, along with the associated infection by the hepatitis D virus, is one of the most common pathogens afflicting humans. ^[39] HBV leads to 650,000 deaths annually as a result of viral hepatitis–induced liver disease. ^[5]

The worldwide annual incidence of acute HCV infection is not easily estimated, because patients are often asymptomatic. An estimated 71 million people are chronically infected with HCV worldwide. ^[18]  About 55-85% of these people infected progress to chronic HCV infection, with a 15-30% risk of developing liver cirrhosis within two decades. ^[18]  China, the United States, and Russia have the largest populations of anti-HCV positive injection drug users (IDUs). It is estimated that 6.4 million IDUs worldwide are positive for antibody to hepatitis B core antigen (HBcAg) (anti-HBc), and 1.2 million are HBsAg-positive. ^[40]

HAV is transmitted commonly most via the fecal-oral route. Cases of transfusion-associated HAV or illness caused by inoculation are uncommon.

HAV infection is common in the less-developed nations of Africa, Asia, and Central and South America; the Middle East has a particularly high prevalence. Most patients in these regions are infected when they are young children. Uninfected adult travelers who visit these regions are at risk for infection.

Epidemics of HAV infection may be explained by person-to-person contact, such as occurs at institutions, or by exposure to a common source, such as consumption of contaminated water or food.

As sanitation has improved, the overall prevalence of hepatitis A in the United States and in other parts of the developed world has decreased to less than 50% of the population. Younger individuals in the United States are better protected from hepatitis A because of guidelines adopted in 2006 recommending universal vaccination of children aged 1 year and older. ^[9]  Unfortunately, many older individuals in the United States still remain at risk.

Infection with HBV is defined by the presence of hepatitis B surface antigen (HBsAg). Approximately 90-95% of neonates with acute HBV infection and 5% of adults with acute infection develop chronic HBV infection. In the remaining patients, the infection clears, and these patients develop a lifelong immunity against repeated infections.

Of the approximately 5% of the world’s population (ie, 350 million people) that is chronically infected with HBV, about 20% will eventually develop HBV-related cirrhosis or hepatocellular carcinoma (HCC). According to the World Health Organization (WHO), HBV is the 10th leading cause of death worldwide. ^[41]

More than 10% of people living in sub-Saharan Africa and in East Asia are infected with HBV. Maintenance of a high HBsAg carriage rate in these parts of the world is partially explained by the high prevalence of perinatal transmission and by the low rate of HBV clearance by neonates.

In the United States, about 250-350 patients die of HBV-associated fulminant hepatic failure (FHF) each year. A pool of approximately 1.25 million chronic HBV carriers exists in the United States. Of these patients, 4000 die of HBV-induced cirrhosis each year, and 1000 die of HBV-induced HCC.

Perinatal transmission

The vast majority of HBV cases around the world result from perinatal transmission. Infection appears to occur during the intrapartum period or, rarely, in utero. Neonates infected via perinatal infection are usually asymptomatic. Although breast milk can contain HBV virions, the role of breastfeeding in transmission is unclear.

Sexual transmission

HBV is transmitted more easily than human immunodeficiency virus (HIV) or HCV. Infection is associated with vaginal intercourse, genital-rectal intercourse, and oral-genital intercourse. An estimated 30% of sexual partners of patients infected with HBV also contract HBV infection. However, HBV cannot be transmitted through kissing, hugging, or household contact (eg, sharing towels, eating utensils, or food). Sexual activity is estimated to account for as many as 50% of HBV cases in the US.

Parenteral transmission

HBV was once a common cause of posttransfusion hepatitis. Screening of US blood donors for anti-HBc, beginning in the early 1970s, dramatically reduced the rate of HBV infection associated with blood transfusion. According to the National Heart, Lung and Blood Institute, the risk that a blood donation is infected with hepatitis B is 1 in 205,000. ^[42]

Patients with hemophilia, those on renal dialysis, and those who have undergone organ transplantation remain at increased risk of HBV infection. IDU accounts for 20% of US cases of HBV. A history of HBV exposure is identified in approximately 50% of IDUs. The risk of acquiring HBV after a needle stick from an infected patient is estimated to be as high as 5%.

Healthcare associated 

Hepatitis B outbreaks have been associated with healthcare settings. Between 2008 and 2015, there were 23 outbreaks and 175 outbreak-associated cases of hepatitis B associated with healthcare settings reported in the United States. ^[43]  Outbreaks were reported in long-term care facilities and outpatient clinic settings. The CDC noted that these numbers likely underestimate the true incidence of healthcare-associated outbreaks because of the asymptomatic course of hepatitis B infection as well as the long incubation period. Additionally, there is no requirement to report these cases to the CDC if they have been investigated by state and local health authorities. ^[43]

Sporadic cases

In approximately 27% of cases, the cause of HBV infection is unknown. Some of these cases, in fact, may be due to sexual transmission or contact with blood.

HCV is the most frequent cause of parenteral non-A, non-B (NANB) hepatitis worldwide. Hepatitis C is prevalent in 0.5-2% of populations in nations around the world. The highest rates of disease prevalence are found in patients with hemophilia and in IDUs.

In the 1980s, as many as 180,000 new cases of HCV infection were described each year in the United States; by 1995, there were only 28,000 new cases each year. ^[44] The decreasing incidence of HCV was explained by a decline in the number of cases of transfusion-associated hepatitis (because of improved screening of blood products) and by a decline in the number of cases associated with IDU. New cases of hepatitis C infection tend to occur in individuals who are young and white, with a history of IDU and opioid use. ^[9]

Transmission via blood transfusion

Screening of the US blood supply has dramatically reduced the incidence of transfusion-associated HCV infection. ^{[19, 45]} Before 1990, 37-58% of cases of acute HCV infection (then known as NANB) were attributed to the transfusion of contaminated blood products; at present, only about 4% of acute cases are attributed to transfusions. The risk of having a blood donation infected with hepatitis C is 1 in 2 million. ^[42]  Acute hepatitis C remains an important issue in dialysis units, where patients’ risk for HCV infection is about 0.15% per year.

Transmission via intravenous and intranasal drug use

IDU remains an important mode of transmitting HCV. The use of intravenous (IV) drugs and the sharing of paraphernalia used in the intranasal snorting of cocaine and heroin account for approximately 60% of new cases of HCV infection. More than 90% of patients with a history of IDU have been exposed to HCV.

Transmission via occupational exposure

Occupational exposure to HCV accounts for approximately 4% of new infections. On average, the chance of acquiring HCV after a needle-stick injury involving an infected patient is 1.8% (range, 0-7%). Reports of HCV transmission from healthcare workers to patients are extremely uncommon.

Sexual transmission

Approximately 20% of cases of hepatitis C appear to be due to sexual contact. In contrast to hepatitis B, approximately 5% of the sexual partners of those infected with HCV contract hepatitis C.

The US Public Health Service (USPHS) recommends that persons infected with HCV be informed of the potential for sexual transmission. Sexual partners should be tested for the presence of antibodies to HCV (anti-HCV). Safe-sex precautions are recommended for patients with multiple sex partners. Current guidelines do not recommend the use of barrier precautions for patients with a steady sexual partner. However, patients should avoid sharing razors and toothbrushes with others. In addition, contact with patients’ blood should be avoided.

Perinatal transmission

Perinatal transmission of HCV occurs in 5.8% of infants born to mothers infected with HCV. ^[46]  The risk of perinatal transmission of HCV is higher (about 18%) in children born to mothers coinfected with human immunodeficiency virus (HIV) and HCV. ^[47] Between 2011 and 2014, the proportion of infants born to HCV-infected mothers increased by 68% nationally, indicating an increase in the number of infants who are at risk for vertical transmission of HCV. ^[46]

Healthcare associated

Hepatitis C outbreaks have been associated with healthcare settings. Between 2008 and 2015, there were 33 outbreaks and 239 outbreak-associated cases of hepatitis C associated with US healthcare settings reported. ^[43]  Outbreaks occurred in outpatient facilities and hemodialysis settings. ^[43]  The CDC noted that these numbers likely underestimate the true incidence of healthcare-associated outbreaks because of the asymptomatic course of hepatitis C infection and its long incubation period. Additionally, there is no requirement to report these cases to the CDC if they have been investigated by state and local health authorities. ^[43]

HDV requires the presence of HBV to replicate; thus, HDV infection develops only in patients who are positive for HBsAg. ^[48] Patients may acquire HDV as a coinfection (at the same time that they contract HBV), or the HDV may superinfect patients who are chronic HBV carriers. Hepatitis D is not a reportable disease in the United States, thus, accurate data regarding HDV infections are scarce. However, it is estimated that approximately 4-8% of cases of acute hepatitis B involve coinfection with HDV. ^{[49, 50, 51]}

HDV is believed to infect approximately 5% of the world’s HBsAg carriers (ie, about 15 million with chronic HBV/HDV). ^{[5, 33]} The prevalence of HDV infection in South America and Africa is high. Italy and Greece are well-studied areas of intermediate endemicity. Only about 1% of HBV-infected individuals in the United States and Northern Europe are coinfected with HDV.

The sharing of contaminated needles in IDU is thought to be the most common means of transmitting HDV. IDUs who are also positive for HBsAg have been found to have HDV prevalence rates ranging from 17% to 90%. Sexual transmission and perinatal transmission are also described. The prevalence of HDV in sex workers in Greece and Taiwan is high.

HEV is the primary cause of enterally transmitted NANB hepatitis. It is transmitted via the fecal-oral route and appears to be endemic in some parts of less-developed countries, where most outbreaks occur. HEV can also be transmitted vertically to the babies of HEV-infected mothers. It is associated with a high neonatal mortality. ^[52]

In one report, anti-HEV antibodies were found to be present in 29% of urban children and 24% of rural children in northern India. ^[53] Sporadic infections are observed in persons traveling from Western countries to these regions.

The prognosis of viral hepatitis varies, depending on the causative virus.

Hepatitis A virus (HAV) infection usually is mild and self-limited, and infection confers lifelong immunity against the virus. Overall mortality is approximately 0.02% ^[9] ; in general, children younger than 5 years and adults older than 50 years have the highest case-fatality rates. Older patients are at greater risk for severe disease: Whereas icteric disease occurs in fewer than 10% of children younger than 6 years, it occurs in 40-50% of older children and in 70-80% of adults with HAV. Three rare complications are relapsing hepatitis, cholestatic hepatitis, and fulminant hepatitic failure (FHF).

The risk of chronic HBV infection in infected older children and adults approaches 5-10%. Patients with such infection are at risk for cirrhosis and hepatocellular (HCC). FHF develops in 0.5-1% of patients infected with HBV; the case-fatality rate in these patients is 80%. Chronic HBV infection is responsible for approximately 5000 deaths per year from chronic liver disease in the United States.

Chronic infection develops in 50-60% of patients with hepatitis C. Chronically infected patients are at risk for chronic active hepatitis, cirrhosis, and HCC. In the United States, chronic HCV infection is the leading indication for liver transplantation. ^[19] In 2014, the number of HCV-related deaths rose to 19,659 from 15,106 in 2007, with over 50% occurring in people aged 55-64 years. ^[9]

Patients with chronic HBV infection who are coinfected with HDV also tend to develop chronic HDV infection. Chronic coinfection with HBV/HDV often leads to rapidly progressive subacute or chronic hepatitis, with as many as 70-80% of these patients eventually developing cirrhosis.

HEV infection is usually mild and self-limited. The case-fatality rate reaches 15-20% in pregnant women. HEV infection does not result in chronic disease.

In general, complications of viral hepatitis may include the following:

Acute or subacute hepatic necrosis

Chronic active hepatitis

Chronic hepatitis

Cirrhosis

Hepatic failure

Hepatocellular carcinoma (HCC) in patients with HBV or HCV infection

Hepatitis B

One of the major complications of hepatitis B is the development of chronic infection. An estimated 240 million people worldwide are chronically infected with HBV. ^[5]  In the United States, 850,000 to 2.2 million people are estimated to have chronic HBV infection. ^[26]  Patients with such infection are at risk for the subsequent development of chronic active hepatitis, cirrhosis of the liver, and eventual HCC. Each year, approximately 650,000 deaths occur worldwide as a result of chronic HBV infection. ^[5]

Patients infected at an early age are at greatest risk for chronic HBV infection: Whereas 90% of those infected at birth  and 30-50% of children infected at age 1-5 years develop chronic HBV infection, only 5% of older children or adults go on to develop chronic infection. ^[9]  The risk of chronic infection is also higher in patients who are immunocompromised.

Patients with chronic HBV infection are at significantly higher risk for HCC. In fact, HCC is the leading cause of cancer-related deaths in areas where HBV is endemic. Globally, HBV is responsible for 45% of the world’s primary liver cancers. ^[5]  Cancer in this setting is postulated to result from repeated bouts of chronic inflammation and cellular regeneration. HCC develops an average of 25-30 years after initial infection.

Another major complication of HBV infection is development of FHF. In approximately 0.5-1% of HBV-infected patients, the disease progresses to FHF, with coagulopathy, encephalopathy, and cerebral edema. The case-fatality rate for these patients approaches 80%. ^[2]

Hepatitis C

Acute infection with HCV may rarely cause FHF. ^[54]  Approximately 75-85% of patients with hepatitis C become chronically infected. ^[19] About 60-70% of patients will have ongoing chronic liver disease with laboratory evidence of fluctuating or persistently elevated liver enzymes. Of those with chronic infection, 5-20% may go on to develop cirrhosis. The progression from initial infection to the development of cirrhosis may take 20-30 years. ^[19]

Cirrhosis related to chronic HCV infection is also strongly linked to the development of HCC, which usually develops after 30 years in patients who are chronically infected. Of patients with HCV-associated cirrhosis, 20-25% may progress to liver failure and death. ^[54]  As noted earlier, in the United States, cirrhosis associated with chronic hepatitis C is a leading indication for liver transplantation. ^[19]

Extrahepatic complications of hepatitis C

Patients with chronic hepatitis C are also at risk for extrahepatic complications. In essential mixed cryoglobulinemia, HCV may form immune complexes with anti-HCV immunoglobulin G (IgG) and with rheumatoid factor (RF). The deposition of immune complexes may cause small-vessel damage. Complications of cryoglobulinemia include rash, vasculitis, and glomerulonephritis.

Other extrahepatic complications of HCV infection include focal lymphocytic sialadenitis, autoimmune thyroiditis, porphyria cutanea tarda, lichen planus, and Mooren corneal ulcer. Some cases of non-Hodgkin lymphoma can be attributed to HCV infection.

Refer patients with infectious hepatitis to their primary care providers for further counseling specific to their disease; the precise etiologic virus is unlikely to be known at the time of discharge from the emergency department.

Counsel patients regarding the importance of follow-up care to monitor for evidence of disease progression or development of complications. Remind them to exercise meticulous personal hygiene, including thorough hand washing. Instruct them not to share any articles that have the potential for contamination with blood, semen, or saliva, including needles, toothbrushes, or razors.

Inform food handlers suspected of having hepatitis A that they should not return to work until their primary care physician can confirm that they are no longer shedding the virus. Instruct patients to refrain from using any hepatotoxins, including ethanol and acetaminophen.

For patient education resources, see the Infections Center, the Digestive Disorders Center, and the Sexual Health Center, as well as Hepatitis A (HAV, Hep A); Hepatitis B (HBV, Hep B); Hepatitis C (Hep C, HCV); Cirrhosis; Childhood Immunization Schedule; and Immunization Schedule, Adults.

Wasley A, Grytdal S, Gallagher K, Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis–United States, 2006. MMWR Surveill Summ. 2008 Mar 21. 57 (2):1-24. [Medline].

Previsani N, Lavanchy D, World Health Organization. Hepatitis B (WHO/CDS/CSR/LYO/2002.2). 2002. [Full Text].

Fattovich G. Natural history of hepatitis B. J Hepatol. 2003. 39 suppl 1:S50-8. [Medline].

[Guideline] Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016 Jan. 63 (1):261-83. [Medline]. [Full Text].

[Guideline] World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. 2015 Mar. [Medline]. [Full Text].

Chen SL, Morgan TR. The natural history of hepatitis C virus (HCV) infection. Int J Med Sci. 2006. 3 (2):47-52. [Medline].

[Guideline] AASLD/IDSA HCV Guidance Panel. Hepatitis C guidance: AASLD-IDSA recommendations for testing, managing, and treating adults infected with hepatitis C virus (updated: April 12, 2017). Hepatology. 2015 Sep. 62 (3):932-54. [Medline]. [Full Text].

Perz JF, Armstrong GL, Farrington LA, Hutin YJ, Bell BP. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006 Oct. 45 (4):529-38. [Medline].

Centers for Disease Control and Prevention. Viral Hepatitis Surveillance United States, 2014 (revised: 9/26/16). Available at https://www.cdc.gov/hepatitis/statistics/2014surveillance/pdfs/2014hepsurveillancerpt.pdf. Accessed: June 12, 2017.

Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008 Dec. 6 (12):1315-41; quiz 1286. [Medline].

Sorrell MF, Belongia EA, Costa J, et al. National Institutes of Health consensus development conference statement: management of hepatitis B. Hepatology. 2009 May. 49 (5 suppl):S4-S12. [Medline].

[Guideline] Lok AS, McMahon BJ. AASLD practice guideline update: chronic hepatitis B: update 2009. Hepatology. 2009 Sep. 50 (3):661-2. [Medline].

Keeffe EB, Dieterich DT, Han SH, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States. Clin Gastroenterol Hepatol. 2004 Feb. 2 (2):87-106. [Medline].

Tabor E. The role of tumor suppressor genes in the development of hepatocellular carcinoma. In: Okuda K, Tabor E, eds. Liver Cancer. New York, NY: Churchill Livingstone; 1997. 89-95.

Chen CJ, Yang HI, Iloeje UH, for the REVEAL-HBV Study Group. Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology. 2009 May. 49 (5 suppl):S72-84. [Medline].

Liaw YF, Sung JJ, Chow WC, et al, for the Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med. 2004 Oct 7. 351 (15):1521-31. [Medline].

Di Marco V, Marzano A, Lampertico P, et al, for the Italian Association for the Study of the Liver (AISF) Lamivudine Study Group, Italy. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine. Hepatology. 2004 Oct. 40 (4):883-91. [Medline].

World Health Organization. Hepatitis C. Fact sheet no 164. Available at http://www.who.int/mediacentre/factsheets/fs164/en/. Updated: April 2017; Accessed: June 12, 2017.

Centers for Disease Control and Prevention. Viral hepatitis: hepatitis C FAQs for health professionals. Available at https://www.cdc.gov/hepatitis/hcv/hcvfaq.htm. Updated: January 27, 2017; Accessed: June 12, 2017.

[Guideline] World Health Organization. Guidelines for the screening care and treatment of persons with chronic hepatitis C infection: updated version (April 2016). 2016 Apr. [Medline]. [Full Text].

World Health Organization. Hepatitis E. Fact sheet no 280. Available at http://www.who.int/mediacentre/factsheets/fs280/en/. Updated: July 2016; Accessed: June 13, 2017.

Kumar A, Beniwal M, Kar P, Sharma JB, Murthy NS. Hepatitis E in pregnancy. Int J Gynaecol Obstet. 2004 Jun. 85 (3):240-4. [Medline].

Kamar N, Selves J, Mansuy JM, et al. Hepatitis E virus and chronic hepatitis in organ-transplant recipients. N Engl J Med. 2008 Feb 21. 358 (8):811-7. [Medline].

Gerolami R, Moal V, Colson P. Chronic hepatitis E with cirrhosis in a kidney-transplant recipient. N Engl J Med. 2008 Feb 21. 358 (8):859-60. [Medline].

Kamar N, Mansuy JM, Cointault O, et al. Hepatitis E virus-related cirrhosis in kidney- and kidney-pancreas-transplant recipients. Am J Transplant. 2008 Aug. 8 (8):1744-8. [Medline].

Centers for Disease Control and Prevention. Viral hepatitis. Available at https://www.cdc.gov/hepatitis/abc/index.htm. Updated: May 26, 2016; Accessed: June 13, 2017.

World Health Organization. Hepatitis A. Fact sheet no 328. Available at http://www.who.int/mediacentre/factsheets/fs328/en/. Updated: July 2016; Accessed: June 12, 2017.

Centers for Disease Control and Prevention. Hepatitis A questions and answers for health professionals. Available at https://www.cdc.gov/hepatitis/hav/havfaq.htm. Updated: July 13, 2016; Accessed: June 13, 2017.

Centers for Disease Control and Prevention. Surveillance for Viral Hepatitis – United States, 2015 (updated: May 11, 2017). Available at https://www.cdc.gov/hepatitis/statistics/2015surveillance/commentary.htm. Accessed: June 12, 2017.

World Health Organization. Hepatitis B. Fact sheet no 204. Available at http://www.who.int/mediacentre/factsheets/fs204/en/. Updated: April 2017; Accessed: June 12, 2017.

Thomas DL, Thio CL, Martin MP, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature. 2009 Oct 8. 461 (7265):798-801. [Medline]. [Full Text].

Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009 Sep 17. 461 (7262):399-401. [Medline].

World Health Organization. Hepatitis D. Fact sheet. Available at http://www.who.int/mediacentre/factsheets/hepatitis-d/en/. July 2016; Accessed: June 12, 2017.

Adhami T, Levinthal G. Hepatitis E and hepatitis G/GBV-C. The Cleveland Clinic Disease Management Project. May 29, 2002.

Previsani N, Lavanchy D, World Health Organization. Hepatitis E (WHO/CDS/CSR/EDC/2001.12.). 2001.

Chivero ET, Stapleton JT. Tropism of human pegivirus (formerly known as GB virus C/hepatitis G virus) and host immunomodulation: insights into a highly successful viral infection. J Gen Virol. 2015 Jul. 96 (pt 7):1521-32. [Medline].

Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016 Sep 10. 388 (10049):1081-8. [Medline].

World Health Organization. World hepatitis day: 28 July. Hepatitis A & E. Available at http://www.who.int/campaigns/hepatitis-day/2014/hepatitis-a-e.pdf?ua=1. 2014; Accessed: June 12, 2017.

Thomas E, Yoneda M, Schiff ER. Viral hepatitis: past and future of HBV and HDV. Cold Spring Harb Perspect Med. 2015 Feb 2. 5 (2):a021345. [Medline].

Nelson PK, Mathers BM, Cowie B, et al. Global epidemiology of hepatitis B and hepatitis C in people who inject drugs: results of systematic reviews. Lancet. 2011 Aug 13. 378 (9791):571-83. [Medline]. [Full Text].

Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat. 2004 Mar. 11 (2):97-107. [Medline].

National Heart, Lung, and Blood Institute. What are the risks of a blood transfusion?. Available at https://www.nhlbi.nih.gov/health/health-topics/topics/bt/risks. Updated: January 30, 2012; Accessed: June 12, 2017.

Centers for Disease Control and Prevention. Healthcare-associated hepatitis B and C outbreaks reported to the Centers for Disease Control and Prevention (CDC) 2008-2015 (updated: July 14, 2016). Available at https://www.cdc.gov/hepatitis/outbreaks/healthcarehepoutbreaktable.htm. Accessed: June 12, 2017.

Alter MJ. Epidemiology of hepatitis C. Hepatology. 1997 Sep. 26 (3 suppl 1):62S-65S. [Medline].

Krawitt EL. Autoimmune hepatitis: classification, heterogeneity, and treatment. Am J Med. 1994 Jan 17. 96 (1A):23S-26S. [Medline].

Koneru A, Nelson N, Hariri S, et al. Increased hepatitis C virus (HCV) detection in women of childbearing age and potential risk for vertical transmission – United States and Kentucky, 2011-2014. MMWR Morb Mortal Wkly Rep. 2016 Jul 22. 65 (28):705-10. [Medline].

Dienstag JL. Sexual and perinatal transmission of hepatitis C. Hepatology. 1997 Sep. 26 (3 suppl 1):66S-70S. [Medline].

Adhami T, Levinthal G. Hepatitis D. The Cleveland Clinic Disease Management Project. May 29, 2002.

Noureddin M, Gish R. Hepatitis delta: epidemiology, diagnosis and management 36 years after discovery. Curr Gastroenterol Rep. 2014 Jan. 16 (1):365. [Medline].

Kushner T, Serper M, Kaplan DE. Delta hepatitis within the Veterans Affairs medical system in the United States: Prevalence, risk factors, and outcomes. J Hepatol. 2015 Sep. 63 (3):586-92. [Medline].

Sultanik P, Pol S. Hepatitis delta virus: epidemiology, natural course and treatment. J Infect Dis Ther. 2016 Mar 3. 4(271):[Full Text].

Khuroo MS, Kamili S, Khuroo MS. Clinical course and duration of viremia in vertically transmitted hepatitis E virus (HEV) infection in babies born to HEV-infected mothers. J Viral Hepat. 2009 Jul. 16 (7):519-23. [Medline].

Mathur P, Arora NK, Panda SK, Kapoor SK, Jailkhani BL, Irshad M. Sero-epidemiology of hepatitis E virus (HEV) in urban and rural children of North India. Indian Pediatr. 2001 May. 38 (5):461-75. [Medline].

Previsani N, Lavanchy D, World Health Organization. Hepatitis C (WHO/CDS/CSR/LYO/2003). 2002.

Previsani N, Lavanchy D, World Health Organization. Hepatitis D (WHO/CDS/CSR/NCS/2001.1). 2001.

Smith BD, Morgan RL, Beckett GA, et al, for the Centers for Disease Control and Prevention. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945-1965. MMWR Recomm Rep. 2012 Aug 17. 61 (RR-4):1-32. [Medline]. [Full Text].

Waknine Y. FDA approves first rapid HCV test (June 25, 2010). Medscape News & Perspectives. Available at http://www.medscape.com/viewarticle/724236. June 28, 2010; Accessed: June 30, 2010.

Friedrich-Rust M, Ong MF, Martens S, et al. Performance of transient elastography for the staging of liver fibrosis: a meta-analysis. Gastroenterology. 2008 Apr. 134 (4):960-74. [Medline].

Bonder A, Afdhal N. Utilization of FibroScan in clinical practice. Curr Gastroenterol Rep. 2014 Feb. 16 (2):372. [Medline].

Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): where does it stand in the United States practice. Clin Gastroenterol Hepatol. 2015 Jan. 13 (1):27-36. [Medline].

Batts KP, Ludwig J. Chronic hepatitis. An update on terminology and reporting. Am J Surg Pathol. 1995 Dec. 19 (12):1409-17. [Medline].

Schmilovitz-Weiss H, Ben-Ari Z, Sikuler E, et al. Lamivudine treatment for acute severe hepatitis B: a pilot study. Liver Int. 2004 Dec. 24 (6):547-51. [Medline].

Fattovich G, Giustina G, Sanchez-Tapias J, et al. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP). Am J Gastroenterol. 1998 Jun. 93 (6):896-900. [Medline].

Janssen HL, van Zonneveld M, Senturk H, et al, for the HBV 99-01 Study Group, Rotterdam Foundation for Liver Research. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial. Lancet. 2005 Jan 8-14. 365 (9454):123-9. [Medline].

Lau GK, Piratvisuth T, Luo KX, et al, for the Peginterferon Alfa-2a HBeAg-Positive Chronic Hepatitis B Study Group. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B. N Engl J Med. 2005 Jun 30. 352 (26):2682-95. [Medline].

Marcellin P, Lau GK, Bonino F, et al, for the Peginterferon Alfa-2a HBeAg-Negative Chronic Hepatitis B Study Group. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004 Sep 16. 351 (12):1206-17. [Medline].

Dienstag JL. Benefits and risks of nucleoside analog therapy for hepatitis B. Hepatology. 2009 May. 49 (5 suppl):S112-21. [Medline].

Jaeckel E, Cornberg M, Wedemeyer H, et al, for the German Acute Hepatitis C Therapy Group. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001 Nov 15. 345 (20):1452-7. [Medline].

Nelson DR, Davis GL, Jacobson I, et al. Hepatitis C virus: a critical appraisal of approaches to therapy. Clin Gastroenterol Hepatol. 2009 Apr. 7 (4):397-414; quiz 366. [Medline].

Nishiguchi S, Kuroki T, Nakatani S, et al. Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet. 1995 Oct 21. 346 (8982):1051-5. [Medline].

Bruno S, Stroffolini T, Colombo M, et al, for the Italian Association of the Study of the Liver Disease (AISF). Sustained virological response to interferon-alpha is associated with improved outcome in HCV-related cirrhosis: a retrospective study. Hepatology. 2007 Mar. 45 (3):579-87. [Medline].

Poynard T, McHutchison J, Davis GL, et al. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C. Hepatology. 2000 Nov. 32(5):1131-7. [Medline].

Mallet V, Gilgenkrantz H, Serpaggi J, et al. Brief communication: the relationship of regression of cirrhosis to outcome in chronic hepatitis C. Ann Intern Med. 2008 Sep 16. 149 (6):399-403. [Medline].

McHutchison JG, Dusheiko G, Shiffman ML, et al, for the TPL102357 Study Group. Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med. 2007 Nov 29. 357 (22):2227-36. [Medline].

Centers for Disease Control and Prevention. HIV and viral hepatitis. Available at https://www.cdc.gov/hiv/pdf/library/factsheets/hiv-viral-hepatitis.pdf. June 2017; Accessed: June 13, 2017.

Curry MP. HIV and hepatitis C virus: special concerns for patients with cirrhosis. J Infect Dis. 2013 Mar. 207 suppl 1:S40-4. [Medline].

Torriani FJ, Rodriguez-Torres M, Rockstroh JK, et al, for the APRICOT Study Group. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med. 2004 Jul 29. 351 (5):438-50. [Medline].

Mindikoglu AL, Regev A, Magder LS. Impact of human immunodeficiency virus on survival after liver transplantation: analysis of United Network for Organ Sharing database. Transplantation. 2008 Feb 15. 85 (3):359-68. [Medline].

Erhardt A, Gerlich W, Starke C, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int. 2006 Sep. 26 (7):805-10. [Medline].

Niro GA, Ciancio A, Gaeta GB, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006 Sep. 44 (3):713-20. [Medline].

Lau DT, Doo E, Park Y, et al. Lamivudine for chronic delta hepatitis. Hepatology. 1999 Aug. 30 (2):546-9. [Medline].

Yurdaydin C, Bozkaya H, Onder FO, et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat. 2008 Apr. 15 (4):314-21. [Medline].

Fiore AE, Wasley A, Bell BP, for the Advisory Committee on Immunization Practices (ACIP). Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006 May 19. 55 (RR-7):1-23. [Medline].

Vento S, Garofano T, Renzini C, et al. Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med. 1998 Jan 29. 338 (5):286-90. [Medline].

Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2009*. Ann Intern Med. 2009 Jan 6. 150 (1):40-4. [Medline].

Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Update: Prevention of hepatitis A after exposure to hepatitis A virus and in international travelers. Updated recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep. 2007 Oct 19. 56 (41):1080-4. [Medline].

Centers for Disease Control and Prevention. Hepatitis B FAQs for health professionals. Available at https://www.cdc.gov/hepatitis/HBV/HBVfaq.htm#recctbl. Updated: August 4, 2016; Accessed: June 13, 2017.

Chang MH, Chen TH, Hsu HM, et al, for the Taiwan Childhood HCC Study Group. Prevention of hepatocellular carcinoma by universal vaccination against hepatitis B virus: the effect and problems. Clin Cancer Res. 2005 Nov 1. 11 (21):7953-7. [Medline].

Bica I, McGovern B, Dhar R, et al. Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis. 2001 Feb 1. 32 (3):492-7. [Medline].

Brown RS Jr, McMahon BJ, Lok AS, et al. Antiviral therapy in chronic hepatitis B viral infection during pregnancy: A systematic review and meta-analysis. Hepatology. 2016 Jan. 63 (1):319-33. [Medline].

Test

CHB HBeAg Positive

CHB HBeAg Negative

Inactive Carrier

HBsAg

+

+

+

Anti-HBs

–

–

–

HBeAg

+

–

–

Anti-HBe

–

+

+

Anti-HBc

+

+

+

IgM anti-HBc

–

–

–

HBV DNA

>2 × 10⁴ IU/mL*

(>10⁵ copies/mL)

>2 × 10³ IU/mL

(>10⁴ copies/mL)

< 2 × 10³ IU/mL

(< 10⁴ copies/mL)

ALT level

Elevated

Elevated

Normal

ALT = alanine aminotransferase; anti-HBc = antibody to hepatitis B core antigen; anti-HBe = antibody to HBeAg; anti-HBs = antibody to HBsAg; CHB = chronic hepatitis B; HBV = hepatitis B virus; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; IgM = immunoglobulin M.

*Increasingly, experts in the field use IU/mL rather than copies/mL.

Grade

Portal Inflammation

Interface Hepatitis

Lobular Necrosis

1 – Minimal

Mild

Scant

None

2 – Mild

Mild

Mild

Scant

3 – Moderate

Moderate

Moderate

Spotty

4 – Severe

Marked

Marked

Confluent

Naga Swetha Samji, MD Physician, Bellin Clinic, Bellin Health Systems

Naga Swetha Samji, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, Wisconsin Medical Society

Disclosure: Nothing to disclose.

Adrienne M Buggs, MD, FACEP, FAAEM Medical Policy Advisor, Office of Merchant Mariner Credentialing, United States Coast Guard

Adrienne M Buggs, MD, FACEP, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American College of Emergency Physicians, American College of Occupational and Environmental Medicine

Disclosure: Nothing to disclose.

Praveen K Roy, MD, AGAF Chief of Gastroenterology, Presbyterian Hospital; Medical Director of Endoscopy, Presbyterian Medical Group; Adjunct Associate Research Scientist, Lovelace Respiratory Research Institute; Clinical Assistant Professor of Medicine, University of New Mexico School of Medicine

Praveen K Roy, MD, AGAF is a member of the following medical societies: American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Eugene Hardin, FAAEM, FACEP Former Chair and Associate Professor, Department of Emergency Medicine, Charles Drew University of Medicine and Science; Former Chair, Department of Emergency Medicine, Martin Luther King Jr/Drew Medical Center

Disclosure: Nothing to disclose.

Douglas M Heuman, MD, FACP, FACG, AGAF Chief of GI, Hepatology, and Nutrition at North Shore University Hospital/Long Island Jewish Medical Center; Professor, Department of Medicine, Hofstra North Shore-LIJ School of Medicine

Douglas M Heuman, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Physicians, and American Gastroenterological Association

Disclosure: Novartis Grant/research funds Other; Bayer Grant/research funds Other; Otsuka Grant/research funds None; Bristol Myers Squibb Grant/research funds Other; Scynexis None None; Salix Grant/research funds Other; MannKind Other

Julian Katz, MD Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

Joseph K Lim, MD Associate Professor of Medicine, Director, Yale Viral Hepatitis Program, Section of Digestive Diseases, Yale University School of Medicine

Joseph K Lim, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Robert M McNamara, MD, FAAEM Chair and Professor, Department of Emergency Medicine, Temple University School of Medicine

Robert M McNamara, MD, FAAEM is a member of the following medical societies: American Academy of Emergency Medicine, American Medical Association, Pennsylvania Medical Society, and Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Sandeep Mukherjee, MB, BCh, MPH, FRCPC Associate Professor, Department of Internal Medicine, Section of Gastroenterology and Hepatology, University of Nebraska Medical Center; Consulting Staff, Section of Gastroenterology and Hepatology, Veteran Affairs Medical Center

Sandeep Mukherjee, MB, BCh, MPH, FRCPC is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada

Disclosure: Merck Honoraria Speaking and teaching; Ikaria Pharmaceuticals Honoraria Board membership

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajeev Vasudeva, MD, FACG Clinical Professor of Medicine, Consultants in Gastroenterology, University of South Carolina School of Medicine

Rajeev Vasudeva, MD, FACG is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, Columbia Medical Society, South Carolina Gastroenterology Association, and South Carolina Medical Association

Disclosure: Pricara Honoraria Speaking and teaching; UCB Consulting fee Consulting

David C Wolf, MD, FACP, FACG, AGAF Medical Director of Liver Transplantation, Westchester Medical Center; Professor of Clinical Medicine, Division of Gastroenterology and Hepatobiliary Diseases, Department of Medicine, New York Medical College

David C Wolf, MD, FACP, FACG, AGAF is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, and American Gastroenterological Association

Disclosure: Nothing to disclose.

Viral Hepatitis

Research & References of Viral Hepatitis|A&C Accounting And Tax Services
Source

Share on Facebook

Tweet

Follow us