#94994: Viral Hepatitis

Hepatitis is an inflammatory state of the liver and may be caused by exposure to toxic chemicals, autoimmune disease, or infection. Many common viral infections in humans are associated with mild, usually transient, secondary inflammation of the liver. The term "viral hepatitis" is applied to infection caused by a set of viruses unique in their primary trophism for the liver and their propensity to cause serious, often prolonged "primary" hepatitis. For clinical purposes, the viruses causing primary hepatitis are grouped and classified alphabetically in accordance with when each was identified: hepatitis A, B, C, D, and E. In 1994, hepatitis F was identified as a cause of fulminant liver failure[1]. This was later found to be a variant subspecies of another virus. Therefore, "F" is now omitted in the hepatitis alphabet. A virus similar in structure to hepatitis C was initially designated hepatitis G; however, this virus has been reclassified as a Pegivirus GB virus-C (GBV-C) [2]. This virus can cause subclinical infection in humans but is not linked to active disease.

This course will provide information describing normal anatomy and physiology of the liver and the effects of acute and chronic inflammation on the liver structure and function. Diagnostic tests commonly used to assess liver function and as markers of liver disease are reviewed. An overview of the viruses now known to cause primary hepatitis is presented. The history, etiology, pathophysiology, and clinical presentation of each type of viral hepatitis will be discussed. Therapeutic options will be presented, and methods of preventing transmission of viral hepatitis will be delineated.

The liver is one of the largest organs in the body. The healthy adult liver typically weighs 1.3–1.8 kg and lies just under the diaphragm in the right upper quadrant of the abdomen, with its left lobe extending several centimeters past midline toward the spleen. At the mid-sternal line, the height of the liver is typically 4–8 cm, while at the right mid-clavicular line, it extends 6–12 cm. On inspiration, the edge of the liver may be just palpable in a healthy adult. Because downward displacement of the liver may occur in several conditions without true enlargement of the liver, percussion along with palpation should be used to estimate the size of the liver. Palpation should also be used to evaluate the consistency of the organ [3].

The liver is made up of small lobules. In the center of each lobule is a central vein. Extending from the vein, like the spokes of a wheel, are the hepatic sinusoids, which receive blood from the hepatic artery and the portal vein. Blood flows through these sinusoids and into the central vein. The blood from the central veins then flows into the hepatic vein.

The portal vein brings products of digestion from the intestines to the liver; in doing so, the blood in the portal vein may also contain small numbers of intestinal bacteria. The lining of the sinusoids consists of both epithelial cells, which permit transfer of nutrients, and Kupffer cells. The Kupffer cells are tissue macrophages—cells of the immune system that scavenge stray bacteria entering the liver through the portal circulation.

There are trapezoid-shaped structures between the sinusoid spokes that contain two columns of hepatic cells, sometimes referred to as the hepatic plate, between which lies the bile canaliculus. Bile canaliculi collect bile produced by the hepatic cells and form a conduit to the bile ducts, located in the fibrous tissue between lobules.

Surrounding the columns of hepatic cells is a narrow space entitled the space of Disse. Excess fluid collects in the space of Disse. These spaces connect to the lymphatic vessels, providing a mechanism for fluid removal from the liver.

The liver has many functions. Because of its vascular nature, the liver serves as a blood reservoir. Normally, the liver contains about 450 cc of blood. Because it is distensible, the liver can expand to accommodate up to a liter of extra blood, providing some compensation for fluid overload in conditions such as congestive heart failure or renal failure. Conversely, during hemorrhage or hypovolemic shock, the vessels in the liver respond to circulating vasoconstrictors (such as norepinephrine and angiotensin II), and blood is shunted from the liver into the general circulation.

The liver is responsible for a myriad of metabolic functions. In carbohydrate metabolism, the liver stores glycogen, converts fructose and galactose to glucose, performs gluconeogenesis (i.e., the conversion of constituent substances, such as fatty acids, into glucose), and forms enzymes and other chemicals from the intermediate products of glucose metabolism.

The liver metabolizes fats by oxidizing fatty acids to supply energy. It also synthesizes cholesterol, lipoproteins, and phospholipids. To enhance storage of nutrients, the liver converts excess ingested carbohydrates and protein to fat.

Protein metabolism is also a function of the liver. The liver modifies amino acids from the ingested proteins into a form that is usable by the body. The liver can also convert one amino acid into another in order to supply the body's needs. Urea formation by the liver facilitates the removal of nitrogenous wastes from the body. The liver is also responsible for monitoring plasma oncotic pressure and regulating the synthesis of albumin.

In addition to serving as a blood reservoir and coordinating metabolism, the liver has several other essential functions. The liver serves as a storage center for iron and vitamins A, D, and B12. At least one dozen substances necessary for normal blood coagulation are formed by the liver. Finally, the liver serves to detoxify the body of many drugs, hormones, and other substances, facilitating removal of these toxins in the urine or feces [4].

Chronic inflammation of the liver or injury from prolonged exposure to toxic substances leads to scarring, a replacement of the functioning lobules with fibrous tissue. This condition is commonly termed cirrhosis. Chronic inflammation and cirrhosis are carcinogenic and confer a substantial risk for the eventual development of hepatocellular cancer.

The role of laboratory tests in establishing a diagnosis of liver disease has gained increasing importance as newer methods of detection and analysis become available. Each of the types of viral hepatitis described in this course has specific tests for the virus and/or the antibody to the virus. The severity of the impact of these viruses upon the liver is measured by less specific tests of general liver function. Patterns of abnormality in liver function tests rather than specific values of a single test permit the clinician to interpret the functional status of the organ. In addition, it is important to note that diseases that are not hepatic in origin can produce abnormalities in liver function tests. These include, but are not limited to, hemolytic diseases, congestive heart failure, sepsis, and other disorders that alter liver perfusion.

Though viral hepatitis can occur without the presence of jaundice, this sign has historically been considered a diagnostic marker for hepatitis. Jaundice results from elevations in the serum bilirubin. The normal level for total serum bilirubin is ≤1.6 mg/dL. In order for clinical jaundice to become detectable, the total serum bilirubin must exceed 2.5 mg/dL. In most cases of viral hepatitis, the peak serum bilirubin does not exceed 10 mg/dL; levels higher than this are indicative of intra-hepatic cholestasis or extra-hepatic biliary obstruction (e.g., stone or tumor) [5].

Hepatic inflammation leads to excessive release of cellular enzymes into the circulation that serve as sensitive markers of hepatic injury and indicators of disease severity. Two such enzyme markers of liver injury used for clinical purposes are alanine aminotransferase (ALT), formerly known as serum glutamic pyruvic transaminase or SGPT, and aspartate aminotransferase (AST), formerly called serum glutamic-oxaloacetic transaminase or SGOT. Elevated serum levels are seen early in the course of viral hepatitis and in other forms of toxic liver injury, such as caused by alcohol, drugs (acetaminophen), and poisonings (carbon tetrachloride). Elevations in ALT and AST are also associated with centrilobular necrosis due to inadequate perfusion in shock states and in cases of biliary obstruction. The normal range for ALT is 7–56 Units/L; the normal range for AST is 5–40 Units/L [6]. There may be slight differences in normal values between men and women.

Albumin levels (normal range: 3.5–5.5 mg/dL) are typically decreased in hepatocellular disease such as hepatitis but are unchanged in uncomplicated obstructive liver disease. Alkaline phosphatase levels (normal range: 44–147 IU/L) remain in the normal range in hemolytic disease, are slightly elevated in hepatocellular disease, and are greatly increased in obstructive liver disease [7].

The presence and degree of liver scarring and cirrhosis are best determined by liver biopsy, though noninvasive imaging techniques are now available to assess this indirectly by measuring organ stiffness. The prothrombin time (PT), which is dependent on clotting factors produced in the liver, is a sensitive screening test for advanced liver disease (cirrhosis). Prolongation of the PT related to inadequate production of clotting factors begins to occur when 80% or more of the synthetic function of the liver has been lost.

Viruses are the cause of some of the earliest disease processes recorded in the medical literature. Though the natural history of diseases such as polio, rabies, measles, and smallpox had been described for millennia, the identification of a viral etiology was not made until the beginning of the 20th century. The knowledge of specific viruses, viral life cycle, and viral/host interaction increased dramatically over the next 50 years, leading to the development of vaccines. More recent techniques such as electron microscopy, electrophoresis, x-ray crystallography, and polymerase chain reaction have permitted in-depth studies of viral structure and more precise identification of the viruses that cause specific diseases [8].

Classification of viruses has changed as knowledge of them has increased. Initially, viruses were primarily classified by size, method of transmission, or organ affected in the disease process. Viruses are now classified in relation to the type of nucleic acid in the viral core, either ribonucleic acid (RNA) or deoxyribonucleic acid (DNA). Other determinants include the method of nucleic acid replication, the presence or absence of an envelope, and the symmetry of the viral capsid (protein coat).

The structure of viral core RNA or DNA consists of either a single strand or double strand of nucleic acid. These nucleic acid strands can be circular or linear. Viruses replicate nucleic acid in one of five different methods. Discussion of these complex methods of replication is beyond the scope of this course, but the method by which a virus replicates contributes to its classification.

In the majority of viruses, the nucleic acid is covered with a protein coat called a capsid. Most capsids are either shaped as a helical spiral or as an icosahedral sphere. Some virus capsids are enveloped in an outer lipid layer (the envelope) derived from the host cell.

Using this classification system, poliovirus is classified as a single-stranded RNA virus with an icosahedral capsid and no lipid envelope. Similarly, the herpes simplex virus is classified as a double-stranded DNA virus with an icosahedral capsid and a lipid envelope.

Viruses are unable to replicate outside the host. Therefore, in order to survive and multiply, the virus must interact with host cells in such a way as to "hijack" the cell's mechanism for nucleic acid replication. The first step of this process is attachment, which occurs when proteins on the surface of the virus attach to receptors on the surface of the host cell. After attachment has been accomplished, the virus penetrates the cell membrane. Within the cell, the virus undergoes a process of uncoating as the capsid is removed. After removal of the capsid, replication of the nucleic acid takes place. Next, the nucleic acid of the new viral particles is coated with a capsid. Finally, the new virus leaves the host cell, either through budding or through rupture of the host cell.

Viruses can be transmitted through inhalation of respiratory droplets, percutaneously, or via direct introduction into the gastrointestinal (GI), genitourinary (GU), or respiratory tract. The virus may cause a localized infection at the area of entrance or may travel through the blood stream, lymphatics, or nerve pathways to the target organ(s). In response to viral invasion, nonspecific defense mechanisms and a specific immune response are activated.

Because viruses are intracellular invaders, phagocytosis, the inflammatory response, and antigen/antibody reactions not only result in destruction of viral particles but also may injure or destroy host cells.

Documents from ancient China describe a contagious jaundice in which the victims experienced symptoms consistent with hepatitis A or E. In the fifth century B.C.E., epidemics of jaundice occurred in Greece and Rome. Outbreaks of jaundice associated with unsanitary conditions during wartime were reported in Europe during the 17th, 18th, and 19th centuries. Analysis of outbreaks of hepatitis during World War II supported the theory that some forms of jaundice resulted from unsanitary conditions while others seemed to be related to a shared percutaneous source of infection (contaminated needle, transfusion, or vaccine). Therefore, hepatitis was classified into two categories: infectious hepatitis and serum hepatitis [9,10].

The virus associated with hepatitis A was initially identified when viewed in an electron microscope in 1973. Since that time, the virus and the body's response to the virus have been extensively studied.

By law, diagnosed cases of HAV must be reported to the local health authorities, who in turn report the incidence to the Centers for Disease Control and Prevention (CDC). Many persons who contract HAV, however, do not have clinical symptoms. Therefore, the CDC must estimate the actual incidence of HAV infection based upon CDC reports and projections. For the 10-year period 1999 to 2009, the CDC estimates that 749,000 cases occurred within the United States [11].

Since the introduction of hepatitis A vaccine in 1995, the incidence of hepatitis A in the United States has declined by 95% [11]. However, after falling to a low of 1,239 cases reported in 2014, there was an 850% increase in incidence by 2018, reaching 12,474 reported cases, the highest number in more than a decade [12]. According to the CDC, the drastic increase in incidence between 2014 and 2018 was "primarily due to unprecedented person-to-person outbreaks reported in 24 states among people who use drugs and people experiencing homelessness" and foodborne transmission [12]. The World Health Organization (WHO) estimates the annual worldwide incidence to be 1.5 million per year [13].

As noted, hepatitis A is transmitted via the fecal-oral route, most commonly from contaminated water or food. After the virus is ingested, it is transported from the intestines to the liver, where it invades the hepatocytes. The virus uses the hepatocytes for viral replication and is then released into the bloodstream and excreted in the stool. The cellular immune system responds with infiltration of the liver by lymphocytes and cytokines. These lymphocytes are toxic to HAV-infected liver cells, thus producing the inflammatory damage to the liver. IgM antibody against HAV is produced, followed by IgG antibody. Levels of IgM antibody appear in the acute stage and decrease to undetectable levels over time. IgG antibody appears later and persists throughout life.

Signs and symptoms of hepatitis A infection can vary from subclinical disease to fulminant (sudden and intense) illness. In symptomatic patients, the incubation period (i.e., time from exposure to onset of illness) is in the range of 15 to 50 days (average: 28 days). Clinical symptoms and signs include nausea, vomiting, headache, fever, chills, abdominal discomfort, hepatomegaly, and right upper quadrant tenderness. For most patients, symptoms are mild and subside in three to seven days. Others will have more significant disease and will progress to an icteric phase (jaundice). For these patients, recovery typically occurs after about three weeks.

Fulminant infection occurs in less than 1% of the cases. Some of these patients may have such severe damage that they require a liver transplant. Fatalities from hepatitis A are extremely rare. There is no known chronic carrier state.

Laboratory studies reflect leukopenia, atypical lymphocytes, and elevated ALT and AST levels. As discussed, anti-HAV IgM can be detected early in the disease, usually appearing in detectable levels 2 to 3 weeks after exposure, then declining to undetectable levels in 12 to 24 weeks. IgG levels begin to rise three to four weeks after exposure and remain elevated throughout life.

Treatment of HAV is supportive and directed at maintaining adequate nutrition and controlling symptoms. Ingestion of alcohol and/or hepatotoxic medications is avoided. For patients with fulminant hepatic failure resulting from HAV, corticosteroids may be used. However, clinical research has not demonstrated improved outcomes in patients receiving corticosteroids when compared to those who did not receive steroid treatment [14].

Like hepatitis A, hepatitis E virus is spread through the fecal-oral route, and like HAV, HEV was also first identified via electron microscope examination of stools of infected patients. HEV has been associated with outbreaks in India, Burma, Pakistan, Russia, China, northern and central Africa, Peru, and Mexico. Outbreaks are usually associated with a contaminated water supply. No outbreaks have occurred in the United States or Western Europe, though individual cases have been identified in persons who have recently traveled to areas in which the virus is endemic [18,19].

HEV most often affects young adults. The incubation period is two to nine weeks, with an average of six weeks. Signs and symptoms are similar to HAV, but with a higher incidence of jaundice, which can be prolonged. The disease is self-limited in the majority of patients. The fatality rate in acute HEV is between 1% and 2%, except in pregnant women. In pregnant women with HEV infection, mortality can reach as high as 30% [19]. No cases of chronic liver disease associated with HEV have been reported.

The treatment of HEV is nonspecific and is directed toward supportive care. Because the incidence of HEV is low and most cases resolve without negative sequelae, the development of a vaccine against HEV has not been a priority for pharmaceutical companies or national and international health agencies. Primary preventive strategies, therefore, concentrate on improved sanitation [19,20].

The first documented outbreak of "serum hepatitis," as hepatitis B was originally termed, occurred in 1833 among shipyard workers in Bremen, Germany, who had received smallpox vaccine administered with contaminated needles [9]. Throughout the early part of the 20th century, clusters of cases were reported in venereal disease clinics and diabetic clinics in which reuse of contaminated needles and/or syringes had occurred.

In 1965, medical researcher Baruch Blumberg identified a specific antigen in the serum of an Australian Aborigine who had received numerous blood transfusions [18]. This "Australia antigen" was later found to be associated with hepatitis B; its discovery led to rapid advancement in the knowledge of HBV. This antigen has now been renamed the hepatitis B surface antigen (HBsAg). The virus, as well as the typical serologic response pattern of the host, has been extensively studied.

The hepatitis B virus is one of the smallest viruses known to cause disease in animals. Ten HBV genotypes have been identified; these have been labeled A through J [21]. The genotype of the virus influences the likelihood of developing cirrhosis and the response of the virus to therapy with interferon.

HBV consists of a core and an envelope. The envelope contains HBsAg proteins, glycoprotein, and lipids. The core of HBV includes viral DNA, enzymes necessary for replication, and antigenic protein particles distinctly different from those found in the envelope. The viral DNA is circular and predominantly double stranded, but with a single-stranded arc. The core antigen is termed HBcAg.

The virus is resistant to heat and cold and has been shown to survive for more than 15 years when frozen. However, infectivity is lost in albumin and serum after heating for 10 hours at 60°C or 20 minutes at 90°C, respectively. When dry heat is used, HBV is destroyed after one hour at 160°C [22].

Prior to the availability of hepatitis B immunization, 75,000 to 160,000 new cases of hepatitis B were acquired in the Unites States each year, with the highest incidence of new HBV cases being among persons 20 to 39 years of age. The rate of new HBV infections declined between 1990 and 2014, following the recommendation for routine vaccination of children. According to the CDC, only 2,157 cases of acute hepatitis B were reported in the United States during 2020, an incidence rate of 0.7 cases per 100,000 population. After adjusting for under-ascertainment and under-reporting, an estimated 14,000 cases of acute hepatitis B infection occurred in 2018 [23].

The natural history of HBV infection is variable and in large part dependent on age at onset. In general, 6% to 10% of persons newly infected will progress to a state of chronic persistent infection [24]. The rate of progression to chronic disease is highest in infants (90%) and children (25% to 50%), with only 5% of adults becoming chronically infected. An estimated 580,000 to 1.17 million people were living with chronic HBV infection in the United States in 2018. Foreign-born people account for 69% of the U.S. population living with chronic HBV infection. There were an estimated 1,752 HBV-related deaths in 2020, which corresponds to an age-adjusted death rate of 0.45 cases per 100,000 population [23]. HBV hepatitis is the leading cause of liver failure leading to transplantation in the world [25].

The U.S. Preventive Services Task Force recommends screening for hepatitis B virus infection in adolescents and adults at increased risk for infection.

(https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-b-virus-infection-screening Last Accessed: February 19, 2024)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

HBV is a bloodborne pathogen that is typically acquired parenterally, perinatally, or through sexual interaction. As with HIV infection, sexual contact and use of contaminated needles for drug injection are the primary risk factors for HBV [26]. However, HBV is considered 50 to 100 times more infectious than HIV, requiring a much smaller inoculum for transmission. Thus, a needlestick injury from a source patient who is coinfected with both HBV and HIV is more likely to transmit HBV, even when the needle is solid (e.g., a suture needle) and even when blood is not visible. Because HBV does not transfer across the placenta, perinatal transmission occurs when an infant is exposed to the blood of an infected mother at the time of delivery. Parenteral exposures include occupational exposure of healthcare workers (1%), use of injected drugs (15%), tattoos, ear and body piercing, acupuncture, and blood transfusions received prior to 1980. Rare cases of transfusion-associated HBV continue to occur, indicating that the virus was present in the blood but with antigen levels below the level of laboratory detection [22].

The CDC recommends that all adults 18 years and older be screened for hepatitis B at least once in their lifetime using a triple panel test [86]. Those at increased risk for infection (e.g., injecting drug users, those with HCV, incarcerated persons) should be screened periodically. In addition, all pregnant patients should be screened for HBsAg during each pregnancy, preferably in the first trimester, regardless of vaccination status or history of testing. Infants born to HBsAg-positive people should be screened for HBsAg and anti-HBs seromarkers [86].

The incubation period for HBV can be as little as 45 days or as long as 180 days, but most commonly is 60 to 90 days. The severity of primary HBV infection varies from subclinical to fulminant illness. The age of the patient, the integrity of the immune system, and the infecting dose of the virus influence the severity of acute disease. Persons younger than 5 years of age exhibit mild symptoms or no symptoms, while 70% of infected adults exhibit significant clinical symptoms [23].

Signs and symptoms associated with acute HBV infection are similar to those of other acute viral hepatitis syndromes and include malaise, nausea, abdominal discomfort, icterus, and dark urine. Physical examination of the patient typically reveals an enlarged, tender liver and a yellowish hue to the skin. The spleen is palpable in some patients. In patients with fulminant hepatitis, progressive signs of hepatic encephalopathy (e.g., somnolence, confusion, stupor, coma) are common.

CHRONIC HEPATITIS B

Persons diagnosed with chronic HBV infection should be counseled regarding the risk of transmission to others through sexual activity or sharing sharps [31]. In addition, the patient should be cautioned to avoid ingesting alcohol or other hepatotoxic substances. If not previously vaccinated, HAV vaccine should be offered. Household members and sexual partners should be offered HBV vaccine as well.

Immune-directed and specific antiviral therapies are available for the treatment of selective patients with chronic HBV infection. The decision to initiate therapy is based on multiple factors, such as serologic profile, genotype, severity of inflammation, anticipated benefit, and the risks of side effects. Regular follow-up and clinical monitoring are necessary to ensure the safety and efficacy of therapy, detect emerging signs of cirrhosis, and screen periodically for hepatocellular carcinoma. Specific clinical guidance is available from the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines for the Treatment of Chronic Hepatitis B [21].

In patients with positive HBsAg and HBcIgG, normal liver enzymes, and a negative hepatitis B early antigen (HBeAg), therapy is usually withheld and the patient's liver function and quantitative HBV-DNA are monitored on a regular basis (every 3 to 6 months). Patients chronically infected with HBV who have abnormal ALT levels should have DNA testing performed to detect pre-core mutants. Pre-core mutants have a defect in the gene necessary to produce HBeAg. Therefore, in patients with a viral type that contains a pre-core mutant, active viral replication of HBV can be occurring without the presence of HBeAg in the blood. This particular mutation of the virus produces a much more rapid demise of the patient's liver and is typically resistant to interferon therapy. A final assessment in the patient with elevated ALT is a liver biopsy to assess the character and extent of liver damage.

At one time, few pharmacologic options were available for the treatment of chronic hepatitis B. Interferon (pegylated in adults, standard for children) is the recommended first-line agent for the treatment of chronic HBV infection, as no other agent with the potential to produce a sustained virologic response (SVR) after the removal of the drug has been identified. SVR is the closest equivalent to a cure for this chronic condition. However, even interferon is less than 40% effective in producing an SVR and is fraught with unpleasant side effects. Because of these factors, patients and providers often choose suppressive therapy instead. The number of medications that can successfully suppress HBV has tripled since 2000, enabling sequential and/or combination dosing for long-term viral suppression.

Immunomodulator therapy with interferon alfa-2b (IFN α2b) has been recognized as helpful in the treatment of chronic HBV since the 1970s. Pegylated interferon contains the addition of a polyethylene glycol, which permits the drug to be administered once weekly rather than the thrice weekly dosing required with standard interferon. Immunomodulators act both by destroying infected hepatocytes and by elevating the body's production of cytokines. Cytokines in turn promote control of viral replication.

After four months of therapy, 32% of persons will demonstrate a sustained loss of HBV from the serum. This viral suppression remains sustained unless the patient becomes immune suppressed. Patients who relapse after PegIFN/IFNα2b therapy and are HBeAg positive will usually respond to reinstitution of therapy [32].

While somewhat successful in clearing HBV from the blood, PegIFN/IFN α2b has significant side effects. These include irritability, flu-like symptoms, nausea, weight loss, cytopenias, depression, suicidal tendencies, thyroid dysfunction, hyperlipidemia, alopecia, skin rash, ophthalmic changes, and dyspnea. Side effects are reportedly milder with PegIFN α2b [21].

The American Association for the Study of Liver Diseases (AASLD) recommends antiviral therapy for adults with immune-active chronic hepatitis B infection (hepatitis Be antigen negative or positive) to decrease the risk of liver-related complications.

(https://journals.lww.com/hep/pages/articleviewer.aspx?year=2018&issue=04000&article=00034&type=Fulltext Last Accessed: February 19, 2024)

Level of Evidence/Strength of Recommendation: Moderate/Strong

Hepatitis B suppressive therapy is accomplished with medications categorized as nucleoside or nucleotide analogues. The available nucleoside and nucleotide analogues target viral transcription of HBV at three different locations in the process of DNA synthesis. Medications available for this indication include adefovir, lamivudine, entecavir, telbivudine, and tenofovir. Entecavir and tenofovir (both tenofovir dipovoxil fumarate [TDF] and tenofovir alafenamide [TAF]) are recommended individually as first line therapy, with TDF the preferred agent for pregnant patients [33]. Adefovir, lamivudine, and telbivudine are classified as "non-preferred" therapy [21]. While the manufacturers of emtricitabine have never sought approval for HBV monotherapy, the drug is very similar chemically to lamivudine and many single-tablet regimens available for treatment of HIV include tenofovir and emtricitabine. Based on these facts, research has been conducted to confirm the efficacy of emtricitabine in the treatment of chronic HBV and have found it to be non-inferior to lamivudine [33]. Studies have shown that combination therapy is only advantageous in limited circumstances in which there is resistance to one of the approved first-line monotherapy agents [16,34,35].

Several of the medications effective in suppressing HBV are also useful in HIV treatment, with higher doses indicated for HIV suppression than for HBV suppression. In persons coinfected with HIV and HBV, utilizing tenofovir along with lamivudine or emtricitabine in the HIV regimen will also produce HBV suppression. Because use of HBV suppressive doses of adefovir, entecavir, lamivudine, tenofovir, and emtricitabine can result in resistance of HIV to these agents and/or other closely related HIV medications, even at the higher HIV dosages, HIV treatment guidelines now recommend that patients with HIV/HBV co-infection persons be placed on an antiretroviral two-drug combination effective against both HBV and HIV [36].

In 1977, a new antigen was detected in patients with hepatitis B. At first it was thought to be a variant of HBV. By 1980, HDV was determined to be a separate virus, but a virus that was dependent upon the presence of HBV in order to replicate [40].

HDV is an RNA virus, the core of which is distinctively different from other viruses. However, due to a defect in replication, HDV is unable to synthesize a viral coat. It must borrow a coat from HBV in order to complete the replication process. Therefore, HDV cannot cause infection independently but instead must exist as a coinfection (acquired at the same time as HBV) or a superinfection (HDV acquired in a patient who is chronically infected with HBV). In the United States, the infection primarily occurs as a coinfection among intravenous drug users. In some areas of the world in which chronic HBV infection is endemic (including the Amazon Basin of South America, China, and Southeast Asia), HDV is more commonly a superinfection [18,41].

Patients coinfected with HBV and HDV tend to have a more severe case of acute hepatitis. The mortality rate in coinfection has been reported to be as high as 20%. Superinfection with HDV results in rapid progression of cirrhosis, with 70% to 80% of coinfected individuals showing signs of liver failure, compared to 15% to 30% of patients with chronic HBV and no cirrhosis [42]. Prevention of HDV is accomplished through the same means as prevention of hepatitis B. A 12-month course of peginterferon alfa-2a is the recommended treatment for patients with elevated HDV-RNA levels and ALT elevation [21]. Nearly 25% of patients involved in an efficacy study of peginterferon alfa-2a treatment showed sustained clearance of HDV RNA over 48 weeks [43]. Given the limited efficacy of current therapies, it is reasonable to refer patients to specialized centers that offer access to experimental therapies for HDV [21]. Immunization against hepatitis B is effective prevention of HDV also because if the individual is immune to HBV, he/she cannot become infected with HDV. Avoidance of bloodborne pathogen exposure through observance of Standard Precautions is a primary mechanism of prevention for persons already chronically infected with HBV.

After the agents responsible for hepatitis A and hepatitis B were identified and laboratory tests to detect the presence of these agents were available, it became obvious that these two viruses were not the only agents associated with hepatitis. Non-A, Non-B hepatitis became the designation for cases of hepatitis that followed a course indicative of a viral cause, but did not produce laboratory evidence of HAV or HBV. Two separate syndromes of non-A, non-B hepatitis were distinguished; one was present in developing countries and resulted from ingestion of contaminated water (this is now known as HEV), and one was related to blood exposures, particularly transfusions. For more than 10 years, attempts to identify the causative agent for chronic post-transfusion non-A, non-B hepatitis were unsuccessful. In 1989, a cooperative effort between the CDC and a private clinical laboratory was successful in discovering the virus-specific antigen for hepatitis C [44]. At this time, seven distinct genotypes and more than 80 subtypes of HCV have been identified [18,45,46].

Hepatitis C virus is the leading cause of end-stage liver disease and the leading reason for liver transplantation in the United States [45,47]. Chronic HCV infection has also been associated with membranoproliferative glomerulonephritis, cryoglobulinemia, and B-cell lymphoma [45]. Coinfection of HCV with HIV occurs in 50% to 90% of persons who acquired HIV through injection drug use [48].

HCV occurs throughout the world, with endemic rates varying widely. The WHO estimates that 10% of the population of the Middle East, Africa, and Eastern Europe are infected with HCV. In the United States, an estimated 1.8% of the population (approximately 4 million people) is infected with HCV, and only about half of those infected are aware that they are. Rates of HCV in the United States have increased dramatically since 2010. This has been primarily attributed to the nation's opioid crisis and increased infection among injecting drug users. In 2021, 5,023 new cases of HCV were reported, compared with 2,194 in 2014, an increase of 129% [49]. After adjusting for under-ascertainment and under-reporting, an estimated 69,800 acute hepatitis C cases occurred in 2021 [49]. The highest incidence rates of newly acquired HCV infection occurs in persons 30 to 39 years of age (3.5 per 100,000 population) followed by persons 20 to 29 years of age (2.5 cases per 100,000 population), similar to the age groups at highest risk for fatal overdose and age at initiation of injection drug use among certain U.S. populations [49]. Compared with 2006, rates in 2021 were substantially higher among all race and ethnicity categories [49]. During 2021, rates of reported cases of acute HCV ranged from a low of 0.3 cases per 100,000 population among non-Hispanic Asian/Pacific Islander persons to a high of 2.7 cases per 100,000 population among non-Hispanic American Indian/Alaska Native persons [49].

The demographic data for those currently living with HCV are somewhat different from that of new cases. The highest prevalence of persons living with HCV is among persons 30 to 39 years of age. The rate is higher among American Indian/Alaska Natives than among other ethnicities and higher among men than women [49]. Educational level and income are independent predictors of HCV acquisition, with the rate of HCV higher in persons who have not completed high school and in those living below the poverty level [50].

The U.S. Preventive Services Task Force recommends screening for hepatitis C virus infection in adults 18 to 79 years of age.

(https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/hepatitis-c-screening Last Accessed: February 19, 2024)

Strength of Recommendation: B (There is high certainty that the net benefit is moderate or there is moderate certainty that the net benefit is moderate to substantial.)

In the United States, the mortality rate attributable to HCV infection is now greater than the rate associated with 60 other infectious diseases reported to the CDC, including HIV infection [51,52]. Individuals born between 1945 and 1964, or "baby boomers," account for the vast majority of HCV fatalities, often acquiring HCV during adolescence or young adulthood through experimentation with injection or inhaled drugs [53]. Between 1999 and 2007, approximately 75% of HCV fatalities occurred among this population, increasing to 82.5% of HCV fatalities between 2014 and 2018 [51]. A 2023 report from the CDC suggests that the majority of people with HCV still have not been cured nearly a decade after direct-acting antiviral agents were first approved in the United States [54]. The U.S. Preventive Services Task Force recommends one-time screening for HCV infection in all adults 18 to 79 years of age regardless of risk level [55]. In addition, the CDC recommends universal HCV screening for all U.S. adults, for all pregnant women during every pregnancy, for any requesting screening, and periodically in those persons with risk factors [45].

HCV is considered a bloodborne pathogen. The most common source of infection is percutaneous or parenteral exposure through transfusion, use of injectable drugs, and occupational injury of healthcare providers with a contaminated sharp object. The blood supply in the United States has been tested for hepatitis C since the early 1990s. Now that more advanced screening tests for HCV are used in blood banks, the risk is considered to be less than 1 chance per 2 million units transfused [45]. Therefore, the annual incidence rate of HCV transmission from transfusion therapy since 1994 is less than one case per 100,000 population. In 2016, the CDC issued a health advisory due to an increasing number of acute HCV infections among persons undergoing hemodialysis [56].

The overall risk of transmission from patients with HCV infection to their infants is approximately 4% to 8% per pregnancy [45]. Transmission occurs during pregnancy or childbirth. There is no prophylaxis available to protect the newborn from infection. The risk is significantly higher if the mother has a high HCV viral load or is co-infected with poorly controlled HIV. Among pregnant women co-infected with HCV and poorly controlled HIV, the rate of transmission ranges from 8% to 15% [57]. Most infants infected with HCV at birth have no symptoms [45]. As such, the CDC recommends testing all infants perinatally exposed to HCV at 2 to 6 months of age, or up to 18 months of age if not previously tested [87].

Transmission of HCV through vaginal intercourse is inefficient, with the transmission rate in long-term mutually monogamous partners who were not using barrier protection reported by various studies as 0% to 21% [44]. HCV is present in menstrual blood; therefore, intercourse during the menstrual period is considered to be higher risk than intercourse when menstrual blood is not present. Studies of transmission among men who have sex with men indicates rates of transmission similar to that in heterosexual intercourse, with the highest incidence of infection among those with more than 50 partners per year [55]. For persons whose first sexual experience occurs before 18 years of age, prevalence of HCV infection is almost three times higher than in those who are celibate until after the age of 18 years [55].

Intranasal cocaine use has been associated with HCV transmission, presumably resulting from sharing nasal straws contaminated with blood. History of tattoo is considered a risk factor for HCV infection, although no cases of transmission have been linked to licensed, commercial tattoo parlors [45]. Unregulated tattooing and piercing (as is done in prisons and other informal settings) is often not in accordance with infection control practices and may be a risk; however, it is unclear the extent to which these practices occur in the United States [45]. Transmission of HCV has also been documented through sharing of toothbrushes or razors [31].

The incubation period for HCV varies widely, from a mean of 7 to 10 weeks and a range of 2 to 20 weeks. HCV antibody is detectable in 80% of cases 15 weeks after exposure and in 97% of cases by 6 months after exposure. People with recently acquired acute infection typically have detectable HCV RNA levels as early as one to two weeks after exposure to the virus [45]. During the acute phase of the infection, 60% to 70% of HCV positive persons will be asymptomatic; approximately 20% of patients will develop mild jaundice, and the remaining persons will have generalized nonspecific symptoms, such as anorexia, nausea, fatigue, malaise, and abdominal pain. During this phase, serum ALT and AST levels are elevated then return to normal range. Fulminant acute hepatitis associated with HCV is rare [30,58].

After the acute infection, 15% to 25% of patients will demonstrate an absence of HCV RNA in the serum and normalization of liver enzymes, indicating resolution of the infection and clearance of the virus from the body. In those persons in whom HCV RNA remains detectable, indicating continued presence of the virus, 30% to 40% will maintain normal ALT levels and will show no evidence of chronic liver disease. The remaining 60% to 70% of chronically infected patients will have fluctuating ALT levels indicative of chronic liver disease and risk of subsequent progression to cirrhosis. On rare occasions, a patient will demonstrate positive HCV RNA without the presence of HCV antibody. Therefore, in a patient who exhibits chronic hepatitis without apparent cause, assessment of HCV RNA may be indicated [45,59].

Chronic hepatitis from HCV infection usually progresses slowly, with cirrhosis developing in 20% to 25% of patients over a period of 20 to 30 years. However, persons with HCV infection whose daily ethanol consumption exceeds 50 g (about 3.5 standard drinks) per day are twice as likely as nondrinkers to develop cirrhosis and progress to cirrhosis more quickly (in as little as 10 years) [60]. Of those with cirrhosis, 25% eventually develop hepatocellular carcinoma. Persons who ingest alcohol or who were older than 40 years of age at the onset of infection have a more rapid progression of cirrhosis. Men have a higher incidence of cirrhosis than women.

Because acute HCV infection can be asymptomatic, the first indication of the presence of chronic HCV infection may be elevated liver enzymes on laboratory testing obtained in connection with another clinical condition or routine health examination. In evaluating the cause of liver enzyme elevation, a hepatitis panel is typically ordered. The first tests FDA approved specifically for HCV infection were tests for HCV antibody (anti-HCV). The presence of anti-HCV does not differentiate between acute, chronic, or resolved HCV infection.

Testing for the presence of HCV RNA has become the accepted method of confirming current HCV infection (acute or chronic) [45]. Qualitative HCV RNA testing determines whether or not hepatitis C viral particles are present in the blood and can therefore differentiate between resolved and continued infection. Quantitative HCV RNA testing evaluates the amount of hepatitis C virus in the blood and can be used to guide therapy [45,61]. Two methods have been developed for performing quantitative tests: polymerase chain reaction (PCR) and branched deoxyribonucleic acid signal amplification (bDNA). Because the two methods are performed using different standards, the results obtained cannot be compared with each other. Therefore, for purposes of monitoring therapy, the same type of quantitative test should be used consistently.

As noted, based upon genetic characteristics, seven genotypes and many different subtypes of HCV virus have been identified. Because the genotypes respond differently to therapy, genotypic testing should be performed for persons with chronic progressive HCV infection who are considering antiviral therapy [45]. In the United States, genotype 1 accounts for 60% to 75% of HCV infections and genotypes 2 and 3 account for about 25% [62].

In 1995, a virus similar to the HCV was identified and designated hepatitis G. This discovery was confirmed by another laboratory the following year. Although this virus was often found in the blood of patients with Hepatitis C, it was never found to independently cause liver disease in humans. Upon further study, the virus was classified within the Pegivirus genus of Flavivirdiae, the same family as HCV but different genus. Because the virus was not implicated in human liver disease, if was renamed GBV-C [75].

This virus is transmitted through blood, either through percutaneous injury or blood transfusion, or through sexual contact. Persons coinfected with GBV-C and HIV-1 exhibit slowed progression of HIV disease. At least eight different mechanisms of GBV-C interference HIV/T-cell interaction have been identified. However, because highly active antiretroviral medications are more effective in preventing HIV progression than GBV-C co-infection, development of an HIV treatment using GBV-C is unlikely [2].

Liver transplantation, one of the most common types of solid organ transplant, is the replacement of the diseased liver by an allograft from a brain-dead donor or a partial replacement of the liver by a living related donor. Dr. T.E. Starzl and associates at the University of Colorado pioneered this treatment modality in the early 1960s. By the end of the decade, surgeons in Pennsylvania and England were performing the procedure. By the beginning of the 21st century, liver transplantation had been performed at dozens of medical centers in the United States, Canada, and Western Europe. Although survival rates in the early programs were only 30%, improvements in technique and timing of the transplant have now brought the one-year survival rate to approximately 90% and the five-year survival rate to approximately 75% [76].

Children and adults who have irreversible liver disease or defects that cannot be overcome or managed by medical options are candidates for liver transplants. In children, the most common reasons for liver transplantation include biliary atresia, neonatal hepatitis, congenital hepatic fibrosis, alpha 1-antitrypsin deficiency, and disorders of metabolism that result in inappropriate storage within the liver or significant liver damage from the buildup of metabolites. The most common diseases necessitating liver transplantation in adults are chronic viral hepatitis (HCV in the United States, HBV in Europe), biliary cirrhosis, alcoholic cirrhosis, sclerosing cholangitis, cryptogenic cirrhosis, Caroli disease, primary hepatocellular malignancies, hepatic adenomas, and hepatic vein thrombosis [25,77]. Biliary atresia remains a common indication for liver transplantation in pediatric patients [78].

The Model for End-Stage Liver Disease (MELD) is a prognostic system that is now widely accepted as a tool for predicting survival of patients with cirrhosis. MELD, in conjunction with international normalized ratio, serum creatinine, serum bilirubin, and sodium, has been evaluated as a prognostic indicator for cirrhosis regardless of cause. Transplant centers utilize the MELD score in prioritizing clients for transplant [76,79]. The Pediatric End-Stage Liver Disease (PELD) is used for children younger than 12 years of age [76].

Though patients may have a disease process that is an indication for liver transplant, the presence of compounding factors may provide a contraindication for the therapy. At one time, HIV disease was considered a contraindication for liver transplant. While patients with advanced HIV disease are not transplant candidates, HIV disease that is in an early stage or is controlled by antiretroviral therapy is no longer a contraindication for transplantation therapy. Similarly, persons older than 60 years of age were at one time excluded from this therapy, but persons older than 60 years of age who are healthy other than their liver disease can now be considered for candidacy. Active drug or alcohol use, metastatic cancer, uncontrolled bacterial or fungal infections, advanced cardiac or lung disease, and uncorrectable life-threatening congenital anomalies remain contraindications for liver transplantation.

Relative contraindications for liver transplantation are those factors that in isolation would not preclude a patient from receiving a transplant but in combination might decrease the probability that the patient would be approved. Examples of relative contraindications include chronic HBV with rapidly replicating virus, significant psychiatric disorder that may interfere with the patient's ability to follow the post-transplant regimen, significant renal disease not associated with the hepatic disease, and previous hepatic or biliary surgery [77].

Historically, donor organs have been obtained from cadavers. In 1998, the use of living related donors became an option in certain cases [80,81]. Partial liver transplantation from living related donors results in a 20% morbidity rate for the donor. Therefore, cadaveric transplant remains the procedure of choice. The following discussion addresses only cadaveric transplants.

In 2020, the Organ Procurement and Transplantation Network implemented a new liver distribution system called the acuity circle policy, which emphasizes the medical urgency of liver transplant candidates and the distance between the donor and transplant hospitals. The new system replaces the use of decades-old geographic boundaries of 58 donation service areas and 11 transplant regions [82]. Under the new policy, livers from all deceased donors will first be offered to the most urgent liver transplant candidates listed at transplant hospitals within a radius of 500 nautical miles of the donor hospital. Following offers to the most urgent candidates, livers from adult donors will be offered to candidates at hospitals within distances of 150, 250, and 500 nautical miles of the donor hospital. These offers are grouped by medical urgency [76].

Donor livers are usually obtained from brain-dead persons younger than 60 years of age who are free from bloodborne pathogen infections (HCV, HBV, HIV), are not septic, have no existing liver disease, and have not recently experienced abdominal trauma. Some centers consider the use of livers from HBV- or HCV-infected donors for recipients infected with the same strain or subspecies of virus [83]. When donor livers are infected but not yet showing signs of cirrhosis, preliminary results indicate that recipient outcomes are not significantly different from those receiving uninfected livers.

Donor and recipient should have compatible body size and A, B, O blood groups. Unlike kidney transplants, however, donor and recipient do not have to have matching tissue types. The liver is viable for up to 20 hours after removal from the donor, but most centers prefer for the transplant surgery to be completed within 12 hours after organ harvest.

Liver transplantation surgery typically requires a procedure of 6 to 12 hours in duration; in more complex circumstances, the surgery has lasted up to 18 hours. During the procedure, the patient is at risk for coagulopathies, electrolyte disturbances, hypoglycemia, and a large volume of blood loss.

Various combinations of immunosuppressive drugs (monoclonal and polyclonal antibodies) have been used to reduce the probability of post-transplant rejection. It is desirable to try to prevent or minimize the adverse effects of these drugs, including infections, malignancy, and general drug toxicity. In the immediate post-transplant period, a common drug regimen includes a combination of a monoclonal antibody, mycophenolate mofetil, corticosteroids, and a calcineurin inhibitor such as cyclosporine or tacrolimus [25]. According to Hanto, the addition of an anti-IL-2 receptor monoclonal antibody (basiliximab or daclizumab) can result in a decrease in rejection rate from 43.5% to 35.1% [84]. Sirolimus is a newer drug that appears to be useful, especially in patients with renal insufficiency.

Chronic suppressive therapy is usually accomplished with tacrolimus and mycophenolate mofetil. Steroids are weaned within a few weeks of transplantation, except in the presence of autoimmune hepatitis. Liver transplant recipients require lower doses of immunosuppressive therapy than patients receiving other solid organ transplants. Nevertheless, providers should be attentive to drug-drug interactions and therapeutic monitoring of these medications [85].

The process of rejection is insidious in the majority of liver transplantation cases; hyperacute rejection rarely occurs. Most episodes of acute rejection occur within the first six months after the transplant (usually between three and six months) but can be reversed with steroids. In approximately 10% to 20% of patients, steroid resistance occurs, requiring treatment with a monoclonal antibody, such as muromonab-CD3, or a polyclonal antibody, such as thymoglobulin [84]. Acute rejection episodes seldom threaten graft survival. Patient survival rates are 84% with living-donor grafts and 83% with deceased-donor grafts at one year and 34% with living-donor grafts and 46% with deceased-donor grafts at five years [85].

Obtaining a detailed patient history is a vital aspect of diagnosing viral hepatitis, particularly those that are rare or that display similar signs and symptoms to other conditions. Furthermore, communication with patients regarding diagnostic procedures, treatment regimens, and prevention of hepatitis depends on clear communication between the patient and clinician. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

In the increasingly multicultural landscape of the United States, interpreters are a valuable resource to help bridge the communication and cultural gap between patients or caregivers and practitioners. Interpreters are more than passive agents who translate and transmit information from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter. When interacting with patients for whom English is a second language, the consideration of the use of an interpreter and/or patient education materials in their native language may improve understanding and outcomes.

Viral hepatitis represents a diverse spectrum of causative agents. These agents can cause an equally diverse spectrum of severity of symptoms and outcomes. Prevention is the most effective strategy for dealing with viral hepatitis. When preventive efforts fail, therapy for acute disease is primarily supportive. Treatment of chronic hepatitis disease is an evolving process, with new medications and combinations producing promising results.