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 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.

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].

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].

Viral hepatitis can be classified by mode of transmission, by the type of virus, and by chronicity. Hepatitis A (HAV) and E (HEV) are both transmitted by the fecal-oral route while hepatitis B (HBV), C (HCV), and D (HDV) are considered bloodborne pathogens. HBV is a DNA virus; HAV, HCV, HDV, and HEV are RNA viruses. Hepatitis A and E cause acute, usually self-limited illness; hepatitis B, C, and D present with both acute and chronic disease manifestations. The hepatitis viruses represent different families of viruses: hepatitis A is a member of the Picornavirus family; hepatitis B is a Hepadnavirus; hepatitis C is a Flavivirus; hepatitis D is sometimes classified as a Hepadnavirus and sometimes as a satellite virus of HBV; and hepatitis E is of the family Calicivirus. The commonality in these viruses is their trophism for the liver and the ability to cause hepatic inflammation. The differences in the individual viruses account for the tremendous variation in outcome of infection, chronicity of the disease, and the ease with which tests to diagnose the virus and vaccines to prevent the virus are developed.

Viral hepatitis can be classified by mode of transmission, by the type of virus, and by chronicity. Hepatitis A (HAV) and E (HEV) are both transmitted by the fecal-oral route while hepatitis B (HBV), C (HCV), and D (HDV) are considered bloodborne pathogens. HBV is a DNA virus; HAV, HCV, HDV, and HEV are RNA viruses. Hepatitis A and E cause acute, usually self-limited illness; hepatitis B, C, and D present with both acute and chronic disease manifestations. The hepatitis viruses represent different families of viruses: hepatitis A is a member of the Picornavirus family; hepatitis B is a Hepadnavirus; hepatitis C is a Flavivirus; hepatitis D is sometimes classified as a Hepadnavirus and sometimes as a satellite virus of HBV; and hepatitis E is of the family Calicivirus. The commonality in these viruses is their trophism for the liver and the ability to cause hepatic inflammation. The differences in the individual viruses account for the tremendous variation in outcome of infection, chronicity of the disease, and the ease with which tests to diagnose the virus and vaccines to prevent the virus are developed.

Viral hepatitis can be classified by mode of transmission, by the type of virus, and by chronicity. Hepatitis A (HAV) and E (HEV) are both transmitted by the fecal-oral route while hepatitis B (HBV), C (HCV), and D (HDV) are considered bloodborne pathogens. HBV is a DNA virus; HAV, HCV, HDV, and HEV are RNA viruses. Hepatitis A and E cause acute, usually self-limited illness; hepatitis B, C, and D present with both acute and chronic disease manifestations. The hepatitis viruses represent different families of viruses: hepatitis A is a member of the Picornavirus family; hepatitis B is a Hepadnavirus; hepatitis C is a Flavivirus; hepatitis D is sometimes classified as a Hepadnavirus and sometimes as a satellite virus of HBV; and hepatitis E is of the family Calicivirus. The commonality in these viruses is their trophism for the liver and the ability to cause hepatic inflammation. The differences in the individual viruses account for the tremendous variation in outcome of infection, chronicity of the disease, and the ease with which tests to diagnose the virus and vaccines to prevent the virus are developed.

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].

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.

The U.S. Food and Drug Administration (FDA) has approved two single-antigen HAV vaccines and one combination vaccine for use in the United States, all of which are inactivated vaccines. The single-antigen vaccines are Havrix and VAQTA. Both are administered to adults in a dose of 1 mL intramuscularly. The dose for children is 0.5 mL. It is suggested that travelers to endemic regions receive the initial injection at least one month prior to travel. A booster dose six months after the initial injection is useful and may provide lifelong protection [15].

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.

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].

As with hepatitis A and E, prevention is the best method for dealing with hepatitis B. Hepatitis B vaccine has been available since the 1980s and has been recommended as a routine childhood immunization since the early 1990s. Hepatitis B vaccine is typically administered as a series of three intramuscular injections, the second and third doses given at one month and six months, respectively, after the first dose [23]. In 2017, a two-dose series hepatitis B vaccine for unvaccinated or incompletely vaccinated individuals 18 years of age and older was approved by the FDA [16,37]. In addition, evidence has indicated that two injections may be sufficient to achieve protection if administered in adolescence [23]. The ACIP recommends all adults 19 to 59 years of age and adults 60 years of age and older with risk factors for hepatitis B infection should receive hepatitis B vaccination [38]. Hepatitis B vaccine and hepatitis B immunoglobulin (HBIG) should be administered to infants born to persons with HBV infection within 12 hours of birth, followed by completion of the vaccine series and postvaccination serologic testing. All neonates should receive hepatitis B vaccination within 24 hours of birth, followed by completion of the vaccine series. All unvaccinated children and adolescents younger than 19 years of age also should receive the vaccine [39].

More than 90% of persons who received HBV vaccine in accordance with the recommended schedule and method of administration will be protected against HBV infection. Therefore, confirmation of protection is not recommended for the general public. Assessment of HBsAb following immunization is recommended for persons who are considered at high risk for HBV exposure, such as healthcare workers. For these persons, the HbsAb level should be assessed one to two months after the third injection. If detectable HbsAb levels are not achieved, the series should be repeated. If the second series fails to produce detectable antibody levels, the individual should be considered a nonresponder, and this fact should be documented in the medical record and in the individual's occupational health record.

Strict adherence to Standard Precautions is recommended in order to prevent exposure to HBV or other bloodborne pathogens. Careful handling of needles is also imperative. Because of the hardiness of HBV even in adverse conditions, caution should be used when cleansing objects contaminated with blood or body secretions, regardless of whether or not the body fluids have dried.

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].

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].

As mentioned in the treatment of chronic hepatitis B, PegIFN α2b, the sustained-release form of the medication, was approved in 2002. It has an injection schedule of only once a week. This form of interferon demonstrates response rates of 25% to 40% when used alone and has fewer patient reports of side effects [67].

In 2011, the FDA approved the first protease inhibitors for the treatment of chronic HCV: boceprevir and telaprevir. Both agents were withdrawn in 2015 due to availability of more effective and better tolerated agents [69]. In 2013, the FDA approved two additional direct-acting antiviral drugs: simeprevir, a protease inhibitor that blocks a specific protein needed for HCV replication, and sofosbuvir, a nucleotide analogue that inhibits HCV NS5B polymerase, an enzyme necessary for viral replication [16]. While simeprevir is no longer recommended by the AASLD and the IDSA, sofosbuvir, in combination with other appropriate agents, is recommended for HCV infection (all genotypes) in limited situations [16]. In 2015, the combination of ombitasvir, paritaprevir, and ritonavir (as a single agent under the brand name Technivie) was approved for use in combination with ribavirin for the treatment of genotype 4 HCV infection [70]. This combination regimen is no longer recommended by the AASLD and IDSA for treatment of HCV infection [16]. It should be noted that none of the drugs were discontinued due to safety profile [16,70].

In 2017, the FDA approved the combination glecaprevir and pibrentasvir, and in 2020, combination sofosbuvir and velpatasvir was approved for the treatment of HCV infection in patients with any of the six HCV genotypes with mild or no cirrhosis [16,65,71,72].

Since 2015, the therapy of chronic HCV infection has advanced further as the results of new clinical trials demonstrate that non-interferon combinations of oral direct-acting antiviral agents can achieve even higher SVR rates in less time with fewer side effects [64,73,74]. These studies selected patients with genotype 1 and include patients with varying degrees of chronic liver disease. All were treated with the combination of sofosbuvir and ledipasvir, an oral direct-acting antiviral drug with potent activity against HCV administered as a single oral dose once daily. Multiple trials of 8-, 12-, and 24-week duration showed consistent and comparable results, with SVR rates of 93% to 99% (without need for interferon or ribavirin) [74]. In previously untreated patients without cirrhosis, an 8-week course of therapy was as effective as 12 weeks (SVR rate 94% vs. 95%).

The efficacy and safety of therapy directed at HCV has improved greatly in recent years with the advent of these newer, highly potent antiviral agents. Standard interferon-based regimens in combination with older antivirals have been superseded by combination oral regimens that are safer, of shorter duration, and achieve SVR rates greater than 90% [73]. The downside of these combination direct-acting antiviral drug regimens is their high cost, which compromises accessibility for some patients [74].

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].