Overview

Liver failure is a primary cause of mortality and morbidity in the United States. Chronic viral hepatitis is the leading cause of liver failure in this country and throughout the world. Six separate viral species, some with numerous subspecies, have been designated as the hepatitis viruses and are identified by the letters A, B, C, D, E, and G. Some of these viruses are associated with only acute liver disease while others are more commonly identified as causes of chronic liver disease. The classification, clinical presentation, and management of viral hepatitis are discussed. Emphasis is given to hepatitis C, now a treatable disorder and the most common cause of chronic hepatitis leading to cirrhosis, hepatocellular carcinoma, and the need for liver transplantation.

Education Category: Infection Control / Internal Medicine
Release Date: 03/01/2015
Expiration Date: 02/28/2018

Audience

This course is designed for dental professionals in all specialties.

Accreditations & Approvals

NetCE is designated as an Approved PACE Program Provider by the Academy of General Dentistry. The formal continuing education programs of this program provider are accepted by AGD for Fellowship, Mastership, and membership maintenance credit. Approval does not imply acceptance by a state or provincial board of dentistry or AGD endorsement. The current term of approval extends from 10/1/2015 to 9/30/2021. Provider ID 217994. NetCE is an ADA CERP Recognized Provider. ADA CERP is a service of the American Dental Association to assist dental professionals in identifying quality providers of continuing dental education. ADA CERP does not approve or endorse individual courses or instructors, nor does it imply acceptance of credit hours by boards of dentistry. Concerns or complaints about a CE provider may be directed to the provider or to ADA CERP at www.ada.org/cerp. NetCE is a Registered Provider with the Dental Board of California. Provider Number RP3841. Completion of this course does not constitute authorization for the attendee to perform any services that he or she is not legally authorized to perform based on his or her license or permit type. NetCE is approved as a provider of continuing education by the Florida Board of Dentistry, Provider #50-2405.

Designations of Credit

NetCE designates this activity for 5 continuing education credits. AGD Subject Code 148. This course meets the Dental Board of California's requirements for 5 unit(s) of continuing education. Dental Board of California course #05-3841-16172.

Course Objective

The purpose of this course is to provide dental professionals with a review of normal liver structure and function, common liver function tests used to assess liver disease, and an overview of the set of viruses known to cause primary hepatitis.

Learning Objectives

Upon completion of this course, you should be able to:

  1. Outline the structure and function of the liver.
  2. Describe the common laboratory tests used to assess liver function and injury and diagnostic tests for identification of viral hepatitis.
  3. Describe the classification of the various hepatitis viruses.
  4. Discuss the epidemiology, management, and prevention of hepatitis A and E.
  5. Identify the appropriate approach to diagnosis and management of hepatitis B and D.
  6. Describe the approach to diagnostic staging and management of chronic hepatitis C infection.
  7. Discuss the current options for, and efficacy of, directed antiviral therapy of chronic hepatitis C.
  8. Evaluate the role of liver transplantation in the treatment of patients with hepatitis.

Faculty

Kalynn Pressly, ARNP, DSN, received an Associate Degree in Nursing from Wallace College in Dothan, Alabama, her BSN from Troy State University, her Masters and Doctoral degrees from University of Alabama at Birmingham, and her Nurse Practitioner education at the University of South Alabama. Dr. Pressly has practiced in a variety of settings, including obstetrics, medical-surgical, dialysis, critical care, nursing education, nursing research, and, most recently, infectious disease. She currently serves as an infectious disease nurse practitioner, employed by the Florida Department of Health.

Faculty Disclosure

Contributing faculty, Kalynn Pressly, ARNP, DSN, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

Division Planner

William E. Frey, DDS, MS, FICD

Division Planner Disclosure

The division planner has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.

About the Sponsor

The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.

Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.

Disclosure Statement

It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.

Table of Contents

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#54991: Viral Hepatitis

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INTRODUCTION

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. A virus similar in structure to hepatitis C has been designated hepatitis G, but information about this virus and its effects on the liver is limited. In 1994, hepatitis F was identified as a cause of fulminant liver failure [36]. This was later found to be a variant subspecies of another virus. Therefore, "F" is now omitted in the hepatitis alphabet.

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

The liver is one of the largest organs in the body. The healthy adult liver typically weighs 1.3 to 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 liver is typically 4 to 8 cm, while at the mid-clavicular line, it extends 6 to 12 cm. On inspiration, the edge of the liver is 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 [4].

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.

Because the portal vein brings nutrients from the intestines to the liver, the blood in the portal vein may also contain intestinal bacteria. Therefore, 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 surround and digest intestinal bacteria that enter the liver through the portal circulation.

Between the sinusoid spokes lay trapezoid-shaped structures that contain two columns of hepatic cells, sometimes referred to as the hepatic plate. Between the two columns of cells lies the bile canaliculus. Bile canaliculi collect bile formed 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 circulating volume.

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 (forming new glucose as needed from other nutrients), 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 creating the plasma proteins.

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. Six 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 [19].

Prolonged inflammation of the liver or excessive exposure of the liver to toxic substances leads to scarring, a replacement of the functioning lobules with fibrous tissue. This condition is commonly termed cirrhosis. Prolonged inflammation can also have a carcinogenic effect on the liver. Therefore, the outcome of chronic liver disease is often cirrhosis or liver cancer.

DIAGNOSTIC TESTS OF LIVER FUNCTION AND DISEASE

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 occur, the total serum bilirubin must exceed 2.5 mg/dL. A total serum bilirubin level less than 10 mg/dL is usually found in viral hepatitis; levels higher than this are typically indicative of hepatic carcinoma or biliary obstruction [39].

Inflammation of hepatic cells 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 to 56 Units/L; the normal range for AST is 10 to 40 Units/L [21]. There may be slight differences in normal values between men and women.

Albumin levels (normal range: 3.5 to 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: 20 to 140 IU/L) remain in the normal range in hemolytic disease, are slightly elevated in hepatocellular disease, and are greatly increased in obstructive liver disease [18].

The degree of liver scarring and cirrhosis is best judged through liver biopsy. A less invasive method of estimating liver damage is through the prothrombin time (PT). As the amount of functional liver tissue decreases, the production of clotting factors decreases, thereby resulting in prolongation of the PT.

OVERVIEW OF VIRUSES AND VIRAL DISEASES

Viruses are the cause of some of the earliest disease processes recorded in the medical literature. Though the natural history of viral diseases such as polio, rabies, measles, and smallpox has been described for millennia, the first viruses were not identified 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 [38].

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 reproduce, the virus must interact with the host's cells. 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.

CLASSIFICATION OF HEPATITIS VIRUSES

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), D (HDV), and G are considered bloodborne pathogens. HBV is a DNA virus; HAV, HCV, HDV, HEV, and HGV are RNA viruses. Hepatitis A and E cause acute illness; hepatitis B, C, and D can have both acute and chronic manifestations. Hepatitis G has not yet been demonstrated to cause acute disease but may be implicated in chronic disease. The hepatitis viruses represent different families of viruses: hepatitis A is a member of the Picornavirus family; hepatitis B is a Hepadnavirus; hepatitis C and G are both Flaviviruses; hepatitis D is sometimes classified as a Hepadnavirus and sometimes as a Satellite virus; and hepatitis E is of the family Calicivirus. The commonality in these viruses is their ability to cause inflammation of the liver. 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.

Because hepatitis A and E share similarities in transmission and absence of chronic sequelae, these disorders, their etiology, pathophysiology, prevention, diagnosis, and treatment will be presented first. The bloodborne hepatitis viruses will then be similarly discussed.

HEPATITIS A

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 or vaccine). Therefore, hepatitis was classified into two categories: infectious hepatitis and serum hepatitis [42,56].

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 has 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 1990 to 1999, the CDC estimates that more than 300,000 cases occurred within the United States each year [41]. Introduction of an effective vaccine appears to have slowed the infection rate, and in 2009 only 56,000 new cases were reported [41]. The World Health Organization (WHO) estimates the annual worldwide incidence to be 1.4 million per year [40].

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, evidence of infection appears 15 to 50 days after ingestion of the organism (the incubation period). Clinical evidence of the disease may include nausea, vomiting, headache, fever, chills, abdominal discomfort, hepatomegaly, and right upper quadrant tenderness. For most patients, symptoms are mild and subside in 3 to 7 days. Others will have more significant disease and will progress to an icteric phase (jaundice). For these patients, recovery typically occurs after about 3 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 3 to 4 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 [35].

As with any other disease, prevention is the most effective strategy. Hepatitis A vaccine is available and is recommended for anyone traveling abroad as well as for healthcare providers and food handlers in areas in which the endemic rate of HAV is high. Persons in other high-risk categories, including men who have sex with men, sewage workers, animal handlers, and individuals with chronic liver disease, should also receive the vaccine. The U.S. Food and Drug Administration (FDA) has approved two HAV vaccines, the first of which was approved in 1995. The available inactivated virus 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 1 month prior to travel. A booster dose 6 months after the initial injection is useful and may provide lifelong protection.

An alternative is Twinrix, which contains inactivated HAV and HBV recombinant vaccines. It is immunogenic against HAV and HBV, but requires three injections of 1 mL intramuscularly. The suggested schedule is an initial injection followed by boosters at 1 and 6 months. This vaccine is not approved for use in children. Immunity is expected to persist for at least 20 years (and possibly longer) in those who receive all 3 doses [42].

Persons who have not been vaccinated but are close (household or intimate) contacts of a person with HAV may receive passive immunization with hepatitis A immunoglobulin. The recommended dose is 0.02 mL/kg [2].

Sanitation strategies are also important in controlling HAV. If in water, the virus is inactivated by boiling the water for five minutes. HAV is also killed by most household grade disinfectants and all hospital grade disinfectants.

HEPATITIS E

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 [2,34].

HEV most often affects young adults. The incubation period is 2 to 9 weeks, with an average of 6 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. During outbreaks, the fatality rate of HEV among pregnant women in their third trimester has reached as high as 20% [34]. 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 [43].

HEPATITIS B

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 [42]. 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 [2]. 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 serological 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. 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 1 hour at 160°C [27].

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. According to the CDC, only 3374 cases of acute hepatitis B were reported in the United States during 2009, an all-time low [12].

After initial acquisition of HBV, 6% to 10% of persons with the virus will progress to a chronic infection [29]. The percentage of cases progressing to chronic disease is highest in infants (90%) and children (25% to 50%), with only 5% of adults becoming chronically infected. At present, it is estimated that 1.4 million persons in the U.S. are chronically infected with HBV. Worldwide, chronic hepatitis B infection affects more than 350 million people. It is the leading cause of liver failure leading to transplantation in the world [12,31].

HBV is a bloodborne pathogen that is typically acquired parenterally, perinatally, or through sexual interaction. Sexual contact and use of contaminated needles for drug injection are the primary risk factors [7]. 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 [27].

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 may be subclinical to fulminant. 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 [12].

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.

Serologic testing in hepatitis B typically follows one of two patterns. Within 2 to 4 weeks after exposure, HBsAg is detectable in the serum. In acute HBV infection, the antigen remains through the course of the clinical illness, then is cleared after 20 to 24 weeks. Persistence of detectable HBsAg is diagnostic of chronic HBV infection.

The IgM core antibody, also known as anti-HBc IgM, is detectable within 2 weeks after the HBsAg. In acute HBV infection, soon after the anti-HBc-IgM begins to rise, clinical symptoms are apparent. Anti-HBc-IgM declines after 3 to 6 months. The IgG core antibody (anti-HBc-IgG) appears within 4 to 8 weeks after exposure and persists indefinitely.

In acute HBV infection, surface antibody (HBsAb) appears concurrently with clearance of HBsAg from the serum. HBsAb does not develop in patients chronically infected with HBV. Persons who have been immunized against HBV also exhibit a positive HBsAb. See Table 1 for summaries of serological measures of acute and chronic HBV disease [1].

SEROLOGICAL MEASURES OF ACUTE AND CHRONIC HBV DISEASE

Disease StateHBsAgHBcIgMHBcIgGHBsAb
Acute HBV infection++ (early)+ (late) 
Resolved acute HBV infection  ++
Chronic HBV infection+ + 
Immunity after vaccination   +

Serological testing for hepatitis B occasionally reveals presence of hepatitis B core IgG antibody alone (HBc-IgG or HBcAb total). According to the CDC, four possible interpretations of this result are possible [12]:

  • A false positive

  • Resolved acute infection in which HBsAb has declined to non-detectable levels (most common)

  • Low-level chronic infection in which the HBsAg level is lower than detectable by the laboratory method used

  • Resolving acute infection in which the HBsAg level has dropped to non-detectable but the HBsAb level has not yet risen to the detectable range

Subsequent testing, guided by patient history, is advised.

As previously stated, approximately 10% to 20% of persons infected with HBV will develop chronic disease. Those who develop chronic HBV infection have few if any acute symptoms. Development of chronic disease occurs most often in infants, children, and persons with immune compromising conditions such as human immunodeficiency virus (HIV). Chronic HBV infection is the leading cause of liver failure and liver cancer in the world [42].

Treatment of acute HBV infection is primarily supportive. Control of nausea and vomiting, maintenance of fluid and electrolyte balance, avoidance of potentially hepatotoxic drugs and alcohol, and extended periods of rest are the typical therapies.

In less than 1% of cases, fulminant acute liver failure develops. Treatment for fulminant hepatic failure includes compensating for coagulation defects, correcting acid-base as well as fluid and electrolyte disturbances, prevention of hypoglycemia, administering prophylactic antibiotics, and therapies to reduce ammonia levels and combat cerebral edema. With aggressive therapy, improved intensive care and the use of orthotopic liver transplantation, the mortality rate for fulminant acute hepatic failure has gone down to 40% [37].

The decision of whether or not to treat a patient with chronic HBV infection is made by weighing the risks of side effects of therapy against the probable benefit of therapy. In patients with positive HBsAg, normal liver enzymes, and a negative hepatitis B early antigen (HBeAg), therapy is usually withheld and the patient's liver function is monitored on a regular basis (every 3 to 12 months). Patients chronically infected with HBV who have abnormal ALT levels should have a viral load assessed to determine the number of phages per mL of blood. In addition, DNA testing can be 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 hepatitis B. Interferon remains the only agent with the potential to produce a sustained virologic response (SVR) after the removal of the drug (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 may choose suppressive therapy instead. The number of medications that can successfully suppress HBV has tripled since 2000, enabling sequential dosing for long-term viral suppression. Combination therapy with either interferon and a suppressive agent or 2 suppressive agents is also being evaluated.

Immunomodulator therapy with interferon alfa-2b (IFN α2b) has been recognized as helpful in the treatment of chronic HBV since the 1970s. Immunomodulators act both by destroying infected hepatocytes and by elevating the body's production of cytokines. Cytokines in turn promote control of viral replication.

Administered subcutaneously, IFN α2b can be prescribed as 5 million units daily or 10 million units 3 times per week. An alternative to traditional IFN α2b, pegylated interferon alfa, may be used subcutaneously once a week [2]. After 4 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 IFN α2b therapy and are HBeAg positive will usually respond to reinstitution of therapy [33].

While somewhat successful in clearing HBV from the blood, 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 the pegylated interferon alfa.

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, amdoxovir, clevudine, elvucitabine, emtricitabine, entecavir, telbivudine, and tenofovir. Although approved to be prescribed as monotherapy, combination therapy with selected agents has been shown to produce a more rapid suppression and delay the development of resistance. Adefovir has been studied in combination with either lamivudine or emtricitabine, with positive outcomes with both combinations. Clevudine and emtricitabine combination therapy has also been successful [49].

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 HIV/HBV coinfected persons be placed on an antiretroviral combination effective against both HBV and HIV, even if the HIV infection does not meet the criteria for treatment [51].

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 3 injections. However, evidence has indicated that 2 injections may be sufficient to achieve protection if administered in adolescence [10]. 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 1 to 2 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.

Persons who have not been immunized (or did not respond to the vaccine) and are exposed to HBV may achieve passive protection from infection by receiving hepatitis B immunoglobulin (HBIG) within 7 days of exposure. The usual dose of HBIG is 0.06 mL/kg. For persons who have not been immunized, an accelerated schedule of immunizations is recommended following the dose of HBIG. For documented nonresponders, a second dose of HBIG is appropriate.

As noted, the FDA has approved the combination HAV/HBV vaccine known as Twinrix. It is administered on the same schedule as hepatitis B vaccine, with doses at 0, 1 and 6 months. Although this vaccine does not shorten the immunization schedule, the combination vaccine provides dual protection with 3 injections instead of 5. This vaccine is particularly popular with travelers. HBV vaccine is also a component of two pediatric combination vaccines. Comvax contains both HBV and Haemophilus influenzae vaccines. Pediarix combines HBV, diphtheria, acellular pertussis, tetanus, and inactivated polio virus vaccines.

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.

HEPATITIS D

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 [24].

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 [2,44].

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 [47]. Prevention of HDV is accomplished through the same means as prevention of hepatitis B. Nearly 25% of patients involved in an efficacy study of peginterferon alfa-2a treatment showed sustained clearance of HDV RNA over 48 weeks [54]. 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.

HEPATITIS C

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 [22]. At this time, at least 6 distinct genotypes and more than 80 subtypes of HCV have been identified [2].

Hepatitis C virus is the leading cause of end-stage liver disease and the leading reason for liver transplantation in the United States [8,15]. Chronic HCV infection has also been associated with membranoproliferative glomerulonephritis, cryoglobulinemia, and B-cell lymphoma [8]. Coinfection of HCV with HIV occurs in 50% to 90% of persons who acquired HIV through injection drug use [16].

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. The highest incidence of newly acquired HCV infection occurs in persons 20 to 39 years of age and, at this time, shows no pattern of ethnicity.

The demographic data for those currently living with HCV is somewhat different from that of new cases. The highest prevalence of persons living with HCV is among persons 30 to 49 years of age, with the rate higher among African Americans than among whites and higher among men than women. 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 [5].

In the United States, the mortality rate attributable to HCV infection is now greater than the rate associated with HIV infection [59]. Between 1999 and 2007, approximately 75% of HCV fatalities occurred among persons born between 1945 and 1964. Many of these "baby boomers" acquired HCV during adolescence or young adulthood through experimentation with injection or inhaled drugs [59]. The U.S. Preventive Services Task Force recommends offering one-time screening for HCV infection to all adults born between 1945 and 1965 regardless of risk level [52].

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. Therefore, the incidence of HCV transmission from transfusion therapy since 1994 is less than one case per 100,000. In 2016, the CDC issued a health advisory due to an increasing number of acute HCV infections among persons undergoing hemodialysis [68].

Transmission from mother to infant is uncommon, occurring in less than 5% of pregnancies of HCV-positive mothers. Studies of perinatal transmission indicate that HCV transmission does not take place in utero but instead occurs at the time of delivery [6]. In mothers who are coinfected with both HIV and HCV, the rate of transmission of HCV to the infant is 22% to 36% [6].

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% [22]. 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 [52]. 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 [52].

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 [8]. 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 [8].

The incubation period for HCV, from exposure to onset of symptoms, is typically 6 to 12 weeks. HCV antibody is detectable in 80% of cases 15 weeks after exposure and in 97% of cases by 6 months after exposure. 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 [3,37].

After the acute infection, 15% to 30% of patients will demonstrate an absence of HCV RNA in the serum and normalization of liver enzymes, indicating resolution of the infection. 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; some will develop progressive liver disease. 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 [26].

Chronic HCV infection usually progresses slowly, with cirrhosis developing in 20% to 25% of patients over a period of 20 to 30 years. 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 only FDA approved tests for HCV infection are tests for HCV antibody (anti-HCV). An enzyme immunoassay (EIA) test is typically performed initially as a screening test. The recombinant strip immunoblot assay (RIBA) is a more specific test for anti-HCV and can be used as a confirmatory test to rule out false positive EIA tests. The presence of anti-HCV does not differentiate between acute, chronic, or resolved HCV infection.

Testing for the presence of HCV RNA has become an accepted alternative to the RIBA as a confirmatory test. 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 [30]. 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, several different 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. In the United States, genotype 1 accounts for 60% to 75% of HCV infections and genotypes 2 and 3 account for about 25% [64].

MANAGEMENT OF PATIENTS WITH CHRONIC HCV INFECTION

Clinical management of HCV-positive patients, including decisions with respect to antiviral therapy, varies in relation to age, severity of the hepatitis and associated fibrosis, and the presence or absence of complications and comorbidities. In healthy patients with normal hepatic enzymes or only mild elevations and no overt evidence of chronic liver disease at the time of HCV diagnosis, some period of expectant management is reasonable while monitoring the clinical course and laboratory parameters every 6 to 12 months. Diet, alcohol use, drugs to avoid, and periodic screening for hepatocellular carcinoma are among routine clinical issues to consider.

Most authorities agree that specific treatment of the HCV infection may not be warranted for patients whose ALT levels persistently remain in normal range [11]. In patients with fluctuating ALT levels or those whose ALT levels remain elevated, a liver biopsy to assess the degree of liver damage is indicated. If the biopsy reveals anything more than mild inflammatory change, such as portal or bridging fibrosis, moderate inflammation, or focal necrosis, then antiviral therapy is recommended. Patients who have developed overt complications indicative of advanced cirrhosis (e.g., ascites, variceal hemorrhage, encephalopathy) have sustained too much liver damage to benefit from drug therapy. Liver transplantation should be considered for these patients.

Coinfection with HIV and HCV results in a much higher rate of progression to liver failure than infection with HCV alone. Low CD4 levels cannot effectively inhibit HCV replication. Hepatotoxicity of antiretroviral agents may also accelerate the rate of fibrosis, even in immunocompetent persons with HIV. Therefore, all patients coinfected with HIV and HCV should be evaluated for HCV therapy [51].

The goal of antiviral therapy in patients with chronic HCV infection is to clear demonstrable viral RNA from the blood stream, reducing the burden of viral replication to low levels such that the patient's own immune system can gain the upper hand and eradicate the infection. This in turn changes the natural history of this chronic illness, alleviating morbidity and complications of cirrhosis and reducing the need for transplantation. The criterion for achievement of this goal is a sustained virologic response (SVR), defined as undetectable HCV RNA by PCR at 12 and 24 weeks after completion of a course of therapy. Patients are candidates for antiviral therapy when there is ongoing evidence of active infection over a 6-month period, as evidenced by detectable HCV viral levels. Selection of treatment options is based on determination of the infecting HCV genotype.

Interferon-Based Regimens for Treatment of HCV Infection

Historically, the medication most commonly prescribed for persons with progressing liver damage from HCV was IFN α2a or IFN α2b, 3 million units administered subcutaneously 3 times a week, for 6 to 12 months. With IFN α2b alone, an SVR and improvement on post-treatment biopsy could be achieved in only about 50% of treated patients. Persons with genotype 1 were less likely to respond to medication therapy than those infected with other genotypes. When therapy was stopped, 50% to 70% of responders experienced a relapse.

The co-administration of an antiviral agent, ribavirin, twice daily in conjunction with the usual IFN regimen received approval by the FDA in 1999. After 24 weeks of dual-drug therapy, 40% of patients previously untreated and 50% of patients who had relapsed after IFN alone demonstrated a sustained response to therapy [5].

As mentioned in the treatment of chronic hepatitis B, pegylated interferon-alpha, the sustained-release form of the medication, 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 [17].

Prior to 2011, the standard treatment for patients with chronic HCV infection was the combination regimen of pegylated interferon and ribavirin. In clinical trials, groups treated with the combination of pegylated interferon and ribavirin showed better drug tolerance and a significantly higher SVR rate than those groups treated with conventional interferon and ribavirin [45].

The limitations of interferon-based (cytokine) therapy alone or in combination with ribavirin are multiple: the need for parenteral administration, long duration of treatment, less than satisfactory sustained response, and high adverse effects profile. Side effects of interferon, as discussed in the treatment of hepatitis B, include irritability, flu-like symptoms, nausea, weight loss, cytopenia, depression, suicidal tendencies, thyroid dysfunction, hyperlipidemia, alopecia, skin rash, ophthalmic changes, and dyspnea. Ribavirin has also been associated with negative side effects, the most profound of which is birth defects. Women should not become pregnant and men should not impregnate a woman during therapy or for 6 months after therapy is discontinued [9]. In addition to the side effects occurring during treatment with an immunomodulator, the risk of hepatocellular carcinoma may increases in persons who have undergone interferon therapy.

Direct-Acting Antiviral Therapy for HCV Infection

In 2011, the FDA approved the first protease inhibitors for the treatment of chronic HCV: boceprevir and telaprevir. These agents act by inhibiting NS3/NS4A HCV protease, an enzyme that plays a crucial role in the viral life cycle. These medications were found to be useful in treatment-naive patients and in those who had previously received therapy but failed to achieve a significant viral response.

Boceprevir is taken orally at a dose of 800 mg three times per day, while telaprevir is administered at 750 mg three times daily. Serum HCV RNA is assessed at baseline, weeks 4, 8, 12, and 24, as well as at the end of treatment and during follow-up [57]. At week 8, treatment may be adjusted. Possible side effects include fatigue, chills, anemia, insomnia, dysgeusia, and nausea [57]. The use of these protease inhibitors in combination with pegylated interferon and ribavirin in a 24- to 48-week course of therapy results in SVR rates of 50% to 80% among patients with HCV genotype 1 (and is slightly higher for genotype 2 and 3 infection) [5].

In 2013, two additional direct-acting antiviral drugs were approved for the treatment of chronic HCV infection [61,62]. Simeprevir is a protease inhibitor that blocks a specific protein needed for HCV replication. Sofosbuvir is a nucleotide analogue that inhibits HCV NS5B polymerase, an enzyme necessary for viral replication. These direct-acting antiviral drugs have proven to be highly effective as components of combination regimens used to treat adults with varying stages of chronic HCV, including cirrhosis, HIV co-infection, and patients with HCV awaiting liver transplantation [63]. Clinical trials with these new agents have achieved SVR rates of 80% to 95% after 12 to 24 weeks of therapy.

Sofosbuvir is administered orally at a dose of 400 mg once daily. It is used in combination with pegylated interferon and ribavirin for treatment-naïve adults with genotypes 1 and 4 infections (12 weeks, SVR 89% to 90%) and in combination with ribavirin alone for treatment of genotype 2 (12 weeks, SVR 82% to 93%) and genotype 3 (24 weeks, SVR 80% to 95%) infections [62,64]. Sofosbuvir may also be used in conjunction with daclatasvir (12 weeks, SVR 89% to 99%) in the treatment of genotype 3 infection, making coadministration of interferon and ribavirin unnecessary [65,66].

Simeprevir is administered orally at a dose of 150 mg once daily. It is approved for use in combination with pegylated interferon and ribavirin for treatment of genotype 1 only. Treatment duration is 24 to 48 weeks (SVR 79% to 86%) depending on prior treatment history and monitored response to therapy [61,64].

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 hepatitis infection [67]. It is approved only for use in patients without liver scarring and cirrhosis.

Since 2013, 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 [20,60]. 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) [60]. 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 are being superseded by combination oral regimens that are safer, of shorter duration, and achieve SVR rates greater than 90% [20]. The downside of these new oral combination direct-acting antiviral drugs is cost; a 12-week course of sofosbuvir alone is $84,000 [60].

Guidance for treatment of chronic HCV is changing frequently. In making treatment decisions, clinicians should review current guidelines provided jointly by the American Association for the Study of Liver Disease and the Infectious Diseases Society of America online at http://www.hcvguidance.org.

For patients with progressive chronic HCV or chronic HBV infection that does not respond to pharmacotherapy, liver transplantation may be indicated. Replacing the liver, however, does not cure the infection. The transplanted liver will also become infected, and immunosuppressive agents facilitate the progression of this infection. Nevertheless, chronic viral hepatitis is the most common diagnosis of persons receiving liver transplants in the United States at this time [8]. Because hepatitis C is a bloodborne pathogen, prevention is similar to that for hepatitis B. Observing Standard Precautions is essential. No vaccine is as yet available for prevention of hepatitis C, nor is gamma globulin effective post-exposure.

HEPATITIS G

In 1995, a virus similar to the HCV was identified and designated hepatitis G. This discovery was confirmed by another laboratory the following year. The virus is transmitted through blood, either through percutaneous injury or through transfusion. Since its discovery, HGV has been identified in approximately 2% of banked blood [32].

HGV has never been associated with fulminant hepatitis, and the role of this virus in chronic liver disease is questionable. The virus remains detectable in the blood, with documented cases of seropositive blood up to 16 years after initial exposure [25]. Though the presence of the virus persists, it has not been shown to independently cause liver failure. Whether or not the virus accelerates the course of chronic HCV infection is yet to be determined [2].

LIVER TRANSPLANTATION

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 88% [58].

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 [14,31].

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, and serum bilirubin, has been evaluated as a prognostic indicator for cirrhosis regardless of cause. Transplant centers utilize the MELD score in prioritizing clients for transplant [50]. In general, persons with a MELD score greater than 20 are excluded from transplantation because of a low probability of survival. A high MELD score that has not yet reached the cut-off of 20 assures the individual of a priority position on the list of recipients.

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 [14].

Historically, donor organs have been obtained from cadavers. In 1998, the use of living related donors became an option in certain cases [23,48]. 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.

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 [28]. 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. 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% [46]. 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 [53].

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 6 months after the transplant (usually between 3 and 6 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 [46]. Acute rejection episodes seldom threaten graft survival. Patient and graft survival rates at one year are 90% and 82% respectively, and 73% and 65% at five years [53].

CONSIDERATIONS FOR NON-ENGLISH-PROFICIENT PATIENTS

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.

CASE STUDIES

HEPATITIS A

Patient A is 19 years of age and a college sophomore who presented to her physician's office with mild jaundice. The patient reports being in good health until a week before, at which time she began having flu-like symptoms of headache, low-grade fever, nausea, loss of appetite, and malaise. She self-treated the fever with acetaminophen. The symptoms persisted. Upon awakening this morning, she noticed that her eyes were yellow. She therefore contacted her physician's office.

In response to her physician's questions, she indicated that her urine has been darker than usual and she has been experiencing joint pain for the last 3 days. She also acknowledged that her stools have been lighter than usual.

Her medical history is positive for mild exercise-induced asthma, for which she uses a prophylactic bronchodilating inhaler. Her only other routine medication is a daily vitamin/mineral supplement. She reports no surgeries. Family history is positive for cardiovascular disease (father and both sets of grandparents) and breast cancer (mother).

Other significant history includes that she was immunized against hepatitis B at 12 years of age and she recently participated in a 2-week mission trip to Central America. Although she was very cautious about the foods she ingested during the mission trip, the patient indicated that a primary recreational activity after the day's work was to swim in the lagoon near the village. The lagoon was fed both by the stream in which the natives washed their clothes and the adjacent bay. Rainfall averaged 2 to 3 inches per day. Patient A returned to the United States 5 weeks ago.

Physical examination revealed a well-developed, well-nourished female who was alert and oriented. Her temperature was 99.7°F; other vital signs were within normal limits. Abnormal physical findings included mild icterus of sclera and skin, abdominal tenderness, hepatomegaly, and palpable spleen. Results of laboratory tests are indicated in Table 2.

PATIENT A LABORATORY TEST RESULTS

TestPatient's ResultsNormal Value or Range
Hematocrit (Hct)40%37% to 47%
Hemoglobin (Hgb)13.3 mg/dL12.0–16.0 mg/dL
White blood cell count6200 cell/microliter4300–10,800 cells/microliter
Aspartate aminotransferase (AST)323 Units/L5–40 Units/L
Alanine aminotransferase (ALT)358 Units/L5–35 Units/L
Total bilirubin3.7 mg/dL0.2–1.6 mg/dL
HBsAgNegativeNegative
HBsAbPositivePositive indicates previous disease or immunization; negative indicates no exposure
Anti-HAV IgMPositiveNegative
Anti-HCV antibodyNegativeNegative
Alkaline phosphatase (ALP)85 Units/mL30–115 Units/mL
Prothrombin time (PT)11.6 secondsControl 10.4 seconds (normal is ±2.0 seconds from control)
Albumin3.8 mg/dL3.5–5.5 mg/dL
Glucose84 mg/dL70–110 mg/dL
Sodium142 mEq/L135–150 mEq/L
Chloride102 mEq/L100–108 mEq/L
Potassium3.8 mEq/L3.6–4.8 mEq/L

Case Study Discussion

Patient A has presented with classic signs and symptoms of acute hepatitis. Based on her past history, travel, and exposure history, the most likely diagnosis is acute hepatitis A infection. The hepatic chemistry profile and serologic studies confirm this diagnosis. Exposure probably resulted from accidental ingestion of contaminated water while swimming in the lagoon.

Because acute viral hepatitis is usually a self-limited disease and Patient A is alert with no evidence of coagulopathy, she can be managed as an outpatient with close follow-up. Liver enzymes and PT should be monitored every 5 to 7 days until liver enzymes return to normal level. Bed rest is not indicated, but the patient should avoid strenuous activity. She should eat a well-balanced diet and abstain from alcohol for the duration of the illness. Because acetaminophen can be toxic to the liver, ibuprofen would be a better alternative for controlling fever. No other alterations in the patient's medications are necessary at this point. If nausea precludes the patient from ingesting food and fluids, IV replacement of fluids and electrolytes may be necessary. In the event the patient develops bleeding tendencies or signs of encephalopathy, she should immediately be taken to the hospital or her physician's office.

Hepatitis A virus is a reportable disease. The health department should be informed of the case immediately. Because the exposure probably occurred outside the geographical area, follow-up will be limited to those with similar exposure (i.e., persons who were also on the mission trip) and to her intimate and/or household contacts. A single dose of HAV immunoglobulin is recommended for close contacts. If immunoglobulin is not available, administration of hepatitis A vaccine may prevent illness or lessen the severity of the contact's symptoms if infection does occur. Immunoglobulin is not recommended for those who may have been exposed on the mission trip, as those exposures occurred more than 2 weeks prior to the diagnosis. Follow-up with these persons is primarily to determine if they too are experiencing symptoms and are possible sources of spreading the disease.

CHRONIC HEPATITIS C

Patient B is a paramedic, 48 years of age. Laboratory work obtained during his annual physical examination reveals hyperlipidemia; CBC, glucose, BUN, and electrolytes were within normal range. With the exception of his weight (15 lbs heavier than indicated for his height), his exam identifies no abnormalities.

After 2 months of a diet and exercise program, his cholesterol level is 256. Therefore, his physician elects to begin a lipid lowering agent. A baseline liver profile is drawn prior to initiation of the lipid lowering agent. The liver profile reveals an AST of 226 Units/L and an ALT of 282 Units/L.

In an effort to determine the cause of his elevated liver enzymes, the physician reviews Patient B's history and medications. He has been a paramedic for 25 years. He was immunized against HBV in 1988. During his career, he has experienced several exposures to blood (usually blood splashes, but also two needlesticks from IV needles), most before the advent of Standard Precautions. His most recent exposure was 2 years ago. An HIV test 6 months post-exposure was negative.

Patient B's surgical history includes a hernia repair in childhood and removal of skin lesions 3 times in the past 8 years. He has had no transfusions. He is the widowed father of two teenage children. His wife died 6 years ago from ovarian cancer.

The patient has never smoked. He drinks about 6 beers per week and rarely drinks hard liquor. He denies any history of illegal drug use. Although the patient has no current prescription medications, he uses several herbal preparations including garlic, ginkgo, and an antioxidant preparation. The patient takes ibuprofen for pain, consuming 6 to 10 tablets (200 mg each) per month.

Although alcohol consumption and herbal antioxidants can both cause liver inflammation, the degree of his liver inflammation is much higher than would be expected from limited use of these two factors. Therefore, the physician orders a hepatitis profile. The results include negative anti-HAV, negative HBsAg, positive HBsAb, and positive anti-HCV. The patient is diagnosed with chronic HCV infection.

In order to evaluate the extent of liver damage and determine an appropriate treatment plan, the physician orders an HCV viral load and genotype as well as a PT and liver biopsy. The PT is within normal range. The liver biopsy reveals chronic inflammatory infiltration of the portal areas with minimal fibrosis. Genotype identifies the virus as type 3. HCV RNA viral load is 350,000 phages/cc.

Because Patient B's biopsy shows only minor fibrosis and type 3 is typically slow to progress, his physician recommends that therapy be postponed. Patient B is advised to eat a nutritious, balanced diet and abstain completely from alcohol. Although he is not currently sexually active, the patient is educated about the low but present risk of sexual transmission of HCV and how to minimize the risk of transmission. Immunization against HAV is also recommended, as acquiring an acute case of HAV in a patient with pre-existing chronic hepatitis can be much more serious that either condition alone. He is also to have serial assessments of liver enzymes every 3 months and assessments of HCV RNA viral load every 6 months.

Eighteen months after the initial diagnosis, Patient B's ALT is 356 Units/L and his AST is 418 Units/L. His ALT and AST levels have been persistently elevated over the last 18 months, though the degree of elevation has been variable. The HCV RNA viral load indicates the amount of circulating virus has increased to 750,000 phages/cc. He is advised to begin interferon and ribavirin therapy, and he concurs. He is instructed about the possible side effects of therapy and cautioned about the necessity of not fathering children during the therapy or for 6 months thereafter.

Because Patient B's virus is type 3, the duration of therapy is 6 months. He receives ribavirin orally twice a day and pegylated interferon subcutaneously weekly. Because of the potential adverse side effects of these medications, CBC is assessed at the end of weeks 1, 2, and 4, and every 4 weeks thereafter. A liver profile and HCV RNA are also assessed monthly.

After 2 weeks, the patient's CBC reveals mild bone marrow suppression, but not sufficient to alter the dosage. After 2 months of therapy, Patient B's ALT is 85 Units/L and his AST is 115 Units/L. His HCV RNA is 118,000 phages/cc. After 4 months of therapy, ALT and AST are both within normal range and HCV RNA is undetectable. Therapy is discontinued at 6 months.

As follow-up, Patient B will continue to have a liver profile every 3 months for a year, then every 6 months thereafter, and an ultrasound of the liver every 6 months. Because his HCV is genotype 3, the probability of relapse is low.

HIV AND CHRONIC HBV COINFECTION

Patient C is a man, 32 years of age, with a history of injection drug use, who participated in a free HIV testing day. His screening test was found to be positive. A confirmatory test conducted at the health department was also positive. He has therefore been referred to the Infectious Disease Clinic of a large university medical center for follow up.

During his first visit, the patient indicates that he injected drugs off and on beginning at 19 years of age. His first two experiences with rehabilitation failed, but he has been "clean" for 2 years, since his best friend died of an overdose. He reports that he also snorted cocaine occasionally during the years he used injected drugs.

The patient's medical history includes a hospitalization for a motorcycle accident at age 24, with surgery on his right leg both on that admission and again about a year later. He received 2 units of blood during the first admission. The patient denies a history of heart disease, neurological disorders, or endocrine disorders. He has had pneumonia both in adolescence and again last year.

The patient's parents are living and in good health. Grandparents all have hypertension, and maternal grandmother has type 2 diabetes. The patient smokes 1/2 to 1 pack of cigarettes per day and consumes 2 or 3 drinks per day. The patient's current medications include acetaminophen or ibuprofen as needed for leg pain and paroxetine for anxiety and depression.

Physical examination reveals no acute distress. Vital signs are within normal limits, and sclerae are non-icteric. Oral cavity is free from thrush and leukoplakia. Cervical lymph nodes are palpable but moveable and nontender. Heart sounds are normal; lungs are clear. Abdomen is soft; both liver and spleen are palpable. Neurological exam is normal. The patient has full function in upper extremities and left leg; right leg has a slight decrease in strength and a moderate decrease in range of motion.

Initial laboratory tests ordered by the nurse practitioner (NP) include an HIV PCR viral load, a CD4 count, a CBC, a chemistry panel, and a liver profile. Because of the high incidence of HCV and/or HBV coinfection in persons whose HIV was acquired percutaneously, the NP also orders a hepatitis profile. A tuberculin skin test (TST) is performed to determine the presence of a tuberculosis infection, and the patient is instructed to return in 72 hours to have the TST read, review lab results, and formulate a treatment plan.

Upon his return, all results except the HIV PCR are available. His CD4 count is 246. Hematocrit is 44%, hemoglobin 15 gm/dL, and WBC is 3800. The liver profile reveals an alkaline phosphatase of 143 Units/mL, AST 358 Units/L, ALT 383 Units/L, total bilirubin 1.2 mg/dL, and albumin 2.8 gm/dL. Hepatitis profile is positive for HBsAg, HBeAg, and total anti-HBc. The anti-HAV, anti-HCV and anti-HBc IgM are negative. The PPD is negative. The remainder of the chemistry panel is unremarkable.

The NP informs Patient C that he is coinfected with HIV and HBV and instructs him about the problems associated with HIV/HBV coinfection. He is given HAV and pneumococcal immunizations and options for antiretroviral therapy are discussed. Because of its effectiveness against both HIV and HBV, a medication regimen including tenofovir with either lamivudine or emtricitabine should be utilized. Tenofovir and emtricitabine are available in a combination tablet, which will be selected in order to decrease pill burden. A third medication for HIV viral suppression should be added, with consideration of the hepatotoxicity profile of the medication. After discussing available options with limited hepatotoxicity, darunavir 800 mg daily boosted by ritonavir 100 mg is selected as the third active agent in the combination.

Information is provided to Patient C regarding safe sex practices. He is also instructed to abstain from alcohol and to use ibuprofen (or no more than 2 g acetaminophen in 24 hours) for pain control. The NP also recommends that a PT and liver biopsy be performed in order to evaluate the progression of the liver disease. The patient is scheduled for a follow-up visit in 4 weeks, after the liver biopsy.

The liver biopsy reveals periportal inflammation with focal necrosis and bridging fibrosis. PT is 15.6 seconds (control: 12 seconds). His baseline HIV PCR is 123,000.

Upon his return to the office, Patient C is advised of the severity and advanced stage of his chronic liver disease and the guarded prognosis. Because of the severity of his liver disease, he is not a good candidate for interferon therapy. The patient's current HIV status precludes his being a transplant candidate at the time. The recommended treatment plan for Patient C is to maximize his HIV suppression while minimizing his continued liver damage. If he is compliant with his therapy, he should be able to maintain a fairly good quality of life for 3 years or more. Prolonging the time until liver failure also provides the opportunity to improve immunocompetency. Some liver transplant centers now accept HIV-positive patients, provided that HIV viral loads are undetectable and CD4 counts are sufficiently high (usually >500). Patient C's future, therefore, depends upon his tolerance of the regimen, his compliance with the treatment plan, and his body's response to therapy.

The patient will initially be followed on a monthly basis. The viral load will be checked 1 month after the initiation of therapy, then every 3 months thereafter. Liver profile, CBC, and amylase will be assessed after 1 month, then bimonthly. If, after 3 months, the viral load is well suppressed, follow-up will be extended to every 2 to 3 months. If the patient's liver function significantly deteriorates, supportive therapy for end-stage liver disease will be instituted.

CONCLUSION

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.

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