Chronic hepatitis: Epidemiology, clinical features, and management

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Chapter 64 Chronic hepatitis

Epidemiology, clinical features, and management

Chronic Hepatitis

Hepatitis, in general, means liver inflammation. Most associate the term with a viral infection; however, a number of different processes and agents can lead to an inflamed liver. Other than viral infections, other relatively common causes of hepatitis include alcohol, hepatotoxins (including medicines), autoimmune disorders, and fat (i.e., steatosis). The other important definition, for purposes of this discussion, is chronic versus acute hepatitis. Chronic hepatitis implies the presence of hepatic inflammation for longer than 6 months. Routinely, this is based on the presence of elevated transaminases: aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Although liver inflammation can certainly occur in the absence of transaminasemia, establishing the diagnosis of chronic hepatitis depends on elevations of the AST and ALT for at least 6 months. Thus the finding of elevated transaminases during an evaluation of a potential patient for surgery should lead to a careful assessment because it pertains to the clinical issues at hand. However, the presence of a single set of elevated transaminases does not necessarily imply an acute or chronic process. For example, a patient with transaminases in the range of 1000 to 1500 IU/L in the face of a common bile duct gallstone causing obstruction is distinctly different from a patient with acute cholecystitis presenting with a history of transaminasemia in the range of three to four times the upper limit of normal and an ultrasound showing fatty infiltration of the liver. Thus the clinical setting and history for any particular patient is of crucial importance when evaluating a patient for hepatobiliary surgery. Having a basic working knowledge of each of the chronic hepatitides facilitates evaluation of the patient facing surgery.

Chronic Hepatitis C


Hepatitis C is an RNA virus and a member of the family Flaviviridae and affects approximately 1.6% of the American population, with estimates at 3 to 4 million infected (Armstrong, 2006). Most commonly, the disease is transmitted by blood-to-blood to contact. Before the availability of the hepatitis C antibody test in the early 1990s, posttransfusion hepatitis C was a common means of contraction. However, the availability of reliable assays has led to a marked decrease in the incidence of posttransfusion hepatitis C (Alter, 1997). Currently, the risk of posttransfusion hepatitis C is approximately 1 in 2 million transfusions. The much more common means of contracting hepatitis C is by intravenous drug use. Other needle-stick exposures, such as with tattoos and occupational exposure, account for a much lower percentage of cases. Sexual transmission is likewise a low risk, particularly among monogamous partners. However, the prevalence of hepatitis C is much higher at sexually transmitted disease clinics, affecting nearly 10% of nonintravenous drug–using patients (Thomas et al, 1994), presumably related to sexual promiscuity and/or traumatic sex, with increased risk of blood to blood exposure. Inhalation of cocaine has been raised as a potential risk factor, based on the transmission via blood on straws used to snort the inhaled agent (Hepburn & Lawitz, 2004). This risk factor has been questioned, with the issue that inhaled cocaine may be associated with other high-risk behaviors that are, in fact, the modes of transmission.


The standard screening study for hepatitis C is an enzyme-linked immunosorbent assay (ELISA) for antibody to hepatitis C. This is the standard test used by blood banks around the country; it has a sensitivity and specificity in high-risk populations ranging from 98% to 100% (Vrielink et al, 1995). If a patient has a known risk factor and elevated transaminase levels, a positive hepatitis C antibody study by ELISA is consistent with the diagnosis of hepatitis C. The presence of hepatitis viremia is checked with a reverse transcriptase polymerase chain reaction (PCR). Unfortunately, the PCR may take days to a week to get results, depending on the frequency of testing at the local lab. Patients can have a positive antibody study without viremia if the acute infection spontaneously resolved, an event that occurs 15% to 40% of the time (Herrine, 2002). Antibody positivity frequently persists indefinitely, but it does not imply infection if viremia is absent, based on an undetectable viral load by PCR. Patients will have one of six genotypes, variants in the hepatitis C genome that mainly reflect responsiveness to antiviral therapy (McHutchison et al, 1998). If screening for hepatitis C, and background on a patient being considered for surgery is all that is needed, a genotype need not be checked. However, if antiviral therapy is being considered, a genotype will provide important information regarding the chance of a virologic response and the length of therapy. Genotype 1 is the most common genotype in the United States, accounting for 70% of cases. Genotype 2 accounts for 15% of cases, and genotype 3 accounts for another 10% (McHutchison et al, 1998). Genotype 4 is occasionally seen in the United States, although it is more commonly seen in the Middle East and northern and central Africa. Genotypes 5 and 6 are seen in the United States, although rarely; prevalence of each is higher in South Africa and Southeast Asia, respectively.


Hepatitis C treatment is centered around the use of pegylated interferon and ribavirin. Routinely, the patient with chronic hepatitis C is started on therapy for one of several reasons; without question, the presence of hepatitis C viremia is the primary consideration for therapy, but careful consideration is also given to genotype, histologic changes, and potential relative and absolute contraindications. For example, patients with genotype 1 have a 45% to 50% chance of achieving a sustained virologic response, or “cure,” if they can complete a course of therapy. However, the profound fatigue and flulike symptoms commonly associated with antiviral therapy often lead to a decision to delay therapy if histologic changes are mild. For example, if a patient has genotype 1 with a high viral load, the most common demographic in American patients, a liver biopsy showing low-grade inflammation and fibrosis often leads to a period of observation that often lasts for years, or until therapeutic breakthroughs occur. If additional comorbidities associated with a poor response are added to this scenario, such as obesity (Charlton et al, 2006) and/or insulin resistance (D’Souza et al, 2005), and the patient is African American (Jeffers et al, 2004), the potential for successful treatment can drop to 20% to 25%, usually leading clinicians to delay therapy until factors that can be modified are changed. In the face of a disease that potentially may not lead to cirrhosis for 20 to 30 years, if ever, the wisdom of such an approach becomes obvious. Genotype 2 and 3 patients, however, respond in the range of 70% to 80% of the time, routinely requiring only 24 weeks of therapy versus the 48 recommended for genotype 1 patients. This higher response rate can be affected by the same cofactors outlined above.

Absolute contraindications to antiviral therapy include anemia, neutropenia, and severe thrombocytopenia. Because of a type of hemolytic anemia that can be induced by ribavirin, patients with a baseline hemoglobin less than 10 to 12 g/dL must be carefully evaluated if treatment is considered. A 2- to 3-g drop of hemoglobin is expected in the face of ribavirin; thus severe anemia is possible if the baseline hemoglobin level is low. Although reduced doses of ribavirin can be given with the hope of minimizing the anemia, reduced doses also lead to lower response rates; thus most experienced clinicians avoid dose reductions and use erythropoietin to increase hemoglobin levels. Neutropenia and thrombocytopenia are due to pegylated interferon and may improve with dose reduction, although similar lower levels of response can be expected. Granulocyte colony-stimulating factor or filgrastim can maintain neutrophil levels and obviate the need for dose reduction. Eltrombopag, a nonpeptide thrombopoietin receptor agonist, has been approved for patients with thrombocytopenia secondary to immune thrombocytopenic purpura and is under study for the treatment of thrombocytopenia secondary to pegylated interferon treatment. This will potentially allow thrombocytopenic patients to receive antiviral therapy.

Other potential contraindications to antiviral therapy include uncontrolled psychiatric illness, renal insufficiency, severe cardiopulmonary disease, and alcohol or substance abuse. Pegylated interferon and ribavirin can induce and exacerbate depression (Renault et al, 1987); thus recent suicidal ideation is an absolute contraindication to therapy. Well-controlled psychiatric disease can be successfully treated with careful follow-up. Renal insufficiency is a relative contraindication because of renal excretion of both interferon and ribavirin (Bino et al, 1982; Glue, 1999). The ribavirin dose must be decreased to avoid severe hemolytic anemia. Unfortunately, strict guidelines are not available, so dosing is often started at a low level, then increased based on patient tolerance. The anemia induced by ribavirin can exacerbate cardiac and pulmonary disease; these patients must therefore be carefully assessed before starting therapy. For example, a patient with congestive heart failure and a left ventricular ejection fraction of 40% may decompensate in the face of a drop in hemoglobin from 14 to 7 g/dL. Finally, patients with a history of alcohol or substance abuse are usually not treated until a period of abstinence can be maintained. Studies have shown a decreased response rate in patients with ongoing alcohol abuse (Pessione et al, 1998). Whether alcohol has a direct effect on drug pharmacokinetics and/or efficacy is unclear; however, the potential effect on compliance is obvious.

Once a patient is deemed an appropriate candidate for therapy, one of two pegylated interferon products is started: pegylated interferon alfa-2a at 180 µg subcutaneously weekly or pegylated interferon alfa-2b at 1.5 µg/kg/week. Although no head-to-head studies have been performed, the agents appear to be equivalent in efficacy and side effects, although clinicians usually have a personal preference. Ribavirin is dosed at 13 mg/kg/day, given orally in divided doses. Because of the myalgias, arthralgias, fever, chills, and sweats that frequently occur after administration of pegylated interferon, patients frequently take an over-the-counter analgesic before the injection. Fatigue and flulike symptoms are usually at their worst in the 24 to 48 hours following the pegylated interferon injection, with milder symptoms for the remainder of the week, until the next scheduled injection. That said, many patients are affected by these symptoms on a nearly daily basis, but others have minimal discomfort. Most patients can maintain their usual activities with only scattered absences. However, a small percentage of patients are nearly disabled, requiring frequent absences from their usual responsibilities. Discontinuation of therapy as a result of intolerable side effects occurs in 5% to 10% of treated cases.

On treatment, laboratory work is followed at least monthly and more often if needed. Thyroid function is assessed quarterly because of the potential for development of hypothyroidism or hyperthyroidism (Marcellin et al, 1992). The addition of growth factors for cytopenias is often clinician dependent. Most clinicians start supplemental erythropoietin with a hemoglobin level less than 10 g/dL, although many clinicians start erythropoietin if a patient has severe fatigue in the face of a drop in hemoglobin of 25% to 40% (e.g., from 18 to 11 g/dL). Absolute neutrophil counts less than 500 mm3 usually lead to supplemental filgrastim, although many clinicians start filgrastim in response to an absolute neutrophil count of less than 1000 mm3. Drops in hemoglobin, absolute neutrophil counts, and platelet counts may lead to dose reduction of pegylated interferon and/or ribavirin, although the current standard of care is to attempt to maintain patients on standard doses unless all other measures fail.

Viral loads are monitored at 4, 12, and 24 weeks of therapy (Ghany et al, 2009). An undetectable viral load after 4 weeks of therapy is associated with an 85% to 90% response rate, if the patient can complete the course of therapy, regardless of genotype (Ferenci et al, 2005). Thus a response at 4 weeks should lead to maximal efforts to maintain a patient at standard doses and a full course of therapy. An undetectable viral load observed at 12 weeks drops the rate of a sustained virologic response to 67% to 80% (Davis et al, 2003), whereas patients with a “late” response at week 24 only respond approximately 18% to 30% of the time (Berg et al, 2006; Pearlman et al, 2007). In patients with the first undetectable viral load at 24 weeks, recent studies suggest that extending therapy for an additional 24 weeks may improve the rate of response by 20%, although patient tolerance for this extended therapy is poor (Berg et al, 2006; Pearlman et al, 2007).

If undetectable viremia is achieved during therapy, viral load is routinely checked 3 to 6 months following the end of therapy. An undetectable viral load at that point is consistent with a sustained virologic response. Long-term studies have shown this response is durable, with undetectable viral loads persisting indefinitely (Desmond et al, 2006), unless the patient is reinfected. Patients who do not respond to antiviral therapy do not benefit from another treatment trial unless specific circumstances resulted in underdosing. New classes of medicines are under study, and when used in combination with pegylated interferon and ribavirin, protease inhibitors appear to increase response rates.

Hepatitis B


Hepatitis B is a DNA virus that represents the number one cause of chronic viral hepatitis worldwide, with more than 2 billion people infected at some point and more than 350 million infected chronically (World Health Organization, 2008). More than 45% of the world’s population lives in endemic areas, particularly in Asia and sub-Saharan Africa (Mahoney, 1999). More than 8% of the population in these areas is positive for hepatitis B surface antigen (HBsAg). The prevalence is much lower in North America, affecting less than 2% of the population overall. In the United States, approximately 73,000 new cases occur each year, with approximately 1.25 million patients infected chronically (McQuillan et al, 1999). However, because of the mobility of the world’s population, the possibility of acute or chronic hepatitis B must be considered in patients who have come to the United States. These changes in patterns of immigration will likely increase the prevalence of the disease by as much as a factor of two.

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