Chapter 171 Hepatitis
Hepatitis refers to inflammation (-itis) of the liver (hepar-). Inflammation lasting less than 6 months is known as acute hepatitis, whereas that lasting longer than 6 months is called chronic hepatitis. In people with acute hepatitis who do not progress to chronic disease, all of the symptoms, signs, and blood test abnormalities return to normal without permanent or long-term sequelae. People who progress from acute to chronic hepatitis are at risk of progressing to cirrhosis and its complications, such as portal hypertension and hepatocellular carcinoma (HCC). Hepatitis is a term that encompasses many inflammatory causes, such as autoimmune liver disease, obesity, alcoholic liver disease, and some medications and herbs. Only hepatitis caused by a virus (viral hepatitis) is potentially infectious to others. This chapter focuses on viral hepatitis A, B, and C.
Hepatitis A is caused by a virus of the Picornaviridae family and is transmitted via the fecal–oral (enteric) route by person-to-person contact. Prior to its identification in 1973, hepatitis A was known as infectious hepatitis. It is the most common cause of acute viral hepatitis in the United States, with approximately one third of adults having evidence of prior exposure, as do almost all people living in areas of poor sanitation. Although infection with the hepatitis A virus (HAV) does not lead to chronic disease, it accounts for an estimated 100 deaths each year in the United States.
Hepatitis B is caused by a virus of the Hepadnaviridae family and is transmitted via the parenteral route through blood or blood products, through sexual contact, or from mother–child transmission during pregnancy and childbirth. Prior to its identification in 1963, it was known as serum hepatitis. Approximately 350 to 400 million people worldwide, including 1.25 million people in the United States, are chronically infected with the hepatitis B virus (HBV), defined through blood work as a positive hepatitis B surface antigen (HBsAg) and a positive hepatitis B core antibody (HBcAb). Chronic HBV infection is the most common cause of cirrhosis and liver cancer worldwide.1
Hepatitis C is caused by a virus of the Flaviviridae family and is transmitted via the percutaneous route through blood-to-blood contact. Intravenous drug users, anyone who received a blood or a blood-product transfusion prior to 1992, individuals born to a mother infected with the hepatitis C virus (HCV), and those who may be at increased risk for exposure to infected blood, such as health care or public safety workers, are at increased risk of infection. Unlike the case with HBV, sexual contact is an inefficient means of HCV transmission. Prior to its identification in 1989, it was known as non-A non-B hepatitis. An estimated 130 million people worldwide, 5 million of whom are in the United States, have been exposed to HCV, and approximately 350,000 to 500,000 people per year die of HCV-related liver disease.2,3
Symptoms and Signs
Acute viral hepatitis may be totally asymptomatic, or may be an extremely debilitating disease manifesting with jaundice, flulike symptoms, decreased appetite, abdominal pain, nausea, diarrhea, vomiting, and fatigue. Typically, the more severely ill and jaundiced a person is during the acute phase of hepatitis, the better his or her chances of not progressing into chronic hepatitis. The probability of developing chronic disease is approximately 1% to 5% in HBV- infected adults and approximately 90% to 95% in HBV-infected infants. Hepatitis A never leads to chronic disease. Hepatitis C progresses to chronicity in 55% to 85% of infected individuals, with females and children being less likely to progress to chronic diseases than male adults.4,5 The symptoms of chronic hepatitis vary from virtually nonexistent to relentless fatigue as well as signs and symptoms of decompensated cirrhosis, such as ascites, variceal bleeding, and hepatic encephalopathy.
A diagnosis of hepatitis is made via a combination of a thorough history and physical examination, laboratory tests including serial liver function tests (aspartate aminotransferase [AST] and alanine aminotransferase [ALT], which are known together as transaminases), and hepatitis-specific serologies in addition to imaging studies. Because these evaluations typically do not accurately correlate with the extent of damage done to the liver, a liver biopsy is often necessary to determine the grade (degree of inflammation) and stage (degree of fibrosis) of the disease as well as the need for therapy.
All people with chronic liver disease or chronic hepatitis of any etiology should receive immunizations for hepatitis A and B if they have not already been exposed to these viruses. The hepatitis A vaccination was first approved by the FDA in 1995. The development of the hepatitis B vaccine represents one of the most important advances in medicine. This is the first and only vaccine in history that can simultaneously prevent liver cancer, cirrhosis, and a sexually transmitted disease, hepatitis B. The FDA approved the hepatitis B vaccine in 1981, and the improved version has been available since 1986.
It is considered safe to administer the hepatitis B vaccine to pregnant women if needed. Infants born to HBsAg-positive mothers should receive both the hepatitis B vaccination and the hepatitis B immune globulin (HBIG) within 12 hours of birth. See Box 171-1 for a list of those at increased risk for hepatitis B and who therefore should receive the hepatitis B vaccination.
BOX 171-1 Groups Recommended to Receive the Hepatitis B Vaccination
• All newborns with HBsAg-positive mothers
• At-risk children age 11 or 12 who did not receive the vaccine at birth
• People of any age who have more than one sex partner within a 6-month period
• People with a sexually transmitted disease
• Immigrants from geographic areas in which HBV is endemic—Asia, sub-Saharan Africa, Middle East, Amazon basin
• Children born in the United States to a person from an HBV-endemic area
• Adopted children from HBV-endemic areas
• Intravenous drug users and their sex partners
• People with blood-clotting-factor disorders
• Those who have intimate or household contact with a person who is an HBV carrier (HBsAg-positive).
• People who work in health care
• Public safety workers who may come into contact with blood
• People receiving hemodialysis
• People who live or work in an institution for the developmentally disabled
There is currently no vaccine available to prevent HCV. One of the major barriers to the development of this vaccine involves the complex HCV population of mutant strains, known as quasispecies, that can exist in a person infected with hepatitis C.
The hepatitis A virus can be killed by boiling infected foods for at least three minutes and by disinfecting surfaces with bleach. It is best to avoid eating raw or partially cooked mollusks (clams, oysters, mussels, and scallops), as these fish often live in HAV-contaminated rivers and seas. When traveling to areas of the world known to have a high incidence of hepatitis A, it is especially important to eat well-cooked foods and to drink only bottled water. Sanitizing diaper-changing tables is also important, as hepatitis A–infected infants are typically a silent source for the spread of hepatitis A infection. Meticulous handwashing is of great importance after using the bathroom, before eating a meal, and before preparing food for others.
The avoidance of unprotected sex will greatly reduce the likelihood of infection with HBV. Employing a barrier such as a condom, dental dam, female condom, and finger cot will decrease the risk of transmission and acquisition of HBV. Although the risk of sexual transmission of HCV is rare, protected sex is recommended if a person engages in anal sex, has multiple sex partners, has frequent prostate infections, has open cuts or sores on the genitalia, or is menstruating. People with hepatitis B or C should avoid sharing anything that may contain even the tiniest amount of their blood, including toothbrushes, razors, and nail clippers.
In order to further reduce the likelihood of spreading hepatitis B and C, people who are using injection drugs should never share needles with others or inject themselves with a used needle. A drop of blood so minuscule that it cannot be seen by the human eye may contain hundreds or even thousands of HBV and/or HCV particles. Even meticulous cleaning may not totally eradicate the virus from a needle. If a person needs unused needles but cannot obtain them, he or she should seek out a needle-exchange program. Alternatively, needle use can be limited to autodestruct syringes. These needles are not reusable. They are designed to self-destruct after one use so that they cannot be reused or shared with others. Of course the best advice for a person who continues to use illicit drugs is to discontinue this activity immediately and seek help at a drug rehabilitation center. Also, anyone who intends to get a tattoo or have a body part pierced should deal only with establishments that are clean and that adhere to meticulous sterilization practices.
The goals of treatment of chronic hepatitis are to achieve sustained viral suppression or total elimination of the virus from the body; to slow or prevent progression to cirrhosis, hepatic decompensation, and HCC; and to prevent transmission to others. Chronic hepatitis B is not curable. Conventional treatment options for hepatitis B include either nucleoside/nucleotide analogues (NAs) or pegylated interferon. Interferons (IFNs) are a family of proteins made naturally by the body that have antiviral, antiproliferative, and immunomodulatory properties. IFN and pegylated IFN have been shown to be effective in reducing HBV replication and inducing disease remission. However, the efficacy of IFN is limited to a narrow population of HBV patients. In addition, its numerous side effects, difficult subcutaneous route of administration, cost, and associated high relapse rate after medication is discontinued have hampered its use for patients with chronic HBV. There are currently five FDA-approved NAs for the treatment of chronic HBV. NAs are quite effective for suppressing HBV replication, induction of disease remission, and the improvement of long-term outcomes. However, the length of time during which patients are treated is not predefined; and is determined by specific parameters that may differ from one patient to another, and treatment may be indefinite for some. Furthermore, long-term use of NAs can be complicated by the selection of antiviral-resistant mutations.
In contrast to hepatitis B, hepatitis C is a curable disease in many patients. This is referred to as a sustained virologic response rate (SVR) and ranges between approximately 20% to 90% (i.e., it is a measure of virus suppression). Length and success of HCV treatment are dependent upon a variety of factors (see Box 171-2). Pegylated interferon (PI) administered subcutaneously once a week, along with oral ribavirin (RBV) pills daily for 24 to 48 weeks, is the current standard of care (SOC) treatment for patients with chronic hepatitis C genotypes 2 and 3, and was the SOC for patients with genotype 1 (G1), the most common and most difficult to cure genotype worldwide. In May 2011, a major advance in the field of hepatology occurred. With the addition of a protease inhibitor, either telaprevir (Incivek, manufactured by Vertex) or boceprevir, (Victrelis, manufactured by Merck), to SOC treatment, SVRs jumped from approximately 42% to as high as 86% for many G1 patients. And, between 44% and 60% of treatment naïve G1 patients are now capable of being cured in just 24 to 28 weeks as opposed to 48 weeks. However, numerous adverse events (AEs), complex treatment regimens, exorbitant costs, and the potential for the development of drug-resistance, may decrease their therapeutic usefulness. This underscores the need for clinicians to be aware of the effects of natural and integrative therapies on the progression of HCV, and of the potential benefits of these therapies either with or without SOC treatment for chronic hepatitis C.
BOX 171-2 Factors Impacting Hepatitis C SVR Rates
Several nutrients and herbs, discussed later, have been shown to inhibit viral reproduction, improve immune system function, and stimulate regeneration of the damaged liver cells.
Experimental studies have demonstrated that sleep deprivation results in poorer immune function, such as reduced natural killer cell activity, suppressed interleukin-2 production, and increased levels of circulating proinflammatory cytokines.6,7 A recent study showed that survival was inversely associated with sleep disturbance among 156 patients with cirrhosis. The study’s authors suggested that tailored behavioral interventions might help to improve overall health-related quality of life and could potentially improve patient outcomes.8 Sleep problems have been reported in patients with chronic hepatitis C, with about 60% to 65% of individuals reporting such complaints. Subjects administered IFN-α demonstrated increased waking after sleep onset, decreased sleep efficiency, and reduced stage 3 and/or 4 sleep.9 Evidence also suggests that impairments in sleep quality exist independent of antiviral therapy with IFN-α and prior to the advanced stages of liver disease.10 Sleep deprivation has also been found to attenuate antibody response to hepatitis A immunization.11 In terms of sleep duration, individuals with less than 7 hours of regular sleep are approximately three times more likely to develop a cold when exposed to nasally introduced rhinovirus than those with 8 hours or more of sleep.12 It may therefore be prudent to encourage proper sleep habits and a duration of 8 hours or more in order to optimize immune and antiviral benefits in the hepatitis patient as well.
The benefits of exercise for people with liver disease are numerous. Studies of patients with hepatitis C incorporating exercise as part of their therapy with SOC show that they can safely participate in an exercise program, create clear changes in the way they perceive their bodies and its capacities, as well as improve their self-confidence, all of which can lead to far-reaching changes in the way this disease and the constraints of treatment are perceived.13 Because fatigue is probably the most common as well as one of the most bothersome symptoms affecting people with chronic hepatitis, exercise can provide a boost of energy and also improve cardiovascular function. Exercise leads to a reduction in total body fat, which is important to all people with liver disease. When total body fat is reduced, the fat content of the liver is also reduced, often resulting in a significant reduction in elevated liver enzymes.13 Thus, it is recommended that all patients with chronic hepatitis incorporate an exercise program combining weight training and aerobics into their daily routine as tolerated once they have been medically cleared by their physicians.
Nutritional treatment decisions for those with acute viral hepatitis should be symptom directed. In general, the focus should be on replacing fluids through consumption of vegetable broths, diluted vegetable juices (diluted with 50% water), and herbal teas in order to avoid dehydration, especially if diarrhea is present. Alcohol should be completely avoided because it can trigger a relapse of acute hepatitis.
Nutritional treatments for chronic viral hepatitis have been shown to have a significant impact on disease progression (e.g., obesity, alcohol consumption, and iron overload) and can worsen the disease, whereas the consumption of caffeine may be helpful. A diet low in saturated fats, simple carbohydrates (e.g., sugar, white flour, fruit juice, honey), oxidized fatty acids (fried oils), sodium, and animal products may be beneficial in patients with decompensated cirrhosis complicated by ascites (fluid retention) and/or hepatic encephalopathy (HE) (brain fog). A diet focused on plant foods (i.e., a high-fiber diet) has been shown to increase the elimination of bile acids, drugs, and toxic bile substances in some patients with decompensated cirrhosis complicated by HE. Alcohol should be completely avoided.
Fruit and Hepatitis C
Blueberries have been found to inhibit the replication of HCV,14 and rats fed diets high in blueberries were protected from developing acute hepatitis.15 This effect may be due to the antioxidant properties of the flavonoid proanthocyanidin that is a component of blueberry leaves.
Naringenin, a flavanoid contained in grapefruit and other citrus fruits, has been found to have antiinflammatory, antioxidant, and lipid-lowering properties and may act as a promoter of carbohydrate metabolism. Naringenin has been found to lower very low density lipoprotein cholesterol. It is suspected that the hepatitis C virus may “hitch a ride” on cholesterol—a theory that has held up in test tube experiments. Studies have demonstrated that naringenin can inhibit or reduce steatosis, (the deposition of fat in the liver),16 in addition to inhibiting HCV viral replication.17 It is important to remember that grapefruit contains furanocoumarins and flavonoids, which can inhibit components of the cytochrome P450 drug metabolism pathway leading to toxic levels of many medications.18,19
Caffeine and Hepatitis C
The mechanism by which caffeine exerts its hepatoprotective effect is under investigation. Data from two population-based studies found that people consuming more than 2 cups of coffee a day were less likely to have elevated serum liver enzymes and were less likely to have chronic liver disease when compared with those who did not drink coffee.20,21 The protective effect of coffee drinking on the development of cirrhosis and its complications, including HCC, has also been shown.22–25
Higher coffee consumption was associated with less hepatic steatosis, a lower ratio of serum aspartate (AST)/alanine aminotransferase (ALT), and lower α-fetoprotein levels in patients with hepatitis C. Patients who drank more than 2 to 3 cups of coffee a day had a lower incidence of disease progression and less fibrosis on histologic evaluation compared with HCV patients who drank less coffee.22,26 Similar results were not seen in patients who got caffeine from other sources or who consumed decaffeinated coffee. Caffeine may also reduce the fatigue associated with HCV and/or chronic liver disease. Although the exact coffee intake necessary to obtain benefits is unclear, it appears reasonable for patients with hepatitis C to drink 2 to 4 cups of regular coffee daily.
A product of the milk curding process, whey may boost immune function, protect against free-radical damage, and improve cellular glutathione levels. A preliminary trial found that 24 g of whey protein daily reduced serum ALT levels and increased plasma glutathione levels in people with hepatitis B but not those with hepatitis C.27
Vitamins C and E
Patients with hepatitis C treated with pegylated interferon and ribavirin were found to have higher SVRs and to be less likely to experience ribavirin-associated anemia when they supplemented this antiviral treatment with vitamins C and E.28,29 It should be kept in mind that vitamin C increases iron absorption and many patients with hepatitis C already have elevated iron stores.
Vitamin E levels have been shown to be low in both serum30 and liver tissue31 in people with hepatitis as well as in those who later develop liver cancer from chronic hepatitis. In one preliminary trial of adults with hepatitis C, administering 1200 IU/day of vitamin E for 8 weeks appeared to reduce liver damage.32 In another study, 544 IU of vitamin E/day for 24 weeks improved the response to interferon/antioxidant therapy, although the results did not reach statistical significance.33