Hepatitis C
Introduction
Hepatitis is an inflammatory process in the liver which is characterized, clinically and histologically, by evidence of diffuse or patchy hepatocellular necrosis affecting all lobules of the liver. Viral hepatitis is a diffuse hepatocellular inflammatory disease caused by at least five different viral agents – A, B, C, D, and E. This is a common and important disease occurring worldwide, with millions of people already infected. For this paper, only Hepatitis C will be discussed.
Hepatitis C (HCV), which was identified in 1988, is now known to be responsible for most cases of transfusion-related hepatitis. It was formerly in the general category of non-A, non-B hepatitis because the disease could not be attributed to infection with either hepatitis A or B virus. Antibodies against the virus (anti-HCV) have since been detected in 71 to 84 percent of transfusion-associated hepatitis. Thus, widespread testing of blood samples for the virus should eliminate about 80 percent of transfusion-associated non-A, non-B hepatitis ( 1991).
Research is identifying increasing numbers of hepatitis viruses. Since hepatitis C was first recognised it has gained increasing significance. The worldwide prevalence is estimated to be around 1 percent, with rates from 1 to 1.6 percent in North America and 10 to 14 percent in North Africa. An estimated 150–170 million people in the world are infected, compared to some 350 million with hepatitis B. Some 4 million people in the United States are presently harboring the virus, the great majority of whom are unaware of the infection. Fortunately, there is evidence that the rate of new infections has decreased by tenfold in the past ten years (2002).
The magnitude of the problem was further compounded by difficulty in obtaining meaningful epidemiologic data: a majority of patients with non-A, non-B hepatitis were anicteric, alanine aminotransferase (ALT) levels fluctuated and no “markers” for the illness existed. The hepatitis C virus is now thought to be responsible for the majority of cases of parenterally transmitted non-A, non-B hepatitis, and for 20 to 50 percent of cases of sporadic viral hepatitis in the United States (1991)
The virus, which causes inflammation in the liver and can lead to more serious illness, primarily is spread by intravenous contact with the blood of an infected person (2003). Hepatitis C is serious not because it attacks the liver acutely but because it is seldom spontaneously eliminated. In fact, the acute disease, even when recognized, tends to be mild. Its persistence leads to cirrhosis in a significant number of those infected; it is a leading cause of that disease. Further, it predisposes to the development of hepatocellular carcinoma ( 2002).
People who are at high risk for hepatitis C are therefore those who inject illegal drugs, those who receive organs from donors whose blood contained HCV, those who get pricked with a needle that has infected blood on it, those who are frequently exposed to blood products, those who “snort” cocaine using shared equipment, those who get a tattoo or body piercing with instruments that were once used on someone infected with HCV, those who use and infected person’s personal effects which may contain blood, and those who engage in high-risk sexual behavior – such as having multiple partners or failing to use a condom (1999).
Hepatitis C can be both acute and chronic. Acute hepatitis C is rarely recognized because its symptoms are usually mild and go unnoticed. Because of this, it is difficult to confidently estimate the total number of infections and the number of people who manage to eliminate the virus. From those cases that have been seen in the acute phase, it appears that not more than 15 percent are able to overcome the virus completely. Chronic hepatitis C, as defined by the liver biopsy, develops in the majority of patients who become infected (2002).
The majority of people who are infected do well. The present treatment regimens, discussed below, are imperfect. We do not recommend treatment for everyone. Because of the large numbers of people involved, chronic hepatitis C is an important public health problem and should not be trivialized. Those who have it should be identified and offered treatment if indicated, but prognosis after infection is better than has been implied in the media. Most who are infected die with the disease but not because of it ( 2002).
Only about 15 percent of those infected with HCV have a short-term infection that goes away by itself and never returns. The other 85 percent become chronically infected, meaning the virus stays in the liver, replicates, and may slowly attack the organ over a period of decades (2001).
Etiology and Pathogenesis
Hepatitis C virus, along with hepatitis B virus, are the major causes for chronic hepatitis. About 75% of cases of hepatitis C become chronic (1999). The mechanism of chronicity is uncertain, but a direct cytopathic effect of the virus appears to be only minor; instead, liver injury is largely caused by an immune-mediated host reaction to the infection.
HCV is an RNA virus with nine major genotypes, designated by the numbers 1–9, of which only the first four (maybe five) are important players. There are at least forty different subtypes within these major types, designated by lowercase letters. The first genotype and subtype clearly identified was designated 1a. It is the most common genotype throughout the world and is associated with disease that is more severe than the others. Genotypes occur with varying frequency around the world and differ in their response to treatment. In the United States, genotype 1 is the most common, with subtype 1a being the most frequent subtype (2002).
Major causes of hepatitis are the types of viruses, alcohol (2001), and drugs. Rarer etiologies include infectious mononucleosis yellow fever, cytomegalovirus, coxsackievirus, other specific viral infections, and leptospirosis. Parasitic infections such as schistosomiasis, malaria, and amebiasis affect the liver but do not cause a true hepatitis.
Various drugs can cause chronic hepatitis, including isoniazid, methyldopa, nitrofurantoin, and possibly acetaminophen. The pathogenesis varies with the drug and may reflect an altered immune response, cytotoxic intermediate metabolites, or genetically determined metabolic defects.
Many cases are idiopathic. A high proportion of these cases have prominent immune features; this is considered a specific variant of the disorder (autoimmune hepatitis). Overwhelming evidence points to immunologic mechanisms of hepatocellular injury in these patients, including coexisting clinical and serologic immune markers; an association with HLA-B8 and -DR3 haplotypes; extensive periportal infiltration with T lymphocytes and plasma cells; complex in vitro defects in cellular immunity and immunoregulatory functions; and response to therapy with corticosteroids or immunosuppressive drugs. Despite this, proof of true autoimmune causation is lacking because auto-antibodies directed uniquely against liver cell antigens have not been proven.
Symptoms and Signs
Clinical features vary. About 1/3 of cases follow acute hepatitis, but most develop insidiously de novo. Many patients are asymptomatic, especially in chronic hepatitis C. Nonspecific malaise, anorexia, and fatigue are common, sometimes with low-grade fever and nondescript upper abdominal discomfort. Jaundice is variable and is often absent (1991).
Signs of chronic liver disease (eg, splenomegaly, spider nevi, fluid retention) may eventually develop, but in many patients the disorder remains subclinical for many years or even decades. In the autoimmune variant, multisystemic or “immune” manifestations often occur, especially in young women. These can affect virtually any body system and include acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis, and hemolytic anemia. A minority of patients develop predominant cholestatic features suggesting primary biliary cirrhosis (1999).
In chronic hepatitis C, Most of those have no symptoms. In people who do, the most common is chronic fatigue that is disproportionate to the amount of disease in the liver. Depression seems to be more frequent than in other diseases. Other symptoms are equally nonspecific and include loss of appetite, nausea with little or no vomiting, vague abdominal discomfort localized over the liver, and joint pains with no swelling.
Methods of Transmission
The sharing of needles during “recreational” drug injection is the most common means of transmission. Many patients today are those who indulged in the “drug culture” of the 1960s (if only for a little while—once is enough). This should in no way be taken to mean that infection with HCV proves that the individual used IV drugs in the past. As with hepatitis B, around 20 to 40 percent of infected persons have no identifiable risk factors. Educational efforts and the appearance of AIDS (1995) have resulted in less sharing of needles and therefore a decrease in the number of new cases of hepatitis C.
Health care personnel can become infected despite careful protective measures. This kind of situation is present even in Hong Kong. Transmission may also occur through kidney dialysis units where considerable amounts of blood are used. In such units, the prevalence of antibodies has been reported to be between 10 and 20 percent compared to 1.5 percent in a similar population not being dialyzed ( 1999).
Transmission by sexual intercourse or to members of a household, while known to occur, is unusual. In monogamous relationships involving one partner who is infected but whose liver tests are normal, the sexual partner is found to be infected in less than 3 percent of cases. Even when the infected spouse has active disease with abnormal liver tests, less than 7 percent of the uninfected spouses acquire the disease if they do not have other risk factors. The incidence of HCV in male and female prostitutes and homosexuals is only slightly higher than in the general population.
Transmission from mothers with the virus to their newborn infants occurs infrequently. It should be noted that, at birth, infants of mothers who have HCV antibodies will also have maternal antibodies that have crossed the placenta but no evidence that the virus is present. These maternal antibodies in the infant will disappear after several months. If the mother is infected with HIV in addition to HCV, a not-uncommon occurrence, the risk to the child of being infected at birth with HCV is markedly increased (2002).
Methods of Diagnosis
The disorder must be differentiated from alcoholic liver disease, recrudescent acute viral hepatitis, and primary biliary cirrhosis. Clinical and laboratory features are helpful, but liver biopsy is essential for definitive diagnosis. Mild cases may have only minor hepatocellular necrosis and inflammatory cell infiltration, usually in portal regions, with normal acinar architecture and little or no fibrosis. Such cases only uncommonly develop clinically important liver disease or cirrhosis.
In more severe cases, biopsy typically shows periportal necrosis with mononuclear cell infiltrates (so-called piecemeal necrosis) accompanied by variable periportal fibrosis and bile duct proliferation. The acinar architecture may be distorted by zones of collapse and fibrosis, and frank cirrhosis sometimes coexists with signs of ongoing hepatitis. In most instances, the specific cause cannot be discerned, although cases caused by HBV can be distinguished by the presence of ground-glass hepatocytes and special stains for HBV components. Autoimmune cases usually have a more pronounced infiltration by lymphocytes and plasma cells.
The signs, symptoms, and laboratory findings of acute hepatitis C are indistinguishable from those of any of the hepatotrophic virus and have been described in chapter 2. Acute cases are seldom seen for reasons already noted, but hepatitis C must be considered in the differential diagnosis of any case of acute hepatitis. Because antibodies against HCV do not appear until about eight to ten weeks after onset of the disease, tests for them are not useful in recently acquired disease.
However, the virus appears in the serum early on and can be quantified by amplification of HCV RNA using the PCR. The PCR is therefore useful for identifying the acute disease. Liver biopsy that shows hepatitis will not define its cause and thus is not helpful. When these tools are used, the diagnosis of acute hepatitis due to HCV is seldom a problem (2002).
Chronic hepatitis C is usually discovered when laboratory tests are done for any reason and abnormal liver tests are found. In most cases, the physical examination is completely normal, but in some, the liver may be moderately enlarged and slightly tender. If extensive fibrosis or cirrhosis is present, the liver and spleen are enlarged and palpable. Signs of cirrhosis include fluid in the abdomen (ascites), swelling (edema) of the legs, and hepatic “spiders.” Tests that could help detect the HCV virus are ELISA, or enzyme-linked immunosorbent assay, and RIBA, or radioimmunoblot assay (2002).
Infection Control Precautions
The incidence of hepatitis C is falling. This is partly because of testing for the presence of the virus in donor blood and in biological agents that are made from blood and injected for various treatments, such as concentrated factor VII for bleeding disorders.
Unfortunately, vaccines are not available. Efforts to develop them continue, but the results are not encouraging. Although the use of gamma globulin has not been specifically tested as prophylaxis against HCV, studies with this preparation several years ago in efforts to prevent posttransfusion hepatitis, which was primarily caused by HCV, were unsuccessful. Since there is no reason to believe that gamma globulin would be helpful, it is not recommended. Tattoos and body piercing have been implicated and should be avoided. The sharing of needles during illicit drug use is now the most common mode of transmission (2002).
Presently, there is no vaccine for hepatitis C, but there are vaccines for hepatitis A and B. The CDC recommends these vaccines, particularly the hepatitis A vaccine, for HCV-positive individuals. Becoming infected with hepatitis A virus can be life threatening for someone with HCV infection. In May, the FDA approved a combined hepatitis A and B vaccine called Twinrix, marketed by SmithKline Beecham Pharmaceuticals in Philadelphia ( 2001).
As discussed briefly in the first parts of this paper, HCV exists in many different forms, called genotypes, confounding researchers in their quest to develop a vaccine effective for all variations. Also, HCV mutates frequently within infected patients, so even if an effective vaccine is developed, it could be rendered useless by a new strain of mutant virus (1999).
A major focus of hepatitis research is development of a cell culture through which scientists can study HCV outside the human body. By understanding how the virus replicates and how it injures cells, researchers may be able to develop ways to control the virus as well as drugs to block it. It is very likely that a vaccine specific to hepatitis C will be developed in the near future. The cost of the research to acquire a vaccine will definitely be justified when you consider all of the demands made upon the healthcare system.
Prognosis
Prognosis is highly variable. With drug etiology, disease may regress completely when offending agent is withdrawn. Cases associated with HBV or HCV tend to progress slowly and are usually relatively resistant to therapy. Autoimmune cases generally improve substantially with treatment. With adequate therapy, patients usually live several years or decades, but hepatocellular failure, cirrhosis, or both eventually develop in many cases (1999).
Treatment
Treatment includes cessation of causative drugs and management of complications (eg, ascites, encephalopathy). Autoimmune hepatitis is best treated by corticosteroids with or without azathioprine. These drugs suppress the inflammatory reaction, perhaps partly by beneficially altering the immune response, and have increased long-term survival.
In most patients, symptoms lessen, biochemical abnormalities largely resolve, and histologic inflammation regresses. However, fibrosis may progress despite apparent clinical and laboratory control, and attempts to discontinue therapy usually lead to relapse; most patients require long-term low-dose maintenance treatment. Drug dosage should be supervised by a specialist.
Therapy for both chronic hepatitis B and C is evolving. Corticosteroids are contraindicated, because viral replication is enhanced. Interferon- is now widely used to suppress viral replication, but overall results are relatively disappointing.
Chronic hepatitis C is treated with a combination of interferon- 3 million IU sc three times weekly plus oral ribavirin 1200 mg daily in two divided doses, which gives better results than interferon alone. This initially suppresses inflammation in about 2/3 of patients. Responders are treated for either 6 or 12 months depending on the specific viral genotype, but most relapse when treatment is stopped; successful long-term disease suppression is only about 30-40% overall. Response depends in part on the viral genotype, viral load, and histologic stage of the disease. Pegylated interferon, a recently developed modification of the drug molecule, will likely replace standard interferon in the near future because it requires injection only once a week and gives marginally better results ( 1999).
In addition to having limited efficacy, interferon- is expensive, must be given by injection, produces bothersome flu-like side effects in most patients, and induces more serious side effects in a minority of cases. Treatment should be supervised by a specialist. Other antiviral and immunomodulatory drugs against HBV and HCV have been evaluated or are being studied, but no major breakthrough appears imminent.
Liver transplantation has not generally been suitable for end-stage liver disease caused by HBV, because of aggressive disease reference in the graft, but treatment with lamivudine can now help ameliorate this problem. Transplantation for advanced hepatitis C is much more successful; although HCV infection universally recurs, the clinical course is generally indolent, and long-term survival rates are relatively high. In many transplant centers, hepatitis C is now the most common indication for adult liver transplantation.
Treatment for hepatitis C is a combination of interferon b and ribavirin. Whether we should treat the disease when it is recognized in its acute phase is arguable. Most of us with experience will do so in the appropriate setting. The hesitancy comes from knowing that in acute hepatitis B, interferon b cannot be used because it temporarily makes that disease worse.
This does not occur in hepatitis C, and, because the majority with acute hepatitis C develop persistent infection and chronic liver disease, use of interferon b seems rational. There have been only a few studies in a relatively small number of patients regarding this issue, but the findings suggest a much higher rate of complete disease remission (39 to 40 percent) in those with acute hepatitis C treated with IFN at an early stage compared with untreated subjects (0 percent).
On the other hand, treatment of the patient with severe cirrhosis and very abnormal liver tests with jaundice (called “decompensated”) should not receive treatment because of the risk of making the inflammatory process temporarily worse and causing the death of the patient (2002).
The goal of treatment is sustained response–meaning that the virus is not measurable in the blood after drug therapy is completed. Those who continue to have measurable levels of the virus after treatment are considered non-responders. Relapsers “clear” the virus during therapy or shortly thereafter, but the virus returns after therapy ends ( 2001).
Evaluation of the safety of clinical practice in my workplace
Health care professionals are among those that are at high risk for hepatitis C. Treating and having to take care of people who are infected with the hepatitis C virus poses a great risk for health care professionals. Safety measures have therefore to be examined within health care institutions. So far, within my workplace, standard operating procedure regarding care of patients infected with HCV have been strictly followed, as well as the handling of specimen which are HCV carriers.
Preventing transmission from healthcare workers to patients has been controversial. Although transmission has been documented, it is rare and limited to case reports. Up to half of the reports were confounded by other factors like contamination of patients’ narcotics used for healthcare workers’ surreptitious habit of IV drug use. The calculated risk for HCV transmission from an RNA-positive surgeon to a patient during an invasive procedure is 0.00018%, which was roughly comparable to the chance of acquiring HCV by transfusion in the United States in the year 2000. It is recommended in some countries that no HCV-infected healthcare professional be restricted from his or her work. Despite this recommendation, some health departments have required HCV-infected physicians to obtain informed consent before performing surgery on their patients ( 2004).
Conclusion
Hepatitis C is dangerous not only because of the damage it inflicts, but because people may be asymptomatic for years before they realize they are suffering from incurable liver disease. It almost exclusively is spread by dirty needles. Currently there is little hope for treatment of hepatitis C. A drug called Interferon Alpha-2B (inferferon is an immunity substance naturally present in small amounts in the body) has proven somewhat successful in combating the virus, but only in about 15 to 20 percent of the cases. While scientists are conducting research to find more-powerful antidotes, the best hope of curbing the spread of the virus continues to lie mainly in prevention. Health care institutions also have to be aware of the specific measures needed to be able to avoid and prevent infection with the hepatitis C virus. Further programs are needed for populations to educate them of the severity of the disease and its complications.
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