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Gay Men's Health Crisis
Liver Disease and HIV
Ian Richardson, T. Melester and David Gold
July 1, 1994
GMHC Treatment Issues 1994 Jul 1; 8(5): 4

The liver, a large organ located in the upper right portion of the abdomen, is the body's chemical factory. Disorders of the liver and the associated bile ducts and gall bladder can have serious complications. They involve many organs in the body, all of which depend on the liver's products to support their activity.

Liver problems are frequent causes of illness and death in people with HIV infection, even in those previously considered healthy.[1] Both physicians and patients should be aware of the symptoms, methods of diagnosis, drug toxicities and available treatments for HIV-related liver conditions. Symptoms such as pain on the right side of the stomach, enlarged liver (hepatomegaly), jaundice (yellowing of eyes or skin), fever of unknown origin, fatigue, malaise, itching and abnormal liver function tests (LFTs) deserve early and complete evaluation.

The Functions of the liver The liver has many critical functions including filtering blood, eliminating toxins, secreting bile (a fluid that helps absorb and digest fat), and making clotting factors. It also converts sugar into triglycerides (lipids) and glycogen (a carbohydrate) to be stored for energy and, between meals, converts triglycerides, glycogen and amino acids into blood sugar to meet the body's immediate energy needs.

The work of the liver is particularly critical to the brain and central nervous system. These tissues receive their energy supply only from sugar, and so are extremely vulnerable to liver failure.

Diagnosing Liver Disorders Various tests are available for persons with liver disorders. These include tests for liver function and viral hepatitis. Computerized tomography (the familiar "cat," or CT, scan) and ultrasound sonograms may also frequently be useful.

Liver chemistry tests are an initial means for measuring the liver's condition. For example, high blood levels of bilirubin, formed by the breakdown of hemoglobin, indicate that the liver is not adequately transferring excess iron from the bloodstream to the bile, and this is a specific indicator of liver disease. High blood levels of two common liver enzymes involved in amino acid breakdown (AST and ALT, also designated as "SGOT" and "SGPT" in lab reports) are a sign of acute liver cell injury. Such damage to cell integrity allows these chemicals to escape from the cells and is associated with viral hepatitis and the toxic effects of drugs and poisons.

Some specialists recommend a liver biopsy for HIV-positive patients with unexplained fever or abnormal liver tests. In this procedure, a segment of tissue is removed with a needle inserted through the skin. The tissue is then examined microscopically. In one 50-biopsy series in people with HIV, 40 percent of tissue samples were found to have mycobacterial infection--a manageable condition that can be fatal if not treated appropriately.[2] Liver Infections The majority of liver diseases in patients with HIV are caused by viruses (especially hepatitis B and hepatitis C) or opportunistic infections (MAC, cryptosporidiosis, CMV). Recent studies suggest that the liver is an important site of HIV replication, too.[3] There have been well-documented cases of liver inflammation during primary HIV infection, the initial flu-like syndrome that often precedes seroconversion, and this is a strong indication that HIV attacks liver cells directly.

Viral Hepatitis Both hepatitis B virus (HBV) and hepatitis C virus (HCV) can result in chronic infection and liver disease. (Hepatitis A virus (HAV), in contrast, almost never results in chronic infection.) It is now known that HIV can significantly affect the development, course of disease and treatment of chronic hepatitis B and C.

Hepatitis B: Once exposed to hepatitis B, HIV-positive individuals are far more likely than others to develop chronic HBV infection.[4,5] One study found that 21 percent of the HIV-positive men who were exposed to HBV developed chronic HBV infection compared to only seven percent of the HIV-negative men.[6] Spontaneous remission of chronic HBV infection can occur,[7] but it too is less likely in HIV-positive patients (11.5 versus 4.8 percent).[8] The risk of chronic HBV infection is that long-term active hepatitis and cirrhosis (degeneration of liver tissue) are likely to develop. Studies of HIV-negative individuals suggest that one in three with chronic hepatitis B infection will develop continuing active hepatitis.[9] It is not known what percentage of people with HIV and chronic HBV infection will experience active hepatitis or cirrhosis. A few studies have suggested that chronic hepatitis B is less severe[10,11] or does not affect survival in people with HIV.[12,13] Some believe that this putative reduction in severity is due to a lowered immune response. During infection with HBV, T-cells attack the liver cells that are infected with HBV, thereby causing liver cell death and clinical symptoms. It is hypothesized that with a lessened immune reaction, clinical symptoms and liver cell death are less likely to occur. Nevertheless, many specialists, including Douglas Dieterich, M.D., of New York University Medical Center, have not seen any lessening of clinical symptoms or liver damage in HIV-positive patients with chronic HBV infection.[14] It is clear, however, that HIV-infected individuals with chronic HBV tend to have higher levels of replicating hepatitis B virus.[15] Bodsworth et al, in a study of 150 gay men with chronic HBV, concluded that chronic hepatitis B appears to be less severe when accompanied by HIV infection but that greater viral replication may make it more contagious and resistant to therapy.

Alpha interferon is the only approved therapy for hepatitis B. It appears to have some usefulness, but lower response rates to alpha interferon therapy are seen in people coinfected with HIV. A twelve- person study of HIV-positive individuals with chronic HBV reported a 25 percent response to alpha interferon. The likelihood of successful treatment seems related to CD4 cell count and the extent of liver damage at the time of beginning treatment.[16] One very small study reported that giving prednisone (a type of steroid) before alpha interferon therapy increases the likelihood of clearance of HBV virus in HIV-positive patients.[17] Corticosteroid treatment may pose risks to HIV-positive patients, though. These include possible reactivation of such infections as herpes, tuberculosis and candidiasis (thrush).

There also are two licensed vaccines for preventing HBV infection: Engerix-B and Heptavax. Both are given in three doses (injections) over six months and are 95 percent protective in immune competent individuals. HBV vaccination is recommended for HIV-infected people who have not been exposed to hepatitis B. Yet, because of a lessened immune response, HIV-positive individuals may have an insufficient antibody response to the vaccine. Some doctors recommend additional doses of the vaccine if the original course does not stimulate sufficient antibody production.

In an alarming finding, individuals with HIV appear to have a strikingly high chance--between 56 and 80 percent according to one study--of developing chronic HBV infection if they are exposed to HBV after the first vaccination dose but before the final dose.[18] Doctors should warn HIV-positive patients receiving the HBV vaccine to be extra careful about risking HBV exposure during the six month vaccination period.

Hepatitis C: Hepatitis C is by far the most serious of the three major hepatitis viruses since well over half of all those infected develop chronic HCV infection. Researchers now believe that the presence of HIV greatly enhances the ability of HCV to cause liver disease. In a study of 223 people with hemophilia, 44 percent (97) were coinfected with HIV and HCV and nine percent (eleven) of these developed liver failure. In comparison, none of the HIV-negative study participants with chronic HCV developed liver failure. The lead researcher in the study, Elaine Eyster, M.D., of the Hershey Medical Center, reports that hepatitis C viral load increases soon after HIV infection and that HIV-infected individuals have a faster progression to liver disease.[19] Alpha interferon is the single approved therapy for chronic HCV. Only about ten to 25 percent of immune competent patients have a long- term response to therapy.[20] In HIV-positive persons with chronic hepatitis C, long-term improvement is still less likely. While an Italian study reported that five of twelve HIV- and HCV-positive patients given alpha interferon had a return to normal liver function tests, four of these five responders had a rebound increase after therapy was stopped.[21] A number of physicians told Treatment Issues that alpha interferon therapy is far more useful in HIV-positive patients with higher CD4 counts. However, a study of alpha interferon treatment in HIV- and HCV-infected patients in Spain reported that in twelve of 30 patients (40 percent), alpha interferon therapy led to a "transient dramatic decline in absolute CD4 count" (but no decline in CD4 percent).[22] This drop was deeper in patients with more than 500 CD4 cells who did not receive AZT.

At least two trials in the New York area are currently studying alpha interferon therapy in individuals with HIV and HCV (St. Vincent's Hospital 212/604-7020 and NYU Medical Center 212/263-8707).

Opportunistic Infections Opportunistic infections of the liver are seriously under-recognized. Studies have found that 40 percent of the livers from deceased people with AIDS contain undiagnosed opportunistic infections, and many of the same pathogens also were found in the bile ducts and gall bladder.[23] The most frequent opportunistic infections of the liver are mycobacterium tuberculosis (TB), mycobacterium avium (MAC) and cytomegalovirus (CMV). Less often, pneumocystis carinii (which causes PCP in the lungs) and leishmania (a parasitic protozoa common in Asia) are present. Some of these conditions are treatable, with prognosis directly tied to how early diagnosis is made. In the case of extrapulmonary tuberculosis (TB outside of the lungs), response to treatment in HIV-positive patients has been shown to be similar to that of HIV-negative patients if diagnosed early.[24] However, if untreated, disease progression is rapid and nearly always fatal.

Also, various unexpected non-viral pathogens (such as fungi, parasites, and bacteria) may be found in the liver following diagnosis of a viral hepatitis. Since these often respond to antibiotic treatments, doctors and patients must carefully watch for such infections.[25] Liver Cancers The cancers most commonly found in the liver of AIDS patients are non-Hodgkin's B cell lymphoma and Kaposi's Sarcoma (KS). Up to one third of people with KS will have some involvement in the liver, but this generally remains asymptomatic, being found only at autopsy.[26] In lymphoma, a cancer which affects five to nine percent of people with AIDS, the gastrointestinal tract and liver are the most common sites of involvement outside of the lymph nodes.[27] For non- Hodgkin's lymphoma, treatment with intensive chemotherapy can be beneficial, with a 52 percent response rate found in one series.[28] Drug-Related Toxicities Since the liver processes toxic compounds absorbed by the body, its cells are particularly sensitive to the side effects of medications. Many drugs used in AIDS therapy induce changes in liver enzyme tests or cause other impairments of liver function. Most of these drug-related liver toxicities can be reversed when the drug is discontinued or the dose is lowered. But effect of drugs taken alone does not necessarily predict the combined effect of several drugs taken together.

Certain therapies commonly used for HIV or AIDS-related purposes are known to be particularly damaging to the liver. These include clarithromycin, dapsone, dilantin, fluconazole, fluctosine, isoniazid, ketoconazole, rifabutin, rifampin and TMP/SMX (bactrim or septra).

Nucleoside Analogs AZT, ddI and ddC do not seem to cause significant liver toxicity in most people with HIV. Still, there are a few published case reports of AZT- and ddI-associated liver failure leading to death.[29,30] According to Daniel Stein, M.D., currently of Albany Medical College and formerly of the Division of AIDS (DAIDS) at the National Institutes of Health, there are a total of at least 40 reported cases of liver failure in HIV-positive patients believed to be associated with nucleoside analog therapy (generally AZT or ddI).[31] At least three cases of liver failure involved participants in AIDS Clinical Trials Group (ACTG) studies. All three of these patients were female, asymptomatic and had been treated with AZT for over six months. None of the patients had any history of chronic hepatitis or liver disease. Dr. Stein reports that males were also among the 40 cases.

While such cases are believed to be rare, physicians are advised to carefully monitor patients on nucleoside analog therapy who have progressively increasing liver function tests and evidence of enlarged livers.

There is also concern that in some people with HIV and hepatitis C, the use of nucleoside analogs like AZT, ddI or ddC may cause additional liver damage. Another study by Dr. Eyster followed thirteen persons with hemophilia who were coinfected with HIV and HCV. Among the five who developed liver disease, four were being treated with AZT.[32] Dr. Eyster told Treatment Issues that when some patients are treated with anti-HIV drugs metabolized by the liver, sub-clinical liver disease may become apparent. "The liver has been progressively damaged by HCV, then HIV treatment tips them over," she suggested. The study, according to Dr. Eyster, "raises the question of whether multiple drug combinations in certain doses are appropriate for HIV- and HCV-infected people with hemophilia." Gall Bladder and Bile Duct Disease The gall bladder is a pear-shaped organ on the interior surface of the liver. It acts as a reservoir for bile. Gall bladder disease without stones (also known as acalculous cholecystitis) is commonly associated with HIV infection. It can cause enlarged bile ducts which block the flow of bile between the liver and the intestine, resulting in jaundice and pain.

It is not known definitively why HIV-related gall bladder disease occurs, but the condition is frequently associated with such opportunistic infections as CMV or cryptosporidiosis (and to a lesser extent MAC, histoplasmosis and other organisms), or direct HIV infection of the gastrointestinal system. Studies at San Francisco General Hospital suggest that more than ten percent of asymptomatic AIDS patients have abnormal bile ducts. Almost 80 percent of patients with pain and elevated blood level of a liver enzyme known as alkaline phosphatase had an abnormal bile duct structure.[33] Symptoms of HIV-related gall bladder and bile duct disease include severe right-side abdominal pain with fever, vomiting, progressive weight loss, intermittent fevers, swollen glands, jaundice and diarrhea. The vagueness of these symptoms makes it easy to misdiagnose this disease.

Although gall bladder disease had once been assumed to occur only in already severely ill patients, it has now been shown that this can also be the first manifestation of AIDS.[34] The possibility of gall bladder disease without stones must be considered in patients with abdominal pain, especially in the presence of elevated serum alkaline phosphatase and the absence of jaundice. Ultrasound and CT scans are effective for evaluating the presence of bile duct disease.[35] Due to the nature of these infections, actual tissue specimens may be necessary in order to make the diagnosis. ERCP (an endoscopic procedure in which dye is injected into the biliary ducts), removal of the infected gallbladder, and liver biopsy may all be required to positively identify the infectious agent and begin appropriate treatment.

If specific organisms can be identified, antibiotic therapy is necessary. Further treatment, such as the surgical removal of the gall bladder or opening of the obstructed bile duct entrance, may be required to eliminate the infectious agent. Removal of the bile duct can help remove reservoirs of infection.[36] In one recent study, twelve month survival after the diagnosis of bile duct infections was only fourteen percent. This figure may be merely a reflection of the under-diagnosis of this condition in healthier HIV-positive individuals. And, of those diagnosed late in the progression of AIDS, opening the obstructed bile duct did manage to relieve abdominal pain in 86 percent of patients.[37] Conclusion Despite the lack of therapy options for many HIV-related liver diseases, there are some treatable conditions that make proper monitoring and diagnosis important. An awareness of symptoms, methods of diagnosis, drug toxicities and interactions, and available treatments will help patients lead longer, healthier lives.

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