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
Liver problems are frequent causes of illness and death in
people with HIV infection, even in those previously considered
healthy. 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
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
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. 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.
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
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. Spontaneous
remission of chronic HBV infection can occur, but it too is
less likely in HIV-positive patients (11.5 versus 4.8
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. 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.
It is clear, however, that HIV-infected individuals with
chronic HBV tend to have higher levels of replicating hepatitis
B virus. 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
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. 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. 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. 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.
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. 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
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). This drop was
deeper in patients with more than 500 CD4 cells who did not
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
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.
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. 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.
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. 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. For non- Hodgkin's lymphoma, treatment
with intensive chemotherapy can be beneficial, with a 52
percent response rate found in one series.
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).
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).
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. 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. 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. 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. 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. 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.
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
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