Evaluation of Patients With Liver Disease

This is a general clinical research protocol to allow for evaluation, investigation and
long-term follow up of patients who have an acute or chronic liver disease. The protocol is
designed to study the natural history and pathogenesis of various liver diseases such as
acute and chronic hepatitis B, C, D and E, primary biliary cirrhosis, primary sclerosing
cholangitis, Wilson's disease, hemochromatosis, nonalcoholic steatohepatitis (NASH),
noncirrhotic portal hypertension, hepatocellular carcinoma, and cryptogenic or poorly defined
forms of chronic liver disease. Patients will initially be seen in the outpatient department
and undergo a medical history and physical examination. They will have a series of blood and
urine tests and abdominal ultrasound. Patients will then be followed in the outpatient
department at intervals appropriate for their clinical status, at which times they will
undergo an interim medical history and brief examination and have blood studies taken. Liver
biopsies will be done as a part of this protocol only if clinically indicated. In addition,
patients may be asked to undergo skin biopsy, plasmapheresis, lymphapheresis, genetic
analysis, and Fibroscan procedures for research purposes only (immunologic, virologic,
genetic, and other studies) and separate consent forms are provided. Patients qualifying for
therapeutic or other trials of antiviral or immunomodulatory agents for their liver disease
will be invited to enter such studies.

- INCLUSION CRITERIA:

An indefinite number of patients with acute or chronic liver disease will be enrolled in
this study. Criteria for selection will be the following:

Age above 2 years, male or female.

Evidence of acute or chronic liver disease on evaluation by the outside referring
physician.

Absence of other significant medical illnesses that might interfere with prolonged follow
up evaluation.

Willingness to enter the study.

EXCLUSION CRITERIA:

There are no specific reasons to exclude any patients from this protocol (exception below
for plasmapheresis and lymphapheresis, and genetic analysis of serum samples) as it does
not entail significant risk to the patient or excessive clinical burden to the Liver
Diseases Branch. Patients who resolve their chronic liver disease, such as patients with
chronic hepatitis B who become negative for HBsAg or patients with chronic hepatitis C who
become negative for HCV RNA will continue to be followed despite lack of apparent disease
or disability. This is to document that clearance of these hepatitis viruses is, indeed,
associated with resolution of the liver disease and lack of long-term adverse effects.
Because there are data suggesting that chronic HBsAg carriers who become HBsAg-negative and
patients with chronic hepatitis C whose liver disease becomes inactive, can still develop
long-term consequences of these diseases (especially hepatocellular carcinoma), following
such patients is important.

Plasmapheresis and lymphapheresis: Patients will have to fulfill the criteria of the NIH
Department of Transfusion Medicine regarding lymphapheresis donors. These include age (less
that 65 years), weight (greater than 120 pounds), hematocrit (greater than 30 percent),
blood pressure (less than 120 diastolic and greater than 90 systolic), and temperature
(less than 37.5 degrees C). Because this is a research procedure to obtain reagents and
assay materials, only patients who are active and relatively fit (i.e. not disabled from
their liver disease) will be asked to undergo this procedure.

The only strict exclusion criterion will be active therapy with interferon. The basis for
this exclusion was the findings from a retrospective analysis of a recent trial of
recombinant human alpha interferon as therapy of chronic hepatitis B. In that study, the
"response rate" or rate of clearance of hepatitis B virus with alpha interferon therapy was
lower among patients who underwent lymphapheresis during therapy (48 percent) (p less than
.01). Lymphapheresis performed before treatment did not seem to affect the outcome of
interferon therapy. These findings were unexpected but have led us to avoid both
plasmapheresis and lymphapheresis in patients receiving alpha interferon therapy. The
reasons why lymphapheresis might interfere with a response to alpha interferon are to
known, but probably relate to the importance of an intact, healthy immune system in the
process of recovery from a chronic viral infection.

Fibroscan: Consecutive adult patients (ages 18 or older) with chronic liver disease who
have had a liver biopsy performed within the previous 6 months or who are scheduled to
undergo liver biopsy will be eligible for participation in this aspect of the study.
Patients with liver biopsies that are inadequate for histological scoring or who have
ascites will be excluded from this aspect of the study.

Genetic Analysis of Serum Samples: All adult subjects with a Hct of less than 30 and
pediatric subjects with a Hct less than 26 will be excluded for phlebotomy that is
necessary for isolation of DNA material from the blood cells. Inability to understand or
sign informed consent will also exclude patients from this aspect of the study.