Ursodeoxycholic Acid (UDCA) for Hepatic Sarcoidosis

Sarcoidosis is a relatively rare, poorly defined autoimmune disease characterized by the
formation of sterile granulomas in affected organs, including the liver. The diagnosis of
hepatic sarcoid is often presumed based upon an elevated liver-specific isoenzyme of alkaline
phosphatase or imaging findings suggestive of portal hypertension, hepatomegaly, or liver
lesions in a patient with known pulmonary sarcoidosis; a minority of hepatic sarcoid cases
are diagnosed through liver biopsy. The mainstay of treatment of systemic sarcoidosis in
those with symptoms is immunosuppression with corticosteroids, which are gradually tapered
over months. The disease course for sarcoidosis can vary; patients who are asymptomatic can
be monitored without therapy, while some require intermittent corticosteroids for flares. The
expert guidelines for treatment of hepatic sarcoid suggest waiting until a patient is
symptomatic or experiencing evidence of liver dysfunction to treat. This approach is in
opposition to the treatment of primary liver diseases in which treatment is often initiated
based upon abnormal lab values even without symptoms, as symptoms of liver disease (ascites,
variceal bleeding, pruritus, jaundice, and encephalopathy) often occur late in the disease.
The approach to the treatment of hepatic sarcoid should be similar to two other autoimmune
liver diseases: autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC). Liver
decompensation can be prevented in both AIH and PBC if the disease is diagnosed and treated
in the early stages. The first-line treatment for AIH is immunosuppression with
corticosteroids and azathioprine; for PBC, it is Ursodeoxycholic acid (UDCA). In a similar
vein, patients with hepatic sarcoid may benefit from earlier initiation of therapy. Given its
excellent safety profile and minimal side effects, UDCA may be the consensus first-line
treatment for hepatic sarcoid, a disease that, like PBC, usually causes a cholestatic liver
injury. There have been case reports and retrospective studies documenting the beneficial
effects of UDCA on hepatic sarcoid. However, thus far, there have been no clinical trials to
evaluate the efficacy of UDCA in hepatic sarcoid. This pilot study will examine the effects
of UDCA in a small sample of patients at the University of Pennsylvania. Patients with a
prior diagnosis of sarcoidosis and lab/imaging findings suggestive of hepatic sarcoid would
be approached. The primary endpoint is a reduction in alkaline phosphatase from baseline.
Secondary endpoints include safety and tolerability of UDCA, new or worsening symptoms of
hepatic sarcoidosis and liver disease, changes in bilirubin and transaminases, and liver
stiffness as measured by Fibroscan. A minimum of ten patients will be enrolled for a
twelve-month study with the total study time of two years. It is hypothesized that UDCA will
lead to modest decreases in alkaline phosphatase levels in patients with hepatic sarcoid with
minimal side effects. Overtime a long-term decline in alkaline phosphatase could decrease the
risk of hepatic decompensation in patients with hepatic sarcoid.

As an exploratory objective and optional sub-study, the investigators will include the
methacetin breath test (MBT), a noninvasive tool to assess microsomal capacity to metabolize
the nonradioactive compound 13-Carbon-labeled Methacetin. The MBT will be used in parallel
with clinical and laboratory parameters (Fibroscan, liver enzymes) to assess subjects liver
function prior to and following intervention with UDCA. Changes in the methacetin breath
tests in all subjects prior to and following intervention with UDCA will be examined as a
secondary exploratory endpoint.

Inclusion Criteria:

1. Systemic sarcoidosis with evidence of liver involvement as denoted by any of the
following:

- Elevated liver-specific alkaline phosphatase

- Granulomas on liver biopsy

- Hepatomegaly on imaging

- Portal Hypertension (via imaging or endoscopy)

2. Stable dose of immunosuppressant, if taking (no dose variation for 6 months)

3. If cirrhotic, absence of hepatocellular carcinoma as indicated by imaging within 6
months of screening

Exclusion Criteria:

1. Female who is pregnant, planning to become pregnant during the study, or breastfeeding

2. Clinically significant abnormalities, co-morbidities, or recent alcohol/drug abuse
that make the subject an unsuitable candidate

3. Concurrent liver disease including hepatitis B, hepatitis C, alcohol-related liver
disease, autoimmune hepatitis, primary biliary cholangitis, primary sclerosing
cholangitis

4. Currently on UDCA

5. Prior intolerance to UDCA

6. Receipt of any investigational product within a time period equal to 10 half-lives of
the product, or 6 weeks (whichever is longer), to study drug administration

7. Current evidence of hepatic decompensation (variceal bleeding, hepatic encephalopathy,
or ascites). In the event potential participant is post-transplant, no evidence of
hepatic decompensation since transplantation