Cholic Acid for Hepatic Steatosis in Lipodystrophy

Lipodystrophies are rare disorders characterized by selective loss of adipose tissue and
predisposition to develop insulin resistance and its associated metabolic complications such
as dyslipidemia, diabetes mellitus and hepatic steatosis. Nonalcoholic hepatic steatosis or
steatohepatitis caused by excessive accumulation of triglycerides in hepatocytes, in fact, is
a common feature of these disorders. Often a cause for significant morbidity and even
mortality in lipodystrophic patients, hepatic steatosis poses a significant therapeutic
challenge. Recent insight into the role of primary bile acids, cholic acid and
chenodeoxycholic acid, which are endogenous ligands for the farnesoid X receptor (FXR), in
regulating hepatic triglyceride homeostasis offers new treatment options for hepatic
steatosis. Cholic acid was shown to inhibit hepatic triglyceride accumulation by more than
50% in a mouse model of hepatic steatosis and hypertriglyceridemia. Cholic acid has been
previously used to treat inborn errors of bile acid synthesis in children without any side
effects. In other studies in adults, cholic acid has been reported to be well tolerated.
Therefore, we propose to investigate a potentially safe therapeutic option for its efficacy
in reducing hepatic steatosis in patients with lipodystrophies.

Inclusion Criteria:

- Patients with lipodystrophies as diagnosed by clinical criteria.

- Hepatic steatosis (>5.6% hepatic triglyceride content) as demonstrated by 1H magnetic
resonance spectroscopy.

- Age 6-70 years.

- Alcohol intake of less than 40 g per week.

Exclusion Criteria:

- Laboratory or other histologic findings highly suggestive of liver disease due to
causes other than non-alcoholic steatohepatitis, such as chronic viral hepatitis,
autoimmune hepatitis, primary biliary cirrhosis, biliary obstruction or genetic liver
diseases such as Wilson's disease, hemochromatosis or alpha-1-antitrypsin deficiency.

- Treatment with drugs associated with steatohepatitis, e.g., corticosteroids, high dose
estrogens, methotrexate, amiodarone, , sulfasalazine, or oxacillin in the 6 months
prior to the study.

- Decompensated liver disease as evidenced by clinical features of hepatic failure
(variceal bleeding, ascites, hepatic encephalopathy etc.) and laboratory
investigations (prolonged prothrombin time, hypoalbuminemia, presence of esophageal
varices etc.)

- Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml
and/or liver mass on imaging study suggestive of liver cancer.

- Use of drugs which can potentially decrease hepatic steatosis during previous 3
months; ursodeoxycholic acid, high-dose vitamin E, betaine, acetylcysteine and
choline. Thiazolidinediones are allowed if dose has been stable for 3 months prior to
screening.

- Significant systemic or major illnesses other than liver disease, such as congestive
heart failure, cerebrovascular disease, respiratory failure, renal failure (serum
creatinine >2 mg/dL), acute pancreatitis, organ transplantation, serious psychiatric
disease, and malignancy, that could interfere with the trial and adequate follow up.

- Acute medical illnesses precluding participation in the studies.

- Known HIV-infected patient.

- Current substance abuse.

- Pregnant or lactating women.

- Hematocrit of less than 30%. - History of weight loss during past 3 months.

- Patients on bile acid binding resins, cholestyramine, colestipol, colesevelam.

- Hypersensitivity or intolerance to CA or any components of its formulation