Natural History of Noncirrhotic Portal Hypertension

Noncirrhotic Portal Hypertension (NCPH) includes a spectrum of chronic liver diseases
characterized by increased pressure within the portal circulation in the absence of
cirrhosis. The complications from NCPH are similar to that of cirrhosis induced portal
hypertension which includes the development of gastrointestinal varices, portal hypertensive
gastropathy, splenomegaly, sepsis and ascites. However, unlike cirrhosis related portal
hypertension, NCPH is characterized by well-preserved hepatic synthetic function. With
increasing recognition both of patients with noncirrhotic portal hypertensive liver diseases,
and mortality due to NCPH, it is clear that the specific mechanism(s) and the natural
history(s) of noncirrhotic portal hypertensive liver disease have yet to be elucidated and
described. At the Clinical Center of the NIH, various cohorts of patients have been
identified to be at increased risk for the development of noncirrhotic portal hypertensive
liver diseases such as those with Cystic Fibrosis (CF), common variable immunodeficiency
(CVID), Turner s Syndrome (TS) and congenital hepatic fibrosis (CHF) to name a few. We
propose to study individuals with NCPH, and those at risk of developing NCPH within these and
other cohorts of patients known to be at risk for NCPH for an indefinite period of time.
Through continued evaluation and scientific discovery, our aim is to provide a greater
understanding of noncirrhotic portal hypertensive liver diseases and the different underlying
biological processes that lead to the development of NCPH. We also aim to further the scant
existing knowledge regarding the natural history of this disease and the global phenomenon of
portal hypertension. From the data obtained from this natural history protocol, future
studies will be planned to evaluate specific hypothesis in specific disease cohorts. Patients
with diseases known to cause cirrhosis will be excluded. Patients 12 years of age and older
thought to be at risk for the development of NCPH will undergo preliminary testing which
includes; History and physical examination, blood, urine and stool tests, radiologic imaging,
echocardiogram and fibroscan. Adults and minors who are likely to have NCPH will also undergo
transjugular or percutaneous liver biopsy with transjugular hepatic venous gradient
measurements and endoscopy. After these evaluations, those without strong evidence of NCPH
will be asked to return for biannual clinic visits for updated history and physical
assessments. Those with evidence of NCPH will be followed every six months with additional
testing that may include imaging and laboratory evaluations. Over time, those individuals
that develop NCPH will be converted to the intensive characterization and monitoring schemata
as described in the protocol. All patients with NCPH will undergo preventative screening
examinations for complications of NCPH. There is no planned treatment for patients with
existing or newly diagnosed NCPH, as no such treatment currently exists. Treatment for
complications of NCPH will be offered according to the standard of care with referrals as
appropriate.

- INCLUSION CRITERIA:

- Age 12 years or above, male or female

- Known diagnosis of NCPH, or to be at the risk for NCPH by virtue of underlying disease
processes such as but not limited to; CGD, SCD, Mastocytosis, CVID, CF, and CHF.

EXCLUSION CRITERIA:

- Evidence of other forms of liver disease that typically result in cirrhosis.

- Evidence of active chronic Hepatitis B infection as defined by the presence of
hepatitis B surface antigen (HBsAg) in serum and elevated HBV DNA (>10,000 IU/mL).

- Hepatitis C as defined by the presence of hepatitis C RNA in serum.

- Primary sclerosing cholangitis as defined by liver histology.

- Primary biliary cirrhosis as defined by cholestasis, +/- antimitochondrial antibody
positivity and liver histology.

- Wilson s disease as defined by ceruloplasmin below the limits of normal and liver
histology and urinary copper consistent with Wilson disease.

- Autoimmune hepatitis as defined by antinuclear antibody (ANA) of 3 EU or greater and
liver histology consistent with autoimmune hepatitis or previous response to
immunosuppressive therapy for autoimmune hepatitis.

- Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy or
homozygosity for C282Y. Patients with iron saturation indices of >45% and serum
ferritin levels of >300 ng/ml for men and >250 ng/ml for women will undergo genetic
testing for hemochromatosis.

- Bile duct obstruction as suggested by imaging studies done within the previous six
months.

- The presence of cirrhosis as demonstrated by liver biopsy.

- Active substance abuse, such as alcohol, inhaled or injection drugs within the
previous one year (assessed during patient interviews by patient self-report).

- Evidence of hepatocellular carcinoma; either alpha-fetoprotein (AFP) levels greater
than 50 ng/ml (normal <6.6ng/ml) and/or ultrasound (or other imaging study)
demonstrating a mass suggestive of liver cancer.

- Evidence of Cholangiocarcinoma as suggested by liver histology.

- Any other severe condition, which in the opinion of the investigators would impede the
patient s participation or compliance in the study.

Inability to comply or give written informed consent.