Natural History of Noncirrhotic Portal Hypertension

Study Overview
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Brief Summary
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Background: - Noncirrhotic Portal Hypertension (NCPH) is caused by liver diseases that increase pressure in the blood vessels of the liver. It seems to start slowly and not have many warning signs. Many people may not even know that they have a liver disease. There are no specific treatments for NCPH. Objectives: - To learn more about how NCPH develops over time. Eligibility: - People age 12 and older who have NCPH or are at risk for getting it. In the past year, they cannot have had other types of liver disease that typically result in cirrhosis, liver cancer, or active substance abuse. Design: Participants will have 2 screening visits. Visit 1: to see if they have or may develop NCPH. Medical history Physical exam Urine and stool studies Abdominal ultrasound Fibroscan. Sound waves measure liver stiffness. <TAB>- Visit 2: Blood tests Abdominal MRI Echocardiogram Questionnaire Liver blood vessel pressure (hepatic venous portal gradient (HVPG)) measurement. This is done with a small tube inserted in a neck vein. They may have a liver biopsy. All participants will visit the clinic every 6 months for a history, physical exam, and blood tests. They will also repeat some of the screening tests yearly. Participants with NCPH will also have: Upper endoscopy test. A tube inserted in the mouth goes through the esophagus and stomach. At least every 2 years: Esophagogastroduodenoscopy. At least every 4 years: testing including HVPG measurements and liver biopsy. Participants without NCPH will also have: Liver biopsy and HVPG measurements to see if they have NCPH. Every 2 years: abdominal MRI and stool studies. The study will last indefinitely.

Detailed Description
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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.

Official Title
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Natural History of Noncirrhotic Portal Hypertension

Conditions
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Cystic Fibrosis, Immunologic Deficiency Syndrome, Turner Syndrome, Congenital Hepatic Fibrosis, Idiopathic Non-Cirrhotic Portal Hypertension

Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult with absence of Portal Hypertension<br>Confirmed absence of Portal Hypertension will have no findings suggestive of non cirrhotic portal hypertension on liver biopsy and on portal pressure measurements on confirmatory examination. | |
| Adult with presence of Portal Hypertension<br>Confirmed Presence of Noncirrhotic Portal Hypertension, through confirmatory testing, tissue diagnosis by liver biopsy and/or portal hypertension (HVPG >5mmHg). | |
| Minors likely to have the absence of Portal Hypertension<br>Minors identified as Confirmed Absence of Noncirrhotic Portal Hypertension will have no abnormal findings on confirmatory examination. | |
| Minors likely to have the presence of Portal Hypertension<br>Minors identified as Confirmed Presence of Noncirrhotic Portal Hypertension, have shown they have the disease with a tissue diagnosis by liver biopsy and/or portal hypertension (HVPG >5). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To study the natural history of non cirrhotic portal hypertension. It is an ongoing study. | natural history study | Ongoing | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Varices, Portal Hypertension, Portal Fibrosis, Liver Disease, Splenomegaly, Natural History