Portal hypertension occurring without cirrhosis is an unusual condition. It is also a broad topic which encompasses a number of different diseases, each of which is even more unusual. The management for each of these diseases is often very different. Non-cirrhotic portal hypertension (NCPH) can be divided into three broad categories depending on the anatomic origin of the portal hypertension, namely pre-hepatic, hepatic, and post-hepatic. Within hepatic causes of NCPH nodular regenerative hyperplasia (NRH) is relatively rare and most knowledge on the topic has derived from case reports and series. There has been limited systematic research. It has become apparent, initially through the consult service of the Liver Diseases Branch, that there are a number of patient cohorts followed at the Clinical Center of the National Institutes of Health (NIH) who are at risk for NRH and NCPH. A more systematic approach has been instituted to evaluate these patients. The first cohort to be evaluated (in a retrospective manner) was patients with Chronic Granulomatous Disease (CGD). This is in collaboration with Drs. Holland and Malech of the National Institute of Allergy and Infectious Diseases. CGD is a genetic disorder affecting the neutrophil oxidative burst, which in turn impedes killing of certain pathogens. It has previously been shown that mortality in patients with CGD is associated with the development of NCPH, likely due to injury to the microvasculature of the liver from repeated systemic and hepatic infections. The slope of decline in platelet count may be a useful measure of progression of portal hypertension over time. We also wish to test this hypothesis in cirrhotic portal hypertension. A second cohort of patients we have found to be at risk for NCPH and NRH is patients with sickle cell disease (SCD). This is in collaboration with Drs Gladwin and Kato of the National Heart Lung and Blood Institute. Although sickle cell anemia is a hematological disease, the chronic hemolytic state and its associated complications can lead to a multisystem disorder affecting all organ systems. Liver disease is difficult to assess in patients with sickle cell disease (SCD) and aside from iron overload the chronic hepatic complications of SCD have not been described in detail. Our initial intention was to provide a detailed description of clinical and pathological hepatic complications of SCD. This might differ from earlier descriptions as patient survival has improved considerably, and in addition blood products are now screened for viral hepatitis thus decreasing the risk of transfusion related viral hepatitis. Patients from a natural history study of SCD at the NIH underwent a systematic liver evaluation, including liver biopsy in the majority. A scoring system for hepatic pathology was developed and correlations and associations between laboratory parameters and biopsy findings were evaluated. Eighty patients were evaluated and 48 liver biopsies were performed, including HVPG measurements in 28. HVPG was elevated in 14 patients and was associated with regenerative changes and portal venopathy on liver biopsy. Relative thrombocytopenia (<250,000/l) and ALP elevation were associated with elevated portal pressure. Liver fibrosis and inflammation were mild. Serum ferritin correlated well with previous blood transfusion history and with liver iron measurements. Hepatitis C infection was present in 10% of patients, 88% of whom had normal ALT values. We concluded that in addition to iron overload and viral hepatitis, patients with SCD develop hepatic regenerative changes and portal venopathy, which may lead to the development of non-cirrhotic portal hypertension. We then set out to determine the association with liver-related parameters and mortality. A large cohort of prospectively followed patients with SCD at the NIH was evaluated. The patients in the descriptive aspect of this study formed a subset of this cohort. The association of mortality with liver enzymes, parameters of liver synthetic function and iron overload was evaluated using Cox regression. Logistic regression was then performed to determine factors associated with determinants of mortality. After controlling for known predictors of mortality in SCD, direct bilirubin, ferritin, albumin and alkaline phosphatase were independently associated with mortality. When combined into a multivariable model, increasing direct bilirubin and ferritin remained significant. Serum ferritin greater than 1,000 ng/ml was associated with increased lifetime blood transfusions, WBC and ALT elevation. Increased direct bilirubin was associated with increased inferior vena cava diameter, lower mean arterial blood pressure and elevated WBC. Direct bilirubin negatively correlated with platelet count and was associated with higher immunoglobulin levels, suggesting it may be a marker portal hypertension. It was concluded that Ferritin and direct bilirubin are independently associated with mortality in SCD. Ferritin likely relates to transfusional iron overload, while direct bilirubin suggests impairment of hepatic synthetic function and pulmonary hypertension, possibly impairing patients ability to tolerate systemic insults. This data is now being submitted for publication. Although neither CGD nor SCD is a primary liver disease it appears that liver disease as a result of the underlying systemic disease impacts mortality in both cases. Of interest is that it is NCPH and more specifically NRH that seem to be the predominant liver lesion. CGD and SCD may serve as a model for the development of NCPH and elucidating the biology of NRH. To further understand the biology of NRH liver biopsies from CGD and SCD patients (and patients with other systemic diseases) with and without NRH have been evaluated and are being correlated with laboratory and clinical findings. In addition laboratory work is being undertaken to further elucidate the underlying biology of NRH. There is one other form of NCPH that is being studied. Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disorder associated with polycystic renal disease. It is typically associated with varices and variceal bleeding is a common cause of death. The renal involvement may be significant and patients may require renal replacement therapy. This is a long term project the aim of which is to prospectively define the natural history of the syndrome and to better understand the pathogenesis. This is in collaboration with Drs. Gunay-Aygun and Gahl of NHGRI.

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