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. Gallin, 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. It has also been shown that platelet slope as a determinant of mortality is knocked out of the mortality model when DHR production is taken into account. This was part of a far larger project looking at the relationship between mortality and individual patients mutations and has now been published. This has exciting implications for the development of liver disease and the mechanisms underlying liver disease progression. The natural history of this cohort continues to be of interest. 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 when clinically indicated. 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. 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. The ongoing laboratory work has become a major focus of the project. In addition it is planned to look at liver disease in two other groups of patients. The first in the setting of bone marrow transplant. In this cohort of patients there are multiple reasons for liver disease, including drug induced liver disease, viral hepatitis, iron overload, and graft versus host disease. The second is in long term survivors of heart surgery for congenital valvular heart disease. Both have features in common with the CGD and Sickle Cell cohorts. In all groups patients are living longer, giving time for liver disease to develop. In all groups there are multiple possible reasons for the development of liver disease. And in all groups it is either now known or there is evidence for liver disease affecting mortality. 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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