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 Hseih and Fitzhugh 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. An initial report was published and patients with sickle cell continue to be followed in our clinic. In addition there is a protocol to follow patients with sickle cell and liver disease before and after stem cell transplant. 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 andmore 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. This work is now being prepared for publication. In addition it is planned to look at liver disease in 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. These patients have features in common with the CGD and Sickle Cell cohorts. In general patients are living longer, giving time for liver disease to develop. There are multiple possible reasons for the development of liver disease in these patients. It is also being explored whether liver disease affects mortality. A collaborative project with Dr Kastner describing the liver involvement in DADA2 has been initiated and the initial manuscript detailing DADA2 has been published. A second manuscript detailing the liver involvement is currently being prepared. 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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