Most studies estimate that between 6 and 77% of all patients with cirrhosis have abnormal hematologic indices (AHI), including anemia, thrombocytopenia and leukopenia. In a homogenous population of patients with compensated Child-Pugh Class (CPC) A/B cirrhosis, as many as 84% have AHI.18,19 The presence of AHI contributes to increased morbidity and mortality in a large proportion of cirrhotic patients. For example, thrombocytopenia can be a limiting factor when considering invasive surgical procedures due to the increased risk for bleeding. Leukopenia increases the risk for infections and chronic anemia contributes to worse outcomes after hemorrhagic episodes.18 Thrombocytopenia and leukopenia have been shown to be associated with death, transplant, clinical decompensation and hepatocellular carcinoma (HCC).19~The pathogenesis of AHI in patients with cirrhosis is often multifactorial, with splenic sequestration, portal hypertension, bone marrow suppression, and changes in hematopoietic stimulating factors contributing to the etiology.18 The severity of cytopenias does not consistently correlate with the degree of cirrhosis and may not correct after liver transplant. Current therapies have variable efficacy in improving cytopenias and management focuses primarily on supportive care with transfusions and growth factors.~Telomeres are repetitive DNA sequences located at the natural ends of linear chromosomes. They function to cap and protect chromosome ends from being recognized as damaged or infected DNA.3 During cell division, the end-replication problem arises as telomeres continually shorten because DNA polymerase cannot fully replicate the 3' end of chromosomes. The telomerase complex counters telomere attrition by elongating the telomere DNA after each cell division. Germline genetic defects in telomere maintenance and repair can cause dyskeratosis congenita, bone marrow failure, liver cirrhosis, pulmonary fibrosis, as well as increased susceptibility to various cancers. 4-5, 24-25~As a major complication of liver disease, cirrhosis is the main risk factor for progressive liver failure and HCC. To better understand the pathogenesis of cirrhosis, the connection between telomere attrition and cirrhosis has been examined in preclinical studies. Rudolph et al. found that telomerase reverse transcriptase (TERT)-deficient mice displayed reduced liver regeneration after partial hepatectomy and increased hepatic fibrosis after carbon tetrachloride exposure. After restoration of telomerase activity, there was improved liver function and cirrhosis reduction.21 Similarly, studies in humans found significantly accelerated telomere shortening and more telomere mutations in livers with cirrhosis and chronic hepatitis compared to normal livers.15 Patients with dyskeratosis congenita, pulmonary fibrosis, aplastic anemia, and short telomeres also showed an increased frequency of liver fibrosis and cirrhosis.~In an analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare database from 1992 through 2009, the development of liver disease was compared between 82,938 men with prostate cancer who did and did not undergo androgen deprivation therapy (ADT).12 Exposure to ADT was significantly associated with an increased subsequent risk of non-alcoholic fatty liver disease (54%), cirrhosis (35%) and any liver disease 47%). These data support a relationship between androgens and liver health, the mechanism of which is likely multifactorial
This is a phase II pilot study designed to assess the safety and efficacy of danazol for treatment of cytopenias in patients with CPC A/B cirrhosis. Subjects with or without telomere mutations and/or shortened telomeres will be treated with danazol 600 mg per day by mouth for a duration of 24 months. The goal will be to treat a total of 10 patients.