Tropical Gastroenterology 2008.29;4:187–193 Quarterly Have hematopoietic growth factors made an Review impact on the management of liver disease? Pankaj Tyagi and Kaushal Madan ABSTRACT Department of Gastroenterology, It is clear that the major indication for the use of hematopoietic growth factors in hepatology GB Pant Hospital & Department of is to counteract the adverse effects of interferons (neutropenia and thrombocytopenia) and Medical Hepatology, ribavirin (hemolytic anaemia) during the treatment of hepatitis C infection. This is important Institute of Liver and Biliary Sciences, because the probability of SVR depends on proper adherence to therapy (at least 80% of the New Delhi requisite dose maintained for at least 80% of the requisite duration) and proper adherence can only be achieved if the side effects are reduced to a minimum. Even though the studies Correspondence: Dr. Kaushal Madan have demonstrated beyond doubt that the use of hematopoietic growth factors does indeed Email: [email protected] reduce the incidence and severity of these adverse effects and helps the patients to complete the course of therapy, the data on improvement of SVR is still limited. There is only one study of darbepoetin and filgrastim showing the beneficial effect on SVR. Even among the hematological side effects, possibly the only significant effect which limits the use of optimal HCV therapy is the hemolytic anaemia induced by ribavirin. The other two main side effects, i.e. neutropenia and thrombocytopenia are not clinically problematic. The use of such growth factors would be particularly effective if patients who have advanced liver disease or cirrhosis are able to receive adequate anti-viral therapy as has been demonstrated in the study of eltrombopag among HCV cirrhotics. Apart from this, other indications of G-CSF or GM-CSF use are still in the experimental stage. So, as of now, apart from erythropoietic factors, the role played by other hematopoietic growth factors in hepatology is limited. But future research, especially in the areas of immunotherapy of liver cancers and stem cell therapy for end- stage liver disease, is surely going to give these factors their due place in hepatology. Introduction these cells can destroy and eliminate pathogenic Therepecific efficacy of haematopoitic growth factors (HGF) in microorganisms. G-CSF is a glycoprotein that plays an the management of cancer and haematological problem have immunomodulatory role by affecting an increase in the been well established. They have been predominantly used leukocyte count, and upregulating phagocyte function during in the treatment of anaemia associated with chronic renal neutropenia. G-CSF is produced primarily by monocytes/ failure and chemotherapeutic drug-induced neutropenia. macrophages, fibroblasts, and endothelial cells and acts on Recently, an orally active thrombopoietin receptor agonist has neutrophil precursors and mature neutrophils. It has been been introduced which can improve platelet levels in produced commercially by recombinant technology for clinical thrombocytopenic patients. There is also a growing area of use in both glycosylated and non-glycosylated forms. use of these growth factors in hepatology, which mainly involves Glycosylation stabilises the molecule by suppressing their use in the management of cytopenias induced during polymerisation and conformational change; this leads to hepatitis C therapy. In addition, even though in the experimental resistance against degradation by human proteases. But both stages, the immunomodulatory actions of some of these forms have similar biological activities. growth factors may be useful in some types of liver disease. The major action of G-CSF is to enhance the numbers and But whether they have made a positive impact on disease functions of neutrophils. G-CSF knockout mice develop chronic outcome is to be seen. In the subsequent sections we shall neutropenia with inability to control Listeria monocytogenes discuss the roles of granulocyte colony stimulating factor (G- infection and failure to mobilise neutrophils during sepsis.1 CSF), erythropoietin (EPO) and eltrombopag in the This property of G-CSF is utilised in the treatment of management of liver diseases. neutropenia due to drug-induced bone marrow suppression. G-CSF has also demonstrated the ability to mobilise CD34+ Granulocyte-colony stimulating factor (G-CSF) hematopoietic stem cells from the bone marrow.2 How this is used for the management of liver disease is discussed later. The body’s major defense mechanisms against infectious G-CSF is considered a safe formulation and except for a agents include polymorphonuclear leucocytes, macrophages, 20%-30% incidence of musculoskeletal pain, it rarely natural killer cells, and cytotoxic lymphocytes. Upon activation, produces life-threatening complications. © Tropical Gastroenterology 2008 188 Tropical Gastroenterology 2008.29;4:187–193 Thrombopoietic growth factors Despite a decline in the incidence of acute HCV infection in recent years, the prevalence of HCV-related chronic liver Recombinant human interleukin 11 is a thrombopoietic growth disease is increasing in those who had acquired the infection factor that stimulates proliferation and maturation of before the introduction of the practice of screening of donor megakaryocytes resulting in increased platelet counts. It has blood and blood products for HCV. Up to 80% of adults with been used for the treatment of severe thrombocytopenia among HCV infection develop chronic viremia. However, only a quarter patients receiving chemotherapy. It has also been used to of chronically infected patients develop chronic hepatitis, a treat HCV-related idiopathic thrombocytopenic purpura. In quarter of whom progress to cirrhosis. The disease in 1–4% doses used by Fontana et al3 in their study it also reduced the of those who develop cirrhosis leads to liver cancer annually.7 HCV RNA levels. But the major drawback of interleukin 11 is In India the prevalence of anti-HCV in the general population the high cost and its propensity to cause fluid retention, which is about 0.87% of which about 81% are viremic.8 Based on may lead to pedal oedema, pulmonary oedema and the these figures, more than 10 million Indians are estimated to capillary leak syndrome. be anti-HCV positive and >5-7 million are expected to be Thromobopoietin-receptor agonist (Eltrombopag) viremic. This is going to result in a large burden of HCV-related (GlaxoSmithKline) is a new, small-molecule, non-peptide, oral complications of cirrhosis and liver cancer in the coming years. platelet growth factor. This drug interacts with the India is moderately endemic for the hepatitis B virus (HBV), thrombopoietin receptor and induces proliferation and with nearly 4% of its population, i.e. about 40 million people differentiation of megakaryocytes and results in an increase acting as chronic hepatitis B virus (HBV) carriers, most of who in platelet production. Eltrombopag therapy has been shown are asymptomatic (high endemicity >8%, intermediate 2%– to stimulate megakaryocyte proliferation and differentiation and 8%, low <2%). Carriers of HBV are at increased risk of to cause a dose-dependent increase in platelet counts in both developing cirrhosis, hepatic decompensation, and animal and human studies.4 ,5 hepatocellular carcinoma (HCC). Although most carriers will not develop hepatic complications from chronic hepatitis B, Erythropoietin 15% to 40% will develop serious complications during their lifetime. HBV is the major cause of chronic hepatitis, cirrhosis Erythropoietin is a glycoprotein produced primarily in the and primary liver cell cancer in India. About 50% of chronic kidneys that stimulates the division and differentiation of liver disease in India is due to HBV infection and 20% due to committed erythroid progenitors in the bone marrow. HCV infection.9 Recombinant human erythropoietin was first licensed as EPOGEN in 1989 for use in patients on renal dialysis, and it HCV therapy: importance of adherence and eliminated the need for repeated transfusions in this complications of treatment population. Recombinant erythropoietin is available commercially as Epogen, Eprex, and Procrit and as a Despite many advances in research on HCV therapy, hyperglycosylated longer-acting form, darbepoetin alfa. These interferons and ribavirin are the mainstay of HCV treatment. drugs have been licensed for the treatment of anaemia Rapid improvement in the treatment of HCV infection during associated with chronic renal failure, chemotherapy for non- last decade includes, optimisation of duration of interferon myeloid cancers, zidovudine treatment of HIV, and to reduce according to prevalent genotype, increase in ribavirin dose the use of allogeneic blood transfusions in surgery patients. and avaialbility of pegylated interferon. The protease inhibitors Epogen is indicated for the treatment of anaemia in dialysis in the management of HCV infection are currently being patients with chronic renal failure. evaluated. These therapies are associated with several Plasma erythropoietin levels remain relatively constant hematopoietic side-effects such as anaemia, when haemoglobin levels remain at or above 12 g/dL but thrombocytopenia and neutropenia, causing interruptions in begin to rise rapidly and markedly when the haemoglobin therapeutic schedule. Such interruptions or dose reductions level falls below 12 g/dL. It takes 3 to 4 days following are known to result in sub-optimal therapeutic efficacy. erythropoietin