GCSF Therapy in Decompensated Cirrhosis - A Double Blinded RCT
GCSF Therapy in Decompensated Cirrhosis - A Double Blinded RCT
Cirrhosis of liver is a leading cause of morbidity and mortality worldwide. Complications
 like ascites, spontaneous bacterial peritonitis, variceal bleed, hepatic encephalopathy,
 hepatorenal syndrome (HRS) and hepatocellular carcinoma (HCC) portend a poor prognosis and
 further decreases survival in these patients. The major causes of cirrhosis include excessive
 alcohol consumption, viral hepatitis and non- alcoholic fatty liver disease.

 Currently the only definitive treatment option for cirrhosis is liver transplantation which
 is limited in its applicability due to donor shortage, exorbitant costs and lack of
 widespread availability. Moreover, it requires lifelong immunosuppression and has
 considerable long term side effects including chronic renal failure, post-transplant
 lymphoproliferative disease and cardiovascular complications.

 The ability of stem cells to differentiate into multiple cellular lineages makes one
 speculate that stem cells can be used for tissue repair and regeneration when tissue-resident
 stem cells become overwhelmed. It has been shown that in response to acute or chronic liver
 damage, bone marrow derived stem cells can spontaneously populate the liver and differentiate
 into hepatic cells, thereby contributing to hepatic regeneration. Thus, apart from
 hepatocytes and intrahepatic stem cells, bone marrow derived stem cells also participate in
 the liver regeneration process.

 Currently, there are two methods to mobilize stem cells from the bone marrow to the liver.
 One is administration of cytokines like granulocyte-colony stimulating factor (G-CSF) and the
 other is the isolation of stem cells from the marrow and their injection into the hepatic
 artery or portal vein after purification. The latter is probably more cumbersome and may be
 potentially risky due to the underlying coagulation abnormalities in cirrhotic patients.
 Improved liver histology and survival has been noted in patients with cirrhosis following
 mobilization of bone marrow stem cells by granulocyte-colony stimulating factor (G-CSF).

 Three recent studies have demonstrated G-CSF induced mobilization of bone marrow stem cells
 (CD34 cells) in peripheral blood and their subsequent increase in liver tissue and improved
 survival in patients with alcoholic hepatitis and ACLF. However, there is a paucity of data
 on whether G-CSF improves survival and prognosis in patients with decompensated cirrhosis.

 Verma, Singh et al have shown in an open label trial that there was significantly better 12
 month transplant free survival in ( GCSF+ Growth hormone + standard medical therapy group )
 and ( G CSF + standard medical therapy group ) as compared to standard medical therapy group
 alone. CD 34+ cells at day 6 of therapy increased as compared to baseline. There was also a
 significant decrease of clinical scores, improvement in nutrition, better control of ascites,
 reduction in liver stiffness, lesser episodes of infection as well as improvement in QOL
 scores in the treatment groups having G CSF as compared to baseline.

 In a recent study by Newsome et al, a multicentre, open label randomized phase 2 trial,
 patients were randomized to standard care, treatment with subcutaneous G CSF or treatment
 with G CSF for 5 days followed by leukaphersis and IV infusion of CD 133 positive
 haematopoietic stem cells. They did not find any difference in MELD score over time in all 3
 treatment groups. Serious adverse effects were more common in the G CSF groups than in
 standard treatment group.

 In a study by Kedarisetty CK et al. a significantly larger proportion of patients with
 decompensated cirrhosis given a combination of G-CSF & Darbopoietin α survived for 12 months
 more than patients given only placebo ( 68% vs. 26.9%; P = 0.001 ). The combination therapy
 also reduced liver severity scores and sepsis to a greater extent than placebo.

 In view of the conflicting results of the above studies and no studies on the use of multiple
 courses of GCSF in patients with decompensated cirrhosis in a double blind manner, the
 present study was undertaken to assess the safety and efficacy of G-CSF in patients with
 decompensated cirrhosis in the form of a double blinded RCT.
Inclusion Criteria:

 • Decompensated Cirrhosis of liver irrespective of etiology

 Exclusion Criteria:

 -  Acute on chronic liver failure (fulfilling either APASL or CANONIC criteria of ACLF)

 -  Splenic diameter of more than 18 cm

 -  Concomitant HCC or other active malignancy

 -  Upper gastrointestinal bleeding in the previous 7 days

 -  Portal vein thrombosis

 -  Severe renal dysfunction as defined by creatnine > 1.5mg/dl

 -  Severe cardiac dysfunction

 -  Uncontrolled diabetes (HbA1c ≥ 9) or diabetic retinopathy

 -  Acute infection or disseminate intravascular coagulation

 -  Active alcohol abuse in last 3 months

 -  Known hypersensitivity to G-CSF

 -  HIV co-infection

 -  Pregnancy

 -  Refusal to give informed consent

 -  Those opting for liver transplant