Please select the eligibility criteria that correspond to the clinical trial below.
Title: Granulocyte Colony Stimulating Factor Plus N-Acetyl Cysteine In Severe Alcoholic Hepatitis
Brief Summary: Alcoholic hepatitis is related to very high mortality rate. About 40% of the patients are died within first 6 months after the detection of the clinical syndrome. Therefore, it is very essential for proper diagnosis and early treatment. In response to acute or chronic liver damage, bone marrow derived stem cells can spontaneously populate liver and differentiate into hepatic cells. Animal and human studies suggested that injured hepatocyte may be replaced by pluripotent bone marrow cells. However, this hepatocyte repopulation is highly dependent on varieties of liver injury and therapeutic conditions6. The studies has suggested Granulocyte-colony stimulating factors (G-CSF) can regenerate hepatocyte by fusing with hematopoietic cells, thereby enhancing the liver histology and survival rate.

G-CSF is a cytokine capable to regulate a number of functions in neutrophils. In three recent studies mobilization of bone marrow stem cells induced by G-CSF was observed in patients with alcoholic hepatitis. In two of this studies there was a survival benefit with the use of G-CSF.

Alcoholism leads to decrease in endogenous antioxidant potential. Alcoholic liver disease (ALD) patients show low endogenous antioxidants. Chronic ethanol consumption cause selective deficiency in the availability of reduced glutathione (GSH) in mitochondria has been reported. This is due to impaired functioning of GSH transporter from cytosol to mitochondrial matrix. The effect on glutathione replenishing potential by N-acetyl cysteine (NAC) can be used to reduce oxidative stress, which also has excellent safety profile. Therefore, NAC can be used for severe alcoholic hepatitis treatment due to its therapeutic potential factor. NAC also inhibit apoptosis and pro-inflammatory cytokine production. In a study high doses of intravenous N-acetyl cysteine therapy for 14 days conferred neither survival benefits nor early biological improvement in severe alcoholic hepatitis patients with adequate nutritional support.However, these results must be viewed with caution, since the study suffered from a lack of power. In a recent study, NAC and corticosteroids combination therapy benefits among patients with severe acute alcoholic hepatitis in 1 month survival, although the final outcome at 6 month survival was not improved. There are no studies on the use of combination therapy of NAC plus G-CSF in patient with severe alcoholic hepatitis.

Therefore we plan to study the safety and efficacy of combination therapy of G-CSF and NAC in the patients with alcoholic hepatitis.


Options:
A: Inclusion Criteria:

* Subjects aged 18-65 years
* All patients who are known to have cirrhosis of liver with portal hypertension and are compensated on presentation with no features of ascites/ jaundice/ bleed/ HE/ HRS.
* Only patients with alcoholic cirrhosis and cryptogenic cirrhosis (etiology work up negative) will be enrolled in the study.

Exclusion Criteria:

* Sepsis ( Any culture positive: blood, urine, any other obvious source of infection: UTI, LRTI)
* Variceal bleed in the past 3 months
* Autoimmune disorders
* HCC (Hepatocellular Carcinoma)
* Multi organ failure
* Any features of decompensation in form of ascites/Jaundice/ HE (grade 3 or 4) / HRS
* HIV seropositivity
* Essential hypertension
* Pregnancy
* Refusal to participate in the study
B: Inclusion Criteria:

Alcoholic hepatitis patients:

1. More than 10 years of heavy alcohol consumption (mean intake ≈ 100 g/day).
2. Elevated aspartate aminotransferase level (but \<500 IU per millilitre) and Ratio ofAST/ALT≥2 times
3. Elevated serum total bilirubin level ≥ 5 mgdL (86 μmol/L)
4. Elevated INR(≥1.5) and
5. Neutrophilia. Patient with Maddrey's DF of≥ 32 will be included in the study, with or without biopsy.

Exclusion Criteria:

1. Age \< 18 and \> 75 years
2. Hepatocellular carcinoma or portal vein thrombosis
3. Refusal to participate in the study
4. Serum creatinine \>1.0 mg%
5. Hepatic encephalopathy- grade 3 or 4
6. Upper gastrointestinal bleed in last ten days
7. Uncontrolled bacterial infection
8. Human immunodeficiency virus, Hepatitis B virus, Hepatitis C virus seropositivity, Autoimmune hepatitis, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency
9. Pregnancy
10. Glucocorticoid treatment
11. Significant co-morbidity
12. Previous known hypersensitivity to G-CSF/NAC
C: Inclusion Criteria:

* Age 18 years to75 years
* Patients of decompensated cirrhosis with CTP ≥6 and ≤ 13
* Liver transplantation not feasible soon (due to financial reasons or unavailability of donors).

Exclusion Criteria:

* Hepatocellular Carcinoma
* Sepsis (Any culture positive: blood, urine, any other obvious source of infection: UTI, SBP): Patients were included after sepsis is controlled.
* Any organ failure
* Grade 3 or 4 Hepatic Encephalopathy, Active Variceal bleed, Hepatorenal Syndrome: Patients might be included after clinical improvement
* HIV seropositivity
* Pregnancy
* Refusal to participate in the study
* Previous known hypersensitivity to G-CSF
D: Inclusion Criteria:

1. Acute-on-chronic liver failure (ACLF) according to the consensus criteria recently defined by the CANONIC study group \[Moreau 2013\]. Patients with acute decompensation of cirrhosis \[defined as acute development of one or more of the following: ascites (onset and/or worsening), hepatic encephalopathy (onset and/or worsening), gastrointestinal haemorrhage, bacterial infection\] are classified as ACLF if one of the following applies:

   * single kidney failure (serum creatinine level ≥ 2 mg/dl) or
   * single failure of one of the following organ systems: liver, coagulation, circulation, or respiration, together with a serum creatinine level ranging from 1.5 to \< 2.0 mg/dl and/or mild to moderate hepatic encephalopathy or
   * single cerebral failure together with serum creatinine level ranging from 1.5 to \< 2.0 mg/dl or
   * two or more organ failures. Organ failures are defined according to the CLIF-C OFs \[Jalan 2014\].
2. Age ≥ 18 years, male or female
3. Written informed consent from patient, legal or authorized representative or a confirmation of justification of trial participation by an independent medical consultant PLEASE NOTE: In case of confirmation by the independent medical consultant a deferred informed consent from patient, legal or authorized representative has to be given

Exclusion Criteria:

1. Prior not curatively treated or active malignancies
2. Sickle cell disease
3. septic shock, defined by the following symptom complex: bacteraemia AND SIRS AND shock
4. WBC-count of \> 50 x 109/L
5. Known HIV infection
6. Known intolerance to filgrastim
7. Suspected lack of compliance
8. Pregnant or nursing women
9. Fertile women (within two years of their last menstruation) without appropriate contraceptive measures (implanon, injections, oral contraceptives, intrauterine devices, partner with vasectomy) while participating in the trial (participants using a hormone-based method have to be informed of possible effects from the trial medication on contraception).
10. Participation in other interventional trials

Answer: B