Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial
Comparison of Bovine Colostrum Versus Placebo in Treatment of Severe Alcoholic Hepatitis: A Randomized Double Blind Controlled Trial
Severe Alcoholic hepatitis, defined by modified Maddrey's Discriminant Function (DF) ≥32, is
 associated with significant morbidity and mortality.(1,2) Of the various treatment modalities
 evaluated for treatment of Severe Alcoholic hepatitis, corticosteroids have been the most
 extensively studied.(1) Five out of 13 randomized controlled trials, and four out of 5
 meta-analysis have shown a survival benefit with corticosteroids, especially in patients with
 DF ≥32 and/ or encephalopathy.(1-4) However, the role of corticosteroids in Severe Alcoholic
 hepatitis still remains controversial.(5-6) Corticosteroid therapy is not considered the
 ideal option by most authors because their beneficial effect seems to be confined to a highly
 select minority group in which the inhibitory effect of corticosteroids on liver inflammation
 is not outweighed by side effects such as weakened defence against infections, anti-anabolic
 effects, and possible ulcer promoting effects.(6) Corticosteroids are usually contraindicated
 in those with DF > 54 or MELD >24 (7) .Also corticosteroids are contraindicated in those with
 renal failure, gastro-intestinal bleed, pancreatitis and active sepsis. Therefore, there have
 been constant efforts to evaluate new therapies for Severe Alcoholic hepatitis (SAH). In a
 recent trial, combination of glucocorticoids plus N-acetylcysteine was found to improve one
 month survival in patients with Severe Alcoholic hepatitis, compared with glucocorticoids
 alone. However, the 6 month survival similar in both the groups.(8) Human colostrum and
 bovine colostrum are rich in protein, immunoglobulin, lactoferrin and growth factors. Recent
 studies suggest that colostrum components, immunoglobulin and growth factor benefits
 physically active person as well as in the treatment of autoimmune disorders. It is used for
 the treatment of a wide variety of gastrointestinal conditions, including non-steroidal
 anti-inflammatory drug-induced gut injury, Helicobacter pylori infection, immune deficiency
 related diarrhea as well as infective diarrhea.(9,10,11) It has also been sucessfully used to
 significantly decrease the level of Endotoxemia - lower levels of Lipopolysaccharides.

 We plan to compare the efficacy of bovine colostrum versus Placebo (Pasteurized milk powder)
 alone in treatment of severe alcoholic hepatitis. Bovine Colostrum is rich in protein,
 immunoglobulin, lactoferrin and growth factors. Recent studies suggest that Colostrum
 components, immunoglobulin and growth factor benefits physically active person and in
 treatment of autoimmune disorders. It is used for the treatment of a wide variety of
 gastrointestinal conditions, including non-steroidal anti-inflammatory drug-induced gut
 injury, H pylori infection, immune deficiency related diarrhea as well as infective
 diarrhea.(9) The guidelines by American College of Gastroenterology (10) and other authors
 (11) have suggested that a combination of Corticosteroids and other drugs, which have
 different mechanisms of action, may be more beneficial for reducing mortality in severe
 alcoholic hepatitis. Hence, the investigators plan to compare the efficacy of combined
 therapy of Corticosteroids and Bovine colostrum versus Corticosteroids alone in treatment of
 severe alcoholic hepatitis.
Diagnosis: The diagnosis of Alcoholic hepatitis is made by the following criteria (12)

 I. Chronic active alcohol abuse - >80 grams in males and > 60 grams in females for > 5 years
 for developing Alcoholic Cirrhosis (13) Alcohol use will be evaluated with the AUDIT score
 (EASL guidelines (14) II. Duration of jaundice < 3 months III. Serum Bilirubin >5 mg/dl IV.
 AST/ALT > 2:1 V. AST <300 IU/L VI. Prolonged PTI/INR VII. Neutrophilicleucocytosis VIII.
 Liver biopsy (Percutaneous or Transjugular). [Optional]

 IAssessment of Severity

 Maddrey's Discriminant Function (15)

 Discriminant Function Index (DFI) was originally described by Maddrey and colleagues in a
 placebo controlled study to assess the benefit of corticosteroids in patients with AH. The
 original formula was 4.6 x prothrombin time (seconds) + serum Bilirubin (mg/dl). It was
 observed that patients with a DFI >93 and treated with placebo had a 28 day survival of 25%,
 whereas those with a DFI < 93 had a 100% survival. Subsequently this score was modified in
 1986 and called Modified Discriminant Function (MDF). MDF = 4.6 x (Patient's PT - Control PT)
 + serum bilirubin (mg/dl). Untreated patients with MDF >32 had a survival of 68%. The
 American College of Gastroenterology9 recommends that patients with MDF > 32 and / or
 Encephalopathy should be treated. The prothrombin time varies greatly depending on the
 sensitivity of the thromboplastin reagent used for the test. This is the drawback of the MDF.

 MELD score (16)

 The model for end stage liver disease (MELD) score predicts survival in patients with
 cirrhosis and is used to prioritize patients for liver transplantation.

 MELD score = (0.957 x log serum creatinine + 0.378 x log serum bilirubin + 1.120 x log INR +
 0.643) x 10. The advantage of MELD score is the use of INR in place of PT. The INR is
 comparable and uniform across laboratories worldwide. The American Association for Study of
 Liver Diseases recommends that a MELD score >20predicts SAH and should be the criterion for
 initiating treatment. Serial monitoring of MELD score with a change of 2 or more points over
 the first week on treatment has independently predicted mortality.

 GAHS score (17)

 Glasgow Alcoholic Hepatitis Score (GAHS) includes age, peripheral Total Leucocyte Count,
 serum Bilirubin (at days 1 and 6-9), blood urea nitrogen and PT. It is a better predictor of
 mortality at 28 days than MDF. GAHS score > 9 has an extremely poor prognosis unless treated
 with Corticosteroids. The drawback is lack of international validation.

 LILLE'S model (18) It is not traditionally used for predicting mortality of SAH. However, it
 helps to predict mortality at 7 days of SAH patients on Corticosteroids .If the score is more
 then 0.45 then Corticosteroids should be stopped.

 The diagnosis of Severe Alcoholic Hepatitis is made by the following criteria

 1. MDF>32, or

 2. MELD>20

 Treatment Abstinence from alcohol This is the most important factor in predicting the outcome
 after surviving the acute alcoholic hepatitis (AH) episode. The incidence of recidivism after
 recovery from the first episode of AH varies from 10 - 70 %. Abstinence will be reinforced by
 giving patient oral/enteral Baclofen (GABA B receptor agonist)

 Nutrition

 Enteral nutrition is the preferred mode for supplemental nutrition. It is cheap, maintains
 gut mucosal integrity. This in turn decreases the risk of bacterial and endotoxin
 translocation resulting in less infections and endotoxemia. Pooled data from 5 RCT's of AH
 have demonstrated improved nutritional status compared to standard dietary intake, but
 without improving survival rates.19 The patient will be given 40k cal/kg diet along with
 1.5gm/kg protiens, emphasizing breakfast and a night time snack with regular oral diet.
 Frequent interval feeding will be given to improved nitrogen balance. B complex multivitamins
 supplementation will be provided to all patients (EASL guidelines (14)

 Pharmacotherapy of Severe Alcoholic Hepatitis

 Corticosteroids

 Corticosteroids are the most extensively used treatment for Severe Alcoholic Hepatitis. 6/13
 Randomized Controlled Trials and 4/6 meta-analysis have supported the use of Corticosteroids
 in Severe Alcoholic Hepatitis. The last meta-analysis of individual patient data from 5 high
 quality Randomized Controlled Trials using Corticosteroids forSevere Alcoholic Hepatitis
 concluded that Corticosteroids confers a 50% relative survival benefit at 1 month (85% versus
 65% survival amongst those treated with Corticosteroids versus untreated patients). The
 number of patients needed to treatedis 5 to reduce one death. Oral Prednisolone 40mg daily or
 parenteral methylprednisolone (for patients unable to take orally) 32 mg intravenously daily
 for 4 weeks is the standard therapy. A Lille score of >0.45 after 7 days of treatment with
 Corticosteroids is an indication of non-response, increased susceptibility to infections and
 diminished survival (20). The Corticosteroids should be stopped if the Lilli score is >0.45.
 The most recent STOPAH trial was unable to show a significant improvement in mortality of SAH
 patients treated with Corticosteroids. There was a trend in favour of Corticosteroids.

 Pentoxifylline

 Pentoxifylline is a phosphodiesterase inhibitor. It is given orally in the dose of 400mg
 thrice a day for 28 days. In a pivotal study of 101 patients of SAH21, it was associated with
 survival benefit of 50%. In another study, it was found to be superior to Corticosteroids
 (22).

 In a recent study involving 50 patients at our center (23), we found that 20% vs 40%
 mortality in patients treated with Pentoxifylline versus controls, after 4 weeks of
 treatment. Acute kidney injury was the cause of death in 20% compared to 70% patients in
 Pentoxifylline group versus controls. Pentoxifylline induces recovery of renal & hepatic
 functions with a trend towards increased survival. However, a metanalysis of 5 Randomized
 Controlled Trials failed to show any benefit with Pentoxifylline24.In a large recent trial
 Corticosteriods plus Pentoxifyllinefor 4 weeks treatment with compared with prednisolone
 alone, did not result in improved 6-month survival.25 The major adverse effects include
 vomiting, diarrhea, abdominal pain, headache and skin rash.

 N-Acetylcyteine

 N-acetylcysteine could have value as an antioxidant in the treatment of acute alcoholic
 hepatitis,because the thiol group in N-acetylcysteine is able to reduce levels of free
 radicals. Administration of N-acetylcysteine might reconstitute the glutathione stocks of the
 hepatocytes. At present, N-acetylcysteine is used in the treatment of acetaminophen induced
 hepatitis. Intravenous acetylcysteine is most often used as an antidote for acetaminophen
 overdose due to its ability to increase levels of glutathione; however, it is also used to
 treat non-acetaminophen-induced acute liver failure (NAI-ALF) and severe alcoholic hepatitis
 and to prevent contrast-induced nephropathy (CIN). Although the i.v.and oral formulations of
 acetylcysteine have been evaluated for these indications, most studies have examined the
 i.v.form. I.V. acetylcysteine is used in the treatment of NAI-ALF to improve oxygenation to
 the liver. A trial to evaluate the efficacy of glucocorticoids plus N-acetylcysteine, as
 compared with glucocorticoids alone, in patients with severe acute alcoholic hepatitis.(26)
 reported improved one month survival in the combined treatment group. However the 6 month
 survival was not different in the two groups.

 Bovine colostrum

 Human colostrum is the first milk produced after birth and is particularly rich in
 immunoglobulin, antimicrobial peptides (lactoferrin and lacto peroxidase) and other bioactive
 molecule, including growth factors which are important for nutrition, growth and development
 of newborn infants and also for passive immunity. Bovine colostrum is produced by the cows
 during the first one day post parturition. This "early" milk has nutrient profile and
 immunological composition substantially different from 'mature' milk. It contains
 macronutrient like proteins, carbohydrate, oligosaccharides, fats and micronutrients like
 vitamins and minerals, also growth factors, anti-microbial compounds and immune regulating
 constituents either not present in mature milk or present substantially in lower
 concentration.(27,28) Bovine colostrum used in the treatment of HIV-positive patients with
 chronic diarrhea,(29) and rotavirus diarrhea in children.(30) Available evidence suggests a
 beneficial effect of supplementation of bovine colostrums in improving body composition,
 aspects of athletic performance, diarrhea in persons with immune-deficiency syndromes,
 NSAID-induced gastrointestinal ulcers, and aspects of the acute phase response that occurs
 secondary to surgery. Specific hyperimmune bovine colostrums, produced to have high
 neutralizing titer activity against Cryptosporidia, H. pylori, measles, rotavirus, and
 Shigella sp., appear to have clinical utility in conditions associated with these infectious
 organisms (31) Historically colostrum has been used for various illnesses in India as well as
 abroad for thousands of years. Ayurvedic physicians of India have used bovine colostrum for
 both medicinal and spiritual purposes since cows were first domesticated. By the late 18th
 century, Western medicine started to take an interest in colostrum and study it for its
 potential health benefits. As a consequence, it was prescribed for many conditions, including
 immune system enhancement. Interestingly, until the development of penicillin and other
 artificial antibiotics in the 20th century, colostrum was commonly used for fighting
 bacterial infections. In the early 20th century it was noted that antibody levels in the
 first milk produced after birth were much higher than levels found in the milk that was
 produced 72 hours later.There are now over 2000 published scientific articles that document
 the safety and efficacy of using colostrum. This seemingly perfect food has been shown to be
 non-species specific (32). In 2005, it was reported that is safe and effective in repair of
 tissues as well as for enhancing immunity.(33) The use of bovine colostrum as dietary
 supplement has increased substantially over the past decades. Bovine colostrum is harvested
 within first few hours of calving from dairy animals. The herds of cows are kept under close
 supervision in good state of hygiene without exposure to antibodies, pesticides and
 anthelmintics. The colostrum collected within 24 hours contains maximum substances but less
 in amounts, colostrum collected later will be more in quantity but contain less
 immunoglobins.(33) Colostrum contains the growth factors that help build lean muscle,
 including insulin-like growth factors (IGF-I & IGF-II) and growth hormone (GH). IGF-I, which
 is found naturally in colostrum, is the only natural hormone capable of promoting muscle
 growth by itself. The IGFs in humans and cows are identical, but bovine colostrum actually
 contains a greater concentration of IGF-I than human colostrum. This fact makes bovine
 colostrum attractive to bodybuilders, athletes and others seeking to gain muscle mass.
 According to a study conducted in Finland, IGF-1 induces protein synthesis, which leads to an
 increase in lean muscle mass without a corresponding rise in adipose (fat) tissue. The growth
 factors in colostrum "shift fuel utilization from carbohydrate to fat. It mean that body will
 burn more fat, including fat made from the carbohydrate and protein that are consumed,
 producing fuel more efficiently.(34) Bovine has hormone factor like gastrin which plays a
 role as a trophic factor for mucosal growth with in stomach. GLP-2 has shown a general
 trophic response with in the gut.

 Peptide growth factors in colostrum can influence the maintenance of mucosal mass and
 integrity. EGF stimulates cell proliferation and also influences crypt fission.(25) Human
 colostrum has higher concentration of growth factors as compared to bovine colostrum. The
 tables and figure below indicate how HC and BC differ in their nutrient content,
 immunological factors and growth factors (9,35,36)

 While BC are considered a rich source of IgG, growth factors, and lactoferrin, currently no
 specific standards exist that define BC dietary supplements with respect to actual
 constituents or amounts of constituents. The following constituents are generally present in
 bovine colostrums: macronutrients; vitamins; minerals; Ig (IgG, IgM, and IgA - including the
 secretory form); cytokines including interleukin-1beta (IL-1β), interleukin- 6 (IL-6), tumor
 necrosis factor-alpha (TNF-α), and interferon-gamma (INF-γ); growth factors including
 insulin-like growth factor (IGF) I and II, transforming growth factor-beta (TGF-β), and
 epidermal growth factor; lactoperoxidase; and lactoferrin. Depending on the health of the
 cows, feeding practices followed, collection period, and the processing/concentration
 practices utilized by specific manufacturers, the actual range and quantities of specific
 macro- and micronutrients, Ig, cytokines, growth factors, and other compounds might vary
 considerably.(37,38,39)

 BC contain relatively high amounts of Ig. Typically, Ig in general, and IgG specifically,
 constitutes the largest contribution to protein content in BC, with lactalbumin and casein
 contributing lesser amounts. Mean percentages of fat, protein, and lactose in colostrum were
 6.7, 14.9, and 2.5, respectively.40 Other reports have estimated Ig concentrations from
 bovine mammary secretions with ranges for IgG1 (52-87 g/L), IgG2 (1.6-2.1 g/L), IgM(3.7-6.1
 g/L), and IgA (3.2-6.2 g/L).41,42 As a rule, the Ig contribution will decline substantially
 in any BC collected more than 24 hours post-parturition and the amount of lactalbumin and
 casein will increase proportionately.

 Detailed research plan (Materials and Methods)

 Study design and setting

 This will be Double blind Randomized Placebo controlled Trial. We are planning a study of 2
 independent groups in the ratio of 1:1. The correct dose appears to be 60 grams and the
 number of patients required to be randomized should be more than 40 patients (10,11). We plan
 to enroll 250 patients.

 We will use an uncorrected chi-squared statistic to evaluate this null hypothesis.

 The study will be conducted on patients of Severe Alcoholic Hepatitis admitted in

 -  Principal Investigator: Sandeep S Sidhu, Dayanand Medical College and Hospital,
 Ludhiana, Punjab, India

 -  Principal Investigator: Barjesh C Sharma, GB pant Hospital, New Delhi

 -  Principal Investigator: Saroj K Sinha, PGI Hospital, Chandigarh, India

 -  Principal Investigator: Sandeep Nijhawan, SMS Hospital, Jaipur, India

 -  Principal Investigator: UshaDutta , PGIMER, Chandigarh, India

 Informed consent shall be taken from the patient/nearest relative of the patient for
 enrollment in the trial.

 Assignment

 Consecutive patients diagnosed to have Severe Alcoholic Hepatitis will be randomized into two
 groups (group A and B). The randomization will be performed using a computer generated random
 sequence with permuted blocks of varying size stratified for each centre.

 Masking Each center will have serially numbered identical vials containing bovine colostrum
 or pasteurized bovine milk arranged by a personnel who are not involved in the study
 according to the random sequence. The drug and the placebo will be identical in color, taste,
 appearance to ensure masking. All study personnel will be blinded to the treatment assignment
 (Bovine colostrum and placebo) for the duration of the study. The study drug will be
 administered by an oral route. The randomization code will be revealed only after the
 completion of recruitment, data collection and data analysis has been carried out.

 Randomization implementation

 Enrolment of patients, assessing eligibility and obtaining informed consent will be carried
 out by Principal Investigator (S.S. Sidhu) and other Centers Principal Investigator.

 Study Intervention

 The patients will be randomized to either

 Experimental arm: Bovine colostrum Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal)
 30-40/day, B complex vitamins daily.

 Pasteurized Bovine colostrum as a freeze dried powder (20 gm thrice a day) for 4 weeks.

 + Antibiotics + Diuretics +Terlipressin for HRS + acid suppression for prophylaxis against
 gastrointestinal hemorrhage + EVL for variceal bleed +drugs for HE if indicated

 Placebo Comparator: Placebo Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal)
 30-40/day, B complex vitamins daily.

 Placebo (Pasteurised Milk Powder) 20 gms thrice a day for 4 weeks

 + Antibiotics + Diuretics + drugs for HE + Terlipressin for HRS + acid suppression for
 prophylaxis against gastrointestinal hemorrhage + EVL for variceal bleed + if indicated.

 Study Methods Enrolment of patients, assessing eligibility and obtaining informed consent
 will be carried out by P.I. of each center Study Intervention

 Treatment for SAH:

 1. Enteral nutrition: Protein 1.5 gm/kg/day, energy (kcal) 30-40/day, B complex vitamins
 daily.

 2. Pasteurized Bovine colostrum (20gm thrice a day) for 4 weeks in one arm or Placebo
 (Pasteurize milk) 20gms thrice a day for4 weeks .

 Laboratory tests

 Liver biopsy: Transjugular liver biopsies will be obtained before start of therapy diagnosis
 of Alcoholic hepatitis [if possible]

 Biochemical tests

 Hemogram, blood glucose, liver function tests, prothrombin time, serum electrolytes, blood
 urea and serum creatinine will be done at baseline, and at and 7th day,14 days, 21 days , 28
 days and then bimonthly for two monthsor earlier if indicated.

 Microbiologic tests:

 A diagnostic paracentesis will be done in all patients with ascites, at baseline, to diagnose
 Spontaneous Bacterial Peritonitis. A repeat cell count (Total and differential) shall be done
 on day 5 in patients diagnosed to have Spontaneous Bacterial Peritonitis. Blood culture,
 urine culture, cultures of aspirates from endotracheal tubes in ventilated patients for
 aerobic and anaerobic bacteria, and fungi shall be done on at admission. A chest radiograph
 shall also be done.

 Endotoxin level estimation, alpha TNF,IL6& IL8 will be done at baseline and at end of
 treatment.

 Tests for etiologic evaluation:

 Etiology of cirrhosis will be taken as alcohol if there is a history of significant alcohol
 intake (20 gm/day for females, and 80 gm/day for males for 10 years or more). Each patient
 will be tested for Hepatitis B surface antigen (HBsAg) and Anti-hepatitis C (HCV) antibody
 using a third generation commercial ELISA. Wherever indicated, autoimmune hepatitis will be
 diagnosed using antinuclear antibody, anti-smooth muscle antibody and anti-LKM; and
 hemochromatosis using serum iron, TIBC, ferritin and transferrin saturation. Each patient
 shall have an abdominal ultrasonography. Upper gastrointestinal endoscopy would be done, if
 indicated.

 Ascitic Fluid analysis:Ascitic Fluid analysis will be done on 1st day and 5th day of
 treatment.

 Outcome measures and endpoints Primary outcome measure

 Survival at 3 month

 Secondary outcome measure

 1. Survival at 1 months

 2. Change in mDF levels/ MELD will be measured at baseline and after 4 weeks of treatment

 3. Change in Endotoxin levels will be measured at baseline and after 4 weeks of treatment

 4. Change in Cytokines levels will be measured at baseline and after 4 weeks of treatment

 5. Number of episodes of sepsis (bacteremia, Pneumonia, SBP, Cellulitis, UTI)

 Study Endpoints

 1. Liver related death

 2. Liver Transplantation

 3. Death due to other causes

 4. Complication of Disease (GI Bleed, Renal failure, Sepsis)

 Monitoring for Adverse Events:

 Any adverse event will be recorded specifying the time of onset, the duration, the severity
 and the relationship to the test medication.

 Tolerability

 Tolerability of the study drug will be assessed by comparison of full blood cell count, liver
 function tests and renal function tests at baseline and at end of treatment.

 Follow-up All patients will be followed up to 3 months or until death. The status alive or
 dead will be assessed by telephoning a family member or by contacting the death registry at
 patients at birth place or place of residence.

 Statistical Analysis:

 Comparisons will be made with the Wilcoxon or t test for continuous variables according to
 the normality of distribution, and the χ2 test or Fisher exact test for qualitative
 variables. All results of continuous variables were expressed as means and 95% confidence
 intervals (CIs) for continuous variables and as the frequencies, percentages, and 95% CIs for
 categorical variables. The primary results will be presented for all analyses as unadjusted.
 The cumulative incidence of death will be estimated by the Kaplan-Meier method in each
 treatment group. The statistical significance of hazard ratio (HR) for treatment allocation
 will be tested using the Cox proportional hazards regression model. The potential
 heterogeneity in the treatment effect according to different study centers will tested by
 adding an interaction center × treatment in the Cox proportional hazards regression model.
 Potential risk factors will be first tested by the Cox proportional hazards regression model
 in univariate analysis. Prognostic variables with a significance at a level of less than 0.10
 in univariate analyses will be included in a multivariable Cox proportional hazards
 regression model after removing variables showing a high degree of co - linearity. Factors
 included in a composite score will not be included in multivariable analysis to avoid bias
 related to the effect of co - linearity. All statistical analyses were performed in the
 intention- to-treat population as well as per-protocol population.

 We are planning a study of 2 independent groups in the ratio of 1:1. Prior data indicates
 that when 40 patients undergoing gastrointestinal surgery were randomized and given 56 g
 daily of Bovine Colostrum for 3 days preoperatively) or placebo and the course of the plasma
 endotoxin levels and the endotoxin neutralization capacity (ENC) were measured daily up to
 the 10th postoperative day10. The results showed that the LPS-levels in the LC1-group,
 expressed as AUC, were significantly lower than those in the control group (p < 0.05). The
 difference between the two groups was apparent on the day of the operation and the day after.
 The fall in endotoxin neutralizing capacity (ENC) was significantly lower in the patients
 treated with the BCC and the return to initial values was faster than in the control group (p
 < 0.006).

 In the second randomized study, 40 gms of Bovine Colostrum were given perioperatively to 60
 open heart surgery patients without any decrease in LPS levels or fall in the ENC.(11) The
 correct dose appears to be 60 grams and the number of patients required to be randomized
 should be more than 40 patients (10,11).

 Sample Size:The Survival rate of patients in standard medical treatment arm was 22% (Am J
 Gastroenterol 2014; 109:1417-1423). There is no contemporary Randomized controlled trial on
 the such type of patient (mDf >60, MELD >30). We consider a 20% increase in survival rate to
 clinically meaningful and sufficient to change practice. To detect a 20% increase in survival
 (from 22% to 42 %) in 3 month, The sample size based on survival at a fixed time point (22%
 vs 42% at 3 months), we require 79 per group + 10% drop outs. The total sample size required
 for the study is 174.
Inclusion Criteria:

 1. Alcoholic hepatitis Jaundice < 3 months Bilirubin > 5 mg/dl PTI (INR) Increased: >1.4
 Leucocytosis >> 11,000/micro L. AST< 300 IU/l ; AST/ALT >2

 2. Hepatic Encephalopathy

 3. Men and women age > 18 years and above

 4. DF>32

 5. MELD≥21

 6. Actively consuming alcohol within 6 weeks of entry into the study

 7. Patient with controlled upper GI bleed, resolved sepsis and acute kidney injury can be
 enrolled

 8. Voluntary informed consent

 Exclusion Criteria

 1. Failure to obtain informed consent

 2. Jaundice more than 3 months

 3. AST>500 IU/L, ALT>300 IU/L

 4. Other concomitant causes of liver disease: viral hepatitis, autoimmune liver disease,
 metabolic liver disease, vascular liver disease

 5. HIV positive

 6. Cow milk allergy or severe lactose intolerance

 7. Active Gastrointestinal bleeding

 8. Acute kidney injury at time of randomization with Creatinine> 1.5 mg/dL

 9. Evidence of acute pancreatitis or biliary obstruction

 10. Subjects who are pregnant or lactating

 11. Significant systemic cardio-pulmonary illness (what if on ventilator for HE or
 respiratory failure) - These are terminally ill patients, hence be excluded

 12. Patients requiring the use of vasopressors or inotropic support in 12 hours prior to
 randomization

 13. Treatment for alcoholic hepatitis within 1 month of study entry with corticosteroids
 use>1 week.

 14. Any patient who has received any investigational drug or device within 30 days
 entering into the study.

 15. Patient who withdraw consent