Stratification and selection of therapies to improve survival in severe alcoholic hepatitis

Table 1 Inclusion and exclusion of major trials on corticosteroids in severe alcoholic hepatitis

Trial	Inclusion criteria	Exclusion criteria
STOPAH trial	Clinical diagnosis of alcoholic hepatitis with mDF > 32	Patients with creatinine > 5.7 mg% or on renal support. Patients with gastrointestinal bleed and creatinine up to 5.7 mg% were not excluded. Also, patients with resolved sepsis were not excluded
Louvet et al[13] 2009	Severe alcoholic hepatitis with mDF > 32 and onset of jaundice within 3 months. Patients with treated infections were included	Gastrointestinal bleed within 15 days, peptic ulcers, Hepatitis B and C, neoplasm
GpreAH study	Clinical or biopsy proven alcoholic hepatitis with mDF < 90	Patients with sepsis, creatinine > 1.5 and recent gastrointestinal bleed were excluded
STASH trial	Clinical diagnosis of alcoholic hepatitis	Acute kidney injury, recent gastrointestinal bleed and active infections were excluded

mDF: Maddrey’s discriminant function.

Table 2 Patients excluded from granulocyte colony stimulating factor therapy in randomized trial

Ref.	Intervention/control arm and inclusion criteria	Exclusion criteria	Survival at day 90
Singh et al[19] (2014)	GCSF+SOC, SMT	Upper gastrointestinal bleeding during the previous 10 days, hepatocellular carcinoma or portal vein thrombosis, hepatorenal syndrome, grade 3 or 4 hepatic encephalopathy, uncontrolled bacterial infection, human immunodeficiency virus infection, and other liver disease etiologies	18/23 (78.2%); 05/23 (21.7%)
Singh et al[18] (2018)	GCSF+SMT, SMT+GCSF+NAC, SMT	Same as above	13/19 (68.42%); 16/18 (88.8%); 6/20 (30%)
Shasthry et al[16] (2018)	GCSF, SMT	Lille score < 0.45 at day 7. Multiorgan failure	9/14 (64.2%); 4/14 (28.4%)
Tayek et al[42] (2022)	GCSF + SMT, SMT	Pregnancy, uncontrolled infection, known human immunodeficiency virus infection, recent upper gastrointestinal hemorrhage, white blood cell > 30000/mm3, creatinine > 2 mg/dL, and AH therapy for more than three days before randomization	12/16 (75%); 15/18 (83.2%)
Mishra et al[17] (2024)	GCSF, GCSF+Predni-solone, Prednisolone	Serum creatinine > 1.5 mg/dL, total leukocyte count > 25000/cmm, mDF > 90, hemoglobin of less than 10 g/dL, active infection, recent upper gastrointestinal bleeding, and the existence of any other liver disease	33/42 (78.5%); 37/42 (88.1%); 27/42 (64.2%)

GCSF: Granulocyte colony stimulating factor; SOC: Standard of care; SMT: Standard medical therapy; NAC: N-acetylcysteine.

Table 3 Plasma exchange in Severe alcoholic hepatitis

Ref.	Inclusion	Exclusion criteria	Survival at day 90 in intervention group
Kumar et al[24]	APASL defined alcohol ACLF	Liver illness due to other causes (such as drug- or virus-induced hepatitis, Wilson's disease, autoimmune hepatitis, or nonalcoholic fatty liver disease), sepsis, bleeding that has occurred recently (within the last three months), cancer, acute pancreatitis, or human immunodeficiency virus infection	35.6%
Kumar et al[24]	EASL defined ACLF	Hepatocellular cancer, patients with PLEX contraindications, such as infection, recent gastrointestinal bleeding, and hypotension	70% with centrifugal plasma exchange
Ramakrishnan et al[23]	ACLF defined by APASL with AARC score 8-10 and not responding to medical therapy	Nonalcoholic etiologies, coexisting hepatocellular carcinoma or extra-hepatic malignancy, bleeding, pregnancy, multiorgan failure (≥ 3 organ failures), severe pre-existing cardiopulmonary disease, APASL-AARC score > 10 or < 8, mechanically ventilated and requiring inotropic support at the time of enrolment were excluded from the study.	64%

APASL: Asian pacific association for study of liver; AARC: Asian pacific association for study of liver acute on chronic liver failure research consortium; EASL: European association for study of the liver; ACLF: Acute on chronic liver failure.

Table 4 Selection criterias for various therapies in severe alcoholic hepatitis

Therapy	Selection criteria	Remarks
Corticosteroids	Severe alcoholic hepatitis with mDF > 32 or MELD > 20 in absence of active sepsis and multiorgan dysfunctions. MELD > 39 should be avoided to exposed to corticosteroids	GI bleed and renal failure are relative contraindications. Corticosteroids can be considered on case to case basis in absence of other contraindications. Patients with resolved infections can be considered for steroid therapy
GCSF	Severe alcoholic hepatitis with mDF > 32 or MELD > 20 in absence of active sepsis and multiorgan dysfunctions. Patients with severe cytopenias, hemoglobin < 8 g/dL or leukocytosis with TLC > 30 k should be avoided for GCSF therapy. Patient with hypersplenism (spleen size > 15 cm) should be avoided	Limited literature exist regarding use of GCSF in resolved infection, GI bleed or Acute kidney injury. Hence it should be avoided till further evidence supports its use
Plasma exchange	Severe alcoholic hepatitis with mDF > 32 or MELD > 20 in absence of active sepsis and multiorgan dysfunctions. ACLF patients with progressive liver failure without extrahepatic failures are best candidates	Patients with acute renal injury in absence of other extrahepatic organ failure may benefit from therapy. Steroid non responders can be considered on case to case basis. Patients with GI bleed or resolved infection can be considered for plasma exchange
Fecal microbiota transplantation	Severe alcoholic hepatitis with mDF > 32 or MELD > 20 in absence of active sepsis and multiorgan dysfunctions	Patient with intestine paralysis should be avoided for FMT

MELD: Model for end stage liver disease; mDF: Maddrey’s discriminant function FMT: Fecal microbiota transplantation GI: Gastrointestinal; ACLF: Acute on chronic liver failure; GCSF: Granulocyte colony stimulating factor; TLC: Total leucocyte count.

Table 5 Fecal microbiota transplantation in severe alcoholic hepatitis

Ref.	Study design and inclusion criteria	Exclusion criteria	Infection rate
Pande et al[26] 2022	RCT, Adults with SAH	Creatinine > 1.5, MELD > 35; mDF > 90, GI bleed within 1 months	18.2%
Sharma et al[28] 2022	Prospective cohort study. Adults with SAH	Other causes of liver disease, uncontrolled infections, uncontrolled upper gastrointestinal bleeding, grade 3 or 4 hepatic encephalopathy, more than two organ failures, malignancy, intestinal paralysis, or perforation	30%
Philips et al[27] 2022	Retrospective. Adults with Steroids ineligible SAH	Hemodialysis at admission, disseminated intravascular coagulation, multi-organ failure, uncontrolled sepsis on inotropes, and other liver disease etiologies were excluded, as was gastrointestinal bleeding within a month	NA

RCT: Randomized controlled trial; SAH: Severe alcoholic hepatitis; MELD: Model for end stage liver disease; mDF: Maddrey’s discriminant function.

Table 6 Expected survival on various therapies and liver transplantation in severe alcoholic hepatitis

Therapy	Expected 28 days survival	Expected 90 days survival	Expected 6 months survival
Corticosteroids[8,17]	80% to 85%	60% to 70%	50% to 55%
GCSF[17,18]	80% to 90%	75% to 80%	60% to 65%
Plasma exchange[23,24]	60% to 70%	35% to 65%	20% to 30%
Fecal microbiota transplantation[26-28]	75% to 80%	70% to 75%	Variable
Liver transplantation	80% to 85%	80% to 85%	69% to 85%