Current concepts and controversies in the treatment of alcoholic hepatitis

Table 1 Immunologic responses and directed therapies in alcoholic hepatitis

Cytokines	Mechanism	Mediators	Treatment
Cytokines
TNFα	Via TNFR1 signaling in hepatocytes and Kupffer cells (KC)	Apoptosis, necrosis, KC production of cytokines, potential cytoprotective effect	Glucocorticoids; Pentoxifylline; Infliximab
IL-6, 8	Lymphocyte and neutrophil activation, release of acute phase reactants	Inflammation, fibrosis	Glucocorticoids
Antigenic adduct	Oxidation of ethanol, binding to proteins forming antigenic adducts	Adaptive immunity	Glucocorticoids
Chemokines	Attract leukocytes and increase adhesion molecules	Inflammation	Glucocorticoids
Oxidative Injury
S-adenosyl-methionine (SAMe)	Precursor for glutathione, defense mechanism against oxidative stress, increase methylation	Protective role of SAMe	SAMe
Hypoxia/ischemic injury	Hypermetabolic state	Insufficient oxygen	Propylthiouracil

Table 2 Sensitivity and specificity of scoring systems for alcoholic hepatitis: sensitivities (Sen)/specificities (Spec)

Study	Patients	Study	Predictive	MELD	DF	CTP	Glasgow	Conclusions
		design	Mortality	Sen/Spec (%)	Sen/Spec (%)	Sen/Spec (%)	Sen/Spec (%)
Sheth et al[21] 2002	34	Retrospective	30 d	≥ 11	≥ 32	N/A	N/A	MELD equivalent to DF
				86/82	86/48
Kulkarni et al[17] 2004	41	Retrospective	28 d	N/A	≥ 33	N/A	N/A	DF ≥ 32 is appropriate.
					66.7/61.5			High mortality in DF < 32
Dunn et al[22] 2005	73	Retrospective	90 d	≥ 21	≥ 37	N/A	N/A	MELD equivalent to DF
				75/75	88/65
Srikureja et al[23] 2005	202	Retrospective	Not given	Admission: ≥ 18	≥ 32	≥ 12	N/A	Admission MELD equivalent
				85/84	83/84	76/80		to DF
				Wk 1: ≥ 20
				91/85
Forrest et al[16] 2005	134	Retrospective	28 d	N/A	≥ 32	N/A	≥ 9	GAHS more accurate in
			84 d		28 d		28 d	predicting mortality compared
					96/27		81/61	to DF
					84 d		84 d
					95/31		78/66
Forrest et al[16] 2005	46	Retrospective	28 d	≥ 11	N/A	N/A	≥ 9	GAHS more accurate in
			84 d	28 d			28 d	predicting 84 d mortality
				92/29			75/68	GAHS equivalent to MELD in
				84 d			84 d	predicting 28 d mortality
				92/29			69/67

Table 3 Randomized controlled glucocorticoid trials in treatment of alcoholic hepatitis (% Death)

Study	Glucocorticoid	Patient	Severity assessment	HE	Placebo	Steroid	RRR (95% CI)	NNT (95% CI)	Quality
					All (%)	All (%)	All %	All	score
					HE (%)	HE (%)	HE %	HE
Porter et al[125] 1971	Methylprednisolone	20	Self derived	16	7/9 (77)b	6/11 (55)b	N/A	N/A	5
					7/8 (88)c	6/8 (75)c
Helman et al[28]a 1971	Prednisolone	37	Self derived	15	6/17 (35)	1/20 (5)	86 (-0.06-0.98)	3 (2-18)	2
					6/6 (100)	1/9 (11)	84 (0.28-0.96)	1 (1-2)
Campra et al[31] 1973	Prednisone	54	Self derived	18	9/25 (36)	7/20 (35)	N/A	N/A	2
					8/10 (80)	4/8 (50)
Blitzer et al[52] 1977	Prednisolone	28	Self derived	5	5/16 (31)	6/12 (50)	N/A	N/A	5
					1/2 (50)	2/3 (67)
Lesesne et al[49]a 1978	Prednisolone	14	Self derived	14	7/7 (100)	2/7 (29)	67 (0.05-0.88)	2 (1-4)	3
					7/7 (100)	2/7 (29)	67 (0.05-0.88)	2 (1-4)
Shumaker et al[30] 1978	Methylprednisolone	27	Self derived	12	7/15 (47)	6/12 (50)	N/A	N/A	5
					4/6 (67)	2/6 (33)
Maddrey et al[13]a 1978	Prednisolone	55	DF	15	6/31 (19)	1/24 (4)	79 (-0.67-0.97)	6 (-3-111)	4
					6/10 (60)	1/5 (20)	67 (-1.1-0.95)	3 (-1-16)
Depew et al[126] 1980	Prednisone	28	Self derived	28	7/13 (54)	8/15 (53)	N/A	N/A	4
					7/13 (54)	8/15 (53)
Theodossi et al[53] 1982	Methylprednisolone	55	Self derived	34	16/28 (57)	17/27 (63)	N/A	N/A	3
					10/14 (71)	17/20 (85)
Mendenhall et al[48] 1984	Prednisolone	178	Self derived	61	50/88 (57)	55/90 (61)	N/A	N/A	3
					10/30 (33)	11/31 (36)
Carithers et al[14]a 1989	Methylprednisolone	66	DF	33	11/31 (36)	2/35 (6)	84 (0.3-0.96)	3 (2-9)	5
					9/19 (47)	1/14 (7)	85 (-0.06-0.98)	2 (2-7)
Ramond et al[15]a 1992	Prednisolone	61	DF	19	16/29 (55)	4/32 (13)	77 (0.4-0.9)	2 (2-5)	5
					7/10 (70)	2/9 (22)	68 (-0.15-0.9)	2 (1-12)

^aP < 0.05 for survival benefit as reported by study authors; Note percent death at 28 d in placebo versus steroids is shown in each box for all cases^b and for those with hepatic encephalopathy.

^cRRR, NNT is calculated from published data of those studies that reported a significant survival benefit. HE: Hepatic Encephalopathy; DF: Maddrey Discriminant Factor; CP: Child Turcotte Pugh; N/A: non significant difference in mortality as reported by study authors; Self derived: Criteria derived by study team not including CP, DF or MELD.

Table 4 Infliximab trials in the treatment of alcoholic hepatitis

Study	Design	Patients	Treatment	Results
Spahr et al[76]	Randomized	20	All patients: prednisone for 28 d	Improved Maddrey score
2002			Randomized d 0	No significant difference in survival, histology or adverse outcomes
			R1: Infliximab 5 mg/kg
			R2: Placebo
Tilg et al[77]	Case Series	12	Infliximab 5 mg/kg	83% (10/12) survived at median 15 mo
2003				No mention of infection
Mookerjee et al[78]	Case Series	10	Infliximab 5 mg/kg times one	72 h assessment
2003				Significant reduction in laboratory parameters
				Increased hepatic and renal blood flow
Naveau et al[79]	Randomized	36	All patients: Prednisone for 28 d	Significantly higher rate of infections in treated group
2004			R1: Infliximab 10 mg/kg	Non-significantly higher rate of death in treated group
			R2: Placebo	Study stopped secondary to adverse events in treatment group

Table 5 Interventional studies on nutrition and alcoholic hepatitis

Study	Design	Patients	Intervention	Findings
Lesesne et al[49] 1978	Randomized	14 patients, alcoholic hepatitis and encephalopathy	7 controls, 1600 Kcal diet	Reduction in mortality in the prednisolone arm
			7 study, prednisolone
Galambos et al[127] 1979	Case series	11 patients, alcoholic hepatitis	4, enteral hyperalimentation	No difference in mortality
			7, parenteral hyperalimentation	Increased nitrogen balance in study group
Nasrallah et al[128] 1980	Randomized	35 patients, alcoholic hepatitis	All received 3000 kcal 100g protein diet	Lower mortality in the study group
			18 control
			17 study, 70-85 gram of intravenous amino acid
Diehl et al[129] 1985	Randomized	15 patients, alcoholic hepatitis	All allowed to consume hospital diet ad libitum	Increased nitrogen balance in study group
			10 controls, glucose solution	No difference in clinical and biochemical markers of liver disease
			5 study, glucose solution + amino acids
Mendenhall et al[94] 1985	Randomized	57 patients, moderate-severe alcoholic hepatitis	34 controls, 2500 cal diet	No difference in mortality
			23 study, Hospital diet + Hepatic Aid	Improvement in nutritional parameters in intervention group
Calvey et al[130] 1985	Randomized	64 patients, alcoholic hepatitis	32 controls, standard diet	No difference in biochemical or clinical parameters
			32 study, standard diet + 2000 kCal + 10 g nitrogen
Soberon et al[131] 1987	Case series	14 patients, alcoholic hepatitis	6 with adequate nutritional status, hospital diet	No difference in mortality
			8 with poor baseline nutritional status, nasoduodenal diet, 35 kCal/kg per day	Increased nitrogen balance in study group
Simon et al[87] 1988	Randomized	12 patients, moderate alcoholic hepatitis 22 patients, severe alcoholic hepatitis	Moderate Group	No difference in mortality
			6 control, standard diet	Improved in biochemical tests in severe group
			6 study, PPN
			Severe Group
			12 control, standard
			10 study, PPN
Bonkovsky et al[67] 1991	Randomized	39 patients, moderate to severe alcoholic hepatitis	9, standard therapy	Improved biochemical parameters
			8, oxandrolone + standard therapy
			10, PPN
			12, oxandrolone + standard therapy + PPN
Mezey et al[88] 1991	Randomized	52 patients, alcoholic hepatitis	28 control, dextrose solution	No difference in mortality during hospitalization and 2 yr after treatment
			26 study, dextrose + amino acid
Mendenhall et al[69] 1993	Randomized	273 patients, severe alcoholic hepatitis	136 control	No difference in mortality overall
			137 study, oxadrolone + enteral nutrition	Improvement in mortality in moderately malnourished group(19%) versus control (51%) at 6 mo post treatment
Cabre et al[54] 2000	Randomized	71 patients, severe alcoholic hepatitis	36, prednisolone	No difference in overall mortality
			35, enteral tube 2000 kCal/d	Higher early mortality in nutrition versus higher follow up mortality on steroids
Alvarez et al[132] 2004	Case series	13 patients, severe alcoholic hepatitis	13, prednisolone + TEN 2000 kCal/d	15% death during treatment
				67% of patients developed infections during treatment -no deaths due to infections