Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

Table 1 Overview of the included studies

Study	Country	Study design	Disease	Intervention and dose		Duration of treatment	Available parameters
Randomized studies
Frezza et al[33], 1990	Italy	Multicenter, randomized, double-blind, placebo-controlled study	Chronic liver disease with IHC (N = 220)	AdoMet 1600 mg oral daily (n = 110)	Placebo (n = 110)	2 wk	ALT, AST, ALP, γGT, fatigue
Manzillo et al[38], 1992	Italy	Multicenter, randomized, double-blind, placebo-controlled study	IHC (N = 343)	AdoMet 800 mg iv daily (n = 180)	Placebo (n = 163)	2 wk	ALT, AST, ALP, γGT
Qin et al[37], 20001	China	Randomized, parallel-group, comparator-controlled study	Intrahepatic cholestatic viral hepatitis (N = 30)	AdoMet 1000 mg iv daily (n = 15)	Potassium magnesium aspartate 20 mL daily (n = 15)	4 wk	ALT, AST, ALP
Non-randomized studies
Podymova et al[34], 19981	Russia	Observational, baseline-controlled study	Chronic liver disease with IHC (N = 32)	AdoMet 800 mg iv daily for 16 d (first phase), then 1600 mg oral daily for 16 d (second phase)		32 d	ALT, AST, ALP, γGT, asthenic syndrome2
Fiorelli[32], 1999	Italy	Multicenter, baseline-controlled, open-label study	IHC complicating chronic liver disease (N = 640)	AdoMet 500 mg im (n = 338) or 800 mg iv (n = 302) daily		15 d	ALT, AST, ALP, γGT
Virukalpattigo-palratnam et al[36], 2013	India	Multicenter, observational, baseline-controlled study	IHC due to chronic NAFLD (N = 250)	AdoMet 800-1200 mg daily for 239/243 (98.4%) patients3		6 wk	ALT, AST, ALP, γGT, fatigue
Perlamutrov et al[31], 2014	Russia	Multicenter, observational, baseline-controlled study	DILI with IHC (N = 105)	AdoMet 400-800 mg iv or im daily for 2 wk (first phase), then 800-1600 mg oral daily for 4 wk (second phase)		6 wk	ALT, AST, ALP, γGT, fatigue, depressed mood
Larionova et al[30], 20151	Russia	Multicenter, observational, baseline-controlled study	DILI due to CT and evidence of IHC (N = 99)	AdoMet 400-800 mg iv or im daily for 2 wk (first phase), then 800-1600 mg oral daily for 4 wk (second phase)		6 wk	ALT, AST, fatigue, low mood
Ivashkin et al[35], 2018	Russia	Multicenter, baseline-controlled, open-label study	IHC due to ALD (N = 72)	AdoMet 1500 mg oral daily or 500/800 mg iv daily for 2 wk, then 1500 mg oral daily for 6 wk		8 wk	ALP, γGT, fatigue, depressed mood

¹Published studies translated to English from original language;

²Typically involving irritability, weakness, fatigue, and unstable mood;

³4/243 patients (1.6%) received doses < 800 mg/d. AdoMet: S-adenosylmethionine; ALD: Alcoholic liver disease; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CT: Chemotherapy; DILI: Drug-induced liver injury; γGT: Gamma-glutamyl transferase; IHC: Intrahepatic cholestasis; im: Intramuscular; iv: Intravenous; NAFLD: Non-alcoholic fatty liver disease.

Table 2 Risk-of-bias assessments for included randomized studies

Study	Risk of bias (domains)
	Inadequate sequence generation	Inadequate allocation concealment	Inadequate blinding	Inadequate handling of incomplete outcome data	Selective reporting of outcomes	Other bias
Frezza et al[33], 1990	Low	Unclear	Low	Low	Low	Low
Manzillo et al[38], 1992	Low	Unclear	Low	Low	Low	Low
Qin et al[37], 2000	Low	Unclear	Unclear	Low	Low	High

Risk of bias within each domain was judged as low, unclear, or high, using the Cochrane risk-of-bias tool for randomized studies[28].

Table 3 Risk-of-bias assessments for included non-randomized studies

Study	Risk of bias (domains)
	Inadequate selection of participants	Inadequate consideration of confounding variables	Inadequate measurement of exposure	Inadequate blinding of outcome assessments	Inadequate handling of incomplete outcome data	Selective reporting of outcomes
Podymova et al[34], 19981	Unclear	Unclear	High	Unclear	Unclear	Low
Fiorelli[32], 1999	High	High	Low	Unclear	Low	Low
Virukalpattigo-palratnam et al[36], 2013	Unclear	Unclear	High	Unclear	High	Low
Perlamutrov et al[31], 2014	Unclear	Unclear	High	Unclear	Low	Low
Larionova et al[30], 20151	Unclear	Unclear	High	Unclear	High	Low
Ivashkin et al[35], 2018	Unclear	Unclear	High	Unclear	Low	Low

¹Published studies translated to English from original language. Risk of bias within each domain was judged as low, unclear, or high, using the risk-of-bias assessment tool for non-randomized studies[29].

Table 4 Summary of outcome data relating to prespecified biochemical liver parameters (randomized studies)

Parameter	Study	Disease	Intervention	Baseline		After treatment		Statistical method	P value
				AdoMet	Placebo / comparator	AdoMet	Placebo / comparator
ALT
ALT (μkat/L)	Frezza et al[33], 1990	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	3.3 ± 0.4 (mean ± SE)	2.8 ± 0.3	2.3 ± 0.2 (Week 1), 1.5 ± 0.1 (Week 2)	2.4 ± 0.2 (Week 1), 2.2 ± 0.2 (Week 2)	Split-plot analysis	Not reported at Week 1, P < 0.05 vs placebo at Week 2
ALT (μkat/L)	Manzillo et al[38], 1992	IHC (N = 343)	AdoMet (n = 180) vs placebo (n = 163)	1.2 (1.1, 1.4) (mean, 95% CI)	1.2 (1.1, 1.4)	0.8 (0.7, 0.9)	1.0 (0.9, 1.2)	Split-plot analysis (MANOVA)	P < 0.01 treatment-to-time interaction vs placebo at Week 2
ALT (U/L)	Qin et al[37], 20001	Intrahepatic cholestatic viral hepatitis (N = 30)	AdoMet (n = 15) vs potassium magnesium aspartate (n = 15)	198.5 ± 75.2 (mean ± SD)	190.6 ± 71.2	127.0 ± 47.5 (Week 2), 48.2 ± 43.5 (Week 4)	130.2 ± 47.2 (Week 2), 67.7 ± 27.2 (Week 4)	x2 test for comparison of rates; t test for comparison of means	NS at Week 2 P < 0.05 vs comparator at Week 4
AST
AST (μkat/L)	Frezza et al[33], 1990	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	2.4 ± 0.2 (mean ± SE)	2.1 ± 0.2	1.8 ± 0.1 (Week 1), 1.3 ± 0.1 (Week 2)	1.8 ± 0.2 (Week 1), 1.7 ± 0.2 (Week 2)	Split-plot analysis	NS vs placebo at Weeks 1 and 2
AST (μkat/L)	Manzillo et al[38], 1992	IHC (N = 343)	AdoMet (n = 180) vs placebo (n = 163)	1.4 (1.2, 1.6) (mean, 95% CI)	1.3 (1.2, 1.5)	0.9 (0.9, 1.1)	1.0 (0.9, 1.2)	Split-plot analysis (MANOVA)	P < 0.05 treatment-to-time interaction vs placebo at Week 2
AST (U/L)	Qin et al[37], 20001	Intrahepatic cholestatic viral hepatitis (N = 30)	AdoMet (n = 15) vs potassium magnesium aspartate (n = 15)	127.0 ± 60.7 (mean ± SD)	118.2 ± 58.7	84.6 ± 33.8 (Week 2), 45.6 ± 28.2 (Week 4)	78.3 ± 38.5 (Week 2), 52.7 ± 25.3 (Week 4)	x2 test for comparison of rates; t test for comparison of means	NS at Week 2 P < 0.05 vs comparator at Week 4
ALP
ALP (μkat/L)	Frezza et al[33], 1990	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	4.5 ± 0.3 (mean ± SE)	4.7 ± 0.3	3.7 ± 0.3 (Week 1), 3.2 ± 0.2 (Week 2)	4.6 ± 0.3 (Week 1), 4.4 ± 0.3 (Week 2)	Split-plot analysis	P < 0.05 vs placebo at Week 1, P < 0.01 vs placebo at Week 2
ALP (μkat/L)	Manzillo et al[38], 1992	IHC (N = 343)	AdoMet (n = 180) vs placebo (n = 163)	4.8 (4.2, 5.5) (mean, 95% CI)	4.9 (4.3, 5.7)	3.9 (3.4, 4.4)	4.0 (3.4, 4.7)	Split-plot analysis (MANOVA)	NS vs placebo at Week 2
ALP (U/L)	Qin et al[37], 20001	Intrahepatic cholestatic viral hepatitis (N = 30)	AdoMet (n = 15) vs potassium magnesium aspartate (n = 15)	203.2 ± 39.5 (mean ± SD)	202.8 ± 39.4	93.5 ± 33.7 (Week 2), 85.6 ± 20.6 (Week 4)	97.5 ± 33.0 (Week 2), 89.1 ± 27.8 (Week 4)	x2 test for comparison of rates; t test for comparison of means	NS vs comparator at Weeks 2 and 4
γGT
γGT (μkat/L)	Frezza et al[33], 1990	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	2.5 ± 0.3 (mean ± SE)	2.2 ± 0.2	1.9 ± 0.3 (Week 1), 1.5 ± 0.2 (Week 2)	1.9 ± 0.1 (Week 1), 1.7 ± 0.1 (Week 2)	Split-plot analysis	NS at Week 1 or Week 2
γGT (μkat/L)	Manzillo et al[38], 1992	IHC (N = 343)	AdoMet (n = 180) vs placebo (n = 163)	1.9 (1.6, 2.2) (mean, 95% CI)	1.8 (1.6, 2.2)	1.2 (1.0, 1.3)	1.3 (1.1, 1.6)	Split-plot analysis (MANOVA)	P < 0.05 treatment-to-time interaction vs placebo at Week 2

¹Published studies translated to English from original language. AdoMet: S-adenosylmethionine; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CI: Confidence interval; γGT: Gamma-glutamyl transferase; IHC: Intrahepatic cholestasis; MANOVA: Multivariate analysis of variance; NS: Not significant; SD: Standard deviation; SE: Standard error.

Table 5 Summary of outcome data relating to prespecified biochemical liver parameters (non-randomized studies)

Parameter	Study	Disease	Intervention	Baseline	After treatment	Statistical method	P value
ALT
ALT (IU)	Podymova et al[34], 19981	Chronic liver disease with IHC (N = 32)	AdoMet	109.3 ± 26.4 (mean ± SD)	74.4 ± 167.0 (Day 17), 40.5 ± 14.5 (Day 33)	NR	P > 0.1 vs baseline at Day 17, P > 0.05 vs baseline at Day 33
ALT (U/L)	Fiorelli[32], 1999	IHC complicating chronic liver disease (N = 640)	AdoMet im or iv	im: 96 ± 6.1, iv: 92 ± 5.6 (mean ± SE)	im: 84 ± 5.3 (Day 7), 76 ± 5.6 (Day 15), iv: 84 ± 4.3 (Day 7), 76 ± 3.6 (Day 15)	Friedman non-parametric test	P < 0.01 vs baseline at Days 7 and 15 for both im and iv
ALT (U/L)	Virukalpattigo-palratnam et al[36], 2013	IHC due to chronic NAFLD (N = 250)	AdoMet	124.4 (mean)	62.1	Wilcoxon signed-rank test	P < 0.05 vs baseline at Week 6
ALT (U/L)	Perlamutrov et al[31], 2014	DILI with IHC (N = 105)	AdoMet	NR	NR	Spearman’s correlation coefficient	P < 0.05 vs baseline at Weeks 2 and 6
ALT (U/L)	Larionova et al[30], 20151	DILI due to CT and evidence of IHC (N = 99)	AdoMet	137.3 (median)	68.5 (Day 14), 55.2 (Day 42)	NR	P < 0.001 vs baseline at Days 14 and 42
AST
AST (IU)	Podymova et al[34], 19981	Chronic liver disease with IHC (N = 32)	AdoMet	105.9 ± 21.5 (mean ± SD)	66.4 ± 13.9 (Day 17), 32.5 ± 10.0 (Day 33)	NR	P > 0.1 vs baseline at Day 17 P > 0.01 vs baseline at Day 33
AST (U/L)	Fiorelli[32], 1999	IHC complicating chronic liver disease (N = 640)	AdoMet im or iv	im: 104 ± 4.2, iv: 116 ± 5.7 (mean ± SE)	im: 96 ± 4.4 (Day 7), 88.0 ± 4.8 (Day 15), iv: 100 ± 4.1 (Day 7), 92.0 ± 4.1 (Day 15)	Friedman non-parametric test	P < 0.01 vs baseline at Days 7 and 15 for both im and iv
AST (U/L)	Virukalpattigo-palratnam et al[36], 2013	IHC due to chronic NAFLD (N = 250)	AdoMet	130.8 (mean)	61.6	Wilcoxon signed-rank test	P < 0.05 vs baseline at Week 6
AST (U/L)	Perlamutrov et al[31], 2014	DILI with IHC (N = 105)	AdoMet	NR	NR	Spearman’s correlation coefficient	P < 0.05 vs baseline at Weeks 2 and 6
AST (U/L)	Larionova et al[30], 20151	DILI due to CT and evidence of IHC (N = 99)	AdoMet	103.3 (median)	49.7 (Day 14), 41.0 (Day 42)	NR	P < 0.001 vs baseline at Days 14 and 42
ALP
ALP (U/L)	Podymova et al[34], 19981	Chronic liver disease with IHC (N = 32)	AdoMet	676.9 ± 154.8 (mean ± SD)	596.5 ± 144.2 (Day 17), 446.2 ± 175.1 (Day 33)	NR	P > 0.1 vs baseline at Day 17, P > 0.1 vs baseline at Day 33
ALP (U/L)	Fiorelli[32], 1999	IHC complicating chronic liver disease (N = 640)	AdoMet im or iv	im: 259.5 ± 10.8, iv: 276.5 ± 13.7 (mean ± SE)	im: 217.0 ± 10.5 (Day 7), 191.5 ± 10.2 (Day 15), iv: 234.0 ± 14.3 (Day 7), 208.5 ± 13.6 (Day 15)	Friedman non-parametric test	P < 0.01 vs baseline at Days 7 and 15 for both im and iv
ALP (U/L)	Virukalpattigo-palratnam et al[36], 2013	IHC due to chronic NAFLD (N = 250)	AdoMet	230.6 (mean)	165.3	Wilcoxon signed-rank test	P < 0.05 vs baseline at Week 6
ALP (U/L)	Perlamutrov et al[31], 2014	DILI with IHC (N = 105)	AdoMet	NR	NR	Spearman’s correlation coefficient	P < 0.05 vs baseline at Week 2, P < 0.05 vs baseline at Week 6
ALP (U/L)	Ivashkin et al[35], 2018	IHC due to ALD (N = 72)	AdoMet	241.2	167.9 (Week 2), 152.2 (Week 8)	ANCOVA	P < 0.0001 vs baseline at Weeks 2 and 8
γGT
γGT (IU)	Podymova et al[34], 19981	Chronic liver disease with IHC (N = 32)	AdoMet	153.5 ± 36.1 (mean ± SD)	145.1 ± 50.1 (Day 17), 51.8 ± 16.1 (Day 33)	NR	P > 0.1 vs baseline at Day 17, P > 0.05 vs baseline at Day 33
γGT (U/L)	Fiorelli[32], 1999	IHC complicating chronic liver disease (N = 640)	AdoMet im or iv	im: 240.7 ± 20.0, iv: 303.4 ± 36.1	im: 195.1 ± 16.0 (Day 7), 160.9 ± 10.0 (Day 15), iv: 218.0 ± 17.7 (Day 7), 189.4 ± 17.3 (Day 15)	Friedman non-parametric test	P < 0.01 vs baseline at Days 7 and 15 for both im and iv
γGT (U/L)	Virukalpattigo-palratnam et al[36], 2013	IHC due to chronic NAFLD (N = 250)	AdoMet	151.5 (mean)	90.8 (mean)	Wilcoxon signed-rank test	P < 0.05 vs baseline at Week 6
γGT (U/L)	Perlamutrov et al[31], 2014	DILI with IHC (N = 105)	AdoMet	NR	NR	Spearman’s correlation coefficient	P < 0.05 vs baseline at Week 2, P < 0.05 vs baseline at Week 6
γGT (U/L)	Ivashkin et al[35], 2018	IHC due to ALD (N = 72)	AdoMet	NR	Mean change ± SD: -197.0 ± 403.5 (Week 2), -233.8 ± 407.1 (Week 8)	ANCOVA	P < 0.0001 vs baseline at Weeks 2 and 8

¹Published studies translated to English from original language. AdoMet: S-adenosylmethionine; ALD: Alcoholic liver disease; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; ANOVA: Analysis of variance; ANCOVA: Analysis of covariance; AST: Aspartate aminotransferase; CI: Confidence interval; CT: Chemotherapy; DILI: Drug-induced liver injury; γGT: Gamma-glutamyl transferase; IHC: Intrahepatic cholestasis; im: Intramuscular; iv: Intravenous; NAFLD: Non-alcoholic fatty liver disease; NR: Not reported; SD: Standard deviation; SE: Standard error.

Table 6 Summary of outcome data relating to prespecified symptoms and consequences of cholestasis

Parameter	Study	Scale / scoring system	Disease	Inter-vention	Baseline		After treatment		Statistical method	P value
					AdoMet	Control	AdoMet	Control
Fatigue
Fatigue (cm)	Frezza et al[33], 19901	10 cm visual analog scale: 0 = lack of symptom to 10 = maximal severity	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	5.5 ± 0.3 (mean ± SE)	5.3 ± 0.3	3.5 ± 0.2 (Week 1), 2.6 ± 0.2 (Week 2)	5.0 ± 0.3 (Week 1), 4.8 ± 0.3 (Week 2)	Fisher’s exact test	P < 0.01 vs placebo at Weeks 1 and 2
Fatigue (% patients)	Virukalpattigopalratnam et al[36], 20132	NR	IHC due to chronic NAFLD (N = 250)	AdoMet	75.8	-	32.5	-	McNemar's test	P < 0.0001 vs baseline at Week 6
Fatigue (% patients)	Perlamutrov et al[31], 20142	Two-degree scale: 0 = absent; 1 = present	DILI with IHC (N = 105)	AdoMet	81.0	-	29.5 (Day 14), 11.4 (Day 42)	-	NR	NR
Fatigue (% patients)	Larionova et al[30], 20152,3	NR	DILI due to CT and evidence of IHC (N = 99)	AdoMet	42.4	-	25.3 (Day 14), 17.2 (Day 42)	-	NR	NR
Fatigue (% patients without)	Ivashkin et al[35], 2018	Six-point scale: 0 = no symptoms to 5 = maximal symptoms	IHC due to ALD (N = 72)	AdoMet	18.1	-	49.2	-	NR	NR
Depressed mood
Asthenic syndrome4 (% patients)	Podymova et al[34], 19982,3	Four-degree scale: 0 = absent to 3 = severe	Chronic liver disease with IHC (N = 32)	AdoMet	100%	-	50 (Day 17), 46 (Day 33)	-	NR	NR
Depressed mood (% patients without)	Perlamutrov et al[31], 20142	Four-degree scale: 0 = absent to 3 = severe	DILI with IHC (N = 105)	AdoMet	12.4%	-	50.5 (Day 14), 74.3 (Day 42)	-	x2 test	P < 0.001 vs baseline at Days 14 and 42
Low mood (No. patients)	Larionova et al[30], 20152,3	NR	DILI due to CT and evidence of IHC (N = 99)	AdoMet	NR	-	No. of patients without low mood increased on Days 14 and 42	-	NR	NR
Depressed mood (% patients without)	Ivashkin et al[35], 20182	Six-point scale: 0 = no symptoms to 5 = maximal symptoms	IHC due to ALD (N = 72)	AdoMet	16.7	-	73.0	-	NR	NR
Pruritus
Pruritus (cm)	Frezza et al[33], 19901	10 cm visual analog scale: 0 = lack of symptom to 10 = maximal severity	Chronic liver disease with IHC (N = 220)	AdoMet (n = 110) vs placebo (n = 110)	5.3 ± 0.3 (mean ± SE)	5.3 ± 0.3	3.5 ± 0.3 (Week 1), 2.7 ± 0.2 (Week 2)	4.8 ± 0.2 (Week 1), 4.1 ± 0.2 (Week 2)	Fisher’s exact test	P < 0.01 vs placebo at Weeks 1 and 2
Pruritus (% patients)	Podymova et al[34], 19982,3	Four-degree scale: 0 = absent to 3 = severe	Chronic liver disease with IHC (N = 32)	AdoMet	63	-	53 (Day 17), 41 (Day 33)	-	NR	NR
Pruritus (% patients)	Virukalpattigopalratnam et al[36], 20132	NR	IHC due to chronic NAFLD (N = 250)	AdoMet	38.9	-	17.3	-	McNemar's test	P < 0.0001 vs baseline at Week 6
Pruritus (% patients)	Perlamutrov et al[31], 20142	Two-degree scale: 0 = absent; 1 = present	DILI with IHC (N = 105)	AdoMet	81.0	-	42.9 (Day 14), 6.7 (Day 42)	-	NR	NR
Pruritus (% patients)	Larionova et al[30], 20152,3	NR	DILI due to CT and evidence of IHC (N = 99)	AdoMet	24.2	-	7.1 (Day 14), 6.1 (Day 42)	-	NR	NR
Pruritus (% patients without)	Ivashkin et al[35], 20182	Six-point scale: 0 = no symptoms to 5 = maximal symptoms	IHC due to ALD (N = 72)	AdoMet	45.8	-	88.9	-	NR	NR

¹Randomized studies;

²Observational studies;

³Published studies translated to English from original language;

⁴Typically involving irritability, weakness, fatigue, and unstable mood. AdoMet: S-adenosylmethionine; ALD: Alcoholic liver disease; CT: Chemotherapy; DILI: Drug-induced liver injury; IHC: Intrahepatic cholestasis; NAFLD: Non-alcoholic fatty liver disease; NR: Not reported; SE: Standard error.