Clin Mol Hepatol > Volume 28(3); 2022 > Article |
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Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Lindor et al. [8] (2004) | NAFLD | Biopsy-proven NASH with ALT >1.5×ULN | 2 years | UDCA 13–15 mg/kg/day (80) | 45.4±12.0 | · Changes in AST (mean, -21.7 U/L vs. -20.7 U/L; P=0.37) and ALT (mean, -32.7 U/L vs. -31.6 U/L; P=0.60) | RCT |
Placebo (86) | 48.5±11.6 | · Changes in steatosis (mean, -0.6 vs. -0.3; P=0.41), inflammation (mean, 0.0 vs. -0.1; P=0.43), and fibrosis (mean, 0.0 vs. 0.0; P=0.50) stages | |||||
Leuschner et al. [58] (2010) | NAFLD | Biopsy-proven NASH with ALT >1.5×ULN | 18 months | UDCA 23–28 mg/kg/day (94) | 41.45 (18–71) | · Difference in modified Brunt score (mean, -0.98 vs. -0.97; P=0.881) | RCT |
Placebo (91) | 45.02 (18–73) | · Difference in NAS (mean, -1.22 vs. -1.03; P=0.355) | |||||
Ratziu et al. [59] (2011) | NAFLD | Biopsy-proven NASH with ALT >50 IU/L | 12 months | UDCA 28–35 mg/kg/day (62) | 49.8±10.2 | · Changes in ALT (-28.3% vs. -1.6%; P<0.001) | RCT |
Placebo (61) | 49.6±12.6 | · Proportion of ALT normalization (24.5% vs. 4.8%; P<0.003) | |||||
· Changes in FibroTest values (median, -10.5% vs. +9.6%; P<0.006) | |||||||
Traussnigg et al. [63] (2019) | NAFLD | ALT >0.8×ULN | 12 weeks | Nor-UDCA 1,500 mg/day (67) | 48.9±12.8 | · Changes in ALT (mean, -17.2 U/L vs. -7.0 U/L vs. +5.3 U/L;P<0.0001) | RCT |
Nor-UDCA 500 mg/day (67) | 44.9±11.6 | · Proportion of ALT < 0.8×ULN (17.5% vs. 14.8% vs. 5.2%) | |||||
Placebo (64) | 48.8±11.4 | · Reduction of hepatic fat fraction by MRS (-23.5% vs. +0.9% vs. -1.0%) | |||||
Fabbri et al. [64] (2000) | CHC | Non-responders to IFN-α with ALT >1.5×ULN | 14 months | IFN-α + UDCA 600 mg/day followed by UDCA 600 mg/ day (53) | 52.6±1.8 | · Proportion of ALT normalization (38% vs. 12%; P<0.01) | RCT |
IFN-α followed by placebo (50) | 45.8±1.8 | · Proportion of ALT relapse after withdrawal of IFN-α (55% vs. 100%; P<0.01) | |||||
Boucher et al. [65] (2000) | CHC | Responders to IFN-α | 12 months | UDCA 10 mg/kg/day (54) | 41±15 | · Proportion of biochemical SR (30% vs. 46%; P=NS) | RCT |
Placebo (53) | 43±15 | · Proportion of virological SR (22% vs. 32%; P=NS) | |||||
· Post-treatment Knodell score (mean, 6.6 vs. 5.6; P=NS) | |||||||
Omata et al. [66] (2007) | CHC | ALT >61 U/L | 24 weeks | UDCA 150 mg/day (195) | 58±12.2 | · Changes in ALT (-15.3% vs. -29.2% vs. -36.2%; P<0.001) | RCT |
UDCA 600 mg/day (198) | 57.7±12.0 | · Changes in AST (-13.6% vs. -25.0% vs. -29.8%; P<0.001) | |||||
UDCA 900 mg/day (193) | 59.8±10.1 | · Changes in GGT (-22.4% vs. -41.0% vs. -50.0%; P<0.001) |
Variables are expressed as median (interquartile range) or mean±standard deviation.
UDCA, ursodeoxycholic acid; NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ALT, alanine aminotransferase; ULN, upper limit of normal; AST, aspartate aminotransferase; RCT, randomized controlled trial; NAS, NAFLD activity score; nor-UDCA, norursodeoxycholic acid; MRS, magnetic resonance spectroscopy; CHC, chronic hepatitis C; IFN, interferon; SR, sustained response; NS, not significant.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Navarro et al. [9] (2019) | NAFLD | NAS ≥4 without cirrhosis | 48–50 weeks | Silymarin 1,260 mg/day (26) | 47.3 (10.8) | · Improvement ≥2 in NAS (19% vs. 15% vs. 12%; P=0.79) | RCT |
Silymarin 2,100 mg/day (27) | 48.2 (11.4) | · Normalized ALT level (8% vs. 25% vs. 5%; P=0.08) | |||||
Placebo (25) | 49.5 (10.9) | · Improved fibrosis stage (12% vs. 26% vs. 28%; P=0.30) | |||||
Wha Kheong et al. [31] (2017) | NAFLD | NAS ≥4 | 48 weeks | Silymarin 2,100 mg/day (49) | 49.6±12.7 | · Decrease ≥30% in NAS (32.7% vs. 26.0%; P=0.467) | RCT |
Placebo (50) | 50.1±10.2 | · Reductions in fibrosis ≥1 stage (22.4% vs. 6.0%; P=0.023) | |||||
· Change in triglyceride level (mean, -0.2 vs. 0.04 mmol/L; P=0.017) | |||||||
Anushiravani et al. [87] (2019) | NAFLD | Grade ≥2 steatosis in ultrasonography | 3 months | LSM (30) | 47.0±9.1 | · Changes in AST (mean, -0.9 vs. -8.3 U/mL; P<0.001) and ALT (mean, -0.6 vs. -9.3 U/mL; P<0.001) levels | RCT |
LSM + silymarin 140 mg/day (30) | · Changes in WC (mean, -1.2 vs. -0.3 cm; P<0.001) | ||||||
Solhi et al. [85] (2014) | NAFLD | AST and ALT >1.2×ULN | 8 weeks | LSM + silymarin 210 mg/day (33) | 43.6±8.3 | · Changes in AST (mean, 62.8 to 30.5 vs. 70.4 to 36.2; P=0.038) and ALT (mean, 91.3 to 38.4 vs. 84.6 to 52.3; P=0.026) levels (U/L) | RCT |
LSM + placebo (31) | 9.4±10.5 | ||||||
Hajiaghamohammadi et al. [28] (2012) | NAFLD | 8 weeks | Pioglitazone 15 mg/day (22) | 33.4±6.6 | · Changes in AST (mean, 55.0 to 37.59 vs. 54.86 to 42.5 vs. 56 to 37.77; P=0.003) and ALT (mean, 77.45 to 52.27 vs. 78.36 to 60.95 vs. 78.73 to 53.05; P<0.005) levels (U/L) | RCT | |
Metformin 500 mg/day (22) | 32.5±6.5 | ||||||
Silymarin 140 mg/day (22) | 33.5±6.3 | · Significant reductions in mean levels of fasting glucose, triglyceride, total cholesterol, and insulin and HOMA-IR in all groups (P<0.01) | |||||
Hashemi et al. [86] (2009) | NAFLD | AST and ALT >1.2×ULN or biopsy-proven NASH | 6 months | Silymarin 280 mg/day (50) | 39.28±11.11 | · ALT (52% vs. 18%; P=0.001) and AST (62% vs. 20%; P=0.0001) level normalization | RCT |
Placebo (50) | 39.0±10.70 | ||||||
Sorrentino et al. [90] (2015) | NAFLD | WC > 94 cm in men or >80 cm in women, triglyceride >150 mg/dL, and fasting glucose >100 mg/dL | 90 days | LSM + silymarin 250 mg/day + vitamin E 60 IU/day (43) | 56.63±12.79 | · Change in hepatic steatosis index (mean, -1.85 vs. -0.19; P=0.0134) | Prospective cohort study |
LSM (35) | 55.40±13.63 | · Changes in BMI (mean, -0.71 vs. -0.004 kg/m2; P=0.022) and WC (mean, -4.81 vs. -1.78 cm; P=0.028) | |||||
Stiuso et al. [88] (2014) | NAFLD | Biopsy-proven NASH | 12 months | Low levels of TBARS: Silymarin 188 mg/day + phosphatidyl choline 388 mg/day + vitamin E acetate 50% 178.56 mg/day (11) | 40.8±10.3 | · Proportion of change in NAS (-29%; NS), portal inflammation (-25%; NS), and fibrosis (-50%; P=0.01) | Retrospective cohort study |
· Proportion of change in AST (-33%; P=0.05), ALT (-14%; NS), and insulin (-8%; NS) levels and HOMA-IR (-11%; NS) | |||||||
High levels of TBARS: silymarin 188 mg/day + phosphatidyl choline 388 mg/day + vitamin E acetate 50% 178.56 mg/day (19) | · Proportion of change in NAS (-70%, P=0.001), portal inflammation (-58%; P=0.001), and fibrosis (-60%; P=0.001) | ||||||
· Proportion of change in AST (-42%; P=0.01), ALT (-31%; P=0.05), and insulin (-40%; P=0.001) levels and HOMA-IR (-42%; P=0.001) | |||||||
Fried et al. [91] (2012) | HCV | ALT ≥65 U/L who were unsuccessfully treated with IFN | 24 weeks | Silymarin 1,260 mg/day (50) | 54.0 (52.0–57.0) | · Proportion of ALT ≤45 U/L (4.0% vs. 3.8% vs. 1.9%; P=0.80), at least 50% ALT decline and ALT <65 U/L at week 24 (2.0% vs. 3.8% vs. 3.8%; P=0.83) | RCT |
Silymarin 2,100 mg/day (52) | 54.0 (48.0–58.0) | ||||||
Placebo (52) | 56.0 (51.5–59.5) | · Changes in ALT (mean, -14.4 vs. -11.3 vs. -4.3 U/L; P=0.75) and HCV RNA (mean, -0.03 vs. 0.04 vs. 0.07 log10 IU/L; P=0.54) levels | |||||
Yakoot and Salem [92] (2012) | HCV | Genotype 4, IFN-naïve or relapsers/nonresponders to IFN or combined therapy | 6 months | Silymarin 420 mg/day (29) | 48±12 | · ETR (3.4% vs. 13.3%; P=0.12) | RCT |
Spirulina 1,500 mg/day (30) | 47±12 | · 3 months virological response (0% vs. 3.3%; P=0.22) | |||||
· Reduction in ALT level (mean, -6.8 vs. -23.7 IU/L; P=0.006) | |||||||
Tanamly et al. [94] (2004) | HCV | Presence of HCV RNA | 12 months | Silymarin 373.5 mg/day (68) | 44.1 | · All physical and mental health variables (SF-36 questionnaire) were improved in both groups. | RCT |
Multivitamin (71) | · Persistent HCV RNA (97.1% vs. 95.8%; P=0.684) and ALT >35 IU/L (13.0% vs. 14.3%; NS) | ||||||
Ferenci et al. [95] (2008) | HCV | Nonresponders to full-dose PegIFN/RBV | 14 days | Silymarin iv 5 (3), 10 (3), 15 (5), 20 (9) mg/kg + 24 weeks PegIFNα-2a 180 µg/week + ribavirin 1–1.2 g/day from day 8 | 52.7±12.8 | · Dose-dependent HCV RNA decrease (log drop after 14 days: mean, 1.63 [5 mg/kg], 4.16 [10 mg/kg], 3.69 [15 mg/kg], and 4.85 [20 mg/kg]; P<0.001) | Prospective cohort study |
· Undetectable HCV RNA in 7 patients on 15 or 20 mg/kg of silymarin at week 12 |
Variables are expressed as median (interquartile range) or mean±standard deviation.
NAFLD, nonalcoholic fatty liver disease; NAS, NAFLD activity score; ALT, alanine aminotransferase; RCT, randomized controlled trial; LSM, lifestyle modification; AST, aspartate aminotransferase; WC, waist circumference; ULN, upper limit of normal; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; NASH, nonalcoholic steatohepatitis; BMI, body mass index; TBARS, thiobarbituric acid-reactive species; NS, not significant; HCV, hepatitis C virus; IFN, interferon; ETR, end-treatment response; PegIFN/RBV, pegylated interferon and ribavirin.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Lee et al. [10] (2014) | CLD | (1) Persistent ALT ≥1.5×ULN more than once during the previous 6 months; (2) ALT ≥1.5×ULN at enrollment | 24 weeks | DDB 750 mg/day (67) | 51 (20–72) | ALT normalization (≤40 IU/L) (80.0% vs. 34.8%; P<0.001) | RCT; double blind, active- controlled |
Kang et al. [108] (2001) | CLD | (1) Biopsy-proven chronic hepatitis or (2) abnormal AST/ALT for >6 months; no evidence of viral hepatitis B or C | 8 weeks | High-dose group: DDB 150 mg + carnitine/orotate complex 900 mg/day (33) | 49.03±9.74 | ALT normalization (88.5% vs. 54.6% vs.44.4%; P=0.0027) | RCT; double blind, phase II |
Low-dose group: DDB 150 mg + carnitine/orotate complex 600 mg/day (30) | 41.58±11.73 | ||||||
DDB 150 mg/day (32) | 44.00±11.55 | ||||||
Park et al. [109] (2001) | CLD | (1) Biopsy- proven chronic hepatitis or (2) ALT elevation (≥1.5×ULN) more than twice during the previous 6 months; no evidence of viral hepatitis B or C | 8 weeks | High-dose group: DDB 150 mg + carnitine/orotate complex 900 mg/day (53) | 44.57±11.49 | ALT normalization (81.13% vs. 67.35% vs. 64.54%; P=0.0407) | RCT; double blind, phase III |
Low-dose group: DDB 100 mg + carnitine/orotate complex 600 mg/day (48) | 43.24±13.01 | ||||||
DDB 100 mg/day (52) | 45.63±13.75 | ||||||
Kim et al. [110] (2014) | CLD | (1) Abnormal ALT or AST in previous 6 months, (2) sonographical findings of chronic hepatitis or fatty liver, or (3) history of being treated for chronic hepatitis for >30 days | 12 weeks | DDB + garlic oil 960 mg/day (100) | 44 (20–79) | ALT normalization (≤40 IU/L) (89% vs. 18.6% vs. 22.9%; P<0.001) | RCT;double blind, placebo- andactive- controlled, phaseIV |
Silymarin 1,018 mg/day (102) | 49 (20–75) | ||||||
Placebo (35) | 44 (24–77) | ||||||
Hong et al. [111] (2014) | NAFLD | Combined with impaired fasting glucose metabolism | 12 weeks | Metformin 750 mg/day and DDB-carnitine orotate complex 900 mg/day (26) | 51.5±9.4 | Decrement of ALT level (mean, 51.5 vs. 16.7; P=0.001) | RCT; double blind, placebo- controlled |
Metformin 750 mg/day and placebo (26) | 52.0±9.6 | ||||||
Bae et al. [112] (2015) | NAFLD | Combined with type 2 diabetes | 12 weeks | DDB-carnitine orotate complex 824 mg/day (39) | 50.6±9.3 | ALT normalization (<30 IU/L in men or <19 IU/L in women) (89.7% vs. 17.9%; P<0.001) | RCT; double blind, placebo- controlled |
Placebo (39) | 52.0±9.4 | ||||||
Jun et al. [113] (2013) | HBV | (1) ALT ≥80 IU/L, (2) ALT < ULN×10, (3) treatment- naïve, and (4) HBV >105 copies/ mL in case of HBeAg-positive result or HBV >104 copies/ mL in case of HBeAg-negative result | 12 months | Entecavir 0.5 mg/day and DDB- carnitine orotate 2,472 mg/ day complex (67) | 43.0 ± 9.8 | ALT normalization (<40 U/L) (100% vs. 85.7%; P=0.0019) | RCT |
Entecavir 0.5 mg/day (63) | 44.9±10.0 |
Variables are expressed as median (interquartile range) or mean±standard deviation.
DDB, dimethyl-4,4’-dimethoxy-5,6,5’,6’-dimethylenedixoybiphenyl-2,2’-dicarboxylate; CLD, chronic liver disease; ALT, alanine aminotransferase; ULN, upper limit of normal; RCT, randomized controlled trial; AST, aspartate aminotransferase; NAFLD, nonalcoholic fatty liver disease; HBV, hepatitis virus; HBeAg, hepatitis B e antigen.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcome | Study design |
---|---|---|---|---|---|---|---|
Muto et al. [11] (2005) | Mixed (mainly HCV) | Decompensated cirrhosis | 2 years | BCAA (314) | 62±8 | Higher/longer event-free survival in BCAA group (death, varix rupture, HCC, hepatic failure) (HR, 0.67; 95% CI, 0.49–0.93, P=0.015) | RCT |
Control (308) | 61±9 | ||||||
Marchesini et al. [144] (2003) | Mixed (mainly viral) | Advanced cirrhosis (CTP B or C) | 1 year | BCAA (59) | 59±1 | Event (death, varix rupture, HCC, hepatic failure) (15.5% vs. 32.1% vs. 27.1%; P=0.037) | RCT |
Lactoalbumin (56) | 60±1 | ||||||
Maltodextrins (59) | 59±1 | ||||||
Ichikawa et al. [145] (2010) | Mixed (mainly viral) | Liver cirrhosis | 8 weeks | BCAA (12) | 66.2±8.2 | Change in ESS (mean, -5.5 vs. 1.2; P<0.05) | RCT |
Control (9) | 67.4±9.8 | ||||||
Yamamoto et al. [154] (2005) | Mixed (mainly viral) | Liver cirrhosis | 1 hour | BCAA (16) | 63±8 | Change in cerebral blood flow (PET) (mean, 0.81 vs. 0.75; P<0.05) | RCT |
Control (13) | 62±9 | ||||||
Kawamura et al. [138] (2009) | Mixed (mainly HCV) | Liver cirrhosis with CTP class A | 1 year | BCAA (27) | 62.7±10.08 | Cirrhosis-related complications (HCC, ascites, varix, HE) (14.8% vs. 30.4%; P=0.043) | RCT |
Control (23) | 62.3±7.3 | ||||||
Les et al. [32] (2011) | Mixed (mainly HCV, alcohol) | Liver cirrhosis with episode of HE within 2 months | 56 weeks | BCAA (21) | 64.1±10.4 | Recurrence of HE (47% vs. 34%; P=0.274) | RCT |
Control, maltodextrin (27) | 62.5±10.4 | ||||||
Nakaya et al. [139] (2007) | HCV | Liver cirrhosis | 3 months | BCAA (19) | 67±9 | Change in albumin level (mean, 3.2 vs. 3.0; P<0.05) | RCT |
Control (19) | 67±8 | ||||||
Takeshita et al. [29] (2012) | HCV | HCV with insulin resistance | 24 weeks | BCAA (14) | 58.6±2.9 | HOMA-IR after treatment (mean, 4.5 vs. 5.3; P=0.047) | RCT |
Control (13) | 64.2±3.0 | ||||||
Koreeda et al. [149] (2011) | Mixed (mainly HCV) | Liver cirrhosis | 6 months | BCAA (17) | 68±10 | Change in Rmax (mean, 0.23 to 0.25; P=0.059) | Prospective cohort study |
Park et al. [142] (2020) | Mixed (mainly alcohol) | Liver cirrhosis with CTP score of 8–10 points | 6 months | BCAA (63) | 60±10 | Higher/longer event-free survival in BCAA group (death, varix rupture, HCC, hepatic failure) (HR, 0.38; 95% CI, 0.22–0.68, P<0.001) | Prospective cohort study |
Control (61) | 58±11 | ||||||
Park et al. [143] (2017) | Mixed (mainly HBV, alcohol) | Liver cirrhosis with CTP score of 8–10 points | 6 months | BCAA (166) | 59±11 | Cirrhotic complication-free survival (median, 19.3 vs. 19.2 months; P=0.973) | Retrospective cohort study |
Control (141) | 60±9 | ||||||
Hanai et al. [277] (2015) | Mixed (mainly HCV) | Liver cirrhosis patients who were not transplantation candidates | 1 year | BCAA (94) | 64 (28–91) | Higher/longer overall survival in BCAA group (log-rank test P=0.02) | Retrospective cohort study |
Control (36) | 66 (33–84) | ||||||
Hanai et al. [148] (2020) | Mixed (mainly HCV, alcohol) | Liver cirrhosis | NA | BCAA (87) | 69 (59–74) | Lower mortality in BCAA group (HR, 0.57; 95% CI, 0.33–0.99, P=0.046) | Retrospective cohort study |
Control (436) | 66 (55–74) |
Variables are expressed as median (interquartile range) or mean±standard deviation.
BCAA, branched chain amino acid; HCV, hepatitis C virus; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; RCT, randomized controlled trial; CTP, Child-Turcotte-Pugh; ESS, Epworth Sleepiness Scale; PET, positron emission tomography; HE, hepatic encephalopathy; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; HBV, hepatitis B virus.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Nelson et al. [12] (2009) | NAFLD | Biopsy-proven NASH | 12 months | Simvastatin 40 mg/day (10) | 52.6±8.6 | · Necroinflammatory activity (mean, 1.4 vs. 1.0; P>0.05) | RCT |
Control (6) | 52.5±13.0 | · Fibrosis stage (mean, 1.50 vs. 1.0; P>0.05) | |||||
Dongiovanni et al. [165] (2015) | NAFLD | Patients who underwent liver biopsy for suspected NASH | ≥6 months | Statin (107) | 53±10 | · Lower presence of steatosis (OR, 0.09; 95% CI, 0.01–0.32; P=0.004), NASH (OR, 0.25; 95% CI, 0.13–0.47; P<0.001), F2–F4 fibrosis (OR, 0.42; 95% CI, 0.20–0.80; P=0.017)* in statin group | Cross-sectional study |
Control (1,094) | 41±16 | ||||||
Nascimbeni et al. [166] (2016) | NAFLD | Biopsy-proven NAFLD with type 2 DM | NA | Statin (154) | 55 (48–61) | · Lower presence of NASH (OR, 0.57; 95% CI, 0.32–1.01; P=0.055) and significant fibrosis (OR, 0.47; 95% CI, 0.26–0.84; P<0.011) in statin group | Cross-sectional study |
Control (192) | 52 (42–58) | ||||||
Ekstedt et al. [167] (2007) | NAFLD | Biopsy-proven NAFLD with elevated ALT and/or AST >41 U/L and/ or elevated ALP >106 U/L | 10.3–16.3 years | Statin (17) | 48.7±9.1 | · Significant reduction of liver steatosis in statin group (20.4% to 11.1%, P=0.001) | Retrospective cohort study |
Control (51) | 46.3±11.8 | ||||||
Rallidis et al. [168] (2004) | NAFLD | Biopsy-proven NASH and abnormal liver enzyme | 6 months | Pravastatin 20 mg/day (5) | 40±8 | · Improvement in the grade of inflammation (75%) and steatosis (25%) | Prospective cohort study |
Hyogo et al. [169] (2008) | NAFLD | Biopsy-proven NASH with lipidemia | 24 months | Atorvastatin 10 mg/day (31) | 52.5 (27–68) | · Significant improvement of steatosis grade (1.6 to 0.8; P<0.001) and NAS (4.1 to 2.9; P<0.001) | Prospective cohort study |
Hyogo et al. [172] (2011) | NAFLD | Biopsy-proven NASH and hyperlipidemia | 12 months | Pitavastatin 2 mg/day (20) | 50.6 (25–75) | · Change of NAS (6.7 to 6.3) and fibrosis stage (2.3 to 2.1) | Prospective cohort study |
Nakahara et al. [170] (2012) | NAFLD | Biopsy-proven NASH and hyperlipidemia | 24 months | Rosuvastatin 2.5 mg/day (19) | 46.3 (20–65) | · Change of NAS (3.89 to 3.44) and fibrosis stage (2.33 to 2.00) | Prospective cohort study |
Kargiotis et al. [171] (2015) | NAFLD | Biopsy-proven NASH and metabolic syndrome and lipidemia | 12 months | Rosuvastatin 10 mg/day (20) | 40.5±5.6 | · Complete resolution of NASH (95%) | Prospective cohort study |
Lee et al. [278] (2021) | NAFLD | Age ≥20 years who participated the NHIS physical health examination | 72 months | NAFLD (164,856) | 41.4±12.4 | · Reduced risk of NAFLD development in statin group (adjusted OR 0.66; 95% CI, 0.65–0.67) | Retrospective cohort study |
Control (824,280) | 41.4±12.4 | ||||||
Zou et al. [175] (2022) | NAFLD | Diabetes or obesity and ICD- 10 codes (K76.0 and K758.1) | 1.92 years | Statin (73,385) | 58.0±12.4 | · Lower risk of HCC development in statin group (HR, 0.47; 95% CI, 0.36–0.60; P<0.001) | Retrospective cohort study |
Control (199,046) | 50.0±14.9 | ||||||
Avins et al. [176] (2008) | Mixed | Patients with evidence of liver disease showing elevated AST or ALT levels or diagnosis of liver disease | 28.8 months (12.1–58.2) | Lovastatin (13,491) | 53.9±11.4 | · Lower incidence of liver function test abnormalities in statin group (incident RR 0.28; 95% CI, 0.12–0.55; P=NA) | Retrospective cohort study |
Control (79,615) | 47.5±13.6 | ||||||
Hsiang et al. [177] (2015) | HBV | 1.6 years | Statin (1,176) | 58.7±12.4 | · Lower HCC development in statin group (subHR 0.68; 95% CI, 0.48–0.97; P=0.033) | Retrospective cohort study | |
4.9 years | Control (52,337) | 37.6±14.1 | |||||
Huang et al. [178] (2016) | HBV | 4.71±3.21 | Statin (22,544) | 52.87±11.51 | · Lower incidence of cirrhosis (RR, 0.433; 95% CI, 0.344–0.515; P<0.001) and decompensated cirrhosis (RR, 0.468; 95% CI, 0.344–0.637; P<0.001) in stain group | Retrospective cohort study | |
4.57±3.20 years | Control (215,802) | 39.73±13.14 | |||||
Butt et al. [273] (2015) | HCV | Received HCV treatment ≥14 days | >24 months | Statin (3,347) | 53 (49–56) | · Higher SVR rate (OR, 1.44; 95% CI, 1.29–1.61; P<0.0001) in statin group | Retrospective cohort study |
Control (3,901) | 52 (48–56) | · Cirrhosis development (17.3% vs. 25.2%; P<0.001) | |||||
· HCC incidence (1.2% vs. 2.6%, P<0.01) | |||||||
Simon et al. [179] (2015) | HCV | Previous non- response to standard interferon therapies and advanced hepatic fibrosis on liver biopsy | 3.5 years | Statin (29) | 54.2±7.2 | · Lower risk of fibrosis progression in statin group (unadjusted HR, 0.32; 95% CI, 0.10–0.97; P=0.048; adjusted HR, 0.31; 95% CI, 0.10–0.97; P=0.044) | Retrospective cohort study |
Control (514) | |||||||
Yang et. el. [180] (2015) | HCV | 2,874,031.7 personyears | Statin (29,204) | Only distribution available | · Incidence rate of cirrhosis (445.5/100,000 person-years vs. 1311.2/100,000 personyears) | Retrospective cohort study | |
Control (197,652) | |||||||
Mohanty et al. [181] (2016) | HCV | 2.6 years | Statin (1,323) | 56 (52–60) | · Lower risk of decompensation (HR, 0.22; 95% CI, 0.17–0.28) and death (HR, 0.39; 95% CI, 0.34–0.44) before matching in statin group | Retrospective cohort study | |
1.9 years | Control (12,522) | 54 (50–58) | · Lower risk of decompensation (HR, 0.55; 95% CI, 0.39–0.77 and death (HR, 0.56; 95% CI, 0.46–0.69) after matching in statin group | ||||
Abraldes et al. [182] (2009) | Mixed (mainly alcohol) | Liver cirrhosis patients with severe portal HTN defined as HVPG of ≥12 mmHg | 30±4 days | Simvastatin (28) | 58±10 | · Change in HVPG (mean, -8.3% vs. -1.6%; P=0.041) | RCT |
Control (27) | 56±10 | ||||||
Pollo-Flores et al. [183] (2015) | Mixed (mainly HCV) | Cirrhosis with portal HTN | 3 months | Simvastatin (14) | 56.5 (IQR, 8.7) | · Decreased HVPG of at least 20% from baseline or to ≤12 mmHg) (55% vs. 0%; P=0.03) | RCT |
Control (20) | 58.5 (IQR, 13.5) | ||||||
Abraldes et al. [184] (2016) | Mixed (mainly alcohol) | Diagnosis of liver cirrhosis, and variceal bleeding within the previous 5–10 days, and plan to start standard prophylactic treatment for variceal bleeding | 371 days | Simvastatin (69) | 57.42±11.31 | · Higher survival (HR, 0.387; 95% CI, 0.152–0.986; P=0.030) in statin group | RCT |
382 days | Control (78) | 57.62±10.59 | · Lower rebleeding risk (HR, 0.858; 95% CI, 0.455–1.620, P=0.583) in statin group | ||||
Kumar et al. [185] (2014) | Mixed (mainly HCV) | Biopsy-proven liver cirrhosis on statin therapy at biopsy and for ≥3 months after biopsy | 36 months | Statin (81) | 59.79±10.91 | · Lower mortality (HR, 0.53; 95% CI, 0.334–0.856; P=0.01) in statin group | Retrospective cohort study |
30 months | Control (162) | 59.64±10.60 | · Lowe risk of decompensation (HR, 0.58, 0.34–0.98; P=0.04) in statin group |
Variables are expressed as median (interquartile range) or mean±standard deviation.
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; RCT, randomized controlled trial; OR, odds ratio; CI, confidence interval; DM, diabetes mellitus; NA, not available; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; NAS, NAFLD activity score; NHIS, National Health Interview Survey; ICD-10, International Classification of Diseases; HCC, hepatocellular carcinoma; HR, hazard ratio; RR, risk ratio; HBV, hepatitis B virus; HCV, hepatitis C virus; SVR, sustained viral response; HTN, hypertension; HVPG, hepatic venous pressure gradient; IQR, interquartile range.
Study | Etiology | Inclusion criteria | Treatment | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|---|
Wong et al. [202] (2013) | NAFLD | Biopsy-proven NASH | Mixture of L. plantarum, L. delbrueckii, L. acidophilus, L. rhamnosus, and B. bifidum | 6 months | Probiotics (10) | 42±9 | · Decreased liver fat contents in probiotics (22.6% to 14.9%; P=0.034) | RCT |
Usual care (10) | 55±9 | · Decreased AST level in probiotics (mean, 83.3 to 46.1; P=0.008) | ||||||
Shavakhi et al. [205] (2013) | NAFLD | Biopsy-proven NASH on metformin | Lactobacillus, Bifidobacterium, Streptococcus | 6 months | Probiotics + metformin (31) | 41.5±12.7 | · Decreased ALT and AST levels (mean, 133.7 to 45.2 vs. 123.1 to 44.2; P<0.001) | RCT |
Placebo + metformin (32) | 55±9 | · Reduction in grade of hepatic steatosis measured by US | ||||||
Nabavi et al. [203] (2014) | NAFLD | NAFLD on US | L. acidophilus and B. lactis | 8 weeks | Probiotic yoghurt (36) | 42.74±8.72 | · Lower AST, ALT, total cholesterol, and LDL-cholesterol levels after treatment in probiotic yogurt groups than control (P<0.05) | RCT |
No probiotics (15) | 44.05±8.14 | |||||||
Abdel Monem [201] (2017) | NAFLD | Biopsy-proven NASH | L. acidophilus | 1 month | Probiotics (15) | 44.20±5.51 | · Decreased ALT level in probiotics (mean, 83.3 to 46.1; P<0.001) | RCT |
No probiotics (15) | 44.33±5.62 | · Decreased AST level in probiotics (mean, 57.1 to 38.2; P=0.03) | ||||||
Manzhalii et al. [210] (2017) | NAFLD | NASH fed a low- fat/low-calorie diet | L. casei, L. rhamnosus, L. bulgaris, B. longum, S. thermophilus and oligofructose | 12 weeks | Probiotic cocktail (38) | 44.3±1.5 | · Greater reduction in AST and ALT levels in synbiotics than placebo (P<0.05) | RCT |
No probiotics (37) | 43.5±1.3 | · Greater reduction in the fibrosis score by TE in synbiotics than placebo (P<0.05) | ||||||
Kobyliak et al. [204] (2018) | NAFLD | Diabetes | Bifidobacterium, Lactobacillus, Lactococcus, Propionibacterium | 8 weeks | Probiotics (30) | 53.4±9.55 | · Decreased AST and GGT levels in probiotics (P<0.05) | RCT |
Placebo (28) | 57.3±10.5 | · Decreased fatty liver index in probiotics (84.33 to 78.73; P<0.001) | ||||||
Ahn et al. [207] (2019) | NAFLD | Obesity and liver fat >5% on proton density fat fraction | Lactobacillus, Pediococcus, Bifidobacterium | 12 weeks | Probiotics (30) | 41.7±12.49 | · Decreased liver fat contents (mean 16.3% to 14.1%; P=0.032) | RCT |
Placebo (35) | 44.71±13.31 | · Greater reduction in the triglyceride level in probiotics than placebo (P=0.003) | ||||||
Duseja et al. [206] (2019) | NAFLD | Biopsy-proven NAFLD | Lactobacillus, Bifidobacterium, Streptococcus | 1 year | Oral multistrain probiotic (19) | 38±10 | · Greater reduction in ALT level in probiotics than placebo (P=0.046) | RCT |
Placebo (20) | 33±6 | · Greater reduction in the NAS and hepatic fibrosis in probiotics than placebo (P<0.05) | ||||||
Malaguarnera et al. [30] (2012) | NAFLD | Abnormal serum aminotransferase levels | B. longum and oligofructose | 24 weeks | Synbiotics + LSM (33) | 46.9±5.4 | · Lower AST and LDL-cholesterol levels after treatment in synbiotics than placebo (P<0.05) | RCT |
Placebo + LSM (33) | 46.7±5.7 | · Greater reduction in HOMA-IR and NASH activity score in synbiotics than placebo (P<0.05) | ||||||
Eslamparast et al. [13] (2014) | NAFLD | NAFLD on US with ALT >60 IU/L for 6 months | Combination of L. casei, L. rhamnosus, S. thermophilus, B. breve, L. acidophilus, B. longum, L. bulgaricus and oligofructose | 28 weeks | Synbiotic capsule (26) | 46.35±8.8 | · Lower AST, ALT and GGT levels after treatment in synbiotics than placebo (P<0.001) | RCT |
Placebo (26) | 45.69±9.5 | · Greater reduction in the fibrosis score by TE (mean, 9.36 to 6.38 vs. 7.92 to 7.16; P<0.001) | ||||||
Asgharian et al. [219] (2016) | NAFLD | Combination of L. casei, L. rhamnosus, S. thermophilus, B. breve, L. acidophilus, B. longum, L. bulgaricus and oligofructose | 8 weeks | Synbiotics (40) | 46.57±1.7 | · Decreased grade of steatosis on US in synbiotics (P<0.005) | RCT | |
Placebo (40) | 47.78±1.7 | |||||||
Mofidi et al. [208] (2017) | NAFLD | BMI ≤25 | Combination of L. casei, L. rhamnosus, S. thermophilus, B. breve, L. acidophilus, B. longum, L. bulgaricus and oligofructose | 28 weeks | Synbiotics (21) | 40.09±11.44 | · Greater reduction in AST and fasting glucose levels in synbiotics than placebo (P<0.05) | RCT |
Placebo (21) | 44.61±10.12 | · Greater reduction in the fibrosis score and steatosis by TE in synbiotics than placebo (P<0.001) | ||||||
Sayari et al. [211] (2018) | NAFLD | Taking sitagliptin | Lactobacillus, Bifidobacterium, Streptococcus and fructooligosaccharide | 16 weeks | Synbiotics + sitagliptin (70) | 42.48±11.41 | · Greater reduction of glucose, AST, total cholesterol, and LDL-cholesterol levels in synbiotics than placebo (P<0.05) | RCT |
Placebo +sitagliptin (68) | 43.42±11.65 | |||||||
Scorletti et al. [33] (2020) | NAFLD | NAFLD diagnosed by histologic confirmation or imaging evidence of liver fat | Bifidobacterium and fructooligosaccharide | 10–14 months | Synbiotic agents (55) | 50.2±12.4 | · No significant difference in MRS-based liver fat reduction between groups | RCT |
Placebo (49) | 51.6±13.1 |
Variables are expressed as mean±standard deviation.
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; AST, aspartate aminotransferase; RCT, randomized controlled trial; ALT, alanine aminotransferase; US, ultrasonography; LDL, low-density lipoprotein; TE, transient elastography; GGT, γ-glutamyl transferase; NAS, NAFLD activity score; LSM, lifestyle modification; HOMA-IR, Homeostatic Model Assessment for Insulin Resistance; BMI, body mass index; MRS, magnetic resonance spectroscopy.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Harrison et al. [233] (2003) | NAFLD | Histologic diagnosis of NASH | 6 months | Vitamin E 1,000 IU/day and C 1,000 mg/day (23) | 50.2 | · Improvement in fibrosis score (47.8% vs. 40.9%; P=0.005) | RCT |
Placebo (22) | 52.5 | · No changes in inflammation (P>0.05) | |||||
· ALT improvement (P=0.007) | |||||||
Sanyal et al. [279] (2004) | NAFLD | Non-diabetic, non-cirrhotic | 6 months | Vitamin E 400 IU/day (10) | 46±13 | · Vitamin E: Improvement in steatosis (P=0.02), ballooning (P=0.055) and portal fibrosis (P>0.05) | RCT |
Vitamin E 400 IU/day + pioglitazone 30 mg/day (10) | 47±12 | · Vitamin E + pioglitazone: Improvement in steatosis (P=0.002), ballooning (P=0.01), and portal fibrosis (P>0.05) | |||||
· Comparison between the two groups: steatosis (P<0.05), ballooning (P>0.05), portal fibrosis (P>0.05) | |||||||
Ersöz et al. [280] (2005) | NAFLD | Histologically proven NAFLD | 6 months | Vitamin E 600 IU/day and C 500 mg/day (28) | 46.3±9.4 | · ALT change (IU/L) (mean, 91.9 to 39.1, P<0.05 vs. 93.7 to 49.1, P<0.05; P>0.05) | Open-label RCT |
UDCA 10 mg/kg/day (29) | 47.9±10.6 | ||||||
Dufour et al. [54] (2006) | NAFLD | Histologic diagnosis of NASH | 6 months | UDCA 12–15 mg/kg/day + vitamin E 800 IU/day (15) | 46±14 | · Decrease in AST and ALT levels (IU/L) (UDCA + vitamin E vs. placebo, P<0.05; UDCA vs. placebo, P>0.05) | Double-blinded RCT |
UDCA 12–15 mg/kg/day + placebo (18) | 47±12 | · Improvement in steatosis (UDCA + vitamin E vs. placebo, P<0.05; UDCA vs. placebo, P>0.05) | |||||
Placebo + placebo (15) | 44±14 | · No improvement in inflammation and fibrosis (P>0.05) | |||||
Balmer et al. [55] (2009) | NAFLD | Histologic diagnosis of NAFLD | 2 years | UDCA 12–15 mg/kg/day + vitamin E 800 IU/day (14) | 47±14 | · Adiponectin level change (ng/mL) (mean, +3,808 vs. -1,626 vs. -687; P<0.03) | Double-blinded RCT |
UDCA 12–15 mg/kg/day + placebo (14) | 47±12 | ||||||
Placebo + placebo (13) | 46±13 | ||||||
Sanyal et al. [14] (2010) | NAFLD | Histologic diagnosis of NASH without diabetes | 96 weeks | Pioglitazone 30 mg/day (80) | 47.0±12.6 | · Improvement in NASH (vitamin E 43% vs. placebo 19%, P=0.001; pioglitazone 34% vs. placebo 19%, P=0.04) | Double-blinded RCT |
Vitamin E 800 IU/day (84) | 46.6±12.1 | · Improvement in fibrosis (vitamin E 41% vs. placebo 31%, P=0.24; pioglitazone 44% vs. placebo 31%, P=0.12) | |||||
Placebo (83) | 45.4±11.2 | · Changes in serum aminotransferase level (IU/L) (mean, vitamin E -37.0 vs. placebo -20.1, P=0.001; pioglitazone -40.8 vs. placebo -20.1, P<0.001) | |||||
Aller et al. [232] (2015) | NAFLD | Histologic diagnosis of NAFLD | 3 months | Silymarin 1,080.6 mg/day + vitamin E 72 mg/day (18) | 47.4±11.2 | · Decrease in fatty liver index (mean, 86.2 to 76.9; P<0.05 vs. 85.2 to 77.5; P<0.05) | RCT |
Control (18) | 43.75±3.5 | · Decrease in NFS (mean, -1.6 to -2.1; P<0.05 vs. -1.0 to -1.5; P<0.05) | |||||
Parikh et al. [34] (2016) | NAFLD | Non-diabetic, non-cirrhotic | 52 weeks | Vitamin E 800 IU/day (100) | 40.19±2.9 | · ALT normalization (14% vs. 19%; P=0.2) | Open-label RCT |
UDCA 600 mg/day (150) | · ALT reduction (56% vs. 63%; P=0.2) | ||||||
Polyzos et al. [229] (2017) | NAFLD | Histologic diagnosis of NASH | 52 weeks | Vitamin E 800 IU/day + spironolactone 25 mg/day (14) | 54.9±1.8 | · NFS reduction (44% vs. 47%; P=0.69) | Open-label RCT |
Vitamin E 800 IU/day (17) | 53.8±3.4 | · ALT reduction (IU/L) (43.5 to 40.0, P>0.05 vs. 66.0 to 42.1, P>0.05; P>0.05) | |||||
Bril et al. [237] (2019) | NAFLD | Histologic diagnosis of NASH and type 2 diabetes | 18 months | Vitamin E 800 IU/day (36) | 60±9 | · NAFLD liver fat score reduction (P=0.028 vs. P=0.61) | Double-blinded RCT |
Vitamin E 800 IU/day + pioglitazone 30-45 mg/day (37) | 60±6 | · Reduction of NAS (vitamin E 31% vs. placebo 19%, P=0.26; vitamin E + pioglitazone 54% vs. placebo 19%, P=0.003) | |||||
Placebo (32) | 57±11 | · Resolution of NASH (vitamin E 33% vs. placebo 12%, P=0.04; vitamin E + pioglitazone 43% vs. placebo 12%, P=0.005) | |||||
Fouda et al. [227] (2021) | NAFLD | Histologic diagnosis of NASH | 3 months | Vitamin E 800 IU/day (34) | 44.8±9.7 | · Fibrosis change (vitamin E 50% vs. placebo 30%, P=0.09; vitamin E + pioglitazone 52% vs. placebo 30%, P=0.07) | Single-blind RCT |
UDCA 500 mg/day (34) | 43.4±11 | · ALT reduction (P<0.05) | |||||
Pentoxifylline 800 mg/day (34) | 45.2±11 | · Inflammatory cytokine reduction (IL-6, CCL-2/MCP-1) (P<0.05) | |||||
Kedarisetty et al. [228] (2021) | NAFLD | Histologic diagnosis of NASH | 1 year | Vitamin E 800 IU/day (33) | 35 (16–64) | · ALT reduction (IU/L) (mean 85.5 to 28 vs. 97 to 24; P=0.23) | Open-label RCT |
Vitamin E 800 IU/day + pentoxifylline 1,200 mg/day (36) | 40 (20–64) | · NAS change (mean 4.3 to 3.1 vs. 5 to 2.8; P=0.45) | |||||
· Fibrosis stage change (mean 1.7 to 1.7 vs. 2.1 to 1.0; P=0.004) | |||||||
· Insulin change (mU/L) (mean 12.4 to 10.8 vs. 12.9 to 7.6; P=0.048) | |||||||
· TNF-α change (pg/mL) (mean 7.14 to 3.83 vs. 7.85 to 1.59; P=0.001) | |||||||
Groenbaek et al. [248] (2006) | HCV | Elevated ALT | 6 months | Vitamin C 500 mg/day + vitamin E 945 IU/day + selenium 200 µg/day (12) | 45 (33–53) | · Change in serum ALT (IU/L) (mean, -8 vs. -6; P=0.60) | Double-blinded RCT |
Placebo (11) | 45 (23–55) | · Change in HCV RNA (log10 eqv/L) (mean, 0.17 vs. 0.41; P=0.24) | |||||
Marotta et al. [246] (2007) | HCV | Cirrhosis, genotype 1, and elevated ALT | 6 months | Vitamin E 900 IU/day (25) | 62 (54–75) | · Improvement of redox status, GSH, GSSG, GSH/GSSG and MDA: vitamin E (P<0.05) and FPP (P<0.05) | RCT |
Fermented papaya preparation 9 g/day (25) | |||||||
Control (10) | |||||||
Bunchorntavakul et al. [249] (2014) | HCV | Genotype 3 | 12 weeks | Vitamin E 800 IU/day (19) | 48.8±8.3 | · Decrease in serum ALT (mean, 105.1 to 96.5; P=0.260 vs. 107.5 to 120.4) | Double- blinded RCT |
Placebo (18) | 49.5±8.6 | · ALT responder (57.8% vs. 29.4%; P=0.106) | |||||
Malaguarnera et al. [245] (2015) | HCV | Received PegIFN- α2b + ribavirin | 12 months | Silybin 47 mg/day + vitamin E 15 mg/day + phospholipid 97 mg/day (32) | 46.4±6.9 | · Decrease in ALT level (IU/L) (mean, 170.2 to 36.9, P<0.001 vs. 161.6 to 69.2, P<0.001; P<0.001) | Double- blinded RCT |
· Decrease in viremia (106 IU/mL) (mean, 5.32 to 1.67, P<0.05 vs. 5.4 to 3.24, P<0.001; P<0.05) | |||||||
Placebo (32) | 45.2±6.7 | · Decrease in TGF-β (ng/mL) (mean, 54.2 to 32.8, P<0.05 vs. 51.8 to 45.2, P<0.05; P<0.05) | |||||
· Decrease in PIIINP (ng/mL) (mean, 43.8 to 33.4, P<0.001 vs. 44.7 to 39.8, P<0.05; P<0.05) | |||||||
· Decrease in TIMP-1 (ng/mL) (mean, 480.2 to 310.6, P<0.001 vs. 487.2 to 421.0, P<0.001; P<0.001) | |||||||
Andreone et al. [251] (2001) | HBV | Positive HBV DNA and raised ALT (1.5×ULN) | 3 months | Vitamin E 600 IU/day (15) | 37±15 | · ALT normalization (47% vs. 6%; P=0.011) | RCT |
Control (17) | 42±14 | · Negative HBV DNA (53% and 18%; P=0.039) | |||||
· Complete response (47% vs. 0%; P=0.0019) |
Variables are expressed as median (interquartile range) or mean±standard deviation.
NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; ALT, alanine aminotransferase; RCT, randomized controlled trial; UDCA, ursodeoxycholic acid; AST, aspartate aminotransferase; NFS, NAFLD fibrosis score; IL-6, interleukin-6; CCL2, C-C motif ligand 2; MCP, monocyte chemoattractant protein; NAS, NAFLD activity score; TNF, tumor necrosis factor; HCV, hepatitis C virus; GSH, glutathione; GSSG, glutathione disulfide, MDA, malondialdehyde; FPP, fermented papaya preparation; PegIFN, pegylated interferon; TGF, transforming growth factor; PIIINP, pro-collagen III N-terminal peptide; TIMP, tissue inhibitor of metalloproteinase; HBV, hepatitis B virus; ULN, upper limit of normal.
Study | Etiology | Inclusion criteria | Intervention period | Arms (n) | Age (years) | Outcomes | Study design |
---|---|---|---|---|---|---|---|
Simon et al. [265] (2018) | Variable | Pooled analysis of cohort | NA | Aspirin (58,855) | 64±8 | · Decreased HCC development in aspirin group (HR, 0.54; 95% CI, 0.36–0.80) | Prospective cohort study |
Control (74,516) | 62±8 | ||||||
Petrick et al. [264] (2015) | Variable | Pooled analysis of cohort | NA | Aspirin (477,470) | NA | · Decreased HCC development in aspirin group (HR, 0.68; 95% CI, 0.57–0.81) | Prospective cohort study |
Control (606,663) | NA | ||||||
Simon et al. [263] (2019) | NAFLD | Biopsy confirmed NAFLD | NA | Aspirin (151) | 59.9±8.6 | · Decreased prevalence of advanced fibrosis in aspirin group (HR, 0.63; 95% CI, 0.43–0.85) | Prospective cohort study |
Control (210) | 48.2±13.5 | ||||||
Shen et al. [262] (2014) | NAFLD | US-confirmed NAFLD | 1 month | NAFLD (2,889) | 54.6±0.3 | · Decreased NAFLD prevalence in aspirin group (HR, 0.62; 95% CI, 0.51–0.74) | Cross-sectional retrospective study |
Control (8,527) | 48.7±0.5 | ||||||
Jiang et al. [256] (2016) | CLD | US-confirmed CLD | 1 month | Aspirin (520) | 46.6±15.4 | · Decreased non-invasive fibrosis index in apsirin group, 0.24 standard deviation lower; 95% CI, -0.42 to 0.06 | Cross-sectional retrospective study |
Control (1,336) | 43.2±14.7 | ||||||
Hui et al. [271] (2021) | CHB | Receiving nucleos(t)ide analog | Over 90 days | Aspirin (1,744) | 62.2±10.8 | · Decreased HCC development in aspirin group (HR, 0.60; 95% CI, 0.46–0.78) | Retrospective cohort study |
Control (33,367) | 52.5±12.5 | ||||||
Choi et al. [267] (2021) | CHB | Over 90 days | Aspirin (7,718) | NA | · Decreased HCC development in aspirin group (OR, 0.92; 95% CI, 0.85–0.99) | Retrospective cohort study | |
Control (24,977) | NA | ||||||
Simon et al. [15] (2020) | Viral hepatitis | CHB, CHC monoinfection | Over 90 days | Aspirin (14,205) | 50.5±13.0 | · Decreased HCC development in aspirin group (HR, 0.69; 95% CI, 0.62–0.76) | Prospective cohort study |
Control (36,070) | 39.6±13.5 | · Decreased liver-related death in aspirin group (HR, 0.73; 95% CI, 0.67–0.81) | |||||
Liao et al. [270] (2020) | CHC | NA | Aspirin (1,991) | NA | · Decreased HCC development in aspirin group (HR, 0.56; 95% CI, 0.43–0.72) | Retrospective cohort study | |
Control (1,991) | NA | ||||||
Lee et al. [268] (2020) | CHC | Over 90 days | Aspirin (2,478) | 63.2±10.0 | · Decreased HCC development in aspirin group (HR, 0.78; 95% CI, 0.64–0.95) | Retrospective cohort study | |
Control (4,956) | 63.2±10.0 | ||||||
Lee et al. [269] (2019) | CHB | Over 90 days | Aspirin (2,123) | 58.9±11.8 | · Decreased HCC development in aspirin group (HR, 0.71; 95% CI, 0.58–0.86) | Retrospective cohort study | |
Control (8,492) | 58.8±11.8 | ||||||
Lee et al. [276] (2017) | CHB | Low-level viremia | Median 38.5 months | Aspirin (343) | 54.2±11.1 | · Decreased HCC development in aspirin group (HR, 0.26; 95% CI, 0.09–0.74) | Retrospective cohort study |
Control (1,116) | 50.3±10.8 |
Variables are expressed as median (interquartile range) or mean±standard deviation.
NA, not applicable; HCC, hepatocellular carcinoma; HR, hazard ratio; CI, confidence interval; NAFLD, nonalcoholic fatty liver disease; US, ultrasonography; CLD, chronic liver disease; CHB, chronic hepatitis B; OR, odds ratio; CHC, chronic hepatitis C.
Seung Up Kim
https://orcid.org/0000-0002-9658-8050
Yoon Jun Kim
https://orcid.org/0000-0001-9141-7773
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