Association of serum bilirubin and non-alcoholic fatty liver disease: A feasible therapeutic avenue?

Table 1 Summary of characteristics of studies on the association of bilirubin with non-alcoholic fatty liver disease

Ref.	Study designTotal number of patients	Study population	Main outcome measure
Chang et al[32]	Cohort-longitudinal	Korean men from a single large semiconductor company (South Korea)	Conjugated bilirubin
	n = 5900
Kwak et al[33]	Cross-section	Health check-general
	n = 17348	Population (South Korea)	Total bilirubin
Duseja et al[34]	Prospective	Hospital setting unclear, probably Tertiary (India)	Unconjugated bilirubin
	n = 67
Hjelkrem et al[35]	Retrospective	Tertiary hospital patients undergoing liver biopsy (United States)	Unconjugated bilirubin
	n = 641
Kumar et al[36]	Cross-sectional	Tertiary hospital, outpatient NAFLD clinic (India)	Unconjugated bilirubin
	n = 204
Chisholm et al[37]	Cross-sectional	Liver biopsy prior to bariatric surgery (United States)	Total bilirubin
	n = 370
Tarantino et al[38]	Cross-sectional	Tertiary hospital, outpatient likely liver clinic (Italy)	Unconjugated bilirubin
	n = 186

NAFLD: Non-alcoholic fatty liver disease.

Table 2 Results and analysis summary of the studies on the association of bilirubin with non-alcoholic fatty liver disease

Ref.	Study analysis	Results
Chang et al[32]	(+) Large sample (+) Prospective (-) NAFLD on US	Hazard ratio for NAFLD comparing the highest to the lower quartile of serum conjugated bilirubin = 0.61 (95%CI: 0.54-0.68), after adjusting metabolic parameters 0.86a (95%Cl : 0.76-0.98) Total bilirubin inversely associated with NAFLD OR = 0.88, 95%CI: 0.80-0.97. An inverse, dose-dependent association between NAFLD and serum total bilirubin levels OR = 0.80b, 95%CI: 0.71-0.90 in the fourth quartile vs lowest quartile
Kwak et al[33]	(+) Large sample (-) NAFLD on US
Duseja et al[34]	(-) Small sample (+) Prospective (+) NASH on biopsy (selected)	Patient sample too small to make any meaningful statistical inference
Hjelkrem et al[35]	(-)Retrospective design (-) Small sample (+) NAFLD on biopsy	Unconjugated hyperbilirubinaemia inversely associated with NASH OR = 16.1b, 95%CI: 3.7-70.8
Kumar et al[36]	(-) Small sample (+/-) NAFLD on biopsy but not all patients	Unconjugated hyperbilirubinaemia (UCHB) and NAS score-negative correlation: r: -0.48b. UCHB and stage of fibrosis: r: -0.28d
Chisholm et al[37]	(-) Small sample (+) NAFLD on biopsy	Binary logistic regression showed independent association of total bilirubin with NASH cP = 0.016 Unconjugated bilirubin elevated in all spectra of NAFLD, except healthy control fP = 0.008 High UCHB in advanced NASH group
Tarantino et al[38]	(-) Retrospective
	(-) Small sample
	(+) NASH on biopsy (selected)

^aP < 0.039;

^bP < 0.001;

^dP = 0.007;

^cP = 0.016;

^fP = 0.008. (+) favourable design; (-) unfavourable design; OR: odds ration; US: ultrasound; r: relative coefficient; P: Probability; NAFLD: Non-alcoholic fatty liver disease; NASH: Non-alcoholic steatohepatitis.