Proton pump inhibitor use increases hepatic encephalopathy risk: A systematic review and meta-analysis

Table 1 Characteristics of included studies

Ref.	Region	Design	n	Male (%)	Mean minimal PPI use duration	Number of episodes	HE level1	Age (yr)	Risk estimate (95%CI)
Dam et al[20], 2016	Denmark	Retrospective case-control study	865	86.7	At least 1 wk prior to HE episode	Follow-up ended at the onset of the first HE episode	2-4	57.4	Current PPI use vs current nonuse, HR: 1.36 (95%CI: 1.01-1.84)
Lin et al[21], 2014	China	Retrospective case-control study	165	78.2	More than 5 d prior to HE episode	Follow-up ended at the onset of the first HE episode	2-4	44.0	PPI use vs nonuse, OR: 4.392 (95%CI: 1.604-12.031)
Nardelli et al[12], 2018	Rome	Prospective observational study	310	71.3	PPI use at least 4 wk prior to the admission	Follow-up ended at the onset of the first HE episode	2-4	62.0	PPI use at least 4 weeks prior to admission vs. PPI nonuse at least 4 wk prior to admission OR: 3.96 (95%CI: 2.27-6.92)
Sturm et al[13], 2018	Germany	Retrospective observational study	397	68.1	NR	Follow-up ended at the onset of the first HE episode	1-4	59.3	PPI use vs nonuse, OR: 2.29 (95%CI: 1.86-6.46)
Tergast et al[14], 2018	Germany	Retrospective longitudinal cohort study	249	67.9	PPI intake within 7 d prior to enrollment	NR	3-4	56.8	PPI dosage > 40 mg/d vs PPI dosage > 10-40 mg/d, HR: 1.85 (95%CI: 0.87-3.66)
Tsai et al[22], 2016	Taiwan	Retrospective case-control study	2332	74.2	PPI intake at least 30 d prior to enrollment	Follow-up ended at the onset of the first HE episode	NR	53.1	(cDDD > 365 vs cDDD ≤ 30) OR: 3.01 (95%CI: 1.78-5.10); 120 < cDDD < 365 vs cDDD ≤ 30, OR: 1.51 (95%CI: 1.11-2.06) 30 < cDDD < 120 vs cDDD ≤ 30, OR: 1.41 (95%CI: 1.09-1.84)
Zhu et al[15], 2018	China	Retrospective case-control study	256	63.3	PPI use during hospitalization	HE episode during hospitalization	2-4	58.3	PPI use during hospitalization vs nonuse during hospitalization OR: 3.481 (95%CI: 1.651-7.340)

¹HE was graded according to the West Haven criteria. cDDD: Cumulative defined daily dose; NR: Not reported; PPI: Proton pump inhibitor; HE: Hepatic encephalopathy; HR: Hazard ratio; OR: Odds ratio; CI: Confidential interval.

Table 2 Quality assessment of included studies using the Newcastle-Ottawa scale

Author (year)	Subject selection	Group comparability	Exposure measurement	Total score
Dam et al[20], 2016	2	2	3	7
Lin et al[21], 2014	3	2	3	8
Nardelli et al[12], 2018	3	2	3	8
Sturm et al[13], 2018	4	2	3	9
Tergast et al[14], 2018	2	2	3	7
Tsai et al[22], 2016	3	2	3	8
Zhu et al[15], 2018	3	2	3	8