Association of proton pump inhibitors with risk of hepatic encephalopathy in advanced liver disease: A meta-analysis

Table 1 Characteristics of included studies

Author, Year	Location	Design	No. of cases/controls	Age of cases/controls	Sex (% male) cases/controls	Type of liver disease	Outcomes analyzed	Definition of PPI use	Follow-up time	Adjusted factors	Quality score
Lin et al[18], 2014	China	Case-control	55/110	46 (37-55)/43 (36-48)	83.6/75.5	HBV-related ACLF	Grades 2-4 HE	Patients using any PPI intravenously for at least 6 d before the occurrence of HE at the admission time	NA	Age, sex, MELD score, infection, hypokalemia, hyponatraemia, ascites, PTA, AFP, lactulose use, branched chain amino acids, and arginine hydrochloride	8
Dam et al[17], 2016	Denmark	Cohort	340/525	58 (50-64)/57 (51-64)	68/69	Cirrhosis with ascites	Grades 1-4 HE; grades 2-4 HE	A patient counted as a PPI user when he or she was using PPIs and as a nonuser when he or she was not	148.2 person-years/186.1 person-years	Sex, age at inclusion, cirrhosis etiology, variceal bleeding, MELD score, serum sodium, albumin, and platelets; and lactulose use, spironolactone dose, furosemide dose, and potassiumsparing diuretic dose	9
Tsai et al[16], 2016	Taiwan	Case-control	1166/1166	53.09 ± 13.80/53.14 ± 13.78	74.2/74.2	Cirrhosis	Grades 1-4 HE	PPI use was defined as > 30 cumulative defined daily doses (cDDDs); PPI non-use was defined as ≤ 30 cDDDs	2.96 ± 3.40/2.87 ± 3.57 yr	Age, sex, income, level of urbanization, the use of PPIs in the past 6 mo before enrollment, Charlson Comobidity Index score, medical comorbidities, use of medication	9
Zhu et al[15], 2018	China	Case-control	128/128	58.34 ± 11.15/58.28 ± 10.97	63.3/63.3	Cirrhosis	Grades 1-4 HE	PPI userswere defined as the patients who used PPIs during hospitalization	NA	Age, gender, Child-Pugh score, hemoglobin, gammaglutamyl transpeptidase, blood urea nitrogen, ammonia, international normalized ratio, and acute upper gastrointestinal bleeding	8
Nardelli et al[14], 2018	Italy	Cohort	125/185	61.5 ± 11.9/63.3 ± 11.6	74.1/67.2	Cirrhosis	Minimal HE; grades 2-4 HE	Patients were considered PPIs users when the treatment started at least 4 wk prior to the admission	14.1 ± 12.3 mo	MELD scores, MHE, previous overt HE, PPIs, age, albumin and sodium levels	9
Sturm et al[13], 2018	Germany	Cohort	303/94	59.2 ± 11.7/59.7 ± 10.2	67.7/69.1	Cirrhosis with TIPS implantation	Grades 1-4 HE	PPI userswere defined as the patients who used PPIs during hospitalization	116 ± 74 /135 ± 65 d	Age, etiology of liver disease, TIPS indication, acute variceal bleeding with early TIPS implantation, covering of the stent graft, portosystemic gradient before and after TIPS, HE before TIPS, MELD score, HE medication, and peri-interventional antibiotic treatment	9
Tapper et al[24], 2018 (abstract)	USA	Cohort	186481	65 (57–73)	55	Cirrhosis	Grades 1-4 HE	Chronic use (> 90 d)	542739 patient-years	Age, sex, race, etiology of cirrhosis, Medicaid coenrollment, hemodialysis, portal hyperten-sion (varices, ascites, TIPS placement), and management by a gastroenterologist	NA
Matei et al[25], 2017 (abstract)	Romania	Case-control	436/327	60.41 (17–91)	63.3	Cirrhosis and ascites	Grades 1-4 HE	PPIs use was defined as the administration of at least 40 mg/day, for minimum 2 wk during the last 3 mo	NA	NA	NA
Shanab et al[23], 2018 (abstract)	UK	Case-control	506/320	53.4 ± 12.0	66	Cirrhosis	Grades 1-4 HE	Current PPI use	NA	NA	NA

HBV: Hepatitis B virus; ACLF: Acute on chronic liver failure; HE: Hepatic encephalopathy; PPI: Proton pump inhibitor; cDDDs: Cumulative defined daily doses; PTA: Prothrombin activity; MELD: Model for end stage liver disease; AFP: Alpha-fetoprotein; TIPS: Transjugular intrahepatic portosystemic shunt; NA: not available.