Liver Enzymes and Risk of All-Cause Mortality in General Populations: A Systematic Review and Meta-analysis

Setor K Kunutsor; Tanefa A Apekey; Dorothy Seddoh; John Walley

Int J Epidemiol. 2014;43(1):187-201.

Abstract and Introduction

Abstract

Background Gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP), commonly used as markers of liver dysfunction, have been implicated with risk of all-cause mortality. The prospective evidence on the associations in general populations has not been reliably quantified.

Methods We conducted a systematic review and meta-analysis of published prospective cohort studies evaluating the associations of baseline levels of these enzymes with all-cause mortality in general populations. Relevant studies were identified in a literature search of MEDLINE, EMBASE and Web of Science up to March 2013. Authors of unpublished studies provided data on request.

Results Nineteen unique cohort studies with aggregate data on over 9.24 million participants and 242 953 all-cause mortality outcomes were included. In a comparison of extreme thirds of baseline GGT and ALP levels, relative risks (RRs) (95% confidence intervals) for all-cause mortality were 1.60 (1.42–1.80) and 1.38 (1.17–1.63), respectively. The corresponding RRs for ALT were 0.82 (0.78–0.86) and 1.43 (1.08–1.90) in North American and Asian populations, respectively. There was no strong evidence of an association of AST with all-cause mortality: RR 1.23 (0.80–1.88). The pooled RRs per 5 U/l increment in GGT and ALP levels were 1.07 (1.04–1.10) and 1.03 (1.01–1.06), respectively.

Conclusions Available data indicate positive independent associations of baseline levels of GGT and ALP with all-cause mortality, consistent with linear dose-response relationships. There were geographical variations in the association of ALT with all-cause mortality which require further investigation. The potential incremental prognostic values of GGT and ALP in mortality risk assessment need evaluation.

Introduction

Assays for gamma glutamyltransferase (GGT), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) are the most common laboratory tests used for the detection of liver diseases. Circulating GGT is present on the external surfaces of most cells, particularly hepatocytes, and in serum, and is used as a biological marker of excessive alcohol intake.^[1] The liver aminotransferases (ALT and AST) are found abundantly within hepatocytes and they catalyze the transfer of amino groups to generate products in gluconeogenesis and amino acid metabolism.^[2,3] Alkaline phosphatase is a hydrolase enzyme that catalyzes the hydrolysis of inorganic pyrophosphate, which is a vascular calcification inhibitor. Serum levels of ALP are commonly used in clinical practice as a marker of liver or bone disease.^[4]

There have been important advances in the understanding of the physiological functions of these liver enzymes and several epidemiological associations have been reported. Several prospective epidemiological associations have been demonstrated between these markers of liver dysfunction and risk of type 2 diabetes mellitus,^[5–7] cardiovascular disease (CVD)^[8–11] or mortality from vascular and nonvascular causes,^[4,12,13] after accounting for important risk factors. Furthermore, baseline circulating levels of GGT, ALT, AST and ALP have been reported to be associated with future risk of all-cause mortality (which is a more ultimate indicator of health than cause-specific outcomes^[14]).^{[11,13,15–22]} However, the majority of these studies were conducted in selected populations such as in the elderly, participants at high vascular risk or those with pre-existing disease.^[17–20,22] Therefore the nature of the individual associations of these enzymes with risk of all-cause mortality among general populations is not very clear. A number of prospective studies have been published reporting on the associations between baseline levels of these enzymes and risk of all-cause mortality in general populations, but their results have been inconsistent.^{[9,11,13,15,17,20,21]} Although they generally have low specificities for the liver, assays for these liver enzymes are sensitive, well standardized, simple, inexpensive and commonly used laboratory tests. These enzymes may be useful for the prediction of all-cause mortality^[23] and the identification of individuals at high risk of dying from all-causes. Although, among the liver enzymes, GGT is a less specific indicator of liver dysfunction, research has largely focused on GGT and the evidence suggests that it may be a strong risk indicator for all-cause mortality. The aminotransferases and ALP (which are often measured simultaneously with GGT) have received less attention and their significance for all-cause mortality is less certain. We therefore, for the very first time, aimed to quantify precisely the nature and magnitude of the associations between baseline levels of GGT, ALT, AST and ALP with the risk of all-cause mortality in general populations using a meta-analytic approach.

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Abstract and Introduction
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Table 1. Characteristics of prospective studies evaluating associations between liver enzymes and all-cause mortality, 1995–2013
Lead author, publication date, reference no.	Study	Location	Year of baseline survey	Baseline age range (yrs)	% male	Follow up years	Total participants	No. of cases	Covariates adjusted for	Study quality
Gamma glutamyltransferase
Wannamethee, 1995⁴⁶	BRHS	UK	1978–80	40–59	100	11.5	5309	462	Age, social class, smoking, PA, HTN treatment, use of other medications, DM, BMI, TC, HDL-C, blood glucose, heart rate, FEV₁	7
Calori, 2011²⁶	Cremona	Italy	1990–91	> 40	44	15	2074	495	Age, sex, alcohol use, fibrinogen, DM, AST, ALT, LDL-C, TC, HDL-C, SBP	9
Fulks, 2008²⁸	CRL	USA	1991–2007	≥18	59.7	9.6	8 922 358	220 216	Age, fructosamine, TC/HDL-C, ALT, AST, ALP	6
Lee, 2007⁴⁴	FHS	USA	1978–82	44^a	48	19	3451	362	Age, sex, BMI, DM, SBP, TC/HDL-C ratio, smoking, alcohol use, CRP	9
Kengne, 2012⁴³	HSE/SHeS	UK	1994/95/98	53.6^a	45	12.7	17 269	2859	Age, sex, DM, SBP, HTN, Hx of CVD, PA, smoking, alcohol use, TC, lipid medication	9
Ruhl, 200⁴⁵	NHANES III	USA	1988–94	–	–	12	14 950	2189	Age, sex, race-ethnicity, BMI, WHR, glucose, TC, HDL-C, SBP, DBP, smoking, alcohol use, caffeine, PA, CRP, transferrin saturation, education	9
Loomba, 2012^{4 9}	RBS	USA	1984–87	70^a	46	13.7	2364	1329	Age, sex, alcohol use, BMI, TC, HDL-C, TG, smoking, SBP, DM, IL-6, CRP	9
Koehler, 2011⁵⁰	Rotterdam	Netherlands	1990–93	≥55	–	18	3867	1825	Age, sex, alcohol use, BMI, HTN, DM, TC, smoking, educational level	9
Haring, 2009¹⁶	SHIP	Germany	1997–2001	20–79	49	7.3	4160	307	Age, WC, alcohol use, PA, educational level, civil status, equalized income, FCI	9
Strasak, 2008⁴⁸	VHM&PP	Austria	1985–2005	42^a	42.5	10.2	76 113	4551	Age, BMI, smoking, occupational status, TG, TC, SBP, DBP, blood glucose	8
Breitling, 2011¹⁵	WCB	Germany	1986–92	25–64	100	20	19 090	2170	Age, nationality, occupation, DM, IHD, HT, BMI, smoking, elevated blood glucose, TG, TC, alcohol	7
Subtotal							9 071 005	236 765
Alanine aminotransferase
Fulks, 2008²⁸	CRL	USA	1991–2007	≥18	59.7	9.6	8 911 194	219 869	Age, fructosamine, TC/HDL-C, GGT, AST, ALP	6
Goessling, 200²¹	FHS Offspring	USA	1978–82	44^a	44	20	2812	283	Age, sex, SBP, HTN, smoking, BMI, DM, lipid txt, alcohol use	9
Schindhelm, 2007⁹	Hoorn	Netherlands	1989–92	50–75	60.9	10	1439	174	Age, sex, alcohol use, smoking, PA, waist, TGs, SBP, FPG, HDL-C	9
Ruhl, 2009⁴⁵	NHANES III	US	1988–94	–	–	12	14 950	2189	Age, sex, race-ethnicity, BMI, WHR, glucose, TC, HDL-C, SBP, DBP, smoking, alcohol use, caffeine, PA, CRP, transferring saturation, education	9
Nakamura, 2006⁴⁷	NHI	Japan	1989–91	40–69	–	10	4524	214	Age, sex, BMI, smoking, alcohol use, SBP, medication for HTN, TC, DM	8
Kim, 2004^{1 3}	KMIC	Korea	1990/1992	35–59	66.5	8	142 055	3786	Age, BMI, smoking, alcohol use, plasma glucose, TC, BP, FHx liver disease	8
Koehler, 2011⁵⁰	Rotterdam	Netherlands	1990–93	≥55	–	18	3867	1825	Age, sex, alcohol use, BMI, HTN, DM, TC, smoking, educational level	9
Ford, 2011²⁰	WOSCOPS	Scotland	–	45–64	100	15	6595	1293	Country, treatment allocation, age, sex, smoking, DM, HTN, BMI, SBP, DBP, HDL-C, LDL-C, TGs, glucose, alcohol	7
Subtotal							9 087 436	229 633
Aspartate aminotransferase
Fulks, 2008²⁸	CRL	USA	1991–2007	≥18	59.7	9.6	8 897 875	219 669	Age, fructosamine, TC/HDL-C, ALT, GGT, ALP	6
Goessling, 2008²¹	FHS Offspring	USA	1978–82	44^a	44	20	2812	283	Age, sex, SBP, HTN, smoking, BMI, DM, lipid txt, alcohol use	9
Kim, 2004^{1 3}	KMIC	Korea	1990/1992	35–59	66.5	8	142 055	3786	Age, BMI, smoking, alcohol use, plasma glucose, TC, BP, FHx liver disease	8
Koehler, 2011⁵⁰	Rotterdam	Netherlands	1990–93	≥55	–	18	3867	1825	Age, sex, alcohol use, BMI, HTN, DM, TC, smoking, educational level	9
Subtotal							9 046 609	225 563
Alkaline phosphatase
Wannamethee, 2013¹¹	BRHS	UK	1998–2000	60–79	100	11	3381	984	Age, smoking, alcohol use, PA, social class, BMI, antihypertensive medication, DM, lung function, SBP, estimated GFR, CRP, vWF	7
Fulks, 2008²⁸	CRL	USA	1991–2007	≥18	59.7	9.6	8 897 875	219 669	Age, fructosamine, TC/HDL-C, ALT, AST, GGT	6
Filipowicz, 2013²⁷	NHANES 1999–2004	USA	1999–2004	≥20	48.9	4.6	9771	438	Age, sex, race, SBP, DBP, WC, estimated GFR, liver disease, Ca, Ph, AST, ALT, GGT, bilirubin, albumin, Hb	9
Tonelli, 2009⁴	NHANES III	USA	1988–94	≥20	49	12	14 716	2064	Age, sex, race, smoking, SBP, antihypertensive medication, GFR < 60 mL min⁻¹ 1.73 m⁻², albuminuria, Hb, RBC distribution width, serum albumin, HDL-C, Ca, Ph, 25-hydroxyvitamin D, DM, bilirubin, CRP ≥ 3 mg/L, alcohol use, ALT, AST	9
Subtotal							8 848 155	221 127
Total^b							9 238 201	242 953

BRHS, British Regional Heart Study; CRL, Clinical Reference Laboratory; FHS, Framingham Heart Study; HSE, Health Survey of England; KMIC, Korea Medical Insurance Corporation; NHANES, National Health and Nutrition Examination Survey; NHI, National Health Insurance; RBS, Rancho Bernardo Study; SHeS, Scottish Health Survey; SHIP, Study of Health in Pomerania; VHM&PP, Vorarlberg Health Monitoring and Promotion Program; WCB, Workmen's Compensation Board; WOSCOPS, West of Scotland Coronary Prevention Study.
ALT, aspartate aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; Ca, calcium; CRP, C-reactive protein; DBP, diastolic blood pressure; DM, diabetes mellitus; FCI, Functional Comorbidity Index; FEV1, forced expiratory volume in 1 s; FHx, family history; FPG, fasting plasma glucose; GFR, glomerular filtration rate; GGT, gamma glutamyltransferase; Hb, haemoglobin; HDL-C, high-density lipoprotein cholesterol; HTN, hypertension; IHD, ischaemic heart disease; IL-6, interleukin-6; LDL-C, lowdensity lipoprotein cholesterol; PA, physical activity; Ph, phosphorus; RBC, red blood cell; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; vWF, von Willebrand factor; WC, waist circumference; WHR, waist-hip-ratio.
^aMean ages at baseline.
^bTotal numbers for the unique studies.

Table 2. Study and assay characteristics of studies contributing data to current analysis, 1995–2013
Lead author, year, reference no.	Study	Sampling method	Year of sample collection	Sample source	Fasting samples	Sample state before analysis, storage, temperature(C) if frozen	Assay method	Assay source (manufacturer)
Wannamethee, 1995⁴⁶	BRHS	Random	1978–80	Serum	No	Fresh	NS	Technicon SMA 12/60 Autoanalyzer (Technicon Instruments Corp., Tarrytown, NY)
Wannamethee, 2013¹¹	BRHS	Complete	1998–2000	Serum	Yes	Frozen, −70	Colorimetric	Hitachi autoanalyzer (Roche Diagnostics, Indianapolis, IN)
Calori, 2011²⁶	Cremona	Random	1990–91	Serum	Yes	Fresh	NS	Hitachi 705 autoanalyser (Hitachi, Tokyo, Japan)
Fulks, 2008²⁸	CRL	Complete	1991–2007	Serum	No	Fresh	NS	Hitachi autoanalyzer (Roche Diagnostics, Indianapolis, IN)
Lee, 2007⁴⁴	FHS	Complete	1978–82	Serum	Yes	Frozen, −20	Spectrophotometry	Quest Diagnostics (MedpaTH, SC)
Kengne, 2012⁴³	HSE/SHeS	Random	1994/95/98	Serum	No	Frozen, −70	DAX nitroanilide	NS
Ruhl, 2009⁴⁵	NHANES III	Random	1988–94	Serum	Yes	Frozen, −20	NS	Hitachi 737 analyzer (Boehringer-Mannheim Diagnostics, Indianapolis,IN)
Tonelli, 2009⁴	NHANES III	Random	1988-–94	Serum	Yes	Frozen, −20	NS	Hitachi 737 analyzer (Roche Diagnostics, Indianapolis, IN)
Filipowicz, 2013²⁶	NHANES	Random	1999–2004	Serum	Yes	Frozen, −20	Beckman Access Ostase	(Beckman Coulter Inc, Carlsbad, CA)
Loomba, 2012^{4 9}	RBS	Complete	1984–87	Serum	Yes	Fresh	Colorimetric	In-house
Strasak, 2008⁴⁸	VHM&PP	Complete	1985–2005	Serum	Yes	Fresh	NS	NS
Breitling, 2011¹⁵	WCB	Complete	1986–92	Serum	NS	Fresh	NS	Hitachi 705/717 instrument
Goessling, 2008²¹	FHS Offspring	Complete	1978–82	Serum	Yes	Fresh	Kinetic method	Beckman Liquid-Stat Reagent Kit
Schindhelm, 2007⁹	Hoorn	Random	1989–92	Serum	Yes	Fresh	Enzymatic Photometry	NS
Nakamura, 2006⁴⁷	NHI	Complete	1989–91	Serum	NS	NS	Ultraviolet method	NS
Kim, 2004^{1 3}	KMIC	Random	1990–92	Serum	Yes	Fresh	NS	NS
Koehler, 2011⁵⁰	Rotterdam		1990–93	Serum	No	Fresh	–	–
Haring, 2009¹⁶	SHIP	Random	1997–2001	Serum	No	Fresh	Spectrophotometry	Hitachi 717 (Roche Diagnostics, Mannheim, Germany)
Ford, 2011²⁰	WOSCOPS	Random	NS	Serum	NS	Fresh	Reaction rate	Hitachi 737 automated analyser

Study acronyms are provided in Table 1; NS, not stated.

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Liver Enzymes and Risk of All-Cause Mortality in General Populations: A Systematic Review and Meta-analysis

Abstract and Introduction

Abstract

Introduction

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Tables

References

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Authors and Disclosures

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