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Table of Contents
ORIGINAL ARTICLE
Year : 2020  |  Volume : 8  |  Issue : 4  |  Page : 179-183

To study gamma-glutamyl transferase levels in heart failure


Department of General Medicine, M. R. Medical College, Gulbarga, Karnataka, India

Date of Submission27-Nov-2019
Date of Acceptance27-Dec-2019
Date of Web Publication23-Oct-2020

Correspondence Address:
Dr. Fida Hussain Mitha Bhai
Department of General Medicine, M. R. Medical College, Gulbarga, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AJIM.AJIM_78_19

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  Abstract 


Background and Aims: Serum gamma-glutamyl transferase (Sr.GGT) is associated with incident cardiovascular diseases and is a potential risk factor for disease mortality. We investigated the relevance of circulating Sr.GGT levels in heart failure (HF) patients. Materials and Methods: About 50 patients admitted with diagnosed HF according to Framingham's clinical criteria, irrespective of etiology, and type of HF were enrolled in the study and their baseline Sr.GGT levels were estimated. They were grouped into ischemic and nonischemic (valvular) cause of HF. Type of HF was based on the ejection fraction (EF%) on echocardiography reduced the EF (<40%), mid-range or preserved EF >40%). Statistical analysis was presented as frequency (percentage) and continuous as mean ± standard deviation. Inferential statistics such as Chi-square test/Fischer's exact test was used. Results: The mean age of the study patients was 58.20 ± 14.98 years. Both genders were homogeneously spread across the different age groups in the study. It was found that Sr.GGT levels were best correlated in the age groups below 65 years. Significant association was seen when patients were studied by stratifying them gender wise, divided into quartiles. Valvular heart disease and its association with Sr.GGT levels were found to be statistically significant (P = 0.001). Whereas no association was found in the given sample between coronary artery disease/ischemic heart disease and Sr.GGT levels. Significant association in patients with comorbid conditions was found, indicative that comorbidities contributed as a confounding factor in the study.Conclusion: This study is limited by its observational nature; it does not permit conclusions on causal relationships. Sr.GGT levels done at baseline in patients with HF may not be helpful to prognosticate HF. Serial follow-up studies in a larger sample size are required.

Keywords: Coronary artery disease/ischemic heart disease, ejection fraction, heart failure, serum gamma-glutamyl transferase, valvular heart disease


How to cite this article:
Bhai FH, Biradar S. To study gamma-glutamyl transferase levels in heart failure. APIK J Int Med 2020;8:179-83

How to cite this URL:
Bhai FH, Biradar S. To study gamma-glutamyl transferase levels in heart failure. APIK J Int Med [serial online] 2020 [cited 2020 Nov 26];8:179-83. Available from: https://www.ajim.in/text.asp?2020/8/4/179/298945




  Introduction Top


Cardiovascular diseases are threating human health with rising morbidity and mortality. The prevalence of heart failure (HF) in India from different causes was about 1.3–4.6 million with an annual incidence of 491,600–1.8 million.[1] Based on the Framingham Heart Study, 30-day mortality is around 10%, 1-year mortality is 20%–30%, and 5-year mortality is 45%–60%.

Recent studies have shown gamma-glutamyl transferase to be involved in the pathogenesis of cardiovascular diseases such as HF, coronary artery disease,[2] hypertension, and metabolic syndrome.[3]

Glutathione (GSH) is a tripeptide comprised three amino acids: gamma-glutamic acid, L-cysteine, and L-glycine. Its primary biological function is to act as a nonenzymatic reducing agent to help keep cysteine thiol side chains in a reduced state on the surface of proteins. GSH also prevents oxidative stress in most cells and helps trap-free radicals that can damage DNA and RNA. The physiological role of GGT is to initiate the hydrolysis of extracellular GSH by cleaving the gamma-glutamyl amide bond of the tripeptide to cysteine and other thiol compounds, which are known to promote low-density lipoprotein oxidation by reducing Fe(III) to redox-active Fe(II).[4]

Recently, catalytically active GGT has been found within atherosclerotic coronary plaques from autopsy studies and surgical endarterectomies.[2]

It has been shown that elevated serum GGT (Sr.GGT) activity exists in the early stages of HF, the final and common pathway of all cardiovascular diseases.[5]

Sr. GGT is associated with severity of HF as assessed by the New York Heart Association class, left ventricular (LV) ejection fraction, and amino-terminal pro-B-type natriuretic peptide levels.

Hepatic congestion is an obvious mechanistic explanation for the elevation of GGT in HF. It has been previously reported that severe HF is associated with a cholestatic liver enzyme profile with elevated plasma levels of GGT, serum alkaline phosphatase (SAP), and bilirubin. Local damage to the bile canaliculi caused by increased pressure within the hepatic sinusoid or ischemia as well as pro-inflammatory cytokine release may be involved in this process.[6]


  Materials and Methods Top


Source of data

Patients clinically diagnosed of HF admitted to Basaveshwara Teaching and General Hospital (BTGH) and hospitals in and around Kalaburagi, Karnataka.

Inclusion criteria

  • Patient's aged above 18 years of age
  • Those patients admitted with diagnosis of HF based on Framingham's clinical criteria, irrespective of etiology of the disease in BTGH.


Exclusion criteria

  • Patients having primary liver parenchymal disease
  • Alcoholic patients.


Study period

The study was conducted from November 2017 to August 2019.

Study design

This was a hospital-based baseline observational study.

Sample size

The sample size was minimum 50 patients.

Method of data collection

Ethical clearance from the IEC, MRMC, and Kalburagi was obtained, and written informed consent was taken from the patients.

Data were collected by detailed history, clinical examination, and investigations done at admission.

Gamma Glutamyl Transferase level Analysis is based on the following principle of photospectrometery explained in [Figure 1].
Figure 1: Analysis of GGT activity in a given sample

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Reference range for normal GGT values at BTGH laboratories:

  • Males <55 IU/L; Females <38 IU/L.


Statistical analysis

Descriptive and inferential statistical analysis has been carried out in the present study. The results were analyzed using SPSS version 18 (IBM Corporation, SPSS Inc., Chicago, IL, USA).

Results on categorical measurement were presented as frequency (percentage) and continuous as mean ± standard deviation. Inferential statistics like

  • Chi-square test
  • Fischer's exact test was used.


P < 0.05 was considered to be statistically significant.


  Results Top


Most of the patients presenting were in their 3rd to 6th decades of life, the mean age of presentation is 58.20 ± 14.98. Both the genders are homogeneously distributed in different age groups. The number of female and male patients presenting with HF were 42% and 58%, respectively. The mean age of presentation in females was about 53.62 ± 13.31, and in male, it was 61.52 ± 15.46.

Sr. GGT levels were classified into five groups using 25th, 50th, 75th, and 90th percentiles as cut points (quartiles with the top quartile split). The cut points were 24.5, 33.8, 43.5, and 68 U/l among men, and 20.5, 26, 34.3, and 47.7 U/l among women for the categories of GGT used, respectively. This gender-stratified approach across quartiles was used to study the different factors and their association with Sr. GGT levels [Table 1].
Table 1: Age and gender distribution

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When checked for the association between ejection fraction and Sr. GGT levels gender wise. It is observed that in males, ejection fraction was significantly associated with Sr. GGT levels (0.031*) [Table 2].
Table 2: Ejection fraction in relation to serum gamma-glutamyl transferase level and gender

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No statistically significant association was seen to exist between valvular heart disease (VHD) and Sr.GGT levels gender wise [Table 3].
Table 3: Valvular heart disease in relation to serum gamma-glutamyl transferase level and gender

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Overall VHD significantly associated with Sr. GGT levels [Table 4].
Table 4: Valvular heart disease and serum gamma-glutamyl transferase levels in overall sample

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No statistically significant association was seen to exist between CAD/IHD and Sr. GGT levels gender wise [Table 5].
Table 5: Coronary artery disease/ischemic heart disease in relation to serum gamma-glutamyl transferase level and gender

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Overall comorbidities had significant association with Sr.GGT levels (P = 0.019) [Table 6] and [Table 7].
Table 6: Comorbidities and serum gamma-glutamyl transferase levels

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Table 7: Comorbidities in relation to serum gamma-glutamyl transferase levels

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  Discussion Top


In the present study, 50 patients diagnosed to have HF according to the Framingham's clinical criteria were recruited. The mean age of the study patients was 58.20 ± 14.98 years. Most of the patients were clustered from 3rd to 6th decade. There were about 42% females and 58% males, which were homogeneously spread across different age groups in the study. The mean age of men presenting with HF was 61.52 ± 15.46, and in females, it was 53.62 ± 13.31 [Table 8].
Table 8: Mean values

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In a similar study done by Poelzlet al .,[6] the mean age of presentation was 59 ± 13, of which there were 73% males and around 27% females. A higher ratio of males, in a cohort of HF, could be attributed to increase the incidence of risk factors like substance abuse in men.

Mean GGT levels were highest in 66–80 years of age group (38.80 ± 26.13), whereas the maximum number of patients having high levels of GGT were found around 36–65 years (22%). Therefore, Sr. GGT is a better indicator of HF below the age of 65 years.

Wang et al .[7] and Poelzl et al. [6] observed a direct association between Sr.GGT and the risk of HF in men and women in Finland, especially in those who aged <60 years.

In accordance with other study,[7] patients with overt signs of clinical failure had values of Sr.GGT within the normal range not having shown significance, but when they were taken in quartiles against EF%, men irrespective of type of HF showed statistically significant (P = 0.031) trend from 25th to 90th quartile. On the other hand, women did not show any significant association with Sr.GGT levels.

Poelzl et al .[6] in their study, found that a significant stepwise increase in GGT levels was observed to decreasing categories of LVEF in men but not in women (P = 0.037 in men vs. P = 0.63 in women).

As increased Sr.GGT activity has been linked within atherosclerotic plaques of coronary artery disease/ischemic heart disease (CAD/IHD135). Patients were divided into nonischemic (valvular) HF and CAD/IHD (ischemic) HF for comparing data.

CAD/IHD was not found to have a significant association with Sr.GGT levels when both overall sample and gender-based quartiles were studied (mean: 38.15 ± 14.05; P = 0.684).

Wang et al .,[7] in their study, 14.5-year follow-up study suggested that the risk of HF significantly increased in relation to Sr.GGT (from the 50th to the 90th percentiles). Even after multivariate adjustments were made for other cardiovascular risk factors, the relation between HF and Sr.GGT levels remained statistically significant (P < 0.001).

Poelzl et al .[6] in their 7-year follow-up study did not find any significant relation between Sr.GGT and IHD/CAD.

In this study, overall sample of valvular heart disease (mean: 30.3 ± 20.14; P = 0.001) was found to have statistical significance, whereas when the same was broken into quartiles and studied gender wise, we did not find any statistical significance. No other study could be found which made comparison between Sr.GGT levels and valvular cause of HF to compare.

In our study, it was found that comorbid conditions such as diabetes, hypertension, chronic obstructive pulmonary disease (COPD), asthma, and cough variant asthma (CVA) were associated with high levels of Sr.GGT. Possibly, they could have acted as confounding factors for increased Sr.GGT levels. Hypertensive patients (41.2 ± 22.4) had the highest mean value among all the comorbid conditions followed by COPD (37.2 ± 9.12), diabetes, and CVA (33.2 ± 11.1).

Higher Sr.GGT activity has been reported in atherosclerotic plaques and foam cells.[8] Furthermore, higher Sr.GGT levels have been associated with a greater incidence of metabolic syndrome and incident diabetes.[9]

In the third Tromso Study,[10] systolic blood pressure was found to be a significant independent predictor of GGT, for both men and women, in multiple regression analysis, which also included body mass index and alcohol use.

In contrast to other studies, we have excluded alcoholic patients from the study.


  Conclusion Top


  • This study is limited by its observational nature, it does not permit conclusions on causal relationships
  • Sr.GGT levels are statistically significant when studied in the age groups below 65 years and do not correlate well when studied in the age groups above
  • Sr.GGT levels done at baseline or at presentation with HF may not be significant to prognosticate HF, and serial follow-up studies are required
  • Hence, more studies in comparison to already established biomarkers (e.g., N-terminal pro-B-type natriuretic peptide [NT-proBNP]) of HF is required (multi-marker approach) before Sr.GGT can be used as a biomarker to diagnose or prognosticate HF at baseline. Most of the studies did not find elevated Sr.GGT levels at baseline. Significant results were seen when the end result (death or cardiac transplantation) was reached or on long-term follow-up studies
  • Therefore, Sr.GGT levels can be used for long-term risk-stratification rather than a biomarker, and it would be suggested that a criteria scoring be considered when using Sr.GGT to prognosticate HF, as there are many other confounding factors (e.g., alcohol, hypertension, and diabetes mellitus) which play a statistically significant role in Sr.GGT levels
  • We found a significance of Sr.GGT levels in valvular heart disease but further studies according to the type of valvular lesion and gradient across valves, post valve repair along with other confounding variables is required before it can be ascertained whether Sr.GGT holds any significance in these group of HF patients
  • CAD/IHD did not show any association with Sr.GGT levels in our study
  • Comorbid conditions, especially hypertension showed association with elevated levels of Sr.GGT, this requires further breakup studies to find which stage of hypertension holds significance, and whether LV hypertrophy and hypertensive retinopathy correlate positively.


Limitations

  • A small sample was selected which was not a true representation of the general population, as the sample was already diagnosed with HF
  • Sr. GGT levels are associated with alcohol consumption, and the selected sample was a nonalcoholic sample. Alcohol itself is an independent risk factor for HF (alcoholic cardiomyopathy and IHD)
  • No other established biomarkers such as NT-proBNP were used to compare with Sr. GGT levels.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Huffman MD, Prabhakaran D. Heart failure: Epidemiology and prevention in India. Natl Med J India 2010;23:283-8.  Back to cited text no. 1
    
2.
Paolicchi A, Emdin M, Ghliozeni E, Ciancia E, Passino C, Popoff G, et al . Images in cardiovascular medicine. Human atherosclerotic plaques contain gamma-glutamyl transpeptidase enzyme activity. Circulation 2004;109:1440.  Back to cited text no. 2
    
3.
Lee DS, Evans JC, Robins SJ, Wilson PW, Albano I, Fox CS, et al . Gamma glutamyl transferase and metabolic syndrome, cardiovascular disease, and mortality risk: The Framingham Heart Study. Arterioscler Thromb Vasc Biol 2007;27:127-33.  Back to cited text no. 3
    
4.
Paolicchi A, Minotti G, Tonarelli P, Tongiani R, de Cesare D, Mezzetti A, et al . Gamma-glutamyl transpeptidase-dependent iron reduction and LDL oxidation – A potential mechanism in atherosclerosis. J Investig Med 1999;47:151-60.  Back to cited text no. 4
    
5.
Makarewicz-Wujec M, Kozlowska-Wojciechowska M. Nutrient intake and serum level of gamma-glutamyltransferase, MCP-1 and homocysteine in early stages of heart failure. Clin Nutr 2011;30:73-8.  Back to cited text no. 5
    
6.
Poelzl G, Eberl C, Achrainer H, Doerler J, Pachinger O, Frick M, et al . Prevalence and prognostic significance of elevated gamma-glutamyltransferase in chronic heart failure. Circ Heart Fail 2009;2:294-302.  Back to cited text no. 6
    
7.
Wang Y, Tuomilehto J, Jousilahti P, Salomaa V, Li B, Antikainen R, et al . Serum γ-glutamyltransferase and the risk of heart failure in men and women in Finland. Heart 2013;99:163-7.  Back to cited text no. 7
    
8.
Paolicchi A, Emdin M, Ghliozeni E, Ciancia E, Passino C, Popoff G, et al . Human atherosclerotic plaques contain gamma-glutamyl transpeptidase enzyme activity. Circulation 2004;109:1440.  Back to cited text no. 8
    
9.
Dhingra R, Gona P. Serum-Glutamyl Transferase and Risk of Heart Failure in the Community: Arterioscler Thromb Vasc Biol 2010;1858.  Back to cited text no. 9
    
10.
Nilssen O, Førde OH, Brenn T. The Tromso Study. Distribution and population determinants of gamma-glutamyltransferase. Am J Epidemiol 1990;132:318-26.  Back to cited text no. 10
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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