Home Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis
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Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis

  • Jiancheng Wang , Nengtai Ouyang , Long Qu , Tengfei Lin , Xianglin Zhang , Yaren Yu , Chongfei Jiang , Liling Xie , Liping Wang , Zhigui Wang , Shuzhen Ren , Shizhi Chen , Jiang Huang , Fang Liu , Weiqing Huang and Xianhui Qin EMAIL logo
Published/Copyright: December 29, 2017
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Journal of Translational Internal Medicine
From the journal Journal of Translational Internal Medicine Volume 5 Issue 4

Abstract

Background and Objectives

The Chinese population typically has inadequate folate intake and no mandatory folic acid fortification. Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key regulatory enzymes in the folate/homocysteine (Hcy) metabolism. Hcy has been implicated in the pathogenesis of cardiovascular disease. We conducted a meta-analysis to assess whether the MTHFR gene A1298C and the MTRR gene A66G polymorphisms affect Hcy levels in the Chinese population.

Methods

This analysis included 13 studies with Hcy levels reported as one of the study measurements. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect models.

Results

Overall, there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials, n = 129), AA (n = 2166; β, −0.51 μmol/L; 95%CI: −2.14, 1.11; P = 0.53), or AC genotype (n = 958; β, 0.55 μmol/L; 95%CI: −0.72, 1.82; P = 0.40). Consistently, compared to those with the MTRR 66 GG genotype (6 trials, n = 156), similar Hcy concentrations were found in participants with the AA (n = 832; β, −0.43 μmol/L; 95%CI: −1.04, 0.17; P = 0.16) or AG (n =743; β, −0.57 μmol/L; 95%CI: −1.46, 0.31; P = 0.21) genotype. Similar results were observed for the dominant and recessive models.

Conclusions

Neither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects Hcy levels in the Chinese population.

Key words: homocysteine; MTHFR gene A1298C polymorphism; MTRR gene A66G polymorphism; Meta-analysis

Introduction

Homocysteine (Hcy) is a sulfur-containing amino acid.[1] Elevated Hcy concentration has been reported to be an independent risk factor for a variety of cardiovascular diseases, including coronary heart disease and stroke.[2, 3] A previous meta-analysis of genetic and prospective studies estimated that, if causal, a 3-μmol/L reduction in serum Hcy concentrations would decrease the risk of stroke by 24%.[3] Possible mechanisms by which Hcy contributes to vascular damage include inhibiting endothelial cell (EC) growth and post-injury endothelial repair,[4, 5] inducing endothelial dysfunction,[6] promoting vascular remodeling,[7] and inflammatory monocyte differentiation.[8, 9]

Methylenetetrahydrofolate reductase (MTHFR) and methionine synthase reductase (MTRR) are the two key enzymes responsible for the remethylation of Hcy to methionine in the one-carbon metabolic pathway.[10] MTHFR converts 5,10-methylene-tetrahydrofolate (THF) into 5-methyl-THF, the dominant circulating form of folate. The 5-methyl-THF product donates a methyl group to Hcy in the generation of S-adenosylmethionine, a major source of methyl groups used for DNA methylation.[11] MTRR regenerates a functional methionine synthase via reductive methylation, which is associated with the Hcy transfer to methionine,[12] Two common polymorphisms of the MTHFR gene are C677T and A1298C. The MTHFR 677C→T polymorphism leads to a reduction in enzyme activity, resulting in increased concentrations of plasma Hcy and lower levels of serum folate.[13, 14] While the effect of the MTHFR C677T gene polymorphism on Hcy levels is very clear, the relationship between the gene polymorphisms MTHFR A1298C and MTRR A66G and Hcy levels are still controversial.

We conducted a meta-analysis to examine whether the MTHFR gene A1298C and the MTRR gene A66G could affect the serum Hcy concentrations in the Chinese population.

Materials and method

Search strategy and selection criteria

Our study followed the Meta-analysis Of Observational Studies in Epidemiology guidelines.[15] A systematic literature search of published studies was undertaken. We searched the databases PubMed, CNKI, Wangfang, and Weipu for studies published up to May 2017 with the following Standard Medical Subject Headings terms: (MTHFR or methylenetetrahydrofolate reductase or MTRR or Methionine Synthase Reductase) and (Homocysteine or total homocysteine or Hcy) and (China or Chinese). Manual searches of bibliographies for all relevant studies and review articles were also conducted. There were no language restrictions. A team of experts in the relevant field was assembled. The results of the search strategy are summarized in Figure 1.

Figure 1 Flow chart of the study selection procedure. CNKI: China National Knowledge Infrastructure
Figure 1

Flow chart of the study selection procedure. CNKI: China National Knowledge Infrastructure

A standard protocol for study selection and data extraction was developed by our multidisciplinary team with relevant expertise in epidemiology, clinical medicine, and biostatistics. Studies that met the following criteria were included: (1) sufficient data for Hcy concentrations (sample size, mean, and standard deviation [SD]) and frequencies of the MTHFR gene A1298C or the MTRR gene A66G; (2) when the same data were used in more than one publication, the latest or largest study was selected.

Data extraction

All data from eligible trials were independently extracted in duplicate by two independent investigators using the standard protocol and reviewed by a third investigator. Discrepancies were resolved by discussion with the multidisciplinary research team who developed the protocol.

The following information was extracted: first author’s name, year of publication, mean age in each group, percentage of female participant, participant sample size, study design, genotyping method, mean and SD of plasma or serum Hcy concentrations in the genotype categories, and concomitant diseases.

Cross-sectional studies (including baseline evaluation of cohort studies and pre-intervention evaluations of randomized controlled trials) and case–control studies were included in the analysis. The methodological quality of the cross-sectional studies was assessed using an 11-item checklist as recommended by the Agency for Healthcare Research and Quality.[16] An item received a score of “0” if answered as “NO” or “UNCLEAR”; if answered as “YES,” the item received a score of “1.” The quality of an article was assessed based on the score as follows: low quality = 0−3; moderate quality = 4−7; high quality = 8−11. The quality of case–control studies was assessed by the Newcastle-Ottawa Scale.[17] In brief, a maximum of 9 points was assigned to each study: 4 for selection, 2 for comparability, and 3 for outcomes. A final score of >6 was regarded as high quality.

Statistical analysis

Our primary outcome was Hcy concentrations in participants within the different genotypes. Summary estimates of weighted mean differences and 95% confidence intervals (CIs) were obtained using random-effect (DerSimonian and Laird) models. Heterogeneity between studies was assessed by Cochran’s Q test with a significance level set at 0.10. The I2 statistics was also examined, and I2 > 50% was considered as relevant heterogeneity. The presence of publication bias was assessed by Egger’s linear regression test. Sensitivity analyses were performed by removing one study at a time to calculate overall homogeneity. The Hardy–Weinberg equilibrium was assessed using Fisher’s exact test.

All statistical analyses were performed using Review Manager (Revman) 5.3.0. A two-tailed P value of <0.05 was considered statistically significant unless otherwise stated.

Results

Characteristics of the included studies

A total of 212 articles were retrieved from the initial searches. From these, 17 were duplicates, leaving 195 articles that required closer inspection by examining the abstract and full text when necessary. From these, there were 40 potential studies for the meta-analysis. Of the 40 studies, 10 were excluded because of lack of genotyping data, 7 were review articles, 5 were not relevant, and 5 deviated from the Hardy–Weinberg Equilibrium (P < 0.05). Finally, 13 studies[10, 12, 14, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27] were suitable for the meta-analysis (Figure 1).

The baseline characteristics of the study participants by MTHFR A1298C are shown in Table 1 and MTRR A66G genotype in Table 2. Among the 13 studies, 7 were case–control studies[12, 14, 23, 24, 25, 26, 27] and 6 were cross-sectional studies.[10, 18, 19, 20, 21, 22] In addition, five manuscripts[10, 12, 14, 21, 22] were published in English, and eight manuscripts[18, 19, 20, 23, 24, 25, 26, 27] were published in Chinese. Hcy was measured by fluorescent polarization immunoassay,[14, 22, 24] high-performance liquid chromatography,[10, 23, 27] enzymatic cycle method,[12, 19, 20, 26] chemiluminescence method,[18] and enzyme-linked immunosorbent assay.[25] Genotype was analyzed by fluorescence quantitative polymerase chain reaction,[12, 18, 26] polymerase chain reaction–restriction fragment length polymorphism,[10, 14, 22, 23, 24, 25, 27] ligase detection reaction,[19] iPLEX gold chemistry,[21] and taqman-minor groove binder.[20]

Table 1

Characteristics of studies included in the meta-analyses on the association between MTHFR A1298C genotypes and homocysteine levels

StudyYearDesignSex (female)AgeSample sizeMethod of plasma measurementHcy MTHFR analysisConcomitant disease
Hou et al. [12]2016Case–control195 (100%)30.6 (5.3)195Enzymatic cycle methodFQ-PCRHealthy controls
Ji et al. [24]2004Case–control55 (31.4%)67.5177FPIAPCR-RFLPCHD/healthy controls
Kasiman et al. [22]2009Cross-sectional145 (34.6%)61.9 (11.6)419FPIAPCR-RFLPIschemic stroke
Li et al. [10]2017Cross-sectional268 (57.3%)56.7468HPLCPCR-RFLPHypertensive patients
Liu et al. [23]2006Case–control17 (42.9%)51.9 (7.5)44HPLCPCR-RFLPDiabetic retinopathy
Nan et al. [27]2007Case–control57 (28.5%)40.0200HPLCPCR-RFLPIschemic stroke/Healthy controls
Wang et al. [25]2010Case–control220 (53.9%)45.1408ELISAPCR-RFLPHypertensive patients/Healthy controls
Wang et al. [18]2014Cross-sectional110 (100%)26.7 (4.6)110Chemiluminescence methodFQ-PCRGeneral population
Wu et al. [19]2016Cross-sectional257 (58.7%)38 (8.6)438Enzymatic cycle methodLDRGeneral population
Xing et al. [20]2014Cross-sectional425 (100%)NA425Enzymatic cycle methodTaqman-MGBGeneral population
Ye et al. [26]2016Case–control192 (100%)28.1192Enzymatic cycle methodFQ-PCRIncipient abortion/healthy controls
Yuan et al. [14]2009Case–control31 (64.6%)71.8 (10.3)48FPIAPCR-RFLPParkinson’s disease
Yuan et al.17 (60.7%)70.6 (9.1)28Parkinson’s disease
Yuan et al.73 (66.4%)70.0 (8.5)110Healthy controls

*For continuous variables, values are presented as mean ±SD;

FPIA: fluorescent polarization immunoassay; LDR: ligase detection reaction; HPLC: high-performance liquid chromatography; FQ-PCR: fluorescence quantitative polymerase chain reaction; PCR-RFLP: polymerase chain reaction–restriction fragment length polymorphism; Taqman-MGB: taqman-minor groove binder.

Table 2

Characteristics of studies included in the meta-analyses on the association between MTRR A66G genotypes and homocysteine levels

StudyYearDesignSex (female)AgeSample sizeMethod of plasma Hcy MTRR analysis MeasurementConcomitant disease
Hou et al. [12]2016Case–control195 (100%)30.6 (5.3)195Enzymatic cycle methodFQ-PCRHealthy controls
Li et al. [10]2017Cross-sectional268 (57.3%)56.7468HPLC PCR-RFLPPatients with hypertension
Ni et al. [21]2017Cross-sectionalNA26.8 (10.6)95NA IPLEX gold chemistryPatients with Epilepsy
Wang et al. [18]2014Cross-sectional110 (100%)26.7 (4.6)110Chemiluminescence FQ-PCR methodGeneral population
Wu et al. [19]2016Cross-sectional257 (58.7%)38 (8.6)438Enzymatic cycle methodLDRGeneral population
Xing et al. [20]2014Cross-sectional425 (100%)NA425Enzymatic cycle methodTaqman-MGBGeneral population

*For continuous variables, values are presented as mean ± SD.

HPLC: high-performance liquid chromatography; FQ-PCR: fluorescence quantitative polymerase chain reaction; PCR-RFLP: polymerase chain reaction–restriction fragment length polymorphism; LDR: ligase detection reaction; Taqman-MGB: taqman-minor groove binder.

In general, much of the eligible data from both cases and controls group were included in the current analysis. However, some of the case or control groups from the included case–control studies were excluded because of the following reasons: (i) the population deviated from the Hardy–Weinberg equilibrium[23] or (ii) either the case or the control group did not provide sufficient data according to the inclusion criteria.[12] In addition, some case–control studies only depicted the gene and Hcy data in the total population.[24, 25, 26, 27]

Quality analysis

The quality of the 13 included studies ranged from 5 to 7 (Supplemental Tables 1 and 2), suggesting that the overall quality of the included studies was acceptable. The mean scores were 6 for the case–control studies and 5.5 for the cross-sectional studies.

Main outcome and subgroup analyses

A total of 12 studies were examined for the association between Hcy levels and the MTHFR A1298C genotype. Figure 2 shows that there were no significant differences in Hcy concentrations between participants with the MTHFR 1298 CC (12 trials, n = 129), AA (n = 2166; β, −0.51 μmol/L; 95%CI: −2.14, 1.11; P = 0.53), or AC genotype (n = 958; β, 0.55 μmol/L; 95%CI: −0.72, 1.82; P = 0.40).

Figure 2 Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTHFR 1298 CC genotype compared with the AA or the AC genotype
Figure 2

Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTHFR 1298 CC genotype compared with the AA or the AC genotype

A total of 6 studies were examined for the association between Hcy levels and the MTRR A66G genotype. As shown in Figure 3, compared to those with the MTRR 66 GG genotype (6 trials, n = 156), similar Hcy concentrations were found in participants with the AA (n = 832; β, −0.43 μmol/L; 95%CI: −1.04, 0.17; P = 0.16) or AG (n =743; β, −0.57 μmol/L; 95%CI: −1.46, 0.31; P = 0.21) genotype.

Figure 3 Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTRR 66 GG genotype compared with the AA or the AG genotype
Figure 3

Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTRR 66 GG genotype compared with the AA or the AG genotype

Similar results were observed for the dominant and recessive models (Figures 4 and 5).

Figure 4 Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTHFR 1298 CC genotype compared with the AC/AA genotype and the MTHFR 1298 CC/AC genotype compared with the AA genotype
Figure 4

Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTHFR 1298 CC genotype compared with the AC/AA genotype and the MTHFR 1298 CC/AC genotype compared with the AA genotype

Figure 5 Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTRR 66 GG genotype compared with the AG/AA genotype and the MTRR 66 GG/AG genotype compared with the AA genotype
Figure 5

Random-effects meta-analysis of weighted mean differences (95% CI) in homocysteine levels with the MTRR 66 GG genotype compared with the AG/AA genotype and the MTRR 66 GG/AG genotype compared with the AA genotype

Publication bias and sensitivity analysis

Egger’s test results suggested the absence of publication bias for the meta-analysis evaluating the association between the MTHFR 1298 CC/AA genotype (P = 0.53), the MTHFR 1298 CC/CA genotype (P = 0.72), the MTHFR 1298 CC+AC/AA genotype (P = 0.37), the MTHFR 1298 CC/AC+AA genotype (P = 0.74), the MTRR 66 GG/AG genotype (P = 0.85), the MTRR 66 GG+AG/AA genotype (P = 0.55), or the MTRR 66 GG/AG+AA genotype (P = 0.34) and Hcy levels. However, the test (P = 0.01) did not provide sufficient evidence against publication bias for the meta-analysis evaluating the relationship between the MTRR 66 GG/AA genotype and Hcy levels.

Sensitivity analyses showed that the results did not substantially alter after removing any one study.

Discussion

Increasing attention has been paid to the association of the MTHFR and MTRR gene polymorphisms with Hcy levels. Our meta-analysis is the first study to examine the relationship between the MTHFR A1298C and MTRR A66G genotypes and plasma Hcy levels in the Chinese population. We found that neither the MTHFR A1298C nor MTRR A66G polymorphism affected the plasma Hcy levels in Chinese populations.

As early as 1969, Hcy, the sulfur-containing amino acid, was postulated to affect atherosclerotic processes.[28] However, findings from trials on Hcy-lowering therapy with folic acid or B-vitamins (containing folic acid) in stroke prevention have been mostly negative.[29, 30, 31] A meta-analysis of relevant trials revealed that most previous trials were conducted in countries with high folic acid consumption[32, 33] and that mandatory folate fortification of the grain supply in those countries may have reduced the Hcy levels in the total population and affected the power of the trials to detect a positive effect. Consistently, our recent meta-analysis found that lowering Hcy concentration by folic acid supplementation significantly reduced the progression of carotid intima-media thickness,[34] the risk of cardiovascular diseases in patients with chronic kidney disease,[35] and the risk of stroke,[36] particularly in those without dietary folic acid fortification. More importantly, a positive association was found between reduction in Hcy levels and the beneficial effect associated with folic acid therapy.[34, 37] There is substantial variability in Hcy levels even within the population without folic acid fortification.[13] Therefore, from a research and population-health perspective, it is important to clarify whether there are certain subgroups of individuals who had higher Hcy levels and might benefit from Hcy-lowering therapy.

Uncertainty remains about the relationship between the MTHFR A1298C and MTRR A66G gene polymorphisms and Hcy concentrations because of limited and inconsistent data. Oliveira et al. suggested that the A1298C polymorphism of the MTHFR gene is not associated with Hcy levels in Brazilian patients with Turner syndrome.[38] Hanson et al. also found that the A1298C polymorphism was not associated with either fasting or post-methionine load Hcy in vascular disease.[39] However, Zappacosta et al. [40] found that Hcy was higher in those with the wild type and lower in those who were homozygous. A report showed negative correlation between MTRR A66G and Hcy levels,[41] whereas other studies showed no significant correlation.[42, 43] These discrepancies may primarily be due to study sample size and/or marked ethnic and geographic variation of the different study cohorts. Furthermore, a recent collaborative study,[44] which analyzed 237 datasets including 59,995 individuals (20,885 stroke events), suggested that the effect of the MTHFR gene variants on Hcy level and stroke risk might be subject to effect modification by prevailing folate concentrations in the population. Typically, the Chinese population has inadequate folate intake and no mandatory folic acid fortification. Such a population provides a unique opportunity to observe the true association between the polymorphisms and the key enzymes in folate/Hcy metabolism. Although our previous studies on Chinese cohorts found that the MTHFR gene C677T polymorphism was a major determinant for both Hcy and folate levels,[45, 46] the current meta-analysis suggests that neither the MTHFR A1298C polymorphism nor the MTRR A66G polymorphism affects plasma Hcy levels in the Chinese population. Hcy has been implicated in the pathogenesis of cardiovascular diseases, cancer, and birth defects.[2, 47, 48] Consistent with our results, Yang et al. found that it was the MTHFR C677T polymorphism, but not the MTHFR A1289C polymorphism, that was associated with most clinical disorders, including cardiovascular diseases, cancer, and birth defects.[49]

The present study has several potential limitations. First, our study was conducted in Chinese populations. Although inadequate folate intake is prevalent in most countries lacking mandatory folic acid fortification of foods, including Asia and other continents, the generalizability of our findings to populations in other countries without folic acid fortification remains to be determined. Second, the MTRR A66G polymorphism is not extensively studied. Therefore, we could not provide sufficient evidence against a publication bias for the meta-analysis regarding the relationship of the MTRR 66 GG/AA genotype with Hcy levels. Furthermore, in general, meta-analyses have some inherent problems, including their retrospective and aggregate nature, moderate to high heterogeneity of some of the analyses, and the inability to adjust for individual variables.

In conclusion, the results of the meta-analysis suggest that both the MTHFR A1298C and MTRR A66G genotypes have no effect on the Hcy levels in the Chinese population. Further confirmatory studies on other ethnic groups are needed.

Supplement materials

Supplemental Table 1

Quality assessment of cross-sectional studies based on the Healthcare Research and Quality (AHRQ) recommendations

Authors (References)Wang et a.Xing et al.Ni et al.Li et al.Kasiman et al.Wu et al.
1. Define the source of information (survey, record review)111111
2. List inclusion and exclusion criteria for exposed and unexposed subjects (cases and controls) or refer to previous publications111111
3. Indicate time period used for identifying patients111111
4. Indicate whether or not subjects were consecutive if not population based010110
5. Indicate if evaluators of subjective components of study were masked to other aspects of the status of the participants000000
6. Describe any assessments undertaken for quality assurance purposes (e.g., test/retest of primary outcome measurements)000010
7. Explain any patient exclusions from analysis111001
8. Describe how confounding was assessed and/or controlled111111
9. If applicable, explain how missing data were handled in the analysis000000
10. Summarize patient response rates and completeness of data collection000000
11. Clarify what follow-up, if any, was expected and the percentage of patients for which incomplete data or followup was obtained000010

Supplemental Table 2

Quality assessment of the case control studies based on the Newcastle-Ottawa Quality Assessment Scale (NOS)

StudySelectionComparabilityOutcomeTotal
Hou et al.★ ★★ ★★5
Ji et al.★ ★★★ ★★ ★7
Liu et al.★ ★★★ ★★6
Nan et al.★ ★★★★5
Wang et al.★ ★★★★ ★6
Ye et al.★ ★★★★ ★6
Yuan et al.★ ★★★ ★★ ★7

Dr. Xianhui Qin, Ph.D., National Clinical Research Center for Kidney Disease; Renal Division, Nanfang Hospital, Southern Medical University, Guangzhou, China
Jiancheng Wang and Nengtai Ouyang are co-first authors.Xianhui Qin and Weiqing Huang contributed equally to this work.

  1. Funding Source: There was no funding source for this study. The corresponding author had full access to all the data used for this meta-analysis and takes full responsibility for the submission for publication.

  2. Conflict of Interest: On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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Published Online: 2017-12-29

© 2017 Jiancheng Wang, Nengtai Ouyang, Long Qu, Tengfei Lin, Xianglin Zhang, Yaren Yu, Chongfei Jiang, Liling Xie, Liping Wang, Zhigui Wang, Shuzhen Ren, Shizhi Chen, Jiang Huang, Fang Liu, Weiqing Huang, Xianhui Qin

This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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https://doi.org/10.1515/jtim-2017-0037
Keywords for this article
homocysteine; MTHFR gene A1298C polymorphism; MTRR gene A66G polymorphism; Meta-analysis
Creative Commons
BY-NC-ND 3.0

Articles in the same Issue

  1. Editorial
  2. Effects of portal vein thrombosis on the outcomes of liver cirrhosis: A Mexican perspective
  3. Commentary
  4. Breaking through restricting bottleneck for better asthma control
  5. Review Articles
  6. Timing of transjugular intrahepatic portosystemic shunt for Budd-Chiari syndrome: An Italian hepatologist’s perspective
  7. Review Articles
  8. Clinical value of ultrasonography in diagnosis of pulmonary embolism in critically ill patients
  9. Original Articles
  10. Comparative computed flow dynamic analysis of different optimization techniques in left main either provisional or culotte stenting
  11. Original Articles
  12. Endoscopic ultrasound-guided pancreatic pseudocyst drainage with lumen-apposing metal stents or plastic double-pigtail stents: A multifactorial analysis
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  14. Effect of MTHFR A1298C and MTRR A66G genetic mutations on homocysteine levels in the Chinese population: a systematic review and meta-analysis
  15. Original Articles
  16. Serum vitamin D levels in treatment-naïve chronic hepatitis B patients
  17. Case reports
  18. Urgent need to define Pretreatment predictors of immune check point inhibitors related endocrinopathies: A case report and review of literature
  19. Case reports
  20. Should vasoconstrictors be considered in a cirrhotic patient with acute non-variceal upper gastrointestinal bleeding?
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