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ORIGINAL ARTICLE
Year : 2017  |  Volume : 30  |  Issue : 4  |  Page : 1226-1231

Role of homocysteine in patients with hepatorenal syndrome


1 Department of Tropical Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
3 Internal Medicine Department, El-Menshawy Hospital, Tanta, Gharbia, Egypt

Date of Submission30-Apr-2017
Date of Acceptance22-Aug-2017
Date of Web Publication04-Apr-2018

Correspondence Address:
Mohamed H Elsbaey Elseady
Basyon, Gharbia Government
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_326_17

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  Abstract 


Objective
The aim of this study was to investigate the role of homocysteine (Hcy) in patients with hepatorenal syndrome (HRS).
Background
Hcy increases in cirrhosis than in noncirrhotic liver diseases. Hyperhomocysteinemia is correlated with the clinical course of liver disease and is characteristically detected at late stages of cirrhosis.
Patients and methods
A total of 78 patients and 20 controls were divided into four groups. Group 1 included 28 cirrhotic patients without ascites. Group 2 included 25 cirrhotic patients with ascites. Group 3 included 25 patients with HRS. Group 4 included 20 healthy participants as a control group. Liver and kidney function tests, complete blood count, viral marker analysis, evaluation of serum Hcy using enzyme-linked immunosorbent assay, and renal duplex ultrasonography were carried out.
Results
Patients with liver cirrhosis showed significantly higher serum Hcy levels in comparison with controls. Positive correlations were found between Hcy and age, child classification, model for end-stage liver disease score, creatinine level, and renal resistive index (RRI), whereas serum Hcy was negatively correlated with creatinine clearance. Hcy at a cutoff value of more than 17 micromol/l could predict patients with HRS with 89% sensitivity and 80% specificity.RRI at cutoff value of more than 0.75 could predict patients with HRS with 85% sensitivity and 80% specificity. The sensitivity was 94%, and accuracy was 87%, when Hcy and RRI were estimated together in patients with HRS.
Conclusion
Hcy can be considered as a predictive marker for patients with HRS.

Keywords: biomarkers, hepatorenal syndrome, homocysteine, liver cirrhosis


How to cite this article:
El-Deeb GS, El-Hamouly MS, Shehata AM, Elsbaey Elseady MH. Role of homocysteine in patients with hepatorenal syndrome. Menoufia Med J 2017;30:1226-31

How to cite this URL:
El-Deeb GS, El-Hamouly MS, Shehata AM, Elsbaey Elseady MH. Role of homocysteine in patients with hepatorenal syndrome. Menoufia Med J [serial online] 2017 [cited 2020 Jun 6];30:1226-31. Available from: http://www.mmj.eg.net/text.asp?2017/30/4/1226/229217




  Introduction Top


Homocysteine (Hcy) is a sulfur-containing amino acid that serves as an intermediate in methionine metabolism[1]. Hyperhomocysteinemia (HHcy) is defined as abnormally high level of Hcy in the blood (>15 μmol/l)[2].

Hepatorenal syndrome (HRS) is reversible impaired renal function that occurs in patients with late stages of liver cirrhosis or in those with fulminant hepatic failure. It is characterized by a marked decrease in the glomerular filtration rate and renal plasma flow in the absence of other causes of kidney failure[3]. The early stages of HRS may be unrecognized because of the late occurrence of creatinine elevation in the HRS[4]. Without treatment, the median survival time of type 1 h is less than 2 weeks and for type 2 h about 6 months[5].

The liver has a fundamental role in methionine and Hcy metabolism. Therefore, liver dysfunction may influence the metabolism of both methionine and Hcy[6]. An Hcy level increase in cirrhosis than in noncirrhotic liver disease and HHcy is correlated with the prognosis of liver disease[7].

HHcy occurs in cirrhosis because of the impairment of trans-sulfuration and remethylation. In cirrhotic patients, increased serum creatinine levels were associated with elevated serum Hcy levels[8]. Increased Hcy level augments the oxidant stress and DNA damage and increases liver cell apoptosis and, thus, contributes to liver fibrosis[9].

One of the most important functions of the kidney is the metabolism and clearance of amino acids. The presence of specific Hcy-uptake mechanisms and Hcy-metabolizing enzymes in the kidney suggests that the kidney has a role in Hcy metabolism[10].

Impairment of kidney function is remarkably observed in patients with advanced liver disease[11]. Renal dysfunction is often underestimated in cirrhotic patients; glomerular filtration rate may be very low whereas serum creatinine levels are still within the reference range because of muscle-mass reduction in these patients. Similarly, blood urea nitrogen levels are an unreliable indicator of kidney function in cirrhotic patients as they can be affected by many factors such as gastrointestinal bleeding and the amount of protein intake in the diet[12].

The aim of the study was to investigate the role of Hcy in patients with HRS to select the category of patients at a high risk for developing renal failure.


  Patients and Methods Top


This study included 78 patients (49 male and 29 female; their ages ranged from 39 to 64 years) with liver cirrhosis who were selected from Tropical Medicine Department, Faculty of Medicine, Menoufia University, between February 2016 and September 2016.

Patients were eligible for this study if they were diagnosed with liver cirrhosis along with chronic hepatitis C virus (HCV) infection. The detection of anti-HCV antibodies and HCV RNA was used to confirm the diagnosis of HCV infection. Diagnosis of liver cirrhosis was based on clinical presentation, biochemical tests, and ultrasonography (US). Exclusion criteria of the patients were having obstructive uropathy, nephrotic syndrome, nephritic syndrome, diabetic nephropathy, diabetes, and hypertension. Liver disease severity was evaluated using Child–Pugh score.

In addition, 20 healthy, age-matched and gender-matched participants were involved in this study as a control group.

The study population was divided into four groups. Group 1 included 28 (15 male and 13 female; aged 40–55 years) cirrhotic patients without ascites. Group 2 included 25 (16 male and nine female; aged 39–62 years) cirrhotic patients with ascites. Group 3 included 25 (18 male and seven female; aged 43–64 years) patients with HRS. Group 4 included 20 (11 male and nine female; aged 23–60 years) healthy participants as a control group.

Patients and controls signed informed consent forms before participation and study approval was obtained from the ethical committee of the Faculty of Medicine, Menoufia University.

Complete history taking, clinical examination, and certain laboratory investigations were carried out for both cases and controls.

The laboratory tests included complete blood count, which was performed using automated CELL-DYN Ruby hematology analyzer (Abbott Diagnostics, Abbott Park, Illinois, USA); and prothrombin time was measured using STA Compact coagulometer (Diagnostica Stago, Asnieres, France). Liver and renal function tests were performed using AU480 Beckman Coulter analyzer (Beckman Coulter Inc, Brea, California, USA), viral markers were assessed using mini VIDAS immunoanalyzer (bioMérieux, Marcy L'Etoile, Craponne, France), and serum Hcy level was determined using enzyme-linked immunosorbent assay (Wkea Med Supplies Corp, Changchun, China) as described by the manufacturer.

Imaging studies were used for the assessment of patients and included abdominal US using equipment with color Doppler capability using convex linear (2.8–5 MHz) transducer (General Electric LOGIQ P6 device GE Healthcare, Little Chalfont, United Kingdom). The renal resistive index (RRI) was automatically calculated by the US equipment[13].

Statistical analysis

Data were expressed in the form of range, mean, and SD for continuous quantitative variables, whereas numbers and percentages were used for the description of qualitative variables. Categorical data were compared using the χ2-test. Analysis of variance test was used for comparing multiple groups of normally distributed quantitative data. In the two-group comparison of normally distributed quantitative data, the Student t-test was used. Pearson's correlation test was used to examine possible correlations between variables. Analyses were done in statistical package for social science (version 20; IBM SPSS, Armonk, New York, USA). P value of less than 0.05 was considered statistically significant.


  Results Top


The study populations were divided into four groups. Group 1 included 28 cirrhotic patients without ascites. Group 2 included 25 cirrhotic patients with ascites. Group 3 included 25 patients with HRS. Group 4 included 20 healthy participants as a control group.

A statistically significant difference was found between the studied groups as regards age (P = 0.001), Child–Pugh classification in cirrhotic patients (P = 0.012), model for end-stage liver disease (MELD) score of cirrhotic patients (P = 0.001), serum Hcy levels (P = 0.001), serum albumin (P = 0.001), serum creatinine (P = 0.001), and creatinine clearance (P = 0.001) [Table 1].
Table 1: Clinical, biochemical, and renal resistive index characteristics of the studied groups

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Serum Hcy concentrations in group 3 (17.91 ± 1.10 μmol/l) were significantly higher than those in group 2 (15.74 ± 1.51 μmol/l) (P< 0.001); and Hcy concentrations in group 2 were significantly higher than those in group 1 (9.08 ± 1.64 μmol/l) (P< 0.001). A statistically significant difference between the studied groups was observed with respect to the RRI (P = 0.001) [Table 1].

There was statistically significant difference between patients with Child A, B, and C, as regards serum Hcy levels (P = 0.001). Serum Hcy concentrations were as follows: Child class-A patients, 8.25 ± 0.89; range: 6.8–10 μmol/l; class-B patients, 13.53 ± 2.16; range: 9.5–16.5 μmol/l; and class-C patients, 17.81 ± 1.05; range: 14.5–19 μmol/l [Table 2].
Table 2: Relation between serum homocysteine level and Child-Pugh classification of patient groups

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Receiver operating characteristic (ROC) curve of Hcy level in the studied patients showed the following:

For a Hcy concentration at cutoff value more than 17 micromol/l, the sensitivity was 89%, specificity was 80%, the PPV was 90%, NPV was 77% and accuracy was 86%. [Figure 1].
Figure 1: Receiver operating characteristic curve of homocysteine level of the studied patients.

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ROC curve of RRI showed that RRI at cutoff value more than 0.75, the sensitivity was 85%, specificity was 80%, PPV was 90%, NPV was 71%, and accuracy was 83%. [Figure 2].
Figure 2: Receiver operating characteristic curve of renal resistive index of the studied patients.

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ROC curve of Hcy after adding RRI showed that the sensitivity was 94%, specificity was 72%, the PPV was 88%, NPV was 86%, and accuracy was 87%. [Figure 3].
Figure 3: Receiver operating characteristic curve of homocysteine after adding renal resistive index of the studied patients.

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In the studied groups 1, 2, and 3, a positive correlation was found between serum Hcy level and the age of patients (r = 0.927 P = 0.001; r = 0.930, P = 0.001; r = 0.448, P = 0.032, respectively), the severity of liver disease as assessed by Child–Pugh classification (r = 0.792, P = 0.001; r = 0.861, P = 0.001; r = 0.687, P = 0.001, respectively) and MELD score (r = 0.663, P = 0.001; r = 0.460, P = 0.021; r = 0.811, P = 0.001, respectively), serum creatinine (r = 0.557, P = 0.002; r = 0.529, P = 0.017; r = 0.858, P = 0.001, respectively) and the RRI (r = 0.953, P = 0.001; r = 0.957, P = 0.001; r = 0.779, P = 0.001, respectively), whereas a negative correlation was observed between serum Hcy level and creatinine clearance (r=−0.921, P = 0.001; r=−0.887, P = 0.001; r=−0.660, P = 0.001, respectively). No correlations were found between serum Hcy and the serum level of sodium and prothrombin time [Table 3].
Table 3: Correlations between serum homocysteine levels and various parameters

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  Discussion Top


In the current study serum Hcy level was significantly increased in patients of group 1, group 2, and group 3 in comparison with the control group. The serum Hcy concentration was positively correlated with the severity of liver disease as expressed by higher Child–Pugh and MELD scores. Further, the serum Hcy level was significantly higher in patients with child C than was its level in child B patients, and in patients with child B was higher than in patients with child A. Other studies reported the same result [7],[14],[15],[16].

Bhanji et al.[17], demonstrated that HHcy was associated with the severity of cirrhosis, reflected by higher Child–Pugh and MELD scores. They attributed this to the effects of HHcy on endothelial cellular damage, reduction in nitric oxide (NO) and decreased vasodilation in the liver.

Our findings were also in agreement with those from a study carried out by García-Tevijano et al.[18], who observed an increased level of Hcy in patients with liver cirrhosis and explained that based on the reduction of expression of the main genes concerned with Hcy metabolism. They also reported that the severity of liver disease was associated with decreased expression of these genes.

These data were also partially in consistency with a study performed by Woitas et al.[19], who found significantly higher Hcy concentrations in cirrhotic patients than in the controls, whereas in contrast to the current study, Woitas et al.[19] found a nonsignificant correlation between Hcy concentration and the severity of liver disease.

The current study results were similar to the results of Culafić et al.[20] who found that the mean plasma Hcy levels were much higher in the patients with cirrhosis than in healthy controls and reported that, in liver cirrhosis, the occurrence of homocysteinemia was multifactorial, affected significantly by decreased catabolic function of the liver.

The elevated Hcy level seen in liver cirrhosis might be caused by tissue damage, which increases Hcy leakage[6]. Alterations of Hcy level in liver cirrhosis is not attributed to plasma levels of cofactors of Hcy metabolism in spite of the disturbed metabolism of these cofactors in liver cirrhosis[8].

The result of this study demonstrates that HHcy was associated with the presence of ascites. Bhanji et al.[17] reported the same result and they attributed this to the aggravation of portal hypertension secondary to impaired vasodilatation and impaired (NO) synthesis caused by HHcy.

The results of the current study showed a significant positive correlation between Hcy level and the age of the patients. Other studies reported the same result [14],[17],[21].

In this study, a significant positive correlation was found between serum Hcy level and serum creatinine. This was in agreement with multiple studies [7],[8],[14],[15],[16],[17],[18],[19],[20],[21],[22] that found cirrhotic patients with elevated creatinine concentrations to have significantly higher Hcy concentrations.

The current study demonstrated negative correlation between serum Hcy level and calculated creatinine clearance; these results were in consistency with the results reported by Molęda et al.[23].

In the present study, the ROC curves for serum Hcy concentration were used to discriminate between patients with HRS from cirrhotic patients. The plasma Hcy threshold for the prediction of HRS was more than 17 micromol/l. For this value, the sensitivity and specificity values were 89 and 80 % respectively. Acurracy was 86%, PPV was 90%, and NPV was 77%.

Both sensitivity and accuracy values showed that this cutoff value can be considered a good predictive point for discrimination of HRS from cirrhotic patients with or without ascites.

There are no other previous studies that demonstrate alteration of Hcy concentration in HRS and determine Hcy level for prediction of HRS. However, Fridman[10] studied Hcy metabolism in patients with normal kidneys as well as in patients with chronic renal failure and concluded that the cause of HHcy in kidney disease is not yet understood, although decreased clearance of plasma Hcy is the most acceptable cause.

The decrease in Hcy plasma clearance and metabolism were attributed to decrease in functioning renal tissue. Another hypothesis demonstrated unknown inhibitory uremic substances that had a role in the prevention of normal extrarenal Hcy metabolism[10].

This study showed that the RRI was significantly high in all patient groups in comparison with the control group. The RRI was significantly high in patients of group 3 than in those of group 2 and group 1, and the RRI was significantly high in group 2 than in group 1. ROC curve of RRI showed that for RRI at a cutoff value more than 0.75, the sensitivity was 85%, and specificity was 80%, also, the PPV was 90%, NPV 71%, and the accuracy 83%; similar results were reported by Ghandour and Arnaout[24].

Comparing these results with that of Hcy, we noticed that Hcy was better as regards sensitivity 89% and accuracy 86%.

ROC analysis of Hcy after adding RRI showed that sensitivity was 94%, NPV was 86%, and accuracy was 87%, which were better than those from using either test alone.


  Conclusion Top


Serum Hcy level was significantly high in patients with HRS compared with cirrhotic patients and serum Hcy concentration was correlated with the severity of liver disease. Hcy level can predict development of HRS at a cutoff value more than 17 micromol/l. For this value the sensitivity and specificity values were 89 and 80% respectively.

Hcy is good and specific predictive tool than renal duplex study for HRS development in patients with hepatic cirrhosis.

The combined use of Hcy and RRI in patients with HRS is recommended for better prediction of HRS development in patients with hepatic cirrhosis than using either test alone.

Further studies are recommended to investigate the possible relationship between serum Hcy level and the survival of patients with HRS.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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