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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 1101-1107

Assessment of N-terminal pro-brain natriuretic peptide level in chronic hepatitis C patients


1 Department of Clinical Biochemistry, National Liver Institute, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission16-Sep-2017
Date of Decision23-Oct-2017
Date of Acceptance29-Oct-2017
Date of Web Publication30-Sep-2020

Correspondence Address:
Shimaa M Hamad
Department of Clinical Biochemistry, National Liver Institute, Menoufia University, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_616_17

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  Abstract 


Objective
The aim of the study was to evaluate N terminal pro brain natriuretic peptide (NT-pro-BNP) level as a predictor of myocardial dysfunction in chronic hepatitis C (CHC) patients.
Background
Hepatitis C virus (HCV) infection represents a major health issue worldwide because of its burden of chronic liver disease and extrahepatic manifestations including cardiovascular diseases. Elevated NT-pro-BNP levels were observed in CHC, free of heart failure.
Patients and methods
This study was carried out on CHC patients (n = 45) (mean age: 45.6 ± 7.3 years) and sex-matched and age-matched healthy controls (n = 35). All participants were subjected to a full assessment of history, clinical examination, ECG and abdominal ultrasound, and FibroScan for cases. Blood samples were obtained for the HCV antibody, hepatitis B surface antigen, liver and renal function tests, fasting blood sugar, lipid profile, NT-pro-BNP, and HCV RNA quantification for cases.
Results
The NT-pro-BNP concentration of the CHC patients (mean: 120.6 ± 72.6 pg/ml) was significantly higher than that of the controls (mean: 36.1 ± 28.1 pg/ml) (P = 0.001). Eighty percent of the CHC patients had high NT-pro-BNP (>65 pg/ml; the cut-off value of NT-pro-BNP) and 28.9% of the CHC patients had high NT-pro-BNP (>125 pg/ml; the proposed cut-off value for heart failure <75 years of age). Multivariate analysis showed that chronic HCV infection was correlated independently with high NT-pro-BNP.
Conclusion
Our study suggests that chronic HCV infection is associated with increased NT-pro-BNP, indicating that it might induce myocardial dysfunction.

Keywords: amino-terminal pro-B-type or brain natriuretic peptide, chronic hepatitis C, hepatitis B surface antigen, hepatitis C virus, ribonucleic acid


How to cite this article:
Raouf AA, El-Shafie MK, Abd El-Hamed AK, Azzam AA, Hamad SM, Ghanem SE. Assessment of N-terminal pro-brain natriuretic peptide level in chronic hepatitis C patients. Menoufia Med J 2020;33:1101-7

How to cite this URL:
Raouf AA, El-Shafie MK, Abd El-Hamed AK, Azzam AA, Hamad SM, Ghanem SE. Assessment of N-terminal pro-brain natriuretic peptide level in chronic hepatitis C patients. Menoufia Med J [serial online] 2020 [cited 2020 Nov 26];33:1101-7. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/1101/296706




  Introduction Top


Globally, hepatitis C is a global public health problem, where about 71 million individuals suffer from chronic hepatitis C virus (HCV). Hepatitis C is prevalent worldwide. The most affected regions are WHO Eastern Mediterranean and European Regions, with a prevalence of 2.3 and 1.5%, respectively [1]. HCV, and its long-term resultant consequences, is a major endemic medical health problem in Egypt [2]. As expected, longitudinal cohort studies observed that chronic hepatitis C (CHC) patients have a high risk of liver-related morbidity and mortality, mostly because of progression toward liver cirrhosis and its complications [3]. However, growing evidence has led to a shift of HCV infection from the traditional picture of a localized disease affecting liver to the concept of a systemic disease capable of producing extrahepatic manifestations [4].

The myocardium may be the target of several types of viral infections. The importance of HCV infection has been noted in patients with hypertrophic cardiomyopathy, dilated cardiomyopathy, myocarditis, and left ventricular diastolic dysfunction [5]. HCV induces necroinflammatory activity locally in the liver and systemically including the cardiovascular system [4].

Amino-terminal pro-B-type natriuretic peptide (NT-pro-BNP) is a hormone that is secreted predominantly by the ventricles. It is synthesized in the heart as a reaction to cardiac wall distension and stretching, and neurohormonal activation. The cardiomyocytes synthesize a pre-pro-peptide (pre-pro-BNP, 134 amino acids), which is divided into a signal peptide and a pro-peptide (pro-BNP, 108 amino acids). During secretion from the cardiomyocytes, pro-BNP is split at a ratio of 1: 1 into the physiologically active BNP (32 amino acids), which corresponds to the carboxyl-terminal fragment, and the biologically inert N-terminal fragment (NT-pro-BNP, 76 amino acids) [6].

Assessment of circulating BNP and its more stable byproduct NT-pro-BNP is recommended by guidelines for the diagnosis and management of patients with heart failure [7]. NT-pro-BNP has emerged as an inexpensive candidate for population screening for heart failure and structural cardiac abnormalities [8].

However, few studies of the association between HCV infection and a high level of NT-pro-BNP have been reported [9].

The aim is to evaluate the level of NT-pro-BNP as a predictor of myocardial dysfunction in patients with chronic HCV infection.


  Patients and Methods Top


Patients

This study was carried out at Clinical and Medical Biochemistry, National Liver Institute, and Faculty of Medicine, respectively, Menoufia University. It included 80 individuals: 45 CHC patients and 35 age-matched and sex-matched apparently healthy individuals. The patients were selected from Outpatient Clinics of Hepatology Department, National Liver Institute, in the period from July 2015 to October 2015.

CHC patients were diagnosed by positive HCV antibody and detectable HCV RNA for more than 6 months. None of the patients had decompensated cirrhosis or cirrhosis identified by large esophageal varices, history of gastrointestinal bleeding, encephalopathy, or hepatocellular carcinoma, active alcohol consumption, positivity for hepatitis B virus surface antigen, chronic hepatitis because of autoimmunity or drug-induced liver disease, antiviral or corticosteroid therapy within the 12 months before inclusion, diabetes mellitus (DM), hypertension, and estimated glomerular filtration rate 60 ml/min/1.73 m 2, or proteinuria.

The participants studied were categorized into the following groups: CHC patients (n = 45, 22 men and 23 women). Their ages ranged from 25 to 60 years, with a mean age of 45.6 ± 7.3 years. Controls were selected on the basis of their health status: those without a clinical history and/or evidence of pre-existing heart disease, renal insufficiency, endocrine disease, liver disease, cancer, or a history of chronic use of medications such as glucocorticoids with normal blood pressure and ECG, and normal blood glucose. Healthy participants were recruited as controls (n = 35) (18 men and 17 women); their ages ranged from 22 to 65 years, with a mean age of 45.9 ± 7.4 years.

An informed written consent was obtained from every participant in this study and the study was approved by the Ethical Committee of Medical Research, Faculty of Medicine, Menoufia University.

Methods

All study participants were subjected to the following: full assessment of history, complete clinical examinations, ECG and abdominal ultrasound, laboratory investigations including liver function tests [(aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), γ-glutamyl transferase (γGT), total bilirubin, direct bilirubin, albumin, total protein], Kidney function tests (urea and creatinine), and fasting blood glucose using the Beckman Coulter AU480 (Beckman Coulter, Fullerton, California, USA). Lipid profile such as total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-c) was measured using standard enzymatic colorimetric kits (Spinreact, Girona, Spain) [10]. Serum low-density lipoprotein cholesterol (LDL-c) was calculated as TG levels not exceeding 400 mg/dl using the following formula: LDL-c = TC-TGs/5 − HDL-c [11]. Viral markers (hepatitis B surface antigen and HCV antibody were determined by electrochemiluminescence immunoassay 'ECLA' using a Cobase immunoassay analyzer (Roche Diagnostic, Berlin, Germany), quantification of HCV RNA levels for cases only using the RealTime HCV assay (Abbott Molecular Inc., Des Plaines, Illinois, USA), transient elastography (FibroScan®; Echosens, Paris, France) for cases only, and specific investigations including quantitative determination of human NT-pro-BNP in serum using the quantitative sandwich enzyme immunoassay technique.

Sample collection

Venous blood (10 ml) was withdrawn from every participant on the morning after at least a 12 h overnight fast and divided into two parts. The first part was collected in a serum separator tube, left to clot, and then centrifuged at 4000 rpm for 5 min for liver and kidney function tests, fasting blood glucose, and lipid profile. The second part was collected in another serum separator tube and left to clot for two hours at room temperature or overnight at 4°C before centrifugation for 20 min at ∼700 rpm and then the clear supernatant sera were separated from the sedimented red blood cells and stored in aliquot at −80°C (≤2 months) to avoid loss of bioactivity and contamination for the NT-pro-BNP immunoassay. In case of patient samples, an additional third part of the sample was collected in another serum separator tube and left to clot; then, the serum was separated within 24 h for an HCV RNA quantitative assay.

Statistical analysis

The data were analyzed using the statistical package for the social sciences (SPSS, version 20; SPSS Inc., Chicago, Illinois, USA) software on an IBM compatible computer. Quantitative data were expressed as mean ± SD and analyzed using a t- test for comparison between two groups of normally distributed variables, whereas for comparison between two groups of non-normally distributed variables, the Mann–Whitney test was applied. Qualitative data were expressed as number and percentage, and analyzed using χ2-test and Fisher's exact test. An receiver operating characteristic (ROC) curve was used to determine cut-off points, and sensitivity (%) and specificity (%) for quantitative variables of interest. Multivariate data analysis refers to any statistical technique used to analyze data that emerge from more than one variable. A P value of less than 0.05 was considered to be statistically significant.


  Results Top


The clinical characteristics of the participants are summarized in [Table 1]. No significant differences in age, sex, BMI, cholesterol, TG, LDL-c, and HDL-c were found between the HCV patients and the controls. [Figure 1] shows that the NT-pro-BNP concentration is significantly higher for the HCV patients (mean: 120.62 ± 72.602 pg/ml) than for the controls (mean: 36.11 ± 28.07 pg/ml) (P = 0.001). Using an ROC curve [Figure 2], the cut-off point of NT-pro-BNP at which sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80, 83, 86, 76, and 81%, respectively, was 65 pg/ml (data not shown). The patient group with chronic HCV infection (n = 45) was divided into two groups according to whether or not they had a high NT-pro-BNP level, more than 65 pg/ml. Nine patients had NT-pro-BNP 65 pg/ml or less and 36 patients had NT-pro-BNP more than 65 pg/ml. BMI and albumin were significantly lower in the NT-pro-BNP more than 65 pg/ml group than in the 65 pg/ml or less group (P = 0.01 and 0.027, respectively). No significant between-group differences were found in age, sex, ECG, TC, LDL, HDL, TG, ALT, AST, ALP, γGT, total protein, urea, creatinine, HCV RNA level, or liver fibrosis level [Table 2]. Multivariate analysis of independent parameters related to a NT-pro-BNP level more than 65 pg/ml, of all studied participants, identified HCV infection, BMI, albumin, and AST (P < 0.0001, 0.025, 0.004, and 0.036, respectively) [Table 3]. We also divided the patient group with chronic HCV infection according to whether or not they had a high NT-pro-BNP level, more than 125 pg/ml, the proposed cut-off value for heart failure [12],[13]. No statistically significant difference was found between the two groups [Table 4]. We also carried out a multivariate analysis to determine independent parameters for NT-pro-BNP level more than 125 pg/ml among HCV patients; however, none were found, including HCV RNA level or histology of liver biopsy (data not shown).
Table 1: Characteristics of patients with chronic hepatitis C virus infection and controls

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Figure 1: Comparison of the serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels of hepatitis C virus-positive patients and controls. Data are shown as box-and-whisker plots. The box indicates the lower and upper quartiles, and the central line is the median value: horizontal lines at the ends of vertical lines are the 2.5 and 97.5% values.

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Figure 2: Receiver operating characteristic (ROC) curve and diagnostic accuracy of N-terminal pro-brain natriuretic peptide.

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Table 2: Characteristics of patients with chronic hepatitis C virus infection with an N-terminal pro-brain natriuretic peptide concentration 65 pg/ml or less and more than 65 pg/ml

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Table 3: Multivariate analysis for independent parameters related to high N-terminal pro-brain natriuretic peptide more than 65 pg/ml among the studied groups

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Table 4: Characteristics of patients with chronic hepatitis C virus infection with N-terminal pro-brain natriuretic peptide concentration less than or equal to 125 pg/ml and more than 125 pg/ml

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  Discussion Top


HCV infection accounts for a high proportion of cases of chronic liver disease worldwide. Moreover, HCV has been reported to be associated with several extrahepatic manifestations. Therefore, HCV-infected individuals have increased risks of developing immune-related disorders, metabolic alterations, neurological/psychiatric disorders, and cardiovascular alterations [4]. In fact, it has been reported that HCV was replicated in myocardial tissue of patients with myocarditis; therefore, HCV infection may contribute toward the development of this unusual form of myocarditis [9]. NT-pro-BNP performs as a screening test for future clinical events and as a predictor of echocardiographic abnormalities among asymptomatic individuals [14].

The present study aimed to evaluate the level of NT-pro-BNP as a predictor of myocardial dysfunction in patients with chronic HCV infection.

The mean age of the participants in this study was nearly 45 years, with a narrow age span in both groups to minimize the influence of age on the NT-pro-BNP value. Previous studies showed a clear age-related increase in NT-pro-BNP concentrations that likely reflects age-related decreases in left ventricular compliance and glomerular filtration rate [15]. Our study found no significant difference in age between the patient and the control groups.

The present study showed no significant difference in the sex distribution between the patient group and the control group. This was in agreement with another study [14]. In this way, we could minimize the effect of sex on the NT-pro-BNP concentration because other studies [16] found that women had significantly higher concentrations of NT-pro-BNP than men.

The BMI range of the participants in our study was 24.58–28.08 for the patient group and 22.23–27.57 for the control group; thus, both groups did not include obese patients (BMI ≥30). The current study also found no significant difference between the patient and the control group in BMI. In this way, we could minimize the effect of BMI on the NT-pro-BNP concentration as the researchers have reported a consistent inverse relationship between obesity (defined as a BMI of ≥ 30) and circulating BNP and NT-pro-BNP levels [15],[17].

In the present study, there was a statistically significant difference between the patient and control groups in liver function tests, with a highly significant increase in ALT, AST, ALP, γGT, and total bilirubin in the patient group compared with the control group. These results are in agreement with the results of previous studies [14],[18],[19].

In our study, patients with renal impairment were excluded. NT-pro-BNP was at least partially cleared from the circulation by the kidney [16].

In the present study, there was no significant difference between the patient and the control group in the lipid profile. Therefore, adjustment of hyperlipidemia as a risk factor that may increase NT-pro-BNP was performed. Moreover, the patients with chronic HCV infection had a slightly more favorable lipid profile than the control group. This is in agreement with other studies [14].

In the present study, ECG abnormality was present in 15.6% of patients, 13.9% of patients with NT-pro-BNP more than 65 pg/ml, and 23% of patients with NT-pro-BNP higher than 125 pg/ml. None of the studied participants had ECG changes suggestive of ischemic, valvular, and hypertensive heart disease. A previous study reported that an abnormal ECG was found only in 9% of the patients with CHC [20].

In the present cross-sectional study, it was found that the NT-pro-BNP levels of anti-HCV-positive patients were significantly higher than those of the anti-HCV-negative controls [Figure 1]. This is in agreement with other studies [2],[9],[14],[21]. Several studies used NT-pro-BNP as a biomarker of heart disease and concluded that NT-pro-BNP is a more sensitive marker of myocardial injury than cardiac troponins in patients with HCV myocarditis [14],[21],[22]. In addition, NT-pro-BNP is an independent predictor of cardiovascular events in the general population [23].

In the current study, as indicated from the ROC curve analysis, the best cut-off value of NT-pro-BNP was 65 pg/ml [Figure 2]. At this cut-off value, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 80, 83, 86, 76, and 81%, respectively (data not shown).

The present study found a significant reduction of albumin in the high NT-pro-BNP (>65 pg/ml) group. Previous studies showed that the more the liver inflammation, the more likely the cardiovascular effects of cardiac chamber enlargement and left ventricular diastolic dysfunction [19]. A combination of factors including cytokine levels, increased inflammation markers (such as low albumin, high globulin, high Erythrocyte sedimentation rate (ESR), etc.), thrombosis, endothelial dysfunction, behavioral, and social risk factors such as alcohol abuse, smoking, malnutrition, and liver problems are likely to be the reasons why patients with hepatitis C have an increased risk of cardiovascular disease [24],[25].

The present study found a significant reduction of BMI in the patient group with an NT-pro-BNP concentration more than 65 pg/ml. This was in consistent with the findings reported by other study [15].

HCV infection, BMI, AST, and albumin independently showed significant relationship to high NT-pro-BNP according to the cut-off value of 65 pg/ml in all study participants through multivariate analysis [Table 3]. A previous study showed a statistically significant increase in AST and ESR levels in HCV seropositive patients with dilated left atrium [19]. A previous study showed that multivariate analysis of independent parameters related to high NT-pro-BNP of all study participants included BMI and chronic HCV infection after adjustment of DM, hypertension, and hyperlipidemia that might increase the NT-pro-BNP concentration [14].

The present study showed no significant influence of HCV RNA levels and liver fibrosis levels on high NT-pro-BNP levels (>65 and >125 pg/ml). This is in agreement with previous studies that showed no significant influence of HCV RNA levels and histology of liver biopsy on high NT-pro-BNP levels as a sensitive marker of myocardial dysfunction [14],[26]. The immune reaction toward HCV varies; thus, the difference might be caused by individual immune responses.

In contrast, previous studies [20],[27] found a direct link between HCV RNA viral load and liver necroinflammatory activity and myocardial injury, suggesting that the proinflammatory and profibrogenic environment leading to fibrogenesis in the liver of patients infected with HCV may also be systemically activated, further enhancing the development of cardiovascular lesions.

There is now a general agreement of a 'rule-out' value of 125 pg/ml for patients younger than 75 years of age suspected of suffering from heart failure in outpatient evaluations and 450 pg/ml for patients 75 years of age or older [12],[13].

In the present study, all participants were younger than 75 years of age, and it was found that 28.8%of the anti-HCV-positive patients had a high value (125pg/ml), whereas none of the anti-HCV-negative controls had this value. Multivariate analysis for risk factors to determine independent parameters related to NT-pro-BNP level more than 125 pg/ml among HCV patients, none were extracted, including HCV RNA level and histology of liver biopsy (data not shown).

This suggests that HCV infection influences cardiac function asymptomatically and that testing for NT-pro-BNP would be useful in identifying patients in an asymptomatic state of cardiac failure. Similar data were obtained from a previous study that found that 18% of the anti-HCV-positive patients had a high value (125 pg/ml), whereas only 1% of the anti-HCV-negative controls had this value [14].

The present study was limited by the small sample size of 80 participants, certain tests such as echocardiography and myocardial biopsy could not performed because of lack of facilities and expertise, the NT-pro-BNP and lipid parameters were measured only once, and thus could reflect random fluctuations and intraindividual variations, and subclinical infection with other viruses could cause elevations in NT-pro-BNP, which would increase the variability in this measure because of lack of facilities.

Finally, in the light of the future availability of very effective and nontoxic therapeutic strategies against HCV infection, these data, if conclusively confirmed, could also lead to treatment of HCV infection not only to repair liver damage but also to reduce extrahepatic and cardiovascular complications.


  Conclusion Top


Our study suggests that chronic HCV infection is associated with increased NT-pro-BNP after exclusion of DM and hypertension, indicating that chronic HCV infection might induce myocardial dysfunction. An accurate evaluation of myocardial function is advisable in all HCV-infected patients.

Acknowledgements

This study was funded by National Liver Institute, Menoufia University.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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