|Year : 2014 | Volume
| Issue : 2 | Page : 458-464
Study of microvascular complications of chronic hepatitis C virus in nondiabetic patients
Nabil Abd El Fatah Al kafrawy1, Mahmoud Abd El-Aziz Kora1, Ashraf Gharib Dala1, Walaa Khalil Mohamed Ali Sultan2
1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Shebin El-Kom Educational Hospital, Menoufia, Egypt
|Date of Submission||19-Mar-2013|
|Date of Acceptance||23-Jun-2013|
|Date of Web Publication||26-Sep-2014|
Walaa Khalil Mohamed Ali Sultan
MBBCh, Arab EL-Raml, Qwesna, Menoufia
Source of Support: None, Conflict of Interest: None
To study the relationship between chronic hepatitis C infection and microvascular complications in nondiabetic individuals.
Several extrahepatic manifestations have been reported in the natural history of hepatitis C virus (HCV) infection. Further, extrahepatic manifestation syndromes could represent the first signal of an HCV infection, as many patients show no hepatic symptoms. As known microvascular complications of diabetes include neuropathy, nephropathy and retinopathy, this study was conducted to evaluate the effect of chronic HCV infection on microvascular complications in nondiabetic patients.
Subjects and methods
Fifty patients with chronic hepatitis C infection were enrolled. All were subjected to full clinical assessment including routine blood tests, fasting and 2 h postprandial blood glucose, HbA1c, HCV-RNA PCR, urinary albumin concentration indicating the presence of microalbuminuria, liver biopsy and fundus examination.
Microalbuminuria was diagnosed in five patients (10%) with chronic hepatitis C, whereas 15 patients (30%) had peripheral neuropathy as diagnosed by clinical examination; no retinopathy was diagnosed in these patients. Peripheral neuropathy correlated with age, HCV viremia and stages of liver biopsy.
Patients with chronic HCV infection had a high incidence of developing microalbuminuria (10%), a very high incidence of developing peripheral neuropathy (30%) and no incidence of developing retinopathy (zero%). Age, the HCV-RNA level and liver fibrosis are prominent risk factors for the occurrence of peripheral neuropathy in chronic HCV-infected patients.
Keywords: Chronic hepatitis C, microalbuminuria, peripheral neuropathy, retinopathy
|How to cite this article:|
Al kafrawy NA, Kora MA, Dala AG, Ali Sultan WK. Study of microvascular complications of chronic hepatitis C virus in nondiabetic patients. Menoufia Med J 2014;27:458-64
|How to cite this URL:|
Al kafrawy NA, Kora MA, Dala AG, Ali Sultan WK. Study of microvascular complications of chronic hepatitis C virus in nondiabetic patients. Menoufia Med J [serial online] 2014 [cited 2019 Dec 7];27:458-64. Available from: http://www.mmj.eg.net/text.asp?2014/27/2/458/141727
| Introduction|| |
Hepatitis C virus (HCV) is a parenterally transmitted, hepatotropic and lymphotropic RNA virus. More than 170 million people worldwide are chronically infected with HCV . In high-endemic areas such as Egypt and southern Italy, local prevalence may reach 30% . In Egypt, genotype 4 constitutes 73.3% of all HCV-positive cases . HCV infection is the most common cause of chronic liver disease, and it accounts for 50% of all primary liver cancers . HCV viremia has been known to provoke a plethora of autoimmune syndromes that have been referred to as extrahepatic manifestations (EHMs), which affect 40-70% of patients with chronic HCV infection, mainly mixed cryoglobulinemia (MCG) [5-7]. About 50-80% of patients with essential MCG are infected with HCV and up to 50% of patients with hepatitis C infection have MCG . In HCV/MCG patients, clinical involvement is mainly characterized by purpura, arthralgias, kidney disease and peripheral neuropathy (PN) .
Neurological complications in HCV-infected patients occur predominantly in the peripheral nervous system. Their prevalence varies, and can be as high as 50% of cases and is primarily associated with MCG . Peripheral nervous system involvement has also been reported in HCV-infected patients without MCG ,. The pathophysiology of HCV-related PN remains largely speculative; vascular deposition of HCV-RNA-containing cryoglobulins (CGs), direct viral infection or perivascular mononuclear inflammatory cells may be at the origin of HCV-associated inflammatory vascular lesions. However, it is likely that HCV neuropathy results from virus-triggered immune-mediated mechanisms rather than from direct nerve infection and in-situ replication . Recent evidence suggests that direct autoantibody reactions may play at least an additional role in affecting neuronal structures . Within humoral autoimmunity to neuronal antigens, serum antiganglioside antibodies have been found in several central and peripheral neurological diseases and autoimmune disorders .
HCV is a significant cause of glomerulopathy in countries with a high prevalence of HCV infection . Several studies have postulated a causal link between HCV infection and renal disease through the induction of cryoglobulinemia . The affinity for the kidney mesangium appears to be a major factor responsible for the precipitation of type II mixed CGs in glomerular structures and the ensuing damage . The principal clinical manifestations of glomerular disease in HCV-infected patients are the presence of protienuria and microscopic hematuria with or without impaired kidney function . However, unlike nephropathy and neuropathy, retinopathy is not known to be one of extrahepatic complications of HCV and platelet adhesion seems to be more important in the pathogenesis of retinopathy (microvascular occlusion, neovascularization and the progression of retinopathy) than in other microvascular complications.
| Aim of the work|| |
To determine the relationship between chronic hepatitis C (CHC) infection and microvascular complication in nondiabetic individuals.
| Patients and methods|| |
This study was carried out on 50 newly diagnosed, treatment-naive HCV infection patients (28 male and 22 female) with a mean age of 36.1 ± 10.7 years. Patients were selected from those being evaluated for antiviral therapy at the Outpatient Clinics of the Internal Medicine department of Shebin El-kom Teaching Hospital, Egypt. Oral approval for patients and approval of the ethics committee in the hospital were obtained before conducting this research.
(a) HCV-RNA-positive patients by PCR; (b) patients who did not receive any treatment for HCV infection.
Patients with advanced liver disease, concurrent hepatitis B or HIV infections, chronic renal disease or a history of dialysis, systemic hypertension, diabetes, obesity, SLE, heart failure, pregnancy, convulsions and other causes of microalbuminuria were excluded from the study.
Patients were subjected to general examination with special attention to hepatic and EHMs of HCV infection. A diagnosis of clinical neuropathy was made when symptoms (weakness, sensory disturbances) and signs (weakness, atrophy, sensory abnormalities and/or reduced/absent tendon reflexes) of peripheral sensory and/or motor and cranial involvement were present .
Laboratory studies included a complete blood picture , fasting and 2 h postprandial blood glucose, the HbA1C level , liver function tests (alanine transaminase, aspartate transaminase, serum albumin, international normalized ratio, bilirubin) , serum creatinine  and a urinary albumin concentration test in a random urine specimen with a cutoff point of 20 mg/l indicating the presence of microalbuminuria .
The quantitative HCV-RNA test is based on the PCR technique and has a lower limit of detection of fewer than 100 copies of HCV-RNA per ml of serum (50 IU/ml). It was classified into weak (100-100 000), moderate (100 000-1 000 000) and high (>1 000 000) .
Liver specimens were obtained from patients for histopathological examination to confirm diagnosis, to exclude other causes and to determine the stage of fibrosis and the grade of inflammation using the metavir score .
Fundus examination was performed by an ophthalmologist.
The data collected were tabulated and analyzed by statistical package for social science, version 17.0 on an IBM compatible computer.
Two types of statistics were performed:
Descriptive statistics: For example percentage (%), mean (X) and SD.
- The c2 was used to study the association between two qualitative variables.
- The Fischer exact test for 2 × 2 tables was used when the expected cell count of more than 25% of the cases was less than 5 and P-value less than 0.05 was considered significant. Quantitative data were presented as mean and SD. Qualitative data were presented as frequency and its related percentage.
- The t-test (Student's test) was used for comparison of quantitative variables between two independent groups.
- The one-way analysis of variance test was used for comparison of quantitative variables among more than two independent groups. Least significant difference from the post-hoc test was used to analyze the significance between each of the two groups.
- The Mann-Whitney test (nonparametric test) is a test of significance used for comparison between two groups not normally distributed having quantitative variables.
P-value greater than 0.05 is insignificant (NS); P-value up to 0.05 is significant (S).
| Results|| |
Sociodemographic characteristics, laboratory findings and results of liver biopsy of the study patients are shown in [Table 1] as follows: The mean age was 36.1 ± 10.7 years in the study group. The mean BMI was 26.8 ± 3.6 kg/m 2 in the study group. According to the sex, there were 28 (56%) male patients and 22 (44%) female patients in the study group.
|Table 1: Sociodemographic characteristics, laboratory findings and liver histopathology of the study group|
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The mean alanine transaminase level was 51.5 ± 39.0. The mean aspartate transaminase level was 45.3 ± 25.0. The mean total bilirubin level was 0.92 ± 0.39. The mean direct bilirubin level was 0.36 ± 0.22. The mean international normalized ratio level was 1.11 ± 0.11. The mean serum albumin level was 4.5 ± 1.3. The mean serum creatinine was 0.81 ± 0.18. The mean HCV-RNA PCR was 660 565 ± 919 944. The mean hemoglobin concentration was 13.5 ± 2.2. The mean white blood cell count was 6030.0 ± 1374.9. The mean platelet count was 207.1 ± 62.5.
According to the metavir score, the staging of fibrosis was 22/50 patients (44%) (score F1/4) (mild fibrosis),18/50 patients (36%) (score F2/4) (moderate fibrosis), 9/50 patients (18%) (score F3/4) (severe fibrosis) and 1/50 patients (2%) (score F4/4) (cirrhotic). The grading of inflammation activity was 17/50 patients (34%) (score A1/3) (mild inflammation), 31/50 patients (62%) (score A2/3) (moderate inflammation) and 2/50 patients (4%) (score A3/3) (severe inflammation).
The number and the percent distribution of PN, microalbuminuria and retinopathy in the study patients are shown in [Table 2] as follows: Clinical PN was diagnosed in 15 patients (30%): all of them with sensory manifestations, and no motor manifestation or cranial nerve affection. The number of patients with no neurological deficit (symptoms or signs) was 35 (70%), microalbuminuria (+ve) was diagnosed in five patients (10%). Microalbuminuria (−ve) was diagnosed in 45 patients (90%), no retinopathy was found in the study group.
|Table 2: The number and percent distribution of peripheral neuropathy, microalbuminuria and retinopathy in the study groups|
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Comparison between PN-positive and PN-negative cases regarding their sociodemographic characteristics, laboratory findings and liver biopsy of the study patients are shown in [Table 3] as follows: The mean age was significantly higher in PN-positive cases (43.9 ± 9.7 years) compared with PN-negative cases (32.8 ± 9.4 years) with a significant difference between them (P = 0.001), and no significant difference between the two study groups according to the sex or the BMI and laboratory findings; liver biopsy shows a significantly increased stage of liver fibrosis in PN-positive patients.
|Table 3: Comparison between peripheral neuropathy-positive and peripheral neuropathy-negative cases regarding their sociodemographic characteristics, laboratory findings and liver histopathology of the study groups|
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| Discussion|| |
Hepatitis C is a disease with a significant global impact. According to the WHO, there are 130-170 million people infected with the HCV, corresponding to 2-2.5% of the world's total population. There are considerable regional differences. In some countries, for example, Egypt, the prevalence is as high as 22% (WHO, 2011). Around 30-40% of patients with CHC have an EHM of HCV . The aim of the present study was to evaluate the effect of chronic HCV infection on the microvascular complications in nondiabetic patients. We conducted this study to examine the relationship between nondiabetic individuals with hepatitis C infection and microalbuminuria.
HCV is known to have a wide variety of manifestations in the kidney. The renal manifestations of HCV include direct effects on the kidney, such as membranous nephropathy, cryoglobulinemia and membranoproliferative glomerulonephritis. This EHM is either related to intrinsic renal disease or cryoglobulinemia.
In the current study, miroalbuminuria was found to be an early predictor of nephropathy in 5/50 patients positive for microalbuminuria (10%). Liangpunsakul and Chalasani  found that the prevalence of miroalbuminuria in patients with hepatitis C infection was 12.4% and older patients and African Americans were independently associated with microalbuminuria in nondiabetic hepatitis C patients. In this study, the incidence of microalbuminuria was close to our results; in the current study it was found that the HCV-RNA level showed a moderate to high viremia in all patients with positive microalbuminuria.
Previous studies have shown that in persons with HCV infection, a higher incidence of microalbuminuria and proteinuria did occur in CHC patients than in those with other forms of liver disease . These studies showed that HCV infection was an independent significant factor associated with proteinuria, and this significance remained even after excluding those diabetic patients; other risk factors of proteinuria also demonstrated the consistent and significant association between HCV infection with both chronic kidney disease prevalence and chronic kidney disease severity.
The infection may be associated with other extrahepatic manifestations such as PN. A subacute, distal sensory, motor polyneuropathy frequently associated with CG is the most common neurological complication, but mono and multiple mononeuritis have also been reported . The present study was designed to assess clinically the prevalence of PN in an unselected, untreated referral HCV population and the correlation between PN and patients' age, sex and the level of HCV viremia.
In the current study, we found that clinical PN was diagnosed in 15 out of 50 HCV-infected patients (30%). The high prevalence of clinical PN among our patients is close to that reported by Cacoub et al. , which was up to 50%. Meanwhile, it was not consistent with previous Egyptian studies. The highest prevalence of PN among Egyptian HCV patients was found in a study by Manal et al. , as clinical PN was diagnosed in 36 out of 80 patients (45%). All of them had electrophysiological evidence of PN. Moreover, electrophysiological examination disclosed a subclinical PN in 18 additional patients (22.5%). In total, 54 patients (67.5%) were diagnosed to have neuropathy by electrophysiological examination in this study, followed by 30% reported by Abul Hassan et al. ,followed by 15.63% in the study of El Ghoneimy et al.  and 10% in the study of Abo Al-Soud et al. . In western countries, Gomes et al.  reported a PN prevalence of 34.6%, whereas other studies reported a prevalence up to 10.6% [36-38]; all of our patients showed sensory PN, and this agrees with Manal et al.  who found that PN was clinically diagnosed in 45% of the HCV patients; 42.5% showed sensory PN, and this also agrees with Sterling and Bralow  who demonstrated that sensory deficiencies are more common than motor loss, and that sensory symptoms may persist for months to years before any motor deficits become clinically evident.
PN was present in 8/15 patients with age greater than 40 years, and this agrees with Frank et al.  who reported an increased prevalence of HCV with age, and they explained it by the possibility of exposure of these groups to schistosomiasis campaigns in Egypt, and the use of contaminated needles or syringes during campaigns. Also, Manal et al.  found that PN was found in 70% of HCV patients over 40 years, which agrees with our study; it was found in our study that 7/15 had a high level of HCV viremia, 6/15 had a moderate level of HCV viremia and 2/15 had a low level of HCV viremia, and so most of the patients with PN in this study had high to moderate viremia, and the significant relation between PN and the virus load supports the mechanism that denotes that HCV may play a direct role in the pathogenesis of neuropathy, which is in accordance with the study by Sterling and Bralow . In the current study, we found that PN increased with increasing stages of fibrosis.
The pathophysiology of HCV-related PN remains largely speculative; vascular deposition of HCV-RNA-containing CG, direct viral infection or perivascular mononuclear inflammatory cells  may be at the origin of HCV-associated inflammatory vascular lesions. However, it is likely that HCV neuropathy results from virus-triggered immune-mediated mechanisms rather than from direct nerve infection and in-situ replication .
Some authors have already noted that older age is a major risk factor for clinical and biological EHMs of HCV. In keeping with these data, we found in our study a strong correlation between older age and PN, which may be interpreted in the hypothesis of an immune-mediated pathological mechanism of HCV-related clinical manifestations .
In the current study, we did not find any case of retinopathy in the 50 patients of chronic HCV as the fundus examination of all patients was normal. However, unlike nephropathy and neuropathy, retinopathy is not known to be one of the extrahepatic complications of HCV as platelet adhesion seems to be more important in the pathogenesis of retinopathy (microvascular occlusion, neovascularization and progression of retinopathy) than in other microvascular complications. In the current study, it was observed that chronic HCV patients had a decreased platelet count, which was caused by decreased production of coagulation factors from the diseased liver. These effects of chronic HCV infection may decrease induced hypercoagulation and premature atherosclerosis induced by factors including increased levels of platelet-derived microparticles and monocyte-derived microparticles, which have been shown to correlate with the extent of retinopathy . This may give the chance for the protective effects of CHC to gain an upper hand, making retinopathy lower in chronic HCV.
In conclusion, our findings demonstrate that chronic HCV infection increases the incidence of nephropathy and neuropathy, but not retinopathy, and this may be associated with or without cryoglobulinemia as there is evidence that CGs are not the unique factor for these complications. In contrast, the current study demonstrated that advanced age and liver fibrosis were the most significant risk factors for PN, and sex and viral load showed no significant difference in chronic HCV patient with PN and nephropathy.
| Acknowledgements|| |
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]