|Year : 2019 | Volume
| Issue : 1 | Page : 7-13
Clinical and neurophysiology study in hepatitis C virus patients
Abdelrahman A Elghorab1, Ahmed M Elshamy1, Raafat A Salah2, Mohamed O Rabie1
1 Department of Neuropsychiatry, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Neuropsychiatry and Tropical Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
|Date of Submission||22-Jun-2017|
|Date of Acceptance||03-Oct-2018|
|Date of Web Publication||17-Sep-2019|
Abdelrahman A Elghorab
Department of Neuropsychiatry, Faculty of Medicine, Tanta University, Tanta
Background Hepatitis C virus is associated with extrahepatic organ involvement including the nervous system especially peripheral nervous system, which is frequently affected due to the presence of hyper cryoglobulinemia (CG). Sensory and axonal neuropathy is the most frequent presentation in association with hyper CG. Peripheral neuropathy (PN) may also be observed in the absence of hyper CG.
Aim The aim of this work was to study peripheral neurological complications related to chronic hepatitis C infection and the possible pathogenic mechanisms of these complications.
Patients and methods This study was conducted on 60 patients with chronic hepatitis C infection who were subdivided into two subgroups: group I is composed of 30 chronic hepatitis C patients with clinically apparent neurological complications and group II is composed of 30 chronic hepatitis C patients, who were neurologically asymptomatic. The patients were subjected to clinical evaluation, estimation of hepatitis markers, cryoglobulins, and nerve conduction studies.
Results Overt peripheral neuropathies occurred in 42 (70%) patients, detected subclinically in 12 (40%) patients. The chronic sensory peripheral neuropathy was the most common type, representing 60% of neuropathic patients. A statistically significant difference was found between groups I (80%) and II (33.3%), regarding the presence of cryoglobulin, being more common in group I. Results of nerve conduction studies have shown that nerves were more affected in group I and in cryoglobulin positive patients especially in the lower limb.
Conclusion Peripheral neuropathies represent the most common hepatitis C virus-related peripheral neurological disorders especially when associated with cryoglobulins
Keywords: cryoglobulinemia, hepatitis C virus, peripheral neuropathy
|How to cite this article:|
Elghorab AA, Elshamy AM, Salah RA, Rabie MO. Clinical and neurophysiology study in hepatitis C virus patients. Tanta Med J 2019;47:7-13
|How to cite this URL:|
Elghorab AA, Elshamy AM, Salah RA, Rabie MO. Clinical and neurophysiology study in hepatitis C virus patients. Tanta Med J [serial online] 2019 [cited 2020 Apr 8];47:7-13. Available from: http://www.tdj.eg.net/text.asp?2019/47/1/7/267022
| Introduction|| |
Hepatitis C virus (HCV) infection is a major global health challenge; it is estimated that more than 80 million people are chronically infected worldwide, with 3–4 million new infections each year .
Hepatitis C infection has been known to induce autoimmune syndromes, which has been referred to as extrahepatic manifestations that affect 40–70% of patients of chronic HCV infection .
Several neurological complications occur in HCV-infected patients including peripheral nervous system, central nervous system, and muscular complications .
The most commonly reported neurological disorder is peripheral neuropathy that is common in older age, with long duration of liver disease, and the most common presentation is a length-dependent symmetric sensory or sensorimotor axonal polyneuropathy, clinically characterized by distal sensory loss and weakness .
The pathophysiology of HCV-related peripheral neuropathy (PN) remains largely speculative; it can be due to a direct viral damage, the presence of hyper cryoglobulinemia, and multiple comorbidities that affect HCV-infected patients .
Hence the aim of this work was to study peripheral neurological complications related to chronic hepatitis C infection by clinical, laboratory, and neurophysiological methods and to study the possible pathogenic mechanisms of these complications.
| Patients and methods|| |
This study was conducted on 60 Egyptian patients with chronic hepatitis C infection from the outpatient Clinic and in-patient wards of Neuropsychiatry and Tropical Medicine Departments at Tanta University Hospitals and Tanta Educational Hospital during the period from January 2016 to July 2016.
Patients were subdivided into two subgroups: group I was composed of 30 patients with clinically apparent neurological complications, while group II was composed of 30 neurologically asymptomatic patients.
Selection of patients suffering from polyneuropathy and HCV infection is made by: history taking of symptoms (weakness and sensory disturbances), signs of weakness including wasting, reduced/absent tendon reflexes, and/or sensory abnormalities of peripheral nerve lesion and Self-Completed Leeds Assessment of Neuropathic Symptoms and Signs questionnaire was used as a diagnostic tool for neuropathic pain.
HCV-RNA-positive patients by PCR.
Patients with advanced liver disease, concurrent hepatitis B or HIV infections, chronic renal disease or a history of dialysis, systemic hypertension, diabetes, obesity, systemic lupus erytherymatosis (SLE), heart failure, pregnancy, convulsions, and other causes of microalbuminuria were excluded from the study.
All the patients were subjected to the following.
Patients were subjected to general examination with special attention to hepatic and extrahepatic manifestations 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 nerves
- General checkup profile: erythrocyte sedimentation rate, glycosylated hemoglobin, and liver function tests.
- Hepatitis markers: HCV-RNA by extraction and reverse transcription and PCR products were collected.
- Cryoglobulins: diagnosis of mixed cryoglobulinemia was defined as a positive result of cryoglobulins search that is cryocrit greater than 1% in at least two determinations .
Nerve conduction studies
- Sensory studies: were done for ulnar, median, and sural nerves of both sides. For each nerve, the following was done: sensory latency and sensory action potential amplitude. Sensory latency normal values are less than 3.1, 3.5, and 3.8 ms for ulnar, median, and sural nerves, respectively. Sensory amplitude normal values are greater than 18, 20, and 10 µV for ulnar, median, and sural nerves, respectively.
- Motor studies: it was done for the ulnar and deep peroneal nerves of both sides. For each nerve evaluation the following was done: motor distal latency (DL) and compound motor action potential amplitude. Motor DL normal values are less than 3.4, 4.2, and 5.5 m for ulnar and deep peroneal, respectively. compound motor action potential amplitude normal values are greater than 4, 4, and 2.5 mV for ulnar and deep peroneal nerves, respectively.
The collected data were organized, tabulated, and statistically analyzed by using SPSS for Windows, version 22 (SPSS Inc., Chicago, Illinois, USA). Graphical presentation was performed using MS-Excel.
Data were described as mean±SD for quantitative (numerical) variables of nerve conduction studies and were expressed as both number and percentage for categorized data. χ2-test was used to study the association between each two variables or comparison between two independent groups as regards the categorized data. The probability of error P less than or equal to 0.05 is significant, P greater than 0.05 is insignificant.
Formal approval from the dean and an official permission letter was obtained and directed to the heads of the selected departments. Participants were informed about the purpose and procedure of the study and benefits of sharing in it. Ethical considerations of the study were carried out according to that of Declaration of Helsinki. Also, the study was carried out after approval of the Research Ethical Committee, Faculty of Medicine, Tanta University.
| Results|| |
Demographic and laboratory investigation results
The studied patients were 34 (56.6%) men and 26 (43.4%) women. Their ages ranged from 28 to 64 years with a mean of 45.9+5.5 with insignificant difference between the two groups. Regarding liver enzyme, international normalized ratio, and glycosylated hemoglobin in the two studied groups: there are no significant difference between the studied groups regarding international normalized ratio, Hba1c but alanine aminotransferase is significantly higher in the symptomatic group than the nonsymptomatic group (P>0.05).
ESR values in the two studied groups: the mean ESR values at the first and second hour are significantly higher in the symptomatic group than the nonsymptomatic group (P<0.05) ([Table 1]).
|Table 1 Sociodemographic characteristics and laboratory findings of the study group|
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Serum-mixed cryoglobulins among the patients’ groups: numbers of cryoglobulin positive patients in the symptomatic group than the nonsymptomatic group (10/33.3%) (P<0.05) ([Table 2]).
|Table 2 Comparison between serum-mixed cryoglobulins among the two groups|
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Duration of hepatitis C virus among the studied groups
The mean duration of HCV infection is significantly higher in the symptomatic group than the nonsymptomatic group 39.6±16.21 versus 27.7±16.12, respectively (P<0.05). Regarding the severity of liver disease in the studied patients: eight (26.7%) patients in group I are not cirrhotic, 22 (73.3%) patients were cirrhotic and they were less but in the asymptomatic group nine (30%) patients were not cirrhotic and 21 (70%) patients were cirrhotic. Although symptomatic patients had a more severe liver disease, the difference was statistically insignificant (P>0.05) ([Table 3]).
The results of nerve conduction studies showed that the nerves were significantly more affected in group I than in group II ([Table 4]).
Frequency of neurophysiological study in symptomatic patients
Neurophysiological study of group I with predominant sensory neuropathy was 60%, followed by sensorimotor in 20%, and sensorimotor mononeuropathy in 10%. Acute inflammatory demyelinating polyneuropathy reported in two (6.7%) patients. Chronic inflammatory demyelinating polyneuropathy was reported in one (3.3%) patient ([Table 5]).
Relation between nerve conduction studies in hepatitis C virus patients with their cryoglobulins
Sensory nerve conduction studies (NCS) are significantly higher in cryoglobulin positive patients than cryoglobulin negative patients (P>0.05). Mean motor NCS are significantly higher in the lower limb of cryoglobulin positive patients than cryoglobulin negative one (P>0.05), but there are no significant differences in mean motor NCS of upper limb (P<0.05) ([Table 6]).
|Table 6 Relation between nerve conduction studies in hepatitis C virus patients with their cryoglobulins|
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Comparison between neurophysiological results and hepatic pathology
NCS of cirrhotic patients reveal nonsignificant decrease in all parameters of examination; except significant decrease in the amplitude, CV of sural and ulnar sensory nerves than noncirrhotic (P>0.05). Also, DL of sural nerve are significantly decreased in cirrhotic noncirrhotic ([Table 7]).
|Table 7 Comparison between neurophysiological results and hepatic pathology|
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Correlation between erythrocyte sedimentation rate and neurophysiological results
There is significant negative correlation between the mean values of ESR, conduction velocity and amplitude of ulnar nerve (sensory), median nerve (sensory), and sural nerve in group I (P<0.05), while there are no significant correlation between the mean values of ESR and the other studied parameters of the examined nerves ([Table 8]).
|Table 8 Correlation between erythrocyte sedimentation rate and neurophysiological results|
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| Discussion|| |
HCV-associated nervous system disorders have been described with increasing frequency in the literature .
The prevalence of peripheral nervous system involvement has varied in the literature, reaching as high as 50% of cases. However, the exact frequency of peripheral neuropathy in HCV patients is difficult to assess, as it varies depending on the definition criteria, the method of ascertainment as clinical examination versus electromyography, and the population studied .
Regarding the age of the studied groups, the study of Yoihenba et al.  revealed that the mean age of their patients were 42.58±7.39 years. This is going with the mean age of patients of the current work (45.9±5.5). The same results were reported by Waked et al.  and Frank et al. .
In the current study, the majority of the patients were men (56.6%%) which is in agreement with Habib et al.  and Kandeel et al.  who found that HCV was more prevalent in men than women in Egypt due to the existence of two common potential HCV exposures for men due to shaving by a community barber using the same razor blade and smoking tobacco with a water pipe (Shisha), which can theoretically result in the exposure to blood from individuals with gingivitis.
The current study shows that the duration of HCV infection is significantly higher in group I than in group II. This finding goes hand in hand with El Ghoneimy et al.  and Jain et al.  who found a significant relation between duration of disease and PN. Also, Biasiotta et al.  who demonstrate the development of peripheral neuropathy was significantly associated with the duration of HCV.
In contrast, Gemignani et al.  and Santoro et al.  assumed that it is a matter of contradictory as the true duration is difficult to establish due to absence of symptoms during the early phase of chronic infection.
Authier et al.  found that the possible underlying pathogenetic mechanism in such HCV-related neurological complications is probably due to an immune-mediated process that is supported by the several findings in this study. First, the frequency of cryoglobulins in neuropathic patients was significantly higher than in non-neuropathic patients and the presence of cryoglobulins was associated with more affection of the peripheral nerves as detected by nerve conduction studies. Second, a statistically significant negative correlation was found between the mean values of ESR, conduction velocity, and amplitude of ulnar nerve (sensory), median nerve (sensory), and sural nerve in group I.
Cryoglobulin positive patients of the present work are 34 in number (56.5%) and are significantly higher in group I than group II. The high frequency of cryoglobulinemia is consistent with pervious Egyptian study by Maher et al.  that was 64%; on the contrary, Weimer et al.  and Mohamoud et al.  found that cryoglobulin was present in 18% and 15% of their study on HCV patients, respectively.
Regarding ESR, the findings coincide with a study by Younis et al.  and El Ghoneimy et al. , as they found significant difference in the mean values of ESR between patients with neuropathy and without neuropathy.
Santoro et al.  stated that pure clinical assessment tends to underestimate PN involvement in HCV population and that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of PN and stressed on the importance of electrodiagnosis for eliciting PN.
The current study confirms this statement as electrophysiological examination of group II shows a subclinical PN in 12/40% patients. This is in agreement with the Egyptian studies made by AbdelKhalek et al.  and Al Kafrawy et al. , as they found that subclinical PN was 45 and 35%, respectively. Also, a similar finding was reported by Yoihenba et al.  and Koşkderelioğlu et al. . They detect subclinical PN by an electrophysiological study in 38 and 50%, respectively.
In contrast to the finding of the present study, Ripault et al.  reported that there is equal frequency distribution of clinical and electrophysiological PN. But, Gomes et al.  found that clinical PN was more diagnostic than electrophysiological diagnosis. Neurophysiological study of group I shows that predominant sensory neuropathy was 60%, followed by sensorimotor (20%) and sensorimotor mononeuritis multiplex (10%). Acute inflammatory demyelinating polyneuropathy was reported in two (6.7%). Chronic inflammatory demyelinating polyneuropathy was reported in one (3.3%).
The predominance of sensory PN in this study agrees with Sterling and Bralow . They demonstrated that sensory deficiencies are more common than motor PN, and that sensory symptoms may persist for months to years before any motor deficit become clinically evident. Also, AbdelKhalek et al. , Al Kafrawy et al. , and Maher et al.  reported sensory PN in 45, 55, and 60% of their patients, respectively.
In contrast, an Egyptian study made by Younis et al.  on 17 HCV patients with peripheral neuropathy revealed that 3/21.4% had only distal sensory neuropathy, 9/64.2% had sensorimotor polyneuropathy with prominent motor affection, and 2/14.2% had multiple mononeuritis.
Another possible underlying pathogenic factor for HCV-related PN could be the degree of associated hepatic pathology, as evidenced in this study by NCS that shows a significant decrease in the amplitude, CV of sural, ulnar sensory nerves and tibial nerve and the DL of sural nerve than the noncirrhotic.
These results are in agreement with Zaltron et al. , Okuse et al. , and Jain et al. , who found that the prevalence and severity of peripheral neuropathy was related to the severity of hepatic pathology.
| Conclusion|| |
Peripheral neuropathies are the most common peripheral neurological complications in HCV patients, especially when associated with cryoglobulins, high ESR, and advanced hepatic pathology.
The authors thank the Head of Neuropsychiatry Department, Faculty of Medicine, Tanta University for his general support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]