Friday, June 8, 2012

Peripheral neuropathy in Egyptian hepatitis C virus patients: Correlation to some clinical and laboratory parameters

Original Article
Prevalence of peripheral neuropathy in Egyptian hepatitis C virus patients: Correlation to some clinical and laboratory parameters

Manal Aly Abdel Khaleka, Amal Mohamad El-barbarya, Ferial Salah Elkallab,
Salwa Abdel-Moneim Essac a Rheumatology and Rehabilitation Department, Faculty of Medicine, Tanta University, Egypt b Tropical Medicine Department, Faculty of Medicine, Tanta University, Egypt c Clinical Pathology Department, Faculty of Medicine, Tanta University, Egypt

Received 24 January 2012. Accepted 2 April 2012. Available online 19 May 2012.

http://dx.doi.org/10.1016/j.ejr.2012.04.001, How to Cite or Link Using DOI

Abstract
Aim of the work

The present study was undertaken to assess prevalence and characteristics of peripheral neuropathy (PN) in Egyptian hepatitisCvirus (HCV) patients.

Patients and methods
Eighty newly diagnosed HCV patients were enrolled, with 20 healthy volunteers. All were subjected to: full clinical examination, neurological examination, laboratory assessment including; routine blood tests, ESR, CRP, RF, ANA, C4, cryoglobulins (CGs), anti-GM1 antibodies, HCV antibodies, Quantitative PCR, abdominal ultrasonography, liver biopsy, and electrophysiological assessment.

Results
Thirty-six patients (45%) had clinical neuropathy, 18 patients (22.5%) had subclinical neuropathy. Thirty-eight out of the 54 PN patients (70.3%) showed axonal neuropathy which is mainly sensory affecting lower limbs. Twelve patients showed +ve cryoglobulinemia, all of them had neuropathy (10 clinical, 2 subclinical). Abnormal titers of anti-neuronal antibodies were associated with electrophysiological abnormalities in 50 out of the 54 PN patients. PN correlated with age, disease duration, ESR, CRP, RF, HCV viraemia, CGs, anti-GM1 and hypocomplementinemia.

Conclusions
PN exists in high prevalence among Egyptian HCV patients, and is associated with CG. It is mainly of axonal sensory type more affecting lower limbs. HCV patients should be investigated for the presence of CGs even in the absence of clinical manifestations.

Discussion Only
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The population of Egypt has a heavy burden of liver disease, mostly due to chronic HCV infection. The overall prevalence of antibody to HCV in the general population is around 15–20% [28]. The majority of the literature reporting on the neurological manifestations of HCV patients points to the PNS and describes painful neuropathies [29]. Antibodies against several neural antigens have been associated with a number of chronic immune-mediated neuropathies [30]. Detection of these anti-neuronal antibodies might provide additional prognostic insights and suggest a new scenario of the pathogenesis of the neurological manifestations of HCV related MCG [14].

In the current study, 70% of our patients were over 40 years which agrees with Frank et al. [28] who reported 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.

The majority of our patients was males (60%). Habib et al. [31], revealed that the HCV is more prevalent in males than females in Egypt due to the existence of two common potential HCV exposures for males: (1) shaving by a community barber using the same razor blade and (2) smoking tobacco with a water pipe (Shisha) which can theoretically result in exposure to blood from individuals with gingivitis.

PN was clinically diagnosed in 45% out of our patients, 42.5% showed sensory PN. The predominance of sensory PN among our patients agrees with Sterling and Bralow [32], who demonstrated that sensory deficiencies are more common than motor loss, and that sensory symptoms may persist for months to years before any motor deficit become clinically evident. On the other hand, the high prevalence of clinical PN among our patients is close to that reported by Cacoub et al. [10], which was up to 50%. Meanwhile, it was not consistent with previous Egyptian studies. The highest prevalence of PN among Egyptian HCV patients was 30% reported by Abul Hassan et al. [33], followed by 15.63% in the study of El Ghoneimy et al. [19] and 10% in the study of Abo Al-Soud et al. [34]. In western countries, Gomes et al. [35] reported PN prevalence of 34.6%, while other studies reported prevalence up to 10.6% [7], [13] and [36].

This wide variability of PN prevalence among different studies can be attributed to the model of patient enrollment, which in our study was based on the presence of HCV infection in untreated patients, independently of the signs or symptoms. It also can be attributed to the use of different methods for PN clinical evaluation.

It was mentioned that pure clinical assessment tends to underestimate PNS involvement in the HCV population [13] and that symptoms alone have relatively poor diagnostic accuracy in predicting the presence of PN and stressed on the importance of electrodiagnosis for its diagnosis [37]. We confirmed this statement when electrophysiological examination of our patients disclosed a subclinical PN in 18 additional patients (22.5%). This is in keeping with some authors who diagnosed subclinical PN in their patients [13] and [34], and disagrees with Ripault et al. [36] who reported equal prevalence of clinical and electrophysiological PN, and with Gomes et al. [35] who found clinical PN to be more than electrophysiological PN.

In the current study, a total of 67.5% (54/80) of our patients were diagnosed to have PN by electrophysiological examination. This finding disagrees with many authors where their percentage ranged from 8% to 37% [13], [34], [35], [36], [38] and [39].

Out of the 54 neuropathy patients, 38 patients (70.3%) showed axonal neuropathy which was mainly sensory affecting lower limbs more than upper limbs. While 16 patients (29.7%), showed mixed axonal and demyelinating sensorimotor polyneuropathy; with the same distribution and predominance of sensory affection. This finding is in accordance with some authors who demonstrated axonal type of neuropathy among their HCV patients with distal sensory or sensory-motor affection [7] and [33] or multifocal mononeuropathy. The underlying pathogenetic mechanisms for this complication are systemic CG and vasculitis [11], [12], [34], [36], [40], [41], [42], [43] and [44]. Peripheral demyelinating neuropathy has been rarely described, most often in CG−ve patients and results from the heterogeneity of the pathophysiological mechanisms of neuropathies [11], [42], [45], [46] and [47].

It has been hypothesized that SRAR can be used for the detection of early axonal loss; because the sural SNAP amplitude will decrease first, thereby also decreasing the SRAR value [48]. Our study showed that sensitivity of H-reflex and SRAR HCV patients was the same (55.5%) but combination of both tests increased sensitivity to 94.4%. This agrees with the study by Kim et al. [49] Moreover, Rutkove et al. [50] reported that an SRAR of less than 0.40 was a strong predictor of axonal polyneuropathy, with 90% sensitivity and 90% specificity, as compared to absolute sural amplitude which had sensitivity of only 66%.

The big variation of PN prevalence in HCV patients among different studies may be due to the fact that, it is a multifactorial disease process. Ripault et al. [36] suggested that the most important factor is the viral factors such as, viral genotypes as there is wide difference between the viral genotypes in Egypt and western countries.

15% of our patients showed positive CGs, which is very close to the findings of Gad et al. [51], who reported CGs prevalence of 14% among HCV genotype 4 Egyptian patients. While, this finding disagrees with many authors who reported CG prevalence ranging from 19% up to 54% among their HCV patients [7], [52], [53], [54] and [55], and with Persico et al. [56] and Verbaan et al. [57], who demonstrated 0.8% and 0% prevalences of CG in their patients consecutively.

The low prevalence of CGs among our HCV population can be attributed to: (a) HCV genotype 4 which is the common type among Egyptian patients is associated with low prevalence of CG compared to high prevalence in Japanese patients infected with genotype 1b [51], and to HCV genotype 2a infected patients. (b) The relatively short disease duration, as Lunel et al. [52] showed that the duration of the disease in HCV patients with MCG was almost twice as long than in patients without MCG and (c) relatively younger age of our patients, which agrees with some studies where it was noted that patients with MCG were of older age while sex was not a risk factor [58] and [59].
All of our CG+ patients had PN (10 clinical, 2 subclinical). None of them showed clinical manifestations of MCG. This agrees with the authors stating that HCV related PN is usually associated with CG [10], [11], [19], [36] and [39] and that the presence of serum CGs is predictive of more severe and widespread neuropathic involvement [12] and [60] and also with those who clarified that the only 13–30% of patients with CG are symptomatic [61].

Our patients showed significantly higher levels of anti-neuronal antibodies which were associated with electrophysiological abnormalities in 50 out of the 54 neuropathic patients. This finding is in keeping with Alpa et al. [62] who reported high plasma IgM and IgG anti-GM1 titers in MCG patients, and 61% of patients having abnormal titers were associated with clinical or subclinical evidence of neuropathy. Moreover, Ortiz et al. [63] concluded that high IgM anti ganglioside titers are involved in the etiopathogenesis of demyelinating neuropathies.

Statistical analysis showed a strong correlation between the presence of PN and age of patients, disease duration, load of viraemia, ESR, CRP, RF, IgM & IgG anti-GM1 and the presence of CGs. In addition; there was significant negative correlation between PN and C4 levels. On the other hand, no significant correlation could be found between PN and ANA, staging of liver fibrosis either by ultrasound scoring system or modified Knodells score.

These results are in keeping with Zaltron et al. [39] who reported a strong correlation between old age and PN although it was unrelated to cryocrit levels or type of CG, and with higher RF and reduced C4 activity, and with Santoro et al. [13] who demonstrated that electrophysiological evidence of PN was significantly associated with older age and virus load, but not with disease duration or CG. Also with Nemni et al. [12] who found that HCV-related neuropathy was significantly associated with diminished serum C4 levels. Nevertheless, Lidove et al. [60], reported that RF was always negative and C4 complement level was always normal among their HCV patients.

The significant relation between PN and virus load supports the mechanism which denotes that HCV may have a direct role in the pathogenesis of neuropathy. Furthermore, it support the immune hypothesis for the pathogenesis of PN as evidenced by the correlation between electrophysiological study and RF & diminished C4, which is in accordance with Sterling and Bralow [32], who found that RF is often positive in chronic HCV.

In conclusion, our findings demonstrate that PN exists in high prevalence among Egyptian HCV patients, and is commonly associated with CG. It is mainly of axonal sensory type with more affection of lower limbs. PN was found to correlate with the age of the patients, disease duration, ESR, CRP, RF, HCV viraemia, IgM and IgG anti-GM1 and hypocomplementinemia. It is recommended that HCV patients should be investigated for the presence of CGs even in the absence of clinical manifestations suggestive of MCG. HCV patients with no clinical evidence of neuropathy should be evaluated by electrodiagnosis, especially if they are CG+ve.

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