INTRODUCTION
Worldwide, 130–170 million people are infected with hepatitis C virus (HCV), 1,2 which represents more than 3% of the world’s population. 3 Hepatitis C virus infection is associated with several extrahepatic manifestations, some of which are neurological and mostly related to immune mechanisms. 4 Hepatitis C virus–related peripheral neuropathy (PN) has been reported with mixed cryoglobulinemia (CG) in 26–86% of cases, although it can occur without CG in up to 9% of HCV-infected individuals but with less severity. 5 In mild CG syndrome, small fiber sensory polyneuropathy (SFSN) is the most common neuropathy, whereas large fiber sensory neuropathy (LFSN) is less frequent. Small fiber sensory polyneuropathy may later progress to LFSN. 6 Restless leg syndrome (RLS) that is a distressing manifestation of SFSN has been reported in HCV-infected patients. Recently, in Japan, India, and the United States, RLS has also been found in liver cirrhosis and in chronic hepatic failure patients. 7–9 The severity and prevalence of autonomic dysfunction paralleled increasing hepatic dysfunction and were independent of the etiology of liver disease. 10 A study showed that PN was more commonly seen in patients with severe hepatic disease than in those with mild hepatic affection, and that the liver disease itself was the cause of neuropathy in these patients. 11
In 2010, there were 285 million diabetic patients worldwide, and 90% of these patients had diabetes mellitus (DM) type II. It is expected that the number of these patients will double by the year 2030. 12 Diabetic complications of the lower extremities are not rare. The National Health and Nutrition Examination Survey 2004, which is a program of many studies aiming to assess the nutritional, health status of both children and adults living in the United States, revealed that peripheral arterial disease is present in up to 10% of patients with diabetes, neuropathy in up to 30%, and open foot ulcers that may require amputation in up to 7%. 13 Thus, it seems important to detect early neuropathy in patients with liver disease, especially if associated with DM.
Sudomotor dysfunction is considered one of the manifestations that occur earlier in neuropathies of small distal fibers. 14 Moreover, sweat glands are innervated by postganglionic unmyleinated cholinergic sympathetic sudomotor C-fibers, and many studies on skin biopsy in diabetic patients showed a significant decrease in epidermal C-nerve fibers. 15 Therefore, a reliable method for evaluation of SFSN is to assess sudomotor function. Sudoscan is a rapid, noninvasive, objective, and quantitative method to assess sudomotor function by providing measures of electrochemical skin conductance (ESC); its performance (diagnostic value, accuracy, and reproducibility) in peripheral SFSN has been evaluated in several clinical studies, especially in patients with DM. 16–18
This pilot study aimed to evaluate the presence of SFSN in HCV-related cirrhotic patients with or without DM and to validate the Sudoscan test as a tool for measuring ESC.
SUBJECTS AND METHODS
This study was carried out on 97 patients with HCV-related cirrhosis (48 cirrhotic patients without DM [group 1] and 49 cirrhotic patients with type II DM [group 2]) and 47 healthy persons as a control group. Written, informed consent was obtained from all participants before any procedures of the study in routine clinical practice in five responsible centers for HCV management. The current study was conducted in accordance with Good Clinical Practice guidelines after the Ethical and Research Committee, National Liver Institute had approved the study (Institutional Review Board [IRB 00221] of National Liver Institute, Menoufia University, Egypt).
Key exclusion criteria included patients with a previous traumatic peripheral nerve lesion, patients with a hand or foot injury, alcoholic patients, patients treated with drugs known to affect the autonomic nervous system (especially drugs with significant anticholinergic effect), pregnant patients, patients with thyroid dysfunction, and patients with Parkinsonism.
All participants underwent a thorough medical history and full clinical examination with a meticulous neurological examination. Routine laboratory investigations including complete blood count, liver function tests, renal function tests, prothrombin time and international normalized ratio, fasting blood glucose, 2-hour postprandial blood glucose, and HbA1c were measured. Assay of serum vitamin B12 levels to all participants before enrollment was performed using the ELISA method, by the use of the kit supplied by Shanghai Sunred Biological Technology Co., Ltd. Catalogue No. 201-12-1720 (Diagnostic Automation/ Cortez Diagnostics, Inc, Woodlands, CA). The kit uses a double-antibody sandwich ELISA as vitamin B12 is routinely at normal levels especially in patients with DM before starting metformin therapy.
Abdominal ultrasonography to assess liver echogenicity, hepatic focal lesions, spleen size, portal vein patency, ascites, and renal parenchymal echogenicity was conducted.
Presence of PN was defined as feet ESC (FESC) < 70 microSiemens (µS), and sudomotor function testing was performed using the Sudoscan device (Impeto Medical, Paris, France) to measure ESC. This method is rapid noninvasive and is based on the electrochemical reaction between feet and hand sweat chloride stimulation of sweat glands by a low voltage current (< 4 V) using stainless steel electrodes for about 2 minutes. Electrochemical skin conductance is a quantitative result (µS) calculated by measuring the ratio between the current and the applied voltages. 16–23
Statistical methods.
Descriptive statistics including mean and SD for quantitative variables, frequencies, and simple percentages for categorical variables were computed. Categorical variables were compared using a chi-square test (χ2).
Normality was tested using the Kolmogorov–Smirnov test. No normally distributed variable was found. Accordingly, the Kruskal–Wallis test was performed to test for a group effect. The Dwass-Steel-Crichtlow-Fligner multiple comparison analysis was performed for pair-wise two-sample comparisons among the three groups.
Spearman’s rank correlation coefficients were used to determine correlations between variables. Data were analyzed using SAS software version 9.4 (SAS Institute Inc., Cary, NC).
RESULTS
Demographic and clinicopathological features of the study population are displayed in Table 1. Percentages of PN observed in each study group were 0% in controls, 39% in group 1%, and 62% in group 2 (P < 0.0001). Feet electrochemical skin conductance was significantly different among the three groups (P < 0.0001). Feet electrochemical skin conductance was decreased in group 1 as compared with controls (67 ± 19 versus 88 ± 7 µS, P < 0.0001) and more severely decreased in group 2: 58 ± 19 µS (P = 0.017 as compared with group 1) (Figure 1).
Study population characteristics
| Normal range | Control group (N = 47) | Group 1 (N = 48) | Group 2 (N = 49) | P-value | |
|---|---|---|---|---|---|
| Age (years) | > 18 | 55.14 ± 10 | 57.86 ± 7.59 | 57.94 ± 8.85 | 0.653* |
| Female | – | 20 (42.6%) | 20 (41.7%) | 23 (46.9%) | 0.8545† |
| Ascites | No | 0 (0) | 28 (58.3%) | 33 (67.35%) | < 0.0001 † |
| Albumin (gm/dL) | 3.5–5 | 4.8 ± 0.5 | 2.9 ± 0.4 | 2.9 ± 0.5 | < 0.0001 * |
| Alanine aminotransferase (u/L) | 0–49 | 20.6 ± 6.1 | 59.1 ± 22.3 | 66.1 ± 63.1 | < 0.0001 * |
| Aspartate aminotransferase (u/L) | 0–34 | 21.9 ± 6.4 | 79.3 ± 33.2 | 92.3 ± 76.2 | < 0.0001 * |
| Bilirubin (mg/dL) | 0.1–1.2 | 0.9 ± 0.1 | 2.2 ± 1.7 | 3.7 ± 4.3 | < 0.0001 * |
| Body mass index (kg/m2) | < 25 | 26.5 ± 3.5 | 28.0 ± 5.5 | 29.4 ± 6.9 | 0.1554* |
| Systolic BP (mmHg) | 120 | 117.9 ± 4.1 | 119.3 ± 18.0 | 113.1 ± 15.5 | 0.1645* |
| Diastolic BP (mmHg) | 80 | 76.9 ± 4.6 | 74.0 ± 8.7 | 72.6 ± 7.6 | 0.0087 * |
| HbA1c (mmol/mol) | 4–5.5 | 4.6 ± 0.4 | 4.6 ± 0.4 | 8.6 ± 1.1 | < 0.0001 * |
| Hb (g/dL) | 12 | 12.0 ± 1.2 | 10.6 ± 1.3 | 10.2 ± 1.4 | < 0.0001 * |
| International normalization ratio | 1 | 1.0 ± 0.2 | 1.8 ± 0.5 | 1.8 ± 0.5 | < 0.0001 * |
| Platelets (×103 cells/mcL) | 150–450 × 10 3 | 245,553 ± 53,721 | 114,581 ± 1,213 | 99,245 ± 50,989 | < 0.0001 * |
| Portal vein diameter (mm) | 12 | 8.8 ± 1.5 | 16.5 ± 1.8 | 15.6 ± 2.1 | < 0.0001 * |
| Spleen size (cm) | Up to 13 | 9.2 ± 1.3 | 17.8 ± 2.1 | 17.5 ± 2.7 | < 0.0001 * |
| Splenic vein (mm) | Up to 10 | 9.4 ± 1.3 | 14.0 ± 1.2 | 13.7 ± 1.7 | < 0.0001 * |
BP = blood pressure; Hb = hemoglobin. N (%) for categorical variables and mean (±SD) for continuous variables. Italic P-values = statistically significant at P ≤ 0.05.
Kruskal–Wallis test.
Chi-square test (χ2).
Box-plots of feet electrochemical skin conductance (FESC) in controls, patients with hepatitis C virus (HCV)–related cirrhosis, and patients with HCV-related cirrhosis as well as diabetes mellitus (DM). Feet electrochemical skin conductance is decreased in HCV-related cirrhosis as compared with controls, and more profoundly decreased in patients with DM in addition.
Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0612
Box-plots of feet electrochemical skin conductance (FESC) in controls, patients with hepatitis C virus (HCV)–related cirrhosis, and patients with HCV-related cirrhosis as well as diabetes mellitus (DM). Feet electrochemical skin conductance is decreased in HCV-related cirrhosis as compared with controls, and more profoundly decreased in patients with DM in addition.
Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0612
Box-plots of feet electrochemical skin conductance (FESC) in controls, patients with hepatitis C virus (HCV)–related cirrhosis, and patients with HCV-related cirrhosis as well as diabetes mellitus (DM). Feet electrochemical skin conductance is decreased in HCV-related cirrhosis as compared with controls, and more profoundly decreased in patients with DM in addition.
Citation: The American Journal of Tropical Medicine and Hygiene 104, 2; 10.4269/ajtmh.20-0612
There was a correlation between FESC and parameters of increased portal pressure and parameters of increased severity of hepatic dysfunction (Table 2).
Spearman’s correlations between FESC and parameters of increased portal pressure and severity of hepatic dysfunction
| Parameters of hepatic dysfunction | FESC Spearman’s rank correlation | |
|---|---|---|
| Spleen size | R | −0.54502 |
| P-value | < 0.0001 | |
| Splenic vein | R | −0.56362 |
| P-value | < 0.0001 | |
| Portal vein diameter | R | −0.46695 |
| P-value | < 0.0001 | |
| HbA1c | R | −0.36729 |
| P-value | < 0.0001 | |
| Thyroid-stimulating hormone | R | 0.14450 |
| P-value | 0.0840 | |
| Haemoglobin | R | 0.49147 |
| P-value | < 0.0001 | |
| Platelets | R | 0.60889 |
| P-value | < 0.0001 | |
| Albumin | R | 0.71604 |
| P-value | < 0.0001 | |
| International normalization ratio | R | −0.64238 |
| P-value | < 0.0001 | |
| Aspartate aminotransferase | R | −0.59935 |
| P-value | < 0.0001 | |
| Alanine aminotransferase | R | −0.55836 |
| P-value | < 0.0001 | |
| Bilirubin | R | −0.71090 |
| P-value | < 0.0001 | |
| Creatinine | R | −0.19716 |
| P-value | 0.0179 | |
| Systolic blood pressure | R | 0.21269 |
| P-value | 0.0105 | |
| Diastolic blood pressure | R | 0.30471 |
| P-value | 0.0002 | |
FESC = feet electrochemical skin conductance; italic P-values = statistically significant at P ≤ 0.05. R = Spearman’s rank correlation coefficient.
DISCUSSION
Hepatitis C virus infection is a major cause of liver disease in all Egyptian areas, 24–26 representing the highest prevalence in the world with about 10% of the population, 27–29 the natural history of HCV infection is affected by viral and host factors. 30,31
Hepatitis C virus infection is associated with neuropsychiatric disorders in about 50% of patients and can cause a wide variety of PN, including mainly SFSN and less frequent large LFSN. 32,33 It is associated with cryoglobulinemia in up to 86% of cases and in 30% of cases without CG. 34 The development of HCV-associated neurological manifestations was known by many mechanisms including immune-mediated processes, direct nerve infection, and glucose neurotoxicity. 35 Sudoscan was used recently as a new device that helps in quick, quantitative, noninvasive assessment of sudomotor function. 22,36
This is a pilot study that demonstrated that there is 1) a decrease in FESC in patients with HCV-related cirrhosis, 2) a more severe decrease in the number patients who have DM in addition to HCV-related cirrhosis, and 3) a significant correlation of FESC with the major parameters of hepatitis.
Peripheral neuropathy can be a complication of viral infection such as chronic hepatitis and liver cirrhosis. Sensory neuropathy is more common than motor axonal neuropathy. 37 Peripheral motor neuropathy leads to weakness, whereas sensory impairment and severe autonomic dysfunction lead to organ failure. 38 In our study, there was a significant correlation between neuropathy, as defined by a decrease in FESC, in HCV-related cirrhosis with decreased platelets and increases in splenic size and portal vein diameter, all of which are indicators of increased portal pressure. This supports a previous study that hepatocellular dysfunction and portosystemic shunting were the main important pathogenic factors in hepatic neuropathy. 39 In this current study, there was also a significant relationship between the severity of liver disease and the severity of neuropathy. Besides the pathology of liver disease itself, metabolic dysfunction in liver disease has been shown to be the predominant cause of neuropathy in hepatic patients. 40
Hepatitis C virus associated with CG is known to cause severe neuropathy and its presentations in the form of mononeuropathy and vasculitis. The pathological roles responsible in inducing vascular inflammation in patients without cryoglobulinemia were immune complex and HCV-induced autoimmune mechanisms through the nervous system phagocytic cells and immune complexes. 41 In our study, there was a significant negative correlation between bilirubin and ESC in HCV cirrhotic patients. However, Mao et al. 42 and Wang et al. 43 found that increases in total bilirubin and unconjugated bilirubin were associated with an increase in FESC (P < 0.05), which was not found with conjugated bilirubin. This discrepancy can be explained: 1) our study population included only HCV-related cirrhosis with or without DM, and there is a link among HCV, metabolic syndrome, and DM; 2) hepatitis C virus can induce liver cirrhosis, and increased bilirubin in liver disease and HCV-related cirrhosis is mainly conjugated and one of the determinants of progressive liver disease; and 3) Mao et al. 42 did not discuss the cause of elevated bilirubin in their series, which was mainly indirect.
Peripheral neuropathy is one of the common complications of DM that can affect up to 70% of patients during their lifetime. 44 Diabetic peripheral neuropathy (DPN) may remain asymptomatic and dormant, leading to vigorous complications. 13,44
Sudomotor dysfunction has been found in prediabetic and diabetic patients, and the American Diabetes Association suggests that the early detection of DPN is through assessment of sudomotor function. 13 Small fiber sensory polyneuropathy is a marker of PN in diabetes 22 ; thus, early detection of small fiber neuropathy would improve treatment of type II diabetic patients and help in the prevention of the development of life-threatening complications. 45 In our study, the mean FESC was decreased in HCV-related cirrhosis with or without DM when compared with the control group. The decrease in ESC was more prominent in patients with DM. The neuropathy in HCV-related cirrhosis with DM could be explained by increasing evidence of a great association between HCV infection and type II DM; in addition, patients with type II diabetes have a 2-fold increased risk of acquiring HCV infection. 46,47 Hepatitis C virus infection induces insulin resistance (IR) and disturbances in glucose, protein, and lipid metabolism. These associations among DM, HCV, and IR lead to increase the risk of development of liver cirrhosis and Hepatocellular Carcinom. 48
In our study, PN was detected in 39% of patients with HCV-related cirrhosis and 62% of patients with DM as well as HCV-related cirrhosis. Thus, it appears particularly important to detect PN as early as possible, especially in HCV cirrhotic patients with or without DM type II to prevent more serious complications.
Our study has some limitations: 1) neurological examination relied solely on the measurement of ESC, 2) the small number of patients, and 3) patients with cirrhosis of a different etiology were not included.
In conclusion, mean FESC are decreased in HCV-related cirrhosis with or without DM when compared with the control group, suggesting small fiber autonomic neuropathy based on sweat function assessment. Sudoscan seems a valuable noninvasive method for early detection of SFSN in asymptomatic HCV-related cirrhosis with or without DM. Long-term follow-up would be useful to evaluate the progression of neurological dysfunction in this population, and future studies are needed to confirm our results in a larger population of hepatic patients with or without cirrhosis of any etiologies, along with a clinical neurological examination.
ACKNOWLEDGMENTS
All authors in this study participated in a good selection of cases, instructive supervision, continuous guidance, valuable suggestions and good instructions. Our article is an extended work of the selected abstract by the 29th Asian Pacific Association for the Study of the Liver (APASL) Committee 2020 in Bali, Indonesia. The selected abstract was orally presented in a session of the Scientific Program under the theme of “Golden Ages of Hepatology” (abstract submission No.: APASL2020-ABS926). 49 The American Society of Tropical Medicine and Hygiene (ASTMH) assisted with publication expenses.
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