Autonomic and sensory nerve dysfunction in primary biliary cirrhosis

AIM: Cardiovascular autonomic and peripheral sensory neuropathy is a known complication of chronic alcoholic and non-alcoholic liver diseases. We aimed to assess the prevalence and risk factors for peripheral sensory nerve and autonomic dysfunction using sensitive methods in patients with primary biliary cirrhosis (PBC). METHODS: Twenty-four AMA M2 positive female patients with clinical, biochemical and histological evidence of PBC and 20 age matched healthy female subjects were studied. Five standard cardiovascular reflex tests and 24-h heart rate variability (HRV) analysis were performed to define autonomic function. Peripheral sensory nerve function on median and peroneal nerves was characterized by current perception threshold (CPT), measured by a neuroselective diagnostic stimulator (Neurotron, Baltimore, MD). RESULTS: Fourteen of 24 patients (58%) had at least one abnormal cardiovascular reflex test and thirteen (54%) had peripheral sensory neuropathy. Lower heart rate response to deep breathing (P = 0.001), standing (P = 0.03) and Valsalva manoeuvre (P = 0.01), and more profound decrease of blood pressure after standing (P = 0.03) was found in PBC patients than in controls. As a novel finding we proved that both time domain and frequency domain parameters of 24-h HRV were significantly reduced in PBC patients compared to controls. Each patient had at least one abnormal parameter of HRV. Lower CPT values indicated hyperaesthesia as a characteristic feature at peroneal nerve testing at three frequencies (2000 Hz: P = 0.005; 250 Hz: P = 0.002; 5 Hz: P = 0.004) in PBC compared to controls. Correlation of autonomic dysfunction with the severity and duration of the disease was observed. Lower total power of HRV correlated with lower CPT values at median nerve testing at 250 Hz (P = 0.0001) and at 5 Hz (P = 0.002), as well as with those at peroneal nerve testing at 2000 Hz (P = 0.01). CONCLUSION: Autonomic and sensory nerve dysfunctions are frequent in PBC. Twenty-four-hour HRV analysis is more sensitive than standard cardiovascular tests for detecting of both parasympathetic and sympathetic impairments. Our novel data suggest that hyperaesthesia is a characteristic feature of peripheral sensory neuropathy and might contribute to itching in PBC. Autonomic dysfunction is related to the duration and severity of PBC

Biodistribution and function of extracellular miRNA-155 in mice

Circulating miRNAs can be found in extracellular vesicles (EV) and could be involved in intercellular communication. Here, we report the biodistribution of EV associated miR-155 using miR-155 KO mouse model. Administration of exosomes loaded with synthetic miR-155 mimic into miR-155 KO mice resulted in a rapid accumulation and clearance of miR-155 in the plasma with subsequent distribution in the liver, adipose tissue, lung, muscle and kidney (highest to lowest, respectively). miR-155 expression was detected in isolated hepatocytes and liver mononuclear cells of recipient KO mice suggesting its cellular uptake. In vitro, exosome-mediated restoration of miR-155 in Kupffer cells from miR-155 deficient mice augmented their LPS-induced MCP1 mRNA increase. The systemic delivery of wild type plasma to miR-155 KO mice also resulted in a rapid accumulation of miR-155 in the circulation and distribution to the liver and adipose tissue. In summary, our results demonstrate tissue biodistribution and biologic function of EV-associated miR-155

Serum leptin, soluble leptin receptor, free leptin index and bone mineral density in patients with primary biliary cirrhosis

Background/aim The pathophysiology of osteoporosis in chronic liver diseases is unknown. Recent data suggest that serum leptin is associated with bone mineral density (BMD). In animal studies leptin was found to be a potent inhibitor of bone formation. We investigated the relationship between serum leptin levels, soluble leptin receptor (sOB-R), free leptin index (FLI) and BMD in patients with primary biliary cirrhosis (PBC). Patients and methods Ninety-four female patients with PBC were included in this study; 122 healthy women served as controls. Serum leptin levels were measured by radioimmunoassay, sOB-R by enzyme-linked immunosorbent assay. BMD was measured by dual energy X-ray absorptiometry in the lumbar spine and femoral neck. Results Serum leptin was significantly lower in patients with PBC compared with healthy controls. No difference was found between the body mass index (BMI) of patients and controls. There was a strong positive correlation between leptin and BMI. In PBC no association was found between leptin, sOB-R and liver function tests, histological stages or the presence of osteoporosis. Osteoporosis was present in 38 patients. A positive correlation was found between serum leptin and femoral neck z-score even after adjustment for BMI, whereas serum sOB-R correlated inversely with the serum leptin level. There was no difference in FLI between the subgroups of PBC patients according to the stages of the disease. Conclusions We found a lower serum leptin level and a higher sOB-R in patients with PBC, which could not be explained by the difference in BMI. As leptin was associated with BMD, it may be hypothesized that leptin is involved in the complex regulation of bone metabolism in PBC

Chronic hepatitis C virus infection associated with autonomic dysfunction

Background: Impaired autonomic function has been described in patients with chronic liver diseases from different aetiologies, and has proven to be a poor prognostic indicator. To date, it is not known how chronic hepatitis C virus (HCV) infection affects the autonomic nervous system. Aims: In the present study, we compared cardiovagal autonomic function in patients with chronic HCV infection and healthy controls and examined the relation between autonomic function and serum levels of aminotransferases, HCV RNA, cryoglobulins, albumin and glucose. Methods: Autonomic function was assessed in 45 treatment-naı¨ve patients with chronic HCV infection and in 40 healthy controls by determining spontaneous baroreflex sensitivity (BRS) and heart rate variability (HRV) indices. The R–R interval was determined by electrocardiogramrecording; continuous radial artery pressure was monitored simultaneously by applanation tonometry. Laboratory analyses and quantitative polymerase chain reaction for serum HCV RNA level were performed by standard procedures. Results: BRS and HRV time and frequency domain indices were lower in patients with HCV infection compared with healthy controls [7.1+/-3.4 vs. 11.5+/-6.5 ms/mmHg for BRS, 168.5+/-160.9 vs. 370.7+/-349.4 ms2 for low-frequency HRV (mean+/-SD); Po0.01]. Multivariate analysis showed that autonomic dysfunction in HCV-infected patients correlated with elevated alanine aminotransferase levels, but was not associated with serum HCV RNA levels and cryoglobulins. Conclusion: Our results suggest that impaired autonomic function is caused by chronic HCV infection. Further studies are needed, however, to identify the underlying mechanisms

Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease

Background/aims Diagnosis of Wilson's disease may be difficult in patients presenting with liver disease and in asymptomatic siblings. The aim of the present study was to assess the impact of genetic testing for diagnosis of the disease in a large cohort (n = 109) from Hungary. Patients/methods One hundred and nine patients with Wilson's disease were studied (65 men and 44 women; mean age at onset of symptoms: 20 9 years). Diagnosis of the disease was based on typical clinical and laboratory features (all had a Wilson's disease score of >=, 4). H1 069Q was assessed by the semi-nested polymerase chain reaction-based restriction fragment length polymorphism assay. H1 069Q heterozygotes and H1 069Q negative samples were then screened for mutations (on exons 6 to 20) by denaturating high-performance liquid chromatography and than sequenced on a genetic analyser. Results Twenty-three different mutations were found. H1 069Q was the most frequent mutation in Hungary, detected in 77 patients (71%). Fourteen further known mutations were found by sequencing. We identified eight new mis-sense mutations not described before: N6761, S693Y, Y715H, M769L, W939C, P1 273S, G1 281 D and G1 341 V. In 36/109 patients (33%) the diagnosis of Wilson's disease was established by adding mutational analysis. The Kayser-Fleischer ring was more frequent in H1 069Q homozygous patients and their mean age at the time of diagnosis was higher than in patients heterozygous or negative for H1069Q. Conclusion Eight novel mutations in addition to the 15 that are already known were found in Hungarian patients with Wilson's disease. Our results underline the importance and usefulness of genetic testing for patients presenting with liver disease and for family screening