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Objective Primary biliary cirrhosis (PBC), a female-predominant autoimmune liver disease, is commonly associated with fatigue, a sensation of weariness from physical activity. In healthy subjects, motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) increase in amplitude during fatiguing exercise and decrease after the exercise due to post-contraction cortical excitability depression. TMS was utilized herein to investigate if unique cortical excitability changes discriminate women with PBC from healthy controls. Methods Twenty-two women (11 with PBC and 11 healthy controls) performed a voluntary submaximal tonic contraction of finger flexor muscles until exhaustion; MEPs were recorded before and during exercise as well as 10 min after exercise discontinuation. All subjects completed questionnaires for quality of life and fatigue evaluation. Results During exercise an increase in MEPs amplitude was observed in all subjects, with no sign of altered peripheral fatigability. Following exercise women with PBC associated with high fatigability showed a significant lack of reduction of MEP size compared to the healthy controls. Conclusions Women with PBC do not manifest post-exercise depression of cortical excitability. Significance We suggest that an impairment of neural mechanisms underlying physiological central fatigue could occur in PBC, possibly leading to the pathological fatigability lamented by some patients.

Primary biliary cirrhosis (PBC) is a female predominant chronic disease of autoimmune pathogenesis and unknown etiology, although data suggest that genetic predisposition and environmental factors concur to its onset. Among nongenetic factors, several lines of evidence spanning from geoepidemiology to experimental findings support the role of xenobiotics, i.e., chemicals that are capable to induce molecular mimicry through cross reactivity. Indeed, specific xenobiotics are hypothesized to substitute lipoic acid residues on PBC-specific autoepitopes thus triggering autoimmunity. This is supported by data obtained with patient sera reactivities as well as animal models. The scenario is further complicated by the possibility that xenobiotic-metabolizing bacteria might also play a role. We will review the available evidence in this intriguing and rapidly growing field of research and critically discuss its potential implications.

Buprenorphine is a semi-synthetic opioid derivative commonly used in the treatment of heroin addiction. Life-threatening complications have been described following overdoses while few cases of hepatotoxicity due to drug use at therapeutic doses have been recently described in hepatitis C virus carriers. In these cases, however, histological assessment was not exhaustive and no extra-hepatic organ failure was observed. We describe herein a case of acute liver and kidney failure in a patient with previously latent hepatitis C virus chronic infection following recommended doses of buprenorphine. Histology did not demonstrate any feature compatible with hepatitis C virus reactivation or liver cirrhosis and suspension of the treatment led to the resolution of both liver and kidney failure. Causality criteria fulfillment indicates a high probability of buprenorphine-induced liver toxicity. No signs of pre-existant kidney impairment or of pre- or post-renal causes were observed. Since buprenorphine is metabolized through cytochrome P450 3A4, we genotyped six genetic polymorphisms previously described in poor metabolizers but could not confirm these pharmacogenetic bases in this case. In conclusion, we surmise that buprenorphine at suggested doses can induce liver and kidney failure in susceptible individuals, possibly through direct mitochondrial toxicity.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease with an autoimmune pathogenesis and an unknown etiology, predominantly affecting postmenopausal women. The term PBC is a misnomer since most cases currently diagnosed have limited probability to develop cirrhosis. Antimitochondrial autoantibodies, elevated IgM and selective destruction of the intrahepatic bile ducts are the hallmarks of PBC. A permissive genetic background is critical in producing susceptibility despite limited associations with alleles within the MHC. The disease has incomplete concordance in monozygotic twins and its geoepidemiology suggests a role for environmental factors in the induction of PBC. This hypothesis is further supported by clinical (risk factors) and experimental evidence. Some of the factors incriminated model molecular mimicry by infectious agents and xenobiotic chemicals. Additional candidates are being proposed through large screening; all proposed associations ultimately require confirmation in animal models and clinical practice.

Chronic and acute inflammation underlies the molecular basis of atherosclerosis. Cocoa-based products are among the richest functional foods based upon flavanols and their influence on the inflammatory pathway, as demonstrated by several in vitro or ex vivo studies. Indeed, flavanols modify the production of pro-inflammatory cytokines, the synthesis of eicosanoids, the activation of platelets, and nitric oxide-mediated mechanisms. A relative paucity of data still characterizes the in vivo implications of these findings albeit there have been studies suggesting that the regular or occasional consumption of cocoa-rich compounds exerts beneficial effects on blood pressure, insulin resistance, vascular damage, and oxidative stress. Accordingly, rigorous controlled human studies with adequate follow-up and with the use of critical dietary questionnaires are needed to determine the effects of flavanols on the major endpoints of cardiovascular health.