Real-world effectiveness and safety of direct-acting antivirals in hepatitis C virus patients with mental disorders

BACKGROUND It is estimated that 58 million people worldwide are infected with the hepatitis C virus(HCV).Patients with severe psychiatric disorders could not be treated with previously available interferon-based therapies due to their unfavorable side effect profile.This has changed with the introduction of direct-acting antivirals(DAA),although their real-life tolerance and effectiveness in patients with different psychiatric disorders remain to be demonstrated.AIM To evaluate the effectiveness and safety of DAA in patients with various mental illnesses.METHODS This was a retrospective observational study encompassing 14272 patients treated with DAA for chronic hepatitis C in 22 Polish hepatology centers,including 942 individuals diagnosed with a mental disorder(anxiety disorder,bipolar affective disorder,depression,anxiety-depressive disorder,personality disorder,schizophrenia,sleep disorder,substance abuse disorder,and mental illness without a specific diagnosis).The safety and effectiveness of DAA in this group were compared to those in a group without psychiatric illness(n=13330).Antiviral therapy was considered successful if serum ribonucleic acid(RNA)of HCV was undetectable 12 wk after its completion[sustained virologic response(SVR)].Safety data,including the incidence of adverse events(AEs),serious AEs(SAEs),and deaths,and the frequency of treatment modification and discontinuation,were collected during therapy and up to 12 wk after treatment completion.The entire study population was included in the intent-to-treat(ITT)analysis.Per-protocol(PP)analysis concerned patients who underwent HCV RNA evaluation 12 wk after completing treatment.RESULTS Among patients with mental illness,there was a significantly higher percentage of men,treatmentnaive patients,obese,human immunodeficiency virus and hepatitis B virus-coinfected,patients with cirrhosis,and those infected with genotype 3(GT3)while infection with GT1b was more frequent in the population without psychiatric disorders.The cure rate calculated PP was not significantly different in the two groups analyzed,with a SVR of 96.9% and 97.7%,respectively.Although patients with bipolar disorder achieved a significantly lower SVR,the multivariate analysis excluded it as an independent predictor of treatment non-response.Male sex,GT3 infection,cirrhosis,and failure of previous therapy were identified as independent negative predictors.The percentage of patients who completed the planned therapy did not differ between groups with and without mental disorders.In six patients,symptoms of mental illness(depression,schizophrenia)worsened,of which two discontinued treatments for this reason.New episodes of sleep disorders occurred significantly more often in patients with mental disorders.Patients with mental illness were more frequently lost to follow-up(4.2%vs 2.5%).CONCLUSION DAA treatment is safe and effective in HCV-infected patients with mental disorders.No specific psychiatric diagnosis lowered the chance of successful antiviral treatment.

Hepatic perfusion disorders: Etiopathogenesis and related diseases

在这篇文章，我们考察了肝的灌注混乱(HPD ) ， HPD 的发病机理和相应疾病。文学的评论基于计算机搜索(PubMed，索引医师) 并且个人经验。我们认为 HPD 在肝的片断，子段和脑叶之中由于动脉的血流的再分配反映灌注差别。HPD 的平凡 CT 扫描调查结果表明低变细的同样三角形或楔形的区域。在提高对比的 CT 扫描上， HPD 表明多重(或单个) 短暂楔形， rotundloid 或不规则的外观，同类的亢奋的变细(在更少的情况中，低亚硫酸钠变细) 在肝的动脉的阶段(幸运) 和 isoattenuated 或稍微亢奋的稀释区域期间在门期间动脉的阶段。动态提高的磁性的回声(先生) 特征类似于提高的 CT 扫描。Angiographic 调查结果在 portograms 或在肝的 angiograms 上的在动脉、实质的的阶段的楔形的部分染色上包括门静脉的 non-opacification。HPD 的原因是 arterioportal 分流(APS ) ，肝内的脉管的压缩和门静脉吸藏，由亢奋的动脉瘤，脉管的变化和任何另外的未知原因偷现象。放射线学者熟悉 HPD 的各种各样的外观避免假损害的假积极的诊断并且不过高估计疾病的程度是很重要的。

Chronic hepatitis C virus infection and neurological and psychiatric disorders:An overview

Hepatitis C virus(HCV)infection is considered a systemic disease because of involvement of other organs and tissues concomitantly with liver disease.Among the extrahepatic manifestations,neuropsychiatric disorders have been reported in up to 50%of chronic HCV infected patients.Both the central and peripheral nervous system may be involved with a wide variety of clinical manifestations.Main HCV-associated neurological conditions include cerebrovascular events,encephalopathy,myelitis,encephalomyelitis,and cognitive impairment,whereas"brain fog",depression,anxiety,and fatigue are at the top of the list of psychiatric disorders.Moreover,HCV infection is known to cause both motor and sensory peripheral neuropathy in the context of mixed cryoglobulinemia,and has also been recently recognized as an independent risk factor for stroke.These extrahepatic manifestations are independent of severity of the underlying chronic liver disease and hepatic encephalopathy.The brain is a suitable site for HCV replication,where the virus may directly exert neurotoxicity;other mechanisms proposed to explain the pathogenesis of neuropsychiatric disorders in chronic HCV infection include derangement of metabolic pathways of infected cells,alterations in neurotransmitter circuits,autoimmune disorders,and cerebral or systemic inflammation.A pathogenic role for HCV is also suggested by improvement of neurological and psychiatric symptoms in patients achieving a sustained virologic response following interferon treatment;however,further ad hoc trials are needed to fully assess the impact of HCV infection and specific antiviral treatments on associated neuropsychiatric disorders.

From chronic liver disorders to hepatocellular carcinoma: Molecular and genetic pathways

Hepatocarcinogenesis is a process attributed to progressive genomic changes that alter the hepatocellular phenotype producing cellular intermediates that evolve into hepatocellular carcinoma (HCC). During the preneoplastic phase, the liver is often the site of chronic hepatitis and/or cirrhosis, and these conditions induce liver regeneration with accelerated hepatocyte cycling in an organ that is otherwise proliferatively at rest. Hepatocyte regeneration is accelerated by upregulation of mitogenic pathways involving molecular and genetic mechanisms. Hepatic growth factors, inhibitors and triggers may also play a role. This process leads to the production of monoclonal populations of aberrant and dysplastic hepatocytes that have telomerase reexpression, microsatellite instability, and occasionally structural aberrations in genes and chromosomes. Development of dysplastic hepatocytes in foci and nodules and the emergence of HCC are associated with the accumulation of irreversible structural alterations in genes and chromosomes even if the genomic basis of the malignant phenotype is largely heterogeneous. Therefore, a malignant hepatocyte phenotype may be produced by changes in genes acting through different regulatory pathways, thus producing several molecular variants of HCC. On these bases, a key point for future research will be to determine whether the deletions are specific, due to particular loci in the minimally deleted regions of affected chromosome arms, or whether they are nonspecific with loss of large portions of chromosomes or entire chromosome arms leading to passive deletion of loci. The final aim is the possibility of identifying a step where carcinogenetic processes could be terminated.

Psychiatric and substance use disorders co-morbidities and hepatitis C: Diagnostic and treatment implications

Chronic hepatitis C virus(HCV) viral infection is the most common blood-borne viral infection and approximately 2%-3% of the world's population or 170-200 million people are infected. In the United States as many as 3-5 million people may have HCV. Psychiatric and substance use disorders(SUDs) are common co-morbid conditions found in people with HCV and are factors in predisposing people to HCV infection. Also, these co-morbidities are reasons that clinicians exclude people from antiviral therapy in spite of evidence that people with HCV and co-morbid psychiatric and SUD can be safely and effectively treated. Furthermore, the neuropsychiatric side effects of interferon(IFN), until recently the mainstay of antiviral therapy, have necessitated an appreciation and assessment of psychiatric co-morbidities present in people with HCV. The availability of new medications and IFNfree antiviral therapy medication combinations will shorten the duration of treatment and exposure to IFN and thus decrease the risk of neuropsychiatric side effects. This will have the consequence of dramatically altering the clinical landscape of HCV care and will increase the number of eligible treatment candidates as treatment of people with HCV and co-morbid psychiatric and SUDs will become increasingly viable. While economically developed countries will rely on expensive IFN-free antiviral therapy, less developed countries will likely continue to use IFN-based therapies at least until such time as IFNfree antiviral medications become generic. The current manuscript discusses the efficacy and viability of treating HCV in people with psychiatric and SUDs comorbidities, the treatment of the neuropsychiatric side effects of IFN-based therapies and the impact of new medications and new treatment options for HCV that offer the promise of increasing the availability of antiviral therapy in this vulnerable population.

Evolution and predictive factors of thyroid disorder due to interferon alpha in the treatment of hepatitis C

AIM:To study predictive factors of thyroid dysfunction associated with interferon-alpha(IFNα) therapy in chronic hepatitis C(CHC) and to describe its long-term evolution in a large population without previous thyroid dysfunction.METHODS:We performed a follow-up of thyroid function and detection of thyroid antibodies in 301 patients treated for CHC with IFNα from 1999 to 2004.RESULTS:Thyroid disorder developed in 30/301(10%) patients with a mean delay of 6 ± 3.75 mo:13 patients had hyperthyroidism,11 had hypothyroidism,and 6 had biphasic evolution.During a mean follow-up of 41.59 ± 15.39 mo,9 patients with hyperthyroidism,3 with hypothyroidism,and 4 with biphasic evolution normalized thyroid function in 7.88 ± 5.46 mo.Recovery rate of dysthyroidism was not modified by treatment discontinuation,but was better for patients with negative thyroid antibodies before antiviral treatment(P = 0.02).Women had signif icantly more dysthyroidism(P = 0.05).Positive thyroid peroxidase and thyroglobulin antibodies were more frequent before antiviral treatment in patients who developed dysthyroidism(P < 0.0003 and P = 0.0003,respectively).In a multivariate model,low fibrosis was found to be a predictive factor of dysthyroidism(P = 0.039).CONCLUSION:In this monocentric population of CHC,dysthyroidism,especially hyperthyroidism,developed in 10% of patients.Low fibrosis was found to be a predictive factor of dysthyroidism.Thyroid disorder recovered in 16/30 patients(53%) and recovery was better in the non-autoimmune form.

Hepatitis C virus-related lymphoproliferative disorders:An overview

Hepatitis C virus (HCV) is a global health problem affecting 3% of the world’s population (about 180 million) and a cause of both hepatic and extrahepatic diseases. B-cell lymphoproliferative disorders, whose prototype is mixed cryoglobulinemia, represent the most closely related as well as the most investigated HCV- related extrahepatic disorder. The association between extrahepatic (lymphoma) as well as hepatic malignancies (hepatocellular carcinoma) has justified the inclusion of HCV among human cancer viruses. HCV-associated manifestations also include porphyria cutanea tarda, lichen planus, nephropathies, thyreopathies, sicca syndrome, idiopathic pulmonary fibrosis, diabetes, chronic polyarthritis, sexual dysfunctions, cardiopathy/ atherosclerosis, and psychopathological disorders. A pathogenetic link between HCV virus and some lymphoproliferative disorders was confirmed by their responsiveness to antiviral therapy, which is now considered the first choice treatment. The aim of the present paper is to provide an overview of extrahepatic manifestations of HCV infection with particular attention to B-cell lymphoproliferative disorders. Available pathogenetic hypotheses and suggestions about the most appropriate, currently available, therapeutic approaches will also be discussed.

Liver-side of inflammatory bowel diseases:Hepatobiliary and druginduced disorders

Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases(IBD),both in Crohn’s disease and ulcerative colitis(UC),and therefore represent a diagnostic challenge.Immunemediated conditions include primary sclerosing cholangitis(PSC)as the main form,variant forms of PSC(namely small-duct PSC,PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis)and granulomatous hepatitis.PSC is by far the most common,presenting in up to 8%of IBD patients,more frequently in UC.Several genetic foci have been identified,but environmental factors are preponderant on disease pathogenesis.The course of the two diseases is typically independent.PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies.Risk of cholangiocarcinoma is significantly increased in PSC,as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis.No disease-modifying drugs are approved to date.Thus,PSC management is directed against symptoms and complications and includes medical therapies for pruritus,endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease.Other nonimmune-mediated hepatobiliary disorders are gallstone disease,whose incidence is higher in IBD and reported in up to one third of IBD patients,non-alcoholic fatty liver disease,pyogenic liver abscess and portal vein thrombosis.Druginduced liver injury(DILI)is an important issue in IBD,since most IBD therapies may cause liver toxicity;however,the incidence of serious adverse events is low.Thiopurines and methotrexate are the most associated with DILI,while the risk related to anti-tumor necrosis factor-αand anti-integrins is low.Data on hepatotoxicity of newer drugs approved for IBD,like anti-interleukin 12/23 and tofacitinib,are still scarce,but the evidence from other rheumatic diseases is reassuring.Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD,and adequate screening and vaccination is warranted.On the other hand,hepatitis C reactivation does not seem to be a real risk,and hepatitis C antiviral treatment does not influence IBD natural history.The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis,but it is of paramount importance to make a quick and accurate diagnosis,as it may influence the therapeutic management.

Reactivation of hepatitis B virus infection – an important aspect of multifaceted problem

In this editorial we comment on the article published in the recent issue of the W orld Journal of Gastroenterology.We focus specifically on the problem of occult hepatitis B virus(HBV)infection,that is a result of previous hepatitis B(PHB)and a source for reactivation of HBV.The prevalence of PHB is underestimated due to the lack of population testing programs.However,this condition not only com-plicate anticancer treatment,but may be responsible for the development of other diseases,like cancer or autoimmune disorders.Here we unveil possible mecha-nisms responsible for realization of these processes and suggest practical approa-ches for diagnosis and treatment.

Experience of a single center with congenital hepatic fibrosis:A review of the literature

Congenital hepatic fibrosis(CHF) is an autosomal recessive inherited malformation defined pathologically by a variable degree of periportal fibrosis and irregularly shaped proliferating bile ducts.It is one of the fibropolycystic diseases,which also include Caroli disease,autosomal dominant polycystic kidney disease,and autosomal recessive polycystic kidney disease. Clinically it is characterized by hepatic fibrosis,portal hypertension,and renal cystic disease.CHF is known to occur in association with a range of both inherited and non-inherited disorders,with multiorgan involvement,as a result of ductal plate malformation.Because of the similarities in the clinical picture,it is necessary to differentiate CHF from idiopathic portal hypertension and early liver cirrhosis,for which a liver biopsy is essential. Radiological tests are important for recognizing involvement of other organ systems.With regards to our experience at Hacettepe University,a total of 26 patients have been diagnosed and followed-up between 1974 and 2009 with a diagnosis of CHF.Presentation with Caroli syndrome was the most common diagnosis,with all such patients presenting with symptoms of recurrentcholangitis and symptoms related to portal hypertension. Although portal fibrosis is known to contribute to the ensuing portal hypertension,it is our belief that portal vein cavernous transformation also plays an important role in its pathogenesis.In all patients with CHF portal vein morphology should be evaluated by all means since portal vein involvement results in more severe and complicated portal hypertension.Other associations include the Joubert and Bardet-Biedl syndromes.

Chronic hepatitis B infection with concomitant hepatic steatosis:Current evidence and opinion

With the increasing incidence of obesity and metabolic syndrome worldwide,concomitant nonalcoholic fatty liver disease(NAFLD)in patients with chronic hepatitis B(CHB)has become highly prevalent.The risk of dual etiologies,outcome,and mechanism of CHB with concomitant NAFLD have not been fully characterized.In this review,we assessed the overlapping prevalence of metabolic disorders and CHB,assessed the risk of advanced fibrosis/hepatocellular carcinoma in CHB patients concomitant with NAFLD,and discussed the remaining clinical issues to be addressed in the outcome of such patients.We also explored the possible roles of hepatitis B virus in the development of steatosis and discussed difficultiesof histological evaluation.For CHB patients,it is important to address concomitant NAFLD through lifestyle management and disease screening to achieve better prognoses.The assessment of progressive changes and novel therapies for CHB patients concomitant with NAFLD deserve further research.

Upregulated hepatic expression of mitochondrial PEPCK triggers initial gluconeogenic reactions in the HCV-3 patients

Objective: To identify the differential expression of candidate gluconeogenic genes which may initiate hepatitis C virus(HCV) related metabolic disorder during early stages of disease. Methods: Patients of diverse age and sex, with positive HCV genotype 3(HCV-3) RNA in serum and with no history of other related infections, co-infections, alcoholism, diabetes or chemotherapeutic treatments were considered for this study. Semi-quantitative reverse transcriptase PCR analysis and quantitative fold change analysis of the fresh liver biopsies of eight chronically infected HCV-3 patients and six healthy individuals were evaluated for three potential biomarkers involved in glucose homeostasis induction, namely mitochondrial phosphoenolpyruvate carboxykinase 2(PCK2), glucose-6-phosphatase catalytic subunit(G6PC) and associated forkhead box protein 01(FOXO1). Results: Symptomatic evaluation, clinical history and blood test were conducted according to general disease prognosis procedures and reported here. Significantly upregulated expression of PCK2 independent of age, sex and viral infectivity levels in all HCV patients was observed, whereas no significant changes in the expression of G6 PC and FOXO1 were found. Conclusions: PCK2 triggers initial gluconeogenic reactions which ultimately result in the accumulation of glycogen in the liver hepatocytes. We therefore suggest that the overproduction of PCK2 has important physiological role in the onset of metabolic disorder in the HCV-3 patients.

A Homozygotic Mutation in KDSR may Cause Keratinization Disorders and Thrombocytopenia: A Case Report

Pathogenic mutations in 3-keto-dihydrosphingosine reductase(KDSR)gene are associated with keratinization disorders and impaired platelet function.However,no case with both homozygotic mutation of KDSR and hepatic hemangioendothelioma has ever been reported due to its low prevalence.Here we report a seven months old Chinese boy with a homozygotic missense mutation in KDSR and both of his parents carry a same heterozygous mutation.He was born with thick plate-like scales overlying erythrodermic skin,but the skin symptoms were resolved spontaneously over the first month of his birth.He was also diagnosed with hepatic hemangioendothelioma at birth and accepted a resection surgery at 2 months old.At birth,his platelet count was severely low(10-20×10~9/L)with recurrent skin and gingival bleeding.Meanwhile,he suffered a mild normocytic,normochromic anemia with normal iron and hematinic levels.The anemia spontaneously recovered over the first 6 months,while the platelet count keeped at a low level(4-20×10~9/L).Treatment with corticosteroids,immunoglobulin or thrombopoietin was all suboptimal.

Diagnosis of hepatic inflammatory pseudotumor by fine-needle biopsy

Hepatic inflammatory pseudotumor(IPT)is a benign lesion characterized by chronic infiltration of inflammatory cells and fibrosis that clinically,radiologically,and pathologically mimics malignancy.However,the epidemiology of IPTs remains unclear.IPTs are often misdiagnosed as malignant lesions because of the lack of characteristic features.We present the case of a 32-year-old man that was misdiagnosed as intrahepatic cholangiocarcinoma by CECT,CEMRI,and CEUS,which was finally confirmed as IPT by fine-needle liver biopsy.In this report,the key factor in the diagnosis of liver inflammatory masses was the presence of hepatic perfusion disorder.

大黄廑虫丸联合抗病毒治疗乙型肝炎肝硬化对凝血功能紊乱、肝硬化程度及门静脉系统相关参数的影响

目的探讨大黄廑虫丸联合抗病毒治疗乙型肝炎(HBV)肝硬化对病人凝血功能紊乱、肝硬化程度及门静脉系统相关参数的影响。方法选择2020年6月至2022年6月于无锡市中医医院接受治疗的100例HBV肝硬化病人,运用随机数字表法将其分为观察组与对照组,各50例。对照组采用常规抗病毒疗法,观察组基于对照组联合大黄廑虫丸,评估两组疗效并进行比较,对比两组凝血功能、HBV-DNA值、肝硬化程度、门静脉系统相关参数变化。结果观察组治疗显效病人占50.00%高于对照组26.00%,差异有统计学意义(P<0.05);治疗前两组病人的血小板计数(PLT)、凝血酶时间(TT)、纤维蛋白原(FIB)、HBVDNA水平比较差异无统计学意义(P>0.05),治疗后PLT[(125.42±24.57)×10^(9)/L比(116.12±21.38)×10^(9)/L]、FIB水平[(2.76±0.56)g/L比(1.80±0.63)g/L]高于对照组,TT[(14.18±4.28)s比(16.61±5.34)s]、HBV-DNA[(2.72±0.43)×10^(5) IU/L比(3.38±0.68)×10^(5) IU/L]小于对照组,差异有统计学意义(P<0.05);两组治疗前后的肝硬化程度和门静脉内径比较差异无统计学意义(P>0.05),治疗后观察组肝脏硬度数值(LSM)(15.32±2.27)kPa比(17.94±2.34)kPa、肝门静脉内径[(12.29±1.98)mm比(13.80±2.15)mm]低于对照组,差异有统计学意义(P<0.05);两组治疗前天冬氨酸氨基转移酶(AST)、丙氨酰氨基转移酶(ALT)水平比较差异无统计学意义(P>0.05),治疗后ALT、AST水平均下降,观察组下降幅度高于对照组,差异有统计学意义(P<0.05)。结论相较于单独抗病毒治疗,联合大黄廑虫丸治疗,疗效较好,改善肝功能,有助于凝血功能的恢复,缩小肝门静脉内径。

Hepatobiliary manifestations in inflammatory bowel disease: The gut,the drugs and the liver

Abnormal liver biochemical tests are present in up to30%of patients with inflammatory bowel disease(IBD),and therefore become a diagnostic challenge.Liver and biliary tract diseases are common extraintestinal manifestations for both Crohn’s disease and ulcerative colitis(UC),and typically do not correlate with intestinal activity.Primary sclerosing cholangitis(PSC)is the most common hepatobiliary manifestation of IBD,and is more prevalent in UC.Approximately 5%of patients with UC develop PSC,with the prevalence reaching up to 90%.Cholangiocarcinoma and colon cancer risks are increased in these patients.Less common disorders include autoimmune hepatitis/PSC overlap syndrome,IgG4-associated cholangiopathy,primary biliary cirrhosis,hepatic amyloidosis,granulomatous hepatitis,cholelithiasis,portal vein thrombosis,liver abscess,and non-alcoholic fatty liver disease.Hepatitis B reactivation during immunosuppressive therapy is a major concern,with screening and vaccination being recommended in serologically negative cases for patients with IBD.Reactivation prophylaxis with entecavir or tenofovir for 6to 12 mo after the end of immunosuppressive therapy is mandatory in patients showing as hepatitis B surface antigen(HBsAg)positive,independently from viral load.HBsAg negative and anti-HBc positive patients,with or without anti-HBs,should be closely monitored,measuring alanine aminotransferase and hepatitis B virus DNA within 12 mo after the end of therapy,and should be treated if the viral load increases.On the other hand,immunosuppressive therapy does not seem to promote reactivation of hepatitis C,and hepatitis C antiviral treatment does not influence IBD natural history either.Most of the drugs used for IBD treatment may induce hepatotoxicity,although the incidence of serious adverse events is low.Abnormalities in liver biochemical tests associated with aminosalicylates are uncommon and are usually not clinically relevant.Methotrexaterelated hepatotoxicity has been described in 14%of patients with IBD,in a dose-dependent manner.Liver biopsy is not routinely recommended.Biologics-related hepatotoxicity is rare,but has been shown most frequently in patients treated with infliximab.Thiopurines have been associated with veno-occlusive disease,regenerative nodular hyperplasia,and liver peliosis.Routine liver biochemical tests are recommended,especially during the first month of treatment.All these conditions should be considered in IBD patients with clinical or biochemical features suggestive of hepatobiliary involvement.Diagnosis and management of these disorders usually involve hepatologists and gastroenterologists due to its complexity.

Immunological alterations in hepatitis C virus infection

A higher prevalence of immunological processes has recently been reported in patients with hepatitis C virus(HCV)infection,focusing the attention of physicians and researchers on the close association between HCV and immune disorders.HCV lymphotropism represents the most important step in the pathogenesis of virusrelated immunological diseases and experimental,virologic,and clinical evidence has demonstrated a trigger role for HCV both in systemic autoimmune diseases,such as rheumatoid arthritis,Sj?gren syndrome,hemolytic anemia and severe thrombocytopenia,and in organ-specific autoimmune diseases,such as autoimmune hepatitis,thyroid disorders and diabetes.This review will outline the principal aspects of such HCVinduced immunological alterations,focusing on the prevalence of these less characterized HCV extrahepatic manifestations.

Alcoholic liver disease and hepatitis C virus infection

Alcohol consumption and hepatitis C virus(HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher(up to 50%) in alcoholic patients than in the general po pulation. However, the presence of advanc e d alcoholic liver disease(ALD) or intravenous drug use(IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefi t from addi tionalsupport during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.

Hepatitis C virus and neurological damage

Chronic hepatitis C virus(HCV) infection exhibits a wide range of extrahepatic complications, affecting various organs in the human body. Numerous HCV patients suffer neurological manifestations, ranging from cognitive impairment to peripheral neuropathy. Overexpression of the host immune response leads to the production of immune complexes, cryoglobulins, as well as autoantibodies, which is a major pathogenic mechanism responsible for nervous system dysfunction. Alternatively circulating inflammatory cytokines and chemokines and HCV replication in neurons is another factor that severely affects the nervous system. Furthermore, HCV infection causes both sensory and motor peripheral neuropathy in the mixed cryoglobulinemia as well as known as an important risk aspect for stroke. These extrahepatic manifestations are the reason behind underlying hepatic encephalopathy and chronic liver disease. The brain is an apt location for HCV replication, where the HCV virus may directly wield neurotoxicity. Other mechanisms that takes place by chronic HCV infection due the pathogenesis of neuropsychiatric disorders includes derangement of metabolic pathways of infected cells, autoimmune disorders, systemic or cerebral inflammation and alterations in neurotransmitter circuits. HCV and its pathogenic role is suggested by enhancement of psychiatric and neurological symptoms in patients attaining a sustained virologic response followed by treatment with interferon; however, further studies are required to fully assess the impact of HCV infection and its specific antiviral targets associated with neuropsychiatric disorders.

Neurological and psychiatric effects of hepatitis C virus infection

Hepatitis C virus(HCV)infection is widespread and affects 71 million people worldwide.Although hepatic manifestations are the most frequent,ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma,it is also associated with several extrahepatic manifestations.Infected patients may present nonspecific neurological symptoms,regardless of the presence of liver cirrhosis.Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized:neuroinvasion,immune-mediated damage,neurotransmitter alterations and cryoglobulinemia.Alterations of the central nervous system include cerebral vasculopathy,acute or subacute encephalopathy and inflammatory disorders.HCV infection may be responsible for neuropathies,of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness.Up to 50%of patients with HCV infection may experience cognitive decline and psychological disorders,such as depression and fatigue.HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy.It can be studied using specific tests that mainly explore executive functions,verbal learning and verbal recall.These disorders significantly reduce the quality of life.The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response.However,the effect of therapy may differ depending on the type of organ involved;neurological symptoms can be irreversible if there is organic liver damage.The aim of this review is to provide a critical overview of physiopathological mechanisms,diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.