Chronic hepatitis C virus infection:Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients

AIM: To assess the prevalence of extrahepatic manifestations in Bulgarian patients with chronic hepatitis C virus (HCV) infection and identify the clinical and biological manifestations associated with cryoglobulinemia. METHODS: The medical records of 136 chronically infected HCV patients were reviewed to assess the prevalence of extrahepatic manifestations. Association between cryoglobulin-positivity and other manifestations were identified using χ2 and Fisher’s exact test. Risk factors for the presence of extrahepatic manifestations were assessed by logistic regression analysis. RESULTS: Seventy six percent (104/136) of the patients had at least one extrahepatic manifestation. Clinical manifestations included fatigue (59.6%), kidney impairment (25.0%), type 2 diabetes (22.8%), paresthesia (19.9%), arthralgia (18.4%), palpable purpura (17.6%), lymphadenopathy (16.2%), pulmonary fi brosis (15.4%), thyroid dysfunction (14.7%), Raynaud’s phenomenon (11.8%), B-cell lymphoma (8.8%), sicca syndrome (6.6%), and lichen planus (5.9%). The biological manifestations included cryoglobulinproduction (37.5%), thrombocytopenia (31.6%), and autoantibodies: anti-nuclear (18.4%), anti-smooth muscle (16.9%), anti-neutrophil cytoplasm (13.2%) and anti-cardiolipin (8.8%). All extrahepatic manifestations showed an association with cryoglobulin-positivity, with the exception of thyroid dysfunction, sicca syndrome, and lichen planus. Risks factors for the presence of extrahepatic manifestations (univariate analysis) were: age ≥ 60 years, female gender, virus transmission by blood transfusions, longstanding infection (≥ 20 years), and extensive liver fi brosis. The most signifi cant risks factors (multivariate analysis) were longstanding infection and extensive liver fi brosis. CONCLUSION: We observed a high prevalence of extrahepatic manifestations in patients with chronic HCV infection. Most of these manifestations were associated with impaired lymphoproliferation and cryoglobulin production. Longstanding infection and extensive liver fi brosis were signifi cant risk factors for the presence of extrahepatic manifestations in HCV patients.

Extrahepatic immune related manifestations in chronic hepatitis C virus infection

The association of chronic hepatitis C with immune related syndromes has been frequently reported.There is a great range of clinical manifestations affecting various systems and organs such as the skin,the kidneys,the central and peripheral nervous system,the musculoskeletal system and the endocrine glands.Despite the high prevalence of immune related syndromes in patients with chronic hepatitis C,the exact pathogenesis is not always clear.They have been often associated with mixed cryoglobulinemia,a common finding in chronic hepatitis C,cross reaction with viral antigens,or the direct effect of virus on the affected tissues.The aim of this review is to analyze the reported hepatitis C virus immune mediated syndromes,their prevalence and clinical manifestations and to discuss the most supported theories regarding their pathogenesis.

HCV Extrahepatic Manifestations

Hepatitis C virus(HCV)has been shown to affect many tissues other than liver.However,of the many extrahepatic manifestations(EMs)that have been associated with HCV,including cryoglobulinemia,lymphoma,insulin resistance,type 2 diabetes and neurological disorders,only a few have been shown to be directly related to HCV infection of extrahepatic tissues.HCV-triggered immune-mediated mechanisms account for most of the EMs.It is estimated that up to 74%of patients with chronic hepatitis C can develop at least one EM.All HCV patients with EMs should be considered for antiviral therapy,although not all will resolve with sustained virological response.

Effect of treating chronic hepatitis C with direct-acting antivirals on extrahepatic cutaneous manifestations

BACKGROUND Hepatitis C virus(HCV)is a disease with a significant global impact,affecting approximately 2%-2.5%of the world’s population.New direct-acting antivirals(DAAs)have been introduced over the past few years with great success in viral eradication.The association of chronic HCV infection with a wide spectrum of cutaneous manifestations has been widely reported in the literature.AIM To assess the effect of treating HCV with DAAs on the extrahepatic cutaneous manifestations of HCV.METHODS This prospective observational study included 1039 HCV positive Egyptian patients who were eligible to receive DAAs.A total of 30 patients were diagnosed with extrahepatic cutaneous manifestations and fulfilled the inclusion criteria of the study.Of these patients,6 had classic lichen planus,8 were diagnosed with psoriasis vulgaris and 16 had pruritus.All patients received DAAs from October 2018 to July 2019 in the form of a three-month course of sofosbuvir/daclatasvir combination.Patients with lichen planus or psoriasis were dermoscopically evaluated before treatment and 6 mo after treatment,while patients with hepatic pruritus were assessed using the 12-Item Pruritus Severity Scale over the same period.RESULTS All patients with psoriasis showed significant improvement in all psoriatic plaques,and all patients with hepatic pruritus scored 0 on the 12-Item Pruritus Severity Scale indicating total improvement of pruritus.In addition,four of six patients with lichen planus showed complete improvement.CONCLUSION Treatment of HCV with DAAs was significantly effective in improving virusrelated extrahepatic cutaneous manifestations.

Extrahepatic manifestations of chronic hepatitis C virus infection：297 cases from a tertiary medical center in Beijing, China

Background Chronic hepatitis C virus （HCV） infection can affect multiple organ systems and cause a variety of extrahepatic manifestations （EMs）.We sought to assess the constituent ratio of EMs in Chinese patients with chronic HCV infection and identify the clinical and biological factors associated with EM.Methods The medical records of 297 patients with chronic HCV infection were analyzed and demographic and epidemiological information was collected.The diagnosis of chronic HCV infection was based on positive anti-HCV combined with a positive HCV-RNA or at least two times of elevated aminotransferases attributable to HCV infection.Patients with HBV and/or HIV coinfection,autoimmune hepatitis,and history of alcohol abuse were excluded.Results Sixty-two percent （184/297） of the patients had at least one EM,including fatigue （29.4％）,type 2 diabetes mellitus （28.2％）,renal involvement （12.5％）,lymphadenopathy （9.6％）,fever （9.4％）,thyroid dysfunction （8.1％）,and arthralgia （7.4％）.Neuropathy,sicca syndrome,B-cell lymphoma,Raynaud＇s phenomenon,and lichen planus were rare.The mean age of patients with EM was older compared with those without EM.Conclusions EMs were common in Chinese patients with chronic HCV infection,particularly fatigue,type 2 diabetes,renal impairment,lymphadenophy,fever,and thyroid dysfunction.Older age was associated with EMs.

Demyelinating neuropathy in patients with hepatitis B virus: A case report

BACKGROUND Hepatitis B rarely leads to demyelinating neuropathy,despite peripheral neuropathy being the first symptom of hepatitis B infection.CASE SUMMARY A 64-year-old man presented with sensorimotor symptoms in multiple peripheral nerves.Serological testing showed that these symptoms were due to hepatitis B.After undergoing treatment involving intravenous immunoglobulin and an antiviral agent,there was a notable improvement in his symptoms.CONCLUSION Although hepatitis B virus(HBV)infection is known to affect hepatocytes,it is crucial to recognize the range of additional manifestations linked to this infection.The connection between long-term HBV infection and demyelinating neuropathy has seldom been documented;hence,prompt diagnostic and treatment are essential.The patient's positive reaction to immunoglobulin seems to be associated with production of the antigen-antibody immune complex.

Realm of hepatitis E:Challenges and opportunities

Hepatitis E virus(HEV),responsible for widespread viral hepatitis,infects approximately 2.3 billion individuals globally,with a significant mortality burden in Asia.The virus,primarily transmitted through contaminated water and undercooked meat,is often underdiagnosed,particularly in immunocompromised patients.Current HEV treatments,while effective,are limited by adverse effects,necessitating research into safer alternatives.Moreover,HEV’s extrahepatic manifestations,impacting the nervous and renal systems,remain poorly understood.This study underscores the imperative for enhanced HEV research,improved diagnostic methods,and more effective treatments,coupled with increased public health awareness and preventive strategies.

Hepatitis E virus: Epidemiology, diagnosis, clinical manifestations, and treatment

The hepatitis E virus(HEV)is the fifth known form of viral hepatitis and was first recognized as the cause of an epidemic of unexplained acute hepatitis in the early 1980s.Globally,it is one of the most frequent causes of acute viral hepatitis.The majority of HEV infections are asymptomatic and lead to the spontaneous clearance of the virus.Among the eight different genotypes identified to date,HEV genotype 1(HEV1),HEV2,HEV3,and HEV4 are the most frequent genotypes causing infections in humans.HEV1 and HEV2 are prevalent in developing regions and able to result in large-scale outbreaks originating from contaminated water supplies.They are also responsible for severe hepatitis in pregnant patients and infants.In contrast,HEV3 and HEV4 are zoonotic,and the transmission of these genotypes to humans occurs mainly through the fecal contamination of water and consumption of contaminated meat from infected animals.Their main reservoir is the pig,and they are mostly encountered in developed countries.The major risk groups for HEV infection and its ensuing adverse consequences are pregnant women,infants,older people,immunocompromised individuals,patients with underlying chronic liver diseases,and workers that come into close contact with HEV-infected animals.In the clinical perspective,HEV infections have diverse clinical manifestations including acute and self-limiting hepatitis,acute-on-chronic liver disease,chronic hepatitis,cirrhosis,and liver failure.Although HEV mainly results in acute selflimiting infection,chronic HEV infection may occur among immunocompromised patients(e.g.,solid-organ transplant recipients).Additionally,HEV-associated extrahepatic manifestations involving various organs have been reported in the last decade,although the causal link for many of them still needs to be proven.Ribavirin and interferon-alpha are the most widely used agents for the treatment of HEV infections with a certain level of success.However,ribavirin is contraindicated in pregnant patients,and interferon-alpha cannot be used in most transplant recipients.Therefore,there is an urgent need for novel antiviral compounds that are safe and effective particularly for patients having contraindications for ribavirin or interferon-alpha and infected by the ribavirinresistant HEV.In this review article,a literature search using PubMed and MEDLINE databases was performed,up to March 2020.Only the articles published in English were reviewed.

Alterations of seminal and hormonal parameters:An extrahepatic manifestation of HCV infection?

AIM： To evaluate the possible influences of HCV infection and relative antiviral treatment on seminal parameters and reproductive hormonal serum levels. METHODS： Ten male patients with HCV-related chronic hepatitis and 16 healthy male volunteers were studied. In all subjects seminal parameters （nemaspermic concentration, progressive motility, morphology） and hormonal levels were determined. Seminal parameters and inhibin B, follicle-stimulating hormone, luteinizing hormone, total and free testosterone, estradiol, prolactine in patients were measured after six and twelve months of antiviral combined （interferon ± ribavirin） treatment. RESULTS： Patients before treatment showed a significantly lower nemaspermic motility and morphology as well as lower inhibin B and free testosterone levels than controls. Inhibin B levels in cases were improved six and 12 mo after treatment in five responders （161.9 ± 52.8 pg/mL versus 101.7 ± 47.0 pg/mL and 143.4 ± 46.1 pg/ mL versus 95.4 ± 55.6 pg/mL, respectively）. Hormonal pattern of patients did not significantly change after treatment, with the exception of estradiol levels with an initial reduction and an overall subsequent increment （19.7 ± 6.4 pg/mL versus 13.6 ± 5.0 pg/mL versus 17.3 ± 5.7 pg/mL）. However in 1-year responders a significant increment of free testosterone （14.2 ± 2.54 pg/mL versus 17.1 ± 2.58 pg/mL） occurred. An impairment of nemaspermic morphology occurred, while other seminal parameters did not change significantly during antiviral treatment. CONCLUSION： Patients with HCV infection show worse spermatic parameters than controls, suggesting a possible negative influence of virus on spermatogenesis, with further mild impairment during antiviral treatment. However therapy could improve the spermatic function, as suggested by the increased inhibin B levels and improved hormonal pattern in responders. Further studies are needed to confirm these preliminary intriguing results.

Neurological manifestations of hepatitis E virus infection:An overview

Hepatitis E virus(HEV)is an important cause of repeated waterborne outbreaks of acute hepatitis.Recently,several extrahepatic manifestations(EHMs)have been described in patients with HEV infection.Of these,neurological disorders are the most common EHM associated with HEV.The involvement of both the peripheral nervous system and central nervous system can occur together or in isolation.Patients can present with normal liver function tests,which can often be misleading for physicians.There is a paucity of data on HEV-related neurological manifestations;and these data are mostly described as case reports and case series.In this review,we analyzed data of 163 reported cases of HEV-related neurological disorders.The mechanisms of pathogenesis,clinico-demographic profile,and outcomes of the HEV-related neurological disorders are described in this article.Nerve root and plexus disorder were found to be the most commonly reported disease,followed by meningoencephalitis.

Evaluation of intrahepatic manifestation and distant extrahepatic disease in alveolar echinococcosis

BACKGROUND The main endemic areas of alveolar echinococcosis(AE)are in Central Europe and Western China.Both the infiltration of intrahepatic vascular and bile duct structures as well as extrahepatic disease can lead to further complications and may increase morbidity in patients with AE.AIM To evaluate vascular/biliary involvement in hepatic AE and its distant extrahepatic disease manifestations in an international collective was the aim.METHODS Consecutively,five experienced examiners evaluated contrast-enhanced abdominal computed tomography(CT)scans for 200 patients with hepatic AE of each of four locations(n=50)in Germany,France and China.Therefore,we retrospectively included the 50 most recent abdominal contrast-enhanced CT examinations at each center,performed because of hepatic AE from September 21,2007 to March 21,2018.AE liver lesions were classified according to the echinococcosis multilocularis Ulm classification for CT(EMUC-CT).Distant extrahepatic manifestations were documented either by whole body positron emission tomography–CT or with the addition of thoracic CT and cranial magnetic resonance imaging.Vascular/biliary involvement of the hepatic disease as well as the presence of distant extrahepatic manifestations were correlated with the EMUC-CT types of liver lesion.Statistical analysis was performed using SAS Version 9.4(SAS Institute Inc.,Cary,NC,United States).RESULTS Distant extrahepatic AE manifestations were significantly more frequent in China than in Europe(P=0.0091).A significant relationship was found between the presence of distant extrahepatic disease and AE liver lesion size(P=0.0075).Vascular/biliary structures were involved by the liver lesions significantly more frequently in China than in Europe(P<0.0001),and vascular/biliary involvement depended on lesion size.Different morphological types of AE liver lesions led to varying frequencies of vascular/biliary involvement and were associated with different frequencies of distant extrahepatic manifestations:Vascular/biliary involvement as a function of lesions primary morphology ranged from 5.88%of type IV liver lesions to 100%among type III lesions.Type IV differed significantly in these associations from types I,II,and III(P<0.0001).With respect to extrahepatic disease,the primary morphology types IV and V of liver lesions were not associated with any case of distant extrahepatic disease.In contrast,distant extrahepatic manifestations in types I–III were found to varying degrees,with a maximum of 22%for type III.CONCLUSION Different CT morphological patterns of hepatic AE lesions influence vascular/biliary involvement and the occurrence of distant extrahepatic manifestations.There are intercontinental differences regarding the characteristics of AE manifestation.

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 lymphoproUferative 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.

Development of multiple myeloma in a patient with chronic hepatitis C: A case report and review of the literature

An association between chronic hepatitis C virus （HCV） infection and essential mixed cryoglobulinaemia and non-Hodgkin lymphoma （NHL） has been suggested. However, a causative role of HCV in these conditions has not been established. The authors report a case of a 50 year-old woman with chronic hepatitis C （CHC） who has been fol- lowed up since 1998 due to a high viral load, genotype lb and moderately elevated liver function tests （LFTs）. Laboratory data and liver biopsy revealed moderate activity （grade： 5/18, stage： 1/6）. In April 1999, one-year interferon therapy was started. HCV-RNA became negative with normalization of LFTs. However, the patient relapsed during treatment. In September 2002, the patient was admitted for chronic back pain. ACT examination demonstrated degenerative changes. In March 2003, multiple myeloma was diagnosed （IgG-kappa, bone marrow biopsy： 50% plasma cell infiltration）. MRI revealed a compression fracture of the 5^th lumbar vertebral body and an abdominal mass in the right lower quadrant, infiltrating the canalis spinalis. Treatment with vincristine, adriamycin and dexamethasone （VAD） was started and bisphosphonate was administered regularly. In January 2004, after six cycles of VAD therapy, the multiple myeloma regressed. Thalidomide, as a second line treatment of refractory multiple myeloma （MM） was initiated, and followed by peginterferon-α2b and ribavirin against the HCV infection in June. In June 2005, LFTs returned to normal, while HCV-RNA was negative, demonstrating an end of treatment response. Although a pathogenic role of HCV infection in malignant lymphoproliferative disorders has not been established, NHL and possibly MM may develop in CHC patients, supporting a role of a complex follow-up in these patients.