Chronic HCV infection and inflammation:Clinical impact on hepatic and extra-hepatic manifestations

The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus(HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways,oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury(fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases(lymphoproliferative disease,atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCVrelated diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.

Neurological Manifestations of Vitamin B12 Deficiency: About a Case

The authors report a case of deficient sensory neuropathy secondary to vitamin B12 deficiency, diagnosed in the neurology department of the Sino-Central African Friendship University Hospital in Bangui. The diagnosis was made possible by electroneuromyography which showed subclinical neurological damage associated with hematological damage (anemia). Through this observation, we recall the diagnostic criteria of the disease in a context of difficult medical practice. .

Coagulation abnormalities and their relationship with bleeding manifestations in patients with dengue-A single center observational study

Objective:To evaluate coagulation abnormalities and their relationship with bleeding manifestations among patients with dengue.Methods:This observational study was conducted on 292 adult dengue patients who were admitted to a tertiary care hospital of Western India from July 2021 to June 2022.Coagulation tests including prothrombin time(PT),international normalized ratio(INR),activated partial thromboplastin time(aPTT),fibrinogen,and D-dimer were performed.Patients were monitored for bleeding manifestations.Results:Coagulation abnormalities were reported in 42.8%of the patients.Overall,prolonged aPTT was the most common coagulation abnormality(40.8%),followed by low fibrinogen(38.7%),raised D-dimer(31.2%),raised INR(26.0%)and prolonged PT(19.2%).Bleeding manifestations were present in 19.9%patients.PT,INR,aPTT and D-dimer levels were significantly higher(P<0.01)and fibrinogen level was significantly lower(P<0.001)in patients with bleeding compared to patients without bleeding.Patients with bleeding had a significantly higher rate of all coagulation abnormalities than patients without bleeding(P<0.01).Conclusions:Patients with bleeding showed a significantly higher frequency of coagulation abnormalities compared to patients without bleeding.Patients with dengue should be assessed for coagulation abnormalities.

Pathogenesis,clinical manifestations,diagnosis,and treatment progress of achalasia of cardia

Achalasia cardia,type of esophageal dynamic disorder,is a relatively rare primary motor esophageal disease characterized by the functional loss of plexus ganglion cells in the distal esophagus and lower esophageal sphincter.Loss of function of the distal and lower esophageal sphincter ganglion cells is the main cause of achalasia cardia,and is more likely to occur in the elderly.Histological changes in the esophageal mucosa are considered pathogenic;however,studies have found that inflammation and genetic changes at the molecular level may also cause achalasia cardia,resulting in dysphagia,reflux,aspiration,retrosternal pain,and weight loss.Currently,the treatment options for achalasia focus on reducing the resting pressure of the lower esophageal sphincter,helping to empty the esophagus and relieve symptoms.Treatment measures include botulinum toxin injection,inflatable dilation,stent insertion,and surgical myotomy(open or laparoscopic).Surgical procedures are often subject to controversy owing to concerns about safety and effectiveness,particularly in older patients.Herein,we review clinical epidemiological and experimental data to determine the prevalence,pathogenesis,clinical presentation,diagnostic criteria,and treatment options for achalasia to support its clinical management.

Liver manifestations in COVID-19 patients:A review article

The coronavirus disease 2019(COVID-19)initially presented as a disease that affected the lungs.Then,studies revealed that it intricately affected disparate organs in the human body,with the liver being one of the most affected organs.This review aimed to assess the association between COVID-19 and liver function,shedding light on its clinical implication.However,its exact pathophysiology remains unclear,involving many factors,such as active viral replication in the liver cells,direct cytotoxic effects of the virus on the liver or adverse reactions to viral antigens.Liver symptoms are mild-to-moderate transaminase elevation.In some patients,with underlying liver disease,more serious outcomes are observed.Thus,liver function should be meticulously considered in patients with COVID-19.

Hepatobiliary manifestations following two-stages elective laparoscopic restorative proctocolectomy for patients with ulcerative colitis:A prospective observational study

BACKGROUND Hepatobiliary manifestations occur in ulcerative colitis(UC)patients.The effect of laparoscopic restorative proctocolectomy(LRP)with ileal pouch anal anastomosis(IPAA)on hepatobiliary manifestations is debated.AIM To evaluate hepatobiliary changes after two-stages elective laparoscopic restorative proctocolectomy for patients with UC.METHODS Between June 2013 and June 2018,167 patients with hepatobiliary symptoms underwent two-stage elective LRP for UC in a prospective observational study.Patients with UC and having at least one hepatobiliary manifestation who underwent LRP with IPAA were included in the study.The patients were followed up for four years to assess the outcomes of hepatobiliary manifestations.RESULTS The patients'mean age was 36±8 years,and males predominated(67.1%).The most common hepatobiliary diagnostic method was liver biopsy(85.6%),followed by Magnetic resonance cholangiopancreatography(63.5%),Antineutrophil cytoplasmic antibodies(62.5%),abdominal ultrasonography(35.9%),and Endoscopic retrograde cholangiopancreatography(6%).The most common hepatobiliary symptom was Primary sclerosing cholangitis(PSC)(62.3%),followed by fatty liver(16.8%)and gallbladder stone(10.2%).66.4%of patients showed a stable course after surgery.Progressive or regressive courses occurred in 16.8%of each.Mortality was 6%,and recurrence or progression of symptoms required surgery for 15%.Most PSC patients(87.5%)had a stable course,and only 12.5%became worse.Two-thirds(64.3%)of fatty liver patients showed a regressive course,while one-third(35.7%)showed a stable course.Survival rates were 98.8%,97%,95.8%,and 94%at 12 mo,24 mo,36 mo,and at the end of the follow-up.CONCLUSION In patients with UC who had LRP,there is a positive impact on hepatobiliary disease.It caused an improvement in PSC and fatty liver disease.The most prevalent unchanged course was PSC,while the most common improvement was fatty liver disease.

Analysis of Manifestations of and Solutions to Chinglish

Chinglish often occurs in the process of English language acquisition.It’s necessary to clarify what Chinglish is and what the major features are.The paper elaborates five major manifestations of Chinglish in terms of phonological difference,lexical redundancy and word misuse,unreasonable sentence structure as well as semantic misuse,and then proposes solutions to Chinglish through improvement of linguistic competence,conversion of thinking modes and enhancement of the awareness of cultural factors.

Osteoarticular manifestations of human brucellosis:A review

Brucellosis is a common global zoonotic disease, which is responsible for a range of clinical manifestations. Fever, sweating and musculoskeletal pains are observed in most patients. The most frequent complication of brucellosis is osteoarticular involvement, with 10% to 85% of patients affected. The sacroiliac(up to 80%) and spinal joints(up to 54%) are the most common affected sites.Spondylitis and spondylodiscitis are the most frequent complications of brucellar spinal involvement. Peripheral arthritis, osteomyelitis, discitis, bursitis and tenosynovitis are other osteoarticular manifestations, but with a lower prevalence. Spinal brucellosis has two forms: focal and diffuse. Epidural abscess is a rare complication of spinal brucellosis but can lead to permanent neurological deficits or even death if not treated promptly. Spondylodiscitis is the most severe form of osteoarticular involvement by brucellosis, and can have single-or multifocal involvement. Early and appropriate diagnosis and treatment of the disease is important in order to have a successful management of the patients with osteoarticular brucellosis. Brucellosis should be considered as a differential diagnosis for sciatic and back pain, especially in endemic regions. Patients with septic arthritis living in endemic areas also need to be evaluated in terms of brucellosis. Physical examination, laboratory tests and imaging techniques are needed to diagnose the disease. Radiography, computed tomography, magnetic resonance imaging(MRI) and bone scintigraphy are imaging techniques for the diagnosis of osteoarticular brucellosis. MRI is helpful to differentiate between pyogenic spondylitis and brucellar spondylitis. Drug medications(antibiotics)and surgery are the only two options for the treatment and cure of osteoarticular brucellosis.

Scrub typhus:pathophysiology,clinical manifestations and prognosis

Scrub typhus is a zoonosis caused by the pathogen Orientia tsutsugamushi(O.tsvtsugamushi). The disease has significant prevalence in eastern and Southeast Asia.Usually presenting as an acute febrile illness,the diagnosis is often missed because of similarities with oilier tropical febrile infections.Many unusual manifestations are present,and these are described in this review,together with an outline of current knowledge of pathophysiology.Awareness of these unusual clinical manifestations will help the clinician to arrive at an early diagnosis,resulting in early administration of appropriate antibiotics.Prognostic indicators for severe disease have not yet been clearly established.

Extraintestinal manifestations in a large series of Italian inflammatory bowel disease patients

AIM:To investigate prevalence,type and time of onset of extraintestinal manifestations(EIMs)in a series of Italian inflammatory bowel disease(IBD)patients.METHODS:Data of 811 IBD consecutive patients,first referred to our Centre from 2000 to 2011,were retrospectively evaluated.RESULTS:Eight hundred and eleven IBD patients(437M,374 F)were studied:595 ulcerative colitis(UC)(73.4%)and 216 Crohn’s disease(CD)(26.6%).Among these,329(40.6%)showed EIMs:210 UC(35.3%)and119 CD(55.1%)(P<0.0001).Considering the time of the diagnosis of IBD,37 EIMs(11.2%)were developed before,229(69.6%)after and 63(19.2%)were simultaneous.The type of EIM were as follows:240 musculoskeletal(29.6%),in 72 CD patients and in 168 UC(P<0.0001);47 mucocutaneous(5.8%),in 26 CD and in21 UC(P=0.0049);26 ocular(3.2%),in 16 CD and in10 UC(CD 7.4%vs UC 1.7%,P=0.0093);6 hepatobiliary(0.8%);10 endocrinological(1.2%).In particular,with regards to the involvement of the musculoskeletal system,arthritis Type 1 was found in 41 CD(19%)and in 61 UC(10.2%)(P=0.0012)and Type 2 in 25 CD(11.6%)and in 100 UC(16.8%)(P=0.0012).CONCLUSION:Mucocutaneous manifestations,arthritis Type 1 and uveitis were significantly more frequent in CD than UC.The complications of the musculoskeletal system were the mostly observed ones,often with symptoms more severe than intestinal ones,confirming the need for close cooperation with rheumatologists.

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.

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.

Rheumatologic manifestations of hepatic diseases

A possible link is suggested between hepatic diseases and rheumatic disease. Polyarthralgia and polyarthritismay be seen during the prodromal period of acute viral hepatitis, especially in hepatitis B virus (HBV). Thesymptoms of arthritis, mild, localized or generalized, mostly involve the small joints of hands. Jointsymptoms frequently precede the onset of jaundice, no residual joint deformities. Circulating immunecomplexes are believed to play a causative role in the development of vasculitis and arthritis.Hemochromatosis is an antosomal recessive disorder of iron. About 43%-81% of patients withhemochromatosis have arthritis. The common extrahepatic manifestations of autoimmune hepatitis arearthralgia and skin rash. The reported prevalence of symptomatic inflammatory arthropathy in patients withprimary biliary cirrhosis ranges from 4% to 50%. Skeletal involvement with Wilson’s disease is common.Such patients may complain of pain and stiffness, mainly in the knee, wrist, or other large joints.Shwachman’s syndrome is a disorder of pancreatic exocrine. Symmetric bone lesions have been reported in10% to 15% of patients. They are involved predominantly at the femoral neck. Rheumatic symptoms areseen in one third of adult patients with cystic fibrosis and arthritis in 2.5% to 12% of patients. The arthritiscaused by pancreatic panniculitis is usually symmetrical and involves the small joints of the hand, wrist, andfeet, but may involve such larger joints as the elbow, ankle, and knee.

Clinical manifestations of patients with chronic pancreatitis

BACKGROUND: Recent advances in molecular and genomic technologies and pancreatic imaging techniques provided some insights into genetic, environmental, immunologic, and pathobiological factors for chronic pancreatitis (CP). This study was undertaken to investigate the clinical manifestations of patients with chronic pancreatitis at our hospital. METHODS: The data of the patients with CP who had been treated at our hospital between 1997 and 2004 were analyzed. RESULTS: The major symptoms of the patients with CP were abdominal pain, dyspepsia, loss of weight, diabetes mellitus, pancreatic pseudocyst, steatorrhea, and calcification. Biliary diseases were found to be the first cause of CP in this study; but alcohol abuse was the major cause of CP in men and biliary diseases were the first etiological factors for CP in women. The etiological difference of constituent ratio between men and women was related to alcohol comsumption (P【0.01). CONCLUSIONS: During the past 8 years, biliary diseases have been the major etiological factors for CP, but their constituent ratio is decreasing, and the constituent ratio of alcohol abuse is increasing gradually. Alcohol tends to replace biliary diseases as the primary etiological factor for CP.

Ocular manifestations of internal carotid artery dissection

Internal carotid artery dissection(ICAD) results from disruption of the intima of the arterial wall, and can lead to intrusion of blood into the arterial wall and form an intramural hematoma. The hematoma can compress the true lumen of the vessel, causing functional stenosis or occlusion. The classic triad signs of ICAD include pain in the ipsilateral neck, head and orbital regions; a(partial) Horner syndrome; and cerebral or retinal ischemia. However, not all ICAD patients present with this classic signs. In some cases, ocular manifestations are the initial(and sometimes the only) findings. We summarize the ocular manifestations associated with ICAD in 3 categories: visual symptoms, oculosympathetic palsy, and ocular motor nerve palsy.

Smoking increases the risk of extraintestinal manifestations in Crohn's disease

AIM:To demonstrate a high prevalence of extraintestinal manifestations(EIMs)in a prospective populationbased cohort of inflammatory bowel disease(IBD)patients at first diagnosis as well as during the early course of the disease.METHODS:EIMs are common in patients with IBD.Data on the frequency of EIMs have mostly been assessed in patients from tertiary centers;however,data about the prevalence of EIMs at first diagnosis as well as factors influencing their incidence during the early course of disease from prospective population-based cohorts are scarce.We present data of patients of our population-based"Oberpfalz cohort"(Bavaria,Germany)from first diagnosis(up to 3 mo after first diagnosis)as well as during the early course of the disease.Possible risk factors were assessed by calculating the relative risk(RR)as well as using logistic regression analysis.RESULTS:In total,data of 257 newly diagnosed patients with IBD were evaluated[161 Crohn’s disease(CD),96 ulcerative colitis(UC)].Median duration of follow-up was 50 mo after first diagnosis.In 63.4%of all patients(n=163),an EIM was diagnosed at any point during the observation period.At first diagnosis,patients with CD had a significantly increased risk of an EIM[n=69(42.9%)]compared with UC patients[n=21(21.9%);P<0.001;RR=1.96;95%CI:1.30-2.98].Active smoking increased the risk of CD patients developing an EIM during the early course of the disease,but notably not of UC patients(P=0.046;RR=1.96;95%CI:1.01-3.79).In addition,using logistic regression analysis,the need for IBD-related surgery and a young age at first diagnosis were identified as risk factors for the development of an EIM in CD patients.No association with EIMs was found for the factors sex,localization of the disease and positive family history of IBD.In contrast,no key factors which increased the risk of development of an EIM could be identified in UC patients.CONCLUSION:We found a high prevalence of EIM in this cohort at first diagnosis and during the early course of the disease.In patients with CD,smoking,need for surgery and younger age at first diagnosis were risk factors for the development of an EIM.

Prevalence and characteristics of ophthalmological extra-intestinal manifestations in Chinese patients with inflammatory bowel disease

AIM:To investigate the prevalence of ophthalmological extra-intestinal manifestations(O-EIMs) in Chinese patients with inflammatory bowel disease(IBD) and to identify risk factors for the development of O-EIMs.METHODS:The study population consisted of Chinese patients with a definite diagnosis of Crohn's disease(CD) or ulcerative colitis(UC) in a large teaching hospital between January 1995 and December 2014.Demographic and clinical characteristics of patients were extracted retrospectively.RESULTS: In this twenty-year cohort,645 IBD patients(517 with UC,128 with CD) were registered.Among them122(18.9%) exhibited at least one EIM.Of 13 patients(2.0%) developed O-EIMs,7 of CD(5.5%) and 6 of UC(1.2%).Clinical ophthalmological manifestations included redness(76.9%),burning(61.5%),pain(38.5%),itching(15.4%) of eyes and vision change(7.7%).O-EIMs included episcleritis(7),uveitis(5) and dry eye(1).OEIMs were more prevalent in female(odds ratio for male0.61,95% confidence interval 0.52-0.73,P <0.0001),and patients who had IBD diagnosis at young age(odds ratio for patients aged >30 years 0.76,95% confidence interval0.65-0.88,P <0.0001).CONCLUSION: The frequency of O-EIMs in Chinese patients with IBD is lower than the rates reported in the studies of European and American countries.Episcleritisand uveitis are the most common O-EIMs.O-EIMs are more frequent in patients with CD and more prevalent in female and patients who have IBD diagnosis at young age.

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.

Extra-skeletal manifestations in mice affected by Clcn7-dependent autosomal dominant osteopetrosis type 2 clinical and therapeutic implications

Autosomal dominant osteopetrosis type 2 (ADO2) is a high-density brittle bone disease characterized by bone pain,multiple fractures and skeletal-related events,including nerve compression syndrome and hematological failure.We demonstrated that in mice carrying the heterozygous Clcn7^G213R mutation,whose human mutant homolog CLCN7^G215R affects patients,the clinical impacts of ADO2 extend beyond the skeleton,affecting several other organs.The hallmark of the extra-skeletal alterations is a consistent perivascular fibrosis,associated with high numbers of macrophages and lymphoid infiltrates.Fragmented clinical information in a small cohort of patients confirms extra-skeletal alterations consistent with a systemic disease,in line with the observation that the CLCN7 gene is expressed in many organs.ADO2 mice also show anxiety and depression and their brains exhibit not only perivascular fibrosis but also β-amyloid accumulation and astrogliosis,suggesting the involvement of the nervous system in the pathogenesis of the ADO2 extra-skeletal alterations.Extra-skeletal organs share a similar cellular pathology,confirmed also in vitro in bone marrow mononuclear cells and osteoclasts,characterized by an impairment of the exit pathway of the Clcn7 protein product,ClC7,through the Golgi,with consequent reduced ClC7 expression in late endosomes and lysosomes,associated with high vesicular pH and accumulation of autophagosome markers.Finally,an experimental siRNA therapy,previously proven to counteract the bone phenotype,also improves the extra-skeletal alterations.These results could have important clinical implications,supporting the notion that a systematic evaluation of ADO2 patients for extra-skeletal symptoms could help improve their diagnosis,clinical management,and therapeutic options.

Intra-hepatic and extra-hepatic cholangiocarcinoma:New insight into epidemiology and risk factors

Cholangiocarcinoma(CCA) is a malignant tumour that arises from biliary epithelium at any portion of the biliary tree.CCA is currently classified as intra-hepatic or extra-hepatic CCA(EH-CCA).Recent evidences suggest that intra-hepatic CCA(IH-CCA) and EH-CCA are biologically different cancers,giving further support to a number of recent epidemiological studies showing large differences in terms of incidence,mortality and risk factors.The purpose of this manuscript is to review recent literature dealing with the descriptive epidemiology and risk factors of CCA with a special effort to compare IH-with EH-CCA.