Idiopathic hyalinizing fibrosclerosis: A systemic steroid-resistant condition distinct from IgG4-related disease.

Since the concept of IgG4-related disease (IgG4-RD) was proposed, that diagnosis has been considered in idiopathic fibroinflammatory diseases in various organs, particularly in cases with multi-organ involvement. We have recently encountered three cases of fibrosing disease of uncertain etiology with shared microscopic appearances. Case 1 (56-year-old man) had an irregular mass at the base of mesentery. Case 2 (29-year-old woman) presented with obstructive jaundice due to an ill-defined mass at the hepatic hilum and two lung nodules. Case 3 (53-year-old man) had multiple solid nodules in the mediastinum, peritoneum, retroperitoneum, and mesentery; he also had diffuse irregular narrowing of the intra- and extra-hepatic bile ducts in keeping with sclerosing cholangitis. Serum IgG4 concentrations were not elevated. Biopsies from the nodular lesions showed extensive hyalinizing fibrosis with an only focal lymphoplasmacytic infiltrate. Thick collagenous bundles are arranged in an irregular or partly whorl pattern. Typical storiform fibrosis or obliterative phlebitis was not observed. The number of IgG4-positive plasma cells was <10 cells/high-power field; the ratio of IgG4/IgG-positive plasma cells was <30%. After the histological diagnosis of sclerosing mesenteritis, pulmonary hyalinizing granuloma, and mediastinal fibrosis was made, they were treated with a trial of steroids, but none showed a significant response. In conclusion, a hyalinizing fibrotic condition can occur at various anatomical sites. They have shared microscopic findings, and are steroid-resistant. Although the clinical presentation may mimic IgG4-RD, the two conditions are likely distinct. We would propose a diagnostic term of 'idiopathic hyalinizing fibrosclerosis' for this under-recognized, rare, systemic condition.

Serologic extracellular matrix remodeling markers are related to fibrosis stage and prognosis in a phase 2b trial of simtuzumab in patients with primary sclerosing cholangitis.

BACKGROUND: Novel noninvasive predictors of disease severity and prognosis in primary sclerosing cholangitis (PSC) are needed. This study evaluated the ability of extracellular matrix remodeling markers to diagnose fibrosis stage and predict PSC-related fibrosis progression and clinical events. METHODS: Liver histology and serum markers of collagen formation (propeptide of type III collagen [Pro-C3], propeptide of type IV collagen, propeptide of type V collagen), collagen degradation (type III collagen matrix metalloproteinase degradation product and type IV collagen matrix metalloproteinase degradation product), and fibrosis (enhanced liver fibrosis [ELF] score and its components [metalloproteinase-1, type III procollagen, hyaluronic acid]) were assessed in samples from baseline to week 96 in patients with PSC enrolled in a study evaluating simtuzumab (NCT01672853). Diagnostic performance for advanced fibrosis (Ishak stages 3-6) and cirrhosis (Ishak stages 5-6) was evaluated by logistic regression and AUROC. Prognostic performance for PSC-related clinical events and fibrosis progression was assessed by AUROC and Wilcoxon rank-sum test. RESULTS: Among 234 patients, 51% had advanced fibrosis and 11% had cirrhosis at baseline. Baseline Pro-C3 and ELF score and its components provided moderate diagnostic ability for discrimination of advanced fibrosis (AUROC 0.73-0.78) and cirrhosis (AUROC 0.73-0.81). Baseline Pro-C3, ELF score, and type III procollagen provided a moderate prognosis for PSC-related clinical events (AUROC 0.70-0.71). Among patients without cirrhosis at baseline, median changes in Pro-C3 and ELF score to week 96 were higher in those with than without progression to cirrhosis (both p < 0.001). CONCLUSIONS: Pro-C3 correlated with fibrosis stage, and Pro-C3 and ELF score provided discrimination of advanced fibrosis and cirrhosis and predicted PSC-related events and fibrosis progression. The results support the clinical utility of Pro-C3 and ELF score for staging and as prognostic markers in PSC.

Primary sclerosing cholangitis with IgG4-positive plasma cells in bile duct biopsies - Frequency and characterization.

OBJECTIVES: Patients diagnosed with primary sclerosing cholangitis (PSC) but with characteristics of immunoglobulin G4 (IgG4)-associated cholangitis (IAC) have been described. IAC often presents with biliary IgG4-positive plasma cell (IgG4+ PC) infiltration and responds to corticosteroids. In PSC, the frequencies or implications of biliary IgG4+ PC are unknown. We aimed to characterize the phenomenon of biliary IgG4+ PC in patients with an established PSC diagnosis. METHODS: Bile duct biopsies from 191 surveillance or therapeutic endoscopic retrograde cholangiography of 58 PSC patients were retrospectively analyzed for IgG4+ PC infiltration. Patients with ≥10 IgG4+ PC per high-power field (HPF) were identified and characterized by clinical parameters, including serum IgG4 and cholangiographic presentations. RESULTS: Altogether 39.7% of the PSC patients showed ≥10 IgG4+ PC/HPF in bile duct biopsies. Patients with biliary IgG4+ PC infiltration were significantly younger at diagnosis of PSC (P = 0.023). There was no association between biliary IgG4+ PC infiltration and transplant-free survival (P = 0.618). Patients with IgG4+ PC infiltration in bile duct biopsies showed significantly higher baseline (P = 0.002) and maximum (P = 0.001) serum IgG4 compared to those without. Biliary IgG4+ PC infiltration was associated with high-grade bile duct strictures (P = 0.05). IgG4-positive plasma cell infiltrations were found multifocally in 72.7% of this subgroup of PSC patients. CONCLUSIONS: IgG4+ PC ≥10/HPF can be found abundantly in bile duct biopsies in PSC. Histological findings correlated with serum IgG4, age, and high-grade bile duct strictures. IgG4+ PC was located multifocally, hinting at a systemic biliary phenotype.

Antimicrobial glycoprotein 2 (GP2) in gallstones, bile fluid and peribiliary glands of patients with primary sclerosing cholangitis.

BACKGROUND: Glycoprotein-2 (GP2) IgA is a predictor of disease severity in primary sclerosing cholangitis (PSC). We examined GP2's occurrence in the biliary tract, the site of inflammation. METHODS: GP2 was analyzed using ELISA, immunoblotting, mass spectrometry, and immunohistochemistry. The samples included: 20 bile and 30 serum samples from PSC patients, 23 bile and 11 serum samples from patients with gallstone disease (GD), 15 bile samples from healthy individuals undergoing liver-donation surgery (HILD), 20 extracts of gallstones (GE) obtained during cholecystectomy, and 101 blood-donor sera. RESULTS: Biliary GP2 concentrations were significantly higher in patients with PSC and GD than in HILD (p < 0.0001). Serum GP2 levels were similar in PSC and GD patients, and controls, but lower than in bile (p < 0.0001). GP2 was detected in all 20 GEs. Mass spectrometry identified GP2 in the bile of 2 randomly selected GD and 2 PSC patients, and in none of 2 HILD samples. GP2 was found in peribiliary glands in 8 out of 12 PSC patients, showing morphological changes in acinar cells, but not in GD-gallbladders. CONCLUSIONS: GP2 is present in bile of PSC and GD patients. It is synthesized in the peribiliary glands of PSC patients, supporting a pathogenic role for biliary GP2 in PSC.

Intergenic risk variant rs56258221 skews the fate of naive CD4+ T cells via miR4464-BACH2 interplay in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is an immune-mediated liver disease of unknown pathogenesis, with a high risk to develop cirrhosis and malignancies. Functional dysregulation of T cells and association with genetic polymorphisms in T cell-related genes were previously reported for PSC. Here, we genotyped a representative PSC cohort for several disease-associated risk loci and identified rs56258221 (BACH2/MIR4464) to correlate with not only the peripheral blood T cell immunophenotype but also the functional capacities of naive CD4+ T (CD4+ TN) cells in people with PSC. Mechanistically, rs56258221 leads to an increased expression of miR4464, in turn causing attenuated translation of BACH2, a major gatekeeper of T cell quiescence. Thereby, the fate of CD4+ TN is skewed toward polarization into pro-inflammatory subsets. Clinically, people with PSC carrying rs56258221 show signs of accelerated disease progression. The data presented here highlight the importance of assigning functional outcomes to disease-associated genetic polymorphisms as potential drivers of diseases.

Increased Active Inflammation in the Colon is Not a Reliable Predictor of an Elevated Risk of Dysplasia in Patients With Primary Sclerosing Cholangitis and Ulcerative Colitis.

Although the increased risk of colorectal neoplasia in patients with both primary sclerosing cholangitis (PSC) and ulcerative colitis (UC; termed PSC-UC) is well documented, the mechanism through which concomitant PSC increases the risk of colorectal neoplasia remains unclear. Given that the risk of colorectal neoplasia in UC is positively correlated with increased histologic inflammation, this study sought to investigate whether increased histologic inflammation could be used to stratify the risk of dysplasia development in patients with PSC-UC. Twenty patients with PSC-UC and dysplasia were compared with 30 control patients with PSC-UC who had no history of neoplasia. For each patient, all surveillance biopsies were scored using a 4-point scoring system: (1) no epithelial neutrophils = 0, (2) cryptitis only = 1, (3) cryptitis plus crypt abscess in <50% of crypts = 2, and (4) crypt abscess in ≥50% of crypts, erosion, neutrophilic exudate, and/or ulceration = 3. A score was designated for each biopsy, and both mean and maximum inflammation scores were calculated from all biopsies taken during each colonoscopy. The inflammation burden score was calculated for each surveillance interval by multiplying the average maximum score between each pair of surveillance episodes by the length of the surveillance interval in years. The average scores derived from all colonoscopies for each patient were used to determine the patient's overall mean, maximum, and inflammation burden scores. In both the dysplasia and control groups, the 3 summative inflammation scores were calculated independently for the entire colon, right colon, and left colon. The dysplasia group consisted of 14 (70%) men and 6 (30%) women, with a mean age of 27 years at UC diagnosis and a long history of pancolitis (mean duration: 17 y). A total of 49 dysplastic lesions were detected in the dysplasia group, and 8 (40%) of the 20 patients had multifocal dysplasia. The majority of dysplastic lesions belonged to nonconventional subtypes (n = 28; 57%) and were located in the right colon (n = 37; 76%). Irrespective of the colon segment, there was no significant difference in the 3 summative inflammation scores between the dysplasia and control groups ( P > 0.05). However, in each group, the 3 summative inflammation scores were significantly higher in the right colon than in the left colon ( P < 0.05). In conclusion, patients with PSC-UC exhibit increased histologic inflammation in the right colon compared with the left colon, regardless of the presence of dysplasia. Although this may provide an explanation for the predominance of right-sided colorectal neoplasia in patients with PSC-UC, increased histologic inflammation does not reliably predict an elevated risk of dysplasia in patients with PSC-UC. These findings reinforce the current recommendation for annual endoscopic surveillance for all patients with PSC-UC, irrespective of the extent and severity of inflammation.

Immune-related adverse event-associated sclerosing cholangitis due to immune checkpoint inhibitors: imaging findings and treatments.

OBJECTIVES: Immune-related adverse event-sclerosing cholangitis caused by treatment with immune checkpoint inhibitors is rare, and the diagnostic criteria and treatment strategy remain unclear. In this study, we confirmed the clinicopathological features of immune-related adverse event-sclerosing cholangitis and clarified its diagnosis and appropriate management. METHODS: We retrospectively evaluated 10 patients diagnosed with immune-related adverse event-sclerosing cholangitis and identified by electronic database searches. RESULTS: Blood tests revealed liver dysfunction with a predominance of biliary tract enzymes in all patients; however, jaundice was present in only one patient. Contrast-enhanced computed tomography revealed diffuse hypertrophy of the extrahepatic bile duct wall as the most frequent finding; however, endoscopic retrograde cholangiopancreatography showed various imaging features, such as the pruned-tree appearance of intrahepatic bile ducts, in all patients. Transpapillary bile duct biopsy showed inflammatory cell infiltration using immunostaining, with a predominance of cluster of differentiation 8-positive T cells in 63% of the cases. Initial steroid therapy was effective in two cases. Mycophenolate mofetil and tacrolimus were used in steroid-refractory cases. Although six patients showed improvements, all of the remaining patients died owing to immune-related adverse event-sclerosing cholangitis. CONCLUSIONS: Various bile duct imaging findings of immune-related adverse event-sclerosing cholangitis were revealed; transpapillary bile duct biopsy may be useful in the diagnosis of immune-related adverse event-sclerosing cholangitis. Despite the combination of multiple immunosuppressive agents, prognosis of immune-related adverse event-sclerosing cholangitis remains poor. Longer follow-up and larger clinical studies are necessary to establish its treatment strategy.

What is the appropriate method of pathological specimen collection for cholangiocarcinoma detection in primary sclerosing cholangitis?

BACKGROUND: In primary sclerosing cholangitis (PSC), it is important to understand the cholangiographic findings suggestive of malignancy, but it is difficult to determine whether cholangiocarcinoma is present due to modifications caused by inflammation. This study aimed to clarify the appropriate method of pathological specimen collection during endoscopic retrograde cholangiopancreatography for surveillance of PSC. METHODS: A retrospective observational study was performed on 59 patients with PSC. The endpoints were diagnostic performance for benign or malignant on bile cytology and transpapillary bile duct biopsy, cholangiographic findings of biopsied bile ducts, diameters of the strictures and upstream bile ducts, and their differences. RESULTS: The sensitivity (77.8% vs. 14.3%, P = 0.04), specificity (97.8% vs. 83.0%, P = 0.04), and accuracy (94.5% vs. 74.1%, P = 0.007) were all significantly greater for bile duct biopsy than for bile cytology. All patients with cholangiocarcinoma with bile duct stricture presented with dominant stricture (DS). The diameter of the upstream bile ducts (7.1 (4.2-7.2) mm vs. 2.1 (1.2-4.1) mm, P < 0.001) and the diameter differences (6.6 (3.1-7) mm vs. 1.5 (0.2-3.6) mm, P < 0.001) were significantly greater in the cholangiocarcinoma group than in the noncholangiocarcinoma group with DS. For diameter differences, the optimal cutoff value for the diagnosis of benign or malignant was 5.1 mm (area under the curve = 0.972). CONCLUSION: Transpapillary bile duct biopsy should be performed via localized DS with upstream dilation for the detection of cholangiocarcinoma in patients with PSC. Especially when the diameter differences are greater than 5 mm, the development of cholangiocarcinoma should be strongly suspected.

Challenges and Pitfalls in Pancreatobiliary Cytopathology.

INTRODUCTION: The advances of minimally invasive endoscopy-guided procedures that usually yield limited diagnostic material changed pancreaticobiliary cytopathology into one of the most challenging areas of cytopathology given the abundance of differential diagnoses to be considered when dealing with limited specimens. CASE PRESENTATION: We describe a few challenging examples of potential pitfalls in pancreatobiliary cytopathology evaluation collected from a busy academic hospital (tertiary) center. Case 1 illustrates the challenges in handling paucicellular specimens from pancreatic solid lesions in which differential diagnoses may include acinar cell carcinoma, neuroendocrine tumors, adenocarcinoma, or even benign pancreatic tissue, among others. Case 2 illustrates the pitfalls in evaluating limited specimens from patients with chronic pancreatitis, specially when distinguishing exuberant reactive atypia from dysplastic changes is mandatory. Case 3 illustrates pitfalls in distinguishing malignancy from reactive changes in biliary brushing specimens from patients with primary sclerosing cholangitis. Finally, cases 4 and 5 highlight the importance of including the possibility of pancreatic metastasis in the differential diagnoses of some pancreatic lesions. CONCLUSION: Over time, there has been an increasing demand for pathologists to render diagnoses on limited specimens obtained through minimally invasive procedures which can be frequently challenging even for the most experienced professionals. In many difficult cases, salvaging additional material for a cell block can turn out to be extremely helpful given the possibility of utilizing additional ancillary tests for diagnostic confirmation.

Periportal macrophages protect against commensal-driven liver inflammation.

The liver is the main gateway from the gut, and the unidirectional sinusoidal flow from portal to central veins constitutes heterogenous zones, including the periportal vein (PV) and the pericentral vein zones1-5. However, functional differences in the immune system in each zone remain poorly understood. Here intravital imaging revealed that inflammatory responses are suppressed in PV zones. Zone-specific single-cell transcriptomics detected a subset of immunosuppressive macrophages enriched in PV zones that express high levels of interleukin-10 and Marco, a scavenger receptor that sequesters pro-inflammatory pathogen-associated molecular patterns and damage-associated molecular patterns, and consequently suppress immune responses. Induction of Marco+ immunosuppressive macrophages depended on gut microbiota. In particular, a specific bacterial family, Odoribacteraceae, was identified to induce this macrophage subset through its postbiotic isoallolithocholic acid. Intestinal barrier leakage resulted in inflammation in PV zones, which was markedly augmented in Marco-deficient conditions. Chronic liver inflammatory diseases such as primary sclerosing cholangitis (PSC) and non-alcoholic steatohepatitis (NASH) showed decreased numbers of Marco+ macrophages. Functional ablation of Marco+ macrophages led to PSC-like inflammatory phenotypes related to colitis and exacerbated steatosis in NASH in animal experimental models. Collectively, commensal bacteria induce Marco+ immunosuppressive macrophages, which consequently limit excessive inflammation at the gateway of the liver. Failure of this self-limiting system promotes hepatic inflammatory disorders such as PSC and NASH.

Comparative histologic features among liver biopsies with biliary-pattern injury and confirmed clinical diagnoses.

Biliary-pattern injury in the liver (eg, duct injury, ductular reaction, cholestasis) can occur in several conditions, including primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), large duct obstruction (LDO), and drug-induced liver injury (DILI). While the histologic changes in these conditions have been individually well described, distinguishing among them remains often challenging, particularly when biopsy samples are limited in size, robust clinical information is unavailable, and/or the pathologist does not feel confident in evaluating liver disease. This study evaluated histologic features that could aid the diagnosis of biliary-pattern injury on biopsy. We reviewed 121 liver biopsies from clinically confirmed cases of PBC, PSC, chronic LDO, or DILI for multiple clinical and histologic parameters. The rates of these histologic findings were then compared among different entities. Onion-skin fibrosis was seen in 14% of PSC in comparison to 0%, 5%, and 0% of PBC, DILI, and chronic LDO (P = 0.031). Florid duct lesions were identified in 21% of PBC compared to 2% of PSC and 0% of DILI and LDO (P = 0.0065). Similarly, 42% of PBC showed lobular granulomas, compared to 7% of PSC, 11% of DILI, and 33% of chronic LDO (P = 0.0001). Cholestasis was more commonly seen in DILI (42%) and chronic LDO (83%) than in PBC (4%) and PSC (16%) (P < 0.0001). Lobular chronic inflammation was found in a significantly higher percentage of PBC and LDO than of PSC and DILI (P = 0.0009). There were significantly fewer cases of PBC showing neutrophils in ductular reaction than PSC, DILI, and LDO (P = 0.0063). Histologic findings that can help suggest a diagnosis in liver biopsies with biliary-pattern injury include florid duct lesions, lobular granulomas, lack of neutrophils in ductular reaction, and lobular chronic inflammation in PBC; onion-skin fibrosis in PSC; cholestasis and feathery degeneration in DILI; and lobular granulomas, lobular chronic inflammation, cholestasis, and feathery degeneration in chronic LDO. These findings are likely most helpful when complicating factors interfere with biopsy interpretation.

COVID-19-associated secondary sclerosing cholangitis with liver transplantation.

We report on two cases of orthotopic liver transplantation (OLTX) due to SARS-Cov2-associated secondary sclerosing cholangitis (SSC) following long-term artificial respiration and extra-corporal membrane oxygenation in intensive care. Under these conditions, SSC is a rapidly progredient biliary disease featuring degenerative cholangiopathy, loss of bile ducts, ductular and parenchymal cholestasis, biliary fibrosis, and finally cirrhosis. Reduced perfusion and oxygenation of the peribiliary plexus, severe concurrent infections, and secondary medico-toxic effects appear to play a crucial role in the pathogenesis of the disease. A direct cytopathic effect of SARS-Cov2 on endothelial cells followed by thrombosis and fibrosing obliteration in all parts of the vascular bed of the liver may enhance the virus-associated liver disease and particularly SSC.

Enteroblastic cholangiocarcinoma: An uncommon, underrecognized subtype of bile duct cancer.

Enteroblastic carcinoma is clinically characterized by an elevated serum level of alpha-fetoprotein (AFP) and is histologically characterized by cancer cells with a clear cytoplasm and 'blastic' coarse chromatin. It sometimes has an element of hepatoid carcinoma; therefore, these two neoplasms are often regarded as sister entities. Although hepatoid carcinoma in the biliary tree has been reported, enteroblastic cholangiocarcinoma is extremely uncommon. In the present study, four cases of enteroblastic cholangiocarcinoma were examined. Tumors were located inside the liver (n = 2) or common bile duct (n = 2). The two intrahepatic cases had a history of primary sclerosing cholangitis, and serum AFP levels were elevated in both. One unresectable case was diagnosed by needle liver biopsy, while the remaining three underwent surgical resection. Histologically, all cases showed similar microscopic features. Cuboidal or polygonal cancer cells with the characteristic clear cytoplasm and subnuclear vacuoles were arranged in a papillary, micropapillary, tubular, or solid architecture. One case had an element of pancreatobiliary-type adenocarcinoma, while a hepatoid carcinoma element was not observed in any cases. All cases were positive for AFP, glypican 3, and SALL4, with SALL4 being the most widely expressed. Heppar-1 and arginase-1 were negative, except for one case, which was positive for Heppar-1. In conclusion, enteroblastic cholangiocarcinoma is an uncommon subtype of biliary tract malignancy. These cases may have been categorized as 'clear cell' cholangiocarcinoma. Although enteroblastic cholangiocarcinoma seems to occur more commonly in extrahepatic regions, including the gallbladder, it may also develop in the liver, particularly in patients with primary sclerosing cholangitis.

Mimickers of immunoglobulin G4-related hepatobiliary disease on biopsy.

With the growing recognition of IgG4-related hepatobiliary disease, establishing a definitive diagnosis relies mainly on a combination of clinical findings, serological markers, and imaging modalities. However, the role of histopathological evaluation remains indispensable, particularly in cases necessitating differential diagnosis or malignancy exclusion. While diagnosing IgG4-related hepatobiliary disease through surgical resection specimens is often straightforward, pathologists encounter substantial challenges when evaluating biopsies. The increasing rarity of surgical interventions exacerbates this due to improved disease recognition and suspicion. Numerous confounding factors, including the absence of the characteristic histologic features, limited tissue sample size, biopsy artifacts, and the limited value of IgG4 counts, further complicate the diagnostic process. Additionally, many other disorders exhibit clinical and histological features that overlap with IgG4-related disease, intensifying the complexity of interpreting biopsy specimens. This article explores the clinical and histomorphologic features of IgG4-related hepatobiliary disease and its potential mimickers. It offers valuable insights for pathologists and clinicians when confronted with biopsy specimens from hepatobiliary organs.

Colangite esclerosante primária em crianças e adolescentes / Primary sclerosing cholangitis in children and adolescents

ABSTRACT BACKGROUND: Primary sclerosing cholangitis is a rare disease, but its prevalence has been underestimated in children and adolescents due to broad variation in clinical presentation as well as diagnostic challenges in this life period. OBJECTIVE: To evaluate children and adolescents with primary sclerosing cholangitis and to describe their clinical, laboratorial, histopathological, and cholangiography conditions. METHODS: This is an observational descriptive research that took place from 2005 to 2016 and included all the patients seen in the Outpatient Unit for Pediatric Hepatology of Hospital das Clinicas of UFMG who had been diagnosed with primary sclerosing cholangitis before the age of 18. Diagnosis was established through clinical, laboratory, radiographic and/or histopathologic criteria. Other chronic liver diseases were excluded, as well as secondary causes of cholangitis. Data analysis used statistic resources in SPSS software. Variables were expressed as averages, standard deviation, absolute frequency, and percentage. RESULTS: Twenty-one patients fulfilled criteria to be included in the research sample. Male patients predominated (3.2:1) and average age at diagnosis was 6.7±3.9 years. Five (23.8%) patients had associated inflammatory bowel disease, four had ulcerative colitis and one indeterminate colitis. Signs and symptoms vary and are usually discrete at presentation. The most frequent symptom was abdominal pain (47.6%) followed less frequently by jaundice (28.6%) and itching (14.3%). The reason for medical investigation was asymptomatic or oligosymptomatic enzyme alterations in 33.3% of patients. All patients presented increased hepatic enzymes: aminotransferases, gamma glutamyl transferase, and alkaline phosphatase. Twenty patients had alterations compatible to primary sclerosing cholangitis in their cholangiography exam; one patient had no alterations at magnetic resonance cholangiography, but presented histopathologic alterations that were compatible to small duct cholangitis. Hepatic fibrosis was present in 60% of 15 patients who were biopsied upon admission; cirrhosis being present in four (26.7%) patients. A total of 28.5% of patients had unfavorable outcomes, including two (9.5%) deaths and four (19%) transplants. CONCLUSION: Primary sclerosing cholangitis is a rare disease in childhood and adolescence and its initial diagnosis may be delayed or overlooked due to asymptomatic or unspecific clinical manifestations. The association with inflammatory bowel disease is common. Prognosis may be unfavorable as the disease progresses and hepatic transplant is the definitive treatment.

RESUMO CONTEXTO: A colangite esclerosante primária é uma doença rara, mas sua prevalência tem sido subestimada em crianças e adolescentes, tanto pela variedade de apresentação clínica quanto pela dificuldade diagnóstica neste período. OBJETIVO: Avaliar crianças e adolescentes com colangite esclerosante primária descrevendo seu quadro clínico, laboratorial, histopatológico e colangiográfico. MÉTODOS: Trata-se de um estudo descritivo observacional, de 2005 a 2016, de todos os pacientes atendidos no Ambulatório de Hepatologia Pediátrica do Hospital das Clínicas da UFMG, com o diagnóstico de colangite esclerosante primária até a idade de 18 anos. O diagnóstico foi estabelecido segundo os critérios clínicos, laboratoriais, radiológicos e/ou histopatológicos. Foi realizada investigação para exclusão de outras doenças hepáticas crônicas e causas secundárias de colangite. A análise dos dados foi efetuada com os recursos estatísticos do software SPSS. As variáveis foram expressas por meio de médias, desvio-padrão, frequência absoluta e porcentagem. RESULTADOS: Vinte e um pacientes preencheram os critérios de inclusão. Houve predomínio no sexo masculino (3,2:1). A média de idade ao diagnóstico foi 6,7±3,9 anos. Cinco (23,8%) pacientes apresentavam doença inflamatória intestinal associada, sendo quatro casos de colite ulcerativa e um de colite indeterminada. Na apresentação, os sinais e sintomas são variados, em geral discretos. O sintoma mais frequente foi dor abdominal (47,6%), seguido menos frequentemente por icterícia (28,6%) e prurido (14,3%). Em 33,3% dos pacientes, o motivo de início da investigação foi alteração de enzimas em pacientes assintomáticos ou oligossintomáticos. Todos os pacientes exibiam aumento das enzimas hepáticas: aminotransferases, gama glutamiltransferase e fosfatase alcalina. Vinte pacientes apresentavam alterações em exame colangiográfico, compatíveis com colangite esclerosante primária; um paciente não apresentava alterações na colangiorressonância, mas apresentava alterações histopatológicas compatíveis com colangite de pequenos ductos. Fibrose hepática já estava presente em 60% dos 15 pacientes com biópsia à admissão; com cirrose estabelecida em quatro pacientes. 28,5% dos pacientes tiveram evolução desfavorável, com dois (9,5%) óbitos e quatro (19%) pacientes transplantados. CONCLUSÃO: Colangite esclerosante primária é uma doença rara na criança e no adolescente, cujo diagnóstico inicial pode ser atrasado ou passar despercebido, principalmente por apresentar manifestações clínicas inespecíficas ou cursar de forma assintomática. É frequente a associação com doença inflamatória intestinal. O prognóstico pode ser reservado com o avançar da doença, sendo o transplante hepático o tratamento definitivo.

¿Beneficio o riesgo del uso de ácido ursodeoxicólico en prevención de cáncer colorrectal en pacientes con colangitis esclerosante primaria/colitis ulcerosa? / Benefit or risk from the use of ursodeoxycholic acid in prevention of colorectal

cancer in patients with primary sclerosing cholangitis/ulcerative colitis? Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intra-and extrahepatic bile ducts. About 70 percent of patients with CEP have idiopathic ulcerative colitis (IUC). PSC is considered a premalignant condition with an increased risk of colorectal cancer (CC). Individuals with PSC and IUC have higher risk of developing CC than IUC patients. There are different positions between American and European experts in the fields of hepatology and inflammatory bowel disease regarding the use of ursodeoxycholic acid (UDCA) in PSC and IUC as a chemo preventive. Studies have shown mixed results about the use of UDCA in preventing CC. The following is an update on the role of UDCA as a chemo preventive in this group of patients.

La colangitis esclerosante primaria (CEP) es una enfermedad crónica hepática colestásica caracterizada por inflamación y fibrosis de ductos biliares intra y extrahepáticos. Alrededor de 70 por ciento de los pacientes con CEP presenta colitis ulcerosa idiopática (CUI). La CEP es considerada una condición premaligna con un incremento del riesgo de cáncer colorrectal (CCR). Individuos con CEP más CUI tienen mayor riesgo de desarrollar CCR que pacientes con sólo CUI. Existen distintas posturas a nivel mundial entre expertos americanos y europeos tanto en el área de la hepatología como en el área de las EII (enfermedades inflamatorias intestinales) frente al uso de ácido ursodeoxicólico (AUDOC) en CEP y CUI como quimioprotector. Estudios han mostrado resultados contradictorios para el uso de AUDOC en la prevención de CCR. Se expone una revisión actualizada sobre el rol de AUDOC como quimioprotector en este grupo de pacientes.

Dolor abdominal e ictericia recurrente como manifestación clínica en un niño con colangitis escleronsante primaria / Abdominal pain and recurrent jaundice as demonstration clinic in a child with primary sclerosing cholangitis

La colangitis esclerosante primaria es una enfermedad hepatobiliar progresiva caracterizada por una inflamación crónica con fibrosis periductal de los conductos biliares intra y extrahepáticos que producen constricciones y ectasia generalizadas del tracto biliar. Se presenta el caso de un escolar masculino de 12 años de edad, quien inicio enfermedad actual a partir de los 5 años de edad cuando presentó dolor abdominal recurrente localizado en epigastrio y mesogastrio, leve a moderada intensidad, tipo cólico. A partir de los 8 años de edad se anexó tinte ictérico en piel y mucosa, con orinas coloreadas en forma intermitente. A los 10 años de edad, el 16/06/2008, el dolor abdominal aumenta en intensidad acompañado de nauseas, recibió tratamiento con sucralfato y ranitidina sin mejoría por lo que el 19/06/2008 se hospitalizó. Se le realizó exámenes de laboratorio que reportó elevación de las transaminasas, fosfatasa alcalina y gamma glutamil transpeptidasa. Tomografía abdominal signos sugestivos de colangitis por lo que se realizó serología para algunos virus hepatotropos, colangioresonancia y posteriormente biopsia hepática corroborándose el diagnóstico de colangitis esclerosante primaria. Aunque es una enfermedad colestásica frecuentes en el adulto debe ser tomada en cuenta en niños para hacer un diagnóstico precoz y posterior seguimiento

Primary sclerosing cholangitis is a disease progressive hepatobiliary characterized by chronic inflammation with bile duct intra periductal fibrosis and extrahepatic that produce widespread biliary tract constrictions and ectasia. The case of a male school of 12 years of age who start current illness from 5 years of age when he presented recurrent abdominal pain located in the epigastrium and mesogastrio, mild to moderate intensity, cramping occurs. From the age of 8 was annexed on skin and mucosa, icteric dye with urine colored intermittently. To 10 years of age, 16/06/2008, abdominal pain increases in intensity accompanied of nausea, he received treatment with sucralfate and ranitidine without improvement for what 06 19, 2008 hospitalized. Laboratory tests which reported elevation of transaminases, alkaline phosphatase and gamma-glutamyl transpeptidase was carried out. Abdominal CT signs suggestive of cholangitis by what took place some virus serology hepatotropic, Magnetic Resonance Cholangiography and then liver biopsy corroborating the diagnosis of primary sclerosing cholangitis. Although is a disease common in the adult cholestatic should be taken into account in children to make an early diagnosis and subsequent follow-up