Autoimmune Hepatitis: Predictors of Native Liver Survival in Children and Adolescents.

OBJECTIVE: To determine predictors of native liver survival (NLS) in children and adolescents with autoimmune hepatitis (AIH). STUDY DESIGN: The medical records of children and adolescents with AIH were reviewed. A questionnaire was used to collect data on clinical presentation, biochemical and histologic findings, and treatment. RESULTS: A total of 819 patients were included, 89.6% with AIH-1 and 10.4% with AIH-2. The median age (months) at onset was 108 (min 6; max 210; IQR 59). The female sex was predominant (75.8%). The overall survival was 93.0%, with an NLS of 89.9%; 4.6% underwent liver transplantation. The risk of death or liver transplantation during follow-up was 3.2 times greater in patients with AIH-1 (P = .024). Greater levels of aspartate aminotransferase, alanine aminotransferase, serum albumin, platelet, and normal international normalized ratio at the initial presentation were associated with longer NLS (P = .046, P = .006, P < .001, P = .001, and P = .019, respectively). Normal C3 levels was associated with longer NLS (P = .017), with a chance of death or liver transplantation during follow-up being 3.4 times greater in patients with C3 below normal. Death or liver transplantation during follow-up was 2.8 times greater in patients with associated sclerosing cholangitis (P = .046). Complete remission favored NLS (P < .001), with a risk of death or liver transplantation 11.7 times greater for patients not achieving remission. CONCLUSIONS: The best predictors of NLS in children and adolescents with AIH were the AIH-2 subtype, a normal C3 at diagnosis, remission during treatment, and normal a cholangiogram during the disease course.

Multiple therapeutic targets in rare cholestatic liver diseases: Time to redefine treatment strategies.

Primary biliary cholangitis and primary sclerosing cholangitis are rare diseases affecting the bile ducts and the liver. The limited knowledge of their pathogenesis leads to limited therapeutic options. Nevertheless, the landscape of novel therapies for these cholangiopathies is now rapidly changing, providing new treatment opportunities for patients and clinicians involved in their care. The aim of this review is to summarize the evidence of novel molecules under investigation for primary biliary cholangitis and primary sclerosing cholangitis and to discuss how they can potentially change current treatment paradigms.

Sclerosing Cholangitis Related to IgG4: Not Always a Curable Entity.

IgG4-related disease is a recently-described fibro-inflammatory condition with characteristic histopathological findings in the organs involved. The most commonly affected organs are pancreas, lymph nodes, and retroperitoneum. Liver disease usually involves bile structures and therefore IgG4-related disease is considered a cause of secondary sclerosing cholangitis. One out of three patients with IgG4 sclerosing cholangitis also presents autoimmune pancreatitis, although it can be associated with manifestations in other organs. One of the main features of IgG4-related disease is its good prognosis due to the great response to glucocorticoid therapy. However, relapse of the disease is not uncommon, especially when steroid therapy is decreased or stopped. Rituximab seems to be an effective treatment to achieve remission of the disease. We report the case of a 74 year-old man diagnosed with IgG4-related disease based on increase of serum IgG4 levels, imaging and histopathological findings, with systemic involvement including sclerosing cholangitis. Despite the absence of liver fibrosis at onset, the early use of glucocorticoids and rituximab therapy, the patient presented clinical and analytical deterioration, leading to secondary biliary cirrhosis. In conclusion, this clinical case highlights the importance of prompt diagnosis and therapeutics for sclerosing cholangitis secondary to IgG4-related disease in order to avoid progression of the disease and development of liver cirrhosis, as well as the refractory, aggressive nature of the disease in some cases as this one.

Ursodeoxycholic Acid Therapy in Pediatric Primary Sclerosing Cholangitis: Predictors of Gamma Glutamyltransferase Normalization and Favorable Clinical Course.

OBJECTIVE: To investigate patient factors predictive of gamma glutamyltransferase (GGT) normalization following ursodeoxycholic acid (UDCA) therapy in children with primary sclerosing cholangitis. STUDY DESIGN: We retrospectively reviewed patient records at 46 centers. We included patients with a baseline serum GGT level ≥50 IU/L at diagnosis of primary sclerosing cholangitis who initiated UDCA therapy within 1 month and continued therapy for at least 1 year. We defined "normalization" as a GGT level <50 IU/L without experiencing portal hypertensive or dominant stricture events, liver transplantation, or death during the first year. RESULTS: We identified 263 patients, median age 12.1 years at diagnosis, treated with UDCA at a median dose of 15 mg/kg/d. Normalization occurred in 46%. Patients with normalization had a lower prevalence of Crohn's disease, lower total bilirubin level, lower aspartate aminotransferase to platelet ratio index, greater platelet count, and greater serum albumin level at diagnosis. The 5-year survival with native liver was 99% in those patients who achieved normalization vs 77% in those who did not. CONCLUSIONS: Less than one-half of the patients treated with UDCA have a complete GGT normalization in the first year after diagnosis, but this subset of patients has a favorable 5-year outcome. Normalization is less likely in patients with a Crohn's disease phenotype or a laboratory profile suggestive of more advanced hepatobiliary fibrosis. Patients who do not achieve normalization could reasonably stop UDCA, as they are likely not receiving clinical benefit. Alternative treatments with improved efficacy are needed, particularly for patients with already-advanced disease.

Linear IgA Bullous Dermatosis Preceding the Diagnosis of Primary Sclerosing Cholangitis and Ulcerative Colitis: A Case Report.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder seen in the pediatric and adult populations that is often linked to a medication, infection, or underlying gastrointestinal, hepatobiliary, or autoimmune disease. In this study, we describe the case of a 23-year-old white man whose presentation and diagnosis of LABD ultimately led to the discovery of underlying primary sclerosing cholangitis (PSC) and ulcerative colitis (UC). His dermatitis resolved with topical steroids and dapsone, and he is undergoing systemic treatment for his UC and PSC. This exceptional case further validates the association between LABD with UC, strengthens that with PSC, and underscores the importance of alerting clinicians to consider conducting a systemic workup in addition to thorough medication history on making the diagnosis of LABD.

Ácido ursodesoxicólico para colangite biliar primária / Ursodeoxycholic acid for primary biliary cholangitis

INTRODUÇÃO: A colangite biliar primária (CBP) é uma doença hepática autoimune colestática rara, caracterizada por inflamação e destruição progressiva dos ductos interlobulares de pequeno e médio calibre, colestase que provoca fadiga e prurido debilitantes, podendo evoluir para fibrose, cirrose, doença hepática terminal e morte. Estudos epidemiológicos de base populacional de diversos países mostrou taxas de incidência que variam de 0,33 a 5,8 por 100 mil habitantes por ano e taxas de prevalência 1,91 a 40,2 por 100 mil habitantes por ano. Atualmente, o SUS oferece apenas alternativas para o tratamento dos sintomas da doença hepática terminal (cirrose), e não possui nenhuma alternativa terapêutica com idicação para CBP. TECNOLOGIA: Ácido Ursodesoxicólico (Ursacol®). PERGUNTA: O uso de ácido ursodesoxicólico (AUDC) é eficaz e seguro em pacientes com colangite biliar primária quando comparado às opções disponíveis atualmente no SUS? EVIDÊNCIAS CIENTÍFICAS: Com base nos critérios de inclusão, na estratégia de busca e nas referências dos artigos selecionados, foram incluídos 13 estudos, 10 já incluídos pelo demandante e três pela Secretaria-Executiva da CONITEC. Mortalidade foi avaliada por seis estudos, três observaram que não houve diferença estatisticamente significante entre AUDC e placebo, em outros três estudos os resultados foram variados. A sobrevida global foi avaliada por três estudos que concluíram que a sobrevida observada foi significativamente (P< 0.001) maior no grupo tratado com AUDC quando comparado ao previsto pelo modelo de Mayo ou grupo não tratado. Os resultados de sobrevida livre de transplante (SLT) de quatro estudos puderam ser meta-analisados, e o tratamento com AUDC apresentou aumento do tempo de SLT no acompanhamento de longo prazo a partir do quinto ano de tratamento, com resultados estatisticamente significantes para os anos 5, 8 e 10 (p< 0,01). Não houve diferença estatisticamente significantes nas meta-análises para proporção de eventos adversos graves quando se comparou AUDC com placebo/não tratamento. AVALIAÇÃO ECONÔMICA: O demandante delineou em sua proposta um estudo de custo-efetividade do AUDC como opção de tratamento em pacientes com CBP sintomáticos. O estudo demonstrou uma RCEI de R$ 9,32 mil por ano livre de transplante salvo e R$ 13,26 mil por ano de vida salvo, quando comparado ao placebo. O modelo possui limitações na fonte de dados de eficácia, no levantamento dos custos e no horizonte temporal usado no modelo que limitam a interpretação do resultado. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A partir das premissas adotadas pelo demandante, o impacto orçamentário incremental com a incorporação do AUDC no SUS seria de R$11,77 milhões no primeiro ano e de R$98,52 milhões no acumulado de cinco anos. Entretanto, análise possui limitações quanto à estimativa da população e a previsão de custos. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: As buscas apontaram haver quatro potenciais medicamentos nas fases 3 ou 4 de desenvolvimento clínico para a indicação terapêutica considerada. Destes, o ácido obeticólico e selaldelpar lisina parecem estar num horizonte mais próximo, dado que obtiveram registro sanitário no FDA e/ou EMA nos últimos dois anos. RECOMENDAÇÃO DA CONITEC: Os membros presentes em sua 68º reunião ordinária, no dia 05 de julho de 2018, deliberaram que o tema fosse submetido à consulta pública com recomendação preliminar desfavorável à incorporação do AUDC para tratamento de pacientes com CBP. CONSULTA PÚBLICA: Foram recebidas 25 contribuições técnico-científicas e 140 contribuições de experiência e opinião durante o período de consulta pública, entre 04 de agosto a 23 de agosto de 2018. Dentre as contribuições, a maioria foram contrárias à recomendação da CONITEC. Os principais argumentos enviados pela empresa fabricante foram: alto custo do medicamento, única opção terapêutica para CBP, melhroa dos parâmetros hepáticos, recomendação de agências internacionais, mudança da história natural da doença e redução dos eventos adversos. O plenário da CONITEC entendeu a necessidade de modificar sua recomendação inicial e deliberaram, por unanimidade, por recomendar a incorporação no SUS do AUDC para CBP. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 68ª reunião ordinária, no dia 04 de julho de 2018, deliberaram, por unanimidade, por recomendar a incorporação do AUDC para tratamento de pacientes com Colangite Biliar Primária. Foi assinado o Registro de Deliberação nº 355/2018. DECISÃO: A Portaria nº 47, de 16 de outubro de 2017, tornou pública a decisão de incorporar o ácido ursodesoxicólico para colangite biliar, no âmbito do Sistema Único deSaúde - SUS. Publicada no Diário Oficial da União nº 200, seção 1, página 44.

Alkaline phosphatase normalization is a biomarker of improved survival in primary sclerosing cholangitis.

UNLABELLED:  Introduction. Recent studies suggest that serum alkaline phosphatase may represent a prognostic biomarker in patients with primary sclerosing cholangitis. However, this association remains poorly understood. Therefore, the aim of this study was to investigate the prognostic significance and clinical correlates of alkaline phosphatase normalization in primary sclerosing cholangitis. MATERIAL AND METHODS: This was a retrospective cohort study of patients with a new diagnosis of primary sclerosing cholangitis made at an academic medical center. The primary endpoint was time to hepatobiliaryneoplasia, liver transplantation, or liver-related death. Secondary endpoints included occurrence of and time to alkaline phosphatase normalization. Patients who did and did not achieve normalization were compared with respect to clinical characteristics and endpoint-free survival, and the association between normalization and the primary endpoint was assessed with univariate and multivariate Cox proportional-hazards analyses. RESULTS: Eighty six patients were included in the study, with a total of 755 patient-years of follow-up. Thirty-eight patients (44%) experienced alkaline phosphatase normalization within 12 months of diagnosis. Alkaline phosphatase normalization was associated with longer primary endpoint-free survival (p = 0.0032) and decreased risk of requiring liver transplantation (p = 0.033). Persistent normalization was associated with even fewer adverse endpoints as well as longer survival. In multivariate analyses, alkaline phosphatase normalization (adjusted hazard ratio 0.21, p = 0.012) and baseline bilirubin (adjusted hazard ratio 4.87, p = 0.029) were the only significant predictors of primary endpoint-free survival. CONCLUSIONS: Alkaline phosphatase normalization, particularly if persistent, represents a robust biomarker of improved long-term survival and decreased risk of requiring liver transplantation in patients with primary sclerosing cholangitis.

Liver failure unmasks celiac disease in a child.

BACKGROUND: Liver involvement in celiac disease (CD) varies from asymptomatic mild non-specific hepatitis to liver failure. Here we report the first child with liver failure due to a sclerosing cholangitis associated with CD. CASE REPORT: An 11 year old girl presented with fatigability for 1 year and jaundice and abdominal distension for 3 weeks. On examination, the growth parameters were below 3rd percentile; she had splenomegaly and severe ascites. Liver function tests revealed elevated liver enzymes (ALT 84 U/L, total bilirubin 98.7 µmol/L, and direct 58.3 µmol/L, gamma-glutamyltransferase 111 U/L, INR 2.7, and albumin 16 g/L). Extensive investigations excluded infectious, metabolic, structural, and endocrine causes of chronic liver disease. Because of the short stature and anemia, CD was suspected, and serological evaluation revealed increased IgA antibodies to tissue transglutaminase (385 units; normal, 0-20 units). Histopathological examination of small intestinal biopsies showed total villous atrophy consistent with celiac disease. Liver biopsy showed bridging fibrosis, portal tract expansion by lymphocytes, plasma cells, and neutrophils, bile ductular proliferation, and periductular fibrosis. Magnetic resonance cholangiography revealed beading and narrowing appearance of intra- and extrahepatic bile ducts. The histopathological and imaging findings are diagnostic of sclerosing cholangitis. The child was initiated on ursodeoxycholic acid, gluten free diet for life, and steroid that was tapered over 3 months. At 3 month follow up, liver function tests completely normalized. CONCLUSION: CD is a potentially treatable cause of liver failure. All patients with severe unexplained liver disease should undergo serological screening for CD.

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

Recurrent liver failure caused by IgG4 associated cholangitis.

Immunoglobulin G4 associated cholangitis (IAC) is an autoimmune disease associated with autoimmune pancreatitis (AIP). It presents with clinical and radiographic findings similar to primary sclerosing cholangitis (PSC). IAC commonly has a faster, more progressive onset of symptoms and it is more common to see obstructive jaundice in IAC patients compared to those with PSC. One of the hallmarks of IAC is its responsiveness to steroid therapy. Current recommendations for treatment of AIP demonstrate excellent remission of the disease and associated symptoms with initiation of steroid therapy followed by steroid tapering. If untreated, it can progress to irreversible liver failure. This report describes a 59 year-old female with undiagnosed IAC who previously had undergone a pancreaticoduodenectomy for a suspected pancreatic cancer and later developed liver failure from presumed PSC. The patient underwent an uncomplicated liver transplantation at our institution, but experienced allograft failure within five years due to progressive and irreversible bile duct injury. Radiology and histology suggested recurrence of PSC, but the diagnosis of IAC was suspected based on her past history and confirmed when IgG4 positive cells were found within the intrahepatic bile duct walls on a liver biopsy. A successful liver retransplantation was performed and the patient is currently on triple immunosuppressive therapy. Our experience in this case and review of the current literature regarding IAC management suggest that patients with suspected or recurrent PSC with atypical features including history of pancreatitis should undergo testing for IAC as this entity is highly responsive to steroid therapy.

Granuloma de Majocchi, asociado a síndrome de Cushing por medicamentos / Majocchiïs granuloma associated to drug-induced Cushing syndrome

Introducción. El granuloma de Majocchi es una dermatofitosis profunda, generalmente causada por dermatófitos del género Trichophyton y asociada a padecimientos y procesos con inmunosupresión.Caso clínico. Se presenta un paciente del sexo femenino de 16 años de edad, con granuloma de Majocchi asociado a síndrome de Cushing medicamentoso (prednisona) y colangitis esclerosante primaria. El diagnóstico se realizó mediante pruebas micológicas: exámenes directos (KOH), y cultivo, aislándose Trichophyton rubrum, confirmado mediante histopatología. El tratamiento fue con terbinafina oral a dosis de 125 mg/día durante 30 días obteniéndose curación clínica y micológica.Conclusión. El granuloma de Majocchi es una tiña profunda, frecuentemente asociada a tratamientos con cortisona y sus derivados. Es un padecimiento raro en niños y adolescentes. Su confirmación es histopatológica y su tratamiento debe ser con antimicóticos sistémicos. Granuloma de Majocchi; granuloma dermatofítico; Trichophyton rubrum; inmunosupresión; terbinafina.

[Physico-chemical properties of ursodeoxycholic acid and its usefulness in hepatopathies]. / Propiedades fisicoquímicas del ácido ursodesoxicólico y su utilidad en las hepatopatías.

The authors of this article reviewed the physico-chemical properties of bile acids, with particular attention to ursodeoxycholic acid. Based on this information they explain the rational for treating some chronic liver diseases, like primary biliary cirrhosis and primary sclerosing cholangitis with bile acids. Finally they discussed the results of the different clinical trials of ursodeoxycholic acid in chronic liver diseases.