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BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare hepatobiliary disorder, whose etiology remains not fully elucidated. Given how rare PSC is in childhood, until the recent publication of a multicenter international collaboration, even data on its characteristics and natural history were scarce. Symptomatic cholelithiasis has not been previously reported as the presentation of PSC. OBJECTIVE: The aim of this study was the diagnosis of PSC following the initial unusual presentation with symptomatic cholelithiasis, that followed an atypical clinical course that could not be explained by cholelithiasis alone. A literature review was also conducted. METHODS: We conducted a retrospective chart review of three patients, who were diagnosed and/or followed at the Clinics Hospital, University of Campinas - Sao Paulo/ Brazil, between 2014 and 2020. Data analyzed included gender, age of presentation, past medical history, imaging findings, laboratory results, endoscopic evaluation, response to medical therapy and follow-up. RESULTS: Age at time of presentation with cholelithiasis varied from 10 to 12 years. In two of the cases reported, a more subacute onset of symptoms preceded the episode of cholelithiasis. Two patients were managed with cholecystectomy, not followed by any surgical complications, one patient was managed conservatively. Percutaneous liver biopsy was performed in all three cases, showing histological findings compatible with PSC. Associated inflammatory bowel disease (IBD) was not seen in any of the patients. The patients have been followed for a mean time of 3.4 years. CONCLUSION: PSC and cholelithiasis are both rare in the pediatric population. This study reports on symptomatic cholelithiasis as a presentation of PSC and raises the importance of suspecting an underlying hepatobiliary disorder in children with cholelithiasis without any known predisposing factors and/or that follow an atypical clinical course for cholelithiasis alone.

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ABSTRACT BACKGROUND: Primary sclerosing cholangitis (PSC) is a rare hepatobiliary disorder, whose etiology remains not fully elucidated. Given how rare PSC is in childhood, until the recent publication of a multicenter international collaboration, even data on its characteristics and natural history were scarce. Symptomatic cholelithiasis has not been previously reported as the presentation of PSC. OBJECTIVE: The aim of this study was the diagnosis of PSC following the initial unusual presentation with symptomatic cholelithiasis, that followed an atypical clinical course that could not be explained by cholelithiasis alone. A literature review was also conducted. METHODS: We conducted a retrospective chart review of three patients, who were diagnosed and/or followed at the Clinics Hospital, University of Campinas - Sao Paulo/ Brazil, between 2014 and 2020. Data analyzed included gender, age of presentation, past medical history, imaging findings, laboratory results, endoscopic evaluation, response to medical therapy and follow-up. RESULTS: Age at time of presentation with cholelithiasis varied from 10 to 12 years. In two of the cases reported, a more subacute onset of symptoms preceded the episode of cholelithiasis. Two patients were managed with cholecystectomy, not followed by any surgical complications, one patient was managed conservatively. Percutaneous liver biopsy was performed in all three cases, showing histological findings compatible with PSC. Associated inflammatory bowel disease (IBD) was not seen in any of the patients. The patients have been followed for a mean time of 3.4 years. CONCLUSION: PSC and cholelithiasis are both rare in the pediatric population. This study reports on symptomatic cholelithiasis as a presentation of PSC and raises the importance of suspecting an underlying hepatobiliary disorder in children with cholelithiasis without any known predisposing factors and/or that follow an atypical clinical course for cholelithiasis alone.

RESUMO CONTEXTO: A colangite esclerosante primária (CEP) é uma doença hepatobiliar rara, cuja etiologia ainda não está totalmente elucidada. Dada a raridade do CEP na infância, até a recente publicação de uma colaboração multicêntrica internacional, mesmo dados sobre suas características e história natural eram escassos. A colelitíase sintomática não foi relatada anteriormente como a apresentação inicial de CEP na infância. OBJETIVO: O objetivo deste estudo foi o diagnóstico de CEP após a apresentação inicial incomum com colelitíase sintomática, que seguiu um curso clínico atípico que não poderia ser explicado apenas pela colelitíase. Também foi realizada uma revisão da literatura. MÉTODOS: Foi realizada uma revisão retrospectiva dos prontuários de três pacientes, que foram diagnosticados e/ou acompanhados no Hospital das Clínicas da Universidade Estadual de Campinas - São Paulo / Brasil, entre 2014 e 2020. Os dados analisados incluíram sexo, idade de apresentação, história médica pregressa, achados de imagem, resultados laboratoriais, avaliação endoscópica, resposta à terapia médica e acompanhamento. RESULTADOS: A idade no momento da apresentação da colelitíase variou de 10 a 12 anos. Em dois dos casos relatados, um início mais subagudo dos sintomas precedeu o episódio de colelitíase. Dois pacientes foram tratados com colecistectomia, não seguida de qualquer complicação cirúrgica, e um paciente foi tratado de forma conservadora. Biópsia hepática percutânea foi realizada em todos os três casos, mostrando achados histológicos compatíveis com CEP. Doença inflamatória intestinal associada não foi observada em nenhum dos pacientes. Os pacientes foram acompanhados por um tempo médio de 3,4 anos. CONCLUSÃO: CEP e colelitíase são raras na população pediátrica. Este estudo relata a colelitíase sintomática como uma apresentação de CEP e levanta a importância da suspeita de doença hepatobiliar subjacente em crianças com colelitíase sem quaisquer fatores predisponentes conhecidos e/ou que seguem um curso clínico atípico.

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Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.

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OBJECTIVE: To evaluate epidemiological, clinical and prognostic characteristics of children with biliary atresia. METHODS: Data regarding portoenterostomy, liver transplantation (LTx), age at last follow-up and survival were collected from the records of patients followed up in six Brazilian centers (1982-2008) and compared regarding decades of surgery. RESULTS: Of 513 patients, 76.4% underwent portoenterostomy [age: 60-94.7 (82.6±32.8) days] and 46.6% underwent LTx. In 69% of cases, LTx followed portoenterostomy, whereas in 31% of cases LTx was performed as the primary surgery. Patients from the Northeast region underwent portoenterostomy later than infants from Southern (p = 0.008) and Southeastern (p = 0.0012) Brazil, although even in the latter two regions age at portoenterostomy was higher than desirable. Over the decades, LTx was increasingly performed. Overall survival was 67.6%. Survival increased over the decades (1980s vs. 1990s, p = 0.002; 1980s vs. 2000s, p < 0.001; 1990s vs. 2000s, p < 0.001). The 4-year post-portoenterostomy survival, with or without LTx, was 73.4%, inversely correlated with age at portoenterostomy (80, 77.7, 60.5% for ≤ 60, 61-90, > 90 days, respectively). Higher survival rates were observed among transplanted patients (88.3%). The 4-year native liver survival was 36.8%, inversely correlated with age at portoenterostomy (54, 33.3, 26.6% for ≤ 60, 61-90, > 90 days, respectively). CONCLUSIONS: This multicenter study showed that late referral for biliary atresia is still a problem in Brazil, affecting patient survival. Strategies to enhance earlier referral are currently being developed aiming to decrease the need for liver transplantation in the first years of life.

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BACKGROUND/PURPOSE: The purpose of the study was to describe the initial experience with a novel approach to the surgical treatment of progressive familial intrahepatic cholestasis (PFIC), avoiding the creation of a permanent stoma. METHODS: Two teenaged patients, aged 15 and 17 years, underwent partial internal biliary diversion to treat uncontrollable pruritus associated with PFIC. The surgical technique involved the creation of an isolated jejunal conduit, anastomosed proximally in a terminolateral fashion to the gallbladder and distally to the ascending colon. This operation combines the advantages of partially diverting the biliary flow from the enterohepatic cycle, avoiding an external biliary fistula. In one of the patients, this technique was used as a primary procedure, whereas in the other, a previous partial external diversion was converted to an internal diversion. RESULTS: Both patients had complete resolution of their pruritus and normalization of hepatic laboratory tests. One of the patients developed a mild choleretic diarrhea that can be controlled with eventual use of cholestyramine. No complications were observed related to this operation. CONCLUSIONS: Biliary diversion appears to be a very attractive surgical option for the treatment of PFIC in children with a normal gallbladder. Long-term follow-up is necessary to evaluate late results and eventual complications of this approach.

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BACKGROUND: Few studies on autoimmune hepatitis have enrolled non-Caucasian groups. AIMS: To evaluate Brazilian children with type 1 and 2 autoimmune hepatitis regarding outcome and clinical and biochemical parameters. PATIENTS AND METHODS: Thirty-six patients were submitted to a protocol that evaluated the clinical history, physical and biochemical data, and the course of the disease. Twenty-four children had type 1 autoimmune hepatitis, seven had type 2 and five had unclassified autoimmune hepatitis. Most patients were females (77%), with a median age at diagnosis of 11 years, and the median duration of symptoms was 5.5 and 8 months for types 1 and 2, respectively. Jaundice and choluria were the most common clinical manifestations. RESULTS: Treatment with azathioprine and prednisone was successful in patients with type 1 and 2 autoimmune hepatitis. AST and ALT decreased after 4 to 8 weeks of treatment compared to pretreatment levels in type 1 autoimmune hepatitis. Increased GGT values returned to pretreatment levels after 1 year in the two types. Three patients died and three other patients underwent liver transplantation. CONCLUSIONS: Non-Caucasian children had a similar disease when compared to Caucasian ones with autoimmune hepatitis. Increased levels of GGT during the first year of treatment should not be the only parameter for the indication of cholangiopathy.

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RACIONAL: A hipoplasia das vias biliares intra-hepáticas é causa de colestase secundária a uma alteração na integridade anatômica do trato biliar. A definição é dada pelo exame histopatológico e, do ponto de vista clínico, pode ser classificada em sindrômica e não-sindrômica onde o prognóstico é, geralmente, mais grave. OBJETIVO: Avaliar a história, características clínicas e bioquímicas, etiologia e evolução de crianças com hipoplasia das vias biliares intra-hepáticas acompanhadas em serviço terciário. CASUÍSTICA E MÉTODOS: Foram avaliadas 11 crianças com hipoplasia das vias biliares intra-hepáticas acompanhadas no ambulatório de Hepatologia Pediátrica do Hospital de Clínicas da Faculdade de Ciências Médicas da Universidade Estadual de Campinas, SP, no período de 1986 a 2001. RESULTADOS: Dos pacientes avaliados, três apresentavam a forma sindrômica e oito a forma não-sindrômica (dois com deficiência de a-1-antitripsina, um com lues, um como secundário a sepse, três com provável etiologia pelo citomegalovírus e um sem etiologia definida). A idade à época da primeira consulta variou de 31 a 1185 dias. O peso de nascimento variou de 1920 g a 3590 g. A maior parte dos pacientes apresentava alteração na coloração das fezes como apresentação inicial do quadro clínico. A mediana da relação ducto/espaço porta foi de 0,14. Com relação à evolução, a maioria das crianças apresentou evolução favorável, independente da forma de apresentação. CONCLUSÃO: A hipoplasia das vias biliares deve ser considerada em crianças com colestase e sua diferenciação com as causas extra-hepáticas de colestase neonatal é importante para se evitar cirurgia. O diagnóstico da forma não-sindrômica não deve ser considerado como de mau prognóstico, pois provavelmente, a evolução deve estar relacionada com a etiologia dessa forma de apresentação.

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BACKGROUND: Intrahepatic cholestasis secondary to paucity of bile duct is an alteration of the anatomic integrity of the biliary tract. Can be defined only histologically and, clinically, two categories are recognized: syndromic and non-syndromic, where the prognosis is generally more severe. AIM: To evaluate the history, clinical and biochemical characteristics, etiology and improvement of children who have paucity of intrahepatic bile duct followed at tertiary center. PATIENTS AND METHODS: Eleven children with paucity of intrahepatic bile duct, followed at the Pediatric Hepatology Service of the University Hospital, Campinas, SP, Brazil, were evaluated in the period from 1986 to 2001. RESULTS: Among the patients, three presented the syndromic and eight the non-syndromic form (two with alpha-1-antitrypsin deficiency, one with lues, one secondary to sepsis, three with probable etiology by cytomegalovirus and one without a definite etiology). Referral ranged from 31 to 1185 days. Birth weights ranged from 1920 g to 3590 g. Most of the patients presented pale stools. The median bile duct/portal tract ratio was 0.14. The majority of the children presented a favorable follow-up, regardless of the form of presentation. CONCLUSION: Paucity of intrahepatic bile ducts should be considered in children with cholestasis and its differentiation from extrahepatic causes of neonatal cholestasis is important in order to avoid surgery. Diagnosis of non-syndromic form should not be regarded as unfavorable prognosis, as the evolution is probably related to the etiology in this form of presentation.

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Caroll's disease is characterized by congenital non-obstructive dilatation of the intrahepatic bile ducts of undefined etiology. It is a rare disease usually affecting the whole liver but it may affect a lobe or a segment (11). This study shows the evolution of 6 cases (2 boys and 4 giris) that were diagnosed with Caroli's disease at a referral service. Their ages ranged from 2 to 16 years--median age 10 years. One of the patients presented with cholangitis, while hepatomegaly was observed in 83% of the cases. Four of the patients presented biliary lithiasis and in one of these cholesterol crystals could be observed in the duodenal secretion. The diagnosis was confirmed in 4 cases by endoscopic retrograde cholangiopancreatography, in 1 by cholangioresonance and 1 by echography. Two of the patients also presented congenital hepatic fibrosis. The outpatient clinic follow-up indicated that all the patients evolved well with the exception of one patient who was selected as a candidate for liver transplantation.

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Carolls disease is characterized by congenital non-obstructive dilatation of the intrahepatic bile ducts of undefined etiology. It is a rare disease usually affecting the whole liver but it may affect a lobe or a segment (11). This study shows the evolution of 6 cases (2 boys and 4 giris) that were diagnosed with Carolis disease at a referral service. Their ages ranged from 2 to 16 years--median age 10 years. One of the patients presented with cholangitis, while hepatomegaly was observed in 83

of the cases. Four of the patients presented biliary lithiasis and in one of these cholesterol crystals could be observed in the duodenal secretion. The diagnosis was confirmed in 4 cases by endoscopic retrograde cholangiopancreatography, in 1 by cholangioresonance and 1 by echography. Two of the patients also presented congenital hepatic fibrosis. The outpatient clinic follow-up indicated that all the patients evolved well with the exception of one patient who was selected as a candidate for liver transplantation.

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Caroll’s disease is characterized by congenital non-obstructive dilatation of the intrahepatic bile ducts of undefined etiology. It is a rare disease usually affecting the whole liver but it may affect a lobe or a segment (11). This study shows the evolution of 6 cases (2 boys and 4 giris) that were diagnosed with Caroli’s disease at a referral service. Their ages ranged from 2 to 16 years--median age 10 years. One of the patients presented with cholangitis, while hepatomegaly was observed in 83

of the cases. Four of the patients presented biliary lithiasis and in one of these cholesterol crystals could be observed in the duodenal secretion. The diagnosis was confirmed in 4 cases by endoscopic retrograde cholangiopancreatography, in 1 by cholangioresonance and 1 by echography. Two of the patients also presented congenital hepatic fibrosis. The outpatient clinic follow-up indicated that all the patients evolved well with the exception of one patient who was selected as a candidate for liver transplantation.

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BACKGROUND: Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. OBJECTIVE: The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. PATIENTS AND METHODS: Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele) and Taq-1 (Z allele). RESULTS: Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ) and two had the S allele with another allele (*S) different from Z. CONCLUSION: These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6 per cent). A correct diagnosis is important for effective clinical follow-up and for genetic counseling.

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