Hepatobiliary disease in children and adolescents with cystic fibrosis / Doença hepatobiliar em crianças e adolescentes com fibrose cística

Abstract Objectives: The aims of the study were to determine the frequency of hepatobiliary disease in patients with cystic fibrosis and to describe the sociodemographic, clinical, and laboratory profile of these patients. Methods: This was a retrospective, descriptive, and analytical study of 55 patients diagnosed with cystic fibrosis, aged between 3 months and 21 years, followed-up from January 2008 to June 2016 in a referral center. Medical records were consulted and sociodemographic, clinical and laboratory data, including hepatobiliary alterations, imaging studies, genetic studies, liver biopsies, and upper digestive endoscopies were registered. Results: Hepatobiliary disease was diagnosed in 16.4% of the patients and occurred as an initial manifestation of cystic fibrosis in 55.6% of these cases. The diagnosis of hepatopathy occurred before or concomitantly with the diagnosis of cystic fibrosis in 88.9% of the children. All patients with hepatobiliary disease were considered non-white, with a predominance of females (77.8%) and median (IQR) of 54 (27-91) months. Compared with the group without hepatobiliary disease, children with liver disease had a higher frequency of severe mutations identified in the CFTR gene (77.8% vs. 39.6%, p = 0.033) and severe pancreatic insufficiency (88.9% vs. 31.6%, p = 0.007). Conclusion: The frequency of hepatobiliary disease was high, with a very early diagnosis of the disease and its complications in the studied series. A statistical association was observed between the occurrence of hepatobiliary disease and the presence of pancreatic insufficiency and severe mutations in the CFTR gene. It is emphasized that cystic fibrosis is an important differential diagnosis of liver diseases in childhood.

Resumo Objetivos: Os objetivos do estudo foram determinar a frequência da doença hepatobiliar em pacientes com fibrose cística e descrever o perfil sociodemográfico, clínico e laboratorial destes. Métodos: Estudo retrospectivo, descritivo e analítico de 55 pacientes com diagnóstico de fibrose cística, entre três meses e 21 anos, acompanhados de janeiro de 2008 a junho de 2016 em um centro de referência. Foi realizada consulta aos prontuários médicos, registrando-se os dados sociodemográficos, clínicos e laboratoriais, incluindo-se alterações hepatobiliares, exames de imagem, estudos genéticos, biópsias hepáticas e endoscopias digestivas altas. Resultados: A doença hepatobiliar foi diagnosticada em 16,4% dos pacientes e ocorreu como manifestação inicial da fibrose cística em 55,6% destes casos. O diagnóstico da hepatopatia ocorreu antes ou concomitante ao diagnóstico da fibrose cística em 88,9% das crianças. Todos os pacientes com doença hepatobiliar foram considerados não brancos, havendo predominância do sexo feminino (77,8%) e mediana (I.I.Q) de idade de 54 (27-91) meses. Em comparação com o grupo sem doença hepatobiliar, as crianças com hepatopatia tiveram maior frequência de mutações graves no gene CFTR identificadas (77,8% vs 39,6%; p = 0,033) e de insuficiência pancreática grave (88,9% vs 31,6%; p = 0,007). Conclusão: A frequência de doença hepatobiliar foi elevada, observando-se um diagnóstico muito precoce da mesma e de suas complicações na casuística estudada. Houve associação estatística entre a ocorrência de doença hepatobiliar e a presença de insuficiência pancreática e de mutações graves do gene CFTR. Enfatiza-se que a fibrose cística represente um importante diagnóstico diferencial de hepatopatias na infância.

Síndrome de Pearson: Reporte de un caso / Pearson syndrome: Case report

Entre las etiologías de anemias en la infancia, las citopatías mitocondriales son poco frecuentes. El síndrome de Pearson se diagnostica principalmente durante etapas iniciales de la vida y es caracterizado por anemia sideroblástica refractaria con vacuolización de células progenitoras en la médula ósea, disfunción del páncreas exocrino y variables alteraciones neurológicas, hepáticas, renales y endocrinas. En el siguiente informe reportamos un nuevo caso de lactante mayor femenino de 14 meses de edad, evaluada de forma multicéntrica con diagnostico clínico y molecular de síndrome de Pearson, con la deleción común de 4.977 pares de bases del ADN mitocondrial. Esta entidad ha sido asociada a diversos fenotipos dentro del amplio espectro clínico de las enfermedades mitocondriales.

Among the etiologies of anemia in the infancy, the mitochondrial cytopathies are infrequent. Pearson syndrome is diagnosed principally during the initial stages of life and it is characterized by refractory sideroblastic anemia with vacuolization of marrow progenitor cells, exocrine pancreatic dysfunction and variable neurologic, hepatic, renal and endocrine failures. We report the case of a 14 month-old girl evaluated by a multicentric study, with clinic and molecular diagnosis of Pearson syndrome, with the 4,977-base pair common deletion of mitochondrial DNA. This entity has been associated to diverse phenotypes within the broad clinical spectrum of mitochondrial disease.

Manifestações gastrintestinais na fibrose cística / Gastrointestinal manifestations in cystic fibrosis

A mutação no gene que codifica a proteína reguladora da condutância transmembrana (CFTR) constitui-se na base das alterações encontradas na fibrose cística (FC), afetando também o sistema gastrintestinal, em especial o pâncreas e o fígado. Cerca de 90% dos pacientes com FC são insuficientes pancreáticos já no 1º ano, e os sinais clínicos são os associados à má-absorção intestinal de nutrientes e gorduras: esteatorreia, flatulência, distensão abdominal, desnutrição e deficiências de vitaminas lipossolúveis. A dosagem de elastase fecal destaca-se no diagnóstico da insuficiência pancreática, e tratamento baseia-se na reposição de enzimas pancreáticas. A dose é individualizada, inicialmente 500 a 1.000 U/kg de lipase nas refeições principais, não ultrapassando 2.500 U/kg/refeição ou 10.000 U/kg/dia, pelo risco de colonopatia fibrosante. A insuficiência pancreática também causa má-absorção de vitaminas lipossolúveis (vitaminas A, D, E, K), sendo necessária suplementação. A doença hepatobiliar costuma iniciar na primeira década de vida, e o critério diagnóstico baseia-se nos aspectos cliínicos, ecográficos e bioquímicos, que devem ser periodicamente revisados. O tratamento da hepatopatia associado à FC com o ácido ursodesoxicólico visa retardar a progressão da doença. No tratamento das complicações da hipertensão porta, como varizes esofágicas, utilizam-se a ligadura elástica e a escleroterapia por via endoscópica, a derivação porto-sistêmica e implantação de shunts intra-hepáticos. Nenhum tratamento previne a progressão de fibrose para cirrose multilobular, sendo o transplante hepático indicado nos casos de hipertensão portal grave e insuficiência hepática, nos pacientes que mantêm função pulmonar preservada.

The gene mutation that codifies the CFTR protein is responsible for the alterations seen in Cystic Fibrosis and affects the gastrointestinal system as well, specially pancreas and liver. Around 90% of the patients with CF are pancreatic insufficient already on their first year of life and the clinical signs are those associated with malabsorption of fat and nutrients presenting flatulence, abdominal distension, malnutrition, and deficiency of fat soluble vitamins. The dosage of pancreatic supplements is tailored to the individual needs, initially the dosage should be tried as 500 to 1000 U/kg of lipase for the main meals, never going above 2,500 U/kg/meal or 10,000U/kg/Day due to the risk of fibrosing colonopathy. The pancreatic insufficiency also causes malabsortion of fat soluble vitamins (A, D, E, K vitamins), so supplementation is necessary. The hepatobiliar disease usually starts on the first decade of life and the diagnostic criteria are based on clinical, ecographic and biochemical aspects that must be reviewed periodically. The treatment of CF-associated liver disease with ursodesoxicolic acid aims to slow down the progress of the disease. For the treatment of portal hypertension complications, such as oesophageal varicose veins, elastic bandages and endoscopic sclerotherapy, porto-systemic derivations and implantation of intra hepatic shunts are used. No treatment is able to prevent the progress from fibrosis to multilobular cirrhosis, so in case of severe portal hypertension and hepatic insufficiency, the liver transplant is recommended, in patients who maintain their pulmonary functions preserved.

A Case of Shwachman-Diamond Syndrome Confirmed with Genetic Analysis in a Korean Child

Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic disorder, consisting of exocrine pancreatic insufficiency, chronic neutropenia, neutrophil chemotaxis defects, metaphyseal dysostosis, short stature, dental caries, and multiple organ involvements. Although SDS is the second most common hereditary abnormality of exocrine pancreas following cystic fibrosis in the Western countries, it has rarely been reported in Asia. We diagnosed a case of SDS in a 42-month-old girl, and genetic analysis including the relatives of the patient confirmed the diagnosis for the first time in Korea. She had short stature, steatorrhea, dental caries, and recurrent prulent otitis media and pneumonias. Laboratory studies revealed cyclic neutropenia, and serum levels of trypsin, amylase, and lipase were decreased. Simple radiography revealed metaphyseal sclerotic changes at the distal femur. A CT scan demonstrated a fatty infiltration and atrophy of the pancreas. On direct sequencing analysis of Shwachman-Bodian-Diamond Syndrome gene exon 2 region, the patient was homozygous for the c.258+2T>C mutation and heterozygous for the c.183_184TA>CT mutation and c.201A>G single nucleotide polymorphism. Treatment with pancreatic enzyme replacement, multivitamin supplementation, and regular to high fat diet improved her weight gain and steatorrhea.