Ermelinda Santos Silva

Demonstration of McCune-Albright mutations in the liver of children with high γGT progressive cholestasis

Two patients presented with neonatal cholestasis and acholic stools as first manifestations of McCune-Albright syndrome. Both went through an extensive evaluation including an exploratory laparotomy with peroperative cholangiography which ruled out biliary atresia. One patient presented from the fourth month of life with the classical café-au-lait spots following Blaschkos lines, while less classical café-au-lait spots were seen in the second patient at the age of 4 years. Bone lesions were seen in one patient at the age of 2.5 years and in the other at the age of 4 years. Despite the severity of presentation, both patients cleared their jaundice within 6 months, but still had mild abnormalities of liver function tests. Both patients showed an activating mutation of codon 201 in the gene encoding the alpha-subunit of the G-protein that stimulates adenylcyclase in liver tissue, suggesting that this metabolic defect could be responsible for the cholestatic syndrome. Similar mutations have been found in other affected tissues in patients with the McCune-Albright syndrome. We propose that McCune-Albright syndrome be included in the list for differential diagnosis of neonatal cholestasis and chronic cholestasis of infancy, as a rare cause.

A case of hepatopulmonary syndrome solved by mycophenolate mofetil (an inhibitor of angiogenesis and nitric oxide production)

The autoimmune lymphoproliferative syndrome (ALPS) is a rare, multisystemic disease, caused by an inherited defect in the Fas apoptotic pathway, characterized by a chronic non-malignant lymphoid accumulation and autoimmune manifestations. Lung, kidney, liver, and gut infiltration is described in severe, multisystemic cases; so far there has been no description of hepatopulmonary syndrome (HPS), for which orthotopic liver transplantation (OLT) is currently the only known effective treatment. A teenage boy, diagnosed with ALPS at 4years of age (lymph nodes enlargement, splenomegaly, immune cytopenias), was stable until 13years of age, when he developed insidious hypoxemia (PaO 2 =46.7mmHg). He was diagnosed with HPS on the basis of hypoxemia, non-cirrhotic liver disease with portal hypertension, and pulmonary vascular dilatation (intrapulmonary shunt=45%). He was treated with oxygen (maximum 6L/min), prednisolone and sirolimus. There was significant regression of all manifestations of ALPS, except for the pulmonary symptoms, therefore, after evaluation in referral centers in England, OLT was proposed. Since he was to undergo major surgery, sirolimus, which has wound-healing problems, was switched to mycophenolate mofetil (MMF). Following this change, we observed a huge improvement in pulmonary symptoms and reduction of oxygen needs. The intrapulmonary shunt decreased from 45% to 0% in less than a year, and it has not changed since (18months after complete normalization), on continued treatment with MMF. Indication for OLT was suspended. In the last year, lymphoid proliferation increased again, with huge splenomegaly, but no recurrence of HPS. The addition of sirolimus to MMF produced again a rapid resolution of lymphoid proliferation. The dramatic and unexpected regression of HPS may have been due to inhibition of angiogenesis and nitric oxide (NO) production by MMF (both important pathways/mediators in HPS pathogenesis). Therefore, we propose to perform clinical trials with MMF, and/or other angiogenesis and NO inhibitors, on a long-term treatment basis, to confirm their potential as a valid alternative to medical treatment of HPS.

Lethal dilated cardiomyopathy due to long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

logical abnormalities including impaired function of lymphocytes, the presence of lupus erythematosus cells and thrombocytopenia. Immunological dysfunctions such as impaired functions of T and B cells, hypofunction of suppressor T cells, and abnormal proliferation of B cells are thought to be due to amino acid imbalance in tissue and cells (Nagata et al 1987). Congenital thymic hypoplasia detected at autopsy is rather interesting and has not been reported in LPI before. The coincidence of this abnormality and LPI is not excluded. In conclusion, these patients must be investigated for further immunological abnormalities including structural thymic disorders.

Alpha-1-Antitrypsin Deficiency Presenting as Neonatal Cholestasis: Predictors of Outcome and Effect of Ursodeoxycholic Acid

Background and objective: Alpha-1-antitrypsin deficiency presenting as neonatal cholestasis occurs in a small percentage of affected individuals. The prognosis is variable, from “healing” to liver cirrhosis and/or severe hepatocellular failure, requiring liver transplantation. We researched for predictors of outcome, including the effect of ursodeoxycholic acid. Methods: Retrospective cohort study of 27 cases of neonatal cholestasis due to alpha-1-antitrypsin deficiency, in the period between 1985 and 2013. Inclusion criteria: patients with neonatal cholestasis and ZZ phenotype. Exclusion criteria: presence of other diagnosis or known risk factors for developing neonatal cholestasis. We analyzed several clinical, biochemical, histological and therapeutic variables. Patients were categorized into two groups: favorable outcome (n=18), unfavorable outcome (n=9). We also divided the patients as treated (n=16), and untreated (n=11) with ursodeoxycholic acid. Results: Splenomegaly at admission (P=0.006) and persistent jaundice at 6 months old (P=0.007) were associated with unfavorable outcome. The values of conjugated bilirubin (P=1.000), aspartate aminotransferase (P=1.000), alanine aminotransferase (P=0.371) and gamma-glutamyltransferase (P=0.667) were not significantly different in both groups of outcome. Early treatm e nt with ursodeoxycholic acid was associated with a favorable outcome (P=0.011). Treated patients did not differ significantly from the untreated-ones in biochemical parameters (conjugated bilirubin, aspartate aminotransferase, alanine aminotransferase and gamma-glutamyltransferase), and had significantly lower alpha-1-antitrypsin serum levels (P=0.015). Conclusion: Splenomegaly at admission and persistence of jaundice at 6 months old were predictive for bad prognosis, and early treatment with ursodeoxycholic acid might have interfered positively in the outcome.

Early onset lysosomal acid lipase deficiency presenting as secondary hemophagocytic lymphohistiocytosis: Two infants treated with sebelipase alfa

Two unrelated infants were diagnosed with and initially treated for hemophagocytic lymphohistiocytosis (HLH), but progressed to cholestasis and liver failure. Early onset lysosomal acid lipase deficiency (EO-LAL-D) was suspected due to lymphocytes with cytoplasmic vacuolation and/or adrenal calcifications and confirmed by enzymatic and genetic analysis. Enzyme replacement therapy with sebelipase alfa was implemented, but both children died, despite initial improvement. Since this inborn error of metabolism progresses rapidly in infants, early diagnosis is crucial, and appropriate treatment should be started as soon as possible. The authors suggest that the diagnosis of EO-LAL-D should be considered in infants with symptoms of HLH.