Correlation between neuroimaging, neurological phenotype, and functional outcomes in Wilson's disease.

INTRODUCTION: Wilson's disease (WD) is associated with a variety of movement disorders and progressive neurological dysfunction. The aim of this study was to correlate baseline brain magnetic resonance imaging (MRI) features with clinical phenotype and long-term outcomes in chronically treated WD patients. METHODS: Patients were retrospectively selected from an institutional database. Two experienced neuroradiologists reviewed baseline brain MRI. Functional assessment was performed using the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) scale, and disease severity was classified using the Global Assessment Scale for Wilson's Disease (GASWD). RESULTS: Of 27 patients selected, 14 were female (51.9%), with a mean (standard deviation [SD]) age at onset of 19.5 (7.1) years. Neurological symptoms developed in 22 patients (81.5%), with hyperkinetic symptoms being the most common (70.4%). Baseline brain MRI showed abnormal findings in 18 cases (66.7%), including T2 hyperintensities in 59.3% and atrophy in 29.6%. After a mean (SD) follow-up of 20.9 (11.0) years, WD patients had a mean score of 19.2 (10.2) on WHODAS 2.0 and 6.4 (5.7) on GASWD. The presence of hyperkinetic symptoms correlated with putaminal T2 hyperintensities (p = 0.003), putaminal T2 hypointensities (p = 0.009), and mesencephalic T2 hyperintensities (p = 0.009). Increased functional disability was associated with brain atrophy (p = 0.007), diffusion abnormalities (p = 0.013), and burden of T2 hyperintensities (p = 0.002). A stepwise regression model identified atrophy as a predictor of increased WHODAS 2.0 (p = 0.023) and GASWD (p = 0.007) scores. CONCLUSIONS: Atrophy and, to a lesser extent, deep T2 hyperintensity are associated with functional disability and disease severity in long-term follow-up of WD patients.

Portal cavernoma in type 1 neurofibromatosis: A fortuitous or causal association?

Neurofibromatosis type 1 (NF-1) is a multisystem genetic disorder affecting the NF1 tumor suppressor gene. Patients typically develop superficial (cutaneous) and internal (plexiform) neurofibromas. The latter may rarely involve the liver locating in the hilum and encasing the portal vessels, leading to portal hypertension. Vascular abnormalities (NF-I vasculopathy) are a well-recognized manifestation of NF-1. Although the pathogenesis is not well-known, NF-1 vasculopathy involves arteries of both peripheral and cerebral territories, with venous thrombosis being exceptionally reported. Portal venous thrombosis (PVT) is the leading cause of portal hypertension in childhood and has been associated with several risk factors. Nevertheless, predisposing conditions remain unknown in more than 50% of the cases. The treatment options are limited, and its management is nonconsensual in the pediatric age. We report the case of a 9-year-old boy with clinically and genetically confirmed NF-1, diagnosed with portal venous cavernoma after an episode of gastrointestinal bleeding. There were no identifiable risk factors for PVT and intrahepatic peri-hilar plexiform neurofibroma was excluded by MRI imaging. To the best of our knowledge, this is the first report of PVT in NF-1. We speculate that NF-1 vasculopathy may have been a pathogenic factor, or instead, it was a fortuitous association.

Incidental hypertransaminasemia in children-a stepwise approach in primary care.

Children with elevated liver enzymes are occasionally discovered through laboratory work-up from different clinical scenarios. Although the majority will have transient and/or benign conditions, a subgroup will have underlying liver disorders. The differential diagnosis is broad and therefore, a systematic approach is of utmost importance. In this article, we reviewed the most recent and relevant literature to provide a comprehensive overview of the main disease processes that cause hypertransaminasemia in children. Ultimately, we propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes in asymptomatic children. The first step is to obtain a complete history along with a thorough physical examination to exclude red flags, which should dictate urgent consultation with a paediatric gastroenterologist or hepatologist.  Conclusion: Hypertransaminasemia is a challenging scenario in the primary care setting. The aetiology can be broad, ranging from hepatic and extrahepatic to transient versus chronic liver disease. Timely referral to a specialised centre is of paramount importance for conducting targeted research and to not miss the chance of identifying a progressive, but still asymptomatic, treatable liver disease. What is Known: • Elevated liver enzyme is a challenging scenario in the primary care setting. • There are few studies guiding the evaluation of asymptomatic hypertransaminasemia in the paediatric population and a standardised approach is lacking. What is New: • We propose a practical stepwise approach to guide primary care physicians in the evaluation of abnormal liver enzymes.

Bile acids profile and redox status in healthy infants.

BACKGROUND: At birth, human neonates are more likely to develop cholestasis and oxidative stress due to immaturity or other causes. We aimed to search for a potential association between bile acids profile, redox status, and type of diet in healthy infants. METHODS: A cross-sectional, exploratory study enrolled 2-month-old full-term infants (n = 32). We measured plasma bile acids (total and conjugated), and red blood cell (RBC) oxidative stress biomarkers. The type of diet (breastfeeding, mixed, formula) was used as an independent variable. RESULTS: Plasma total bile acids medium value was 14.80 µmol/L (IQR: 9.25-18.00). The plasma-conjugated chenodeoxycholic acid percentage (CDCA%) correlated significantly and negatively with RBCs membrane-bound hemoglobin percentage (MBH%) (r = -0.635, p < 0.01) and with RBC-oxidized glutathione (r = -0.403, p < 0.05) levels. RBC oxidative stress biomarkers (especially MBH%) were predictors of conjugated CDCA%, and this predictive ability was enhanced when adjusted for the type of diet (MBH, r = 0.452, p < 0.001). CONCLUSIONS: Our data suggest that the bile acid profile might play a role in the regulation of redox status (or vice versa) in early postnatal life. Eventually, the type of diet may have some impact on this process. IMPACT: The conjugated CDCA% in plasma is negatively correlated with biomarkers of RBC oxidative stress in healthy infants. Specific biomarkers of RBC oxidative stress (e.g. MBH, GSH, GSSG) may be promising predictors of conjugated CDCA% in plasma. The type of diet may influence the predictive ability of hit RBC oxidative stress biomarkers (e.g. MBH, GSH, GSSG). Our findings suggest a link between plasma bile acids profile and the RBC redox status in healthy infants, eventually modulated by the type of diet. The recognition of this link may contribute to the development of preventive and therapeutic strategies for neonatal cholestasis.

Case report: NAFLD and maple syrup urine disease: Is there an interplay between branched-chain amino acids and fructose consumption?

Background: The worldwide increase in pediatric overweight and obesity, in parallel with the global increase in the consumption of sucrose and fructose, is associated with non-alcoholic fatty liver disease (NAFLD). Elevated branched-chain amino acids (BCAAs) are a metabolic feature related to obesity and an early risk factor for insulin resistance and NAFLD. However, few studies have assessed metabolic risk factors and nutritional status in maple syrup urine disease (MSUD) patients under restricted BCAA and high carbohydrate diets. Methods and results: Herein, we present a pilot report of a 17-year-old boy with classic MSUD with poor diet compliance and high fructose consumption, mainly during early adolescence. At that time, he was overweight and developed features of metabolic syndrome, including persistently elevated liver enzymes and hepatic steatosis. He underwent liver transplantation at the age of 13 years to prevent the risk of progressive cognitive impairment. Two months later, NAFLD relapsed in the graft, despite a better BCAA balance and weight loss. Nevertheless, 6 months after dietary restriction of fructose consumption, NAFLD had sustainably improved. Conclusion: Childhood overweight and fructose overconsumption are wellestablished driving forces in the development of pediatric NAFLD. However, their role in the early onset and progression of NAFLD in the allograft remains to be established. Furthermore, it is not known whether the dysmetabolic state associated with elevated BCAAs may be contributory. Further studies are required with a cohort of MSUD subjects to validate our findings and to ascertain the possible interaction between a BCAA imbalance and dietary intake in the development of NAFLD.

Incidental Liver Lesions in children: A practical and evidence-based approach.

Incidental liver lesions are increasingly being discovered in the context of the increased use of ultrasound studies and the majority are benign. In children, although individually rare, the differential diagnosis is broad and therefore a systematic approach is of utmost importance to reduce the radiological and disease burden in children and their families. This review article collected current evidence and provides fundamental information for the clinician regarding specific differential diagnoses and unique imaging features of benign liver lesions in children. Ultimately, we propose a practical stepwise approach mainly involving clinical and radiological workup. Laboratory tests and histopathological examination may be necessary in the presence of red flags or in indeterminate lesions.

Neonatal cholestasis: development of a diagnostic decision algorithm from multivariate predictive models.

Despite the recent advances involving molecular studies, the neonatal cholestasis (NC) diagnosis still relays on the expertise of medical teams. Our aim was to develop models of etiological diagnosis and unfavourable prognosis which may support a rationale diagnostic approach. We retrospectively analysed 154 patients born between January 1985 and October 2019. The cohort was divided into two main groups: (A) transient cholestasis and (B) other diagnosis (with subgroups) and also in two groups of outcomes: (I) unfavourable and (II) favourable. Multivariate logistic regression analysis identified the lower gestational age as the only variable independently associated with an increased risk of transient cholestasis and signs and/or symptoms of sepsis with infectious or metabolic diseases. Gamma-glutamyl transferase serum levels > 300 IU/L had a positive predictive value for both diagnosis of biliary atresia and for alpha-1-antitrypsin deficiency (A1ATD) and for unfavourable prognosis. A model of diagnosis for A1ATD (n = 34) showed an area under the ROC curve = 0.843 [confidence interval (CI): 0.773-0.912].Conclusion: This study identified some predictors of diagnosis and prognosis which helped to build a diagnostic decision algorithm. The unusually large subgroup of patients with A1ATD in this cohort emphasizes its predictive diagnostic model. What Is Known • The etiological diagnosis of neonatal cholestasis (NC) requires a step-by-step guided approach, and diagnostic models have been developed only for biliary atresia. • Current algorithms neither address the epidemiology changes nor the application of the new molecular diagnostic tools. What Is New • This study provides diagnostic predictive models for patients with A1ATD, metabolic/infectious diseases, and transient cholestasis, and two models of unfavourable prognosis for NC. • A diagnostic decision algorithm is proposed based on this study, authors expertise and the literature.

Neonatal Cholestasis Over Time: Changes in Epidemiology and Outcome in a Cohort of 154 Patients From a Portuguese Tertiary Center.

Introduction: In the last two decades there have been advances in the diagnosis and management of neonatal cholestasis, which may have changed its epidemiology, diagnostic accuracy, outcomes, and survival. Our goal was to characterize these changes over time in our setting. Methods: Retrospective cohort study in a tertiary center, enrolling patients born between January 1985 and October 2019. The cohort was divided into two periods, before (A; n = 67) and after (B; n = 87) the year 2000; and in two groups, according to patient's outcome (favorable, unfavorable). Overall survival and survival with and without orthotopic liver transplant (OLT) were evaluated in the two periods (A and B) and in different subgroups of underlying entities. Results: We found that the age of cholestasis recognition decreased significantly from period A to period B [median 43 days and 22 days, respectively, (p < 0.001)]; the changes in epidemiology were relevant, with a significant decrease in alpha-1-antitrypsin deficiency (p < 0.001) and an increase in transient cholestasis (p = 0.004). A next-generation sequencing (NGS) panel available since mid-2017 was applied to 13 patients with contributory results in 7, but, so far, only in 2 patients led to conclusive diagnosis of underlying entities. The number of cases of idiopathic cholestasis did not vary significantly. Over time there was no significant change in the outcome (p = 0.116). Overall survival and survival without OLT had no significant improvement during the period of observation (in periods A and B, 86 vs. 88%, and 85 vs. 87%, respectively). However, in period B, with OLT we achieved the goal of 100% of survival rate. Conclusions: Our data suggest that transient cholestasis became a very important subset of neonatal cholestasis, requiring specific guidance. The NGS panels can provide important inputs on disease diagnosis but, if applied without strict criteria and expertise, they can open a Pandora's box due to misinterpretation. Despite all the advances in accurate diagnosis and timely management-including early recognition of cholestasis-the improvement in patient outcomes and survival were still not significant.

European lipodystrophy registry: background and structure.

BACKGROUND: Lipodystrophy syndromes comprise a group of extremely rare and heterogeneous diseases characterized by a selective loss of adipose tissue in the absence of nutritional deprivation or catabolic state. Because of the rarity of each lipodystrophy subform, research in this area is difficult and international co-operation mandatory. Therefore, in 2016, the European Consortium of Lipodystrophies (ECLip) decided to create a registry for patients with lipodystrophy. RESULTS: The registry was build using the information technology Open Source Registry System for Rare Diseases in the EU (OSSE), an open-source software and toolbox. Lipodystrophy specific data forms were developed based on current knowledge of typical signs and symptoms of lipodystrophy. The platform complies with the new General Data Protection Regulation (EU) 2016/679 by ensuring patient pseudonymization, informational separation of powers, secure data storage and security of communication, user authentication, person specific access to data, and recording of access granted to any data. Inclusion criteria are all patients with any form of lipodystrophy (with the exception of HIV-associated lipodystrophy). So far 246 patients from nine centres (Amsterdam, Bologna, Izmir, Leipzig, Münster, Moscow, Pisa, Santiago de Compostela, Ulm) have been recruited. With the help from the six centres on the brink of recruitment (Cambridge, Lille, Nicosia, Paris, Porto, Rome) this number is expected to double within the next one or 2 years. CONCLUSIONS: A European registry for all patients with lipodystrophy will provide a platform for improved research in the area of lipodystrophy. All physicians from Europe and neighbouring countries caring for patients with lipodystrophy are invited to participate in the ECLip Registry. STUDY REGISTRATION: ClinicalTrials.gov (NCT03553420). Registered 14 March 2018, retrospectively registered.

Fatty Liver Caused by Glycogen Storage Disease Type IX: A Small Series of Cases in Children.

BACKGROUND: The prevalence of non-alcoholic fatty liver disease (NAFLD) affecting children and adolescents has increased dramatically in recent years. This increase is most probably related to the obesity pandemic and the high consumption of fructose. However, hepatic steatosis has some rare causes (e.g., some metabolic diseases) of which clinicians should be aware, particularly (but not only) when patients are non-obese or non-overweight. Differential diagnosis is notably important when pathologies have a specific treatment, such as for glycogenosis type IX (GSD-IX). AIMS: To contribute to the knowledge on the differential diagnosis of NAFLD in paediatric age and to the clinical, biochemical, molecular, and histological characterisations of GSD-IX, a rare metabolic disorder. METHODS: We performed a retrospective study of a small series of cases (n = 3) of GSD-IX diagnosed in the past 6 years, who were currently being followed up in the Units of Gastroenterology or Metabolic Diseases of the Paediatric Division of our hospital and whose clinical presentation was NAFLD in paediatric age. RESULTS: Three male patients were diagnosed with NAFLD before 2 years of age, 2 with confirmed diagnosis before the age of 3 years (alanine aminotransferase [ALT], liver ultrasound, and molecular analysis) and 1 whose diagnosis was confirmed at 11 years (ALT, liver ultrasound, liver histology, and molecular analysis). None of the patients were obese or overweight, and the daily fructose consumption was unknown. The outcome was favourable in all 3 patients, with follow-up periods ranging from 2 to 6 years. CONCLUSION: The decision on how far the search for secondary causes of NAFLD should go can be difficult, and GSD-IX must be on the list of possible causes.

Fatty Liver and Autoimmune Hepatitis: Two Forms of Liver Involvement in Lipodystrophies.

INTRODUCTION: Lipodystrophies are a heterogeneous group of rare diseases (genetic or acquired) characterized by a partial or generalized deficit of adipose tissue, resulting in less energy storage capacity. They are associated with severe endocrine-metabolic complications with significant morbidity and mortality. In the pathogenesis of the acquired forms, immunological disorders may be involved. CASE 1: A 13-year-old female was diagnosed with acquired generalized lipodystrophy and observed for suspicion of portal hypertension. She presented with generalized absence of adipose tissue, cervical and axillary acanthosis nigricans, and massive hepatosplenomegaly. Laboratory tests revealed AST 116 IU/L, ALT 238 IU/L, GGT 114 IU/L, HOMA-IR 28.2, triglycerides 491 mg/L, and leptin < 0.05 ng/mL. Upper gastrointestinal endoscopy saw no signs of portal hypertension. Hepatic histology showed macrovesicular fatty infiltration (60% of hepatocytes) and advanced fibrosis/cirrhosis. Her clinical condition worsened progressively to diabetes requiring treatment with subcutaneous insulin and hepatopulmonary syndrome. CASE 2: A 15-year-old female, diagnosed with acquired partial lipodystrophy, Parkinson syndrome, autoimmune thyroiditis, and autoimmune thrombocytopenia was observed for hypertransaminasemia since the age of 8 years. She had absence of subcutaneous adipose tissue in the upper and lower limbs and ataxia. Laboratory tests showed AST 461 IU/L, ALT 921 IU/L, GGT 145 IU/L, HOMA-IR 32.6, triglycerides 298 mg/dL, normal leptin levels, platelets 84,000/µL, IgG 1,894 mg/dL, positive anti-LKM and anti-LC-1. Hepatic histology was suggestive of autoimmune hepatitis, without steatosis. She progressed favorably under metformin and immunosuppressive treatment. CONCLUSION: Early recognition and adequate characterization of liver disease in lipodystrophies is essential for a correct treatment approach. In acquired generalized lipodystrophy, the severe endocrine-metabolic disorder, which leads to steatohepatitis with cirrhotic progression, may benefit from recombinant leptin treatment.

INTRODUÇÃO: As lipodistrofias sao um grupo heterogeneo de doencas raras (formas geneticas e adquiridas) caracterizadas por defice parcial ou generalizado de tecido adiposo, resultando em menor capacidade de armazenamento energetico. Estao associadas a complicacoes endocrino-metabolicas graves com morbilidade e mortalidade significativas. Na patogenese das formas adquiridas poderao estar envolvidos disturbios imunologicos. CASO 1: Adolescente de 13 anos, sexo feminino, com diagnostico de lipodistrofia generalizada adquirida, observada por suspeita de hipertensao portal. Apresentava ausencia generalizada de tecido adiposo, acantose nigricans cervical e axilar, e hepatoesplenomegalia volumosa. Do estudo destacavam-se: AST 116 UI/L, ALT 238 UI/L, GGT 114 UI/L, HOMA-IR 28.2, triglicerideos 491 mg/L e leptina < 0.05 ng/mL. A endoscopia digestiva alta nao evidenciou sinais de hipertensao portal. Histologia hepatica com esteatose macrovesicular (60% dos hepatocitos) e fibrose avancada/cirrose. A sua condicao clinica evoluiu progressivamente para diabetes com necessidade de tratamento com insulina subcutanea e sindrome hepatopulmonar. CASO 2: Adolescente de 15 anos, sexo feminino, com diagnostico de lipodistrofia parcial adquirida, sindrome parkinsonico, tiroidite autoimune, e trombocitopenia autoimune, observada por elevacao das transaminases desde os 8 anos. Apresentava ausencia de tecido adiposo subcutaneo nos membros superiores e inferiores, ataxia e tremor das maos, sem sinais de doenca hepatica. Do estudo destacavam-se: AST 461 UI/L, ALT 921 UI/L, GGT 145 UI/L, HOMA-IR 32,6, triglicerideos 298 mg/dL, leptina normal, plaquetas 84,000/µL, IgG 1,894 mg/dL, anticorpos anti-LKM e anti-LC1 positivos. Histologia hepatica sugestiva de hepatite autoimune, sem esteatose. A doente evoluiu favoravelmente com metformina e tratamento imunossupressor. DISCUSSAO: O reconhecimento precoce e a caracterizacao adequada da doenca hepatica nas lipodistrofias sao fundamentais para uma correta abordagem terapeutica. Na lipodistrofia generalizada adquirida, o disturbio endocrino-metabolico grave responsavel por esteatohepatite com evolucao cirrogenea podera beneficiar do tratamento inovador com leptina recombinante.

Metabolic liver diseases presenting with neonatal cholestasis: at the crossroad between old and new paradigms.

Metabolic liver diseases (MLD) are an important group of disorders presenting with neonatal cholestasis (NC). The spectrum of liver involvement is wide and the presumptive diagnosis is traditionally based on clinical and laboratory findings. Recently, next-generation sequencing (NGS) panels have emerged as an appealing tool to diagnose neonatal/infantile cholestatic disorders. The aim of this study was to identify clinical phenotypes of liver injury and contribute to find a diagnostic methodology that integrates new molecular diagnostic tools. We retrospectively analyzed the clinical and biochemical features of 16 patients with MLD and NC. Patients were categorized into three groups: A-NC with liver failure (N = 8): tyrosinemia type I (n = 2), classic galactosemia (n = 5), mitochondrial DNA depletion syndrome (n = 1); B-NC evolving with chronic liver disease (N = 5): argininemia (n = 2); mitochondrial cytopathy (n = 1); congenital disorders of glycosylation type Ia (n = 1); Zellweger syndrome (n = 1); and C-transient NC (N = 3): Niemann-Pick type C (n = 2), citrullinemia type II (n = 1).Conclusion: MLD presenting with NC can be categorized into three main clinical phenotypes of liver injury. We highlight transient NC as a clue for MLD that must be pursued. New molecular diagnostic tools can play a key role, but application criteria must be established to make them cost-effective. What is Known: • Metabolic liver diseases are an important group of disorders presenting with neonatal cholestasis. • The diagnostic approach is challenging and traditionally based on clinical and laboratory findings. Next-generation sequencing is a recent and rapidly developing tool in pediatric hepatology. What is New: • We provide a liver-targeted characterization of metabolic liver diseases presenting with neonatal cholestasis, categorizing them into three clinical phenotypes that may narrow the diagnostic possibilities. • A clinical decision-making algorithm is proposed, in which the NGS technology is integrated.

Insights Into Pediatric Autoimmune Gastritis: Is There a Role for Helicobacter pylori Infection?

OBJECTIVES: Autoimmune gastritis (AIG) is a chronic inflammatory condition of the gastric mucosa, mainly described in adults presenting with pernicious anemia. It results from antibody-mediated destruction of parietal cells, but the precise initiating event is unknown. The pathogenicity of Helicobacter pylori (H pylori) has been suggested but not established. This study aimed to better characterize AIG in pediatric patients and to address the possible role of H pylori infection. METHODS: Descriptive single-center study, retrospectively describing 20 patients with a diagnosis of AIG based on positivity for anti-parietal cell autoantibodies, in addition to analytical and/or histological findings of oxyntic mucosa atrophy. RESULTS: In the majority (18/20), AIG diagnosis was suggested during investigation of refractory iron-deficient anemia. One patient had dyspepsia and none of the others had gastrointestinal symptoms. Fifty-five percent (11/20) were H pylori positive, but there were no significant differences regarding mean hemoglobin values at presentation (10.6 ±â€Š2.5 vs 9.5 ±â€Š1.0 g/dL, P > 0.05), analytical indicators of gastric atrophy (gastrin, 564.4 ±â€Š184 vs 721.2 ±â€Š220.6 pg/mL, P > 0.05), or in the presence or the grade of oxyntic mucosa atrophy. CONCLUSIONS: Our findings highlight that AIG may have an age-dependent presentation; thus, we can consider a pediatric phenotype that in contrast to adults, is manifested by refractory iron-deficient anemia and associated with parietal cell autoantibody positivity, but not intrinsic factor autoantibodies. A correlation between H pylori and AIG was not evident in the current study and it is still unclear whether H pylori is a trigger for AIG.

Childhood Fructoholism and Fructoholic Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is an emerging entity, becoming the most prevalent pediatric chronic liver disease. Its broad spectrum of histological findings, comorbidities, and complications, including cirrhosis and liver failure, can occur in childhood, emphasizing the severity of pediatric NAFLD. Current lifestyle and diet modifications have been linked to the increasing prevalence of NAFLD, including the rise of fructose consumption, a monosaccharide present in foods that contain added sugar, such as sugar-sweetened beverages. Excessive fructose consumption is believed to cause addiction like alcohol and other drugs. As such, the new term "fructoholism" refers to the consumption of a substance (fructose) that can cause psychological and physical damage and become a major public health concern, highlighting the seriousness of the excessive consumption of fructose in the pediatric age. Hepatic fructose metabolization leads to hepatic steatosis and progression to fibrosis through mechanisms comparable to alcoholic liver disease, hence the term "fructoholic liver disease." Conclusion: The importance of implementing reliable global strategies, such as education campaigns to promote healthy diet, increasing taxes on foods that contain added sugars, subsidies to promote accessibility to fruit and vegetables, and strict food industry regulation to reduce sugar intake in children and adolescents, cannot be overemphasized.

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.

Clinical practices among healthcare professionals concerning neonatal jaundice and pale stools.

Jaundice and pale stools are major indicators of neonatal liver disease. Prognosis depends on timely diagnosis and management. We evaluated the clinical practices among healthcare professionals concerning jaundiced newborns and their ability to recognize pale stools. We supplied a questionnaire and a panel with eight photographs of stools, both locally validated, to physicians and nurses of the National Healthcare Service. Analysis was conducted according to professional status, specialization and years of experience of professionals and level of healthcare. Questionnaires were administered to 266 participants (100 physicians, 166 nurses). The decision to send patients to medical observation depended on the intensity of jaundice for a significant percentage of nurses. Concerning jaundiced newborns breastfed and otherwise healthy, 28.9% of physicians would never request a conjugated bilirubin assay, and only 43.3% would request it after 14 days old; for those with other signs/symptoms of disease, only 69.1% of physicians would request it immediately. Multiple linear regression analysis identified specialization as an independent variable significantly associated with the ability to recognize pale stools. CONCLUSION: A significant percentage of healthcare professionals assumed clinical practices that preclude the timely recognition of cholestasis/pale stools, reinforcing the idea of educational needs. Specialization, rather than years of experience of professionals, was associated with better skills and practices. What is Known: • Neonatal cholestasis is a condition with some rare underlying entities having high mortality and morbidity. Early diagnosis is crucial to improve prognosis. Yet, many cases remain late recognized and referred. • Studies evaluating the ability of healthcare professionals to recognize neonatal cholestasis are scarce. What is New: • In this study, a significant percentage of professionals assumed clinical practices that preclude timely recognition of neonatal cholestasis and pale stools, reinforcing the idea of educational needs. • Specialization of professionals was associated with better skills and practices.

A New Mutation Causing Progressive Familiar Intrahepatic Cholestasis Type 3 in Association with Autoimmune Hepatitis.

BACKGROUND: Some patients exhibit features of both autoimmune hepatitis (AIH) and primary sclerosing cholangitis (PSC). Similarly, patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) may share histological features with PSC. CASE REPORT: We report the case of a 22-year-old man who, since he was 5 years of age, has presented with pruritus, an approximately ninefold elevation of aminotransferases, and γ-glutamyl transferase levels ~10 times the upper limit. Initially he was diagnosed with an overlap syndrome of small duct PSC plus AIH. However, fluctuations in liver enzymes were observed over the following years. Analysis of the ABCB4 gene indicated the diagnosis of PFIC3, revealing a mutation not previously reported. CONCLUSION: With this case report we aim to describe a new mutation, raise awareness of this rare pathology and highlight the importance of genetic testing of the ABCB4 gene in patients with autoimmune liver disease (mainly small duct PSC) with incomplete response to immunosuppressive treatment. LEARNING POINTS: Autoimmune liver diseases have a wide spectrum of manifestations.Cholangiopathies such as ABCB4 deficiency have histological features quite similar to those seen in small duct primary sclerosing cholangitis.The new mutation of the ABCB4 gene described in this article is compatible with the diagnosis of progressive familial intrahepatic cholestasis type 3, which is probably less rare than usually thought.

Elevation of gamma-glutamyl transferase in adult: Should we think about progressive familiar intrahepatic cholestasis?

BACKGROUND: There are three types of progressive familial intrahepatic cholestasis (PFIC). Type 3 is characterized by elevated gamma-glutamyl transferase (γ-GT) and it can be diagnosed in adolescence/adulthood. The genetic defect of PFIC 3 appears to explain the pathogenesis of intrahepatic cholestasis of pregnancy (ICP). AIMS: Draw attention to this rare disease, especially in adulthood, and clarify the association between ICP and PFIC 3. RESULTS: We describe a series of cases from a Portuguese northern family with two brothers presenting chronic cholestasis since adolescence. Brother 1: since 15-years-old with pruritus and elevated γ-GT ∼6x. Brother 2: pre-term, due to severe maternal pruritus and jaundice, since 13-years-old with pruritus, jaundice and ∼8x γ-GT elevation. Common causes of cholestasis were excluded and liver histologies were nonspecific. Research for mutation on ABCB4 gene showed mutations in both alleles. CONCLUSION: Disease and mechanisms that determine cholestasis are complex and their understanding may provide new therapeutics.