Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations.

CONTEXT: Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. OBJECTIVE: To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. SETTING: Twelve tertiary pediatric endocrine referral centers. PATIENTS: Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. MAIN OUTCOME MEASURES: Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. RESULTS: Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = -3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: -2.35, median BMI SDS: -0.52 SDS) with 20/29 (69%) cases having growth retardation. CONCLUSION: We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.

Cholestasis in the Premature Infant.

Liver dysfunction is a common problem in the sick premature infant. The dysfunction is usually multifactorial and often underlies a combination of liver immaturity, comorbidities, and/or the presence of primary liver disease. The liver of the preterm infant has a paucity of bile ducts, low levels of many hepatic enzymes and transporters, and a small bile acid pool. Many other organ systems are immature as well and do not respond to stress the way they would later in infancy. This articles discusses how prematurity affects the liver, how it responds to secondary insults, and approaches to evaluation.

[Consensus on hyperbilirubinemia of the first trimester of life]. / Consenso de hiperbilirrubinemia del primer trimestre de la vida.

Neonatal jaundice may be due to different causes, ranging from physiological conditions to severe diseases. In term neonates with persistent jaundice beyond 14 days of life, it should be determined whether hyperbilirubinemia is unconjugated or conjugated, in order to study the etiology and start early treatment. In the majority of cases, conjugated hyperbilirubinemia (cholestasis) is a sign of liver dysfunction possibly associated with alterations in the bile flow secondary to structural or molecular abnormalities of the liver and/or the biliary tract. Over the past decade, new molecular studies have revolutionized the approach of cholestatic patients, leading to the identification of different genetic entities. It is important to determine the etilogy of neonatal hyperbilirubinemia since in many cases early treatment will substantially improve morbidity and mortality.

La presencia de ictericia en la etapa neonatal puede responder a diversas causas, desde situaciones fisiológicas hasta enfermedades graves. En los neonatos de término que persisten ictéricos más allá de los 14 días de vida, debe determinarse si la hiperbilirrubinemia es no conjugada o conjugada para establecer, a la brevedad, el plan de estudios etiológicos y la terapéutica correspondiente. La hiperbilirrubinemia conjugada (colestasis) refleja una disfunción hepática en la mayoría de los casos, cuyas consecuencias son alteraciones del flujo biliar secundarias a anormalidades estructurales o moleculares del hígado y/o del tracto biliar. Durante la última década, los nuevos estudios moleculares revolucionaron el abordaje de los pacientes colestáticos, lo que permitió el diagnóstico de diversas entidades genéticas. La etiología de la hiperbilirrubinemia del primer trimestre debe determinarse con urgencia, ya que, en muchos casos, el tratamiento instituido de modo precoz puede modificar sustancialmente la evolución de la enfermedad o salvar la vida del paciente.

[Biliary atresia and congenital cholestatic syndromes : Characteristics before, after and during transition]. / Gallengangatresie und angeborene Cholestasesyndrome : Besonderheiten vor, nach und während der Transition.

BACKGROUND: A growing number of patients with biliary atresia and congenital cholestatic syndromes are reaching adulthood. These patients often have a number of typical medical features, including specific characteristics of liver transplantation medicine. OBJECTIVE: What are the special features in the care of adults suffering from liver diseases with manifestation in childhood and adolescence, both before and after liver transplantation (LTX). How does the progression of individual diseases differ depending on age at manifestation? What are specific aspects following pediatric LTX? PATIENTS AND METHODS: Evaluation and discussion of existing guidelines and recommendations of the individual disciplines and professional societies as well as the current literature. Joint discussion of the recommendations between disciplines (gastroenterology, pediatric gastroenterology, surgery). Inclusion of center-specific experiences with transition from existing transition outpatient departments and training. RESULTS: The recommendations are presented specifically for each disease. Special features in individual diseases after LTX are also discussed. Diagnosis-independent general treatment concepts for cholestasis and chronic liver disease are presented. CONCLUSION: Patients with biliary atresia and congenital cholestatic syndromes have a life-long chronic liver disease with and without LTX and require specific medical care. The patients benefit from the pooling of expertise in the individual disciplines.

Liver Donation and Transplantation in Poland: Numbers, Indicators, and Trends.

We aim to provide a panorama of liver donation and transplantation in Poland, where each year around 300 liver transplantations from deceased donors and 20 liver fragment transplantations from living donors are performed. This means about 9 transplantations per population of 1 million. Each year, the number of deceased donors reaches more than 500. In more than 50% of cases, livers are used. The law allows liver procurement from living donors. Until the end of 2013, liver fragments were recovered from 236 living donors and transplanted mainly to pediatric recipients (n = 232). A living-donor registry was created to monitor and assess the health condition of donors. The range of the national waiting list and allocation is nationwide. It is managed with the use of the Web tool www.rejestry.net. There are 2 modes of recipient referral: "urgent" and "elective." Allocation is either patient oriented and center oriented. Disease groups, which comprise the most frequent indications for transplantation in adults, include the cirrhosis group (48%), in which the highest number of procedures was performed for patients with hepatitis C virus (24%); alcohol-induced cirrhosis (14%); alcohol-induced hepatitis (8%), and hepatitis B virus cirrhosis (7%). Among pediatric recipients, the most frequent indications were congenital cholestatic diseases, which made up 38% of all transplantation indications. The results of liver transplantations are collected in the national transplant register. The 1-year graft and recipient survival with deceased donor transplantation are 81% and 84% and with living donor transplantation 86% and 89%. The 5-year graft and recipient survival in deceased donor transplantation are 69% and 73%, and in living donor transplantation are 80% and 83%.

Bartonella henselae AS A PUTATIVE CAUSE OF CONGENITAL CHOLESTASIS.

Severe anemia and cholestatic hepatitis are associated with bartonella infections. A putative vertical Bartonella henselae infection was defined on the basis of ultrastructural and molecular analyses in a three-year-old child with anemia, jaundice and hepatosplenomegaly since birth. Physicians should consider bartonellosis in patients with anemia and hepatitis of unknown origin.

Common misdiagnoses of biliary atresia.

OBJECTIVES: Discrimination of biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. We aimed to analyze the clinicopathological findings in cholestatic infants who were provisionally diagnosed with BA and then excluded by intraoperative cholangiography compared with those with a definitive diagnosis of BA and to shed light on common misdiagnoses of BA. METHODS: We retrospectively analyzed the data of infants diagnosed preoperatively with BA and referred to surgery between the years 2009 and 2013. On the basis of intraoperative cholangiography results, infants were divided into those with a definitive diagnosis of BA and those misdiagnosed with BA. RESULTS: Out of 147 infants, there was a misdiagnosis of BA in 10 (6.8%) infants. Alanine transaminase was significantly higher in the non-BA group, whereas other clinical and laboratory findings were comparable in both groups. Hepatomegaly and abnormal gallbladder in ultrasound, and ductular proliferation and advanced grades of portal fibrosis in liver biopsy were significantly higher in infants with BA. However, giant cells were more common in the non-BA infants. Nonetheless, the frequency of clay stool, hepatomegaly, abnormal gallbladder, ductular proliferation, and advanced portal fibrosis was remarkable (100, 70, 40, 70, and 50%, respectively) in the misdiagnosed infants. The misdiagnoses were idiopathic neonatal hepatitis, progressive familial intrahepatic cholestasis type 3, cytomegalovirus hepatitis, Alagille syndrome, and a cholangitic form of congenital hepatic fibrosis. CONCLUSION: A meticulous preoperative workup should be performed to exclude other causes of NC even if signs of BA are present, especially if features such as giant cells in histopathology are present. This involves completing the NC workup in parallel involving all common causes of NC rather than performing them in series to avoid loss of valuable time and efforts.

Efficacy of the seven feature, fifteen point histological scoring system and CD56 in interpretation of liver biopsies in persistent neonatal cholestasis: a five-year study.

CONTEXT: Neonatal cholestasis (NC) lasting more than 2 weeks affects one in 2500 live births. Extrahepatic biliary atresia (EHBA) and idiopathic neonatal hepatitis account for about 70% of all cases of NC. Differentiating these two conditions is important as patient management is very different for both the conditions. AIMS: To assess the usefulness of the seven-feature, 15-point histological scoring system in the interpretation of liver biopsy in NC and usefulness of immunostaining with CD56 (N-CAM) in EHBA. SETTINGS AND DESIGN: Retrospective study of 5 years' duration at a pediatric referral institute, where the case load of NC is high and definitive surgery for EHBA is undertaken after histological confirmation. MATERIALS AND METHODS: The study is of a 5-year duration conducted between June 2007 and May 2012. A total of 210 cases of NC were clinically diagnosed during this period. All the slides were reviewed with reference to a seven-feature, 15-point histological scoring system assessing its usefulness in the interpretation of liver biopsy in NC and utility of the immunohistochemical marker CD56 was also assessed as an aid in the characterization of bile ductular proliferation in EHBA. STATISTICAL ANALYSIS: Statistical analysis was performed and sensitivity and specificity of the histological scoring system for EHBA was analyzed. RESULTS: Of the 210 liver biopsies reviewed using the scoring system, 122 cases were diagnosed as EHBA and 88 cases were diagnosed as other causes of NC. The overall sensitivity of this scoring system was 95.5%, specificity was 93.1% and diagnostic accuracy was 94.6%. CONCLUSIONS: The seven-feature, 15-point histological scoring system has good diagnostic accuracy in the interpretation of liver histology in NC as advanced histopathological findings even at younger age require immediate surgery. CD-56 is a useful marker in the assessment of bile ductular proliferation in EHBA.

Diagnóstico de endocrinopatía congénita en neonatos con ictericia prolongada e hipoglucemia / Diagnosis of congenital endocrinological disease in newborns with prolonged jaundice and hypoglycaemia

Introducción: La asociación de ictericia neonatal prolongada e hipoglucemia recurrente puede ser secundaria a una patología endocrinológica subyacente. La insuficiencia hipofisaria y la insuficiencia adrenal primaria son las principales patologías que se deben descartar. Material y métodos: Se analizaron retrospectivamente las características clínicas y de laboratorio de 13 pacientes derivados a la división de endocrinología del Hospital de Niños Ricardo Gutiérrez entre los años 2003 y 2008 con ictericia neonatal e hipoglucemia secundaria a insuficiencia hipofisaria en 12 pacientes y en uno a insuficiencia adrenal primaria. Resultados: Todos los pacientes tuvieron hipoglucemia en el periodo neonatal. En 10 pacientes la hiperbilirrubinemia fue de predominio directo y 6 pacientes presentaron elevación de transaminasas. La insuficiencia hipofisaria fue múltiple en los 12 pacientes. El tratamiento de remplazo hormonal normalizó la función hepática, resolvió la ictericia en todos los niños y ninguno requirió biopsia hepática. Los episodios de hipoglucemia también cedieron al iniciar el tratamiento sustitutivo. Conclusiones: El binomio ictericia prolongada o colestásica e hipoglucemia recurrente exige descartar insuficiencia hipofisaria múltiple e insuficiencia suprarrenal primaria. La terapia sustitutiva correspondiente resuelve el problema colestásico en la mayor parte de los casos, así como los problemas derivados de la hipoglucemia recurrente y las deficiencias hormonales(AU)

Introduction: The association of prolonged neonatal jaundice and hypoglycaemia may be secondary to an endocrinological disease. Pituitary insufficiency and primary adrenal insufficiency are the most likely endocrine diseases that need to be ruled out. Material and methods: We retrospectively analysed the clinical and laboratory characteristics of thirteen patients referred to the Hospital de Niños Ricardo Gutiérrez between years 2003 and 2008 due to prolonged neonatal jaundice and hypoglycaemia secondary to pituitary insufficiency in twelve patients, and in one secondary to primary adrenal insufficiency. Results: All patients had a history of neonatal hypoglycaemia. Ten patients had conjugated hyperbilirubinaemia and six also had elevated transaminases. Combined pituitary hormone deficiency was observed in the twelve hypopituitarism patients. Hormonal replacement normalised liver function and resolved the prolonged jaundice in all the patients. None of them underwent liver biopsy. Hypoglycaemia also remitted after hormonal therapy. Conclusions: Prolonged or cholestatic jaundice associated with neonatal hypoglycaemia is highly likely to be due to pituitary hormone deficiency or primary adrenal insufficiency. Early diagnosis and treatment of these children reverts the prolonged jaundice and prevents morbidity and mortality due to recurrent hypoglycaemia and hormone deficiencies(AU)

Congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

Neonatal lupus erythematosus is an uncommon disease caused by transplacental passage of maternal anti-Ro (SS-A), anti-LA (SS-B), or anti-U1RNP antibodies. Cutaneous findings of neonatal lupus are variable, but annular, erythematous plaques occurring within a few weeks of birth are most typical. Cutaneous lesions of congenital onset lupus erythematosus can differ from that of neonatal lupus erythematosus, presenting with atrophy or scarring, and less commonly, erosions. We report an unusual case of congenital lupus erythematosus presenting at birth with widespread erosions, pancytopenia, and subsequent hepatobiliary disease.

Concurrent course of transient neonatal diabetes with cholestasis and paucity of interlobular bile ducts: a case report.

We report for the first time a patient with both transient neonatal diabetes mellitus (TNDM) and idiopathic neonatal cholestasis, with both features resolving over a similar time course. Cholestasis was due to paucity of interlobular bile ducts (PILBD). Genetic analysis was consistent with a uniparental disomy of chromosome 6. Paucity of interlobular bile ducts is common in Alagille syndrome but also occurs by unknown mechanisms in a wide spectrum of other diseases. We propose a shared explanation for this patient's TNDM and PILBD mediated by the noted chromosomal abnormality. We suggest that hepatobiliary function be evaluated in patients with TNDM to determine the prevalence and course of cholestasis of the disease.

Evaluation of ultrastructural changes by electron microscopy in neonatal cholestasis.

BACKGROUND: Biliary atresia (BA) and idiopathic neonatal hepatitis (NH) account for 50-70% of all cases with neonatal cholestasis. The treatment of the former is early surgical intervention, while the latter requires non-surgical supportive care. Failure to differentiate the two conditions may result in avoidable surgery in NH, which may significantly increase morbidity. The lack of differentiating clinical features, biochemical markers and other specific investigations to distinguish the two is still a major problem. AIM: This study was thus initiated to evaluate electron microscopic changes in the liver in patients with NH and BA, to correlate these with changes on light microscopy and look for specific differentiating features between the two. METHODS: Ten patients with neonatal cholestasis whose liver specimens were available for electron microscopic analysis were included in the study. There were 6 patients with BA and 4 patients with NH. RESULTS: Among the biochemical parameters, serum alkaline phosphatase and gamma glutamyl transpeptidase were significantly higher in BA than in patients with NH. On light microscopy, giant cell transformation was seen in 75% patients with NH and 33.3% of patients with BA. Even in BA, intracellular cholestasis was more prominent than ductular cholestasis (100% vs. 50%). Ductular proliferation was seen in 50% of NH patients and all patients of BA. Electron microscopy revealed prominent endoplasmic changes in all patients with NH and to a milder degree in BA. Changes in mitochondria and glycogen content were similar in both groups. CONCLUSION: Ultrastructural changes in neonatal cholestasis seen through electron microscopy are largely non-specific and do not differentiate BA from NH.

Wide spectrum of clinical features in a case of arthrogryposis-renal tubular dysfunction-cholestasis syndrome.

Arthrogryposis-renal tubular dysfunction-cholestasis syndrome is a rare multisystem disorder, originally described in 1973 and to date only 62 patients have been reported. Herein, we reported on a neonate with arthrogryposis-renal tubular dysfunction-cholestasis syndrome presenting very early after birth. Recurrent febrile illnesses, failure to thrive, ichthyosis, hypothyroidism, and bilateral hearing loss were among other associated findings. Blood films revealed abnormally large platelets. Polyhydramnios, hybrid type of renal tubular acidosis and hypothyroidism found in this case are not usually seen. We propose to expand the acronym of this syndrome and name it as arthrogryposis-renal dysfunction-cholestasis-hypothyroidism-ichthyosis-deafness or dysmorphic features syndrome.

Screening of BCS1L mutations in severe neonatal disorders suspicious for mitochondrial cause.

The BCS1L gene encodes a chaperone responsible for assembly of respiratory chain complex III (CIII). A homozygous point mutation (232A-->G) has been found as the genetic etiology for fetal growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death (GRACILE) syndrome (MIM 603358). Variable phenotypes have been found with other mutations. Our aim was to assess whether 232A-->G or other BCS1L mutations were present in infants (n = 21) of Finnish origin with severe, lethal disease compatible with mitochondrial disorder. A further aim was to confirm the GRACILE genotype-phenotype constancy (n = 8). Three new cases with homozygous 232A-->G mutation were identified; all had the primary GRACILE characteristics. No other mutations were found in the gene in other cases. All infants with GRACILE syndrome had the typical mutation. In conclusion, the rather homogenous population of Finns seems to have a specific BCS1L mutation that, as homozygous state, causes GRACILE syndrome, whereas other mutations are rare or not occurring. Thus, the novel clinical implication of this study is to screen for BCS1L mutations only if CIII is dysfunctioning or lacking Rieske protein, and to assess 232A-->G mutation in cases with GRACILE syndrome.

Congenital cholestatic syndromes: what happens when children grow up?

Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum of severity of liver disease can be expected, from cirrhosis (almost universal in adults with biliary atresia who have not required liver transplantation) to mild and subclinical (eg, in the previously undiagnosed affected parent of an infant with Alagille syndrome). Complications associated with portal hypertension and nutritional deficiencies are common, and other associated features of the cholestatic syndrome may require appropriate attention, such as congenital heart disease in Alagille syndrome. Indications for liver transplantation include synthetic failure, progressive encephalopathy, intractable pruritus, recurrent biliary sepsis and recurrent complications of portal hypertension. Improved understanding of biliary physiology will hopefully translate into improved therapy for children and adults with cholestasis.

The course of neonatal cholestasis in congenital combined pituitary hormone deficiency.

BACKGROUND: Neonatal cholestatic hepatitis is frequently associated with congenital combined pituitary hormone deficiency (CCPHD). Data on the course of this hepatopathy are scarce. AIM: We retrospectively analyzed the data of all CCPHD infants with cholestasis who presented at the University Children's Hospital, Tuebingen. RESULTS: All infants (n = 9; 2 females) presented with early and prolonged jaundice, failure to thrive and recurrent hypoglycemia. All males had micropenis and 3/7 cryptorchidism. Median age at diagnosis was 1.4 months. Cholestasis began at a median age of 13 days (range 5-31) and resolved at 88 days (54-174). Maximum direct bilirubin level was 6.9 mg/dl (2.4-11.6). Peaks of ALP (median 721 U/l), ALT (148 U/l) and AST (195 U/l) occurred 2-4 weeks later, while GGT levels were elevated in only two infants (167 U/l). Functional liver parameters were always normal. Liver biopsies (n = 4) showed canalicular cholestasis and mild portal eosinophilic infiltration. TEBIDA radioisotope excretion into the intestinal tract was blocked. Substitution with Lthyroxine, hydrocortisone and growth hormone seemed to accelerate the cure from cholestasis. Liver function at follow-up (median 4 yr) stayed normal. CONCLUSION: Cholestasis in CCPHD follows the course described here, frequently with normal GGT levels.