Oral findings in children with congenital cholestatic disease: A systematic review of case reports and case series.

Multiple causes of congenital neonatal cholestasis have been identified, and are classified as extrahepatic or intrahepatic. Biliary atresia (BA), Alagille syndrome (AGS), and progressive familial intrahepatic cholestasis (PFIC) are the most common of these. Many factors associated with cholestatic diseases are known to degrade the oral health of these children. What are the oral manifestations associated with these diseases in the pediatric population? The aim of this article was to evaluate the impact of congenital cholestasis on oral health in pediatric patients. A systematic review of case reports and case series was carried out in PubMed, the Cochrane Library, and the Web of Science to identify relevant articles in French and English published up to April 2022. The review included 19 studies, 16 case reports, and three case series. Only studies dealing with BA and AGS were found. These studies showed an impact on jaw morphology, dental structure, and periodontal health. The facial dysmorphism observed in AGS was specific. Exposure to high levels of bilirubin during the period of dental calcification led to particular coloration. Regarding periodontal status, gingival inflammation was common in these patients, probably resulting from the use of certain treatment-associated drugs and poor oral hygiene. Cohort studies are needed to confirm the classification of these children as being at high individual risk of caries. Many major oral manifestations are found in children with AGS and BA, confirming the need to include a dentist in the care team of patients with congenital cholestatic disease as early as possible. It appears necessary to carry out individual prospective studies of each phenotype in order to confirm and better describe the oral impact of these cholestatic diseases and provide adequate medical care.

[A case of congenital bile acid synthesis disorder type 2 and literature review].

OBJECTIVE: To summarize the clinical features, biochemical change and genetic mutations of a neonate with congenital bile acid synthesis disorder type 2. METHODS: Clinical features, blood biochemical index, gene analysis and treatment of the patient were reviewed. RESULTS: The patient presented with the symptoms of jaundice 3 days after birth but without skin itching. Pale stool was noted. Subsequently, he presented with hepatomegaly, blood coagulation disorders, left cochlear nerve damage, liver cirrhosis and remarkable growth retardation. Serum biochemistries showed that bilirubin and transaminase were elevated, while γ -GT and total bile acid was normal. Abdominal ultrasonography indicated decline of gallbladder contraction. Cholangiography showed normal extra- and intrahepatic bile ducts and patent biliary tract. Liver biopsy showed intrahepatic cholestasis. Gene testing has identified a homozygous mutation in AKR1D1 gene. CONCLUSION: Congenital bile acid synthesis disorder should be suspected when a neonate has presented with jaundice, elevated bilirubin and transaminase, normal or reduced TBA and γ -GT. Genetic testing and urine mass spectrometry analysis can diagnose congenital bile acid synthesis disorder. Early therapy is crucial to patients with congenital bile acid synthesis disorder.

Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2.

OBJECT: The authors report the case of a boy with PFIC type 2 or BRIC type 2 who suffered from liver dysfunction at 2 months after birth. METHODS AND RESULTS: A liver biopsy specimen revealed mild liver cirrhosis, and the findings resembled those observed in Byler disease. Genetic examination revealed a normal familial intrahepatic cholestasis-1 gene, but a heterozygous mutation for the ABCB11, C1620A (F540L), was observed. Therefore, the patient was initially diagnosed with PFIC type 2. For 3 years after the diagnosis, he had severe pruritus, an increased serum bile acid, and normal serum values of gamma-glutamyl transaminase. At the age of 2, treatment with administration of ursodeoxycholic acid was started; subsequently, a gradual improvement in his liver function was observed. At the age of 3, he suffered from massive intestinal and pulmonary hemorrhage, which improved immediately after the administration of vitamin K. He was then admitted to our hospital for liver transplantation. At 1 month after the admission, his liver dysfunction showed further improvement, except for a mild increase in the serum bile acid level. This condition did not show any change during the 5-year follow-up period. In addition, the patient showed severe growth failure and was diagnosed with growth hormone deficiency. Hence, he receives growth hormone administration. CONCLUSION: The patient could be genetically diagnosed with bile salt export pump disease of PFIC type 2 or BRIC type 2. Various clinical features are observed in PFIC or BRIC patients with ABCB11 mutation.

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.

Effect of living donor liver transplantation on outcome of children with inherited liver disease and hepatocellular carcinoma.

We described six children with heritable liver disease and hepatocellular carcinoma treated with living-related liver transplantation. Underlying liver diseases were type-1 tyrosinemia (three patients), progressive familial intrahepatic cholestasis type II (two patients), and Wilson's disease (one patient). Two of the tumors were found incidentally during liver transplantation. Number of nodules was 12, 15, 3, 2, and 1 (in two patients). Three patients were treated with chemotherapy before the procedure. Chemotherapy was not given to any patient after liver transplantation. The mean follow-up was 17.7 +/- 6 months (range: 7-24). All patients are tumor recurrence free. Both graft and patient survival rates are 100% at a median of 18.5 months follow-up. Physicians in charge of treating children with heritable liver disease should screen them periodically for the development of hepatocellular carcinoma. Liver transplantation may offer these children better survival rates.

Evaluation of risk for atherosclerosis in Alagille syndrome and progressive familial intrahepatic cholestasis: two congenital cholestatic diseases with different lipoprotein metabolisms.

OBJECTIVES: To evaluate the risk for atherosclerosis in Alagille syndrome (AGS) and progressive familial intrahepatic cholestasis (PFIC) on the basis of lipoprotein metabolism and by ultrasonography. STUDY DESIGN: Five patients with AGS and 5 with PFIC, ages 3 to 4 years, were enrolled. Intimal-medial thickness and wall stiffness of the common carotid artery were examined by ultrasonography. Serum levels of lipids and lipoproteins were determined. Further, the chemical composition of LDL and its ability to transform macrophages into foam cells were determined. RESULTS: Intimal-medial thickness and wall stiffness were increased in patients with PFIC but not in patients with AGS. Total cholesterol, LDL cholesterol, HDL cholesterol, and lipoprotein X were remarkably increased in patients with AGS, whereas in patients with PFIC, an increase in triglyceride and a decrease in HDL cholesterol were the prominent findings. However, despite the normal LDL cholesterol level, oxidized LDL level was strikingly high in patients with PFIC. LDLs from patients with PFIC had high TG contents and exhibited high abilities to transform macrophages into foam cells. CONCLUSIONS: These findings suggest that patients with PFIC are at high risk for cardiovascular disorders involving atherosclerosis.

Hyporegenerative anemia associated with Rh hemolytic disease: treatment failure of recombinant erythropoietin.

A postnatal hyporegenerative anemia may complicate Rh hemolytic disease. Intramedullary hemolysis, bone marrow suppression, and erythropoietin deficiency have been implicated etiologically. Treatment with recombinant erythropoietin (r-EPO) has yielded encouraging preliminary results. The authors describe an infant with Rh isoimmunization who developed severe hyporegenerative anemia unresponsive to a 5-week course of r-EPO. Two additional doses at 12 weeks resulted in brisk reticulocytosis, coinciding with a 16-fold decline in the anti-Rh(D) antibody titer. Thus, treatment with r-EPO may be ineffective when anti-Rh(D) antibody titers are high. The authors also show that erythropoietin deficiency in hyporegenerative anemia is not as frequent and severe as originally thought.

Neonatal intrahepatic cholestasis caused by citrin deficiency: severe hepatic dysfunction in an infant requiring liver transplantation.

UNLABELLED: Adult-onset type 2 citrullinaemia (CTLN2) is caused by a deficiency of the citrin protein encoded by the SLC25A13 gene. Citrin, an aspartate glutamate carrier in mitochondria, is an essential component of the malate-aspartate NADH shuttle. Recently, citrin deficiency has been reported to manifest as neonatal intrahepatic cholestasis. We report here five cases with neonatal intrahepatic cholestasis caused by citrin deficiency. Genetic diagnosis revealed compound heterozygotes of 851del4/IVS11 + 1G-->A in two patients, IVS11 + 1G-->A/E601X, and IVS11 + 1G-->A/unknown in each one patient and homozygote for S225X in one patient. All cases revealed high levels of alpha-fetoprotein, which are not observed in CTLN2 patients. The condition was self-limiting and spontaneously disappeared after 5-7 months of age in four patients. However, one patient developed hepatic dysfunction from the age of 6 months and required a living-related liver transplantation at the age of 10 months. The patient showed complete recovery after transplantation, and now at the age of 3 years, shows normal growth and mental development. CONCLUSION: we report the first case of neonatal intrahepatic cholestasis caused by citrin deficiency with severe hepatic dysfunction requiring a living-related liver transplantation. Patients with this disorder should be followed up carefully, even during infancy.

[Progressive familial intrahepatic cholestasis (Byler disease): current genetics and therapy]. / Die Progressive Familiäre Intrahepatische Cholestase (Morbus Byler): Aktuelles zu Genetik und Therapie.

Progressive familial intrahepatic cholestasis (PFIC) is a congenital liver disease. First symptoms can frequently be seen shortly after birth. Quality and expectation of life are substantially reduced due to severe pruritus and the complications of progressive liver cirrhosis. PFIC is diagnosed on the basis of characteristic clinical and laboratory parameters and genetic analysis after exclusion of other liver diseases leading to intrahepatic cholestasis. Medical therapy is only effective in a proportion of children with PFIC. Partial biliary diversion (PBD) is nowadays considered the therapy of choice in patients with therapy-refractive pruritus. If performed in time, damage to the liver can be delayed or arrested, thus orthotopic liver transplantation (OLT) can be postponed or even avoided in at least some patients with PFIC. Besides providing a current overview of PFIC, we report on three patients who were successfully treated surgically. One patient was subjected to a new technique of PBD (cholecysto-appendicostomy), the other two had OLT.

Colestase neonatal prolongada: estudo prospectivo / Prolonged neonatal cholestasis: prospective study

Em razão da urgência de se decidir por um tratamento clínico ou por uma intervenção cirúrgica imediata, o estudo da colestase neonatal prolongada envolve dois objetivos básicos: o diagnóstico diferencial entre atresia biliar e hepatite neonatal e a pesquisa dos agentes etiológicos associados. Desta maneira, através de estudo prospectivo desenvolvido na década de 1970 foram avaliadas 77 crianças portadoras de colestase neonatal prolongada para estabelecer o diagnóstico diferencial entre atresia biliar e hepatite neonatal e, numa segunda fase, 108 crianças, visando esclarecer a etiopatogenia da colestase neonatal prolongada. Os resultados do diagnóstico diferencial revelaram que, dos 18 atributos avaliados, apenas oito mostraram-se bons indicadores de atresia biliar, em ordem decrescente: ductos proliferados (espaço-porta), fibrose (espaço-porta), colestase (espaço-porta), cor das fezes - acolia, hepatomegalia, colestase canalicular (lóbulo), infiltrado (espaço-porta), células gigantes (lóbulo). Estes oito atributos foram então compostos, mediante uma ponderação, em um único indicador de grande poder discriminativo, capaz de decidir o diagnóstico diferencial em 99 por cento dos casos. Quanto à etiopatogenia, registrou-se: vírus rubéola 0 por cento, vírus herpes simples 0 por cento, listeriose 0 por cento, citomegalovirose 2,2 por cento, vírus hepatite B 2,4 por cento, toxoplasmose 2,8 por cento, deficiência de alfa-I antitripsina 13,1 por cento, sífilis 21,1 por cento, auto-anticorpos hepáticos 58,4 por cento. O trabalho desenvolvido mostra que as 8 variáveis mais decisivas, como indicadores diferencias entre atresia biliar e hepatite neonatal, permanecem como índices fundamentais, auxiliando, em conjunto com novos métodos diagnósticos, na composição de uma estratégia multifatorial cada vez menos invasiva e mais precisa. O estudo da etiopatogenia, dependente das condições epidemiológicas locais e da época, com a introdução de novos métodos diagnósticos, torna-se atualmente cada vez mais completo e abrangente, evoluindo para a ideal diminuição progressiva dos processos idiopáticos.

[Prolonged neonatal cholestasis: prospective study]. / Colestase neonatal prolongada: estudo prospectivo.

Due to the urgency in choosing either clinical treatment or immediate surgical intervention, the study of the prolonged neonatal cholestasis involves two basic aims: the differential diagnosis between biliary atresia and neonatal hepatitis and the research into the associated etiological agents. So, in a prospective trial carried out in the 70's, 77 children with prolonged neonatal cholestasis were studied in order to establish the differential diagnosis between biliary atresia and neonatal hepatitis, followed by the evaluation of 108 children towards a pathogenesis of the prolonged neonatal cholestasis. The results of the differential diagnosis showed that within 18 items examined only 8 proved to be good biliary atresia indicators. They are as follows (in decreasing order): ductular proliferation (portal tracts), fibrosis (portal tracts), cholestasis (portal tracts), stools colour--acholia, hepatomegaly, canalicular cholestasis (lobule), infiltrate (portal tracts), giant cells (lobule). These eight items were then gathered in a sole indicator of great discriminative power, with a confidence level of 99%. The figures regarding the pathogenesis are: rubella virus 0%, herpes simplex virus 0%, listeriosis 0%, cytomegalovirus 2.2%, hepatitis B virus 2.4%, toxoplasmosis 2.8%, alpha-1-antitrypsin deficiency 13.1%, syphilis 21.1%, autoantibodies against the liver 58.4%. Such work thus revealed that those eight most important factors when differentiating biliary atresia from neonatal hepatitis remain as fundamental indicators and, when employed alongside other diagnostic methods, can help in the assembling of a multifactorial strategy less and less invasive and more precise. The pathogenic study, with its heavy dependency on time and place, has become more complete with the introduction of new diagnostic methods, evolving to the ideal progressive reduction of idiopathic processes.

Operative treatment of congenital stenoses of the intrahepatic bile ducts in patients with choledochal cysts.

BACKGROUND: Postoperative complications including intrahepatic calculi may develop after the complete excision of a choledochal cyst. Since congenital stenoses of the intrahepatic bile ducts are more likely the cause of intrahepatic calculi, operative procedures for intrahepatic stenoses are reported. METHODS: There were 16 patients with choledochal cysts who underwent surgery for stenoses of intrahepatic bile ducts. The stenoses were excised at the opening of the common hepatic duct. RESULTS: In the 16 patients, 25 of the 26 stenoses that involved an intraluminal membrane or septum could be excised from the divided end of the common hepatic duct at the hepatic hilum. In 1 patient, the stenosis could not be accessed from the hepatic hilum, and a left hepatic lobectomy was required. In postoperative follow-up, all 16 patients were in good health. CONCLUSIONS: Stenoses of the intrahepatic bile ducts should be treated from the divided end of the common hepatic duct at the initial operation for choledochal cysts. The need for a second operation or hepatic lobectomy may thus be avoided.

[Long-term ursodeoxycholic acid treatment of cholestatic liver diseases in childhood--clinical and biochemical effects]. / Langfristige Ursodeoxycholsäurebehandlung cholestatischer Lebererkrankungen des Kindesalters--klinische und biochemische Effekte.

BACKGROUND: In adults with chronic cholestatic liver disorders, controlled studies have shown a reduction of clinical, biochemical and possibly histological parameters during long-term medication with ursodeoxycholic acid (UDCA). It is not yet clear, however, whether similar effects can be achieved in children. Therefore, we retrospectively evaluated the use of UDCA in typical liver diseases of childhood. METHOD: 20 children were treated for at least 6 months (age at start of therapy 5-87, median 24 months; diagnosis: biliary atresia n = 10, Alagille's syndrome n = 4, intrahepatic biliary hypoplasia n = 3, Byler disease n = 3). Pruritus, liver cell injury, cholestasis, synthetic liver function and weight and height for age before medication with UDCA (7-26, mean 13 mg/kg BW/d) was compared to values after 3, 6, 12, 18 and 24 months of therapy, with special attention towards possible adverse effects. RESULTS: No adverse effects of UDCA necessitating modification of therapy were encountered. During the first year of medication, weight for age improved in 15 patients, but pruritus in only four. During UDCA treatment, GIDH and gamma GT decreased significantly. GOT and GPT declined in the majority of patients. No significant changes of bilirubin and parameters of liver synthesis were seen. CONCLUSION: Long-term medication with UDCA appears to be safe in children. Thus, controlled studies of UDCA medication in children are justified, and are urgently needed to further investigate the prognostic significance of the positive effects of UDCA identified in this retrospective analysis.

[Long-term follow-up of a boy with recurrent hypoglycemia and cholestasis in congenital growth hormone deficiency]. / Langzeitbeobachtung eines Knaben mit rezidivierenden Hypoglykämien und Cholestase bei angeborenem Wachstumshormonmangel.

We report on a four-year-old boy with congenital growth hormone deficiency who first presented at age 13 weeks with jaundice and recurrent hypoglycemia. Growth hormone deficiency was diagnosed two years later, after cholestasis and hypoglycemia had almost completely disappeared, but length deficiency became apparent. The reason for the association of cholestasis with growth hormone deficiency remains unexplained. Cholestasis can, especially in combination with hypoglycemia, be a first sign of congenital growth hormone deficiency.

Intrahepatic cholestasis by paucity of interlobular bile ducts in infancy.

On the basis of an extensive review of the literature and their personal experience, the authors consider that neonatal PILBD should not be regarded as merely a malformative anomaly of the bile excretory system, but as a delayed growth of the pars cystica of the hepatic bud in comparison with the normal growth pattern of the cranial part of the same hepatic bud. This leads to the development of hepatocytes and ductal plate, and these, in turn, are the origin of the perilobular or terminal bile ducts (Hering's ampullae) which eventually fuse with interlobular bile ducts for establishing the continuity of the bile duct system. The authors base this hypothesis on their L.M. and E.M. investigations and the casual observation of two cases in which the well documented bile duct anomaly eventually turned into a normal liver histology.

[Liver cholestasis in neonates and young children]. / Cholestáza jater u novorozencu a malých detí.

Liver cholestasis was found in 50 autopsies (23 per cent) among 221 neonates and infants who died in intensive care units. It developed from the 4th postnatal day, was mostly mild and present in biliary capillaries as well as in small interlobular biliary ducts, later there was found phagocytosis of biliary pigment by Kupffer cells. In protracted jaundice there was an irregular increase of small cholangioles derivable from a ductal transformation of periportal hepatocytes. Bile ducts proliferation was connected with a slight widening of portal tracts in infants surviving until the 6th and 8th week. The cause of cholestatic liver lesion remained obscure.