Parenteral nutrition-associated cholestasis in preterm neonates: evaluation of ursodeoxycholic acid treatment.

BACKGROUND/OBJECTIVE: Parenteral nutrition is an integral part of the care of premature infants. Cholestatic liver disease is a frequent complication of prolonged parenteral nutrition, especially in premature infants. It has been suggested that ursodeoxycholic acid may alter the course of parenteral nutrition-associated cholestasis in children and adults. We attempted to determine the efficacy of ursodeoxycholic acid in premature infants with parenteral nutrition-associated cholestasis. METHODS: Retrospective chart review of all infants receiving ursodeoxycholic acid for parenteral nutrition-associated cholestasis in a 40 bed neonatal intensive care unit. Efficacy of ursodeoxycholic acid was evaluated by response of bilirubin, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase over a treatment period of at least 1 month. RESULTS: Six infants with parenteral nutrition-associated cholestasis who had received ursodeoxycholic acid for one month were identified. Doses of ursodeoxycholic acid ranged from 15-30 mg/kg/day. Cholestasis appeared at a mean age of 47 +/- 17 (mean +/- SD) days after a mean of 42 +/- 15 days of parenteral nutrition. Transaminase levels decreased in three, and either increased or did not change in the other three infants. Bilirubin levels decreased in all infants. Alkaline phosphatase showed a non significant trend to decreased levels. Consistent improvement in all infants was noted only after 10 days of full enteral nutrition. No toxicity was found during ursodeoxycholic acid treatment. CONCLUSIONS: Ursodeoxycholic acid treatment in premature infants appears to be safe, and leads to an early sustained decrease in bilirubin levels by two weeks of therapy. The response of transaminase levels was not sustained in our small cohort.     

PATHOLOGY OF LETHAL FETAL GROWTH RETARDATION SYNDROME WITH AMINOACIDURIA, IRON OVERLOAD, AND LACTIC ACIDOSIS (GRACILE)

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q 33-37. The basic defect of the disease remains unknown.     

Renal transplantation experience in a patient with factor V Leiden homozygous,MTHFR C677T heterozygous,and PAI heterozygous mutation

Vascular complications are important causes of allograft loss in renal transplantation. A two and a half‐month‐old boy was diagnosed with posterior urethral valve and progressed to end‐stage renal disease at eight yr of age. During the HD period, a central venous catheter was replaced three times for repeated thrombosis. The boy was found to be homozygous for FVL and heterozygous for both MTHFR (C677T) and PAI. At the age of 12, renal transplantation was performed from a deceased donor. Postoperative anticoagulation therapy was initiated with continuous intravenous administration of heparin at the dose of 10 IU/kg/h. HD was performed for the first three days. By the fourth day of transplantation, his urine output had increased gradually. Heparin infusion was continued for 18 days during hospitalization at the same dosage. Thereafter, he was discharged with LMWH. On the third month after transplantation, his serum creatinine level was 1.1 mg/dL and eGFR was 75.7 mL/min/1.73 m². He has still been using LMWH, and his eGFR was 78.7 mL/min/1.73 m² eight months after transplantation. Postoperative low‐dose heparin treatment is a safe strategy for managing a patient with multiple thrombotic risk factors.     

新生儿小肠造瘘术后肠衰竭相关性肝病的营养管理、关瘘手术时机和结局

目的 探讨新生儿小肠造瘘术后肠衰竭相关性肝病营养管理和关瘘手术的相关问题,并评估结局.方法 选取2016年1月至2018年12月解放军总医院第七医学中心附属八一儿童医院基础外科18例诊断为肠衰竭的高位肠造瘘合并肠衰竭相关性肝病新生儿的临床资料进行回顾性分析.所有患儿于小肠造瘘术后予以营养支持,并尝试逐步向肠内营养过渡....     

Progressive tubulointerstitial nephropathy with hepatic involvement in an infant

We describe an infant with renal and liver disease who died at the age of 10 months from chronic renal failure. Hepatosplenomegaly was present along with biochemical findings of cholestasis and cytolysis. The diagnosis of tubulointerstitial nephropathy with cortical microcysts associated with hepatic fibrosis was based upon laboratory, radiological, and histological data. This rarely described disorder is characterized by an early clinical onset and unfavourable progression to end-stage renal failure before the age of 2.     

Henoch-Schönlein purpura nephritis in children: risk factors, prevention and treatment

Aim:  To identify risk factors for a child with Henoch-Schönlein purpura (HSP) either to develop nephritis (HSPN) or to contract progressive course and to obtain the currently available evidence on the efficacy of treatment options in both preventing and treating the established renal disease.
Method:  Review of the literature published over the last two decades.
Results:  Persistent or recurrent purpura, severe abdominal symptoms and an older age proved as the most significant risk factors for later HSPN. The risks of long-term renal impairment are the highest in children having at presentation nephritic/nephrotic syndrome and/or more than 50% of glomeruli occupied by large crescents or sclerosing lesions. Randomized controlled trials (RCT) do not support short course prednisone at presentation of HSP in preventing persistent renal disease. Many uncontrolled studies using various treatment regimens have reported outcomes considered better than expected. However, the data from RCTs are sparse and no treatment options for the established renal disease can be currently recommended based on RCTs.
Conclusion:  Severity and/or duration of extrarenal HSP symptoms and an older age are the most significant risk factors for developing HSPN, whereas clinical and histological severity at HSPN onset are in general predictive of a long-term renal impairment. The existing evidence does not support of short course prednisone in preventing persistent renal disease. A well-designed RCTs are needed in children with moderately severe or rapidly progressive (crescentic) HSPN.     

Total parenteral nutrition cholestasis: a cause of mechanical biliary obstruction

In a newborn baby with Hirshsprung's disease obstructive jaundice developed following prolonged parenteral nutrition. At laparotomy, thick inspissated bile was flushed from the biliary tree and prompt resolution of the jaundice followed. To our knowledge, this is the first reported case in which inspissated bile appeared to be a complication of total parenteral nutrition. Mechanical obstruction must be recognized as an extreme in the spectrum of total parenteral nutrition cholestasis.     

Idiopathic infantile arterial calcinosis. A rare cardiovascular disease of uncertain etiology--case report and review of the literature]

IIAC is a rare cardiovascular disease characterized by calcification of the membrana elastica interna and intimal proliferation in smaller and bigger arteries. This report describes a premature infant of 36 week gestational age with IIAC, which developed a hypertrophic-obstructive cardiomyopathia, acute renal failure and renovascular hypertension due to complete occlusion of both renal arteries, and eventually died at an age of 85 days. To date 86 cases of IIAC have been published. In 42 patients whose case records have been reported since 1960, cardiac failure and myocardial ischemia or infarction were the most commun clinical signs. In 54% of cases the electrocardiogramm showed myocardial ischemia. Characteristically neonates or young infants were affected by this disease, the mean onset of symptoms was 2 months, the mean time of survival was 4.2 month of age. Coronary arteries were calcified in 85% of cases; in addition, typical morphological changes were found in the arteries of lung, kidney, extremities, mesenterium, spleen, brain and the aorta. Extravascular calcification (kidney, soft tissue) could be demonstrated in 37% of the patients. The etiology of this rare disease is unknown.     

Decreased cholestasis with enteral instead of intravenous protein in the very low-birth-weight infant

Thirty to 50% of very low-birth-weight infants have parenteral nutrition-associated cholestasis. To test the hypothesis that the incidence of cholestasis would be decreased if parenteral amino acids were avoided and protein given enterally, infants with a gestational age of less than 30 weeks were randomized to two groups. One group received amino acid-free parenteral nutrition and whey protein enterally with added premature infant formula. The control group received standard parenteral nutrition with amino acids and enteral premature formula. At the end of 3 weeks of parenteral nutrition, infants who had a direct serum bilirubin level of greater than 3 mg/dl were considered to have significant cholestasis. Twenty-nine infants required parenteral nutrition for 3 weeks, 17 in the whey group and 12 in the control group. No instances of significant cholestasis were observed in the whey group (0/17), whereas seven of 12 infants (58%) in the amino acid control group had cholestasis (p less than 0.001).     

Arc syndrome without arthrogryposis,with hip dislocation and renal glomerulocystic appearance: a case report

Introduction  Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome is a rare multisystem disorder first described in 1979 and recently ascribed to mutation in VPS33B whose product acts in intracellular trafficking. It exhibits wide clinical variability. Arthrogryposis, spillage of various substances in the urine, and conjugated hyperbilirubinemia define an ARC core phenotype, in some patients associated with ichthyosis, central nervous system malformation, deafness, and platelet abnormalities. Many patients with different associations of cholestasis, renal tubular acidosis, and dysmorphic morphology may be underdiagnosed. Case report  We report the third patient of ARC syndrome from Turkey with an incomplete form with renal tubular dysfunction and cholestasis in the absence of arthrogryposis but exhibiting other rare features. Conclusion  Our case highlights that the variability of involvement of different systems in ARC syndrome is well described; however, the renal glomerulocystic appearance has not been reported previously. Knowledge of this rare condition can benefit the practitioner as well as the patient.     

The changing pattern of diagnosis of infantile cholestasis

OBJECTIVE: Cholestatic liver disease in infancy is caused by a wide range of conditions. This study reviews the pattern of diagnosis of infants with cholestasis presenting to a tertiary referral paediatric hospital in Sydney, Australia, during a 12-year period (1985-96). METHODOLOGY: Infants aged less than 6 months with cholestasis were identified retrospectively from hospital records and data retrieved from the medical records. RESULTS: There were 205 infants identified as having cholestatic liver disease. The aetiology of the cholestasis was idiopathic in 25%, metabolic/genetic in 23%, and due to obstruction in 20%, parenteral nutrition in 20%, infection in 9% and bile duct hypoplasia in 3%. CONCLUSIONS: This study highlights the changing patterns of diagnosis of cholestatic liver disease in infants at a tertiary paediatric facility, demonstrating that up to 50% of cases are now due to genetic/metabolic diseases or parenteral nutrition, and a high proportion are due to idiopathic disease.     

Nephrogenic systemic fibrosis with multiorgan involvement in a teenage male after lymphoma, Ewing's sarcoma, end-stage renal disease, and hemodialysis.

Nephrogenic systemic fibrosis (NSF) is a rare condition that always occurs after acute or chronic renal failure with or without dialysis. The vast majority of cases in the literature are adults, and postmortem findings have been reported in only 5 cases. We report a 15-year-old male who developed NSF with multiorgan involvement after successful treatment of renal lymphoma and a subsequent sacral Ewing's sarcoma, and end-stage renal disease treated with hemodialysis. At autopsy, he was found to have diffuse dural osseous metaplasia, transmural bronchiolar fibrosis, diaphragmatic central tendon fibrosis, and fibrous plaques of the mitral valve. These previously unreported findings expand the spectrum of multiorgan involvement in NSF providing additional evidence that it is an emerging systemic disorder.     

Two Japanese Patients with Gitelman Syndrome

Gitelman syndrome (GS) is a renal tubular disorder characterized by hypokalemia, hypomagnesemia, metabolic alkalosis and hypocalciuria due to defective tubular reabsorption of magnesium and potassium. This disease is caused by mutations of the thiazide-sensitive Na-Cl cotransporter (NCCT) gene, SLC12A3. Manifestations of GS are heterogeneous, from asymptomatic to mild symptoms of cramps and easy fatigue, to tetany and paralysis. Polydipsia, polyuria, and nocturia are also frequent in GS patients. Here we describe two Japanese patients with GS followed as nocturnal enuresis. In the first patient, occasional muscle cramps, easy fatigue and headache led to the diagnosis of GS. The parents of this patient reported that he had been affected by polydipsia and polyuria, especially nocturnal enuresis from early childhood. The second patient was referred to our clinic because of muscular weakness and cramps. He had a past history of transient muscle weakness and muscle cramps. He had also suffered from nocturnal enuresis since 3 yr of age. Laboratory findings of these patients were consistent with those of GS. Sequencing analysis of the SLC12A3 gene from two patients showed four mutations, which were previously reported. In our two patients, their manifestations had been underestimated and the correct diagnosis was delayed. GS is generally likely to be benign, however signs of GS are found in early childhood. Especially, we must recognize that nocturnal enuresis is frequent in symptoms of GS.     

Absence of cytochrome c oxidase activity in a boy with dysfunction of renal tubules,brain and muscle

We report on a boy who developed proximal renal tubular acidosis with loss of carnitine at the age of about 6 months. A few months later he began to suffer from progressive muscular weakness and neurological disturbances. Blood biochemistry showed elevated lactate and -hydroxybutyrate with increased lactate/pyruvate and -hydroxybutyrate/acetoacetate ratios. A high urinary excretion of lactate and citric acid cycle intermediates was found. These results indicated a defect of the mitochondrial respiratory chain. Analysis of biopsy material from skeletal muscle revealed low activities of all respiratory chain complexes. In muscle and fibroblasts cytochrome c-oxidase (complex IV) was absent. Despite high dose multi-vitamin therapy the boy died at the age of 30 months from central respiratory failure. At autopsy the neuropathological diagnosis of Leigh disease was made.     

Congenital central hypoventilation syndrome (Ondine's curse syndrome) in two siblings: Delayed diagnosis and successful noninvasive treatment

Congenital central hypoventilation syndrome (CCHS, Ondine's curse syndrome) is a rare respiratory disorder; less than 100 cases have been reported. Familiality of the disease has been discussed, but only few familial cases have been reported so far. In this report we describe the occurrence of CCHS in two male siblings. Diagnosis was established only at the age of 4 years in the first case, although the patient had disease related symptoms since early infancy. The second patient was one of dizygotic twins, he was diagnosed with CCHS at the age of 8 months. Up to that age only moderate desaturations had been observed. The other twin was unaffected by the disease. Both patients were successfully treated by nocturnal positive-pressure ventilation via a specially adapted face mask. They show satisfactory physical and neurologic development.     

Improvement of nutritional status in cholestatic children with supplemental nocturnal enteral nutrition

Protein energy malnutrition is a common complication in cholestatic children in a hepatic transplant program, and may be detrimental to the postoperative outcome. Improvement of the nutritional status may be of obvious importance to improve the prognosis. This study compared oral nutrition with oral nutrition supplemented with nocturnal enteral feeding in children with prolonged cholestasis. In six children with prolonged cholestasis (conjugated bilirubin over 25 mg/L and/or GGT over 110 IU/L in infants aged less than 3 months or over 50 IU/L in older infants and/or alkaline phosphatase over 500 IU/L, for more than 3 months), we compared a 4 to 6 month period with oral nutrition and similar periods with 10 to 12 h nocturnal enteral feeding given at home as an energetic supplement. Energy intake during the second period was 180-200% of recommended dietary allowances. No ascites was found in the six patients during the study period. The Z scores of body weight, weight expressed as percent of ideal body weight (IBW), weight/height2, and arm circumference/head circumference were calculated at the beginning and at the end of each period. With only oral nutrition, a diminution in percentage of ideal W/H and a diminution in Z score for the body weight were observed in five of six patients. At the end of the second period, the average of all of the nutritional indexes was increased and the Z score for the body weight was also increased in four of six patients. Significant statistical differences (p less than 0.05) were found in W as percentage of IBW and the Z score for log W/H2.(ABSTRACT TRUNCATED AT 250 WORDS)     

Parenteral nutrition-associated cholestasis--what do we know, what can we do?

In the early days of parenteral nutrition of children liver disease resulting in steatosis and cholestasis was assumed to be an inevitable complication of the procedure. Since then, the management of parenteral nutrition has improved so much that nowadays adolescents have a fair chance of surviving more than 15 to 20 years without severe liver disease. Nevertheless, we still see cases of parenteral nutrition-associated cholestasis (PNAC) due to various conditions such as recurrent infections, inflammatory response, inappropriate composition of the nutrient mixture, contaminants of the nutrient solution, and toxic substances from infusion bags and tubes. Recent research indicates that the administration of ursodesoxycholic acid and cysteine can prevent or even improve the cholestasis. A reversal of PNAC has been documented in an adolescent after small bowel transplantation from Japan. There is ample opportunity for prevention of PNAC with respect to the various pathophysiologic aspects: prevention, early detection, and management of infections, avoiding glucose overloads, cyclic infusion of nutrients, light protection of the solution, choice of paediatric amino acid solutions, and most important, oral or enteral feeding to support the bile flow by stimulating the cholecystokinine release.     

Benign recurrent intrahepatic cholestasis

Benign recurrent intrahepatic cholestasis (BRIC) is a rare cause of cholestasis in children. The disease may start in infancy or early childhood. Jaundice persists or recurs throughout life but does not lead to chronic liver disease or cirrhosis. Treatment is mostly symptomatic. The condition has not been reported in Indian children. We report an interesting case of BRIC in a 9-year-old boy who had recurrent episodes of jaundice since when he was 1 yr old.     

Short-term pulmonary effects of total parenteral nutrition in children with cystic fibrosis

Indices of respiratory muscle strength, pulmonary function, and pulmonary diffusing capacity were measured in 11 malnourished children (age 10 to 17 years) with cystic fibrosis, before and after improvement of nutritional status with supplemental parenteral nutrients for 1 month. During this time, the children received 120% of estimated energy requirements (either 3.75% or 22.5% as lipid) and amino acids 2.5 gm/120 kcal by central venous catheter, plus as much of their usual diet as desired. With nutritional supplementation, body weight, triceps skinfold thickness, and mid-arm muscle circumference increased (mean 15%, 62%, and 95%, respectively). Maximum inspiratory airway pressure also increased (mean 29%; P less than 0.01), suggesting improvement in respiratory muscle strength. However, none of the indices of pulmonary function improved. Pulmonary diffusing capacity did not change during parenteral nutrition regardless of the amount of parenteral energy intake supplied by lipid, but arterial oxygen saturation decreased (mean of 93.5% to 91.5%; P less than 0.005). During the month following parenteral nutrition, weight, skinfold thickness, and mid-arm muscle circumference, but not MIP, decreased and arterial oxygen saturation returned to the initial value (P less than 0.01).     

Atherosclerosis Causing Recurrent Catastrophic Aortopulmonary Shunt Dehiscence in a Patient with Alagille Syndrome

Alagille syndrome (ALGS) is an autosomal dominant disorder associated with cholestatic liver disease, pulmonary valvar stenosis or atresia, vasculopathy, and renal disease. Although the liver and cardiac manifestations contribute to overall morbidity and mortality during their life span, these patients also carry a burden of important but often underappreciated vascular abnormalities. This report describes a 3 year-old girl with Alagille syndrome, hepatic cholestasis, systemic hypertension, hypercholesterolemia, hypertriglyceridemia, and tetralogy of Fallot, pulmonary atresia, and major aortopulmonary collaterals (TOF/PA/MAPCAs). She presented for bilateral pulmonary artery plasty and central shunt upsizing. She then experienced three shunt dehiscence episodes, necessitating emergent intervention. Autopsy showed diffuse atherosclerosis and significant atherosclerotic plaque at the site of shunt dehiscence. This is the first reported case of ALGS with TOF/PA/MAPCAs and catastrophic shunt dehiscence due to significant generalized vasculopathy caused by dyslipidemia and atherosclerosis. Dyslipidemia, a known comorbidity in ALGS, is one of few modifiable risk factors that should be screened for and treated, particularly before cardiac surgery.