Histidinaemia: Study of Relation Between Clinical and Biological Findings in 7 Subjects

Seven subjects with raised plasma histidine and low skin histidase levels (histidinaemia) are described: 4 were severely retarded, 2 showing in addition features of an early infantile psychosis (autism); 3 were of normal intelligence. There were no biochemical differences between the two groups.In view of these findings and a study of patients reported in the literature, attention is drawn to the difficulty in making a decision about treatment of a neonate detected by screening and shown to have the biochemical features of histidinaemia. The natural history of the condition is further examined, particularly the question of deterioration at time of seizures or infection.     

EVALUATION OF A NATION-WIDE NEONATAL METABOLIC SCREENING PROGRAMME IN SWEDEN 1965–1979

ABSTRACT. Aim, J. and Larsson. A. (Department of Paediatrics, Karolinska Institute, St. Goran's Children's hospital, and the PKU Section, Department of Bacteriology, National Bacteriological Laboratory, Stockholm, Sweden). Evaluation of a nation-wide neonatal metabolic screening programme in Sweden 1965–1979. Acta Paediatr Scand, 70:601,.–In Sweden, neonatal screening for phenylketonuria was started in 1965 and a total of 1326000 infants were studied up to 1979. During various periods of time, screening was also carried out for galactosaemia, hereditary tyrosinaemia, histidinaemia, and homocystinuria. In screening for phenylketonuria and galactosaemia no false-negative results were obtained and the incidences were 1/30850 and 1/81100, respectively. In screening for hereditary tyrosinaemia only 1 out of 6 patients was identified by screening and the incidence was 1/106 710. Two cases of histidinaemia were detected, which corresponds to an incidence of 1/36 840. Both children developed normally without any treatment. No child with homocystinuria was detected in the screened population of more than 300 000 newborn infants. A screening programme involving phenylketonuria and galactosaemia was considered to be optimal among the tested disorders.     

Histidinaemia: a benign metabolic disorder

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

Chromatographic screening of 70,328 neonates for inborn errors of amino acid metabolism

Between the years 1974 and 1984, amino acid chromatography was performed from dried blood spots and partly from urine of 70 328 neonates. Six cases of phenylketonuria, one histidinaemia, one hyperglycinaemia and three cystinurias were found. Since all these could have been detected by other methods, the regional screening was discontinued in agreement with international recommendations.     

Histidinaemia: a benign metabolic disorder.

Histidinaemia is a relatively common inherited metabolic disorder with an incidence similar to phenylketonuria. This paper reports the long term outcome of patients diagnosed by newborn screening in the north west of England. Between 1966 and 1990, 108 infants were diagnosed as having histidinaemia by a regional neonatal screening programme (incidence 1:11,083). A further five children were detected following diagnosis in a sibling. Of the 113, nine were lost to follow up. Infants diagnosed before 1981 (n = 47) were placed on a low histidine diet (225 mg/kg/d) for an average period of 21 months (SD 4.5). All patients were reviewed regularly, Griffiths developmental quotients (DQ) were assessed at 2 and 4 years, and WISC-R intelligence quotients (IQ) at 8, 12, and 18 years. IQ data were converted to standard deviation scores (IQ SDS) to account for increasing IQ norms with time. Neither DQ nor IQ correlated with plasma histidine at diagnosis or with the mean plasma histidine throughout life. Growth was normal in all patients. There was no apparent benefit from a low histidine diet in early childhood. In contrast to other studies, there was no excess of clinical symptoms. On the basis of these findings, histidinaemia is a benign metabolic disorder that does not require treatment.     

Screening for inherited metabolic disease in Wales using urine-impregnated filter paper.

Urine specimens from 135 295 infants have been collected on filter papers and tested for 7 abnormal urinary constituents using spot tests and paper chromatography. The method has detected 5 infants with phenylketonuria, 4 with histidinaemia, 5 with cystinuria, 5 with diabetes mellitus, and one with alcaptonuria. Transient abnormalities such as tyrosyluria, generalized aminoaciduria, cystinuria, and glycosuria have been noted. 2 phenylketonuric infants failed to excrete a detectable quantity of o-hydroxyphenlacetic acid at the time of testing. The findings show that the detection of this compound in urine is an unreliable method of screening for phenylketonuria.     

Neonatal mass screening for metabolic disorders

The present situation of neonatal mass screening for metabolic disorders in eleven European countries is presented. The only disease screened for on a population wide basis in almost all countries is phenylketonuria. Screening for congenital hypothyroidism has been started in most countries or is under active consideration. A priority list of disorders that should be screened for routinely in all newborns comprises congenital hypothyroidism, hyperphenylalaninaemia, galactosaemia and maple syrup urine disease. Other disorders, like adrenogenital syndrome, cystic fibrosis. Duchenne's muscular dystrophy, histidinaemia, or tyrosinaemia cannot be recommended for mass screening at present because of an unsatisfactory test procedure or lack of effective treatment.     

The relationship of diaphragmatic defect,liver growth,and lung hypoplasia in nitrofen-induced congenital diaphragmatic hernia in the rat

Reduced lung size (lung hypoplasia, LH) is the main cause of mortality in newborns with congenital diaphragmatic hernia (CDH). However, it is unclear which mechanisms lead to LH. To assess this, we analyzed the relationship of LH and liver mass in correlation to the size of the diaphragmatic defect in rats with nitrofen-induced CDH. A total of 266 newborn Sprague-Dawley rats (30 litters) were exposed to nitrofen on day 11.5 of pregnancy. After spontaneous delivery at term (22 days), all newborns were microdissected. Using a computerized morphometric device, the area of the thoracic cavity, the lung, the intrathoracic liver, and the diaphragmatic defect were measured. The lungs, the intrathoracic, and the extrathoracic portion of the liver were weighed. After nitrofen exposure, 160 newborn rats presented with CDH (60.2%). They were divided into five groups according to the intrathoracic content of intraabdominal organs. We observed a significant increase of the total liver and decrease of the lung weight in the severely affected groups. A significant correlation between the size of the defect and the weight of the intrathoracic part of the liver could be demonstrated. Nitrofen alone had no effect on liver weight. Our results indicate that (1) the presence of liver inside the thoracic cavity is not the result of dislocation but rather of growth of liver tissue through the defect, and (2) the observed correlation between the size of the defect and the intrathoracic liver weight may be part of the pathogenesis of LH in CDH.     

Studies on Carbohydrate Metabolism in Infants with Congenital Heart Disease Part II. Effects of hypoxia on growth, hepatic glycogen storage, and transaminase activities in serum and liver, of rats

To ascertain the harmful effects of hypoxia on liver function and growth, an experimental study was performed using young female rats. Body weight, food intake, hepatic glycogen content, and GOT, GPT and LDH in the serum and liver of rats reared in a hypoxic condition were compared with those of controls. The following results were obtained.

• 1) Although the food intake of rats in a hypoxic condition was almost equal to that of the controls, the mean weight gain of hypoxic rats was lower than that of the controls.
• 2) Glycogen storage in the liver of rats in a hypoxic condition was significantly deficient when compared with that of the controls.
• 3) GOT and GPT activity in serum and liver of hypoxic rats were elevated.
• 4) The deficiency of glycogen storage in the liver was histologically demonstrated. To sum up, hypoxia induced growth retardation, deficiency of glycogen storage in the liver of rats, and hepatic dysfunction. Hypoxia in infants with congenital heart disease may be one of the most important causes of their growth retardation. (Acta Paediatr Jpn 23(2): 172–176 1981)

     

Ultrasonography,laboratory, and cholangiography correlation of biliary complications in pediatric liver transplantation

The aim of this study is to correlate the US, laboratory, and cholangiography findings in pediatric liver transplant patients with biliary complications, trying to identify reliable decision‐making tools for the management of these complications. Retrospective review was carried out of US results in 39 consecutive patients, from 2011 to 2013, with biliary complications after LT, documented by PTC. According to US biliary dilation, patients were classified as: mild, moderate, and severe, and according to laboratory findings as: normal or abnormal serum bilirubin and level of serum GGT. Data were correlated with PTC findings, divided in three groups: mild, moderate, and severe/occlusive BDS. There was no statistically significant correlation between the US findings and the laboratory findings and between US findings with PTC. There was a statistically significant correlation between GGT and cholangiography. In our series, abnormal US could not predict the severity of BDS on PTC. Bilirubin results were not able to predict the US findings either. GGT results demonstrated a statistically significant correlation with the severity of BDS found on PTC. These findings emphasize the role of GGT in the evaluation and decision of biliary interventions in pediatric liver transplant recipients.     

Picolinic carboxylase activity in rat liver and kidney. I. Influence of growth, sex, gestation, lactation, and nutritional imbalance

Picolinic acid (PA) is a metabolite of tryptophan that chelates trace metals, including zinc. Several recent observations have suggested a role for PA in zinc metabolism. The enzyme responsible for its formation is picolinic carboxylase (PC). We have measured PC in rats under a variety of conditions, using tissues that play a role in zinc metabolism. PC activity was demonstrated in liver and kidney and was not detectable in pancreas and brain. Activity was most pronounced in kidney. In male suckling rats, PC increased gradually, reaching maximum levels on the 21st day of life. Only liver PC showed marked variations under different physiological conditions. Liver PC was higher on the 21st day of life than in adulthood. It was higher in female than in male adult rats. In pregnant rats, liver PC decreased gradually toward the end of gestation, reaching the lowest point near delivery; however, a 12-fold increase occurred during lactation. Liver PC activity of rats with symptoms of pellagra showed a fivefold increase over controls with similar body weight, whereas liver PC of chronically starved rats showed only a twofold increase over controls with twice their body weight.     

Nondeformable red blood cells do not interfere with uteroplacental blood flow in the awake, late-pregnant guinea pig

The fractional entrapment of rigidified [relative to control (labeled)] red cells after the intravascular bolus injection of a cocktail of these cells, and the concomitantly induced changes in cardiac output and its distribution (microspheres) were studied in 14 awake, late-pregnant guinea pigs. In a preceding validation study in eight nonpregnant guinea pigs, it was demonstrated that with this technique reproducible data could be generated on the fractional entrapment of rigidified red cells in all organs in this species except for lungs, liver, and spleen. In response to a bolus injection with rigidified and control red cells, only the brain showed preferential entrapment of rigidified red cells, together with a small but consistent increase in blood flow. In other organs (lungs, liver, and spleen excluded), neither preferential entrapment of rigidified red blood cells nor a consistent change in blood flow could be demonstrated. The results of our study suggest that circulating nondeformable red cells have no measurable adverse effect on the perfusion of the nondiseased hemochorial placenta in the awake, late-pregnant guinea pig. This does not exclude the possibility that rigidified red cells may increase the resistance to flow in a microcirculation that has been pathologically changed by some underlying disease.     

The postnatal development of rats born preterm and postterm. II. Liver, brain, heart and kidneys

Groups of 3 preterm (duration of gestation 22 days), 3 term (23 days), and 3 postterm (24 days) rats have been fed together by 1 mother rat. The postnatal growth of liver, brain, heart and kidney has been studied up to the 30th day of life. The postnatal loss of water shows good correlation with the maturation of each organ. The postnatal loss of water is marked in brain and kidneys, but only slight in liver and heart. The pronounced growth spurt of the brain at the about 10th day of life is probably due to the opening of the eyes. The growth spurt of the liver at the 15th day may be due to the supplementary food at the time of weaning. The effect of intrauterine undernutrition in postterm rats is most strikingly demonstrated in the liver. Postnatal undernutrition in preterm rats causes a retardation of growth of the liver and kidneys.     

Alpha1-antitrypsin deficiency and liver disease in children: phenotypes, manifestations, and prognosis.

Among 424 children with liver disease, 20 had alpha1-antitrypsin deficiency associated with protease inhibitor ZZ phenotype. This disorder manifested itself as cholestasis in early infancy in 19 children. Jaundice and pruritus cleared in 16 of these by 7 months of age, but hepatomegaly and laboratory evidence of mild hepatic dysfunction persisted in all. Biliary cirrhosis and portal hypertension eventually developed or was suspected in eight, and hypoplasia of intraheptic bile ducts was demonstrated in another four. Routine screening revealed intermediate alpha1-antitrypsin deficiency in 16 other children with various types of liver disease. The phenotype in these patients was MZ, MS, or SZ. PAS-positive granules were present in liver of all patients with the ZZ phenotype and in none with other phenotypes. The findings indicate that manifestations and prognosis of this inherited liver disease are extremely variable.     

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??The true incidence of fulminant hepatic failure in the pediatric population is unknown?? though fulminant hepatic failure is a rare but devastating syndrome??such as hepatic encephalopathy??DIC??MODS?? that results in the death of most children affected. The mainstay of the treatment is liver transplantation??however?? organ shortage limits its use.The purpose of this review is to introduce the current situation of fulminant liver failure in children??focusing on assessing the application of artificial liver??which is considered to play a pivotal role in the treatment of fulminant liver failure.According to its classification??we mainly discussed the application of non-biological artificial liver?? including its indications??advantages and disadvantages??especially the MARS. At present?? the artificial liver treatment also faces many problems. None of the ELS techniques has yet been evaluated systematically in children??and survival benefits have not yet been demonstrated.     

Graft reduction in pediatric hepatic transplantation: value, technique and results]

The benefit of liver transplantation in children with end-stage liver disease is now well established. A few years ago, the scarcity of suitable pediatric donors was responsible for death in 30 to 50% of children on the waiting list and most of them died before the age of 3 years. Since 1981, the use of reduced-size graft in pediatric liver transplantation allowed a dramatic decrease of the pretransplant mortality rate which is now 2 to 14%. The choice of the reduction technique is based on two parameters; the first one is the donor recipient body weight ratio, the second one is the intra-operative measurement of the recipient's internal transverse basithoracic distance. Nowadays, 30 to 50% of the children undergoing a liver transplant, receive a reduced-size graft. The results of reduced-size orthotopic liver transplantation are comparable with full-size orthotopic liver transplantation; the one-year survival rate is 70 to 85%. These results justify the continued use of reduced-size liver transplantation in children with end-stage liver disease. Transplantation of two patients with one liver (bipartition) and liver transplantation from living related donor, which represents an improvement of the reduction technique, was recently performed successfully and may become a useful concept in pediatric liver transplantation.     

Wolman's disease: Clinical,biochemical and ultrastructural studies in an unusual case without striking adrenal calcification

A case of Wolman's disease is described in a German infant who died at the age of 4 months. Hepatosplenomegaly, abdominal distention, gastrointestinal symptoms, dyserythropoietic changes in the bone marrow, but not adrenal calcification on X-ray were present. Stored lipid material could be demonstrated in liver, spleen, intestine, adrenals, thymus, kidneys, blood cells, but not in the central nervous system. Cholesterylesters and triglycerides were markedly increased in liver and spleen. Lysosomal acid lipase was found to be decreased in leucocytes and liver to less than 10% of normal, when measured with synthetic and natural substrates.This work was supported by the Deutsche Forschungsgemeinschaft (Be 100/28)     

Distribution of the longevity gene product, SIRT1, in developing mouse organs

A longevity gene product, Sir2 (silent information regulator 2) is a NAD-dependent histone deacetylase involved in longevity in yeasts, worms and flies. The mammalian homolog of Sir2, SIRT1(sirtuin 1), has been shown to play important roles related to anti-aging effects (regulating apoptosis, stress tolerance, insulin resistance, and fat metabolism). Recently, SIRT1 expression has been demonstrated to occur at as early as embryonic day 10.5 in mice. SIRT1 during developing period may be involved in the mechanism of developmental origins of adult diseases, such as diabetes and cardiovascular disease. To investigate the contribution of SIRT1, it is important to reveal the distribution of this protein during development. In the present study, we demonstrated the distribution of immunoreactivity of SIRT1 in mouse organs during prenatal and neonatal development by staining a wide variety of serial sections. The SIRT1 immunoreactivity was strongly observed in the neuroepithelial layer, dorsal root ganglion, trigeminal ganglion, eyes, roots of whiskers, and internal organs, including the testis, liver, heart, kidney, and lung during the fetal period. Neurons which had finished migrating still showed relatively strong immunoreactivity. The immunoreactivity was completely absorbed by the blocking peptide in an absorption test. During the postnatal period, the immunoreactivities in most of these organs, except the heart and testis weakened, with the liver most dramatically affected. As SIRT1 expression was demonstrated in a wide variety of developing organs, further study to investigate prenatal factors which affect SIRT1 expression and its activity is important.     

Neonatal coagulopathy in preterm,small-for-gestational-age infants

Our aim was to determine if antenatal hypoxia was associated with liver dysfunction and coagulation abnormalities in small-for-gestational-age (SGA) infants. Sixteen SGA infants, median gestational age 30 (range 26-32) weeks, who consecutively had had umbilical artery Doppler studies in the week before delivery, were compared to appropriate-for-gestational-age (AGA) controls, who were each matched to an SGA infant for gestational age. The median international normalised ratio (INR) was significantly higher (1.9 vs. 1.3, p < 0.001) and the neutrophil (p = 0.003) and platelet counts (p < 0.001), alkaline phosphatase (p < 0.001) and albumin (p < 0.02) levels significantly lower in the SGA compared to the AGA group. The umbilical artery pulsatility index (PI) was elevated, indicating antenatal hypoxia, in all but 1 of the SGA infants. Multiple linear regression analysis demonstrated that the INR was significantly related to the umbilical artery PI independent of the other variables (p = 0.0002, R(2) = 0.71). These results suggest that the coagulopathy seen in preterm SGA infants might at least be partially explained by antenatal hypoxia affecting the liver and hence vitamin K-dependent coagulation.