Epicardial adipose tissue in patients with end-stage renal disease on haemodialysis.

PURPOSE OF REVIEW: Epicardial adipose tissue (EAT) is the visceral fat of the heart, sharing many of the pathophysiological properties of other visceral fat depots. EAT is a metabolically active paracrine and vasocrine organ that causes local cardiac inflammation and is strongly implicated in the pathogenesis of coronary atherosclerosis. This article highlights the findings of recent observational studies in patients on haemodialysis that link the quantity of EAT to increased rates of cardiovascular and coronary artery disease and review the proposed methods of pathogenesis and the possible role of EAT quantification to improve cardiovascular risk assessment. RECENT FINDINGS: Increasing volumes of EAT in patients on haemodialysis correlate with increased inflammatory mediators, higher rates of cardiovascular disease and coronary artery calcification, independent of general adiposity. EAT is an independent predictor of mortality and a potentially modifiable target for therapeutic interventions. SUMMARY: EAT is likely to play a central role in the pathogenesis of cardiovascular disease in patients on haemodialysis, adds incrementally to conventional cardiovascular risk stratification models and is a potential target for therapeutic intervention.

Rickets as an unusual initial presentation of abetalipoproteinemia and hypobetalipoproteinemia.

OBJECTIVE: Description of rickets as an unexpected initial manifestation in two children with abetalipoproteinemia and hypobetalipoproteinemia, and elucidation of its pathophysiology in these conditions. METHODOLOGY: Two infants aged two and six months with abetalipoproteinemia and hypobetalipoproteinemia respectively had clinical rickets at presentation, confirmed radiologically and biochemically. Vitamin D intake and serum levels were measured and other causes of rickets were looked for. RESULTS: Vitamin D intake and laboratory studies levels were suggestive of rickets due to calcium deficiency instead of vitamin D deficiency. Healing of rickets occurred with dietary treatment of the malabsorption, without any dietary calcium or significant vitamin D supplementation. CONCLUSION: Steatorrhea-induced calcium malabsorption seems to be the most likely cause of rickets in this entity.

Hepatic expression of ErbB3 is repressed by insulin in a pathway sensitive to PI-3 kinase inhibitors.

ErbB3 is an epidermal growth factor receptor-related type I tyrosine kinase receptor capable, in conjunction with ErbB2 or epidermal growth factor receptor, of transmitting proliferative and differentiative signals in a variety of cell types. We previously showed that ErbB3 messenger RNA and protein increase in cultured hepatocytes during the first 12 h in culture, as does the binding of heregulin beta1, a ligand for ErbB3. Insulin inhibits the increase in heregulin beta1 binding, as well as the increase in ErbB3 messenger RNA and protein. Two models of insulin deficiency in vivo (diabetes and fasting) demonstrated elevated levels of hepatic ErbB3 protein, strengthening the relevance of our observations in vitro. Using chemical activators or antagonists, we sought to identify the signaling pathways that link insulin to ErbB3 expression. The PI-3 kinase inhibitors, wortmannin and LY294002, completely blocked the inhibition of ErbB3 protein expression by insulin, suggesting a role for PI-3 kinase in the regulation of this growth factor receptor. Rapamycin, an inhibitor of p70 S6 kinase, an enzyme downstream of PI-3 kinase, failed to block the effect of insulin on ErbB3 expression. These results suggest a complex regulatory paradign for ErbB3 that includes PI-3 kinase and may be linked, via insulin, to the metabolic status of the animal.

Role of initial near total (95%) pancreatectomy in persistent neonatal hyperinsulinism (PNH).

A retrospective analysis of data on all infants with persistent neonatal hyperinsulinism (PNH) in our hospital during a nine-year period (July 1983 to June 1992) was carried out. The extent of pancreatectomy and outcome based on long-term follow-up were reviewed. Fourteen of the 18 cases, diagnosed at our facility according to the established criteria of PNH, underwent surgery. Two patients who were managed medically because of milder disease and reluctance of parents for surgery and two patients who were diagnosed and operated upon outside our facility were excluded from this study. One patient, operated upon in 1985, needed re-surgery after 95% pancreatectomy because of recurrent hypoglycaemia unresponsive to medical treatment. This case influenced our management in a subsequent patient in whom we performed total pancreatectomy as an initial procedure. Both these patients are still diabetic. Three more patients had recurrence of hypoglycaemia after 95% pancreatectomy, two were managed successfully with a short course of diazoxide, the third had associated carnitine deficiency and his hypoglycaemia resolved after a short period of carnitine therapy. The first patient in our series had 85% pancreatectomy, the other 11 patients had 95% pancreatectomy as an initial procedure. The 12 patients are normoglycaemic and off all medication. We conclude that 95% pancreatectomy as an initial procedure for PNH offers the best prognosis and that recurrence of hypoglycaemia does occur following 95% pancreatectomy and can easily be managed medically.

Mutations in subunits of the epithelial sodium channel cause salt wasting with hyperkalaemic acidosis, pseudohypoaldosteronism type 1.

Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the alpha or beta subunits of the amiloride-sensitive epithelial sodium channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease.

The molecular basis for familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a glucose metabolism disorder in neonates characterized by inappropriate insulin secretion in the presence of profound hypoglycemia. Loss of function mutations in the sulfonylurea receptor (SUR) gene recently have been implicated as a cause for familial PHHI in nine independent families. This review will describe the combined positional cloning and candidate gene strategy used to identify the SUR gene as the one responsible for PHHI. Potential roles for SUR in other disorders of insulin secretion remains to be determined.

Mutations in the sulfonylurea receptor gene in familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), an autosomal recessive disorder characterized by unregulated insulin secretion, is linked to chromosome 11p14-15.1. The newly cloned high-affinity sulfonylurea receptor (SUR) gene, a regulator of insulin secretion, was mapped to 11p15.1 by means of fluorescence in situ hybridization. Two separate SUR gene splice site mutations, which segregated with disease phenotype, were identified in affected individuals from nine different families. Both mutations resulted in aberrant processing of the RNA sequence and disruption of the putative second nucleotide binding domain of the SUR protein. Abnormal insulin secretion in PHHI appears to be caused by mutations in the SUR gene.

Homozygosity mapping, to chromosome 11p, of the gene for familial persistent hyperinsulinemic hypoglycemia of infancy.

Familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI) is a rare, autosomal recessive disease of unregulated insulin secretion, defined by elevations in serum insulin despite severe hypoglycemia. We used the homozygosity gene-mapping strategy to localize this disorder to the region of chromosome 11p between markers D11S1334 and D11S899 (maximum LOD score 5.02 [theta = 0] at marker D11S926) in five consanguineous families of Saudi Arabian origin. These results extend those of a recent report that also placed PHHI on chromosome 11p, between markers D11S926 and D11S928. Comparison of the boundaries of these two overlapping regions allows the PHHI locus to be assigned to the 4-cM region between the markers D11S926 and D11S899. Identification of this gene may allow a better understanding of other disorders of glucose homeostasis, by providing insight into the regulation of insulin release.

Familial nesidioblastosis: more evidence for autosomal recessive inheritance.

Severe neonatal hypoglycaemia in five Saudi Arab infants of both sexes belonging to two families of consanguineous parents is reported. All of these infants needed sub-total pancreatectomy to maintain normoglycaemia. Histopathological studies with immunohistochemistry proved diffuse nesidioblastosis of the pancreas in all five infants. Data obtained from these families and other families reported in the literature strongly suggest that familial nesidioblastosis is an autosomal recessive disorder. Knowledge of the inheritance pattern is important both for genetic counselling and for making a prompt diagnosis in subsequently affected siblings, as delay in appropriate treatment may have serious consequences.

Convulsion as a possible manifestation of vitamin D deficiency rickets in infants one to six months of age.

During the 42 months of January 1985 through June 1988, five infants between the ages of one and six months had hypocalcemic convulsions associated with vitamin D deficiency rickets. Despite abundant sunlight, convulsions as a manifestation of vitamin D deficiency in young infants are not uncommon in Saudi Arabia and should be considered as a probable cause for hypocalcemic seizure in breast fed infants.

Cystic fibrosis presenting with recurrent vomiting and metabolic alkalosis.

Between January 1980 and December 1987, ten Saudi Arabian children at Saudi Arabian Oil Co. (Saudi Aramco) health care facilities in the Eastern Province of Saudi Arabia had cystic fibrosis (CF). The incidence of CF in Saudi Arab children less than or equal to 14 years was 1 in 4243. Five of the ten children had hypoelectrolytaemia and metabolic alkalosis on initial presentation. Two of the five had recurrent vomiting, hypoelectrolytaemia and metabolic alkalosis alone and initially no chest symptoms. Early exclusion of CF should be part of the workup in any child, especially in an infant with hypoelectrolytaemia and metabolic alkalosis.

Complications of diazoxide treatment in persistent neonatal hyperinsulinism.

Seven infants with persistent neonatal hyperinsulinism were treated in Dhahran Health Centre from 1983 to 1986. The insulin:glucose ratio (serum insulin concentration pmol/l) divided by the blood glucose concentration (mmol/l) ranged from 12 to 636, mean (SD) 177 (201). To control hypoglycaemia, diazoxide (12-24 mg/kg/day) was given in a continuous intravenous glucose infusion (12-22 mg/kg/min) on 11 separate occasions, four infants twice each and three infants once each. An increase of more than one standard deviation in the heart and respiratory rates, together with other symptoms of heart failure, was considered to be evidence of diazoxide toxicity. Cardiorespiratory failure (toxicity) occurred on eight of the 11 occasions (73%) in seven infants. The average daily fluid intake, weight change, respiratory rate and heart rate before treatment were similar whether or not the infant developed toxicity. A diazoxide toxicity index was obtained by multiplying the dose of diazoxide by the insulin:glucose ratio to relate the diazoxide dose to the severity of the disease. In all instances when the toxicity index was more than 1533 (mean (SD) 3732 (2741) cardiac toxicity developed. In contrast, infants with a toxicity index of less than 675 (mean (SD) 364 (270), had no symptoms of toxicity. Symptoms were significantly related to the severity of the disease and the diazoxide dose. It is possible to use the toxicity index to predict the risk of toxicity and to calculate a safe dose of diazoxide in infants with persistent neonatal hyperinsulinism.

Neonatal diabetes mellitus in first cousins.

The cases of two first cousins with neonatal diabetes mellitus are presented in this report. In one child the condition was transient, whereas the other has permanent diabetes mellitus. It seems unlikely that the difference in outcome was related to the degree of diabetic control early in the course of the disorder. The possibility of genetic influence in the etiology of neonatal diabetes is stressed. Chlorpropamide was not useful in curing neonatal diabetes mellitus in one case.

Persistent neonatal hyperinsulinism.

Over a 3-year period, the diagnosis of persistent neonatal hyperinsulinism (PNH) was made in seven infants, from an unselected cohort of 18,726 births, all of Saudi Arabian origin. Thus the incidence of PNH was one in 2,675 births. The high incidence, associated consanguinity, and occurrence in siblings suggest that PNH may be inherited as an autosomal recessive disorder.

Hypoparathyroidism in Arab children.

Four children with hypoparathyroidism are reported. We believe that this is the first report of this condition from Kuwait or Saudi Arabia. Treatment and course of disease are discussed. Two children have hypoparathyroidism as part of DiGeorge Syndrome.

Ethnic differences in congenital malformations.

Perinatal deaths and major lethal and non-lethal congenital malformations occurring in this hospital from 1979-82 inclusive were related to the ethnic group of the 15 438 mothers. The highest crude perinatal mortality rates occurred in Indian and Pakistani populations (18.3 per 1000 and 24.1 per 1000 respectively). The highest incidence of congenital abnormality also occurred in these groups (13.3 per 1000 and 12.8 per 1000 respectively), but there was considerable variation in the distribution of different malformations.

Adrenal insufficiency possibly due to lipoid adrenal hyperplasia: a case report.

An infant who presented with adrenal insufficiency possibly due to lipoid adrenal hyperplasia at the age of 66 days is described. This is the first time that this very rare disorder is reported from Saudi Arabia. Adrenocorticotrophic hormone (ACTH) stimulation test is useful in the ante-mortem diagnosis of this condition.

Ethnic differences in the distribution of congenital malformations.

Major lethal and non-lethal congenital malformations occurring in babies born in Dudley Road Hospital in 1979, 1980 and 1981 were related to the ethnic group of the mother. There was an increased incidence of gastrointestinal malformations in the Indian group and an increased incidence of abnormalities that could be associated with consanguinity and increased maternal age in the Pakistani group. A sample population (2000 mothers) was obtained in the first 7 months of 1982 to determine the maternal age distribution and consanguinity rates in the various ethnic groups.