HYPERINSULINEMIC HYPOGLYCEMIA,REPORT OF 22 CASES Zaman TZ 1 , Rahmanifar AR 2 1 Metab Unit ,Tehran Univ, Tehran, Iran, Islamic Republic of 2 Iranian National Research Society,Div Me, Tehran, Iran, Islamic Republic of Background: Hyperinsulinemic hypoglycemia is the most important cause of hypoglycemia in the neonatal period or early infancy. It is a heterogeneous disorder with two different types of histopathological lesions; focal(islet-cell hyperplasia),always sporadic, and diffuse,a heterogenous disorder, recessively inherited, or rarely dominantly HI, including glutamate dehydrogenase gene involvement, when hyperammonemia is associated. These are clinically indistinguishable. Objective: The aim was to review clinical presentations, laboratory findings and outcome of 22 patients with hyperinsulinemic hypoglycemia. Methods: A Retrospective study of all patients diagnosed to have (PHH) between (19902010). Results: Total 22 patients;Male 11(50%);age at onset, 13(61%)in the first week,16(76%)in first 3 months and 22(100%)in first 6 months; related parents, 70%; birth weight >4 kg,54%. The most common presentation was seizures,95% followed by cyanosis,57%; insulin level,(10-25 micro IU/ml,mean 17.5). Plasma ammonia level was 2-3 times increased in 5/11 cases. All cases after emergency treatment were treated with Diazoxide, 13/ 22 were diazoxide sensitive and 9 underwent surgical intervention (pancreatectomy). Pancreatic biopsy was performed in 9 cases; Island hyperplasia,7 cases; B cells hyperplasia,2. 20 year FU; well in 18. Conclusion: 75% became symptomatic in the first week and 100% up to 6 months. Early detection and treatment are very important to prevent severe brain damage. It has been reported that rapid genetic analysis of ABCC8 and KCNJ11 genes could improve the clinical management of congenital hyperinsulinism (CHI). We evaluated retrospectively 5 patients (pts) with diazoxide-unresponsive CHI treated at our Centre in the last 30 years with respect to genetic analysis. Genetic analysis was performed after CHI management, at Royal Devon & Exeter NHS, UK and in 2 pts at Baylor College, Texas. Between 1981-2001, 2/5 pts (pts 1,2) underwent total pancreasectomy (TP) after multiple partial resections. Pt 3 underwent TP after medical treatment awaiting spontaneous remission. These pts showed diffuse CHI at histological examination. Pts 4 and 5 did not show focal CHI at venous pancreatic sampling (pt 2, 1995) or 18 F-Dopa PET/CT (pt 5, 2008) . Case 4 showed early CHI remission, pt 5 is stable on low dose octreotide. Pts 1-3 are homozygous for nonsense mutations (E51X case 1; A187V cases 2-3, sisters) on KCNJ11 gene. Pt 4 is heterozygous for nonsense mutation Q444H and pt 5 compound heterozygous (E529K and H125Q), both on the ABCC8 gene. In our pts rapid genetic analysis could be helpful to indicate the correct management (near-total pancresectomy or medical treatment), in combination with 18 F-DOPA PET/CT. Specific treatment of the acute porphyria attack is based on oral or intravenous carbohydrate loading. The rationale for this treatment has been unveiled in experimental animals; fasting of mice induces aminolevulinic acid synthase-1 (ALAS1) through actions of the peroxisome proliferatoractivated receptor-gamma coactivator-1alpha (PGC-1alpha). The aim of this study was to investigate the direct effect of glucose and insulin on mRNA levels of ALAS-1 in human hepatocytes. The rationale for carbohydrate loading in treatment of the acute porphyria attack was confirmed in primary human hepatocytes including a direct downregulatory effect of insulin on ALAS1 and PGC-1alpha. There was a linear correlation between ALAS1 and PGC-1alpha mRNA levels confirming a coregulation of ALAS1 and PGC-1alpha. The fact that increased expression of PGC-1alpha by dexamethasone at normophysiological levels of glucose (5 mM) and insulin (0.3 nM) did not increase ALAS1 points to importance of the mechanism of insulin stimulated export of the ALAS1 transcriptional regulator, forkhead box protein O1, from the nucleus. On the other hand, the potentiation of the phorphyrogenic action of phenobarbital by dexamethasone-induced expression of PGC-1alpha suggests that the role of PGC-1alpha in ALAS1 regulation extends to induction via the nuclear receptors pregnane X receptor and/or the constitutive androstane receptor. Glucokinase (GCK) is the enzyme controlling insulin release. Mutations in GCK gene can result in various phenotypes with autosomal dominant inheritance. Both persistent hyperinsulinemic hypoglycemia of infancy and hyperglycemia (MODY-2, PNDM) are observed, depending on the type of DNA changes. Activating mutations cause oversecretion of insulin despite hypoglycemia, with good response to pharmacological treatment. The prevalence of GCK-HH is 1.2% out of all HH cases. We present a girl, born at time to unrelated young parents. Father's history revealed serious HH in childhood, treated initially with diazoxide but finally pancreatectomy had to be performed. He developed insulindependent diabetes in age of 26 years. Some family members are probably also affected but not diagnosed Hyperinsulinemic hypoglycemia was diagnosed in our patient from first days of her life but was milder that in her father. DNA analysis revealed activating mutation in GCK gene, with protein effect: Val455Leu in both patients. Diazoxide therapy was introduced with good clinical response. Conclusions: 1.The identification of a GCK mutation provides information on the prognosis of the disease and helps therapeutic decision. 2.It implies also the diagnostic procedures for hypoglycemia directed to other family members. 3.In each case of neonatal hyperinsulinism, genetic counseling should be recommended.