Síndrome de hipoglucemia autoinmune asociado al consumo de ácido α lipoico / Autoimmune hypoglycemia syndrome associated with α lipoic acid consumption

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Hyperinsulinism as a common cause of hypoglycemia in children - pathogenesis, diagnosis and treatment.

Hypoglycemia is a heterogenic metabolic syndrome with the complicated pathogenesis, diagnosis and treatment. It comprises a broad spectrum of disorders and requires multidisciplinary assessment including pediatrics, endocrinology and diabetology, metabolic medicine and genetics. There are various classifications of hypoglycemia. Commonly it is divided into fasting and postprandial hypoglycemia with or without hyperinsulinemia. Congenital hyperinsulinism (HI) is the commonest cause of severe hypoglycemia in a newborn period. There are many different genetic mutations causing inappropriate insulin secretion. The type of genetic mutation determines diagnostic pathway and management of hyperinsulinemic hypoglycemia. Since recurrent hypoglycemia may cause a serious brain damage in children, it is essential to properly diagnose affected children in order to prevent further attacks of hypoglycemia.

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.

The laparoscopic approach toward hyperinsulinism in children.

Hyperinsulinemic hypoglycemia (HH) in children requiring surgery is rare. Early HH can be the result of focal or diffuse pancreatic pathology. A number of genetic abnormalities in early HH have been identified, but in the majority of patients no abnormality is found. The sporadic focal and diffuse forms as well the autosomal recessive form are particularly therapy-resistant and demand for early surgery. Preoperative discrimination between focal and diffuse disease in early HH is difficult. 18 F DOPA PET in combination with CT is promising as is laparoscopic exploration of the pancreas. Frozen section biopsy analysis has not been uniformly beneficial. If macroscopically no focal lesion is found, limited laparoscopic distal pancreatectomy provides tissue for definitive pathologic examination. Subsequent near total laparoscopic spleen-saving pancreatectomy surgery is not particularly difficult. Later HH may occur in the context of the MEN-1 syndrome and is then multifocal in nature. In MEN-1 patients, a distal spleen-saving pancreatectomy with enucleation of lesions in the head seems justified. Insulin-producing lesions in non-MEN-1 patients should be enucleated. There should always be a suspicion of malignancy. Also, in older children, surgery for hyperinsulinism should be performed laparoscopically.

Acute insulin responses to calcium and tolbutamide do not differentiate focal from diffuse congenital hyperinsulinism.

Congenital hyperinsulinism (CHI) is related to two main histological pancreas anomalies: focal adenomatous hyperplasia and diffuse beta-cell hypersecretion. Pharmacological tests to measure acute insulin responses (AIR) to peripheral i.v. injections of glucose, calcium, and tolbutamide have been reported as potential means to distinguish between these histological forms. In patients with defects in ATP-sensitive potassium channels, tolbutamide will fail to induce insulin release in affected portions of the pancreas, whereas calcium gluconate will enhance insulin release through spontaneously active voltage-gated Ca(2+) channels. Consequently, in focal CHI patients, calcium should promote AIRs from the lesion, whereas tolbutamide should act to promote insulin secretion from the healthy region of the pancreas (outside the focal hyperplasia). We therefore studied AIRs to calcium and tolbutamide stimulation tests in 16 children with focal (n = 9) or diffuse (n = 7) CHI before pancreatic surgery. We found hypervariable AIRs to glucose and calcium stimulation in both focal and diffuse CHI patients. AIRs to tolbutamide stimulation were found modest in focal CHI patients, which might account for beta-cell quiescence in the healthy portion of the pancreas of these patients. We conclude that AIRs to calcium and tolbutamide stimulation tests are not sufficient to differentiate the focal from the diffuse CHI patients.

The molecular basis of persistent hyperinsulinemic hypoglycemia of infancy and its pathologic substrates.

Recent advances in molecular genetics have established a molecular basis for persistent hyperinsulinemic hypoglycemia of infancy (PHHI) and resulted in the identification of a number of well-defined genetic defects. On the basis of the available information on the molecular changes so far described, an attempt has been made to classify PHHI patients according to their genotype and phenotype, with reference to molecular genetics, pancreatic pathology and clinical appearance. This classification has resulted in the differentiation of three groups of PHHI patients, two with diffuse beta cell hyperfunction and one with focal beta cell hyperfunction.