Octreotide-related exocrine pancreatic insufficiency (EPI) in congenital hyperinsulinism.

Background Congenital hyperinsulinism (CH) is the most frequent cause of persistent hypoglycemia in the newborn. Octreotide, a long-acting somatostatin receptor analog (SSRA), is a second line treatment for diazoxide unresponsive CH patients. Although it has been found to be a safe and effective treatment, long-term benefits and side effects, have not been thoroughly evaluated. Case presentation Some authors have indicated that exocrine pancreatic insufficiency (EPI) is a common but under-recognized adverse reaction in adults treated with octreotide. However, no pediatric patient with SSRA-induced EPI has been reported to date. Here we report a case of an infant with diazoxide unresponsive, diffuse CH, caused by a heterozygous pathogenic paternally inherited mutation in the ABCC8 gene (NM_000352.4:c.357del), that developed exocrine pancreatic insufficiency and secondary vitamin K deficiency associated to chronic octreotide therapy. Conclusions We point out the atypical clinical onset with a cutaneous hemorrhagic syndrome, emphasizing the clinical relevance of this potential side effect.

Identification of Resistance to Exogenous Thyroxine in Humans.

Background: Thyroxine (T4) to triiodothyronine (T3) deiodination in the hypothalamus/pituitary is mediated by deiodinase type-2 (D2) activity. Dio2(-/-) mice show central resistance to exogenous T4. Patients with resistance to exogenous thyroxine (RETH) have not been described. The aim of this study was to identify hypothyroid patients with thyrotropin (TSH) unresponsiveness to levothyroxine (LT4) and to characterize the clinical, hormonal, and genetic features of human RETH. Methods: We investigated hypothyroid patients with elevated TSH under LT4 treatment at doses leading to clinical and/or biochemical hyperthyroidism. TSH and free T4 (fT4) were determined by chemiluminescence, and total T4, T3, and reverse T3 (rT3) by radioimmunoassay. TSH/fT4 ratio at inclusion and T3/T4, rT3/T4, and T3/rT3 ratios at follow-up were compared with those from patients with resistance to thyroid hormone (RTH) due to thyroid hormone receptor-ß (THRB) mutations. DIO2, including the Ala92-D2 polymorphism, selenocysteine binding protein 2 (SECISBP2), and THRB were fully sequenced. Results: Eighteen hypothyroid patients (nine of each sex, 3-59 years) treated with LT4 showed elevated TSH (15.5 ± 4.7 mU/L; reference range [RR]: 0.4-4.5), fT4 (20.8 ± 2.4 pM; RR: 9-20.6), and TSH/fT4 ratio (0.74 ± 0.25; RR: 0.03-0.13). Despite increasing LT4 doses from 1.7 ± 1.0 to 2.4 ± 1.7 µg/kg/day, TSH remained elevated (6.9 ± 2.7 mU/L). Due to hyperthyroid symptoms, LT4 doses were reduced, and TSH increased again to 7.9 ± 3.2 mU/L. In the euthyroid/hyperthyrotropinemic state, T3/T4 and T3/rT3 ratios were decreased (9.2 ± 2.4, RR: 11.3-15.3 and 2.5 ± 1.4, RR: 7.5-8.5, respectively) whereas rT3/T4 was increased (0.6 ± 0.2; RR: 0.43-0.49), suggesting reduced T4 to T3 and increased T4 to rT3 conversion. These ratios were serum T4-independent and were not observed in RTH patients. Genetic testing was normal. The Ala92-D2 polymorphism was present in 7 of 18 patients, but the allele dose did not correlate with RETH. Conclusions: Human RETH is characterized by iatrogenic thyrotoxicosis and elevated TSH/fT4 ratio. In the euthyroid/hyperthyrotropinemic state, it is confirmed by decreased T3/T4 and T3/rT3 ratios, and elevated rT3/T4 ratio. This phenotype may guide clinicians to consider combined T4+T3 therapy in a targeted fashion. The absence of germline DIO2 mutations suggests that aberrant post-translational D2 modifications in pituitary/hypothalamus or defects in other genes regulating the T4 to T3 conversion pathway could be involved in RETH.