Erythrocyte incorporation of ingested stable isotope of iron (58Fe)

Because of a possible hazard from the use of radioisotopes to determine iron absorption by infants, the use of stable isotopes for this purpose has much appeal. We have applied the method of inductively coupled plasma mass spectrometry (ICP/MS) to determine the mass ratio, 58Fe/57Fe, in blood before and after oral administration of 58Fe. From the increase in erythrocyte enrichment with 58Fe, we have calculated percentage absorption of iron. We have shown that the coefficient of variation of measured mass isotope ratio is 0.1-1.0%, depending on the conditions of the measurement. The method has been applied to a feasibility study involving four infants. Each infant was given 58Fe either as a single dose or as one dose on each of two consecutive days. Each dose provided 1.945 mg iron and 1.440 mg 58Fe. Samples of blood were obtained before isotope administration and at 14, 42, and 60 days thereafter. Isotopic analysis of the samples demonstrates that this approach results in a sufficiently large isotope enrichment to permit satisfactory measurement of iron availability. It is concluded that this new method is highly promising for studies of iron availability in infants and children.     

Effects of lifestyle interventions and long‐term weight loss on lipid outcomes – a systematic review

Weight and lipids are critical components of the metabolic syndrome, diabetes and cardiovascular disease. Past reviews considering weight loss on lipid profiles have been for ≤1 year follow‐up and/or were for very overweight, obese or morbidly obese participants. This systematic review includes lifestyle interventions for adults (18–65 years), with a mean baseline BMI < 35 kg/m², with weight and lipid differences over 2 years. Between 1990 and 2010, 14 studies were identified. Mean differences for weight and lipids were modest. However, weight loss at 2–3 years follow‐up, produced significant beneficial lipid profile changes. These were similar to previous reviews conducted on heavier target groups and/or over shorter follow‐up periods; cholesterol (1.3% decrease per kg lost) and triglycerides (1.6% fall per kg). Weight loss sustained longer than 3 years was not associated with beneficial lipid changes, suggesting that other lifestyle changes not just weight loss needs maintaining. Evidence linking lifestyle induced sustained weight loss with lipid profile changes in the long‐term for this group is limited. Probable within‐group differences (treatment vs prevention), would make further group separation prudent. Individual patient data analysis would facilitate this, uncover baseline, medication and confounding effects, and may identify successful program components enabling more effective obesity prevention and treatment strategies.     

Comparative efficacy of five long‐term weight loss drugs: quantitative information for medication guidelines

Quantitative information is scarce in current obesity medication guidelines, and they do not clearly reflect the differences in the efficacy characteristics among various drugs. This study quantitatively assessed the efficacy characteristics of five FDA‐approved long‐term weight loss drugs. Potentially eligible studies were obtained from public databases. Using the differences in the weight change from baseline between the drug group and the corresponding placebo group as the major indicator of efficacy, a time‐effect model was established, and crucial pharmacodynamic parameters, such as the maximal efficacy, drug onset time and rate of body weight regain after the maximal efficacy point, were used to reflect the differences in efficacy among the five drugs. Finally, 50 reports (involving 43,443 participants) were included. After deducting the placebo effects, the maximal efficacies (95% CI) of orlistat (120 mg), lorcaserin, naltrexone–bupropion, phentermine–topiramate (PT, 7.5/46 mg) and liraglutide were ?2.94 (?5.82, ?1.27), ?3.06 (?4.39, ?1.71), ?6.15 (?9.78, ?3.25), ?7.45 (?9.76, ?3.88) and ?5.50 (?10.62, ?2.97) kg at weeks 60, 54, 67, 59 and 65 respectively, and their rates of body weight regain were 0.51, 0.48, 0.91, 1.27and 0.43 kg per year respectively. The 1‐year dropout rates of orlistat, lorcaserin, naltrexone‐bupropion, PT and liraglutide were 29.0, 40.9, 49.1, 34.9 and 24.3% respectively. In addition, a significant dose–effect correlation was observed for orlistat and PT. This study provides valid quantitative information for medication guidelines.     

The TMPRSS6 variant (SNP rs855791) affects iron metabolism and oral iron absorption – a stable iron isotope study in Taiwanese women

Genome wide studies have associated TMPRSS6 rs855791 (2321 C>T) with iron status and hepcidin. It is unclear whether this polymorphism affects iron absorption. We administered standardized ricebased test meals containing 4 mg of labeled ⁵⁷Fe or ⁵⁸Fe as FeSO₄ on alternate days in non-anemic Taiwanese women (n=79, 44 TT variant, 35 CC variant). Fractional iron absorption was measured by erythrocyte incorporation of the tracers 14 days after administration. Compared to the CC variant, iron and transferrin saturation were lower (P=0.001; P<0.001, respectively) and serum hepcidin/transferrin saturation and serum hepcidin/serum iron ratios were higher (P=0.042; P=0.088, respectively) in the TT variant. Serum hepcidin did not differ between the groups (P=0.862). Geometric mean (95% Confidence Interval [CI]) fractional iron absorption, corrected to a serum ferritin of 15 μg/L, was 26.6% (95% CI: 24.0-29.5) in the CC variant and 18.5% (95% CI: 16.2-21.1) in the TT variant (P=0.002). Overall, predictors of iron absorption were: serum ferritin (P<0.001); genetic variant (P=0.032); and hepcidin (P<0.001). In the models by variant, in the CC variant the model explained 67-71% of variability in absorption and serum ferritin was the only significant predictor (P<0.001); while in the TT variant, the model explained only 35-43% of variability, and hemoglobin (P=0.032), soluble transferrin receptor (P=0.004) and hepcidin (P<0.001) were significant predictors. Women with the TMPRSS6 rs855791 (2321 C>T) polymorphism show altered iron homeostasis which affects oral iron absorption and may increase their risk for iron deficiency. The trial was registered as clinicaltrials gov. Identifier: {"type":"clinical-trial","attrs":{"text":"NCT03317873","term_id":"NCT03317873"}}NCT03317873, and funded by the Kaohsiung Chang-Gung Memorial Hospital, Kaohsiung, Taiwan, (grant CMRPG8F0721) and ETH Zurich, Switzerland.     

Complete loss of insulin secretion capacity in type 1A diabetes patients during long‐term follow up

Aim/Introduction

Patients with type 1 diabetes are classified into three subtypes in Japan: acute onset, fulminant and slowly progressive. Acute‐onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese patients with long‐standing type 1A diabetes is unclear. The aim of the present study was to clarify the course of endogenous insulin secretion during long‐term follow up and the factors associated with residual insulin secretion in patients with acute‐onset type 1 diabetes (autoimmune).

Materials and Methods

We retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute‐onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C‐peptide levels and the results of glucagon stimulation test in 71 patients.

Results

In the first year of disease, the child‐ and adolescent‐onset patients had significantly more in residual insulin secretion than the adult‐onset patients (34 patients in total). C‐peptide levels declined more rapidly in patients whose age of onset was ≤18 years than in patients whose age of onset was ≥19 years. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at >15 years after onset (61 patients in total).

Conclusions

Most patients with acute‐onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset might affect the course of insulin secretion.     

Subcellular location of heme oxygenase 1 and 2 and divalent metal transporter 1 in relation to endocytotic markers during heme iron absorption

Background and Aim: Heme is an important dietary micronutrient, although its absorptive mechanisms are poorly understood. One hypothesis suggests enterocytes take up heme by receptor‐mediated endocytosis (RME) which then undergoes catabolism by heme oxygenase (HO) inside internalized vesicles. This would require the translocation of HO‐1 or HO‐2 to endosomes and/or lysosomes and the presence of a transporter, possibly divalent metal transporter 1 (DMT1), to transfer released iron to the cytoplasm. Currently, the location of HO‐1 and HO‐2 in enterocytes is unknown. Methods: We studied the subcellular location of HO‐1, HO‐2, and DMT1 in the proximal small intestine of rats by confocal immunofluorescence microscopy up to 4 h after a dose of heme or ferrous iron. Double‐labeling was performed with endocytotic (EEA1, Lamp1) and structural markers (F‐actin). Results: HO‐1 was distributed evenly throughout the cytoplasm of enterocytes and did not colocalize with endocytotic markers in any condition. HO‐2 staining remained constant with dosing, presenting as a dense band in the apical cytoplasm that colocalized extensively with endosomes. DMT1 staining was markedly reduced by ferrous iron, but not heme and did not exhibit colocalization with endocytotic markers. Conclusion: The subcellular location of HO‐2 is consistent with the RME hypothesis for heme uptake and may suggest a possible role for this enzyme in heme degradation. The lack of translocation of DMT1 with heme dosing suggests another protein may be present to transport iron released from heme.     

Response loss and development of neutralizing antibodies during long‐term treatment with romiplostim in patients with immune thrombocytopenia: a case series

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts resulting from both immune‐mediated platelet destruction and inappropriate bone marrow platelet production. Therefore, in patients with ITP failing immunosuppressants/splenectomy, an alternative approach is to enhance platelet production stimulating thrombopoiesis. Studies on the development of recombinant thrombopoietins (rhTPO) were halted as a minority of patients developed an autoantibody that neutralized pegylated rhTPO and also cross‐reacted with and neutralized endogenous TPO resulting in thrombocytopenia. Clinical use of romiplostim, a second‐generation TPO‐RAs, has shown that during long‐term treatment, it may elicit the development of neutralizing antibodies to this agent resulting in acute thrombocytopenia. In our case series of 47 primary adult patients with ITP treated with romiplostim, 28 of 47 are evaluable for response loss. Among these, we observed eight patients who either progressively (3 of 8) or abruptly (5 of 8) lost response which accounts for a prevalence of 28.5%. Neutralizing antibody testing could be performed in 4 of 8 patients and 3 of 4 tested positive. These antibodies did not cross‐react with endogenous TPO and retesting of 2 patients at 9 and 7 months yielded a negative result. At follow‐up, 5 of 8 patients – including the 3 patients with neutralizing antibodies – went into long‐term complete response when switched to a different therapy while 3 of 8 patients never regained a response on subsequent lines of therapy. Response loss does not seem to be so rare an event during romiplostim administration (28.5% in our series) and in a minority of patients, it can be associated with development of drug neutralizing antibodies. Although recognized by the manufacturer as a possible adverse event ensuing during romiplostim administration, development of neutralizing antibody in everyday clinical practice has so far not been specifically addressed in reports on romiplostim use outside controlled studies. Unfortunately, testing for these antibodies requires adhesion to strict procedures which is not easily accomplished in everyday clinical practice. This complexity represents a significant drawback in extending antibody testing to all patients who lose response to romiplostim.     

Conservative management of caustic substance ingestion in a pediatric department setting,short‐term and long‐term outcome

Patients with caustic substance ingestion are usually referred to surgery departments where endoscopic evaluation is the first step towards appropriate treatment. The aim of this study was to evaluate the safety and efficacy of conservative management of caustic substance ingestion in a pediatric department setting following a standard protocol including endoscopy in selected cases and conservative treatment based on clinical and endoscopy criteria. In this single center observational study, all children admitted for caustic substance ingestion to a pediatric department over an 8‐year‐period were managed according to a standard protocol that included endoscopy within 24 hours, if the endoscopy criteria were met, and conservative treatment as judged appropriate according to endoscopic classification. Patients were followed up for 8–10 years. Of the 24 patients (age 4/12 to 6 years) admitted, 14 met the endoscopy criteria. Grade II and III esophageal burns were found in 10/14 patients, and they were treated with H2‐blockers, antibiotics, corticosteroids, and nutritional support (parenteral in 8/10). Patients with grade II or III esophageal burns necessitated prolonged hospitalization (x ± standard deviation, 23 ± 3 days; range, 21–30 days). Complications included esophageal strictures (n = 1), treated successfully with dilatations, and bleeding (n = 1) treated conservatively. During the 8‐ to 10‐year follow‐up all patients were recorded being well. Based on the study findings it is concluded that conservative management of children with caustic substance ingestion using a standard protocol, including endoscopy as indicated, is feasible within the pediatric department, and conservative treatment on demand is safe and effective in preventing short‐term and long‐term complications.