Cases with Hb Toranomon show abnormal HbA1c levels measured by upgraded high-performance liquid chromatography models

Abstract

Aims Hb Toranomon [b112 (G14) Cys ? Try] was the variant hemoglobin first reported by Harano et al. (Hemoglobin 20:361-369, 1996). Since 2004 there have been successive reports of Hb Toranomon based on abnormal HbA1c levels measured by high-performance liquid chromatography (HPLC). HbA1c levels are known to vary depending on the HPLC model used. We compared the HbA1c measured by new and old HPLC models in patients with Hb Toranomon. Method Eight patients with Hb Toranomon (5 men, 3 women; 4 with diabetes and 4 without diabetes; 7 heterozygotes, 1 homozygote) were studied. HbA1c levels measured using the old HPLC models (Arkray HA-8150 and Tosoh GHb III) and the new HPLC models (Arkray HA-8160 or later, Tosoh GHbV or later) were compared with the results of immunoassay, enzymatic assay, affinity assay of HbA1c, and glycated albumin (GA). Results HbA1c levels measured by the old and new Arkray models were 10 and 30% lower, respectively, and those measured by the new Tosoh models were 30% higher than the results of immunoassay. The same trends were found in comparisons with the HbA1c results of enzymatic and affinity assays or GA. Conclusion Glycated variant hemoglobins, such as Hb Toranomon, may have previously been measured as HbA1c and are difficult to identify because of the low divergence from other glycemic control indicators in the old HPLC models. The recent detection of successive Hb Toranomon patients is likely due to the abnormally low or high HbA1c levels by the upgraded measuring models.

A Rare Case of Variant Hemoglobin (Hb Yahata) Suspected Based on Inconsistent Plasma Glucose and HbA1c Levels

“…To date, three Hb variants with amino acid substitutions at the 112th position of the β chain have been reported: Hb Yahata, Hb Toranomon and Hb Indianapolis (11)(12)(13)(14)(15)(16)(17). In this case, Hb Yahata [β112 TGT (Cys) TAT (Tyr)] (heterozygote) was diagnosed.…”

“…In our patient, the isopropanol precipitation test was positive; however, he did not appear anemic. Hb Toranomon has also been reported to be a silent hemoglobinopathy, with abnormal HbA1c values obtained using glycol-HPLC methods (12)(13)(14). Patients heterozygous for Hb Indianapolis [β 112 (G14) Cys Arg] reportedly have a very unstable variant with a phenotype similar to that of severe β-thalassemia (15).…”

“…The amino acid at the 112th position of the β chain is an internal residue in the G helix that forms the central cavity and participates in the contact of α1β1 with Hb molecules. Therefore, the substitution of hydrophobic cysteine by another amino acid, such as arginine, tyrosine or tryptophan, likely results in inadequate adaptation and some degree of hemoglobin instability (10)(11)(12)(13)(14)(15)(16)(17).…”

Committee on Diabetes Mellitus Indices of the Japan Society of Clinical Chemistry-recommended reference measurement procedure and reference materials for glycated albumin determination

“…1 GA is also a useful alternative glycaemic marker in patients with anaemia and variant haemoglobin, whose HbA1c values are inaccurate due to the altered lifespan of red blood cells. 2,3 HbA1c also reflects lower values in haemodialysis patients because of the increase in immature erythrocytes associated with erythropoiesis stimulating agent treatment. 4 The Japan Society for Dialysis Therapy published a guide entitled 'Guide: Best Practice for Diabetic Patients on Hemodialysis 2012' 5 and recommended glycaemic control levels of no more than 9.99-11.1 mmol/L as a predialysis casual plasma glucose concentration and 20% as a GA value (24% for patients with a history of cardiovascular events and hypoglycaemic episodes).…”