In 2010, a 57-year-old female patient presented with mild polydipsia, polyuria, blurred vision, and weight loss. Diabetes mellitus was diagnosed by oral glucose tolerance test results (OGTT, determination of glucose and insulin at 0 and 120 min). The HbA1c level at that time was 3.6% and glycated albumin (GA) was 16.3% (normal range: 10.8-17.1%). Type 1 diabetes-associated antibodies such as Islet Cell Antibodies (ICA), Glutamic Acid Decarboxylase antibodies (GAD), Insulin Autoantibodies (IAA), and insulinoma-antigen 2 (IA2A) were all negative. Total bilirubin (TBil) was 38.7 umol/L (normal range: 5.1-22.2) and direct bilirubin (DBil) was 11.6 umol/L (normal range: 0-6.8). Other laboratory tests including serum alanine transaminase (ALT), albumin, and renal function test were all within the normal range. Upon diagnosing her with diabetes mellitus, the primary doctor prescribed nateglinide to control the hyperglycemia. In recent years, her HbA1c level were found repeatedly reduced, while the level of GA remained high. Hemoglobin (Hgb) and albumin were still in the normal range, and the bilirubin level was found slightly elevated. In terms of screening for diabetic complications, the patient had completed the fundus examination, renal ultrasound, cardiac ultrasound, lower limb artery ultrasound, 24 h urine protein, and urine albumin-to-creatinine ratio, and no abnormalities were found. However, the carotid ultrasound showed the presence of atherosclerotic plaques. Past medical history showed the patient suffered from keratoconjunctivitis sicca for 10 years and carotid atherosclerosis for 3 years. The family history showed her mother also suffered from diabetes mellitus with similarly low HbA1c level (3.4%) and slightly decreased Hgb (102 G/L). Her mother also had Sjogren syndrome and passed away at age of 70 years old without further investigation of the causes of low HbA1c. In addition, both her mother and daughter had hyperbilirubinemia. The complete blood count of the daughter showed that normal Hgb (156 G/L) and increased reticulocyte (169.9 x 109/L, normal range: 24.0-84.0 x 109/L), normal white blood cell (6.55 x 109/L) and Platelet (321 x 109/L).
After recent hospitalization in our medical center, the abnormally low HbA1c levels attracted our attention. To confirm the problem, we performed repeated HbA1c test by both ion-exchange chromatography and immunization method. However, the low HbA1c level persisted. Hemoglobin electrophoresis revealed no abnormality. After excluding laboratory error and variation of hemoglobin, we performed further laboratory examinations (Table 1): Hgb was 129 G/L, reticulocyte was 265.4 x 109/L (normal range: 24.0-84.0 x 109/L), TBil was 29 umol/L, DBil was 7.6 umol/L, and the life span of red blood cells measured by CO breath test was significantly shortened to 43 days (normal range: > 75 days). All these results above indicated the presence of hemolytic anemia. However, screening for common causes (erythrocyte osmotic fragility, 6-phosphate glucose dehydrogenase test and plasma free hemoglobin test, Ham test, Rous test, and Coombs test were all in normal range) of acquired hemolytic disease led to exclusion of autoimmune hemolysis, glucose-6-phosphate dehydrogenase deficiency, paroxysmal hemoglobinuria, and so on. Pancreatic MRI showed slightly atrophied pancreatic body, but iron deposition in the pancreas was normal (23.7 ms at T2 *). Both the patient and her daughter showed heterozygous variant in PIEZO1 gene (c.6017T > A, p.V2006D) by whole exome sequencing of the blood with confirmation of sanger sequencing (Figure 1), which is associated with dehydration hereditary stomatocytosis (DHS). After this diagnosis, nateglinide was changed to sitagliptin to reduce the burden of the pancrea islet function.