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Hemoglobin Himeji as a cause of interference in the measurement of glycated hemoglobin
Hemoglobina Himeji como causa de interferencia en la medición de la hemoglobina glicosilada
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Arriba, resultado del primer caso en 2018, interpretado como hemoglobina J (Hb J). Abajo, resultados del segundo caso interpretados en 2015 como posible hemoglobina Shephers Bush (izquierda), en 2016 como posible hemoglobina Andrew Minneapolis (centro) y en 2018 como posible hemoglobina Fannin Lubbok (derecha). En condiciones normales no existe el pico de hemoglobina J y más del 95% corresponde a hemoglobina A (Hb A). 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Above, result for the first case in 2018, interpreted as haemoglobin J (Hb J). Below, results for the second case interpreted in 2015 as possible haemoglobin Shepherds Bush (left), in 2016 as possible haemoglobin Andrew-Minneapolis (centre) and in 2018 as possible haemoglobin Fannin-Lubbok (right). Under normal conditions, there is no haemoglobin J peak and more than 95% corresponds to haemoglobin A (Hb A). Haemoglobin A2 (Hb A2) was normal in all cases.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">The term “glycosylated haemoglobin” (HbA<span class="elsevierStyleInf">1c</span>) describes haemoglobin irreversibly bound to glucose through a non-enzymatic reaction.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Its levels are measured to evaluate blood glucose control in patients with diabetes mellitus, as it reflects blood glucose in the past 120 days (corresponding to the half-life of erythrocytes).<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> It is considered a useful marker for determining the risk and progression of chronic complications related to this disease.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> Various factors that might interfere with the reliability of HbA<span class="elsevierStyleInf">1c</span> measurement have been reported,<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1,2</span></a> including different haemoglobin variants that may be responsible for falsely high or low HbA<span class="elsevierStyleInf">1c</span> levels.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">We report the cases of two related patients with discrepant levels of both plasma and capillary blood glucose and HbA<span class="elsevierStyleInf">1c</span> due to haemoglobin Himeji, a very rare, clinically silent haemoglobinopathy with approximately three times the glycosylation of haemoglobin A.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">The first case corresponds to a 39-year-old native of Portugal in follow-up for controlled HIV infection. He was on antiretroviral treatment with efavirenz, tenofovir and emtricitabine.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Routine testing revealed that the patient had high HbA<span class="elsevierStyleInf">1c</span> levels yet normal plasma and capillary blood glucose levels. Hygiene and dietary measures were put in place immediately. The patient’s elevated HbA<span class="elsevierStyleInf">1c</span> levels persisted, so treatment was started with metformin 850 mg every 12 h and the patient was referred to endocrinology. Prior laboratory tests had shown HbA<span class="elsevierStyleInf">1c</span> levels of 12% (April 2015), 11.5% (January 2016), 11.8% (June 2016) and 11.9% (April 2018) with fasting glucose levels of 89 mg/dl, 96 mg/dl, 93 mg/dl and 99 mg/dl, respectively. Due to this incongruence, a decision was made to place a flash glucose monitor. This confirmed that the patient had blood glucose levels in a normal range. His serial complete blood count and clinical chemistry, including kidney and liver function tests, were also normal.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Haemoglobin electrophoresis was performed, detecting a haemoglobin variant interpreted as haemoglobin J (haemoglobin in zone 12: 39.2%) and only 52% haemoglobin A (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">With these results, a gene sequencing study was ultimately conducted which identified the heterozygous mutation c.422C>A (p.Ala141Asp) in the human beta-globulin (<span class="elsevierStyleItalic">HBB</span>) gene, a pathological variant associated with the production of haemoglobin Himeji in clinical databases.</p><p id="par0035" class="elsevierStylePara elsevierViewall">The second case is that of a 74-year-old woman, the mother of the above patient and a native of Portugal with a history of ischaemic heart disease (having had episodes of unstable angina in 2007 and 2015), hypertension and type 2 diabetes mellitus being treated with oral antidiabetic drugs as of its diagnosis in 2005 up to 2016, when it was replaced with basal insulin (glargine). While on basal insulin, the patient had frequent evening episodes of hypoglycaemia, none of them serious. Her regular treatment included omeprazole, bisoprolol, acetylsalicylic acid, amlodipine, valsartan, hydrochlorothiazide and rosuvastatin.</p><p id="par0040" class="elsevierStylePara elsevierViewall">She was referred for diabetes management and also showed a discrepancy between her fasting glucose levels, which ranged from 120 to 160 mg/dl, and her HbA<span class="elsevierStyleInf">1c</span> determinations from recent years, which persistently exceeded 11%. Furthermore, she showed abnormalities on haemoglobin electrophoresis that were interpreted on different occasions as possible haemoglobin Shepherds Bush, Andrew-Minneapolis or Fannin-Lubbok (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Her serial complete blood count showed no abnormalities of interest.</p><p id="par0045" class="elsevierStylePara elsevierViewall">In light of these results, the discrepancy with the patient’s blood glucose test results and awareness of her son’s haemoglobinopathy, an automated genetic sequencing study was conducted in the patient and detected the same heterozygous mutation associated with the production of haemoglobin Himeji.</p><p id="par0050" class="elsevierStylePara elsevierViewall">At present, there are more than 1300 known haemoglobin variants.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Approximately 80% are asymptomatic; the remaining 20% are associated with diseases such as haemolytic anaemia, polycythaemia and methaemoglobin.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,4</span></a> Widespread determination of HbA<span class="elsevierStyleInf">1c</span> levels has led to a gradual increase in recent years in identification of clinical silent haemoglobin variants.<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3,7</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Depending on the method of detection used, the same haemoglobinopathy might cause HbA<span class="elsevierStyleInf">1c</span> results to be unexpectedly high or low compared to blood glucose determinations.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,4</span></a> Although some of these abnormalities in measurement can be detected and it is possible to take steps to correct them,<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,5</span></a> if an abnormality in haemoglobin affects its ability to be glycosylated or if factors affecting the rate of erythrocyte turnover are involved, the results will be inaccurate regardless of the detection method employed.<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">“Haemoglobin J” refers to a group of abnormal haemoglobins that all have faster electrophoretic mobility than haemoglobin A. Haemoglobin Himeji was first reported in 1986 in a Japanese male with diabetes mellitus;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> later on, cases in two Japanese families, cases in two members of a Portuguese family and another isolated case also in Portugal were reported as well.<a class="elsevierStyleCrossRefs" href="#bib0035"><span class="elsevierStyleSup">7–10</span></a> It is a variant with a higher oxygen affinity, a certain molecular instability and an increase in glycosylation of the NH<span class="elsevierStyleInf">2</span> end of the β chain,<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5,9</span></a> which would account for the falsely elevated HbA<span class="elsevierStyleInf">1c</span> results obtained in our cases.</p><p id="par0065" class="elsevierStylePara elsevierViewall">In patients who are carriers of haemoglobin Himeji, blood glucose control can be estimated more accurately using commercial methods that measure glycosylated serum proteins (fructosamine or glycosylated serum albumin).<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2,3</span></a> However, these tests only reflect mean glucose over approximately the past two weeks, and none of them has been correlated with the risk of developing chronic complications of diabetes mellitus.<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1–3</span></a> In these patients, therefore, self-monitoring of blood glucose or using a continuous glucose monitoring system is more important in evaluating the effectiveness of the treatment of the disease.</p><p id="par0070" class="elsevierStylePara elsevierViewall">As they do not show symptoms, most patients who are carriers of haemoglobin Himeji are not aware of it. It has been reported, however, that they could have higher rates of haemolysis and lower rates of erythrocyte survival. Hence, in situations of haematological stress, compensatory reticulocytosis might not be adequate and this would create a predisposition to developing anaemia more easily and of a more severe nature than under normal conditions.<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: García Urruzola F, Ares Blanco J, Bernardo Gutiérrez Á, Álvarez Álvarez S, Menéndez Torre E. Hemoglobina Himeji como causa de interferencia en la medición de la hemoglobina glicosilada. Endocrinol Diabetes Nutr. 2021;68:671–672.</p>" ] ] "multimedia" => array:1 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1109 "Ancho" => 2500 "Tamanyo" => 69932 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Haemoglobin electrophoresis. Above, result for the first case in 2018, interpreted as haemoglobin J (Hb J). Below, results for the second case interpreted in 2015 as possible haemoglobin Shepherds Bush (left), in 2016 as possible haemoglobin Andrew-Minneapolis (centre) and in 2018 as possible haemoglobin Fannin-Lubbok (right). Under normal conditions, there is no haemoglobin J peak and more than 95% corresponds to haemoglobin A (Hb A). 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 0 | 6 |
| 2024 October | 30 | 7 | 37 |
| 2024 September | 24 | 9 | 33 |
| 2024 August | 22 | 5 | 27 |
| 2024 July | 25 | 5 | 30 |
| 2024 June | 19 | 2 | 21 |
| 2024 May | 17 | 3 | 20 |
| 2024 April | 30 | 4 | 34 |
| 2024 March | 20 | 4 | 24 |
| 2024 February | 27 | 4 | 31 |
| 2024 January | 17 | 1 | 18 |
| 2023 December | 15 | 2 | 17 |
| 2023 November | 15 | 10 | 25 |
| 2023 October | 23 | 3 | 26 |
| 2023 September | 12 | 0 | 12 |
| 2023 August | 12 | 4 | 16 |
| 2023 July | 8 | 0 | 8 |
| 2023 June | 17 | 0 | 17 |
| 2023 May | 16 | 5 | 21 |
| 2023 April | 19 | 4 | 23 |
| 2023 March | 19 | 5 | 24 |
| 2023 February | 15 | 2 | 17 |
| 2023 January | 8 | 3 | 11 |
| 2022 December | 7 | 4 | 11 |
| 2022 November | 8 | 7 | 15 |
| 2022 October | 16 | 6 | 22 |
| 2022 September | 9 | 4 | 13 |
| 2022 August | 11 | 12 | 23 |
| 2022 July | 11 | 7 | 18 |
| 2022 June | 14 | 14 | 28 |
| 2022 May | 31 | 7 | 38 |
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