|Year : 2013 | Volume
| Issue : 2 | Page : 88-93
The continuous glucose monitoring system (CGMS) in patients with beta-thalassemia major
Waleed I Albaker1, Abdullah A Yousef2, Ammar H Khamis3, Abdulmohsin F Aldilaijan1, Nouf K AlMaghlouth1
1 Department of Internal Medicine (Endocrinology Division), University of Dammam, Saudi Arabia
2 Department of Pediatrics, University of Dammam, Saudi Arabia
3 Department of Biostatistics, University of Dammam, Saudi Arabia
|Date of Web Publication||25-Dec-2013|
Waleed I Albaker
Department of Internal Medicine, King Fahad Hospital of the University, University of Dammam, P. O. Box 4166, Dammam 31442
Background: Blood transfusion-dependent beta Thalassemia Major (BTM) patients are at risk of hemosiderosis. Hemosiderosis of pancreas results in impaired glucose homeostasis tolerance and diabetes mellitus (DM).
Since glycosylated hemoglobin has limited role in patients with hemoglobinopathies, this study was conducted as a first attempt worldwide to understand glucose homeostasis and evaluate efficacy of Continuous Glucose Monitoring (CGM) system as a diagnostic tool of abnormal glucose homeostasis in these patients.
Materials and Methods: A case series study of six non-diabetic, transfusion-dependent beta-thalassemia patients aged 9-13-year-old. Clinical and laboratory data were collected on admission for their monthly transfusion. Patients were connected to CGM systems for one day.
Findings: Using CGM and based on American Diabetes Association guidelines, three patients were found to have abnormal glucose levels of diabetic range. The other three showed impaired glucose tolerance. Among all patients, glycosylated hemoglobin (HbA1C) readings have an inverse relationship to CGM and calibration readings.
Conclusion: CGM could be a promising tool for evaluating BTM patients. Larger studies are recommended.
هذه دراسة سلسلة من الحالات لمرضى بيتا تلاسيميا الكبرى معتمدين على نقل الدم وغير مصابين بالسكري. جميع المرضى اظهروا علاقة عكسية بين متوسط الهيموجلوبين التراكمي وقراءات مراقبة الجلوكوز المستمرة. أظهرت الدراسة أن مراقبة الجلوكوز المستمرة قد تكون أداة واعدة لتقييم مرضى بيتا تلاسيميا الكبرى. يوصي الباحثون بإجراء دراسات موسعة في هذا الشأن.
Keywords: Continuous glucose, glycosylated, hemoglobin, monitoring, Thalassemia
|How to cite this article:|
Albaker WI, Yousef AA, Khamis AH, Aldilaijan AF, AlMaghlouth NK. The continuous glucose monitoring system (CGMS) in patients with beta-thalassemia major. Saudi J Med Med Sci 2013;1:88-93
|How to cite this URL:|
Albaker WI, Yousef AA, Khamis AH, Aldilaijan AF, AlMaghlouth NK. The continuous glucose monitoring system (CGMS) in patients with beta-thalassemia major. Saudi J Med Med Sci [serial online] 2013 [cited 2019 Apr 26];1:88-93. Available from: http://www.sjmms.net/text.asp?2013/1/2/88/123654
| Introduction|| |
Beta thalassemia is a serious form of hereditary anemia caused by defects in hemoglobin production  affecting multiple organs and associated with considerable morbidity and mortality.  The disease was described first by Cooley and Lee, in which the manifestations of the disease will start within the first year of life, upon the presentation of anemia, hepatosplenomegaly, jaundice, growth retardation and bone changes.  Transfusion and iron-chelating therapy for patients with beta-thalassemia showed improvement and prolongation of the quality of life in this disease, mainly due to reduction in mortality from heart failure. ,, Iron deposit in visceral organs (mainly heart, liver, and endocrine glands) causes tissue damage and ultimately organ dysfunction and failure.  Patients with beta-thalassemia major have a higher incidence of multi-endocrine dysfunction as reported in children, adolescents and young adults. ,, One of the main endocrine dysfunctions is the glucose intolerance and overt diabetes, as a consequence of iron deposition in pancreas.  The glucose homeostasis in transfusion-dependent patients is greatly affected by the high level of serum ferritin and the presence of hepatitis C infection that has diabetogenic effect. ,, Hepatitis C virus has a synergistic effect with the iron-induced hepatic damage, together leading to hepatic dysfunction, which is influenced by the development of insulin resistance. ,,,
The mechanism of abnormal glucose homeostasis in beta-thalassemia is still undetermined, but the attribution of toxic effects of iron on the pancreas and the insulin resistance has been demonstrated. ,, About 2.3-24% of those patients have an impaired glucose metabolism, depending on the age of patient, duration of blood transfusion, types of chelating therapy, level of iron stores and dose of iron-chelating therapy. ,, Good clinical and public health outcomes can be observed in those patients with identified risk factors, to be targeted for better screening and preventive measures.  The use of the new guideline of the American Diabetes Association (ADA) for diagnosing an abnormal glucose tolerance in thalassemic patients has been considered unreliable method,  due to the questionable accuracy of HbA1c in patients with homozygous hemoglobinopathies, giving higher or lower levels secondary to short erythrocytic life span compared to normal variants. , Some studies have recommended the use of fructosamine for better control measures, but in the other hand, its uses have been limited as it reflects 3-week period of glycemic control rather than 3-month period by other means. , Nowadays, a new method is introduced in the market, the continuous glucose monitoring system (CGM), which enables more diagnostic accuracy and a better achievement of an optimal glycemic control with the privilege of having 288 glucose readings in 24 hours. ,
In Saudi Arabia, beta thalassemia is considered one of the common hereditary diseases with serious mortality and morbidity rates among the population, affecting mainly adolescents and young adults.  This study aims at measuring the glucose homeostasis in non-diabetic beta-thalassemia major patients for better evaluation and to correlate the findings with different variables such as serum ferritin, hepatitis C, HbA1c, fructosamine, C peptide level and family history of diabetes mellitus.
| Materials and Methods|| |
Transfusion-dependent patients with beta-thalassemia major were recruited between December 2010 and December 2011 from both adult and pediatric hematology clinics, since CGM wasn't available before that period in our institution. This is a case series study of beta-thalassemia major patients, with the exclusion of those who already have been diagnosed with diabetes mellitus, those who underwent bone marrow transplantation or those having advanced co-morbidities (e.g. chronic renal failure) or diagnosed to have sickle beta-thalassemia. Twenty nine patients were recruited to the study. As we had very strict exclusion criteria, the following were excluded (6 patients with sickle/β-thalassemia, 4 patients with Type 2 diabetes, 6 patients with end-organ damage by hemosiderosis). Seven patients refused to participate in the study.
There were six patients who met the inclusion criteria and consented to participate, two females and four males. All patients were interviewed upon admission. A well-structured data collection form containing clinical variables, including risk factors of diabetes mellitus, was used to collect data for each patient. Medical histories were obtained from hospital's medical records. Age, sex, age at first blood transfusion, frequency, use of chelating therapy, mean serum ferritin level within one year, HbA1c, fructosamine, C peptide level, existence of hepatitis C antibody and risk factors of DM were all collected.
Following admission, each participant was connected to CGM system through insertion of a glucose oxidase-based sensor in the subcutaneous area of the abdomen. The system was recording over 24 hours continuously. All candidates were instructed to follow the hospital regular diet schedule (lunch at 12 pm, dinner at 8 pm and breakfast at 7 am, and no meals allowed in between). Calibration of the sensor with the Glucometer was done after 2 hours, 8 hours and 12 hours, respectively, to assure accuracy and avoid result by chance. Sensor was removed after the completion of 24 hours. By using Medtronic Diabetes, CareLink software, the recorded data were obtained and downloaded. Both fasting blood glucose level and highest random reading were estimated by the individual with 24-hour graph of each participant. Identifying fasting blood glucose as no caloric intake over 8 hours was recorded using the graphs at 7 am.
Data were interpreted using the Clinical Practice Recommendations by American Diabetes Association, diabetic care, (2012) and World Health Organization Criteria, three categories of Glucose tolerance as shown in [Table 1]. Iron overload was assessed two to seven times over one year.
|Table 1: Categories of glucose tolerance according to ADA and WHO recommendations|
Click here to view
This study was approved by the Institutional Research and Ethical Committee of College of Medicine, University of Dammam, Saudi Arabia.
| Results|| |
All patients have successfully completed the study, with the use of CGM system over at least 22:30 hours. Under close observation there was no evidence of inflammation or infection at the site of the insertion and the system was well tolerated by all candidates. The results are shown in [Table 2] & [Table 3] and [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6].
Family history of DM was the only risk factor identified in three patients (Patient nos. 2-4-6). Viral serology of both hepatitis B and C was negative in all subjects; except HBs, antibodies was positive in only one patient (No. 2).
Regarding the highest record of random blood glucose level during the day, one patient showed the lowest level among others and it was a normal reading of 122 mg/dL (No. 1). Patient numbers 2 to 4 showed impaired glucose levels of 148, 150, 155 mg/dL, respectively. Two patients (Nos. 5 and 6) showed abnormal glucose readings of diabetic range, 202 and 235 mg/dL, respectively.
In contrast, HbA1c readings had an inverse relationship to CGM and calibration readings. Three patients (Nos. 1 to 3)
were considered to have abnormal HbA1C readings of diabetic range: 7.2%, 6.7% and 6.5%, respectively. The other three patients (Nos. 4-6) were found to have an impaired glucose tolerance of 6.4%, 6.1% and 6.4%, respectively.
Two of the six patients included in the study (Nos. 1 and 2) were found to have an impaired fasting glucose of 110 mg/dL. Two other patients (Nos. 3 and 6) were found to have abnormal levels of 138 and 128 mg/dL, respectively.
Fructosamine was high in all patients except in the first patient (256 mg/dL). Mean serum ferritin level ranged between 2111 and 5859 ng/ml.
It was found that the earlier the first transfusion, the higher is the HbA1c readings. The study showed a direct relationship between the time of the first transfusion and the CGM results. In patient number 1 to 3, the time of first blood transfusion were 2, 4, and 2-month-old, respectively, which coincide with the lowest CGM readings. Iron-chelating therapy was started in all except in patient number 4 and good compliance to the therapy was reported in patient numbers 2 and 6 only. However, patient number 4, who was not started on iron-chelating therapy, had the highest C-peptide level of 8.74 ng/ml, and a low mean serum ferritin level in comparison to others.
| Discussion|| |
The use of CGM records was helpful to detect three patients with abnormal glucose homeostasis of diabetic range. Patient number 6 had abnormal fasting and random readings throughout the day, number 5 had abnormal random reading and number 3 had abnormal fasting and impaired random level. The other three patients showed impaired random or fasting glucose levels. No patient had normal random or fasting blood glucose levels.
It was noticed that all patients had high levels of serum ferritin, but no relationship was found with CGM readings.
Either separately or together, family history of diabetes mellitus and compliance to iron-chelating therapy are important factors of abnormal glucose homeostasis in these patients.
All patients were followed up in outpatient clinics for management of abnormal glucose levels.
Until now, little is known about the efficacy of CGM as a useful measure for detecting the variability of glucose fluctuations in 24 hours and for assessment of glucose homeostasis in transfusion-dependent beta thalassemia patients, especially due to the lack of clear guidelines.
The use of CGM system in transfusion-dependent beta-thalassemic patients was conducted worldwide by two studies. A case report in Oman studied the use of CGM as a follow-up tool in a thalassemic patient with abnormal glucose homeostasis,  and in another descriptive study conducted in Italy, thalassemia and impaired blood glucose was observed in six patients using CGM.  Both studies suggested that CGM is a useful method to detect glucose levels in these patients, and were concluded by changing management of patients and suggested larger studies.
To the best of our knowledge, this attempt to study glucose homeostasis in non-diabetic patients with beta thalassemia major using continuous glucose monitoring is perhaps the first study of its kind.
The study planned to identify the relationship between the hepatitis B and C infections and the abnormal glucose tolerance, but unfortunately, none of the included patients was exposed. Only one patient was vaccinated against Hepatitis B. Liver enzymes were elevated in all patients. The limitation that we faced in this study was the limited number of patients included and that was because of the high cost of the CGM since it is new modality and the rigorous inclusion criteria in the study.
| Conclusion|| |
The study suggests that CGM might be a promising tool for evaluating glucose homeostasis in patients with beta-thalassemia major, compared to HbA1c.
This preliminary study needs to be followed by a larger group to make the results more representative and reliable.
| References|| |
|1.||Rund D, Rachmilewitz E. Beta-thalassemia medical progress. N Engl J Med 2005;353:1135-46. |
|2.||Cunningham MJ, Macklin EA, Neufeld EJ, Cohen AR. Thalassemia Clinical Research Network. Complications of β-Thalassemia major in North America. Blood 2004;104:34-9. |
|3.||Cooley TB, Lee P. A series of cases of splenomegaly in children with anemia and peculiar changes. Trans Am Pediatr Soc 1925;37:29-30. |
|4.||Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Survival and causes of death in Thalassemia major. Lancet 1989;2:27-30. |
|5.||Borgna-Pignatti C, Rugolotto S, De Stefano P, Piga A, Di Gregorio F, Gamberini MR, et al. Survival and disease complications in thalassemia major. Ann N Y Acad Sci 1998;850:27-231. |
|6.||Malik S, Syed S, Ahmed N. Complications in transfusion-dependent patients of β-thalassemia major: A review. Pak J Med Sci 2009;25:678-82. |
|7.||Italian Working Group on Endocrine Complications in Non-Endocrine Diseases. Multicenter study on prevalence of endocrine complication in Thalassemia Major. Clin Endocrinal 1995;42:581-6. |
|8.||Vullo C, De Sanctis V, Katz M, Wonke B, Hoffbrand AV, Bagni B, et al. Endocrine abnormalities in thalassemia. L Ann NY Acad Sci 1990;612:293-310. |
|9.||Chern JP, Lin KH, Lu MY, Lin DT, Lin KS, Chen JD, et al. Abnormal glucose tolerance in transfusion-dependent beta-thalassemic patients. Diabetic Care 2001;24:850-4. |
|10.||Labropoulou-Karatza C, Goritsas C, Fragopanagou H, Repandi M, Matsouka P, Alexandrides T. High prevalence of diabetes mellitus among adult b-thalassemic patients with chronic hepatitis C. Eur J Gastroenteol Hepatol 1999;11:1033-6. |
|11.||Suda K. Hemosiderin deposition in the pancreas. Arch Pathol Lab Med 1985;109:996-9. |
|12.||Ladis V, Theodorides C, Palamidou F, Frissiras S, Berdousi H, Kattamis C. Glucose disturbances and regulation with glibenclamide in thalassemia. J Pediatr Endocrinol Metab 1998;11(Suppl. 3):871-8. |
|13.||Merkel PA, Simonson DC, Amiel SA, Plewe G, Sherwin RS, Pearson HA, et al. Insulin resistance and hyperinsulinemia in patients with Thalassemia major treated by hypertransfusion. N Engl J Med 1988;318:809-14. |
|14.||Ko TM, Xu X. Molecular study and prenatal diagnosis of a- and b-thalassemia in Chinese. J Formos Med Assoc 1998;97:5-15. |
|15.||Dmochowski K, Finegood DT, Francombe W, Tyler B, Zinman B. Factors determining glucose tolerance in patients with thalassemia major. J Clin Endocrinol Metab 1993;77:478-83. |
|16.||Eshed I, Elis A, Lishner M. Plasma ferritin and type 2 diabetes mellitus: A critical review. Endocr Res 2001;27:91-7. |
|17.||Fernandez-Real JM, Lopez-Bermejo A, Ricart W. Cross-talk between iron metabolism and diabetes. Diabetes 2002;51:2348-54. |
|18.||Wilson JG, Lindquist JH, Grambow SC, Crook ED, Maher JF. Potential role of increased iron stores in diabetes. Am J Med Sci 2003;325:332-9. |
|19.||Lukens JN. The thalassemia and related disorders. In: Jonathan W, Pine Jr, editors. Wintrobe's clinical hematology. 10 th ed. USA: Williams and Wilkins; 1999. p. 1405-49. |
|20.||Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxaamine. Haematologica 2004;89:1187-93. |
|21.||Arrigo T, Crisafulli G, Meo A, Sturiale M, Lombardo F, Miceli M, et al. Glucose tolerance, insulin secretion and peripheral sensitivity in thalassemia major. J Pediatr Endocrinol Metab 1998;11:863-6. |
|22.||Jehn ML, Guallar E, Clark JM, Couper D, Duncan BB, Ballantyne CM, et al. A Prospective Study of Plasma Ferritin Level and Incident Diabetes. Am J Epidemiol 2007;165:1047-54. |
|23.||Kosecki SM, Rodgers PT, Adams MB. Glycemic monitoring in diabetics with sickle cell plus betathalassemiahemoglobinopathy. Ann Pharmacother 2005;39:1557-60. |
|24.||Al-Fadhli SM, Ahmad AA, Al-Jafar HA. Effect of sickle cell trait and β-thalassemia minor on determinations of HbA1c by an immunoassay method. Saudi Med J 2001;22:686-9. |
|25.||Chen HS, Chen RL, Chang ZY, Li HD. A comparison of fructosamine and HbA1c for home selfmonitoring blood glucose levels in type 2 diabetes. Zhonghua Yi XueZaZhi (Taipei) 2002;65:151-5. |
|26.||Edelman SV, Bell JM, Serrano RB, Kelemen D. Home testing of fructosamine improves Glycemic control in patients with diabetes. Endocr Pract 2001;7:454-8. |
|27.||Al-Futaisi A, Wali Y, El-Beshlawi I, Al-Riyami S, Almahrezi A. Case study: Using A Continuous Glucose Monitoring System In A Patient With Diabetes and Beta-Thalassemia Hemoglobinopathy. Pediatr Hematol Oncol 2009;26:515-9. |
|28.||Rimondi F, Banin P, Gamberini MR, De Sanctis V. The Continuous Glucose Monitoring System (CGMS) in Patients with beta- Thalassemia Major and Impaired Glucose Hemostasis: Preliminary Results. Pediatr Endocrinol Rev 2008;6:190-2. |
|29.||Al-Awamy B. Thalassemia syndrome in Saudi Arabia, Meta-analysis on the local studies Saudi Med J 2000;21:8-17. |
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
[Table 1], [Table 2], [Table 3]
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