Falsely lowered glycated hemoglobin levels in a patient with hemochromatosis and type 2
diabetes mellitus
Beverly Mielke Kocarnik MD, MPH1*, Dawn DeWitt MD, MSc2, Irl B. Hirsch MD3
1Department
of Internal Medicine, Residency Training Program, University of Washington
School of Medicine, Box 356421, 1959 NE Pacific St, Seattle, WA, 98195, 2Rural Health
Academic Centre, Melbourne Medical School, The University of Melbourne, 49 Graham Street,
Shepparton VIC 3632, Australia, 3Division of Metabolism, Endocrinology, & Metabolism,
University of Washington School of Medicine, 4225 Roosevelt Ave NE, Suite 101, Seattle, WA,
98105,
Running title: Glycated hemoglobin and hemochromatosis
Email: Beverly Mielke Kocarnik bmielke@u.washington.edu; Dawn DeWitt
ddewitt@unimelb.edu.au; Irl B. Hirsch ihirsch@u.washington.edu
*Corresponding author: Beverly Mielke Kocarnik MD, MPH
Department of Internal Medicine
Residency Training Program
University of Washington School of Medicine
Box 356421
1959 NE Pacific Street
Seattle, WA 98195
Email: bmielke@uw.edu
Phone: 971-404-7060
Fax: 206-685-8652
Abstract word count: 187
Article text word count: 1166
Number of tables and figures: 2
Keywords: hemochromatosis, glycated hemoglobin, diabetes mellitus
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Abstract
Diabetes occurs in approximately 50% of patients with hereditary hemochromatosis.
Glycated hemoglobin (A1C) measurements are inaccurate in these patients since they undergo
intermittent phlebotomy with secondarily induced red cell production. Most primary care
physicians will care for at least one patient with these concomitant diseases, and this case
demonstrates the difficulty of interpreting A1C values in this population. A 59 year old
Caucasian male with a history of type 2 diabetes and hereditary hemochromatosis was referred
for evaluation of discordant fasting blood glucose and A1C levels. His A1C level decreased from
7.4% to 6.1% during a 2 month period while fasting home blood glucose levels were stable at 712 mmol/liter. Minimal changes had been made to his medications, and he had made no
significant lifestyle changes to account for this decrease. He received phlebotomy twice during
this interval. Since most primary care physicians will care for several patients with hereditary
hemochromatosis and diabetes mellitus, we hope to increase awareness about the challenges
of A1C interpretation in this patient population. A1C is unreliable in patients with
hemachromatosis and should not be used for diagnosis, monitoring, and treatment decisions.
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Introduction
Hereditary hemochromatosis is an autosomal recessive disorder that affects between 1
in 200 and 1 in 500 Caucasians.1 Half of these patients will have either type 1 or type 2
diabetes.2 Therefore, an average primary care panel with 1,500 patients will include
approximately 4 patients with both hereditary hemochromatosis and diabetes.
In this report, we discuss a patient with concurrent hereditary hemochromatosis and
diabetes whose glycated hemoglobin levels (A1C) appeared to be inaccurate relative to his
home capillary blood glucose readings and fasting blood glucose values. Since the vast majority
of primary care physicians will have several patients with these concurrent diseases, it is
important to understand the optimal management and diabetes monitoring for such patients,
especially in light of the American Diabetes Association recommendation that A1C can be used
for diagnosis of diabetes.3
Case Presentation
A 59 year old Caucasian male with hemochromatosis and diabetes was referred for
discordant fasting blood glucose and glycated hemoglobin levels (A1C). He was diagnosed with
diabetes fifteen years previously and had been treated with oral agents for several years. His
A1C remained below 7% until 6 months prior to consultation. At the time of referral, he was
taking metformin 1500 mg daily and glimepiride 2 mg every morning. Additional medications
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were hydrochlorothiazide/irbesartan 12.5 mg/300 mg daily, aspirin 100 mg daily, and sildenafil
50 mg as needed. The patient’s physical examination showed truncal obesity with a BMI of 38,
but was otherwise unremarkable without hyperpigmentation.
When the patient’s A1C rose above 7%, he began recording his home blood glucose
readings. Morning fasting glucose values ranged from 7.0 mmol/L to 12.0 mmol/L, with an
average of 8.7 mmol/L over 105 morning readings during the prior 6 month. Three fasting
plasma glucose levels during this time period were significantly elevated (9.4 to 10.6 mmol/L).
However, his A1C levels over that time period were 6.8%, 7.0%, 7.4%, and 6.1% in chronological
order. Table 1 shows a time-correlation of patient results and treatment.
The most pronounced change in his A1C levels was the decrease from 7.4% to 6.1%.
Despite this decrease in A1C, there had been no change in his home blood glucose reading
measurements. The readings corresponding to the 3-month period before the A1C value of
7.4% showed a mean glucose of 8.74 mmol/L with a standard deviation of 0.98 mmol/L, and
readings corresponding to the 3-month period before the A1C value of 6.1% had a mean of 8.77
mmol/L (SD 0.88). His medication regimen was changed from glimepiride 2 mg every morning
to gliclazide 60 mg daily 26 days prior to the lower A1C value (6.1%). This change was effectively
equivalent to a lower dose of sulfonylurea.4 The only other recent change in his medication
regimen was the initiation of amlodipine 5 mg daily for hypertension.
The patient’s hemochromatosis was diagnosed approximately 11 years prior on
laboratory testing for the evaluation of arthropathy, which had since resolved. Liver function
tests were normal on three occasions in the past year. His diabetes may be due to obesity or
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hemochromatosis. He typically undergoes phlebotomy every 3 to 4 months, although had
closely spaced phlebotomy in December 2010 and January 2011 and has not required
phlebotomy since then.
Other laboratory studies revealed a C-peptide in the low normal range at 0.6 nmol/L
(normal 0.3-2.3 nmol/L). Fructosamine was 349 umol/L (normal 205-285 umol/L) when his A1C
was 7.4%. Concurrent thyroid stimulating hormone and fasting lipids were within normal limits
except for an elevated triglyceride level of 1.9 mmol/L (normal <1.5 mmol/L).
Discussion
This patient’s A1C does not appear to accurately reflect the average blood glucose levels
for this patient as evidenced by the drop in his A1C from 7.4% to 6.1% over a 2 month time
period. The only changes during this period were a switch in his sulfonylurea regimen and
phlebotomy 26 days prior to the lower A1C. One milligram of glimepiride is equivalent to 80 mg
of gliclazide, so his dosage of sulfonylurea was relatively lower with the change and does not
explain the decrease in his A1C4. Therefore, his phlebotomy with subsequent red cell
production is the most likely explanation for the “improved A1C”, given the nearly identical
home glucose monitoring values with different A1C readings. See table 2 for the correlation of
A1C and average blood glucose. The discrepancy between his A1C and fructosamine in the
context of his home blood glucose tests is also consistent with a falsely low A1C.
5
The most likely explanation for the lower values of A1C after phlebotomy is the
subsequent induction of increased red blood cell production. These new cells have less time
available for glycation, so the A1C appears falsely low.5,6 Conditions resulting in a shorter
lifetime of an average red blood cell have been shown to decrease A1C, although
hemochromatosis is often omitted.7 Additionally, red blood cell production in patients with
hemochromatosis, as measured by reticulocyte count prior to phlebotomy, is highly
inconsistent and probably contributes to false A1c readings.8
We hope this case will alert health care professionals to the inaccuracies of A1C among
patients with hemochromatosis who are undergoing regular phlebotomy. Iron-deficiency
anemia with hypoproliferation of red cells results in a higher than expected A1C but
hemochromatosis, especially with phlebotomy (and increased reticulocytes) should cause a
falsely low A1c in most patients. Increasing frequency of phlebotomy should theoretically lead
to increasingly inaccurate A1C results. Practitioners should keep this in mind when evaluating
and optimizing glycemic control in patients with hemochromatosis. Importantly, as physicians
move to the new recommendations for using A1C for diagnosis, we recommend that standard
glucose diagnostic measures (fasting, random or glucose tolerance test) be used in patients
with hemochromatosis, who would be under-diagnosed using A1C. Finally, this patient’s A1C
appears to be approximately 0.5% lower (at least) than expected from home blood glucose
monitoring. If a decrease of A1C by 1% lowers complications by 30% then this patient’s A1C
treatment goal should be 6-6.5% rather than the standard <7% when receiving phlebotomy.9
This goal is validated by the patient having virtually no hypoglycemia with an A1C at 6.1%.
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Conclusion
Inappropriately low A1C values in patients with hereditary hemochromatosis and type 2
diabetes mellitus should be expected when patients are undergoing regular phlebotomy since
the younger population of red blood cells has less time to be glycated. In addition,
hemochromatosis itself may result in false A1c levels, but further research is required. Since
most primary care physicians will care for several patients with concurrent diabetes mellitus
and hemochromatosis, awareness of the inaccuracies of measurement among this patient
population is important. A1c should not be used for diagnosis, monitoring, or treatment. Home
blood glucose monitoring should be the major method used to assess glycemia. In the future,
other tests such as fructosamine, glycated albumin and 1,5-anhydroglucitol may be useful as
other measures of glucose control, but further validation is required. We hope this case report
leads to greater awareness of the inaccuracy of A1c testing among patients with
hemochromatosis and promotes further research about the optimal care of this population.
Acknowledgments and Conflicts of Interest
We would like to thank the patient discussed in this case report for granting permission to
present his case.
Beverly Mielke Kocarnik and Dawn DeWitt report that they have no conflicts of interest to
disclose. Irl Hirsch has received research support from Novo Nordisk, Halozyme, SanofiDiabertes. He is a consultant for Johnson & Johnson, Roche, Abbott Diabetes Care, and
Cellnovo.
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References
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glucose metabolism in patients with hereditary hemochromatosis. Metabolism Clinical and
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2. Capell P: Case study: Hemochromatosis in type 2 diabetes. Clinical Diabetes 2004, 22:101102.
3. American Diabetes Association. Standards of medical care in diabetes- 2011. Diabetes Care
2011,34:S11-S61.
4. Robkamp R, Wernicke-Panten K, Drager E: Clinical profile of the novel sulfonylurea
glimepiride. Diabetes Res Clin Pract 1996, 31(Suppl):s33-s42.
5. Eschwege E, Saddi R, Wacjman H, Levy R, Thibult N, Duchateau A: Haemoglobin A1c in
patients on venesection therapy for haemochromatosis (author’s transl). Diabete Metab
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6. Saddi R, Wajcman H, Eschwege E, Levy R, Duchateau A: Glycated haemoglobin in patient on
venesection therapy for haemochromatosis. Lancet 1980, 316:141-2.
7. Gallagher EJ, Le Roith D, Bloomgarden Z: Review of hemoglobin A1c in the management of
diabetes. Journal of Diabetes 2009;1:9-17.
8. Sargent T, Saito H, and Winchell HS: Iron absorption in hemochromatosis before and after
phlebotomy therapy. Journal of Nuclear Medicine 1972;12:660-7.
9. UK Prospective Diabetes Study (UKPDS) group. Intensive blood glucose control with
sulphonylureas or insulin compared with conventional treatment and risk of complications in
patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
10. Nathan DM, Kuenen J, Borg R, Sheng H, et al. Translating the A1C assay into estimated
average glucose values. Diabetes Care, 2008;31.8:1473(6).
11. American Diabetes Association. DiabetesPro Glucose Calculator. Available at:
http://professional.diabetes.org/GlucoseCalculator.aspx. Accessed December 13, 2011.
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Tables
Table 1. Comparative measures of the patient’s diabetes status.
Clinic visits
A1C 46%
Glucose readings
HBG or FBG1
(mmol/L)
Fructosamine
(Normal = 205285 umol/L)
Comments
July 2010
(referral
information)
7.0%
FBG 8-10
Hb 158 = Hct 47; ferritin = 114
Phlebotomy Aug 10, 2010
Nov 25 2010
7.4%
HBG Average 8.74 349 (Dec 3
+ 0.98 (SD)
2010)
Sulfonylurea switched (dose
equivalent actually lower); cpeptide 0.6 nmol/L (0.3-3.20);
BMI 38
Phlebotomy Dec 15, 2010
Jan 20 2011
Jan 31 2011
Insulin glargine initiated at 10
units (bedtime) with selftitration to fasting goal < 6
mmol/L FBG
6.1%
HBG Average
8.77± 0.88 (SD)
Phlebotomy Jan 5, 2011
April 15 2011 6.4%
July 17 2011
1HBG
6.1%
Phlebotomy 3 months prior;
Hb 156 = Hct 45; BMI 36.
Insulin glargine dose 22 units
nightly.
HBG Average 7.4
= 30 day meter
average
(25% fasting)
287
Ferritin 100; iron 27.7; Hb
155=Hct 45; MCV 90; BMI 35.6
= home blood glucose; FBG = fasting (capillary) blood glucose
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Table 2. Correlation of A1C with glucose.10,11 Mean A1C in adults without diabetes is ~5%
(average blood glucose = 4 mmol/L).
A1C
Average blood glucose*
5%
5.4 mmol/L
97 mg/dL
6%
7.0 mmol/L
126 mg/dL
7%
8.6 mmol/L
154 mg/dL
8%
10.2 mmol/L
183 mg/dL
9%
11.8 mmol/L
212 mg/dL
10%
13.4 mmol/L
240 mg/dL
*Estimated Average blood glucose: mmol/L ABG = 2 x A1C – 6 mmol/L
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