Is an elevated serum transferrin saturation associated with the development of diabetes?

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Original Research

Is an elevated serum transferrin saturation associated with the development of diabetes?

J Fam Pract. 2002 November;51(11):933-936

By

Arch G. Mainous III, PhD

OBJECTIVES: Diabetes mellitus is a common comorbid condition of hemochromatosis and is often identified as a complication of untreated hemochromatosis. However, there are few primary data examining the development of diabetes secondary to hemochromatosis. Our objective was to determine the likelihood of developing diabetes in a nationally representative cohort of patients who have an elevated serum transferrin saturation rate but no current diagnosis of diabetes.
STUDY DESIGN: This is a retrospective cohort study based on merging the National Health and Nutrition Examination Survey I (1971–1974; NHANES I) with the NHANES I Epidemiologic Followup Study (1992).
POPULATION: Individuals aged 25 to 74 years at the time of the NHANES I without diabetes (n = 9274).
OUTCOMES MEASURED: The outcome was development of diabetes according to patient report, proxy report, or death certificate by the time of the follow-up interview.
RESULTS: The incidence of diagnosed diabetes in the cohort was 10.2%. Among individuals with serum transferrin saturation levels above 55%, 7.5% developed diagnosed diabetes compared with 10.2% with a serum transferrin saturation of no more than 45% (P = .38). The relation remained nonsignificant in models adjusted for risk factors of diabetes and in analyses that assumed 10% of patients had received treatment for hemochromatosis.
CONCLUSIONS: In this nationally representative cohort of adults, elevated serum transferrin saturation was not significantly associated with the development of diabetes.

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References

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KEY POINTS FOR CLINICIANS

Diabetes is a common comorbid condition of hemochromatosis and is suggested to be a complication of untreated hemochromatosis.
Diabetes does not seem to be a complication of hemochromatosis.
Screening for and treatment of hemochromatosis are justified for several complications but not indicated as a way to prevent development of diabetes.

Hemochromatosis is an autosomal recessive abnormality of iron regulation that results in excessive intestinal absorption and cellular deposition of iron.¹ Although hemochromatosis was once thought to be rare, many screening studies have established that it is among the most common inherited metabolic abnormalities.^2-6 The College of American Pathologists has recommended population-based screening for hemochromatosis with the use of the serum transferrin saturation level.⁷ Although prevalent in the population, hemochromatosis is rarely diagnosed.⁸ The pathologic iron accumulation resulting in hemochromatosis affects many organs including the liver, pancreas, and heart.^9-12 Because primary hemochromatosis is a common comorbid condition with diabetes,^13-15 most work on the relation between hemochromatosis and diabetes has focused on screening patients with diabetes for hemochromatosis.^16,17

Clinical reviews have stated that, because diabetes is a serious complication of hemochromatosis, screening patients without diabetes for hemochromatosis might be a useful strategy to decrease the likelihood that they will develop diabetes.^15,18-20 However, there are few primary data to support this contention. There is some evidence to indicate that hemochromatosis has the pathogenic features of impaired insulin secretion and insulin resistance due to iron accumulation in the liver.²¹ One study indicated that, in individuals with hemochromatosis but neither cirrhosis nor diabetes (n = 7), phlebotomy treatment normalizes serum ferritin levels, acute insulin response to glucose, and glucose tolerance.²² In patients with hemochromatosis and newly diagnosed diabetes, phlebotomy did not affect glucose tolerance or insulin resistance. In a nationally representative cohort, we examined the likelihood that patients with an elevated serum transferrin saturation rate but no current diagnosis of diabetes would develop diabetes during 20 years of follow-up.

Methods

This retrospective cohort study followed individuals without a diagnosis of diabetes, aged 25 to 74 years at the time of the index interview. We used the National Health and Nutrition Examination Survey I (1971–1974; NHANES I) merged with the NHANES I Epidemiologic Followup Study (1992; NHEFS).

The NHANES I was conducted between 1971 and 1975 and allowed for representative estimates of the non-institutionalized civilian US population. The NHEFS is a national longitudinal study of individuals assessed at the NHANES I baseline. The NHEFS initial population included the 14,407 participants who were 25 to 74 years of age when first examined in NHANES I. More than 98% of the individuals in the initial NHANES I cohort were traced and supplied data for the NHEFS.

The follow-up information was gathered in 3 ways. Surviving subjects were interviewed. If the subject was deceased or alive but incapacitated, a slightly modified version of the subject questionnaire was administered to a proxy respondent. For individuals who had died in the period between the NHANES I index interview and the follow-up interview, information from death certificates was recorded. A total of 1,681 proxy respondents was interviewed in the NHEFS.

Serum transferrin saturation was measured in the original NHANES I. We defined elevated serum transferrin saturation as greater than 45%, greater than 50%, greater than 55%, greater than 60%, or greater than 62%. All of these cutoff values had previously been proposed or used in population-based studies of elevated serum transferrin saturation.^4,5,23

Diabetes was operationalized as a positive response to the question, Has a doctor ever told you that you have diabetes? This question was asked in the original NHANES I and in each wave of the follow-up survey (1982–1984, 1986, 1987, and 1992). For individuals who could not participate, proxy respondents were queried. In terms of individuals who died before the follow-up survey, we operationalized the development of diabetes as an ICD-9 diagnosis of 250.XX for underlying cause of death or any of the 20 other diagnoses listed on the death certificate.

We also assessed risk factors for diabetes available in the NHANES I, including obesity represented by a body mass index greater than 27 kg/m 2 , race, sex, age, physician diagnosis of hypertension, and total serum cholesterol above 240 mg/dL as a way to increase our understanding of diabetes mellitus as a consequence of hemochromatosis.

Our index sample was limited to men and women 25 to 74 years of age in the NHANES I, who had a serum transferrin saturation rate recorded in the NHANES I, did not have diabetes at the initial index interview, and had information on the development of diabetes (n = 9724).