Diabetes Care
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Diabetes Care 29:464-466, 2006
DOI: 10.2337/diacare.29.02.06.dc05-1417
© 2006 by the American Diabetes Association
This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hahn, J.-U.
Right arrow Articles by Kerner, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hahn, J.-U.
Right arrow Articles by Kerner, W.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

Letters: Observations

Evaluation of a Diagnostic Algorithm for Hereditary Hemochromatosis in 3,500 Patients With Diabetes

Jan-Uwe Hahn, MD1,2, Michael Steiner, MD3, Sabine Bochnig2, Hartmut Schmidt, MD4, Peter Schuff-Werner, MD3 and Wolfgang Kerner, MD2

1 Klinikum Suedstadt Rostock, Center for Vascular Medicine, Rostock, Germany
2 Clinic for Diabetes and Metabolic Diseases Karlsburg, Karlsburg, Germany
3 Institute of Clinical Chemistry and Laboratory Medicine, University of Rostock, Rostock, Germany
4 Clinic for Transplantation Hepatology, University of Muenster, Muenster, Germany

Address correspondence to Dr. Jan-Uwe Hahn, Clinic for Diabetes and Metabolic Diseases Karlsburg, Greifswalder Str. 11, 17495 Karlsburg, Germany. E-mail: januwe.hahn{at}t-online.de

Hereditary hemochromatosis may lead to hepatic cirrhosis, cardiomyopathy, diabetes, arthritis, and impotence (1, 2). In the Caucasian population, HFE gene mutations (C282Y and H63D) are present in the majority of patients demonstrating phenotypic expression (3–6). Conversely, the clinical penetrance in mutation carriers is low (7).

In the precirrhotic stage, ~20% of hemochromatosic patients demonstrate hyperglycemia, with the prevalence increasing to >70% in the presence of liver cirrhosis (8). Two mechanisms contribute to the development of hyperglycemia and diabetes. Liver iron overload leads to insulin resistance, and the pancreatic ß-cell iron accumulation results in cell damage and diminished insulin secretion (1). The prevalence of genotypic and phenotypic hemochromatosis is higher in diabetic versus nondiabetic populations (9–11).

In an attempt to distinguish patients with hemochromatosis-associated secondary diabetes from other forms of diabetes, we applied a screening program to diabetic patients aged ≥40 years. The present report summarizes our first 3 years’ experience.

From the year 2000, in-hospital patients with diabetes have been invited to participate in the screening program (12). The initial phenotypic screening consisted of serum iron and transferrin analyses and calculation of the transferrin saturation. Elevated transferrin saturation defined as >45% was confirmed by an independent second analysis, which included determinations of serum ferritin and liver enzymes (alanine aminotransferase, aspartate aminotransferase, and {gamma}-glutamyl transpeptidase). Patients with a phenotype indicative of iron overload were genotyped for the presence of aberrant HFE gene variants (C282Y, H63D, and S65C) (13, 14).

Among 3,500 diabetic patients, elevated transferrin saturation at two occasions was observed in 22 male (aged 52.9 ± 11.6 years) and in 12 female (aged 49.1 ± 14.0 years) subjects, resulting in an iron overload phenotype in 0.97% of the patients. Mutations in the HFE gene were identified in seven patients (20.6%), with five of them demonstrating homozygosity for the variant allele at position 282. In addition, one case of compound heterozygosity was documented (C282Y/H63D). The new splice site HFE gene mutation (IVS5 + 1 G/A) in one patient of Vietnamese origin has been reported separately (15). Serum ferritin concentration was increased in five of seven patients, whereas pathological liver enzyme activities were noted in four patients. The remaining 27 patients were characterized by the absence of the three most common HFE gene mutations. Among them, 13 patients demonstrated elevated serum ferritin concentrations and 12 patients pathological liver enzyme activities.

Phenotype- and genotype-based screening programs have variably been used to investigate the relationship between iron overload, hemochromatosis, and its clinical manifestations including diabetes (16). Using transferrin saturation as a clinically useful initial screening parameter (12, 16) to detect iron overload, we obtained evidence for iron overload in only 1% of a large number of diabetic patients. Approximately half of these patients demonstrated liver damage as reflected by increased liver enzyme activities. Genotyping for the most common HFE gene mutations revealed hereditary hemochromatosis in only one in seven of these patients, equal to 0.2% of the overall diabetic population investigated in the present study.

The screening program can be performed at a reasonable price and is considered efficient in detecting iron overload in diabetic patients. Direct laboratory costs amount to $2.50 U.S. per patient for the laboratory screening profile (transferrin saturation and liver enzymes) and $5.00 U.S. for the analysis of serum ferritin. The genotyping approach (HFE C282Y, H63D, and S65C) results in $40.00 U.S. of additional costs in selected patients. The cost-effectiveness of screening programs for hereditary hemochromatosis was previously assessed. A study (17) of the cost-effectiveness of a population screening approach concluded that screening was an effective strategy for asymptomatic subjects if the prevalence of hemochromatosis was at least 0.3%, accompanied by a probability of disease manifestation >0.4 and test costs <$12.00 U.S. In another study (18), the cost-effectiveness of genetic testing as a screening method was evaluated using a decision model. The model estimated that initial genetic testing would be cost-effective if the cost per test was <$28.00 U.S. Based on the assumption that diabetes is the manifestation of hereditary hemochromatosis, we conclude that a stepwise laboratory diagnostic approach is a cost-effective method for the screening of hereditary hemochromatosis among diabetic patients. In hemochromatosic patients with hyperglycemia/diabetes, it may open the possibility to treat iron accumulation with the aim to prevent further damage to the liver and pancreatic ß-cells, which in turn may be expected to contribute to preservation of the remaining insulin secretion, which even at low concentrations may delay the development of diabetes complications (19). Interventional trials should be performed to test the clinical outcome of a combined screening/treatment approach.

References

  1. Bacon BR: Hemochromatosis: diagnosis and management. Gastroenterology 120:718–725, 2001[Medline]
  2. Barton JC, Edwards CQ (Eds.): Hemochromatosis: Genetics, Pathophysiology, Diagnosis, and Treatment. Cambridge, U.K., Cambridge University Press, 2000
  3. Gottschalk R, Seidl C, Löffler T, Seifried E, Hoelzer D, Kaltwasser JP: HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis. Tissue Antigens 51:270–275, 1998[Medline]
  4. Bacon BR, Powell LW, Adams PC, Kresina TF, Hoofnagle JH: Molecular medicine and hemochromatosis: at the crossroads. Gastroenterology 116:193–207, 1999[Medline]
  5. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK: A novel MHC class I-like gene is mutated in patients with hereditary. Nat Genet 13:399–408, 1996[Medline]
  6. Mura C, Nousbaum JB, Verger P, Moalic MT, Raguenes O, Mercier AY, Ferec C: Phenotype-genotype correlation in haemochromatosis subjects. Hum Genet 101:271–276, 1997[Medline]
  7. Bradley LA, Haddow JE, Palomaki GE: Population screening for haemochromatosis: a unifying analysis for published intervention trials. J Med Screen 3:178–184, 1996[Medline]
  8. Strohmeyer G, Niederau C: Diabetes mellitus and hemochromatosis. In Hemochromatosis: Genetics, Pathophysiology, diagnosis, and Treatment. Barton JC, Edwards CQ, Eds. Cambridge, U.K., Cambridge University Press, 2000, p. 268–277
  9. Conte D, Manachino D, Colli A, Guala A, Aimo G, Andreoletti M, Corsetti M, Fraquelli M: Prevalence of genetic hemochromatosis in a cohort of Italian patients with diabetes mellitus. Ann Intern Med 128:370–373, 1998[Abstract/Free Full Text]
  10. O’Brien T, Barrett B, Murray DM, O’Sullivan DJ: Usefullness of biochemical screening of diabetes patients for hemochromatosis. Diabetes Care 13:532–534, 1990[Abstract]
  11. Singh BM, Grunewald RA, Press M, Muller BR, Wise PH: Prevalence of amongst patients with diabetes mellitus. Diabetes Med 9:730–731, 1992[Medline]
  12. Powell LW, George DK, McDonnell SM, Kowdley KV: Diagnosis of hemochromatosis. Ann Intern Med 129:925–931, 1998[Abstract/Free Full Text]
  13. Lynas C: A cheaper and more rapid polymerase chain reaction-restriction fragment length polymorphism method for the detection of the HLA-H gene mutations occurring in hereditary hemochromatosis. Blood 90:4235–4236, 1997[Free Full Text]
  14. Mura C, Raguenes O, Ferec C: HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 93:2502–2505, 1999[Abstract/Free Full Text]
  15. Steiner M, Ocran K, Genschel J, Meier P, Gerl H, Ventz M, Schneider ML, Buttner C, Wadowska K, Kerner W, Schuff-Werner P, Lochs H, Schmidt H: A homozygous HFE gene splice site mutation (IVS5+1 G/A) in a hereditary hemochromatosis patient of Vietnamese origin. Gastroenterology 122:789–795, 2002[Medline]
  16. Adams PC, Reboussin DM, Barton JC, McLaren CE, Eckfeldt JH, McLaren GD, Dawkins FW, Acton RT, Harris EL, Gordeuk VR, Leiendecker-Foster C, Speechley M, Snively BM, Holup JL, Thomson E, Sholinsky P, the Hemochromatosis and Iron Overload Screening (HEIRS) Study Research Investigators: Hemochromatosis and iron-overload screening in a racially diverse population. N Engl J Med 352:1769–1778, 2005[Abstract/Free Full Text]
  17. Phatak PD, Guzman G, Woll JE, Robeson A, Phelps CE: Cost-effectiveness of screening for hereditary hemochromatosis. Arch Intern Med 154:769–776, 1994[Abstract]
  18. Adams PC, Valberg LS: Screening blood donors for hereditary hemochromatosis: decision analysis model comparing genotyping to phenotyping. Am J Gastroenterol 94:1593–1600, 1999 (see comments)[Medline]
  19. Madsbad S: Prevalence of residual B-cell function and its metabolic consequences in type I (insulin-dependent) diabetes. Diabetologia 24:141–147, 1983[Medline]

Add to CiteULike CiteULike   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?



This Article
Right arrow Extract Freely available
Right arrow Full Text (PDF)
Right arrow Purchase Article
Right arrow View Shopping Cart
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hahn, J.-U.
Right arrow Articles by Kerner, W.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hahn, J.-U.
Right arrow Articles by Kerner, W.
Social Bookmarking
Add to CiteULike   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum