Dr. Ron’s Research Review – July 2, 2014

© 2014

This week’s research review focuses on iron overload.

Iron overload is a risk factor for diabetes. Iron plays a direct and causal role in diabetes pathogenesis mediated both by beta cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. (Simcox and McClain, 2013) (Fleming and Ponka, 2012)

In the past, hemochromatosis was usually recognized at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus ("bronze diabetes"), and hepatic cirrhosis. Cutaneous hyperpigmentation is present in 70 percent of patients. (Chacon et al., 2013)

Unliganded iron associated with high serum ferritin both contributes to the pathology of Alzheimer's disease (AD) and also changes the morphology of erythrocytes (RBCs). (Bester et al., 2013)

Hereditary hemochromatosis is associated with an increased risk of celiac disease (OR = 2.30; 95% CI = 1.53-3.45). (Ludvigsson et al., 2013)

An article published in 1961 describes hypochromic anemia and hemochromatosis that responds to combined testosterone, pyridoxine, and liver extract therapy. (Gardner and Nathan, 1961)

 

Dr. Ron


 

Articles

High ferritin levels have major effects on the morphology of erythrocytes in Alzheimer's disease.
            (Bester et al., 2013) Download
Introduction: Unliganded iron both contributes to the pathology of Alzheimer's disease (AD) and also changes the morphology of erythrocytes (RBCs). We tested the hypothesis that these two facts might be linked, i.e., that the RBCs of AD individuals have a variant morphology, that might have diagnostic or prognostic value. Methods: We included a literature survey of AD and its relationships to the vascular system, followed by a laboratory study. Four different microscopy techniques were used and results statistically compared to analyze trends between high and normal serum ferritin (SF) AD individuals. Results: Light and scanning electron microscopies showed little difference between the morphologies of RBCs taken from healthy individuals and from normal SF AD individuals. By contrast, there were substantial changes in the morphology of RBCs taken from high SF AD individuals. These differences were also observed using confocal microscopy and as a significantly greater membrane stiffness (measured using force-distance curves). Conclusion: We argue that high ferritin levels may contribute to an accelerated pathology in AD. Our findings reinforce the importance of (unliganded) iron in AD, and suggest the possibility both of an early diagnosis and some means of treating or slowing down the progress of this disease.

Acquired hemochromatosis with pronounced pigment deposition of the upper eyelids.
(Chacon et al., 2013) Download
HEMOCHROMATOSIS MAY BE CLASSIFIED INTO TWO GROUPS: primary (hereditary) or secondary (acquired). The acquired type most commonly occurs after massive intake of iron supplements or blood transfusions and is also known as transfusional iron overload. In the past, hemochromatosis was usually recognized at an advanced stage by the classic triad of hyperpigmentation, diabetes mellitus ("bronze diabetes"), and hepatic cirrhosis. Cutaneous hyperpigmentation is present in 70 percent of patients due to two different mechanisms: (1) hemosiderin deposition resulting in diffuse, slate-gray darkening and (2) increased production of melanin in the epidermis. A 47-year-old woman who receives regular transfusions due to low iron and chronic, unresolving anemia and who subsequently developed pronounced hyperpigmentation of the upper eyelids is described. The presentation, diagnosis, pathogenesis, and treatment options of hyperpigmentation due to secondary hemochromatosis are discussed.


Iron overload in human disease.
(Fleming and Ponka, 2012) Download
Iron-overload disorders are typically insidious, causing progres-sive and sometimes irreversible end-organ injury before clinical symptoms de-velop. With a high index of suspicion, however, the consequences of iron toxic-ity can be attenuated or prevented. Some iron-overload disorders are quite common(e.g., HFE-associated hereditary hemochromatosis and β-thalassemia), whereasothers are exceedingly rare. An understanding of the pathophysiology of these dis-orders is helpful in directing the workup and in identifying scenarios that meritconsideration of the less common diagnoses. Since many of the molecular partici-pants in iron metabolism have been characterized only in the past several years, we first review the current understanding of iron metabolism and then discuss spe- cific iron-overload diseases.

 

Hypochromic anemia and hemochromatosis--response to combined testosterone, pyridoxine, and liver extract therapy.
            (Gardner and Nathan, 1961) Download

Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients.
            (Ludvigsson et al., 2013) Download
BACKGROUND AND AIM: Case reports suggest an association between hereditary hemochromatosis (HH) and celiac disease (CD), but estimates of association are lacking. We estimated the association between HH and CD in a population-based study. MATERIAL AND METHODS: Case-control study. We identified 29,096 individuals with biopsy-verified CD (equal to villous atrophy, Marsh stage III) through biopsy reports from all 28 pathology departments in Sweden. We then investigated the risk of a clinical diagnosis of HH in CD and in 144,522 controls matched for age, sex, county and calendar year. Conditional logistic regression was used to calculate odds ratios (ORs) for CD in patients with HH. RESULTS: HH was seen in 30 patients with CD and in 60 matched controls. HH was hence associated with an increased risk of CD (OR = 2.30; 95% CI = 1.53-3.45). Restricting HH to individuals with at least two records of HH, the OR for CD was 2.54 (95% CI = 1.57-4.11), with a similar risk estimate when we only looked at HH diagnosed before CD (and matched date in controls) (OR = 2.64; 95% CI = 1.24-5.60). CONCLUSION: HH seems to be associated with an increased risk of CD.


Iron and diabetes risk.
(Simcox and McClain, 2013) Download
Iron overload is a risk factor for diabetes. The link between iron and diabetes was first recognized in pathologic conditions-hereditary hemochromatosis and thalassemia-but high levels of dietary iron also impart diabetes risk. Iron plays a direct and causal role in diabetes pathogenesis mediated both by beta cell failure and insulin resistance. Iron also regulates metabolism in most tissues involved in fuel homeostasis, with the adipocyte in particular serving an iron-sensing role. The underlying molecular mechanisms mediating these effects are numerous and incompletely understood but include oxidant stress and modulation of adipokines and intracellular signal transduction pathways.

 

References

Bester, J, et al. (2013), ‘High ferritin levels have major effects on the morphology of erythrocytes in Alzheimer’s disease.’, Front Aging Neurosci, 5 88. PubMedID: 24367334
Chacon, AH, B Morrison, and S Hu (2013), ‘Acquired hemochromatosis with pronounced pigment deposition of the upper eyelids.’, J Clin Aesthet Dermatol, 6 (10), 44-46. PubMedID: 24155994
Fleming, RE and P Ponka (2012), ‘Iron overload in human disease.’, N Engl J Med, 366 (4), 348-59. PubMedID: 22276824
Gardner, FH and DG Nathan (1961), ‘Hypochromic anemia and hemochromatosis--response to combined testosterone, pyridoxine, and liver extract therapy.’, Trans Am Clin Climatol Assoc, 73 121-35. PubMedID: 13896897
Ludvigsson, JF, et al. (2013), ‘Does hemochromatosis predispose to celiac disease? A study of 29,096 celiac disease patients.’, Scand J Gastroenterol, 48 (2), 176-82. PubMedID: 23256862
Simcox, JA and DA McClain (2013), ‘Iron and diabetes risk.’, Cell Metab, 17 (3), 329-41. PubMedID: 23473030