1. Micronutrients
Anson Lowe
Medicine
October 06, 2015

2. The biology of iron metabolism Vitamin B12
Calcium; vitamin b12; iron

3. IRON FUNCTONS component of oxygen carrying proteins
(hemoglobin and myoglobin)
a co-factor in electron transport (cytochromes)
co-factor in other enzymatic reactions

4. IRON and Disease
Excessive iron is a source of oxidative damage

5. N Engl J Med (1999), 341:

6. Distribution of iron-containing compounds
(mg Fe / kg body weight)
Compound Men Women
Storage complexes
Ferritin
Hemosiderin
Transport protein
Transferrin <1 <1
Functional compounds
Hemoglobin
Myoglobin
Respiratory enzymes
Total
MMWR vol. 47 / no. RR-3

7. IRON BALANCE
~1mg of iron is lost/day in the feces and desquamated cells.
an additional mg is lost by women in the childbearing years due to menstrual losses

8. IRON DEFICIENCY developmental delays and behavioral disturbances
increase risk of lead poisoning
anemia (microcytic, hypochromic)

9. Iron Deficient Anemia Incidence in the United States
3.3 million women of childbearing age
240,000 children aged 1-2 years

10. Causes of Iron Deficiency
Increased iron requirements Inadequate iron absorption
Blood loss Diet low in bioavailable iron
Menstruation Impaired absorption
Gastrointestinal tract Intestinal malabsorption
Blood donation Gastric surgery
Hookworms Hypochlorhydria
Genitourinary tract
Respiratory tract
Growth
Pregnancy
MMWR vol. 47 / no. RR-3

11. National Health and Nutrition Examination Survey, 1988–1994
Sex and age (years) Iron deficiency Iron-deficiency anemia
Both sexes
1– *
3– <1
6– <1
Nonpregnant females
12– *
16– * 3*
20– *
50–
≥ * *
Males
12– <1
16–19 <1 <1
20– <1 <1
50– ≥
*Prevalence in nonblacks is 1 percentage point lower than prevalence in all races.
MMWR vol. 47 / no. RR-3

12. Iron absorption by infants fed formula or milk
Substance Iron content Bioavailable Absorbed
(mg/L) iron (mg/L) iron (mg/L)
Nonfortified formula 1.5–4.8* ~ –0.48
Iron-fortified formula† 10.0–12.8* ~ –0.51
Whole cow’s milk ~
Breast milk 0.5 ~
*Values are given for commonly marketed infant formulas.
† Iron-fortified formula contains ≥1.0 mg iron/100 kcal formula ( 8 ). Most iron-fortified formulas contain approximately 680 kcal/L, which is equivalent to ≥6.8 mg iron/L.
MMWR vol. 47 / no. RR-3

13. N Engl J Med (1999), 341:

14. Iron Regulation There is no mechanism that controls iron excretion
Sloughing of intestinal mucosal cells
Menses

15. Iron Regulation
The absorption of heme iron (10-30%) is more efficient than inorganic iron (0-10%)
The absorption of inorganic iron can be greatly enhanced
Iron can only be absorbed in the reduced form, Fe+2

17. Nature 1997;388:482–488

18. Nature 1997;388:482–488

19. Nature 1997;388:482–488

20. DMT1=DCT1=NRAMP2

21. Nature 1997;388:482–488

22. Fe+2 uptake is coupled with protons
DMT1 can also transport other divalent cations such as Zn+2, Mn+2, Cu+2, Co+2, Cd+2, and to a lesser extent Ni+2, and Pb+2.

23. Iron deficiency is associated with achlorhydria
Chronic Atrophic Gastritis
atrophy of the gastric glands
association with anti-parietal cell antibodies is common (H:K-ATPase)
achlorhydria
25% are iron deficient

24. FIGURE 1. Intestinal iron absorption An individual enterocyte is depicted
Donovan, A. et al. Physiology 21: ;
doi: /physiol
Copyright ©2006 American Physiological Society

25. N Engl J Med (1999), 341:

26. IRON OVERLOAD
hemochromatosis is the most common genetic mutation observed
the mutation results in excessive absorption of iron despite high total body stores
one million persons in the United States may be affected
results in cirrhosis, hepatoma, heart failure, diabetes

27. Gastroenterology 1999;116:193–207

28. N Engl J Med (1999), 341:

29. Increased Height in HFE Hemochromatosis
N Engl J Med Aug 22;369(8): doi: /NEJMc

30. Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98,
Copyright ©2001 by the National Academy of Sciences

31. Hepcidin
Produced mainly by the liver
Mol. Wt. = 9,400
secreted

32. Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98,
Copyright ©2001 by the National Academy of Sciences

33. FIGURE 3. The hepcidin-ferroportin axis In hemochromatosis, hepcidin is deficient or absent, resulting in increased ferroportin on the cell surface and accelerated iron release
Donovan, A. et al. Physiology 21: ;
doi: /physiol
Copyright ©2006 American Physiological Society

34. Ferroportin Distribution

35. FIGURE 2. Regulation of hepcidin expression Hepatic production of the peptide hormone hepcidin is influenced by iron needs and stores
Donovan, A. et al. Physiology 21: ;
doi: /physiol
Copyright ©2006 American Physiological Society

36. Case 70year old man referred for iron deficiency anemia.
Pan endoscopy is negative
What do you do?

37. Case 70year old man referred for iron deficiency anemia.
Gross endoscopy survey is negative
Evaluate for iron malabsorption.
Evaluate for chronic atrophic gastritis (biopsies for pathology, screen for antiparietal cell antibodies).
Helicobactor pylori infection.
Celiac disease

38. Celiac Sprue

39. Case
55 year old man with alcoholic cirrhosis presents with iron saturations of 80% and ferritin of 5,000, both of which are abnormally high.
Why?

40. FIGURE 2. Regulation of hepcidin expression Hepatic production of the peptide hormone hepcidin is influenced by iron needs and stores
Donovan, A. et al. Physiology 21: ;
doi: /physiol
Copyright ©2006 American Physiological Society

43. Vitamin B12 Methylation Intramolecular rearrangement
conversion of homocysteine to methionine
Intramolecular rearrangement
isomerization of methylmalonyl coenzyme A to succinyl CoA

45. Vitamin B12 Source

48. Pernicious Anemia Loss of gastric parietal cells
Often associated with anti-intrinsic factor and parietal cell antibodies.
Antibodies specific for H:K-ATPase are believed to be the cause
Achlorhydria - loss of acid secretion
Loss of intrinsic factor secretion
Most common cause of vitamin B12 deficiency

49. Schilling Test Patient with low vitamin B12 levels
Absorption of B12 is first tested with the ingestion of radioactive vitamin B12
Urinary excretion of B12 is examined as a measure of absorption
If abnormal, the test is repeated with the addition of intrinsic factor

50. Megaloblastic Anemia-1
Autosomal recessive disorder
Mutations in cubilin result in defective IF-B12 binding
Normal intrinsic factor levels
Megaloblastic anemia
Neurologic abnormalities

52. Folate An important cofactor for one-carbon transfers
Present in green leafy vegetables
Storage for 4 months

53. Folate Absorption Two different receptors have been isolated
12 transmembrane domains and is present in the intestine in addition to a wide variety of other tissues.
A second receptor is linked to the membrane by a GPI-linkage and is present in caveolae in all cells

54. Proton – Coupled Folate Transporter

55. Folate Deficiency Folate reserves are limited, ~ 4 months
Clinical expression of folate deficiency
megaloblastic anemia
birth defects of the neural tube
cancer?