M
Anson Lowe Medicine October 06, 2015

 The biology of iron metabolism  Vitamin B12  Calcium; vitamin b12; iron

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

• Excessive iron is a source of oxidative damage

N Engl J Med
(1999), 341:1986-1995

Distribution of iron-containing compounds (mg Fe / kg body weight) Men Women Compound
Storage complexes Ferritin Hemosiderin Transport protein Transferrin Functional compounds Hemoglobin Myoglobin Respiratory enzymes
Total
9 4 <1 31 4 2
50
4 1 <1 31 4 2
42
MMWR vol. 47 / no. RR-3

• ~1mg of iron is lost/day in the feces and desquamated cells.
• an additional 0.3-0.5 mg is lost by women in the childbearing years due to menstrual losses

• developmental delays and behavioral disturbances • increase risk of lead poisoning • anemia (microcytic, hypochromic)

• Incidence in the United States – 3.3 million women of childbearing age – 240,000 children aged 1-2 years

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

National Health and Nutrition Examination Survey, 1988 –1994 Sex and age (years
) Both sexes 1 –2 3 –5 6 –11 Nonpregnant females 12 –15 16 –19 20 –49 50 –69 ≥70
Iron deficiency
9 3 2 9 11* 11 5 7*
Iron-deficiency anemia
3* <1 <1 2* 3* 5* 2 2* Males 12 –15 16 –19 20 –49 50 –69 ≥70 1 <1 <1 2 4 <1 <1 <1 1 2 *Prevalence in nonblacks is 1 percentage point lower than prevalence in all races.
MMWR vol. 47 / no. RR-3

Iron absorption by infants fed formula or milk
Substance
Nonfortified formula Iron-fortified formula † Whole cow’s milk Breast milk
Iron content (mg/L)
1.5
–4.8* 10.0
–12.8* 0.5 0.5
Bioavailable iron (mg/L)
~10 ~ 4 ~10 ~50
Absorbed iron (mg/L)
0.15
–0.48
0.40
–0.51
0.05
0.25
*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

N Engl J Med
(1999), 341:1986-1995

 There is no mechanism that controls iron excretion ◦ Sloughing of intestinal mucosal cells ◦ Menses

 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

Nature
1997;388:482 –488

Nature
1997;388:482 –488

Nature
1997;388:482 –488

Nature
1997;388:482 –488

 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 .

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

FIGURE 1. Intestinal iron absorption An individual enterocyte is depicted
Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006; doi:10.1152/physiol.00052.2005

N Engl J Med
(1999), 341:1986-1995

• 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

Gastroenterology
1999;116:193 –207

N Engl J Med
(1999), 341:1986-1995

Increased Height in HFE Hemochromatosis N Engl J Med. 2013 Aug 22;369(8):785-6. doi: 10.1056/NEJMc1303066.

Copyright ©2001 by the National Academy of Sciences
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98, 8780-8785

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

Copyright ©2001 by the National Academy of Sciences
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98, 8780-8785

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
Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006; doi:10.1152/physiol.00052.2005

Ferroportin Distribution

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: 115-123 2006; doi:10.1152/physiol.00052.2005
Copyright ©2006 American Physiological Society

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

 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

 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?

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: 115-123 2006; doi:10.1152/physiol.00052.2005
Copyright ©2006 American Physiological Society

  Methylation ◦ conversion of homocysteine to methionine Intramolecular rearrangement ◦ isomerization of methylmalonyl coenzyme A to succinyl CoA

     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

 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

 Autosomal recessive disorder  Mutations in cubilin result in defective IF-B12 binding ◦ Normal intrinsic factor levels ◦ Megaloblastic anemia ◦ Neurologic abnormalities

 An important cofactor for one-carbon transfers  Present in green leafy vegetables ◦ Storage for 4 months

• 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

Proton – Coupled Folate Transporter

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