m icronutrients anson lowe medicine october 06, 2015
TRANSCRIPT
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MICRONUTRIENTS
Anson LoweMedicine
October 06, 2015
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The biology of iron metabolismVitamin B12
Calcium; vitamin b12; iron
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IRON FUNCTONS
• component of oxygen carrying proteins• (hemoglobin and myoglobin)
• a co-factor in electron transport (cytochromes)• co-factor in other enzymatic reactions
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IRON and Disease
• Excessive iron is a source of oxidative damage
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N Engl J Med (1999), 341:1986-1995
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MMWR vol. 47 / no. RR-3
Distribution of iron-containing compounds(mg Fe / kg body weight)
Compound Men Women
Storage complexes Ferritin 9 4 Hemosiderin 4 1Transport protein Transferrin <1 <1Functional compounds Hemoglobin 31 31 Myoglobin 4 4 Respiratory enzymes 2 2
Total 50 42
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IRON BALANCE
• ~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
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IRON DEFICIENCY
• developmental delays and behavioral disturbances• increase risk of lead poisoning• anemia (microcytic, hypochromic)
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Iron Deficient Anemia
• Incidence in the United States– 3.3 million women of childbearing age– 240,000 children aged 1-2 years
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MMWR vol. 47 / no. RR-3
Increased iron requirements Inadequate iron absorption
Blood loss Diet low in bioavailable ironMenstruation Impaired absorptionGastrointestinal tract Intestinal malabsorptionBlood donation Gastric surgeryHookworms HypochlorhydriaGenitourinary tractRespiratory tract
GrowthPregnancy
Causes of Iron Deficiency
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MMWR vol. 47 / no. RR-3
National Health and Nutrition Examination Survey, 1988–1994
Sex and age (years) Iron deficiency Iron-deficiency anemiaBoth sexes1–2 9 3*3–5 3 <16–11 2 <1Nonpregnant females12–15 9 2*16–19 11* 3*20–49 11 5*50–69 5 2≥70 7* 2*Males12–15 1 <116–19 <1 <120–49 <1 <150–69 2 1≥70 4 2*Prevalence in nonblacks is 1 percentage point lower than prevalence in all races.
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MMWR vol. 47 / no. RR-3
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* ~10 0.15–0.48Iron-fortified formula† 10.0–12.8* ~ 4 0.40–0.51Whole cow’s milk 0.5 ~10 0.05Breast milk 0.5 ~50 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.
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N Engl J Med (1999), 341:1986-1995
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Iron Regulation
There is no mechanism that controls iron excretion◦ Sloughing of intestinal mucosal cells◦Menses
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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
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Nature 1997;388:482–488
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Nature 1997;388:482–488
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Nature 1997;388:482–488
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DMT1=DCT1=NRAMP2
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Nature 1997;388:482–488
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Fe+2 uptake is coupled with protonsDMT1 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.
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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
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Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006;doi:10.1152/physiol.00052.2005
FIGURE 1. Intestinal iron absorption An individual enterocyte is depicted
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N Engl J Med (1999), 341:1986-1995
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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
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Gastroenterology 1999;116:193–207
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N Engl J Med (1999), 341:1986-1995
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Increased Height in HFE Hemochromatosis
N Engl J Med. 2013 Aug 22;369(8):785-6. doi: 10.1056/NEJMc1303066.
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Copyright ©2001 by the National Academy of Sciences
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98, 8780-8785
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Hepcidin
• Produced mainly by the liver• Mol. Wt. = 9,400• secreted
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Copyright ©2001 by the National Academy of Sciences
Nicolas, Gaël et al. (2001) Proc. Natl. Acad. Sci. USA 98, 8780-8785
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Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006;doi:10.1152/physiol.00052.2005
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
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Ferroportin Distribution
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Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006;doi:10.1152/physiol.00052.2005
FIGURE 2. Regulation of hepcidin expression Hepatic production of the peptide hormone hepcidin is influenced by iron needs and stores
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Case
70year old man referred for iron deficiency anemia.◦Pan endoscopy is negative◦What do you do?
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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
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Celiac Sprue
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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?
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Copyright ©2006 American Physiological Society
Donovan, A. et al. Physiology 21: 115-123 2006;doi:10.1152/physiol.00052.2005
FIGURE 2. Regulation of hepcidin expression Hepatic production of the peptide hormone hepcidin is influenced by iron needs and stores
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Vitamin B12
Methylation◦conversion of homocysteine to methionine
Intramolecular rearrangement◦ isomerization of methylmalonyl coenzyme A to
succinyl CoA
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Vitamin B12 Source
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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
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Schilling Test
Patient with low vitamin B12 levelsAbsorption of B12 is first tested with the
ingestion of radioactive vitamin B12◦Urinary excretion of B12 is examined as a measure of
absorptionIf abnormal, the test is repeated with the
addition of intrinsic factor
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Megaloblastic Anemia-1
Autosomal recessive disorder Mutations in cubilin result in defective IF-B12
binding◦Normal intrinsic factor levels◦Megaloblastic anemia◦Neurologic abnormalities
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Folate
An important cofactor for one-carbon transfersPresent in green leafy vegetables◦Storage for 4 months
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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
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Proton – Coupled Folate Transporter
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Folate Deficiency
• Folate reserves are limited, ~ 4 months• Clinical expression of folate deficiency
• megaloblastic anemia• birth defects of the neural tube• cancer?