m icronutrients anson lowe medicine october 06, 2015
TRANSCRIPT
MICRONUTRIENTS
Anson LoweMedicine
October 06, 2015
The biology of iron metabolismVitamin B12
Calcium; vitamin b12; iron
IRON FUNCTONS
• component of oxygen carrying proteins• (hemoglobin and myoglobin)
• a co-factor in electron transport (cytochromes)• co-factor in other enzymatic reactions
IRON and Disease
• Excessive iron is a source of oxidative damage
N Engl J Med (1999), 341:1986-1995
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
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
IRON DEFICIENCY
• developmental delays and behavioral disturbances• increase risk of lead poisoning• anemia (microcytic, hypochromic)
Iron Deficient Anemia
• Incidence in the United States– 3.3 million women of childbearing age– 240,000 children aged 1-2 years
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
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.
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.
N Engl J Med (1999), 341:1986-1995
Iron Regulation
There is no mechanism that controls iron excretion◦ Sloughing of intestinal mucosal cells◦Menses
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
Nature 1997;388:482–488
Nature 1997;388:482–488
Nature 1997;388:482–488
DMT1=DCT1=NRAMP2
Nature 1997;388:482–488
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.
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
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
N Engl J Med (1999), 341:1986-1995
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
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
Hepcidin
• 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
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
Ferroportin Distribution
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
Case
70year old man referred for iron deficiency anemia.◦Pan endoscopy is negative◦What do you do?
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
Celiac Sprue
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?
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
Vitamin B12
Methylation◦conversion of homocysteine to methionine
Intramolecular rearrangement◦ isomerization of methylmalonyl coenzyme A to
succinyl CoA
Vitamin B12 Source
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
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
Megaloblastic Anemia-1
Autosomal recessive disorder Mutations in cubilin result in defective IF-B12
binding◦Normal intrinsic factor levels◦Megaloblastic anemia◦Neurologic abnormalities
Folate
An important cofactor for one-carbon transfersPresent in green leafy vegetables◦Storage for 4 months
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
Proton – Coupled Folate Transporter
Folate Deficiency
• Folate reserves are limited, ~ 4 months• Clinical expression of folate deficiency
• megaloblastic anemia• birth defects of the neural tube• cancer?