8/5- Iron Metabolism, Iron Deficiency and Iron Overload Flashcards Preview

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Flashcards in 8/5- Iron Metabolism, Iron Deficiency and Iron Overload Deck (58):

Iron is a key component in what?

Hemoglobin & Myoglobin


NADH dehydrogenase


Superoxide dismutase

Ribonucleotide reductase

Fatty acid desaturases



Iron functions in what processes?

Oxygen transport & storage

Energy generation


Free radical detoxification

Synthesis of DNA

Synthesis of “liquid”

FA Signal transduction


What are some problems in iron metabolism? Solutions?

- Ferric iron (3+) is insoluble at neutral pH

- Ferrous iron (2+) is soluble but reactive

Solutions: Most iron in the body is bound to protein or porphyrin

- Intracellular: ferritin

- Circulation: transferrin 


Total body Fe is how much?

- RBCs

- Bound to transferrin:

- Remainder is found where

Total body iron: 3,000-4,000 mg

- RBCs: 2,000- 3,000 mg

- Bound to transferrin: 2-3 mg

- Remainder: macrophages and heptaocytes; stored as cytoplasmic ferritin


Daily iron losses (amounts and methods)?

Daily iron losses = 1-2 mg/day

- Desquamation of intestine/skin

- Menstruation/minor bleeding


What is the iron requirement for daily erythropoiesis?

20 mg/day


Regulation of iron uptake is done via what?



What are daily dietary iron needs for men? Menstruating women?

How much is absorbed?

- Men: 8 mg/day

- Menstruating women: 18 mg/day

Absorb 1-2 mg iron/day


How is iron strictly conserved (what cells)?

Strict conservation of Fe by scavenging RBCs:

- 20-25 mg of iron/day

- Plasma iron turns over ~ every 2 hrs


What are some problems from iron deficiency?

- Anemia

- Decreased muscle performance

- Maintenance of epithelia


What are some problems from iron excess?

Toxic to liver, heart, and endocrine organs

(Limiting iron controls microbial proliferation)


Where in the body is (dietary) iron absorbed?

How much?

Duodenum; 1-2 mg/day


What transporter is respsponsible for absorbing iron in the duodenum?

DMT1 (Divalent metal transporter 1)

((May also transport zinc; too much zinc may limit iron transport/uptake)) 


Erythroid precursors have what receptors relevant to iron?

Transferrin receptor 


Hepatocytes have what receptors relevant to iron?


Iron uptake/storage process in macrophage?


What is hepcidin?

- Made by what cells

Negative regulator of iron absorption in duodenum and release from macrophages

- 25 AA peptide

- Synthesized by hepatocyte

- Increased in inflammatory states (thus, decreased levels of iron in the bloodstream)

Decreased levels (from lower absorption and release from macrophages and the resultant low iron levels in the blood helps prevent the growth of microorganisms 


What are relative hepcidin levels in the following states:

- Inflammation:

- Anemia/hypoxia:

- Iron excess:

Relative hepcidin levels in the following states:

- Inflammation: increased

- Anemia/hypoxia: decreased

- Iron excess: increased 


How does the liver regulate hepcidin production/synthesis?

- IL-6 (inflammatory marker) binds to receptor to increase hepcidin synthesis

- Iron sensing mechanism involves transferrin receptors 1/2 that signal nucleus for hepcidin synthesis/inhibition

- Baseline iron absorption involves BMP and HJV receptors; more complex


Inherited iron overload states are due to what?

Hepcidin deficiency or hepcidin resistance


What is the most common form of inherited iron overload?

- Gene

- Inheritance pattern

- Mechanism

Type 1 or "Classic" iron overload

- HFE gene

- Autosomal recessive

- Low hepcidin


Basic genes/inheritance/mechanism for other inherited iron overload states?

Type 2/JH

Type 3/Tfr2

Type 4 Classical nonsclassical

Type 2/JH

- HJV gene

- AR

- Reduced HAMP activation

Type 3/Tfr2

- TfR2

- AR

- ?iron sensing

Type 4 Classical nonsclassical

- SLC40A1

- AD

- Reduce Fe export from macrophages; hepcidin resistance


Back to classic Hemachromatosis (type 1):

- Mutations in what genes:

- Demographics

- Hepcidin levels

- Penetrance

- Phenotypic expression affected by

- Mutations in the HFE gene or gene for TfR2

- 1/200 Northern Europeans and 1/250 of the general population are homozygotes

- Hepcidin is detectable but lower than normal

- Not highly penetrant; affects males > females

- Increased phenotypic expression correlated with male sex and alcohol intake


What is juvenile hemochromatosis?

- Mutations in what genes

- Hepcidin levels

- Penetrance

- Associations

- Mutations in Hemojuvelin gene (HJV) or Hepcidin gene (HAMP)

- Little or no hepcidin detectable

- Highly penetrant; affects males = females

- Endocrinopathies and cardiomyopathies develop in late childhood/early adulthood


What are some secondary iron overload syndromes?


What is beta thalassemia?

- Because of the erythropoietic signal, iron overload develops even in the absence of transfusion

- The erythropoeitic signal “trumps” iron overload and lowers serum hepcidin

- Tissue Iron Loading may be influenced by Hepcidin concentration with low levels favoring parenchymal cells and high levels favoring macrophages

- Iron Overload best treated with Chelators


What are some clinical effects of iron overload? (tissue-level, broadly)

Iron is toxic to tissues:

- Lipid peroxidation

- Increased collagen formation

- Interaction of ROS, iron, and DNA


- Liver

- Endocrine

- Joint

- Cardiac

- Skin

- Cancer


Affects of iron overload on liver?

Cirrhosis (does not reverse with phlebotomy)


Affects of iron overload on endocrine?

- Diabetes (may improve with phlebotomy)

- Hypogonadism due to pituitary, hypothalamic, or gonadal dysfunction


Affects of iron overload on joint?

- Predilection for 2nd, 3rd metacarpal joints

- Pain, stiffness, bony enlargement

- Osteoporosis relatively common due in part to (hypogonadism)


Affects of iron overload on cardiac?

- Restrictive and Dilated Cardiomyopathy

- Arrhythmias and Heart Failure

- Reversal can occur with phlebotomy


Affects of iron overload on skin?

Increased pigmentation (in sun-exposed areas)- bronze or slate gray)


Affects of iron overload on cancer?

- Increased risk of liver cancer

- Alcohol abuse, viral hepatitis, age increase risk


Algorithm for management of iron overload?

(Don't need to memorize)


What does this show? 

Hereditary hemochromatosis (liver biopsy)

- Hepatocellualr deposition is blue in this Prussian blue-stained section of early stage (parenchymal architecture is normal)


Treatment for iron overload?


- Women with SF under 200 mg/L or men under 300 mg/L do not need treatment

- 1-2 times/wk until SF is under 50 mg/L

- Maintenance 2-4 times/yr

Dietary modification

- Avoid iron supplements, vitamin C, red meat

Screening adult siblings of pt with hemochromatosis

Liver transplant (if so much cirrhosis and liver damage from iron overload)

*Remember that hepcidin concentrations are subject to iron levels, so eventually with phlebotomy, iron deficiency will lower hepcidin even more


Epidemiology of iron deficiency:

- Worldwide

- Genetics

- US by gender/age

- Worldwide, iron deficiency is the most common iron disorder; ~3 billion people are affected worldwide

- Genetics may modulate susceptibility to iron deficiency

- USA: toddlers (3%), teenage girls (2-5%), women of childbearing age


Causes of Iron Deficiency?


What are some GI causes of iron deficiency?

- Hemorrhagic telangiectasia

- Esophageal: ulcer/erosion, cancer, Mallory-Weiss tear, varices

- Peptic ulcer disease

- Liver disease

- Agiodysplasia

- Diverticular disease

- Meckel's diverticulum

- Inflammatory bowel disease

- Colorectal cancer

- Hemorrhoids 


Clinical manifestations of iron deficiency?

- Pallor, fatigue, exercise intolerance

- Cardiomegaly

- Pica: craving of non-nutritive substances (e.g. ice, corn starch, chalk, clay)

- Impaired psychomotor development, cognitive impairment

- Defects in leukocyte/lymphocyte function

- Plummer Vinson syndrome- triad of koilonychia, atrophic glossitis, esophageal web

- Cerebral vein thrombosis


What is this? 

Koilonychia- typical "spoon nails"

- caused by iron deficiency


What is this?

Angular cheilosis- fissuring and ulceration fo the corner of the mouth

- caused by iron deficiency


What is this? 

Paterson-Kelly (Plummer-Vinson) syndrome: barium swallow X-ray showing a filling defect caused by a postcricoid web

- caused by iron deficiency


Lab findings in iron deficiency?

- Low hemoglobin/hematocrit

- Low MCV (microcytosis), MCH

- Low reticulocyte count

- Peripheral smear: microcytic, hypochromic anemia; anisocytosis, poikilocytosis, cigar-shaped/pencil cells

- Thrombocytosis (more commonly; body trying to stop bleeding, perhaps)

- Thrombocytopenia (less commonly)

- Low serum iron, ferritin, transferrin saturation; high serum transferrin, TIBC


What is this? 

Normal peripheral smear

- Can see lymphocyte (RBC about the size of the lymphocyte nucleus)


What is this? 

Iron deficiency anemia seen on peripheral smear

- Microcytic, hypochromic RBCs


Diagnosis of iron deficiency?

- CBC, reticulocyte count, peripheral smear

- Therapeutic trial

- Complete evaluation: iron panel (serum iron, ferritin, TIBC, transferrin saturation)

- Other tests: Erythrocyte protoporphyrin, serum transferrin receptor, reticulocyte hemoglobin content (rarely used)

- Screening for lead poisoning, stool occult blood

**Iron deficiency in an Adult Male or a Postmenopausal Woman is GI loss unless proven otherwise**


Treatment for iron deficiency (broad categories)?

- Oral therapy

- Parenteral iron

- Blood transfusion


Oral therapy for iron deficiency?

- Ferrous sulfate: 4-6 mg/kg/day of elemental iron, in 2-3 daily doses, in between meals, preferably with juice (with vitamin C)

- Adults this is Ferrous Sulfate 325 mg 3x/day

- Iron preparations may cause nausea, constipation, rarely diarrhea

- Treat until hemoglobin normalizes for additional 2-3 months to supplement body iron stores


Parenteral iron for iron deficiency:

- When used

- Side effects

- Preparations

Use when: severe anemia

- Intolerance to oral supplements

- Malabsorption, poor compliance, dialysis pts

Side effects: anaphylaxis

Various preparations:

- Iron dextran (high and low MW)

- Ferric gluconate

 - Iron sucrose


Blood transfusion for iron deficiency

- When used

- Method of infusion

Do when Hb is < 5 gm/dL or in the presence of cardiac failure

- Infuse slowly

- Follow-up with oral iron


What conditions/diseases may cause anemia of inflammation?

- Rheumatologic disorders

- Inflammatory Bowel Disease

- Infections

- Cancer


Classic results from anemia of inflammation (types of anemia and reactions to therapy)?

- Hepcidin levels

- Treatment

- Mild/moderate anemia

- Normocytic (though sometimes microcytic)

- Resistant to iron therapy

- Hepcidin increases are transient

- Treatment rests on treating underlying disease


Mechanism underlying anemia of inflammation (biochem)?

- Decreased release of iron from macrophages to plasma

- Decreased absorption of iron in the gut

- Hepcidin induced by cytokines, released from liver, decreases release of iron from macrophages

- Reduced RBC life span

- Inadequate erythropoietin response to anemia due to the effects of IL-1, TNF, g interferon


What is this showing? 

Anemia of chronic inflammation


How are the following affected in Iron deficiency anemia vs. Anemia of chronic disease? 


What causes anemia of chronic kidney disease?

- Historically attributed to decreased EPO (made by kidney)

- But many pts require supratherapeutic doses of EPO to maintain their hematocrit

- Now thought that decreased clearance of hepcidin restricts iron availability

- Inflammation from HD itself may increase hepcidin levels and make matters worse


For the future...