Iron Metabolism and Diseases

Iron Metabolism:

• ~4000 mg of iron per person

  • Mostly stored in the erythrocytes (~2700 mg) and liver (~1000 mg)

• Homeostasis is balance between absorption vs. loss

  • Absorption is regulated

    • Intestinal absorption can fluctuate in response to

      • Iron status

      • Erythropoietic demand

      • Hypoxia 

      • Inflammation

      • Normally absorb 1-2 mg iron/day

  • Loss is unregulated

    • Physiologic exfoliation (hair, skin)

    • Bleeding (physiologic, hemorrhage)

    • Reproductive (iron needed to make a new human)

• Transferrin and ferritin solubilize iron in aqueous environments and minimize reactivity of iron.

  • Transferrin carries iron thru circulation

  • Ferritin stores iron within cells

• Intestinal iron absorption occurs in enterocytes in the duodenum.

• Heme iron is most easily absorbed

• Elemental iron needs to be reduced from ferric (Fe³⁺) to ferrous (Fe²⁺) for absorption.

• Hepcidin, a liver-derived peptide hormone, regulates systemic iron homeostasis by down regulating the ferroportin 1 (FPN1) receptor on the basolateral side of enterocytes. 

  • High hepcidin levels (in response to iron overload or inflammation) → hepcidin binds to FPN1 → FPN1 degradation → blocks iron export → reducing iron absorption.

    • Therefore iron stored within the cell as ferritin (or goes back into the intestine and excreted)

  • Low hepcidin levels → allow FPN1 to remain on the membrane → facilitating iron absorption.

• Macrophage iron recycling is a major source of iron

  • From old or damaged RBCs

  • Iron recovered by macrophages may be stored as ferritin or exported into the plasma

  • Also mediated by hepcidin, which inhibits macrophage iron release into blood stream via ferroportin

Iron Deficiency

• Early: No anemia, but may see changes in RDW

• Late: Frank anemia

  • Microcytosis, anisopoikilocytosis, pencil/target cells

• Inadequate absorption can be through:

  • Poor bioavailability

    • Cows milk in infants

    • High pH due to gastrectomy

    • Excess Fe3+ (not enough heme iron)

  • Absorption surface dysfunction

    • Duodenectomy

    • Celiac Disease

    • Hepcidin excess (anemia of chronic disease)

      
      

Iron replacement:

• Ganzoni equation:

  • Formula to calculate total iron deficit in patients who require IV iron therapy

  • Total iron dose (mg)= Weight (kg) ×[Target Hb−Actual Hb] ×2.4 +500

• Route of administration:

  • Oral (preferred)

    • Low dose, no more than daily preferred

    • Too much iron can lead to upregulation of hepcidin → reduce absorption

  • Parenteral

• In pregnancy:

  • IV Iron generally does not start until the second or third trimester (and in case of severe anemia and oral iron intolerance).

• Medications:

  • Iron Dextran

    • Category C for pregnancy

    • Can give up to 1000 mg in one dose

    • Requires test dose

    • Low price

  • Iron Gluconate (Ferrlecit)

    • Category B for pregnancy

    • Max dose of 125 mg

    • No test dose required

  • Iron Sucrose (Venofer)

    • Category B for pregnancy

    • Max dose of 300 mg

    • Can be given in short intervals

  • Ferumoxytol (Feraheme)

    • Category C for pregnancy

    • Max dose of 510 mg

    • Can be given in short intervals

    • Expensive

  • Iron Carboxymaltose (Injectafer)

    • Category C for pregnancy

    • Max dose of 750 mg

    • Can be associated with hypophosphatemia

  • Iron Isomaltoside

    • Dosed 20 mg/kg up to 1000 mg

    • Can be associated with hypophosphatemia

Iron Overload

Primary:

Hereditary hemochromatosis:

• Chronic inappropriate increase in intestinal absorption of dietary iron

• Pathophysiology:

  • Excess iron due to relative hepcidin deficiency phenotype

  • Associated with HFE gene mutation (C282Y, H63D polymorphism, S65C polymorphism) 

  • H63D: Less severe phenotype, lower penetrance

• Diagnosed by:

  • High transferrin

  • High ferritin >800

  • Liver biopsy

  • Gene testing

• Symptoms:

  • Depression, arthritis, liver disease, endocrinopathies (bronze diabetes, hypogonadism), cardiomyopathy

  • Symptoms are more common and severe in males

    • Physiologic blood loss in females

    • Testosterone mediated suppression of hepcidin in males

• Other related diseases:

  • TFR2 found in hepatocytes:

    • Autosomal recessive

    • Leads to increased intestinal absorption of iron

    • Earlier onset

  • HJV (Juvenile hemochromatosis):

    • Autosomal recessive

    • Younger presentation, more severe phenotype, full penetrance

  • Ferroportin hemochromatosis:

    • Autosomal dominant

    • Associated with high hepcidin levels

    • Affects iron egress into bloodstream thru FPN1

• Treatment:

  • Goal is prior to onset of irreversible organ dysfunction

  • Phlebotomy (goal ferritin <100)

  • Diet: avoiding iron supplementation, vitamin C intake, alcohol consumption

    • Avoiding raw shellfish (Vibrio vulnificus)

      • If infected, need antibiotic therapy (tetracycline and third-generation cephalosporin)

    • Also at risk for infections with Yersinia enterocolitica (liver abscess)

  • Chelation generally not done, unless phlebotomy contraindicated

    • If chelation: goal ferritin <1000

  • IVIG in pregnancy prevents complications of neonatal hemochromatosis

Secondary:

Excess transfusion:

• Monitor volume of RBCs transfused

  • Each unit of RBCs contains 200-250 mg of iron

    • Keep in mind: Normally absorb 1-2 mg of iron per day

• Serum ferritin every 1-3 months

• Hepatic MRI (q6-12 months)

• Cardiac MRI (q6-24 months depending on severity)

• Clinical Pearls:

  • Iron related cardiac complications are the most common cause of death in thalassemia

  • Endocrinopathy and liver disease more common in thalassemia than sickle cell disease

• Iron loading anemias (Thalassemia intermedia, MDS, Sideroblastic anemia)

  • Pathophysiology:

    • Erythroferrone is a hormone produced by proliferating erythroblasts

    • Regulates iron metabolism by inhibiting hepcidin expression

• Iron staining shows iron in macrophages

• Treatment:

  • Chelation

    • Prevents excess iron accumulation, removes excess stored iron, reverse iron-related organ dysfunction

    • Usually implemented when:

      • Serum ferritin >1000 ng/ml

      • MRI liver iron concentration of >3 mg/g dry weight

      • Cardiac T2 is less than 20 milliseconds

      • After patient receives 10 units of pRBCs (or greater than 100 cc/kg/year) 

    • Goal ferritin <1000-500 ng/ml, liver iron concentration 2-7 mg/g dry weight

  • Medications:

    • Deferoxamine (SubQ or IV)

      • Dose adjustment in renal disease

    • Deferiprone (Oral, TID)

      • Side effects: GI symptoms, elevated hepatic enzymes

      • Causes neutropenia/agranulocytosis

      • No dose adjustment in renal disease

    • Deferasirox (Oral, daily)

      • Side effects: GI symptoms, elevated hepatic enzymes, renal toxicity

        • Contraindicated in patients with eGFR <40

Atransferrinemia /Hypotransferrinemia:

• Autosomal recessive

• Causes iron overload and microcytic/hypochromic anemia

• Treatment: FFP infusion, iron chelation

Sideroblastic anemia:

• Ringed sideroblast in bone marrow

• Most patients have iron overload

• Respond to Vitamin B6

Porphyria

Genetic enzymatic defects in the heme biosynthetic pathway

Erythropoietic Porphyria:

• Anemia is a hallmark of the erythropoietic porphyrias

  • Congenital erythropoietic porphyria (CEP)

  • Erythropoietic protoporphyria (EPP)

Hepatic Porphyrias:

• Four subtypes of porphyria present with acute hepatic features:

  • Acute intermittent porphyria (AIP)

  • Hereditary coproporphyria (HCP)

  • Variegate porphyria (VP)

  • δ-ALA dehydratase porphyria

• Hepatic porphyrias and porphyria cutanea tarda do not usually present with anemia.

  
  

Porphyria subtypes:

• Acute Intermittent Porphyria:

  • Autosomal dominant disorder that affects production of heme

  • Deficiency of the enzyme porphobilinogen deaminase

  • Symptoms: nausea/vomiting, abdominal pain, dark urine, photosensitivity, peripheral neuropathy, headache, seizures

  • Diagnosis involves: urine porphobilinogen and total porphyrin

    • If elevated: plasma and fecal porphyrins should be measured

    • Treatment:

      • Dextrose

      • Hemin (repression of ALAS1 synthesis) in severe cases

      • Givosiran (small interfering RNA directed against 5-ALA synthase-1 which results in decreased delta DLA and porphobilinogen)

  • Associated with risk for HCC

• Hereditary coproporphyria:

  • Autosomal dominant

• Variegate porphyria:

  • Autosomal dominant

• δ-ALA dehydratase porphyria:

  • Only acute porphyria that is inherited in autosomal recessive manner

  • δ-ALA dehydratase deficiency in the absence of lead poisoning

• Erythropoietic Protoporphyria:

  • Most commonly seen in children

  • Results from ferrochelatase gene mutation

• Congenital erythropoietic protoporphyria:

  • Autosomal recessive

  • Due to deficiency in uroporphyrinogen III synthase

  • Severe cutaneous photosensitivity and deposition of porphyrins in teeth (reddish brown teeth)

  • Treat with transfusion and discuss HSCT

• Porphyria cutanea tarda:

  • Deficiency in uroporphyrinogen decarboxylase (UROD)

  • Associated with blistering photosensitivity, especially on backs of hands/sun-exposed areas

  • Should receive phlebotomy or chelation to keep ferritin <50

  • Treat Hep C if associated (can be initial triggering factor)

  • Some patients treated with hydroxychloroquine and not require phlebotomy

  • Subtypes:

    • Sporadic (Type 1)

      • UROD deficiency seen in liver cells

      • Also with HFE deficiency

    • Familial (Type 2)

      • UROD reduced throughout the body (autosomal dominant)

    • Type 3 (familial)

      • Due to familial inheritance without UROD mutation

      • Likely other etiology such as HFE mutation or shared acquired factors