Introduction – iron is a transition metal, which serves as a catalyst for oxygenation, hydroxylation and other pathways

• an essential element required by all human cells
• reversibly cycles between the ferrous (Fe+2) and ferric (Fe+3) states
• can form in free radical species when in excess Þ cell damage

Distribution of Body Iron – mg/kg

• Absorption - absorbed as both heme iron and nonheme iron through the bush border of the upper small intestine
• Heme iron - is 20-30% more absorbable than nonheme iron and is little affected by other elements of the diet
• Nonheme iron - 99% of dietary iron and is affected by other components of the diet
• Inhibitors of iron absorption: Phytates, tannates and phosphates inhibit iron
• Enhancers of iron absorption: amino acids and ascorbic acid
• Excretion – no effective means of excreting iron; physiologic loss occurs primarily by sloughing of cells into the GI tract, urinary tract and skin
• women lose iron through pregnancy and menstration

• Transferrin – transporter protein which carries iron in the plasma and ECF to supply tissue needs
• three forms:
• (1) Apotransferrin
• (2) Monferric
• (3) Diferric
• Transferrin receptor – glycoprotein on cell membranes which binds the transferring-iron complex, is internalized in a vesicle where the iron is released and then returns to the cell membrane, liberating apotransferrin into the plasma
• present on all cells; greatest concentration found on erythroid precursors, placental tissue and the liver
• receptor number Ý dramatically in dividing cells
• Ferritin – water soluble iron storage protein which sequesters iron in a non-toxic form which is readily available for use
• each ferritin molecule can store up to 4500 iron atoms
• hemosiderin is a water-insoluble storage compound with a higher iron content and slower turnover than ferritin

• Major Pathway (unidirectional): Plasma transferrin Þ erythron Þ monocyte-macrophage system Þ plasma transferrin
• storage iron in the macrophages of the liver, bone marrow and spleen is derived almost entirely from phagocytosis of senescent erythrocytes or defective developing red cells
• the macrophage has a limited ability to take up iron from plasma transferrin (most macrophage iron is from phagocytosis of erythrocytes); in contrast, hepatocytes both donate iron to and receive iron from plasma transferrin
• macrophages exchange 5X as much iron as hepatocytes
• Minor Pathways (equal exchange of iron absorption and loss):
• Plasma Þ Extravascular Transferrin Compartments Þ Parenchymal Tissues (can also go in opposite direction)

• Three Stages of Iron Deficiency
• (1) Iron Depletion: ß iron storage without a decline in the level of functional iron compounds
• (2) ß iron stores leading to limited production of Hgb and other metabolically active compounds which require iron; iron deficiency erythropoiesis develops; may be difficult to detect the effect on Hgb production
• (3) Frank iron deficiency anemia
• Epidemiology – most common cause of anemia in the US and worldwide
• 30% of world population or 4.5 billion people are anemic and 50 to 15% are iron deficient
• Ý prevalence Þ ß bioavailable iron, people who suffer chronic GI blood loss due to helminth infections, children undergoing growth spurts, and women of child bearing ages
• Etiology and Pathogenesis of iron deficiency anemia
• Menorrhagia
• GI Tract Bleeding (esophagitis, esophageal varices, hiatus hernia, peptic ulcer, inflammatory bowel disease, hemorrhoids, CA of the stomach, esophagus, colorectal region)
• GI tract malabsorption (celiac disease, gastritis)
• growth spurts (especially premature infants)
• pregnancy
• strict vegetarians
• hematuria
• infection (hookworm infections are the most common cause of iron deficiency worldwide)
• Pregnancy: lose 500 mg of iron Þ 270 mg is donated to the fetus, 90 contained in cord and placenta and 150 mg is lost at delivery
• Clinical Presentation – may be asymptomatic; symptoms often insidious in onset and prolonged in duration before diagnosis
• Symptoms common to all anemias Þ pallor, palpitations, tinnitus, anginal chest pain, headaches, weakness and ß exercise tolerance, dizziness and heart failure
• Symptoms from depletion of iron in nonerythroid tissues
• glossitis
• koilonychia (concave nails)
• postcricoid esophageal webs or strictures
• angular stomatitis (sores at the corner of the mouth)
• blue sclera (Impaired collagen synthesis)
• gastric atrophy
• pica (compulsive chewing or ingestion of nonfood substances)
• pagophagia – variant of pica in which ice is consumed
• Plummer-Vinson syndrome (Patterson-Kelley Syndrome) – glossitis, sore or burning sensation in the mouth, dysphagia and iron deficiency
• Non hematologic Consequences: impaired immunity, behavioral and neuropsychiatric abnormalities
• Differential Diagnosis of Iron Deficiency
• early iron deficiency Þ normocytic normochromatic anemia
• late iron deficiency Þ microcytic, hypochromic anemia
• differential diagnosis for microcytic, hypochromic anemia:
• ß body iron stores Þ iron deficiency anemia
• normal or Ý body iron stores
• Impaired iron metabolism (anemia of chronic disease, defective absorption, transport or utilization or iron)
• Disorders of globin synthesis (Thalassemia, microcytic hemoglobinopathies)
• Disorders of heme synthesis: siderblastic anemias (hereditary, acquired, lead intoxication
• Anemia of chronic disease: disorder of iron utilization rather than a lack of body iron
• commonly seen in patients with infections, chronic inflammatory disorders or malignancy
• mediated by cytokines that inhibit release of iron from macrophages
• characterized by ß serum iron and TIBC and Ý serum ferritin which is an acute phase reactant
• Diagnosis of Iron Deficiency (see table 4 in syllabus for normal and pathologic values)
• Common Tests: Serum iron level, total iron binding capacity (TIBC), ferritin and % saturation of hemoglobin
• Other tests: ß MCV, ß reticulocyte count, Ý RDW and occasionally thrombocytosis
• Treatment of Iron Deficiency - supply sufficient iron to repair the hemoglobin deficit and replenish storage iron
• Oral iron is the treatment of choice Þ effective, safe and cheap; 150 to 200 mg of elemental iron daily in divided doses on an empty stomach; continue oral iron for 4 to 6 months or until plasma ferritin is > 50m g/L
• 3 mg/kg daily for children
• Parenteral Iron – risk of local and systemic adverse reactions; reserved to patients who can not tolerate or absorb oral iron
• may cause anaphylactic reaction

• Introduction – iron requirements are limited and human lack a physiologic means of excreting excess iron Þ a sustained Ý in intake may eventually result in an accumulation of iron
• Causes in Adults and Children – Ý absorption of dietary iron, parenteral administration or a combination of both
• Causes in Neonates and Infants – rare disorder resulting from abnormality in iron balance between mother and fetus
• Epidemiology – in US, most common form is the homozygous state for hereditary hemochromatosis; 3-7.7/1000
• Thalassemia major and other iron-loading anemia are an important public health problem in countries bordering Mediterranean and from southwest Asia and Indian subcontinent to southeast Asia
• Sub-Saharan Africa – dietary iron overload from beverages brewed in iron containers
• Disorders of Iron Overload
• Hereditary hemochromatosis (HH)
• Iron-loading anemias (Thalassemia syndromes)
• Defects of Iron transport + Metabolism
• Excessive Iron Intake
• Porphyria cutanea tarda
• Liver disease
• Clinical Presentation of Overload
• Skin – hyperpigmentation in 30-40%; scant facial, pubic and axillary hair; atrophy of dermis and epidermis
• Liver – hepatomegaly; deposits of hemosiderin in hepatocytes (later in Kuppfer cells, macrophages and bile ducts); micronodular and macronodular cirrhosis; alcoholic liver disease; fibrosis; hyperestrogenism (spider angiomas, gynecomastia); hepatcellular carcinoma (200X risk and most common cause of death in treated patients)
• Pancreas – diabetes in 30-60%; insulin resistance (due to excess iron in hepatocytes) and impaired insulin secretion
• Endicrinopathies – hypogonadism; loss of libido, testicular atrophy, impotence, amenorrhea; spares body hair
• Joints – arthropathy in 40-70% resembling degenerative joint disease; chondrocalcinosis (50%); pseudogout
• Cardiac – hypertrophy in 20-30%; often presenting sign and cause of early death; congestive cardiomyopathy, arrhythmias
• Other – abdominal pain in 10-20%; gram (-) bacterial infections esp. Yersinia enterocolitica; ß CD8 cell function
• Treatment of Iron Overload
• phlebotomy is treatment of choice for HH, iron-loading anemia (if the Hbg concentration is high enough), porphyria cutanea tarda and for African dietary iron overload
• Iron Chelators desferrioxime – for transfusion dependent refractory anemia, most patients with iron –loading anemias and for patients with HH where phlebotomy is impossible
• Prognosis – poor for non-treated (18% 5 year survival and 6% 10 year survival)
• Phlebotomy – 62% are alive 15 years; 80% 10 year survival when iron levels reduced to near normal
• some symptoms show improvement while others do not
• Marked improvement – weakness, fatigue, lethargy, Ý serum hepatic enzymes, hepatomegaly, abdominal pain, hyperpigmentation
• Little or No change – hepatic cirrhosis, Ý risk for primary liver CA, abnormal serum iron levels, excess absorption and storage of nonferrous metals, risk of infections

Hereditary Hemochromatosis (HH) – first recognized as diabetes, skin bronzing and cirrhosis

• General: autosomal recessive disorder associated with HLA-A3; gene mutation on Chromosome 6
• normal body stores in adults are between 3 to 4 gm; in HH the iron content is between 15 to 50 gm which mobilizable iron stores of 20 to 30 gm by age 40 to 60; rate of iron accumulation is earliest in the early adult years
• phenotypic expression depends on genetic status (homozygote vs. heterozygote), amount of bioavailable iron in the diet, age of subject and extent of iron losses from the body
• 50% of affected males and 12% of affected females will become clinically ill with iron overload
• Genetic Aspects of HH – candidate HFE gene is located on chromosome 6; associated with HLA-A3 (also on chrom. 6)
• HFE encodes an HLA class-I like molecule; two mutation of the HFE gene have been described
• 82% of patients are homozygous for Cys282Tyr and 4% are compound heterozygotes for Cys282Tyr and His63Asp; 13% of patients with HH do not carry either mutation
• homozygous rate of 3 to 7.7/1000 and heterozygous rate of 106-160/1000
• Screening for HH – Ý prevalence in Caucasians Þ screening of unselected asymptomatic patients is not unreasonable
• serum ferritin and serum transferrin saturation are indicators of abnormal iron stores
• genetic testing now most specific test; HLA typing used to be used
• Diagnosis of HH – Laboratory testing: plasma transferrin saturation Þ greater than 70% on repeat testing is diagnostic
• Plasma transferrin saturation greater than 60% requires further investigation
• Serum ferritin > 200 in women and > 300 in men is suggestive
• Liver biopsy is gold standard:
• Hepatic iron index (HII) = m mol iron/dry weight/age in years – always greater 2 in HH
• Differential Diagnosis of HH – alcoholic liver disease Þ Ý serum iron and ferritin levels and Ý hepatic iron stores but not as high as HH and HII < 2
• chronic viral hepatitis Þ Ý serum iron and ferritin levels; HII < 2

• Epidemiology + Etiology - population is sub-Saharan Africa traditionally consume alcoholic beverages that were brewed in iron drums containing absorbable iron
• Distribution of Iron Deposition – differs from that in HH; predominantly found in the reticuloendothelial system
• Clinical Symptoms Þ cirrhosis, portal HTN, less diabetes, cardiomyopathy, hepatocellular Ca
• Screening and diagnostic tests are similar to HH
• Treatment – effects of phlebotomy are not well understood