Iron and Heme Metabolism Disorders

Disorders of Iron and Heme Metabolism

• Covers iron metabolism, dietary iron absorption, transport, storage, loss, excretion, and human requirements.
• Analyzes the optimal time of draw and specimen type for iron testing.
• Evaluates the six iron status laboratory assays, including methodology and normal ranges.
• Provides means of identifying cells and corresponding clinical disorders using patient history and/or clinical laboratory results.
• Examines various therapies for anemias related to abnormal iron metabolism.
• Includes lead intoxication in children and adults, covering pathophysiology, clinical and physical findings, and laboratory correlations.
• Aims to assess lab results that can diagnose the five most common porphyrias.

Iron Metabolism

• Iron is essential for all living organisms for cellular growth, oxygen transport, and RBC proliferation.
• An average adult has a total body iron content of 3500-4000 mg
• 2/3 of total body iron is found in hemoglobin
• 1/3 is in bone marrow, liver, and spleen
• The majority of iron comes from recycling.

Iron Requirements

• The minimum daily requirement of Fe depends on age, sex, weight, health, and physiological states like menstruation, pregnancy, and lactation.
• The MDR for adults is 1 mg.
• Factors affecting daily iron requirements are chronic blood loss, increased need, and inadequate intake.
• Serum iron (Fe) levels show both monthly and diurnal variation so labs for must be drawn first thing in the am & while fasting.

Iron Metabolism and Storage

• Iron is ingested as Fe3+
• Stomach acid (pH 4) reduces Fe3+ to Fe2+ for absorption in the gut.
• Gut mucosal cells oxidize Fe2+ back to Fe3+.
• Iron transported by transferrin distributes to body tissues or is stored in bone marrow, liver, or spleen.
• 80% of the iron carried by transferrin is used for heme synthesis.
• Two atoms of ferric iron can bind to one transferrin molecule.
• Iron not used by erythropoiesis is stored as ferritin or hemosiderin.
• Ferritin is the major storage form of iron, is water-soluble, and is easily used by the body although, it is only seen via electron microscopy (Apoferritin + Fe = Ferritin).
• Hemosiderin is not water-soluble, is less readily available, represents iron aggregates, and is seen with Prussian blue stain
• It becomes available in iron-deficient patients.

Iron Molecules and Compounds

• Dietary Iron, either Fe2+ or Fe3+, is located in the upper GI and its function is myoglobin/Hgb/enzymes.
• Hemoglobin is Fe2+, located in RBCs and binds oxygen.
• Transferrin is Fe3+, located in serum transporting iron (Fe).
• Ferritin is Fe3+, located in serum/tissue for iron storage.
• Hemosiderin the iron storage, is Fe3+ located in bone marrow.

Laboratory Evaluation of Iron

• The standard "Fe Panel" includes Serum Fe, TIBC, Serum Ferritin, & % Transferrin Saturation.
• Serum Fe measures transferrin-bound iron, the normal range is 50-160 ug/dL although the assay is not especially sensitive for IDA.
• Total Iron Binding Capacity (TIBC) measures total iron that can be bound by transferrin.
• TIBC indirectly evaluates transferrin concentration; the normal range is 250-400 ug/dL.
• Increased TIBC means the body wants more iron.
• Serum Ferritin is an immunoassay that evaluates body iron stores.
• Despite being intracellular, its concentration in circulation is proportional to storage amount
• Advantage: the first lab test that becomes abnormal when iron stores decrease, normal range is 40-400 ng/mL.
• Ferritin is an acute phase reactant, so it is elevated during any inflammatory response
• % Transferrin Saturation is measured as the maximum iron amount bound in plasma or serum
• The normal range is 20-55% saturation.
• Calculation: % saturation = serum iron/TIBC X 100%
• Free Erythrocyte Protoporphyrin (FEP) or Zinc Protoporphyrin (ZPP) means Iron is not available to be incorporated into the protoporphyrin ring to form heme causing excess protoporphyrins to form and complex with zinc.
• The FEP/ZPP value correlates inversely with the ferritin level so the worse the IDA, the more protoporphyrin is left over!
• It can be useful when measured fluorometrically to differentiate IDA from Thalassemia, normal range: (NR = < 80 ug/dL).
• Soluble Transferrin Receptor is a measurement of transferrin receptors which Is inversely proportional to the amount of body iron.
• Numbers increase in relation to IDA severity
• Transferrin receptor levels remain normal in Anemia of Chronic Inflammation, so this assay can distinguish the two states.

Approach to Anemia

• It can be difficult to focus on different morphology but certain anemias can look alike
• Definition according to WHO criteria:
• Men, Hb < 13.0 g/dL or Hct < 40%
• Women, Hb < 12.0 g/dL or Hct < 36%
• Useful measurements include :
• MCV (mean corpuscular volume): 80-100 fl
• RDW (red cell distribution width): increased value indicates RBCs of differing sizes
• Reticulocytes: indicates the bone marrow’s ability to respond

Iron Deficiency Anemia

• IDA is the most common anemia affecting 2 billion people worldwide
• Occurs whenever iron (Fe) loss or need exceeds intake.
• Causes include:
• States of increased physiologic demand such as rapid growth in infants and children, and during pregnancy and lactation
• Prenatal iron stores run out in the first few months after birth
• Inadequate intake of iron including, iron deficient diets from conditions such as anorexia, being impoverished or elderly
• Inadequate absorption due to GI dysfunction
• Chronic blood loss, such as increased menstrual flow, bleeding from gastric ulcers or GI carcinoma
• Frequent blood donation, or chronic hemolysis from malaria or paroxysmal nocturnal hemoglobinuria.
• Hookworm infestation as caused by Necator americanus or Ancylostoma duodenale is a cause

Clinical Symptoms of IDA:

• Common symptoms of all anemias (related to less oxygen delivery) include pallor, weakness, and fatigue.
• Severe anemias can lead to dyspnea and dizziness.
• Characteristic IDA symptoms include pica which is persistent, compulsive desire to eat a single food or nonfood item.
• Another characteristic IDA symptom is koilonychia (flattened, spooned nails).

Anemia Lab Findings in IDA

• Microcytic hypochromic anemia will be present
• MCV: 55 – 74 fL
• MCHC: 22 – 31 g/dL
• MCH: 14 – 26 pg
• Presence of moderate aniso with increased RDW (red cell distribution width)
• Blood smear shows poikilocytosis with codocytes/target cells, elliptocytes or ovalocytes, and dacrocytes/teardrop cells.
• RPI (reticulocyte production index) < 2
• Iron deficiency can progress in stages from normal iron status to stage 3 iron deficiency anemia.
• With iron depletion, serum ferritin decreases and TIBC increases. Later, serum iron decreases as does transferrin saturation.
• As Fe deficiency develops, FEP increases, bone marrow sideroblasts decrease and Hgb and MCV results decrease.
• Primary approach to IDA treatment is to treat the underlying and contributing causes along with prescribing oral iron supplements.
• Transfusions are only to be given in life threatening emergencies
• The retic count should increase within reaching maximum in about 10 days.
• Dimorphic population of red blood cells becomes evident as new "Fe (iron) normal" red blood cells increase in number, while the old "Fe deficient" red blood cells die off.

Anemia of Chronic Inflammation (ACI)

• The 2nd most common anemia
• ACI is associated with chronic infections and other states of chronic inflammation
• Its central feature is sideropenia
• The release of iron stores is defective even with abundant iron stores
• ACI is not due to bleeding, hemolysis, or bone marrow replacement by cancer or leukemia.
• The body withholds iron from inflamed/tumor cells in an attempt to starve them to death!
• Hepcidin, a hormone produced by hepatocytes decreases the amount of iron absorbed from the small intestine while Influencing the ability of macrophages and hepatocytes to retain iron.
• Hepcidin is an acute-phase reactant, so during inflammation (unrelated to iron levels), there is a decrease in iron absorption & macrophages retain iron.
• In ACI, Low measured Fe is not be the problem rather, Fe availability/release is the problem.
• Clinical signs and symptoms for ACI include decreased serum iron and % Tf saturation, having normal to increased ferritin levels and also decreased TIBC levels.
• ZPP and Tsr are normal or increased.
• It can cause mild to mod anemia with no reticulocytosis (body somehow knows it isn't really Fe deficient)
• To treat must treat the underlying condition
• The most effective course of treatment involves first, treating the underlying conditions in the patient, can give EPO, however must also supply iron supplements concurrently, which is most effective by doing that all at the same time
• Taking iron supplements alone (w/out EPO) could be harmful, even fatal

Anemias: IDA vs ACI

• IDA = Iron deficiency anemia (IDA), is due specifically to a deficiency of Fe
• Translation is not enough materials or resources
• ACI = Anemia of chronic inflammation is due to the defective release of stored iron from macrophages
• Translation is the access is cut off There are key differences that separate these two disorders In IDA, ferritin is ↓ & TIBC is ↑ In ACI, it's opposite! The common results also look very different IDA:
• Increased FEP (ZPP)
• Decreased % Tf sat
• Decreased serum Fe
• Decreased serum Ferritin
• Increased TIBC
• N to low of MCV & MCHC
• Low bone marrow Fe levels ACI
• Increased FEP (ZPP)
• Decreased % Tf sat
• Decreased serum Fe
• N to slightly increased serum Ferritin
• Decreased TIBC
• N to low MCV & MCHC
• Increased bone marrow Fe levels

Sideroblastic Anemias

• SA is due to defective usage of Fe within the bone marrow sideroblast Translation = they are broken or damaged (wont work)
• Two conditions to be considered in relation to discussing abnormal iron metabolism Lead Intoxication
• Actually a type of sideroblastic anemia Hemochromatosis
• Excessive iron overload

Sideroblastic Anemia

• Sideroblastic anemia is a diverse anemia group characterized by hypochromic anemia, and ineffective erythropoiesis, and an increase in serum and tissue iron.
• Also presence of ringed sideroblasts
• Very diverse with numerous disorders as well from inherited and acquired forms too

Sideroblastic Anemia Pathophysiology

• Involves abnormalities of the enzymes regulating heme synthesis Identified deficiencies of 6-ALA synthetase and uropophyrinogen decarboxylase Ringed Sideroblast (sieroblasts which iton is accumulated in the mitochondria that surround the nucleas)

Sideroblastic Anemia Definitions

• Sideroblast:
• normoblast containing free Fe granules (not incorporates into heme) in its mitochondria in red bone marrow and not in peripheral blood
• Siderocyte:
• mature RBC in peripheral blood - containing free Fe granules, "sideritic" - granules in its mitochondria and can be found in bone marrow and not PB

Sideroblastic Anemia- Hereditary

• Defect of δ-ALA synthetase typically due to autosomal or X-linked genetic disorder that leads to an impaired Heme synthesis
• Iron entering the erythroid precursor cannot be incorporated in the heme molecule because protoporphyrin ring cannot be formed -> iron builds up in mitochondria, it is very rate Treatment:
• Pyridoxine (B6), death is common and caused by Fe (iron) overload which results in cardiac arrhythmias liver disease and multiple organ failure Acquired (Idiopathic)
• RARS: refractory Anemia w/ Ringsted sideroblasts Rarely done due to non progressive and incpacilitating with treatment, may convert to leikemia

Sideroblastic Anemia Findings

• The findings are:

• Mod - severe anemia in peripheral blood, w/ WBC, platelets, and other components are normal +Micro, Hypo with dimorphic pop: so RDW ranges between low to normal +Anisocytosis with poikilocytosis, target cells and pappenheimer body and basophilic stippling/ stain +TIBC is normal or decreased slightly Ferritin, serum iron, % Tf sat are all increased for different reasons

Lab findings in sideroblastic Anemia

• These are Excessive iron bone Marrow " Normab Lasts" (N)

Lead Intoxication

• Lead in the blood effects Pb affects 3 main tissues Renal Hematopoetic Central Nervous System:
• Pb inhibits activity of 3 enzymes in heme synthesis

Pb Intoxication:

• Pb clinical: Abdominal pain that is called Lead colic Constipation of blood and/or vomiting Muscle weakness and motor disturbances
• Leadline: blue/ black deposit of lead sufide: gums ner teeth or nail beds- may cause psychiatric disturbances/ seizures and
• crosses placenta that effects severe cases for birth defects:

Lead Intoxication:

• Lead causes:
• Mild --> moderate "Micro" but there
• Serum feratin but elevated
• Hallmark in basophilic stippling that comes back up again: but it's heavier in
• Pb in the pathway
• Normal w/ TIBC

Other Tests for Porphyrias

• Rare hereditary (inherited) conditions due to an Impaired production of heme
• When enzyme is missing produces are called accumulative of earlier stages

Hemochromatosis

• Inappropriate " Abnormal accumulation of excess iron"
• Results in tissues damage
• Excess I stored that causes damage in liver as well Bronze skin pigmentation

Hemochromatosis Facts

• Hereditary can occur at 1:300
• Tf' REceptors or " Turned on" --> " Hyporfereimic" --> Absorbs normal but transfer more

Heredity hemocromatosis (HFE) on crs 6 Found with increase iron stores in excess More iron in the plasma

Hemochromatosis Etiology

acquired vs inherited secondary to other inherited hemolytic anemia with anemia efffectivness transfusions increase ion storage The pathogenesis

When you have excess Increase Ferritin Free and cells have the requirement and effects more iron Superoxide, free radicals cell causes cell damage as Symptoms Complain Joint or chromic fatigue Show majority in CVD --> CARDIAC arrhythmias, liver, cancer, cancer --> "10% of all diabetes" Early menopause and depre

Clinical Features (Hemochromatosis)

• High level "Tf" formula is indirect estemate " First Lab critera for diagnosis is: "" normal TIBC is a Normal and body needs it

Treament:

1- REMove excess iron from body aggressive Phlembotomy One has the Serum feritin

Treatment:

• IV" reduce stored stores"