Hematology Lecture PDF

Disorders of Iron Kinetics and Heme Metabolism General Concepts in Iron-related Disorders Anemia RBC life span is shortened or loss of RBC Lack of raw materials for hemoglobin assembly Iron is the limiting factor Anemia develops when the iron loss exceed iron intake Anemias are called “iron-restrict...

Disorders of Iron Kinetics and Heme Metabolism General Concepts in Iron-related Disorders Anemia RBC life span is shortened or loss of RBC Lack of raw materials for hemoglobin assembly Iron is the limiting factor Anemia develops when the iron loss exceed iron intake Anemias are called “iron-restricted” o Iron deficiency anemia o Anemia of chronic inflammation o Iron-loading anemias – impaired iron kinetics ▪ Involve chronic erythroid hyperplasia Seen in HEMOGLOBINOPATHIES and THALASSEMIAS o Heritable affecting globin chain Inadequate production of protoporphyrin – diminished production of heme and hemoglobin o With a relative excess of iron ▪ Sideroblastic Excess Iron metabolism without anemia o Hemochromatosis Iron-Restricted Anemia Chronic blood loss o Iron deficient - develops with repeated blood donations, chronic hemorrhage or hemolysis ▪ Results loss amounts of heme iron ▪ Excessive heme iron can be lost through repeated blood donations; chronic gastrointestinal bleeding from ulcers, tumors, parasitosis, diverticulitis, ulcerative colitis, or hemorrhoids gastritis caused by alcohol or aspirin ingestion UTI with kidney stones, tumors, or chronic infections. ▪ In women, prolonged menorrhagia (heavy menstrual bleeding) or conditions such as uterine fibroid tumors or uterine malignancies can also lead to heme iron loss ▪ Individuals with chronic intravascular hemolytic processes paroxysmal nocturnal hemoglobinuria - loss of iron in hemoglobin passed into the urine Iron Deficiency Anemia Pathogenesis Inadequate intake o Erythron is slowly starved o Each day, 1mg of iron is lost – in mitochondria o 1% of cells dying – anemia becomes apparent Increased need relative to iron supply o Rapid growth o Functional Iron Deficiency – iron stores are adequate but not adequate to support normal erythropoiesis Impaired absorption o Inability to absorb through enterocyte o Celiac disease – pathologic malabsorption o Matriptase-2 protein – inherited mutation that lead to production of hepcidin ▪ Caused ferroportin in enterocyte to be inactivated – no iron absorption in intestine o Diseases that decrease stomach acidity impair iron absorption ▪ By decreasing the conversion of dietary ferric iron to the absorbable ferrous form ▪ Normal aging – loss of acidity Gastrectomy or bariatric surgeries can impair iron absorption dramatically ▪ stomach acid reducers can inhibit iron absorption by decreasing gastric acidity Iron is distributed among three compartments: o storage compartment - ferritin in the bone marrow macrophages and liver cells o transport compartment – serum transferrin o functional compartment - hemoglobin, myoglobin, and cytochromes Hemoglobin iron, intracellular ferritin, hemosiderin 90% of the total distribution of iron Maintains iron balance by accelerating iron absorption from the intestine through a decrease in hepcidin production in the live A, A, K|3C 1 of 12 Stages of Iron Depletion ○ Stage 1 - Progressive loss of storage iron RBC production and development are normal; but no new iron is added Serum ferritin levels drop – indicates decline in storage iron Detected through iron stain of the bone marrow prevalence of stage 1 iron deficiency in the U.S has been estimated in toddlers (12 to 23 months) as 15.1%, in nonpregnant women (15 to 49 years) as 10.4%, and in pregnant women (12 to 49 years) as 16.3%.6 Decrease Normal Serum Ferritin Levels Rbc production and Development ○ Increase Stage 2 - Exhaustion of the storage pool of iron Rbc production continues as normal – relies on transport compartment and recycled dying cells Hemoglobin content of reticulocytes begins to decrease – onset of iron-restricted erythropoiesis Anemia is still not evident RDW begin to increase Iron dependent tissues such as muscles – begin to be affected Serum iron and serum ferritin levels decrease Total iron-binding capacity (TIBC), an indirect measure of transferrin – increases Free erythrocyte protoporphyrin (FEP) - the porphyrin into which iron is inserted to form heme Begins to accumulate w/o iron to complete heme formation Transferrin receptors increase as they try to capture as much available iron Soluble transferrin receptor (sTfR) levels increase Prussian blue stain of the bone marrow in stage 2 shows essentially no stored iron, and iron-restricted erythropoiesis Hepcidin measurably decreases iron deficiency in stage 2 is subclinical (latent iron deficiency) use of automated hypochromia measures reported with the complete blood count (CBC) to detect early iron-restricted erythropoiesis Decrease Normal Increase Hemoglobin content of reticulocytes Rbc Production RDW TIBC Transferrin Receptors FEP (Accumulation) sTfR Serum Iron and Serum Ferritin Hepcidin ○ Stage 3 - Frank anemia Hct and Hgb conc. are low relative Depletion of storage iron and diminished levels of transport iron Prevent normal development of rbc precursors RBCs become MICROCYTIC and HYPOCHROMIC As their ability to produce hemoglobin is restricted serum ferritin levels are exceeding low Free erythrocyte protoporphyrin (FEP) and Soluble transferrin receptor (sTfR) continues to increase hemoglobin content of reticulocytes will continue to drop automated hypochromia parameters will be increased A,A,K|3C 2 of 12 Decrease Hct and Hgb conc. Serum Ferritin levels Hepcidin would be decreased. patient experiences the nonspecific symptoms of anemia fatigue, weakness, and shortness of breath, especially with exertion. Pallor is evident in light-skinned individuals but also can be noted in the conjunctivae, mucous membranes, or palmar creases of dark-skinned individuals sore tongue (glossitis) - due to iron deficiency in the rapidly proliferating epithelial cells of the alimentary tract and inflamed cracks at the corners of the mouth (angular cheilosis) Koilonychia (spooning of the fingernails) Patients also may experience cravings for nonfood items, called pica. dirt, clay, laundry starch, or, most commonly, ice (craving for the latter is called pagophagia) Normal Increase FEP sTfR Automated-Hypoc hromia ○ Hemoglobin content of reticulocyte Hepcidin If women of childbearing age do not receive proper iron supplementation, pregnancy and nursing can lead to a loss of nearly 1200 mg of iron Cow’s milk is not a good source of iron ○ breast milk is a better source of iron than cow’s milk infants need to be placed on iron- supplemented formula by about age 6 months ○ fetal stores of iron become depleted Iron deficiency is relatively rare in men and postmenopausal women ○ lose only about 1 mg/day Gastrointestinal disease ○ ulcers, tumors, or hemorrhoids ○ suspected iron-deficient ○ Regular aspirin ingestion and alcohol consumption can lead to gastritis and chronic bleeding Elderly individuals ○ May not eat a balanced diet, thus, there’s dietary defiency ○ Loss of gastric acidity w/ age can impair iron absorption Iron deficiency is associated with infection by hookworms ○ Necator americanus and Ancylostoma duodenale ○ worm attaches to the intestinal wall and literally sucks blood from the gastric vessels Iron deficiency is also associated with infection with other parasites ○ Trichuris trichiura, Schistosoma mansoni, and Schistosoma haematobium ○ heme iron is lost from the body as a result of intestinal or urinary bleeding. Soldiers subjected to prolonged maneuvers and long-distance runners also can develop iron deficiency ○ Exercise-induced hemoglobinuria, also called march hemoglobinuria develops when RBCs are hemolyzed by foot-pounding trauma and iron is lost as hemoglobin in the urine. Laboratory Diagnosis Epidemiology Menstruating women are at especially high risk Growing children are also at high risk– increased iron needs associated with growth Early stages of iron deficiency ○ detected with tests such as ferritin not likely to be ordered there’s virtually no physiologic evidence suggesting a declining iron state Tests for iron deficiency can be grouped into three general categories ○ screening, ○ diagnostic, and ○ specialized Screening for iron deficiency anemia ○ CBC results begin to show evidence of anisocytosis, microcytosis, and hypochromia declining values for the MCV, MCH, and MCHC ○ iron deficiency anemia in stage 3 includes a decreased hemoglobin concentration RDW greater than 15% elevated RDW can be an early and sensitive indicator A,A,K|3C 3 of 12 ○ ○ ○ ○ Polychromasia may be apparent early Poikilocytosis target cells and elliptocytes Thrombocytosis Results from chronic Bleeding Not a diagnostic parameter White blood cells are typically normal in number and appearance no consistent shape changes to the RBCs Biochemical markers of Iron deficiency anemia DIAGNOSTIC TESTING FOR IRON DEFICIENCY Biochemical Iron Studies remain the backbone for diagnosis of iron deficiency, though some argue that modern automated blood cell analyzers can supplant the biochemical studies Biochemical Analyses Transferrin levels increase when the hepatocytes detect low iron levels resulting in a decline in the iron saturation of transferrin that is more dramatic than might be expected simply from the decrease in serum iron level. Rarely assayed on non-anemic patients, though some results (such as serum ferritin) are abnormal during the latent period. Sensitive and quantitative detection of hypochromia and microcytosis A parameter that instrument manufacturer have developed that can be reported with a CBC to enhance detection of latent iron deficiency and that are even more sensitive to iron deficiency anemia These are also early indicator of impending anemia Provide early alert during latent period Serum Iron Reticulocyte parameter a measure of the amount of iron bound to transferrin (transport protein) in the serum TIBC an indirect measure of transferrin and the available binding sites for iron. Transferrin Saturation The percent of transferrin binding sites occupied by iron can be calculated from the total iron and the TIBC: Support the diagnosis of iron deficiency. Low absolute reticulocyte count = diminished rate of effective erythropoiesis because this is non regenerative anemia Amount of hemoglobin in reticulocyte can be assess on some automated blood cell analyzer Hemoglobin content of reticulocytes is analogous to MCH ( MEAN CELL HEMOGLOBIN) but for reticulocytes only. o MCH – average weight of hemoglobin per cell across the entire RBC population Stage 2 iron deficiency = hemoglobin content of reticulocyte is low. NOTE: Serum Ferritin Ferritin provides an intracellular storage repository for metabolically active iron. Yet ferritin is secreted into blood, and serum levels reflect the levels of iron stored within cells. Serum ferritin is an easily accessible surrogate for stainable bone marrow iron. IRON STUDIES used collectively to assess the iron status of an individual. Sideropenia serum ferritin and serum iron values are decreased in iron deficiency anemia Post transcriptional response to low iron levels Some RBC are nearly 120 days old whereas some other are 1 to 2 days old If iron deficiency is developing = MCH does not change until substantial proportion of the cells are deficient and the diagnosis is effectively delayed for weeks or months after iron-restricted erythropoiesis begins Measuring the hemoglobin content of reticulocytes enables detection of iron-restricted erythropoiesis within days as the first iron-deficient cells leave the bone marrow ➔ a sensitive indicator of iron deficiency. Specialized Test for Iron Status Abnormalities in tests for accumulated porphyrin precursors to heme are significant in differential diagnosis. A,A,K|3C 4 of 12 Free erythrocyte protoporphyrin (FEP) levels rise when iron is unavailable. In iron deficiency, FEP may form zinc protoporphyrin (ZPP) when preferentially chelated with zinc. FEP and ZPP can be assessed fluorometrically, although they are not particularly valuable in the diagnosis of iron deficiency. Soluble transferrin receptor (sTfR) can be assay using immunoassay and the levels increase progressively with the disease, reflecting increased iron uptake attempts by cells. Bone marrow assessment isn't routinely recommended for suspected uncomplicated iron deficiency. A therapeutic trial of iron is less invasive and less expensive for diagnosis. Marrow examination for iron is typically performed when a bone marrow specimen is collected for other reasons. With the routine stains, the Iron-deficient bone marrow appears hyperplastic initially with decreased myeloid-to-erythroid ratio due to increased erythropoiesis. As iron deficiency progresses, hyperplasia diminishes(subsides), leading to slowed red blood cell (RBC) production. Polychromatic normoblasts (rubricytes) exhibit profound morphologic changes, including nuclear-cytoplasmic asynchrony, with delayed cytoplasmic maturation lagging behind nuclear maturation Without pink provided by the hemoglobin = cytoplasm remains bluish after the nucleus began to condense Cell membranes appear irregular and usually described as shaggy Treatment and Its Effect TREATMENT The first therapy for iron deficiency is to treat any underlying contributing cause, such as hookworms, tumors, or ulcers. As in the treatment of simple nutritional deficiencies or increased need, dietary supplementation is necessary to replenish the body’s iron stores. Oral supplements of ferrous sulfate are the standard prescription. The supplements should be taken on an empty stomach to maximize absorption. Many patients experience side effects such as nausea and constipation, however, which leads to poor patient compliance. Vigilance on the part of the health care providers is important to ensure that patients complete the course of iron replacement, which usually lasts 6 months or longer. Use of oral bovine lactoferrin to provide iron supplementation has been studied in developing nations. The intestinal side effects are reduced compared with ferrous sulfate while being equally effective in correcting iron deficiency. In rare cases in which intestinal absorption of iron is impaired (e.g., in conditions like gastric achlorhydria, celiac disease, or matriptase-2 mutations causing iron-refractory iron deficiency anemia or IRIDA), intravenous administration of iron dextrans can be used, although the side effects of this therapy are notable. Because of the risks associated with RBC transfusions, they are rarely warranted for the correction of uncomplicated iron deficiency unless the patient’s hemoglobin level has become dangerously low, like the patient in this chapter’s case study Response to Treatment When optimal treatment with iron is initiated, the effects are quickly evident. The hemoglobin content of reticulocytes will correct within 2 days. A,A,K|3C 5 of 12 Reticulocyte counts (relative and absolute) begin to increase within 5 to 10 days. The anticipated rise in hemoglobin appears in 2 to 3 weeks, and levels should return to normal for the individual by about 2 months after the initiation of adequate treatment. The peripheral blood film and indices still reflect the microcytic RBC population for several months, with a biphasic population including the younger normocytic cells. The normocytic population eventually predominates. Iron therapy must continue for another 3 to 4 months to replenish the storage pool and prevent a relapse. It is common and reasonable for care providers to assume that iron deficiency is due to dietary deficiency because that is the case in most instances of iron deficiency. Thus supplementation should correct it. If the patient has been adherent to the therapeutic regimen, the failure to respond to iron treatment points to the need for further investigation. The patient may be experiencing continued occult loss of blood or inadequate absorption, justifying additional diagnostics. The rare, but likely underdiagnosed, hereditary causes of iron deficiency should be considered. Alternatively, causes of hypochromic, microcytic anemia unrelated to iron deficiency, such as thalassemia, should be investigated. ANEMIA OF CHRONIC INFLAMMATION Contributors Impaired ferrokinetics Hepcidin Anemia Associated with systemic disease including chronic inflammation condition such as rheumatoid arthritis, chronic infection such as tuberculosis or human immunodeficiency virus infection, and malignancy Cartwright first to suggest that although the underlying diseases seem quite disparate, the associated anemia may be from a single cause, proposing the concept of anemia of chronic disease. Etiology Anemia associated with chronic systemic disorders was originally labeled as anemia of chronic disease. Chronic blood loss does not lead to the anemia of chronic disease; it results in quantitative iron deficiency. Anemia of chronic disease is more accurately termed anemia of chronic inflammation due to inflammation's role among the conditions causing it. The central feature of anemia of chronic inflammation is sideropenia despite abundant iron stores. The cause is primarily impaired ferrokinetics, leading to iron-restricted erythropoiesis. Impaired erythropoiesis and shortened RBC life span are additional contributors to the condition. Impaired erythropoiesis Diminished erythropoiesis Shortened red blood cell life span is a hormone produced by hepatocytes to regulate body iron levels, particularly absorption of iron in the intestine and release of iron from macrophages and hepatocytes interacts with and causes degradation of transmembrane protein ferroportin, which exports iron from enterocytes into the blood, thus reducing the amount of iron absorbed into the blood from the intestine Macrophages and hepatocytes also use ferroportin to export and recycle iron into blood and are affected by hepcidin An acute phase reactant ❖ During inflammation, the liver increases the synthesis of hepcidin in response to interleukin-6 produced by activated macrophage NOTE When systemic body iron levels decrease, hepcidin production by hepatocytes decreases, and enterocytes export more iron into the blood Macrophage and hepatocyte release of iron also increases. When systemic iron levels are high, hepcidin increases, enterocytes export less iron into the blood, and macrophages and hepatocytes retain iron The increase in hepcidin occurs regardless of systemic iron levels in the body. As a result, during inflammation, there is a decrease in iron absorption A,A,K|3C 6 of 12 from the intestine and iron release from macrophages and hepatocytes. Although there is plenty of iron in the body, it is unavailable to developing RBCs because it is sequestered in the macrophages and hepatocytes The elevation of hepcidin during inflammation may be a nonspecific defense against invading bacteria Hepcidin rise is not harmful during disorders of short duration, chronically high levels of hepcidin sequester iron for long periods, which leads to diminished production of RBCs. Lactoferrin A second iron-related acute phase reactant seems to contribute to anemia of chronic inflammation, although probably to a much smaller extent than hepcidin Important to prevent phagocytized bacteria from using intracellular iron for their metabolic processes. Provide protection for the phagocyte from oxidized iron that forms when reactive oxygen species (ROS) are produced during phagocytosis During infection and inflammation, neutrophil lactoferrin is released into the blood and extracellular spaces with the death of neutrophils When it is carrying iron, lactoferrin binds to macrophages and liver cells that take up and salvage the iron. Because of high hepcidin, macrophages and hepatocytes cannot export iron and it remains sequestered away from erythroblasts o Erythroblasts cannot acquire iron salvaged by lactoferrin directly because they do not have lactoferrin receptors o Resulting of these effects during chronic inflammation is a functional iron deficiency; iron is present in abundance in storage but unavailable to developing erythroblasts Inflammatory cytokines, including tumor necrosis factor-alpha and interleukin-1 from activated macrophages and interferon-gamma from activated T cells, hinder erythroid progenitor cell proliferation. They reduce the responsiveness of these cells to erythropoietin and decrease kidney production of erythropoietin. Shortened RBC life span A third factor in chronic inflammation-related anemia is a shortened RBC life span, attributed to an extracellular mechanism. Increased production of hemophagocytic macrophages is linked to inflammation, potentially influencing RBC life span. Despite the role of inflammatory suppression and shortened RBC life span, impaired ferrokinetics is deemed the primary cause of chronic inflammation-related anemia LABORATORY DIAGNOSIS o There it scavenges iron that would otherwise induce oxidative damage. In this way, lactoferrin is anti-inflammatory NOTE Diminished erythropoiesis This maldistribution of iron can be seen histologically with iron stains of bone marrow that show iron in macrophages but not in erythroblasts o effect on the developing erythroblasts is essentially no different from a mild iron deficiency because they are effectively deprived of the iron. So, like iron deficiency anemia, this is iron-restricted erythropoiesis Anemia of chronic inflammation presents as mild anemia with hemoglobin concentration typically 8 to 10 g/dL, lacking reticulocytosis, and featuring normocytic, normochromic cells. Microcytosis and hypochromia, if present, often indicate coexistent iron deficiency alongside inflammation. Inflammatory conditions leading to anemia may also induce leukocytosis, thrombocytosis, or both. Iron studies reveal low serum iron and total iron-binding capacity (TIBC) values, reflecting abundant iron stores in hepatocytes due to regulated transferrin production. Transferrin saturation may be normal or low, while serum ferritin levels, as acute-phase reactants, are typically increased, indicating the inflammatory condition. Failure to incorporate iron into heme leads to elevated free erythrocyte protoporphyrin (FEP), though not typically used diagnostically. Reticulocyte hemoglobin content is decreased, indicating iron-restricted erythropoiesis, while soluble transferrin receptor (sTfR) levels remain normal, reflecting normal intracellular iron. Bone marrow exhibits RBC hypoproliferation, with abundant iron stores in macrophages but not RBC precursors, although not typically required in diagnosis. Diagnosis of iron deficiency anemia in the presence of inflammation poses challenges due to increased serum ferritin levels. Measurement of sTfRs in serum can aid in distinguishing the two conditions. Additional modifications to the sTfR assay have been developed to better differentiate iron deficiency, latent iron deficiency, and anemia of chronic inflammation, with the sTfR/log ferritin ratio aiding in diagnosis. The Thomas plot, graphing hemoglobin content of reticulocytes against sTfR/log ferritin, may distinguish A,A,K|3C 7 of 12 When an enzyme in heme synthesis is missing, the products from the earlier stages in the pathway accumulate that actively produce heme, such as erythrocytes and hepatocytes. The excess porphyrins leak from the cells as they age or die and may be excreted in urine or feces which allows diagnosis. The accumulated products also deposit in the body tissues and some products are fluorescent. Accumulation during childhood leads to fluoresence of developing teeth and bones. Their deposition in the skin can lead to photosensitivity with severe burns on exposure to sunlight. Only three of the porphyrias have hematologic manifestations; the others have a greater effect on liver cells. Even in those with hematologic effects, the hematologic impact is relatively minimal, and photosensitivity is a greater clinical problem. The fluorescence of some accumulated compounds can be used diagnostically, for example, to measure FEP. In a BM spx, the erythroblasts will appear bright red under fluorescent microscope. IRON OVERLOAD (TABLE 17.2) - May be primary like hereditary hemochromatosis, or secondary to chronic anemias, and their treatments. the toxic effects of excess iron lead to serious health problems as lipids, proteins, nucleic acids, and heme iron become oxidized ETIOLOGY Excess Iron Result from acquired or hereditary conditions in which the body’s rate of iron acquisition exceeds the rate of loss, which is about 1mg/day. Regardless of the source of iron, the body’s first reaction is to store excess iron in the form of ferritin and hemosiderin within the cells. - Once storage system is overwhelmed, parenchymal cells are damaged in organs such as the liver, heart, and pancreas. Acquired condition; occurs when there is a need for repeated transfusions Treatment of anemias eg. Sickle Cell Anemia and B-Thalassemia Major. The iron present in the transfused RBCs exceeds the usual 1 mg/day of iron typically added to the body's stores by a healthy diet. This is sometimes called transfusion-related hemosiderosis. A,A,K|3C 9 of 12 Hereditary Hemolytic Anemias - Innately iron loading, even without transfusion therapy. Hemolytic anemias causes the BM to develop a compensatory erythroid hyperplasia. Erythroblasts can downregulate hepcidin production by secreting erythroferone. If >erythroblast, as in compensatory erythroid hyperplasia, then erythroferrone is increased, hepcidin is decreased, and more than the usual amount of iron is absorbed and recycled. Table 17.3 describes the known forms of hemochromatosis, its mutated protein, age of onset, inheritance pattern, the nature of the mutation, and its effect. Mutations of the HFE gene remain the most common. Involves mutated proteins that impair hepcidin regulation of ferroportin activity. Other iron overload conditions like hemochromatosis type 5 and hypotransferrinemia Involve mutations of proteins involved in iron kinetics but NOT the ferroportin axis. - - In Chronic Hemolytic Anemia, this will lead to excessive accumulation of iron. Though it is seen most often in hereditary hemolytic anemias, the iron loading is secondary to the hereditary condition that causes the hemolysis. If hemolysis is controlled, the iron loading subsides. Thus, this is ACQUIRED iron overload in HEREDITARY anemia. Hemochromatosis may be a result of mutations in genes for proteins controlling iron kinetics A true hereditary iron overload. Homozygous Hereditary Hemochromatosis Involved the HFE gene occurs in approx. 5 of 1000 Europeans. Heterozygosity approaches 13% First 2 mutations are known to produce the hereditary hemochromatosis phenotype involve HFE, a gene on the short arm of chromosome 6 which encodes an HLA class I like molecule that’s closely linked to HLA-A. Most common of the two mutations substitutes tyrosine to cysteine at position 282 and the other substitutes aspartate for histidine at position 63. HFE should bind with B2-microglobulin intracellularly Binding is necessary for the HFE to appear on the cell surface which will interact with Transferrin receptor 1, A,A,K|3C 10 of 12 then TfR1 will bind with transferrin, then HFE is released. It will be associated with TfR2, bone morphogenetic protein and its receptor, and hemojuvelin. This complex initiates a signal for hepcidin production, which reduces iron absorption. The MUTATED HFE either does not bind B2-Microglobulin - LABORATORY DIAGNOSIS - PATHOGENESIS - - - - - - - - Process described leads to increased amounts of iron in parenchymal cells throughout the body. 1st cellular reaction to excess iron is to form(degenerated and non-metabolically active form) ferritin and hemosiderin. Ferrous iron accumulates intracellularly when cells exhaust the capacity to store iron as hemosiderin. In the presence of oxygen, ferrous iron initiates the generation of superoxide and other free radicals, which then result to peroxidation of membrane lipids. The membranes affected include the mitochondrial, nuclear, and lysosomal membranes. Since cell respiration is compromised, lysosomal enzymes are released intracellularly. Vit. E and C can act to moderate the effects and interrupt the reaction, but in iron overload, these protective mechanisms are overwhelmed. And this will result to cell death caused by irreversible membrane damage. The tissues most affected are the skin, where hemosiderin deposition gives skin a golden color; the liver, where cirrhosis-induced jaundice and subsequent cancer may develop; and the pancreas, where damage can cause DM. Hemochromatosis is characterized as “bronzed diabetes.” The heart muscle is also vulnerable to excessive iron, which leads to congestive heart failure. Hepatocellular carcinoma occurs more in patients with Hemochromatosis because of the contribution of mutation of the p53 tumor suppressor gene. In Classic Hereditary Hemochromatosis, Patients usually harbor 20-30g of iron by the time their disease becomes severe at the age of 40-60 years. 10 times greater than a healthy individual’s iron (1 to 2 mg/day) In Slower-Developing Diseases, Phenotypic expression of the tissue damage is more common in men but frequency is NOT HIGHER in men. Blood loss associated with menstruation and childbirth prevents excess iron in affected women. In each sex, homozygous individuals develop clinical disease faster than heterozygous. Amount of iron available in the diet for absorption affects the rate at which disease develops. Substances such as ascorbic acid and alcohol can promote iron absorption even in normal individuals. In transfusion-related hemosiderosis, the frequency of transfusions over time affects the CD development rate. - - - - - Lab testing in hemochromatosis serves four purposes: 1. Screen for the condition 2. Diagnose the cause of organ damage 3. Pinpoint the mutation for family genetic counseling 4. Monitor treatment Elevations of transferrin saturation or serum ferritin can be used for as a screening test for HEREDITARY HEMOCHROMATOSIS. Individuals with undiagnosed HH may come to medical attention because of organ function problems leading to non-specific physical complaints (abdominal pain). Disease MAY be discovered with routine Lab testing; abnormal result on liver function test (↑ alanine transaminase level) may be the first lab finding. Diminished levels of liver synthetic products, such as albumin, can also be helpful. Genetic Testing: provides confirmation of the diagnosis for patients with HH. Whether hemochromatosis is acquired or hereditary, the serum ferritin provides an assessment of the degree of Iron Overload and can be monitored after treatment to reduce stored iron. Hgb concentration and Hct are inexpensive tests that can also be used to monitor treatment. Liver biopsy assessment of iron staining and degree of scarring in liver spx is essential to determine the degree of organ damage. TREATMENT - Treatment for secondary tissue damage (i.e., liver cirrhosis and heart failure) follows standard protocol. Hereditary Hemochromatosis - - withdrawal of blood by phlebotomy provides a simple, inexpensive, and effective means of removing iron from the body. weekly phlebotomy early in treatment to remove about 500 mL of blood per treatment. Maintenance: required for 3 months for life! Hgb levels should be monitored, and MILD anemia should be sought and maintained. A,A,K|3C 11 of 12 Individuals who rely on transfusions to maintain Hgb levels and prevent anemia CANNOT be treated with phleb. ○ IRON-CHELATING DRUGS are used to bind excess iron in the body for excretion. ○ Deferoxamine, a classic treatment. The drug is administered subcutaneously with an infusion pump over 8 to 12 hours to maximize exposure time for iron binding. ○ When absorbed in the blood stream with its bound iron, it is readily excreted in the urine. ○ Oral iron chelators have been developed. Though they have side effects, the convenience of oral administration with the potential for improved patient outcomes may lead to a greater reliance. A,A,K|3C 12 of 12