Hematology I (SCIE2020) Harmening Chapter 6 - PART B

Hematology I (SCIE2020) Harmening - Chapter 6 : Part B (5TH ED) Harmening – Chapter 7 : Part B (6TH ED) Iron Metabolism and Hypochromic Anemia Define Define anemia of chronic disease List List come disorders associated with anemia of chronic disease...

Hematology I (SCIE2020) Harmening - Chapter 6 : Part B (5TH ED) Harmening – Chapter 7 : Part B (6TH ED) Iron Metabolism and Hypochromic Anemia Define Define anemia of chronic disease List List come disorders associated with anemia of chronic disease Define Define sideroblastic anemia State State the morphological finds for: anemia of chronic disease and sideroblastic anemia Compare and Compare and contrast iron studies for iron deficiency anemia, contrast Define OBJECTIVES anemia of chronic disease, and sideroblastic anemia Define porphyria Compare and Compare and contrast the hypochromic anemias contrast Describe Describe iron overload and hereditary hemochromatosis List List the causes of iron overload List List the characteristics of iron overload and hereditary hemochromatosis Recall…. Last day we learned about IDA Source; Harmening: Table 6 -19, p. 132 *Possibly Normal Anemia of Chronic Disease Anemia of Chronic Disease (ACD)  A common hematological disorder – Secondary to other disorders / diseases  Anemia of Chronic Disease (ACD) is the second most prevalent anemia after Iron Deficiency Anemia (IDA)  It is associated with chronic infections, autoimmune disease, chronic inflammation, and malignant neoplasms  It may presents 1-3 months after the onset of a chronic disease  Anemia is characterized by decreased serum iron levels, decreased TIBC, and decreased saturation of transferrin  Serum ferritin levels, however, are usually increased as a result of the iron being trapped in the RES cells of the bone marrow  This iron can be visualized in bone marrow aspirates stained with Prussian Blue Anemia of Chronic Disease (Cont’d) Pathophysiology  Some reference say the exact pathogenesis of ACD is unclear  It has been suggested that chronic disease states block the transfer of storage iron to erythroid precursors within the bone marrow Some possible causes of ACD include:  Shortened red cell survival (for some)  Failure of the bone marrow to increase red blood cell production  Impaired release of iron from the reticuloendothelial system (RES) Some Disorders/Conditions associated with Anemia of Chronic Disease Infections Tuberculosis Chronic osteomyelitis Fungal infections Burns Neoplasms Carcinomas / cancers Malignant lymphomas Multiple myeloma Autoimmune Disorders Systemic lupus erythematosus (SLE) Rheumatoid arthritis Sarcoidosis See Harmening Table 6-12, p 127 Anemia of Chronic Disease (Cont’d) Clinical Features  Anemia may be present for several months after the development of a chronic disorder  ACD may present as a mild-to-moderate anemia  In some cases, the anemia presents as a normocytic normochromic and in some other cases, the anemia presents as a microcytic hypochromic (Harmening p. 127)  The signs and symptoms of the disease are associated with the underlying cause Laboratory Findings  Anemia of chronic disease (ACD) is defined by an aggregate of clinical, morphological, and laboratory findings  Harmening Table 6-13, p.127 (also next slide)  Source: Harmening Table 6-13, p 127 Micro/Hypo Or Norm/Norm Source: Harmening Table 6-16 p. 130, Table continued on next slide ACD Source: Harmening Table 6-16 p. 130 D AC Source: Harmening: Table 6 -13, p. 127 Source; Harmening: Table 6 -19, p. 132 *Possibly Normal *Possibly Normal  Micro / Hypo or Norm / Norm Source: Harmening Figure 6-9 Normochromic, normocytic red blood cells in a patient with anemia of chronic disease. (Wright's stain, ×200) Anemia of Chronic Disease (Cont’d) BONE MARROW In the bone marrow there is:  an adequate number of erythroid precursors  the M:E ratio may be increased because of decreased erythropoiesis  Sideroblasts are decreased but the macrophages appear to have an increased amount of storage iron  Hemosiderin is the long-term storage of iron and may appear as very coarse aggregates of iron (Fig 6-10 next slide).  In contrast, hemosiderin is expected to be absent in IDA Source: Harmening Figure 6-10 Increased reticuloendothelial iron in a patient with anemia of chronic disease. (Prussian blue stain, ×200), p. 128 Anemia of Chronic Disease (Cont’d) Treatment  When possible, treatment for ACD is to fix the underlying disease first!  Blood transfusions may possibly be given for a rapid and effective intervention. Transfusions are helpful when there is a severe or life-threatening anemia. Sideroblastic Anemia Sideroblastic Anemia The sideroblastic anemias are:  A group of disorders characterized by a hypochromic anemia, ineffective erythropoiesis, an increase in serum and tissue iron, and the presence of ringed sideroblasts in the bone marrow.  Very diverse group of anemias and can be inherited or acquired.  The inherited sideroblastic anemias include sex-linked congenital sideroblastic anemia and autosomal recessive sideroblastic anemia.  The acquired sideroblastic anemias can be primary (also referred to as idiopathic) or secondary (see table 6- 4).  The secondary sideroblastic anemias are typically the result of toxins or drugs, such as chloramphenicol. Pathophysiology Sideroblastic anemias involve:  abnormalities of the enzymes regulating heme synthesis.  The “ringed sideroblast” is a characteristic of this group of anemias.  Have identified enzyme deficiencies,  including deficiencies of delta 5-aminolevulinic acid synthetase (ALA)  This enzyme initiates the heme synthetic pathway  Heme synthesis is impaired as iron enters the erythroid precursor which cannot be incorporated in the heme molecule because the protoporphyrin ring cannot be formed. Iron then accumulates in the mitochondria.  Sideroblastic Anemia (cont’d)  Iron then accumulates in the mitochondria.  The ringed sideroblasts are sideroblasts in which iron is accumulated in the mitochondria that surround the nucleus (Fig 6- 11).  These siderotic granules are visible with Prussian Blue stain.  Molecular defect involves the enzyme 5-aminolevulinic synthetase (ALA), an enzyme that initiates the heme synthetic pathway  Heme synthesis is impaired and iron cannot be incorporated into the heme molecule and iron accumulates in the mitochondria of developing erythroblasts Ringed Sideroblast in BM (Prussian Blue stain) Figure 6-11 Ringed sideroblast as detected by Prussian blue staining of a bone marrow aspirate. (Prussian blue stain, ×1000) Source: Harmening Table 6-14 p. 128 24 Sideroblastic Anemia (cont’d) Laboratory Findings PERIPHERAL BLOOD  The anemia is moderate-to-severe  The red blood cells are dimorphic, ranging from microcytes to normocytes  The MCV, MCH, and MCHC are usually normal  The RDW is increased, representing the dual population of red blood cells  Other abnormalities of the red cells include anisocytosis, poikilocytosis, target cells, Pappenheimer bodies (iron deposits in the red cell), and basophilic stippling  The WBC and platelet counts are usually normal In this one, we can see dual populations of RBCs Source: Harmening Figure 6-13 Dimorphic population of red blood cells with a striking hypochromic component in a patient with sideroblastic anemia. Moderate anisopoikilocytosis is also present. (Wright's stain, ×200), p. 129 Lead poisoning and sideroblastic anemia:  Lead poisoning impairs heme synthesis at several steps  The heme enzymes involved are 5-aminolevulinic acid dehydrase and ferrocheletase Basophilic stippling of the RBCs is also a common feature of lead poisoning. Source: Harmening Figure 6-12 Prominent basophilic stippling is found with defective heme synthesis. Sideroblastic Anemia (cont’d) BONE MARROW  The primary feature common to all sideroblastic anemias is the characteristic ringed sideroblasts in bone marrow aspirates  Ineffective erythropoiesis, erythroid hyperplasia, and increased stainable bone marrow iron are also characteristic of sideroblastic anemia  Iron stains reveal more than 15% ringed sideroblasts IRON STUDIES  Iron studies show increases in serum iron, increased ferritin, normal to decreased TIBC, and an increase in percent saturation levels.  Serum soluble transferrin receptor levels are usually normal or decreased. CLINICAL PRESENTATION  Variable, as it could be acquired or inherited Sideroblastic Anemia (cont’d) Treatment  It is important to know whether the anemia is hereditary or acquired  For example, in the case of secondary sideroblastic anemia caused by drugs, rapid improvement can be seen with the discontinuation of the offending medication  Anderson’s Atlas, p. 251 2nd Ed. p. 226-228 Sideroblastic Anemia 3rd Ed. p. 216-218 For Your Reference 30  Anderson’s Atlas, p. 252 2nd Ed. P. 227 3rd Ed. P. 216-218 For Your reference Ineffective erythropoiesis, Erythroid hyperplasia, Sideroblasts/ringed sideroblasts 31  Sideroblast nucleated RBC that has iron granules, Source:  Positive (+) with Prussian Blue stain Anderson’s Atlas, 2nd Ed. p. 226; 3rd Ed. p. 216 Siderocyte = anucleated RBC with iron granules,  Positive (+) with Prussian Blue stain 32  And back to the table we started with!  Summary and Comparison of Iron Studies in Microcytic-Hypochromic Anemia’s and Hemochromatosis Marrow Iron Transferrin Transferrin Saturation Stainable Receptor Disorder Ferritin Serum Serum Bone TIBC ZPP Iron Iron deficiency anemia D D I D I I Absent Anemia of chronic D I or N N/D N/D N/D I N/I disease I Sideroblastic anemia I I N/D I N/D V Ringed sideroblast Hereditary I I N/D I N/D N I hemochromatosis D = decrease; I = increase; N = normal; V = variable; TIBC = total iron-binding capacity; ZPP = zinc protoporphyrin 33 The Porphyrias   Rare disease; various subtypes; caused by disorders in heme synthesis  Essentially, it’s a disorder due to disruption of the Porphyrias normal heme biosynthesis pathway  Buildup of toxic metabolites/byproducts  For example, caused by mutations in the enzymes needed to metabolize aminolevulinic acid (ALA) and porphobilinogen (PBG) into heme so there’s a buildup of intermediate metabolites that have a variety of physiologic symptoms/effects   Classification: Neuro-visceral (abdominal pain with neurological symptoms) to Cutaneous (skin manifestations - lesions, skin blistering, lesions, pain) Porphyrias Spectrum of clinical symptoms: Acute attacks  may be neurologic (fatigue, mental confusion, seizures) or gastrointestional (abdominal pain/nausea/vomiting, constipation)  Acute Intermittent Porphyria (AIP) – inherited; get elevations in ALA and PBG – which is what causes the acute attacks (and these attacks could last for hours, days, weeks); could be life-threatening   Diagnosis: Acute attacks characterized by ALA or PBG (porphobilinogen) in urine “red wine color”; can test serum and stool; genetic testing; elevated liver enzymes; diagnosed during an attack Porphyrias  Management includes avoidance of precipitating factors/eliminating triggers (for example, alcohol, steroids, estrogen), treatment of acute symptoms, administering medication for pain and nausea The Porphyrias  Are a group of rare inherited disorders that involve a block in porphyrin synthesis that is due to a defect in the enzymes in the pathway of heme synthesis (see Harmening fig. 6-14)  This causes porphyrin heme precursors to accumulate in tissues and large amounts are excreted in urine and feces  Are classified as acute or nonacute according to their clinical presentation, and as erythropoietic or hepatic, depending on the site of abnormal metabolism  The porphyrias are associated with neurovisceral attacks which include photosensitivity, motor dysfunction, sensory loss, mental disturbances, and abdominal pain  The classification and characteristics of the porphyrias are summarized in (see Harmening table 6-17, p. 131)  The most common is acute intermittent porphyria characterized by abdominal pain, vomiting, diarrhea, constipation, and central nervous system involvement. get elevated PBG get elevated ALA Source: Harmening Figure 6-14 Erythropoietic porphyria. Note the precipitated porphyrins in the cytoplasm. Hereditary Hemochromatosis Hereditary Hemochromatosis  One of the most common genetic disorders in persons with European ancestry and a major inherited disorder  Almost always a diagnosis of exclusion  Autosomal recessive disorder carried on chromosome 6  May be inherited: Homozygous (* / *) or Heterozygous ( * / N)  Homozygotes more prone to iron overload  Iron absorption and storage become unbalanced due to the inheritance of an abnormal gene, HFE, the gene that regulates the amount of iron absorbed from the diet  Two mutations, C282Y and H63D  Iron is constantly loaded into the storage sites  Leads to multi-organ damage Symptoms  Chronic fatigue and weakness  Cirrhosis of the liver  Hyperpigmentation  Diabetes  Impotence  Sterility  Cardiac arrhythmias  Tender swollen joints  Hair loss  Abdominal symptoms Laboratory Diagnosis Screening for iron status Serum iron, serum ferritin, and transferrin saturation will be elevated, while TIBC and transferrin will fall in the normal reference range Liver biopsy Treatment  Untreated can be fatal (!)  Advanced iron overload leads to liver cancer (!)  Treatment of choice: Therapeutic phlebotomy, or “blood-letting” as it used to be termed  Goal of this procedure is to reduce the serum ferritin level  Harmening Table 6-18, p. 131 Classification of Hemochromatosis Hereditary Hemochromatosis Classical hemochromatosis type 1 Juvenile type 2 Transferrin receptor type 3 African overload type 4 Secondary Hemochromatosis Hereditary disorders Thalassemia Sickle cell anemia Sideroblastic anemia Enzyme-deficiency anemia Hereditary spherocytosis Acquired Disorders Anemia not due to blood loss in which multiple transfusions are required Dyserythropoietic anemia 47 49 Iron Overload and Hemochromatosis  Iron overload is defined as the accumulation of excess iron in reticuloendothelial cells in varying tissues.  Describes a clinical disorder that results in tissue damage resulting from excess iron.  In this disorder of iron storage, there is an inappropriate increase in intestinal iron absorption that leads to excess iron in the tissues.  Iron overload may be primary or inherited or secondary to the chronic anemias and their treatment. The excess iron is stored in liver, heart, and pancreas and damages these organs. Hereditary Hemochromatosis  In 1996, a mutant gene linked to the HLA-A locus on the short arm of chromosome 6, called the HFE gene, was first described in patients with hereditary hemochromatosis.  This mutation is a single-base change that results in the substitution of tyrosine for cysteine at position 282 of the HFE protein (C282Y). The C282Y mutation alters the conformation of the HFE protein and interferes with its function of regulation of iron absorption. Hereditary Hemochromatosis (cont’d) Pathophysiology  The disease is caused by a gradual accumulation of iron in the tissues which leads to chronic liver disease, arthritis, diabetes, pituitary damage, congestive cardiac failure, and cardiac arrhythmias (fig 6-15).  Patients with HH absorb two to three times as much dietary iron as normal individuals. The end result is intestinal absorption of iron that generally exceeds iron loss by approximately 3 mg per day.  Four stages of the disorder have been described. The first stage is a genetic predisposition with no abnormality other than increased serum transferrin saturation. The second stage involves 2 to 5 g of iron overload without symptoms. The third stage is iron overload with early symptoms that include lethargy and arthralgia. The last stage is iron overload with organ damage and cirrhosis. The liver organ is commonly implicated and hepatomegaly is present in 95% of cases. Source: Liver biopsy from a patient with idiopathic hemochromatosis and cirrhosis. Note the excess deposits of iron. (Ferric ferricyanide stain) Image: Liver biopsy with slightly increased iron stores, post-transfusion Hereditary Hemochromatosis (cont’d) Clinical Features  Signs and symptoms of HH usually occur in midlife. The most common complaint is joint pain. They may include fatigue, bronze discoloration of the skin, etc.  As the disease progresses, hepatomegaly develops, which leads to cirrhosis and fibrosis of the liver. Iron deposit in the heart tissue causes cardiomyopathy. Other complications are diabetes mellitus and hypoparathyroidism. Laboratory Findings  Although iron metabolism is abnormal, erythropoiesis is normal and hematologic abnormalities are usually not seen. Other laboratory abnormalities include increased liver function enzyme tests, such as aspartate aminotransaminases (AST). IRON STUDIES  In patients with HH, serum iron, serum ferritin and serum transferrin levels are increased. TIBC is usually within normal limits. Increased percent transferrin saturation is an important hallmark of the disease. The laboratory criteria for diagnosing HH include transferrin saturation greater than 50% for females and transferrin saturation greater than 60% for males. Diagnosis can be confirmed by direct analysis of the HFE gene. Treatment  The goal of treatment of iron storage disease is to remove the excess amount of iron from the body. Patients who have symptoms of HH require therapeutic phlebotomy.  The goal is to have the serum ferritin less than 50 μg/L and transferrin saturation below 30%. Once this is achieved, phlebotomy frequency is reduced to two to four times per year (patient depend).  In the event that therapeutic phlebotomy is not appropriate, desferrioxamine, a chelating agent, is used to reduce iron stores. Secondary Hemochromatosis  Secondary hemochromatosis can be acquired or secondary to other inherited hemolytic anemias.  The common characteristics of secondary hemochromatosis are:  Anemia  Ineffective erythropoiesis  Iron overload.  Secondary hemochromatosis patients are transfused repeatedly. This leads to increased iron storage because there is no mechanism for iron excretion.  Iron overload from transfusion therapy may be treated with chelation therapy. LAB THIS WEEK  The Reticulocyte Count   My Additional Notes Harmening Chapter 6  Part B  My Additional Notes Harmening Chapter 6  Part B