2023-2024 MLS 511 Haematology II TSU PDF

MLS 511 MEDICAL LABORATORY HAEMATOLOGY II BY PEYOU AMED [email protected] 1  OUTLINE  Anaemias  Microcytic Anaemia (Disorders of Iron metabolism)  Macrocytic Anaemia (Vitamin B12 and Folate deficiencies) ...

MLS 511 MEDICAL LABORATORY HAEMATOLOGY II BY PEYOU AMED [email protected] 1  OUTLINE  Anaemias  Microcytic Anaemia (Disorders of Iron metabolism)  Macrocytic Anaemia (Vitamin B12 and Folate deficiencies)  Haemolytic anaemia  Haemoglobinopathies  Haemochromatosis and related storage disorders  Radioisotopes in Haematology  Automation in Haematology 2  ANAEMIA  Anaemia is a condition in which the number of red blood cells or the haemoglobin concentration within them is lower than normal.  Hemoglobin is a protein found in red cells that carries oxygen from the lungs to all other organs in the body.  Anemia is a problem of not having enough healthy red blood cells or hemoglobin to carry oxygen to the body's tissues.  Anaemia results from a lack of red blood cells or dysfunctional red blood cells in the body. 3  CLASSIFICATION OF ANAEMIA Microcytic- hypochromic Anaemias Morphology Normocytic- normochromic Anaemias Macrocytic- normochromic Anaemias ANAEMIA Dyshaemopoietic Classification anaemia (deficiencies impairing Decrease development) red cell production Hypoproliferative anaemias (BM failure) Haemolytic anaemia Etiology Acute Post Haemorrhagic Anaemia Dilutional anaemia 4  Blood Formation 1. Intrauterine life: – Blood cells are formed in the liver and spleen up to the fifth months. – After 5th month: bone marrow shares in the formation of these cells. 2. After birth: – Formation of these cells will be restricted to the bone morrow. 3. Adulthood – The active bone morrow will be restricted to axial skeleton: flat bones, vertebrae, ribs, sternum and ilia. – Some extension to the proximal ends of long bone mainly femur. 5  Blood Formation (Ctnd) –Extramedullary haemopoiesis: When demand for blood formation is increased the active red BM extends into the shafts of the long bones. –The spleen and liver will regain their ability to produce blood elements when bone morrow is affected by some diseases. 6 BLOOD CELLS FORMATION 7  Erythrocytopoiesis Normal erythrocytopoiesis depends on: Healthy BM: normal stem cells and architecture. Regulatory hormones: EPO, Androgen thyroxin, cortisol and ACT. Nutritional elements: Protein (high biological value). Minerals (Iron, copper, zinc, selenium) Vitamins (B, Folic acid, vit. C) 8 9 ERYTHROPOIESIS 10 ORIGIN OF BLOOD CELLS & HAEMOGLOBIN SYNTHESIS 11  Classification A- By etiology: 1- Decreased red cell production  Dyshaemopoietic anaemia a) Mineral deficiency: iron, zinc, selenium, cupper b) Vitamin deficiency: B12, folic acid, Vit C & pyridoxine c) Hormonal deficiency: anemia of renal diseases, pituitary, thyroid or suprarenal deficiency. d) Protein deficiency: high class  Hypoproliferative anaemia a) Aplastic anaemia. b) Myelophthisic anaemia (bone-marrow infiltration replaces heamopoietic cells leading to anemia). c) Anemia of chronic diseases 12  Classification (Ctn’d) 2- Haemolytic anaemia: – Short life-span of RBCs 3- Acute post haemorrhagic anaemia: – Loss of RBCs 4- Mixed anaemia. – eg. Megalobastosis associated with haemolysis 5- Dilutional anaemia: (relative anemia: volume is high but cell mass remains the same) – Pregnancy – Oliguric RF – Volume-overload 13  Classification (Ctn’d) B- By Morphology 1- Microcytic-hypochromic anaemias: a) Iron deficiency anaemia. b) Thalassaemia. c) Anaemia of chronic disease. d) Sideroblastic anaemia: Hereditary Chronic lead poisoning. 2- Normocytic-normochromic anaemias: – Anaemia of chronic diseases. – Acute post –haemorrhagic anaemia. – Haemolytic anaemia. – Aplastic anaemia. – Myelophthisic anaemia. 14  Classification (Ctn’d) 3- Macrocytic- normochromic anaemias: – Megaloblastic anaemia. – Marked reticulocytosis. – Myelodysplastic syndromes. – Myxoedema. – Acquired sideroblastic anaemia. 15  Pathophysiology In Anaemia Tissue Hypoxia – Impaired functions of the tissues, the degree of impairment depends on the degree of dependency on O2, so CVS, CNS and skeletal muscles are much affected. Compensatory mechanisms – Increased Cardiac Out Put. (explaining high output cardiac failure) – Increased O2 delivery from HB to the tissue. – Increased erythropoietin production with stimulation of erythropoiesis. (Explaining the accompanying reticulocytosis) – Increased plasma volume. – Redistribution of the blood from less to more vital organs. 16  Pathophysiology In Anaemia (Cnt’d) Rate of blood loss: – The rapid the rate of blood loss, the more the severe symptoms will occur especially in elderly. While the slowly falling HB allows for haemodynamic compensation with less symptom. Factors related to a specific cause. 17  Symptoms of Anaemia Neurological: – Dizziness, fainting, lack of concentration – Blurred or diminished vision – Headache, tinnitus – Paraesthesia in the fingers and toes – Insomnia, irritability. CVS: – Angina, dyspnea, palpitation and intermittent claudication by exertion – Heart Failure in severe cases or presence of other organic cardiac disease, it is high COP failure. Musculo skeletal: – Easy fatigability. – Tiredness and lassitude. GIT: – Dyspepsia and anorexia Genital – Loss of libido & impotence – Menstrual abnormalities like amenorrhea. May be polyuria. 18 Microcytic Anaemias 19  I- IRON DEFICIENCY ANEMIA A. SOURCES, ABSORPTION AND METABOLISM: – Red meat and liver, bread, eggs and green vegetables, mainly in ferric form. – Daily minimum requirement 10-12mg of which about 1mg is absorbed. – In the stomach the iron is released from its complex form and is reduced to ferrous form (action of gastrin and HCl). – Iron absorption takes place in the duodenum and proximal jejunum. – Iron absorption is under regulatory system (Apoferritin- Transferrin system) present in the intestinal mucosa and regulates absorption of the iron according to body requirement. 20 Factors enhancing iron absorption – Pregnancy – Iron deficiency anemia – Increased erythropoiesis – Vit. C. Factors reducing iron absorption: – Excess phosphate, tannates, phytate in diet – Iron overload haemochromatosis – Decreased erythropoies eg a plastic anaemia – Malabsorption syndrome – Decreased HCI atrophic gastritis. 21 Conditioned deficiency (normal demand and intake but there are defective absorption and utilization) Not common: – Ferric form cause. – Decreased HCL – Iron binder: phosphate, phytate, tannates – Malobsorption syndrome. Relative deficiency: (increased requirement) common cause. – Menstruating females. – Pregnancy, labor. – Growing children. – Convalescence from disease. – Chronic blood loss: the commonest cause 22 Frank blood loss: – Menorrhagia – Repeated GI bleeding, hematemesis, epistaxis, and hematuria. – Bleeding tendencies – Repeated blood donation Occult blood loss via GIT: – Anckylstoma & schistomiasis – Oozing OV, PU. – Neoplasm. – Inflammatory bowel disease ulcerative colitis – TB enteritis. 23  B. Investigations for Iron Defiency Anaemia Complete Blood Count: The red cells are microcytic, (MCV15 Eosinophilia is present in cases of ankylostoma infestation. 24 Bone Marrow: Absent iron store Normoplastic hyperplasia Decreased Hb in maturely erythroblasts. Serum iron study Decreased serum iron (Normal =70-170 mg %). Increased total iron binding capacity (TIBC). (Norm.=250-450mg %). Decreased serum ferritin levels. – Reflect iron stores. – The normal values are 30-300 mg/L in males and 15-200 mg/L in females and investigation of gastrointestinal tract are often required. – Falsely raised value in cases of acute phase reactant e.g malignancy. Decreased transferrin saturation (Norm. =25-50%). 25 Investigations for specific causes: Stool analysis: – Occult blood, ankylstoma & Bilharizasis. GI cause: – Imaging: barium swallow, meal or enema. – Endoscopic studies: upper and lower. – Achlorhydria: histamine test. Hemostatic profile. 26 II- Anemia Of Chronic Disease – This type of anemia may be microcytic hypochromic or more common normocytic normochromic. – Endocrinal disorders: hypothyroidism, hypocorticalism, hypogonadism in male. – Inflammatory diseases: collagenosis, Chron’s disease. – Rheumatological diseases. – Chronic infection: as TB, sarcoidosis, oestomylitis. – Neoplastic diseases. – Malabsorption. – Organ failure, liver and kidney 27  Laboratory Findings of Anemia of Chronic Disease Decreased serum iron and TIBC. Normal or raised serum ferritin Normal BM iron. 28  III- Sideroblastic Anemia  It is a refractory microcytic hypochromic anemia characterized by the presence of sideroblasts in the bone marrow. Sideroblasts are Erythroblasts inside, which iron accumulates into the mitochondria of erythroblasts owing to disordered haem synthesis. A ring of iron granules is formed around the nucleus.  Types: Inherited: X-linked disease transmitted by females. Acquired: 1. Primary: one of the myelodysplastic syndromes 2. Secondary: – Other types of myelodysplasia – Myeloproliferative disorders – Myeloid leukemia – Drugs as isoniazid, alcohol, lead. 29 Macrocytic Anemia 30  Macrocytic Anemia  The peripheral blood film shows macrocytes with hypersegmented polymorphs with six or more lobes in the nucleus. If severe there may be leucopenia and thrombocytopenia (deficient DNA synthesis) Causes include: Vitamin B12 deficiency. Folic acid deficiency Congenital enzyme deficiencies in DNA synthesis or drugs interfering with DNA synthesis (hydroxyurea, azathioprine). Myelodysplasia due to dyserythropoiesis 31  I- Vitamin B12 deficiency Sources: meat, fish, eggs, and milk. Not destroyed by cooking. Daily requirement is 1-2 mg / day. Absorption and transport: Vit. B12 is liberated in the stomach, bound to intrinsic factor (IF) and absorbed through the terminal ileum, transported by transcobalamin I (and to lesser extent by transcobalamin II and III) to be utilized by the tissues. It is essential for: – Hematopoiesis – GIT mucosa integration – Formation of myelin of nervous system. Storage: the average adult stores 2-3 mg in the liver, it may take two years or more before B12 deficiency develops as the daily loss are small (1-2mg). 32  Causes of Vit. B12 Deficiency Dietary deficiency: Malabsorption syndrome. (Celiac) Crohn’s disease Gastric pathology: Rare congenital enzyme deficiency. Increased loss: Hemodialysis Decrease of stores. Far advanced chronic liver diseases. 33  Investigations of Vit. B12 Deficiency 1. CBC RBCs: – Macrocytic normochromic anemia. – Poikilocytosis and anisocytosis – Howell-Jolly bodies may be present WBCs: – Moderate Leucopenia. – Shift to the right (hypersegmented neutrophils). Platelets – Moderate thrombocytopenia. – Giant platelets Reticulocytes are decreased but increased by treatment with vit. B12 2. Bone marrow: Show megaloblastic erythropoiesis. The most characteristic is dissociation between nuclear & cytoplasmic development in erythroblasts with the nucleus maintaining a primitive appearance despite maturation and haemoglobinization of the cytoplasm. Erythroid hyperplasia, maturation defect in erythropoiesis, giant metamyelocytes, atypical megakaryocytes with hypersegmented nuclei. 34 3. Estimation of serum B12 level Low using radioisotope dilution or immunological assays. 4. Biochemistry Serum iron is high, more than 175-mcg/100 ml. Increased serum indirect bilirubin reflects mild hemolysis and ineffective erythropoiesis. Increased serumlactic dehydrogenase (LDH) reflecting ineffective megaloblastic erythropoiesis. 5. Immunology. (Imp. For diagnosis of pernicious anemia). Parietal cells antibodies and gastrin receptor antibodies, present in 70% of patients. (Not specific) Intrinsic factor antibodies type I blocking (more specific) and type II precipitating antibodies. 35 6. Other investigations Gastric biopsy: proximal 2/3 of stomach is atrophic. Augmented histamine test: achlorhydria. Schilling test for pernicious anemia. High homocystine (also seen in folate deficiency) High methylmalonate in urine. 36  II- Folate Deficiency Folates are produced by plants and bacteria, hence dietary leafy vegetables (spinach, broccoli, and lettuce), nuts, yeast, fruits (bananas, melons) and animal protein (liver, kidney) are a rich source. Minimum daily requirements 100-200 ug. An average Western diet contains more than the minimum daily requirement but excess cooking destroys folates. Most dietary folate is present as polyglutamates; these are converted to monoglutamate in the upper small bowel (mostly in the jejunem) and actively transported into plasma. Plasma folate is loosely bound to plasma proteins such as albumin and there is an entero-hepatic circulation. Total body stores of folate are small and deficiency can occur in a matter of weeks. It is essential for DNA synthesis and cell maturation. Its deficiency leads to nuclear maturation defect of blood cells and GIT mucosal cells. 37  Causes of Folate Deficiency: Decreased intake – Particularly in infancy, old age, poor social conditions, starvation, alcohol excess and in psychiatric patients. Increased demand – Physiological: pregnancy, lactation, prematurity – Pathological: Hematological disease with excess red cells production e.g hemolysis. Malignant disease with increased cell turnover Inflammatory diseases e.g. rheumatoid arthritis. Metabolic disease e.g. homocystinuria (rare congenital defect in the conversion of homocysteine to cystathion folate). Decreased absorption – Small bowel disease especially celiac disease. 38 4. Drugs affecting folate metabolism. Anticonvulsants (e.g. phenytoin may inhibit intestinal conjugase inhibiting conversion of polyglutamates into monoglutamates), methotrexate (cytotoxic), pyrimethamine and trimethoprim (inhibit the enzyme responsible for the conversion of dihydrofolate into tetrahydrofolate) and oral contraceptives. 5. Increased loss Plasma folate is loosely bound to plasma proteins such as albumin; thus, Hemodialysis or peritoneal dialysis can cause loss. 39  Investigations of Folate Deficiency Essentially as in vit B12 deficiency. Howell Jolly bodies and target cells in the blood film would suggest splenic atrophy (coeliac disease) Bone marrow shows megaloblastic changes. Reduced folate levels: (N= 2.5-25mg/ml) serum levels are labile (a single folate rich meal could normalize the lvls even in a truly deficient person) and red cell levels are better reflection of tissue folate by radioisotope dilution or immunological methods. 40  HEMOLYTIC ANAEMIA The hemolytic anemias are a group of diseases in which red cell life span is shortened. Pathophysiology: Hemolysis of RBC can occur either. – Intravascular i.e. within the circulation. – Extravascular i.e. by phagocytes in RES in the liver, bone, spleen. Bone marrow compensatory reactions: – Erythriod hyperplasia in BM, can increase erythropoiesis several times, so that anemia may not develop till RBCs life span is less than 20 days – Reticuylocytosis is a hallmark. – Slight macroytosis in the peripheral blood 41  Consequences Low Hb. Excess hemolysis increases bilirubin (unconjugated) since the liver can increase its capacity several times; the jaundice is mild if there's any at all. The intravascular liberated Hb is bound to haptoglobin. Hb-haptoglobin is rapidly cleared from the circulation by RES, and plasma level of haptoglobin is reduced. In cases of excessive IV haemolysis, haptoglobin is depleted. Haemoglobinuria and dark urine. 42  Causes of Haemolytic Anaemia A- CORPUSCULAR CAUSES I- Congenital Abnormalities 1. Membrane defects – Hereditary spherocytosis – Hereditary elliptocytosis – Hereditary stomatocytosis 2. Haemoglobinopathies – Sickle cell anemia – Thalassemia 3. Enzymopathies – Abnormal aerobic glycolysis e.g. G6PD deficiency – Abnormal anaerobic glycolysis e.g pyruvate kinase deficiency – Non glycolytic enzymopathies 43 II- Acquired Abnormalities Paroxysmal nocturnal haemoglobinuria (abnormal membrane) Vitamin E deficiency. B- EXTRACORPUSCULAR CAUSES: I- Immune mechanisms 1. Alloantibodies: – Incompatible blood transfusion – Hemolytic disease of the newborn – After allogeneic BM or organ transplantation 2. Autoantibodies: a. Warm antibodies (react at 37º C and do not cause agglutination. Type of AB= IgG). – Primary: Idiopathic – Secondary: » CLL, Lymphoma, SLE and rheumatoid disease » Drugs e.g methyldopa. 44 b. Cold antibodies (react at 32ºC (best at4ºC) and usually agglutinates and hemolyse red cells. Type of AB = IgM). – Cold haemoagglutinin disease – Primary: Idiopathic – Secondary (mycopolasma pneumonia infection, infectious mononucleosis and lymphomas. – Paroxysmal cold haemoglobinuria Idiopathic Secondary (some viral infections congenital & tertiary syphilis). 3. Immunochemical mechanisms: drug induced hemolytic anemia. II- Non-immune mechanism Acquired Abnormal membrane – Paroxysmal Nocturnal haemoglobinuria 45  Investigations CBC – Normocytic normochromic anemia with reticulocytosis – Microcytic anaemia: thalassaemia, spherocytosis. – Macrocytic + reticulocytosis: megaloblastic crisis – Reticulocytopenia: aplastic crisis. – Morphological evidence of RBC damage: as red cell fragment, cell containing malarial parasites. – Morphology of RBCs: eg spherocytes & sickle cells – WBC and thrombocytes are normal but may increase due to bone marrow stimulation. 46  Short life span of RBCs: – Measured by radioactive chromium51 labeled RBCs Bone marrow – Hypercellular normabloastic marrow. – Hypocellular in a plastic crisis. – Megaloblastic in folate deficiency. Increased serum LDH Incresesd serum biliurbin, fecal stercobilinogen and urinary urobilinogen. In intravascular haemolysis vs. extravascular the following parameters are presents. – Haemoglobinuria and haemosiderinuria – Reduced plasma haptoglobin and haemopexin – Presence of methaemalbumin in plasma. 47  Tests for the cause – RBC morphology. – Osmotic fragility. – Hb electrophoeresis. – Estimation of G6PD. Coomb’s test. 48 HAEMOGLOBINOPATHIES 49  Normal Hemoglobin Globin: protein, which is formed from 4 polypeptide chains. Two alpha and two non- alpha globin chains. Alpha globin chains are produced throughout life, including in the fetus, so severe mutations may cause intrauterine death. Production of non-alpha chains varies with age; fetal haemoglobin (HbF-αα/γγ) has two gamma chains, while the predominant adult haemoglobin (HbA- αα/ββ) has two beta chains. Thus, disorders affecting the beta chains do not present until after 6 months of age. 50  Normal Hemoglobin (Cnt’d) A constant small amount of haemoglobin A2 (HbA2- αα/δδ, usually less than 2%) is made from birth. Haem: iron-protoporphyrin complex 51 ORIGIN OF BLOOD CELLS & HAEMOGLOBIN SYNTHESIS 52  Electrophoresis Pattern Normal electrophoresis pattern in an adult: Hemoglobin A (96%): α2/β2 (normal hemoglobin) Hemoglobin F (3%): α2/γ2 (normal till 6 months of age) Hemoglobin A2: α2/δ2. 53  Haemoglobinopathies Haemoglobinopathies are clinical syndromes resulting from abnormalities in the structure of globin molecule or with a reduction in the rate of production of one or other of the globin chains. There are three main categories: – Structural variant of Hb: e.g. HbS. – Failure to synthesize Hb: e.g. Thalassemia. – Failure to switch from fetal Hb (HbF) to adult Hb (HbA) : Heridetary persistence of Fetal Hb (HPFH). 54  1. Sickle Cell Anemia A hereditary autosomal recessive disorder characterized by the presence of HbS (formed by substitution of valine for glutamic acid in the sixth position of the β – hemoglobin chain), which on exposure to hypoxia, the deoxygenated Hbs forms insoluble aggregates that distort the erythrocytes and increase their rigidity causing sickling deformation and subsequent fragmentation. In addition, the unyielding elongate crescentic erythrocytes form aggregates that block terminal arterioles, capillaries and veins, resulting in tissue infractions and perivascular oedema in the involved organs (vascular occlusion) 55  1. Sickle Cell Anemia (Ctn’d) Symptoms vary from a mild asymptomatic disorder to severe haemolytic anaemia and recurrent severe painful crises. Signs of SCA: – Splenomegaly/Sludging – Infection Cholelithiasis/acute Chest syndrome – Kidney (haematuria, papillary necrosis) – Liver congestion/Leg ulcer – Eye changes 56  1. Sickle Cell Anemia (Ctn’d) People with sickle cell trait (heterozygous sickling disorder) have no symptoms unless extreme circumstances cause anoxia such as flying in a non- pressurized aircraft or problems with anaesthesia. Sickle cell trait protects against plasmodium falciparum malaria. (Controversy) – 60% Hb A and 40% Hb S – The blood count and film are normal – The diagnosis is made by a positive sickle test or by Hb electrophoresis. 57  Investigations Features of hemolytic anemia. CBC – The level of Hb is in the range 6-8gm/dl with high reticulocytic count 10-20%. – Sickling of red cells on a blood film can be induced in the presence of sodium metabisulphite, which cause hypoxia. Hb electrophoresis: – There is no Hb A, 80-85% Hb S and 2-20% HbF. – The parents of the affected child will show features of sickle cell trait. 58  2- Thalassaemias The Thalassaemias are anemias originally found in people living on the shores of the Mediterranean, now known to affect people throughout the world. The defective synthesis of globin genes in thalassaemia leads to imbalanced globin chain production leading to precipitation of globin chains within the red cell precursors and resulting in ineffective erythropoiesis. Precipitation of globin chains in mature red cell leads to haemolysis. There are two α genes and one β gene on each chromosome, making a total of four α genes and two β genes. In alpha-thalassaemia, disruption of one or both alleles on chromosome 16 may occur, with production of some or no alpha globin chains. In beta- thalassaemia, defective production usually results from disabling point mutations causing no (β1) or reduced (β–) beta chain production. 59  α-Thalassemia In contrast to β -thalassaemia it is caused by gene deletions. If all four genes are absent ( / ) there is no α-chain synthesis and Hb Barts (γ4) is present. Hb Barts cannot carry oxygen and is incompatible with life and infants are either stillborn or die very shortly after birth. (hydrops fetalis) If three genes are deleted ( /_α) there is moderate anaemia and splenomegaly (Hb H disease). Hb A, Hb Barts and Hb H (β4) are present, Hb A2 is normal or reduced 60  α-Thalassemia (Cnt’d) If two genes are deleted ( /αα) (α - thalassaemia trait), there is microcytosis with or without mild anaemia. (αα/__) thalassemia trait is more common in Asians. (α_/ α_) is more common in Africans) If only one gene is deleted (αα /α _), the patient is usually asymptomatic. 61  β-thalassemia There is defective production of beta-chain with excess production of Hb F and Hb A2. 1. β-thalassaemia major (Cooley's anemia) – Homozygous (2 abnormal gene) – Hb F > 80-90% – The onset is during the first year of life (3-6 mouth) – The children fail to thrive, (stunted growth) mongoloid faces, bone deformities. – Feature of hemolytic anaemia, jaundice and huge splenomegaly. – Extramedullary haematopoiesis: that soon causes hepatosplenomgaly, bone expansion giving rise to classical thalassaemic facies (mongoloid facies). 62  β-thalassemia (Ctn’d) – Feature of iron overload: liver cirrhosis, bronze skin, and cardiomegaly. – The disease is more common among Mediterranians. – Positive family history. – Usually recurrent bacterial infection. 2. β-thalassaemia intermedia Heterozygous (only one abnormal gene) – Both Hb F (10%) and Hb A2 (10%). – Presented in adults by mild Microcytic hypochromicmic anemia and splenomegaly. – Commonly symptomatic and require treatment. 63  β-thalassemia (Ctn’d) 3. β-Thalassaemia minor (trait) – This common carrier state is asymptomatic, anaemia is mild or absent, the red cells are hypochromic and microcytic with a low MCV and MCH. – DD: Iron deficiency anemia. Must be excluded. – Rarely requires treatment. 64 HAEMOCHROMATOSIS AND RELATED DISORDERS 65  Haemochomatosis Normal iron absorption occurs in the proximal small intestine at a rate of 1-2 mg per day. Excess iron absorbed is reserved in storage forms (ferritin and haemosiderin) in the liver, spleen, bone marrow and skeletal muscle. Total body iron store is maintained within the range of 3- 5g by carefully down-regulating the absorption to avoid accumulation. This is because there is no physiological mechanism for eliminating excess iron from the body. Iron store in excess of 5g is considered as an iron overload. 66  Haemochromatosis Cnt’d Haemochromatosis is a metabolic disorder affecting iron absorption, and resulting in the accumulation/deposition of excess iron in the liver, thyroid, heart, pancreas, gonads, hypothalamus and joints. In people with haemochromatosis, the absorption rate can reach 4–5 mg `per day with progressive accumulation to 15–40 grams of iron in the body. This may be as a result of a genetic or acquired abnormality of iron absorption. In the presence of excessive iron stores, reactive oxygen species are generated, especially the hydroxyl radical which are thought to be involved in damaging enzymes, DNA, mitochondria, endoplasmic reticulum and lipid peroxidation. Lipid peroxidation induces cell degeneration, cell death, and 67  Symptoms of Haemochromatosis The clinical manifestations of haemochromatosis usually appear after significant iron accumulation, generally after the age of 40. Symptoms appear earlier in males than in females due to the loss of iron through menstruation in women. Many patients with haemochromatosis are asymptomatic and are diagnosed accidently. Early signs are nonspecific and can include: Weakness, increased skin pigmentation, hair loss, impotence, joint pains, vertiligo, and loss of memory. 68  Symptoms of Haemochromatosis Cnt’d Iron deposition in heart muscle may cause arrhythmias or degeneration of the muscle itself (resulting in cardiomyopathy). Patients with haemochromatosis are also at increased risk for diabetes and pancreatic cancer. Iron deposition in the liver leads to enlargement and elevation in liver enzymes. This may cause right upper quadrant pain and predispose patients to fibrosis, cirrhosis and cancer. Hepatocellular carcinoma develops in 30% of patients with cirrhosis due to haemochromatosis, and the incidence of hepatocellular carcinoma increases with age, reaching almost 50% in patients over 60 years of age. 69  Causes of Haemochromatosis The cause of haemochromatosis was vigorously debated, however genetic and non-genetic causes were identified. Acquired haemochromatosis may occur due to multiple red cell transfusions, excessive parenteral iron therapy and excessive iron absorption (due to ineffective erythropoiesis and consumption of traditional home brewed beer which causes African iron overload). The genetic haemochromatosis is an autosomal recessive disorder which may be inherited homozygously or heterozygously with homozygotes being more prone to the disease. 70  Causes of Haemochromatosis The basic cause of iron accumulation in haemochromatosis is the failure to down-regulate duodenal enterocyte absorption of iron. After iron absorption remains elevated for many years, liver iron storage sites become overloaded, and iron accumulates in the spleen, myocardium, pancreas, anterior pituitary, and other organs. Individuals with haemochromatosis may have a body iron burden that is more than ten times normal. Usually, such individuals do not develop symptoms until after they have been iron loaded for four to five decades. This suggests that heavy iron overload must be present for many years before sufficient organ damage occurs to cause recognizable symptoms or signs. 71