Approach to Patients with Anemia Prof Dr Nabil

Approach to Patients with Anemia Prof. Dr / Nabil Lymon

Blood Cells and Hemoglobin structure

Definitions: - Anemia : is defined as the lowering of hemoglobin concentration below the established normal levels: In male < 13. 5 gm/dl & In female < 11. 5 gm / dl. - Anemia is a clinical sign not a diagnostic entity. - Hematocrit (Hct): is the proportion, by volume, of the blood occupied by red blood cells. The hematocrit (Hct) is expressed as a percentage, normal levels are : 0. 4 - 0. 54 in Adult male & 0. 37 - 0. 47 in Adult female For example, a hematocrit of 25% means that there are 25 milliliters of red blood cells in 100 milliliters of blood.

Definitions: Red Cell Indices Are measurements that indicate the size and hemoglobin content of red cells: M. C. V (Mean Corpuscular Volume) M. C. H (Mean Corpuscular Hemoglobin) M. C. H. C (Mean Corpuscular Hemoglobin Concentration)

M. C. V (Mean Corpuscular Volume): Referred to the average volume of red cells , normally = 76 - 96 fl It can be calculated from an independently-measured blood cell count and hematocrit: MCV (femtoliters) = 10 x HCT(percent) ÷ RBC (millions/µL) MICROCYTOSIS & MACROCYTOSIS : By definition, microcytosis is taken to mean the presence of RBCs with a MCV less than normal, while macrocytosis means the presence of RBCs with an MCV greater than normal.

M. C. H (Mean Corpuscular Hemoglobin): or "mean cell hemoglobin" (MCH), is a measure of the mass of hemoglobin contained by a red blood cell. It is diminished in microcytic anemias, and increased in macrocytic anemias. It is calculated by dividing the total mass of hemoglobin by the RBC count : - MCH=Hb/RBC A normal value in humans is 27 to 32 picograms/cell

M. C. H. C (Mean Corpuscular Hemoglobin Concentration): is a measure of the concentration of hemoglobin in a given volume of packed red blood cell. It is diminished ("hypochromic") in microcytic anemias, and normal ("normochromic") in macrocytic anemias (due to larger cell size, though the hemoglobin amount or MCH is high, the concentration remains normal. ( It is calculated by dividing the hemoglobin by the hematocrit : M. C. H. C = Hb / Hct

Signs &Symptoms of Anemia - Cardiovascular : Exertional Dyspnea Orthopnea Tachycardia Claudications Cardiomegally Murmurs edema Palpitations Angina Bounding peripheral Pulses Vascular bruits Pedal - Neurological : Headache Tinnitus Faintness Fatigue Sensitivity Loss of Concentration Dizziness Cold

Signs &Symptoms of Anemia - Skin : Pallor of skin , mucous membranes, nail beds and palms. - Gastrointestinal : Anorexia Diarrhea Nausea Constipation - Respiratory : Increased Respiratory Rates - Genitourinary : Menstrual irregularity Amenorrhea Loss of libido or potency Menorrhagia - Fundus Examination : Retinal Exudates Rarely Papilloedema

Is the patient Anemic or not ? Anemic means single or total decrease in : - Hb - Hct - RBCs count in millions But…? What Type of Anemia. . ? This depends on the RBCs indices

Red Cell Indices According to MCV & MCH Normal Decreased Normocytic Normochromi c Anemia Increased Macrocytic Anemia Microcytic Hypochromic Anemia

Normocytic Normochromic Anemia It may be due to : e Blood Loss - Aplastic Anemia - Hemolytic Anemia ( Except Thalasemia) - A. O. C. D (Anemia Of Chronic Diseases) Which of Which …. ? Do Reticulocytic Count Normal A. O. C. D e. g. : TB, SLE, Malignancy, Rh. Arthritis Note: - Evidence of the cause - Anemia May be Microcytic Hypochromic Low or Absent B. M. F “Aplastic Anemia” - Acute Blood Loss BM biopsy or BM aspiration show : Acellular or Hypocellular BM - Hemolytic Anemia High ( search for evidence of the cause)

Hemolytic Anemia - low Hb &/or Hct & /or RBCs count - Normal RBCs indices - Reticulocytosis Do Indirect Serum Billirubin Unconjugated Hyper-billirubinemia “ jaundice” Other Evidences of Hemolysis e. g. : - Hemoglobinuria - Hemoglobinemia (increased free Hb) - Decreased Haptoglobin. What is the Further Step………. . ? Coombs Test

Coombs Test Positive Immune Hemolytic Anemia: - Iso immune - Auto immune Negative Non-immune Hemolytic Anemia: May be due to : - Membrane Defect e. g. Spherocytosis (lab show increased O. F. ) & P. N. H - Enzyme Defect e. g. G 6 PD (lab : Enz. assay) - Hb Defect (Hemoglobinopathy) e. g. Sickle Cell Anemia (lab: Hb Electrophoresis). - Others : Malaria (lab: Bl. Film)

Red Cell Indices According to MCV & MCH Decreased Increased Macrocytic Anemia Microcytic Hypochromic Anemia

Microcytic Hypochromic Anemia - The Commonest Cause is: Iron Deficiency Anemia -Other Causes: - Thalasemias - Sedroplastic Anemia - Lead Poisoning - A. O. C. D Which of Which …. ? Do Iron Studies: Serum Iron - Serum Ferritin - T. I. B. C (Total Iron Binding Capacity) - Transferrin Saturation

According to Iron Studies Iron Deficiency Anemia Thalassemia Sideroplastic Anemia A. C. O. D Serum Ferritin Normal T. I. B. C Normal Transferrin Saturation N or

Iron Deficiency Anemia

Iron Deficiency Anemia Iron Studies Serum Ferritin T. I. B. C Transferrin Saturation Notes: - Search For The Cause: e. g. : Chronic Blood Loss Ankylostoma Cancer Colon Nutritional causes - Severe Aniso-cytosis and Poikilo-cytosis: Increased R. D. W(N ≤ 13%)

Anisocytosis with hypochromia and microcytes (IDA)

Spoon Nails: If nails look scooped out, like a spoon, it could be a sign of iron-deficiency anemia.

Plummer Vinson Syndrome Left : Spoon shaped finger nails Right : Showing angular cheilitis, and dry skin

Plummer Vinson Syndrome

Iron Deficiency Anemia

Thalassemia Iron Studies Serum Ferritin T. I. B. C Transferrin Saturation Notes: - Hb Electrophoresis will show: Persistence of Hb[f] - Specific Clinical Features of Thalasemia: Huge Spleen Mongoloid Faces Hemosedrosis

Thalassemia minor is an inherited form of hemolytic anemia that is less severe than thalassemia major. This blood smear from an individual with thalassemia shows small (microcytic), pale (hypochromic), variously-shaped (poikilocytosis) red blood cells. These small red blood cells (RBCs) are able to carry less oxygen than normal RBCs

Thalassemia, being a genetic disease, runs in a family. Most are silent carriers or suffer mild anemia. Severe cases such as the Hemoglobin H disease with enlarged spleen, small body and malnourished look shows more prominent symptoms. [Pic below: Enlargement of spleen, small body]

Sideroplastic Anemia Iron Studies Serum Ferritin T. I. B. C Transferrin Saturation Notes: Sedroplastic Anemia is due to: - B 6 Deficiency Normal - Drugs e. g. : INH - Inherited Normal Blood film show: RBCs contain Iron Granules Treated by: B 6 supply

Many rounded sideroblasts are present in this field. This is the hallmark feature of sideroblastic anemia

Lead Poisoning Notes: - History is Suggestive. - Elevated Serum Lead level. - Purely Motor Neuropathy (foot and wrist drop) - Blood Film show: Basophilic Stippling of RBCs

Basophilic Stippling of RBCs Basophilic stippling appears as round, dark-blue granules in red blood cells on smears stained with supra vital stains such as brilliant cresyl blue. They may be observed in lead poisoning, exposure to some drugs, severe burns, anemia, or septicemia. The granules are precipitated ribosomes and mitochondria

Red Cell Indices According to MCV & MCH Increased Macrocytic Anemia

Macrocytic Anemia - In Which : - low Hb &/or Hct & /or RBCs count - Increased RBCs indices - Causes : # Folic Acid Deficiency # B 12 Deficiency - Search For The Cause: # Pregnancy # Mal-absorption Syndrome # Chronic Gastritis # Atrophic Gastritis # Cancer Stomach # Iliac Resection # Drugs: Methotrexate / Metformin / Epanutin - To be sure do the following tests: Serum Folic Acid / Serum B 12 / Schilling test / FIGLU test

Schilling Test The Schilling test is performed to evaluate vitamin B 12 absorption. B 12 helps in the formation of red blood cells, the maintenance of the central nervous system, and is important for metabolism. Normally, ingested vitamin B 12 combines with intrinsic factor, which is produced by cells in the stomach. Intrinsic factor is necessary for vitamin B 12 to be absorbed in the small intestine. Certain diseases, such as pernicious anemia, can result when absorption of vitamin B 12 is inadequate

FIGLU test a test of vitamin b 12 deficiency, folic acid deficiency, liver disease, or genetic deficiency of glutamate formiminotransferase, based on urinary excretion of formimino-glutamic acid (figlu), an intermediate metabolite in histidine catabolism in the conversion of histidine to glutamic acid, with the formimino group being transferred to tetrahydrofolic acid.

1 - (commentary) n n A healthy 52 year old man presents to the doctor’s office complaining of increasing fatigue for the past 4 5 months. He exercise every day but lately he has noticed becoming short of breath while jogging. He denies orthopnea. Paroxysmal nocturnal (PND), or swelling in his ankles. The patient reports occasional joint pain for which he uses over the counter ibuprofen. He denies bowel changes, melena or bright red blood per rectum, but reports vague left side abdominal pain for a few months off and on, not related to food intake. The patient denies fever, chills, nausea or vomiting. He has lost a few pounds intentionally with diet and exercise.

Cont. n n n n On examination, his weight is 90 kg and he is aferbrile. There is slight pallor of conjunctiva, skin and palms. No lymphadenopathy is noted chest is clear to auscultation bilaterally. Cardiovascular system: regular rate and rhythm, with no rub or gallop. There is a II/IV systolic ejection murmur. His abdomen is soft, nontender and without hepato splenomegaly. Bowel sounds are present. He has no extremity edema, cyanosis or clubbing. His peripheral pulses are palpable and symmetric. A hemoglobin level is 9. 2 g/dl, MCV 75µ 3

n What is the differential diagnosis such case? n Investigations of insulin malabsorption

Comprehension Questions 1 A 25 year old man with a history of a duodenal ulcer is noted to have a hemoglobin level of 10 g/dl. Which of the following is most likely to be seen on laboratory investigation? a Reticulocyte count of 4%. b Elevated total iron binding capacity (TIBC). c Normal serum ferritin. d MCV of 105 f. L.

2 A 22 years old Woman is pregnant and 14 weeks gestation. Her hemoglobin level is 9 g/dl. She asks why she could have iron deficiency when she is no longer menstruating. Which of the following is the best explanation: a Occult gastrointestinal blood loss. b Expanded blood volume and transport to the fetus c Hemolysis

3 A 35 year old man has undertaken a self imposed diet for 3 months previously, he has been healthy, but now complains of fatigue. His hemoglobin level is 10 g/d. L and his MCV is 105 f. L. Which of the following is the most likely etiology of his anemia? a Iron deficiency b Folate deficiency c Vitamin B 12 deficiency d Thalassemia e Sideroblastic anemia

Match the following laboratory parameters (a to e ) to the clinical picture (4 to 6) MCV Ferritin TIBC RDW a- Elevated Decreased b- Decreased Elevated Increased c- Normal Elevated Normal d- Decreased Increased Normal e- Elevated Increased Decreased Increased 4 A 20 year old woman with heavy menses. 5 A 34 year old man of Mediterranean descent with a family history of anemia. 6 A 50 year old man with severe rheumatoid arthritis.

Conclusions Anemia is a clinical finding, not a diagnosis and requires some investigation to determine the underlying etiology. n Iron deficiency anemia in men or postmenopausal women is primarily a result of gastrointestinal blood losses; therefore, finding iron deficiency anemia in this patient population warrants a through GI workup. n Iron deficiency anemia in women of reproductive age is most often caused by n

Cont. The fecal occult blood testing (FOBT) is negative in about 50% of patients with GI cancer. Therefore, a negative FOBT in the presence of iron deficiency anemia should not discourage you from pursuing a through GI workup. n The mean corpuscular volume, RDW and the reticulocyte index are important parameters in the evaluation of anemia. n

Polycythaemia

Polycythaemia refers to an increase in red cell count, haematocrit and usually haemoglobin. n There are two main types of polycythaemia, the classification depending on the results of measurement of red cell mass and plasma volume: n Relative (pseudo) polycuthaemia: due to decrease in plasma volume. n True polycythaemia: the red cell mass in increased. n (True polycythaemia may either a primary or secondary).

Primary true polycythaemia In the meloproliferative disorder polythaemia rubra vera (PRV), there is uncontrolled production of red cells by the marrow, even though erythropoietin is switched off. n Clinical features: hypertension, splenomegaly, arterial and venous thrombosis, pruitus, plethoric features, peptic ulceration, gout. n Laboratory features: there is high red cell count, haemoglobin, haematovril, whole blood viscosity and uric acid. The white cell count, platelete count and neutrophil alkaline phosphates are also increase and the latter three parameters help to distinguish PRV from

Secondary true polycythaemia n This condition is associated with increased levels of erythropoietin, which is produced by other the kidney or an ectopic tumor.

Cause of secondary polycythaemia Increased renal erythrpoietin production due to hypoxia Inappropriate erythropoietin production • Physiological Adaptation to altitude in neonates • From the kidney (eg pyonephrosis, renal cysts, renal artery stenosis after renal transplantation) • Congential cyanotic heart disease (eg Fallot’s tertragoly, Eisenmenger’s complex) • From a tumor (ectopic erythropoietin secreted in an uncontrolled fashion) (eg carcinoma of the kideny, giant uterine fibroids, hepatoma, cerberallar haemangioma) • Respiratory related Smoking COPD • High- affinity haemoglobins (eg haemoglobin M)

Relative polycythaemia n A reduction in circulating plasma volume can be to pyrexia, diarrhoea, vomiting and diuretic therapy. Gaisbok’s polycythaemia n Refers to a from of stress polycythaemia; this has been noticed in middle aged men who have stressful occupations, a chronically reduced plasma volume of uncertain cause. Treatment of polycythaemia n Treatment is indicated for polycythaemia as high blood viscosity leads to an increased incidence of thrombosis, hypertension, stroke and

n Venesction to a great haematocril: the packed cell volume is more closely related to the blood viscosity than is the haemoglobin (as repeated vensection may result in iron deficient red cells with a low haemoglobin content). Venesection may be traditional or isovolamic (with saline replaement). The latter is used in patients with cardiovascualr risk factors (eg angina or hypertension), in those who are taking drugs that may impair physiological response to vensection (ACE inhibitors, beta blockers), or in patients with relative polycythaemia.

Cytotoxic agent (particularly hydroxyurea): this presuppose erythropoiesis ad cause a macrocytosis which is not related to vitamin B 12 or folate deficiency. Unlike other cytotoxic agents (eg busslfan) it is unlikely to be leukaemogenic. n Aspirin and anticoagulants: if the patient presents with thrombosis. n

Multiple myeloma

Myeloma n In myeloma there is a clonal proliferation of plasma cells and the clinical manifestations of disease "= are Mated to substances secreted by the plasma cells as much as to the effects of marrow infil tration. Clonality (all diseased cells originating from one parent plasma cell) may be confirmed by: n n the presence of a paraprotein (monoclonal) band on serum electrophoresis, or by Immunopheno typing the increased numbers of plasma cells in the bone marrow, and finding, . that they all express either kappa or lambda light chains rather than a mixture of the two.

Paraprotein sub-types n The normal immunoglobulin concentrations in serum parallel the relative frequency of the three main sub classes of myeloma paraprotein. Hence, Ig. G is the most common form of myeloma, followed by Ig. A, with Ig. M being the least common type.

n Plasma hyperviscosity syndrome may be found This: consists of confusion, capillary bleeding, oedema and renal impairment. The incidence of hyperviscosity syndrome relates to the size of the immunoglobulin molecule as well as its concentration. As Ig. M is the largest molecule (750, 000 daltons) this syndrome is seen relalatively frequently in Ig. M myeloma, less frequently in Ig. A myeloma and rarely in Ig. G myeloma: . Transfusion should be avoided in patients with plasma hyperviscosity syndrome, as it will, cause a big increase in whole blood viscosity.

n Cryoglobulin: rarely, the paraprotein may be a cryoglobulin, so that the protein precipitates from plasma in the cold. This may be a cause of vasculitis. Some myeloma paraproteins precipitate within tissue to form amyloid.

n n Bence-Jones protein Sometimes, the malignant plasma cells are so defective that they cannot make a complete immunoglobulin molecule and are only able to make light chains. The latter are small enough to he filtered within the glomerulus and to appear in the urine as Bence Jones proteinurias. They may obstruct the renal tubules and contribute to the renal failure which is often found in myeloma.

Role of cytokines in myeloma n Osteoclast-activating factors stimulate the normal osteoclasts to dissolve bone and lead to bone pain, hypercalcaemia and pathological fractures in myeloma. In other myeloma cases, IL -6 may be produced in excess by bone marrow stromal cells infected with human herpes virus (HHVB).

Treatment of myeloma n Inn younger patients, most centers are moving away from single agent melphalan therapy towards continuous low dose combination chemotherapy such as VAD (Vincristine, Adriamycin and Dexamethasone) or ZDex (oral idarubicin and dexamethasone). Malignant cells are most sensitive to the action of chemotherapy when they are dividing; as plasma cells divide relatively infrequently, it is necessary to administer the chemotherapy over several days in order to maximise the chances of treatingg dividing cells.

n n Thalidomide has a proven role in myeloma treatment although its mechanism of action remains uncertain. It is likely to inhibit cytokine release, but an anti angiogenesis activity has not been ruled out. Bisphonates, such as monthly intravenous pamidronate, have an important role in the prevention off pathological fractures and in the treatment of myeloma associated hypercalcaemia.

n n Monoclonal gammopathy of undetermined significance (MGUS) A common clinical problem is the differentiation between myeloma and MGUS (benign monoclonal gammopathy) in patients found to have a paraprotein. Ten per cent of patients with MGUS develop myeloma at 5 years, and 50% at 15 years. It is probable that most patients would eventually develop myeloma but many die of other causes before this occurs.

Differentiation of myeloma from MGUS Low level of paraprotein (< 20 g/I for an Ig. G paraprotein) Paraprotein level remains stable over a period of observation depressed (months or years) Other immunoglobulin levels are normal No clinical evidence of myeloma (bone disease, renal disease) Myeloma High level of paraprotein Level rises Other immunoglobulin levels are depressed Clinical evidence of myeloma

Commentary n A healthy 52 year old man presents to the doctor’s office complaining of increasing fatigue for the past 4 5 months. He exercises every day but lately he has noticed becoming short of breath while jogging, he denies orthopnea, paroxysmal nocturnal (PND), or swelling in his ankles. The patient reports occasional joint pain for which he uses over the counter (OTC) ibuprofen, he denies bowel changes, melena or bright red blood per rectum, but reports vague left side abdominal pain for a few months off and on, not related to food intake.

n The patient denies fever, chills, nausea or vomiting, he has lost a few pounds intentionally with diet and exercise. On examination, his weight is 90 kg and he is aferbrile. There is slight pallor of conjunctiva, skin and palms. No lymphadenopathy is noted chest, is clear to auscultation bilaterally, regular rate and rhythm of pluse with no rub or gallop, There is a grade II/IV systolic ejection murmur, his abdomen is soft, nontender and without hepato splenomegaly, bowel sounds are present. He has no extremity edema, cyanosis or clubbing, his peripheral pulses are palpable and symmetric. A hemoglobin level is 9. 2 g/dl, MCV 75µ 3, MCH 25 Pgm. n n Discuss the most likely diagnosis. Differential diagnosis of this case.

n The typical features of acute hepatic failure include, except: n n n Onset within 8 weeks of the initial illness. Hepatoplenomegaly and ascitis. Encephalopathy and fetor hepaticus. Nausea, vomiting and renal failure. Cerebral oedema without papilloedema. The typical feature of primary biliary cirrhosis include: n n n Xanthomata of the palmar creases and eyelids. Poor prognosis even in asymptomatic patients. Hepatomegaly without splenomegaly. Dilated bile ducts on ultrasonography. Improved survival rate without immunosuppressant therapy.

n The clinical features of acromegaly include, except: n Arthropathy and myopathy. n Hypertension and impaired glucose tolerance. n Goiter and cardiomegaly. n Increased sweating and headache. n Skin atrophy and decreased sebum secretion. n Causes of short stature in childhood include, except; n Klinefelter's syndrome. n Turner's syndrome. n Emotional deprivation. n Cushing's syndrome. n Primary hypothyroidism.

n Which of the following studies is most sensitive for detecting diabetic nephropathy: n n n Serum creatinine level Creatinine clearance Urine albumin Glucose tolerance test Ultrasonography Haematocrit value of 45% means that: n n 45% of the Hb in the plasma. 45% of the total blood volume is made up of blood cells. 45% of the Hb is in the red blood cell.

n An anaemic subject has R. B. Cs count 3. 5 millom/mm 3, PCV 42% & Hb 14 gm%, by using the blood indices this subject most probably has? n n n Aplastic anaemia. Macrocyric hyperhormic anaemia. Normocytic normochromic anaemia. Microcytic hypochromic anaemia. If a man's plasma agglutinates both A and B red cells, he is group: n n B A AB O

n Clinical features suggesting severe aortic stenosis include, except: n n n Early systolic ejection click. Pulsus bisferiens. Heaving displaced apex beat. Syncope associated with angina. Which of these is not a peripheral sign of infective endocarditis? n n n Osler's nodes. Splinter haemorrhages. Janeway lesions. Clubbing. Palmar erythema.

n Thrombin is required for activation of all the following except: n n n Plasminogen Fibrinogen Clot retraction Factor III All the following drugs for the treatment of peptic ulcer disease alter gastric acid p. H except: n n n Calcium carbonate Cimmetidine Omeprazole Pirenzepine Sucralfate

n Characteristic feature of cholestatic jaundice include, except: n n n Dark green stool. Dark brown urine. Conjugated hyperbilirubinaemia. Serum alkaline phosphatase concentration increased >2. 5 normal. Increased serum bile acid concentrations. The typical clinical features of diabetic ketoacidosis include, except: n n n Abdominal pain and air hunger. Rapid weak pulse and hypotension. Dry skin and polyuria. Vomiting and constipation. Coma with extensor plantar response.

n Cause of polyuria include, except: n n n Chronic hyperglycaemia. Chronic renal failure. Hypercalcaemia. Hypothyroidism. Lithium toxicity. All the following drugs are associated with an increased risk of osteoporosis in adults except: n n n Cyclosporine Dilantin Herparin Presnisone Ranitidine

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