Anemia - Clinical Features and Diagnosis PDF

Clinical Features of Hemolytic Anemia Hereditary: longstanding mild to moderate hyperbilirubinemia with possible jaundice Autoimmune: gradual onset of fatigue Pallor Splenomegaly Dark urine from hemoglobin in the urine (seen in intravascular hemolysis)...

Clinical Features of Hemolytic Anemia Hereditary: longstanding mild to moderate hyperbilirubinemia with possible jaundice Autoimmune: gradual onset of fatigue Pallor Splenomegaly Dark urine from hemoglobin in the urine (seen in intravascular hemolysis) 1  Autoimmune Hemolysis 'Warm Antibody' -- usually IgG – Idiopathic (SLE, lymphoma, CLL and others) – Drug induced (PCN, Quinidine) 'Cold Antibody' -- usually IgM – Cold Agglutinin Disease (rare) – Secondary Mycoplasma infection Viral infections CLL Lymphoma 2  Coombs Test: Detecting Antibodies to RBCs Direct: – antibody (or complement) bound to RBC surface components Indirect: – antibody circulating in serum reactive with RBC surface components 3  Lab Analysis of Hemolytic Anemia – Bilirubin; accumulates in unconjugated form when large amounts of heme are released/metabolized from destroyed RBC – Haptoglobin; serum scavenger of free Hgb; rapidly cleared by the liver when bound to Hgb – Polychromatophilia; appearance on blood smear of increased number of purple-hued young RBC, reflecting increased marrow production and release of young RBC – Reticulocyte count; number of young RBC (reticulocytes) expressed either as an absolute count or % of total RBCs – Hemosiderin; storage Fe sloughed intro urine from Fe overloaded renal tubule cells Laboratory Evaluation of Hemolysis Extravascular Intravascular HEMATOLOGIC Routine blood film Polychromatophilia Polychromatophilia Reticulocyte count   Bone marrow examination Erythroid hyperplasia Erythroid hyperplasia PLASMA OR SERUM Bilirubin  ,Unconjugated , Unconjugated Haptoglobin , Absent Absent Plasma hemoglobin Normal,   Lactate dehydrogenase , (Variable)  , (Variable) URINE Bilirubin Absent Absent Hemosiderin Absent + Hemoglobin Absent + in severe cases  Treatment Suppress the Immune System –High Dose Steroids (with slow taper) Splenectomy Monoclonal anti lymphocyte antibodies –Anti-CD20 Chemotherapy 6  Case 3 You are called to see a 70-year-old gentleman because of severe anemia. Lately he has had malaise, frequent upset stomach, occasional headaches, shortness of breath on exertion and vague abdominal pain. His memory is not as sharp as before and he has been falling. He denies any bleeding but does bruise easily. He has had no fevers or night sweats. He has lost about 18 lbs over the past 9 months. He does not have any other medical problems. Social and family history is unremarkable. 7  Case 3 (cont.) On physical exam he is awake but slow to answer and speaks in short sentences. Vital signs are normal. His tongue shows a shiny smooth surface. His chest is clear and cardiac exam reveals a soft 2/6 holosystolic murmur. The abdomen is remarkable for diffuse tenderness but is soft, without palpable masses or enlarged organs. The extremities show moderate arthritic changes. His neurologic exam reveals decreased vibratory sensation. His gait is wide based. He cannot maintain standing balance with his feet together and his eyes closed. His CBC is as follows: WBC slightly low at 3.7, normal WBC differential count. RBC was low at 2.3 million/l; Hgb low at 7.3 g/dL; MCV 110 fL; MCH 30.5; MCHC 34.4; RDW 18.3; platelets moderately low at 98 k/l. 8 9 Modified from First Aid 2016 Edition. 10 Clinical features of Megaloblastic Anemia Anemia GI: Vague discomfort; diarrhea; anorexia; wt loss Neurologic: Extremity numbness, paresthesia Ataxia; loss of position and vib. sense Memory loss, dementia, psychosis – Neurologic symptoms of B12 deficiency can present in patients with normal MCV and Hemoglobin levels – Neurologic symptoms do not occur in pure folate deficiency! – 10-30% of pts > 70 yrs have metabolic evidence of B12 deficiency B12 nl to low normal Elevated serum homocysteine & methylmalonic acid levels B12 administration improves neuropsychiatric abnormalities The Megaloblastic Anemias Mature RBCs and their precursors are larger than normal in megaloblastic anemias – cell size determined by rate of cytoplasmic protein synthesis (largely unaffected by disruptions in DNA synthesis) – Nuclear division is slowed in Megaloblastic Anemias – The cytoplasm thus gets ahead of the nucleus and cell maturation time is longer, giving time for more cytoplasmic production Mature RBC’s and their precursors are characteristically oval in shape in megaloblastic anemia  The Megaloblastic Anemias although bone marrow cellularity is increased; most blood cell production is abortive resulting in ineffective erythropoiesis WBC mature forms, in particular granulocytes (neutrophils), have nuclear irregularity manifest as hypersegmentation  Megaloblastic Anemias Most megaloblastic anemias are due to inadequate intake or absorption of folate and or B12, respectively Drugs that impair DNA metabolism (chemotherapy) – purine antagonists: 6-mercaptopurine, azathioprine, etc. – pyrimidine antagonists: 5-fluorouracil, cytosine arabinoside, etc. – others: procarbazine, hydroxyurea, acyclovir, zidovudine  Megaloblastic Anemias Metabolic disorders (rare) – hereditary orotic aciduria – Lesch-Nyhan syndrome – Others Megaloblastic anemia of unknown etiology – refractory megaloblastic anemia – Di Guglielmo's syndrome (a rare form of acute leukemia) – congenital dyserythropoietic anemia  Pathophysiology of B12 and folate deficiency both B12 and folate are required for DNA synthesis shortages of one or both impair maturation of blood cells (…and others) slowed cell division; normal cytoplasmic growth large cells with immature or hypersegmented nuclei  Causes of Folic Acid Deficiency inadequate intake: unbalanced diet (common in alcoholics, teenagers, some infants) increased requirements – Pregnancy – Infancy – Malignancy – Increased hematopoiesis (chronic hemolytic anemias) – Chronic exfoliative skin disorders – Hemodialysis  Causes of Folic Acid Deficiency Malabsorption – tropical sprue; non-tropical sprue – drugs: Phenytoin, barbiturates, ethanol Impaired metabolism – inhibitors of dihydrofolate reductase: methotrexate, pyrimethamine, triamterene, pentamidine, trimethoprim – alcohol – rare enzyme deficiencies: dihydrofolate reductase, others  Causes of B12 Deficiency Inadequate intake: vegetarians (rare) Malabsorption – defective release of cobalamin from food gastric achlorhydria partial gastrectomy drugs that block acid secretion – inadequate production of intrinsic factor (IF) pernicious anemia total gastrectomy congenital absence or functional abnormality of IF (rare)  Causes of B12 Deficiency Malabsorption (cont.) – disorders of terminal ileum tropical sprue; non-tropical sprue regional enteritis intestinal resection neoplasms and granulomatous disorders (rare) – Competition for cobalamin Fish tapeworm (Diphyllobothrium latum) Bacteria: ``blind loop'' syndrome Drugs: p-aminosalicylic acid, colchicine, neomycin  Causes of B12 Deficiency Others – Nitrous oxide – Transcobalamin II deficiency (rare) – Congenital enzyme defects (rare) Diagnosis of Megaloblastic Anemia Anemia (!) Elevated MCV; many oval macrocytes Elevated RDW Low reticulocyte count (young RBCs) Ineffective erythropoesis – Hypercellular bone marrow – Elevated unconjugated bilirubin – Elevated LDH (isoenzyme 1) Low serum folate, and or B12 Elevated serum homocystine, methymalonic acid Pernicious anemia: anti-IF Ab, anti-Parietal cell Ab  Vitamin B12 Preparations: cyanocobalamin injection I.M. or S.C. oral cyanocobalamin: once daily nasal spray (Nascobal): Expensive  Folic Acid Clinical Uses: – prevention & treatment of folate deficiencies – prevention of neural tube defects in infants: recommended for prophylactic use in all women of child-bearing ages: “spina bifida”– 2,500/yr. By January 1998, FDA required all products made from enriched grains in the USA to be supplemented with folic acid. – MAY reduce the risks of occlusive vascular disease: Folate ↓ serum homocysteine which may ↓ risk of CHD  Folic Acid (cont.) Preparations: folic acid (generic) – oral – parenteral (Folvite): rarely used Adverse Reactions: Non-toxic Treatment of B12/Folate deficiency Treatment: – Give B12 intramuscularly weekly x 4 then monthly – Give Folate Orally 1 mg/day Treat B12 def. first before giving Folic acid otherwise neurological symptoms will worsen 26  Case 4 A 20-year-old African-American gentleman comes to the emergency room because he developed sudden severe pain in his hands and feet. He had been well until earlier in the week, when he developed a fever, runny nose and productive cough which have not yet resolved. He frequently comes to the emergency room for these “pain episodes” His physical exam shows that he is writhing in pain, has a temp of 101.2, RR of 22, HR of 115 and BP of 100/60. He has mild scleral icterus , his chest is clear, his cardiac exam has a 2/6 holosystolic murmur. His extremities are remarkable for exquisitely tender, slightly swollen hands and feet. His neurologic exam is unremarkable. The CBC shows a WBC of 17.5 with 80% neutrophils, Hgb of 6.7g/dL MCV of 100 fL and Hct of 20.1% with platelets of 445 k. The reticulocyte count is elevated in 17%. His serum electrolytes, BUN, creatinine and glucose are normal. The Liver Function Tests (LFT) are normal except for a Total Bilirubin level of 3.2. His chest x-ray is clear. The patient is admitted to the hospital, given Oxygen at 2 liters per minute by nasal prongs, intravenous hydration with normal saline and intravenous morphine sulfate to control the pain. 27  DDx Anemia Increased production – retics are way up Increased destruction – elevated LDH Sickle Cells 29  Hemoglobinopathies Hemoglobinopathies result from inherited mutations in or near coding regions of globin genes which cause: 1) Altered structure (amino acid sequence) of synthesized protein: Structural Hemoglobinopathies OR 2) Altered Production: reduced or absent rate of synthesis Thalassemias Modified from First Aid 2016 Edition. 31  Hemoglobinopathies Mutated gene → Abnormal Hgb → Abnormal RBC Disease signs and symptoms – Most mutations are inherited from one or both parents – Rarely, these disease arise from a new mutation in embryogenesis Common Hemoglobin Forms & Variants Hemoglobin % (nl) Composition Comment A 97% 22 Major adult Hgb A2 2% 2 Minor adult Hgb F 1% 22 Major fetal Hgb S 226 glu val or 22S d i C 226 glu lys or 22C s E 2226 glu lys or 22E e a H 4 s Bart 4 e  Pathophysiology of Hgb SS Decreased solubility at low pO2 and pH soluble ‘jello-like’ monomers to polymerized ‘hard plastic-like’ polymers Increased stiffness of RBC makes capillary transit more difficult Increased stickiness of RBC membranes increased adherence to vessel walls Permanently deformed RBC shape increased destruction by spleen and elsewhere Modified from First Aid 2016 Edition. 36  Sickle Cell Anemia (Hgb SS) Life-long Hemolytic Anemia RBC Life span ~ 17 days Variable symptom free periods Punctuated by painful vaso-occlusive crisis Multisystem effects Spleen: functionally asplenic CNS: stroke (~8%) retinal bleeding and detachment Sickle Cell Anemia (Hgb SS) GU priaprism hyposthenuria renal papillary necrosis painless hematuria (also in Hgb AS) hypogonadism Bone abnormalities hand-foot Syndrome aseptic necrosis femoral head  Sickle Cell Anemia (Hgb SS) Cardio-Pulmonary cardiomegaly with murmurs acute chest syndrome MEDICAL EMERGENCY fever, chest pain, leukocytosis, hypoxia Skin leg and ankle ulcers GI bilirubin gallstones (50% of Adult Hgb SS) hepatic crisis  Sickle Cell Anemia (Hgb SS) Infectious complications –most common cause of Morbidity and Mortality –bacterial pathogens: H. flu; S. pneumo; Salmonella; S. aureus; M. pneumo Functional asplenia Impaired antibody and complement response Osteomyelitis: Staph. is most common; Salmonella is unique Sickle Cell Anemia Diagnosis Family History Look at the Smear Hgb Electrophoresis  Sickle Cell Trait (Hgb AS) One copy of normal  globin gene on chromosome 11 One copy of (abnormal) s globin gene (glu -> val at AA 6) Hgb AS (Electrophoresis reveals 25-40% Hgb S) 8% African American Population carry Hgb S gene Most are completely well Painless hematuria Normal microscopic RBC appearance in peripheral blood  Treatment Acute Crisis – Pain Medication – Hydration – Oxygen – Transfusion (occasionally exchange transfusion) Chronic treatment – Hydroxyurea – Bone marrow Transplantation 43