Chapter 6-13: Underproduction Anemias (MCV) PDF

Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­13: Underproduction Anemias (framed using Mean Corpuscular Volume [MCV]) Jeremy Smith A. Microcytic anemias (MCV < 80 mcm3) 1. Iron deficiency 2. Thalassemia 3. Anemia of inf...

Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­13: Underproduction Anemias (framed using Mean Corpuscular Volume [MCV]) Jeremy Smith A. Microcytic anemias (MCV < 80 mcm3) 1. Iron deficiency 2. Thalassemia 3. Anemia of inflammation/chronic disease (more often normocytic) 4. Sideroblastic anemia (congenital, lead exposure, medications)—rare 5. Copper deficiency or zinc poisoning—rare B. Macrocytic anemias (MCV > 100 mcm3) 1. Megaloblastic anemias (due to abnormalities in DNA synthesis; hypersegmented neutrophils also occur) a. Vitamin B12 deficiency b. Folate deficiency c. Antimetabolite drugs, such as methotrexate or zidovudine 2. Nonmegaloblastic anemias (no hypersegmented neutrophils) a. Alcohol abuse b. Liver disease c. Hypothyroidism d. Myelodysplastic syndrome (often causes pancytopenia) C. Normocytic anemias 1. Anemia of inflammation/chronic disease (chronic kidney disease, infection, inflammation, malignancy, aging) 2. Early iron deficiency 3. Bone marrow suppression a. Invasion by malignancy or granulomas b. Acquired pure red cell aplasia (parvovirus B19, HIV, medications [mycophenolate mofetil, trimethoprim­sulfamethoxazole, phenytoin, recombinant human erythropoietins], thymoma, other malignancies, immune disorders) c. Aplastic anemia (often causes pancytopenia) Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­13: Underproduction Anemias (framed using Mean Corpuscular Volume [MCV]), Jeremy Smith 4. Endocrine (hypopituitarism or hypothyroidism) ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 1 / 2 a. Invasion by malignancy or granulomas Universidad Peruana de Ciencias Aplicadas Access Provided by: b. Acquired pure red cell aplasia (parvovirus B19, HIV, medications [mycophenolate mofetil, trimethoprim­sulfamethoxazole, phenytoin, recombinant human erythropoietins], thymoma, other malignancies, immune disorders) c. Aplastic anemia (often causes pancytopenia) 4. Endocrine (hypopituitarism or hypothyroidism) Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­13: Underproduction Anemias (framed using Mean Corpuscular Volume [MCV]), Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 2 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­12: Sickle Cell Anemia Jeremy Smith TEXTBOOK PRESENTATION Sickle cell anemia is often identified at birth through screening. Adult patients generally seek medical attention for pain or some of the complications. Occasionally, patients have very mild disease, and sickle cell is diagnosed late in life when evidence of a specific complication, such as sickle cell retinopathy, is identified. DISEASE HIGHLIGHTS A. Epidemiology 1. There are 5 haplotypes, 4 African, and 1 Asian (Arab­Indian). 2. Common genotypes include a. Sickle cell anemia (homozygous HbS gene) b. SC disease (HbS + HbC genes) c. HbS­beta­thalassemia (HbS + beta0 or beta+ thalassemia gene) d. HbSO Arabia (HbS + HbO Arabia genes) e. HbSD Los Angeles [Punjab] (HbS + HbD genes) 3. In African Americans, the gene frequency of HbS is 4%, of HbC is 1.5%, and of beta­thalassemia is 4%; the incidence of sickle cell anemia is about 1 in 600, with the incidence of all sickle cell disease genotypes approaching 1 in 300. 4. In non­Hispanic white births, the gene frequency for sickle cell or thalassemia is 0.17%. B. Pathophysiology (Figure 6­2) of sickle cell disease 1. Vaso­occlusion with ischemia­reperfusion injury a. Vascular obstruction is caused by precapillary obstruction by sickled cells and inflammatory triggers. b. Episodic microvascular occlusion and ischemia is followed by restoration of blood flow, leading to further injury during reperfusion as oxidases, cytokines, and other inflammatory mediators are activated. 2. Hemolysis a. Contributes to progressive vasculopathy b. Patients with high hemolytic rates are more anemic and have more cholelithiasis, leg ulcerations, priapism, and pulmonary hypertension than patients with lower hemolytic rates. c. Patients with lower hemolytic rates tend to have more episodes of acute pain and possibly acute chest syndrome. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 C. Prognosis Chapter 6­12: Sickle Cell Anemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility 1. Median age at death is 42 for men and 48 for women. 2. Genetic factors can affect prognosis. Page 1 / 7 a. Contributes to progressive vasculopathy Universidad Peruana de Ciencias Aplicadas b. Patients with high hemolytic rates are more anemic and have more cholelithiasis, leg ulcerations, priapism, and pulmonary hypertension Access Provided by: than patients with lower hemolytic rates. c. Patients with lower hemolytic rates tend to have more episodes of acute pain and possibly acute chest syndrome. C. Prognosis 1. Median age at death is 42 for men and 48 for women. 2. Genetic factors can affect prognosis. a. Higher levels of fetal hemoglobin are associated with increased life expectancy, fewer acute pain episodes, and fewer leg ulcers; levels range from 1% to 30%. b. Coexistent alpha­thalassemia (30% of patients of African origin, 50% of patients of Arabian or Indian origin) leads to decreased rates of hemolysis and increased hemoglobin levels; pain frequency is not reduced, but the rates of stroke, gallstones, leg ulcers, and priapism are lower. D. Clinical manifestations of sickle cell anemia 1. Hematologic a. HCT usually 20–30%, with reticulocyte count of 3–15%; patients with HbSC disease and HbS­beta+­thalassemia tend to be less anemic. b. Hb levels decrease slightly during acute pain episodes and episodes of acute chest syndrome; acute, marked decreases can occur due to transient aplasia from parvovirus B19 infections or sudden sequestration by the liver or spleen. c. Unconjugated hyperbilirubinemia, elevated LD, and low haptoglobin are present. d. Hb F level usually slightly elevated. e. WBC and platelet count usually elevated. f. Hypercoagulability occurs due to high levels of thrombin, low levels of protein C and S, abnormal activation of fibrinolysis and platelets. 2. Pulmonary a. Acute chest syndrome 1. Defined as a new pulmonary infiltrate accompanied by fever and a combination of respiratory symptoms, including cough, tachypnea, and chest pain. 2. Most common cause of death in sickle cell patients 3. Clinical manifestations in adults shown in Table 6­5. a. About 50% of patients in whom acute chest syndrome develops are admitted for another reason. b. Over 80% have concomitant pain crises. c. Up to 13% require mechanical ventilation; 3% die. 4. Etiology a. Fat embolism (from infarction of long bones), with or without infection in 12% b. Infection in 27%, with 8% due to bacteria, 5% mycoplasma, and 9% chlamydia c. Infarction in about 10% d. Hypoventilation and atelectasis due to pain and analgesia may play a role, as might fluid overload e. Unknown in about 50% of patients Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­12: Sickle Cell Anemia, Jeremy Smith 5. General principles of management ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility a. Supplemental oxygen Page 2 / 7 b. Infection in 27%, with 8% due to bacteria, 5% mycoplasma, and 9% chlamydia Universidad Peruana de Ciencias Aplicadas c. Infarction in about 10% Access Provided by: d. Hypoventilation and atelectasis due to pain and analgesia may play a role, as might fluid overload e. Unknown in about 50% of patients 5. General principles of management a. Supplemental oxygen b. Empiric treatment with broad­spectrum antibiotics c. Incentive spirometry (can be preventive) d. Bronchodilators for patients with reactive airways e. Transfusion b. Sickle cell chronic lung disease 1. 35–60% of patients with sickle cell disease have reactive airways. 2. About 20% have restrictive lung disease, and another 20% have mixed obstructive/restrictive abnormalities. 3. Up to 30% have pulmonary hypertension, with a very high risk of death compared to patients without pulmonary hypertension. Echocardiographic screening of adults should be performed in patients with symptoms or signs of pulmonary hypertension. 3. Genitourinary a. Renal 1. Inability to concentrate urine (hyposthenuria), with maximum urinary osmolality of 400–450 mOsm/kg 2. Type 4 renal tubular acidosis 3. Hematuria is usually secondary to papillary necrosis, but renal medullary carcinoma has been reported. 4. Microalbuminuria is common in childhood, with up to 20% of adults developing nephrotic range proteinuria, so all patients above age 10 should be screened annually for proteinuria; angiotensin­converting enzyme (ACE) inhibitors should be used if proteinuria is found without other cause. 5. Chronic kidney disease develops in 30% of adults. b. Priapism 1. 30–40% of adult males with sickle cell disease report at least 1 episode. 2. Bimodal peak incidences in ages 5–13 and 21–29. 3. 75% of episodes occur during sleep; the mean duration is 125 minutes. 4. Treatment approaches include hydration, analgesia, transfusion, and injection of alpha­adrenergic drugs. 4. Neurologic a. Highest incidence of first infarction is between the ages of 2 and 5, followed by another peak in incidence between the ages of 35 and 45. b. Hemorrhagic stroke can also occur. c. Recurrent infarction occurs in 67% of patients. d. Silent infarction is common (seen in 18–23% of patients by age 14); cognitive deficits also common. e. Patients between 16 should undergo annual transcranial Doppler screening to assess stroke risk. Downloaded 2023­12­1 12:6the A ages YourofIP2isand 52.36.32.128 Chapter 6­12: Sickle Cell Anemia, Jeremy Smith ©2023 McGraw Hill. Allwith Rights Reserved. TermsDoppler of Use velocities • Privacy (> Policy • Notice 1. Patients elevated transcranial 200 cm/s) are•atAccessibility high risk. Page 3 / 7 2. Regular transfusions to keep the HbS level below 30% reduces the risk of stroke in such patients by 90% (10% stroke rate in control b. Hemorrhagic stroke can also occur. c. Recurrent infarction occurs in 67% of patients. Universidad Peruana de Ciencias Aplicadas Access Provided by: d. Silent infarction is common (seen in 18–23% of patients by age 14); cognitive deficits also common. e. Patients between the ages of 2 and 16 should undergo annual transcranial Doppler screening to assess stroke risk. 1. Patients with elevated transcranial Doppler velocities (> 200 cm/s) are at high risk. 2. Regular transfusions to keep the HbS level below 30% reduces the risk of stroke in such patients by 90% (10% stroke rate in control group, 1% in treatment group, number needed to treat (NNT) = 11). 5. Musculoskeletal a. Bones and joints often the sites of vaso­occlusive episodes. b. Avascular necrosis of hips, shoulders, ankles, and spine can cause chronic pain. 1. Often best detected by MRI 2. May require joint replacement 6. Other a. Retinopathy 1. More common in patients with HbSC disease than with sickle cell (SS) disease 2. Treated with photocoagulation 3. Patients should be screened by an ophthalmologist for retinopathy every 1–2 years. b. Leg ulcers 1. Present in about 20% of patients 2. Most commonly over the medial or lateral malleoli c. Cholelithiasis: nearly universal due to chronic hemolysis d. Splenic sequestration and autosplenectomy: seen in children; leads to increased risk of infection with encapsulated organisms and the need for antibiotic prophylaxis e. Liver disease: multifactorial, due to causes such as iron overload or viral hepatitis E. Sickle cell trait 1. 8% of African Americans have sickle cell trait 2. Patients with sickle cell trait are not anemic, do not have pain crises, and do not have increased mortality rates. 3. Most cannot concentrate urine normally due to impairment of free water reabsorption, but this is clinically important only if hydration is inadequate. 4. Benign, self­limited hematuria due to papillary necrosis is common; however, renal medullary cancer, stones, glomerulonephritis, and infection should be ruled out. 5. There is no need to routinely screen for sickle cell trait prior to surgery. 6. Patients with sickle cell trait have a 2­fold increased risk for venous thromboembolism. Figure 6­2. Pathophysiology of sickle12:6 cell disease. Theisroles of HbS polymerization, hyperviscosity, vaso­occlusion, hemolysis, and endothelial dysfunction are Downloaded 2023­12­1 A Your IP 52.36.32.128 Page 4 / 7 Chapter 6­12: Sickle Cell Anemia, Jeremy Smith shown. Deoxygenation causes HbS to polymerize, leading to sickled erythrocytes. Vaso­occlusion results from the interaction of sickled erythrocytes ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility with leukocytes and the vascular endothelium. Vaso­occlusion then leads to infarction, hemolysis, and inflammation; inflammation enhances the expression of adhesion molecules, further increasing the tendency of sickled erythrocytes to adhere to the vascular endothelium to worsen vaso­ 5. There is no need to routinely screen for sickle cell trait prior to surgery. Universidad Peruana de Ciencias Aplicadas 6. Patients with sickle cell trait have a 2­fold increased risk for venous thromboembolism. Access Provided by: Figure 6­2. Pathophysiology of sickle cell disease. The roles of HbS polymerization, hyperviscosity, vaso­occlusion, hemolysis, and endothelial dysfunction are shown. Deoxygenation causes HbS to polymerize, leading to sickled erythrocytes. Vaso­occlusion results from the interaction of sickled erythrocytes with leukocytes and the vascular endothelium. Vaso­occlusion then leads to infarction, hemolysis, and inflammation; inflammation enhances the expression of adhesion molecules, further increasing the tendency of sickled erythrocytes to adhere to the vascular endothelium to worsen vaso­ occlusion. Reperfusion of the ischemic tissue generates free radicals and oxidative damage. The damaged erythrocytes release free hemoglobin into the plasma, which strongly bind to nitric oxide, causing functional nitric oxide deficiency and contributing to the development of vasculopathy. Reproduced with permission, from Rees DC, Williams TN, Gladwin MT. Sickle­cell disease. Lancet. 2010; Dec 11;376(9757):2018–2031. Table 6­5. Clinical manifestations of acute chest syndrome in adults. Symptom or Sign Frequency (%) Fever (mean temperature 38.8°C) 70 Cough 54 Chest pain 55 Tachypnea 39 Shortness of breath 58 Limb pain 59 Abdominal pain 29 Rib or sternal pain 30 Respiratory rate > 30 breaths per minute 38 Crackles 81 Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Wheezing Chapter 6­12: Sickle Cell Anemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Effusion 16 27 Page 5 / 7 Universidad Peruana de Ciencias Aplicadas Access Provided by: Table 6­5. Clinical manifestations of acute chest syndrome in adults. Symptom or Sign Frequency (%) Fever (mean temperature 38.8°C) 70 Cough 54 Chest pain 55 Tachypnea 39 Shortness of breath 58 Limb pain 59 Abdominal pain 29 Rib or sternal pain 30 Respiratory rate > 30 breaths per minute 38 Crackles 81 Wheezing 16 Effusion 27 EVIDENCE­BASED DIAGNOSIS A. Newborn screening 1. Universal screening identifies many more patients than screening targeted at high­risk groups. 2. Homozygotes have an FS pattern on electrophoresis, which is predominantly Hb F, with some Hb S, and no Hb A. 3. The FS pattern is not specific for sickle cell disease, and the diagnosis should be confirmed through family studies, DNA­based testing, or repeat Hb electrophoresis at 3–4 months of age. B. Testing in older children and adults 1. Cellulose acetate electrophoresis separates Hb S from other variants; however, S, G, and D all have the same electrophoretic mobility. 2. Only Hb S will precipitate in a solubility test such as the Sickledex. TREATMENT A. General principles 1. All pediatric patients should receive prophylactic penicillin to prevent streptococcal sepsis. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 2. Indications forCell transfusion transfusions and those for stroke prevention are evidence­based; other indications are based on6 / 7 Page Chapter 6­12: Sickle Anemia,(preoperative Jeremy Smith opinion orRights clinicalReserved. practice) Terms of Use • Privacy Policy • Notice • Accessibility ©2023 expert McGraw Hill. All a. Acute transfusions: acute exacerbation of anemia, acute chest syndrome, acute stroke, multiorgan failure, preoperative management, acute TREATMENT Universidad Peruana de Ciencias Aplicadas Access Provided by: A. General principles 1. All pediatric patients should receive prophylactic penicillin to prevent streptococcal sepsis. 2. Indications for transfusion (preoperative transfusions and those for stroke prevention are evidence­based; other indications are based on expert opinion or clinical practice) a. Acute transfusions: acute exacerbation of anemia, acute chest syndrome, acute stroke, multiorgan failure, preoperative management, acute splenic sequestration with severe anemia, intrahepatic cholestasis, aplastic crisis; do not transfuse for uncomplicated painful crisis, asymptomatic anemia, or priapism b. Chronic regular transfusions: previous clinically overt stroke c. Patients should be monitored for iron overload and treated as needed. 3. Patients of all ages should be vaccinated against Streptococcus pneumoniae, due to functional hyposplenism. 4. Hydroxyurea a. In patients with moderate to severe sickle cell disease, hydroxyurea therapy reduces the rate of pain crises and development of acute chest syndrome by about 50%. b. Hydroxyurea use is associated with a lower mortality rate. 5. Stem cell transplant is an experimental therapy. B. Management of vaso­occlusive crises 1. The general approach should be similar to that used in patients with other causes of severe pain, such as cancer. a. Rapidly initiate analgesics, while ruling out other causes of pain. b. If patients have mild to moderate pain and report relief with NSAIDs, continue NSAIDs provided there is no contraindication. c. If patients have severe pain, start IV opioid analgesics, combined with NSAIDs, with frequent reassessments and dose adjustments as needed. d. In this setting, patient­controlled analgesia (PCA) or scheduled dosing is preferred to as­needed dosing. e. Remember that patients who use opioids long­term become tolerant and often require high doses for acute pain. f. A multidisciplinary approach to pain management involving nurses and social workers may help optimize pain management. 2. Oral hydration is preferable to IV hydration. 3. Oxygen is indicated only if the patient is hypoxemic. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­12: Sickle Cell Anemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 7 / 7 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­11: Iron Deficiency Anemia Jeremy Smith TEXTBOOK PRESENTATION The most classic presentation would be a young, menstruating woman who has fatigue and a craving for ice. Typical presentations include fatigue, dyspnea, and sometimes edema. DISEASE HIGHLIGHTS A. The CBC varies with the degree of severity of the iron deficiency. 1. In very early iron deficiency, the CBC is normal, although the ferritin is already decreasing. 2. A mild anemia then develops, with an Hb of 9–12 g/dL, and normal or slightly hypochromic RBCs. 3. As the iron deficiency progresses, the Hb continues to decrease, and hypochromia and microcytosis develop. B. Causes of iron deficiency 1. Blood loss, most commonly menstrual or GI 2. Malabsorption a. May be seen in patients with celiac disease, Helicobacter pylori infection, or inflammatory bowel disease b. May occur after some bariatric surgery procedures c. May also occur in patients taking proton pump inhibitors or H2­blockers 3. Inadequate intake, typically found in resource­poor settings or in people on restricted diets a. Males need 1 mg/day (need to consume 15 mg/day; absorption rate 6%). b. Females need 1.4 mg/day (need to consume 11 mg/day; absorption rate 12%). c. Iron is more bioavailable from meat than vegetables. 4. Increased demand, seen with pregnancy, infancy, adolescence, erythropoietin therapy EVIDENCE­BASED DIAGNOSIS A. Bone marrow exam for absence of iron stores is the gold standard but is rarely necessary. B. The serum ferritin is the best serum test. 1. The LR+ for a decreased serum ferritin is very high, with reports ranging from LR+ of 51 for a ferritin < 15 ng/mL to a LR+ of 46 for a ferritin < 30 ng/mL. 2. Thus, a2023­12­1 low ferritin12:6 rules iron IP deficiency anemia. Downloaded A inYour is 52.36.32.128 Chapter 6­11: Iron Deficiency Anemia, Jeremy Smith 3. In generalHill. populations, LR– for a serum ng/mL is very low (0.08). ©2023 McGraw All Rightsthe Reserved. Terms ferritin of Use >• 100 Privacy Policy • Notice • Accessibility 4. Thus, in general populations, a ferritin > 100 ng/mL greatly reduces the probability the patient has iron deficiency. Page 1 / 3 B. The serum ferritin is the best serum test. Universidad Peruana de Ciencias Aplicadas Access Provided by: 1. The LR+ for a decreased serum ferritin is very high, with reports ranging from LR+ of 51 for a ferritin < 15 ng/mL to a LR+ of 46 for a ferritin < 30 ng/mL. 2. Thus, a low ferritin rules in iron deficiency anemia. 3. In general populations, the LR– for a serum ferritin > 100 ng/mL is very low (0.08). 4. Thus, in general populations, a ferritin > 100 ng/mL greatly reduces the probability the patient has iron deficiency. 5. However, because ferritin is an acute phase reactant that increases in inflammatory states, interpreting it in the presence of such illnesses is difficult. a. There is a wide range of reported LRs, with many studies finding ferritin is not helpful in diagnosing iron deficiency in the presence of chronic illness. b. The level at which the serum ferritin suggests iron deficiency is probably much higher in patients with chronic illness, but the level may vary depending on the underlying illness. c. In chronic kidney disease, iron abnormalities are defined using the transferrin saturation (serum iron/total iron­binding capacity [Fe/TIBC]) and ferritin. 1. Absolute iron deficiency, due to dietary deficiency, poor absorption, GI or other bleeding: transferrin saturation < 20%, ferritin < 100 ng/mL 2. Functional iron deficiency, due to impaired iron transport to erythroblasts and inhibited intestinal absorption: transferrin saturation < 20%, ferritin ≥ 100 ng/mL C. Other tests 1. The serum iron, MCV, transferrin saturation, red cell protoporphyrin, red cell ferritin, and RDW all are less sensitive and specific than ferritin. 2. The best of these is transferrin saturation ≤ 5%, with an LR+ of 10.46. 3. Response to a therapeutic trial of iron replacement can also be used to confirm the diagnosis in unclear cases. In patients without chronic inflammatory diseases, the serum ferritin is the best single test to diagnose iron deficiency anemia. TREATMENT A. Iron deficiency anemia is generally treated with oral iron replacement, with IV iron therapy reserved for patients who demonstrate malabsorption or who are unable to tolerate oral iron. B. Transfusion is necessary only if the patient is hypotensive or actively bleeding; has angina, dizziness, syncope, severe dyspnea or severe fatigue; or a very low hemoglobin < 7 g/dL. C. The best­absorbed oral iron is ferrous sulfate; the optimal dose is unclear but ranges from 15–150 mg of elemental iron every 1–2 days (325 mg of iron sulfate contains 65 mg of elemental iron). D. There can be significant GI side effects, including nausea, abdominal pain, and constipation; these can be reduced by taking the iron with food, reducing the dose, or increasing the dosing interval; switching to IV iron may be necessary. E. There should be an increase in reticulocytes 7–10 days after starting therapy and an increase in Hb and HCT by 14 days. F. If there is no response, reconsider the diagnosis, keeping in mind that adherence with iron therapy is often low. G. It is necessary to take iron for 6 months in order to replete iron stores, though Hb levels may return to normal by 6–8 weeks. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­11: Iron Deficiency Anemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 3 E. There should be an increase in reticulocytes 7–10 days after starting therapy and an increase in Hb and HCT by 14 days. Universidad Peruana de Ciencias Aplicadas F. If there is no response, reconsider the diagnosis, keeping in mind that adherence with iron therapy is Access oftenProvided low. by: G. It is necessary to take iron for 6 months in order to replete iron stores, though Hb levels may return to normal by 6–8 weeks. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­11: Iron Deficiency Anemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 3 / 3 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­10: Hemolytic Anemias (framed using pathophysiology) Jeremy Smith A. Hereditary 1. Enzyme defects, such as pyruvate kinase or glucose­6­phosphate dehydrogenase (G6PD) deficiency 2. Hemoglobinopathies, such as sickle cell anemia 3. RBC membrane abnormalities, such as spherocytosis B. Acquired 1. Hypersplenism 2. Immune a. Autoimmune: warm IgG, cold IgM, cold IgG b. Drug induced: autoimmune or hapten 3. Mechanical a. Macroangiopathic (marching, prosthetic valves) b. Microangiopathic: disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS) 4. Infections, such as malaria 5. Toxins, such as snake venom and aniline dyes 6. Paroxysmal nocturnal hemoglobinuria Figure 6­1 outlines the approach to evaluating anemia, assuming acute bleeding has been excluded. A. Symptoms in chronic anemia are due to decreased oxygen delivery to the tissues. 1. Fatigue is a common but not very specific symptom. 2. Dyspnea on exertion often occurs. 3. Exertional chest pain occurs most often in patients with underlying coronary artery disease or severe anemia or both. 4. Palpitations or tachycardia can occur. 5. Edema is sometimes seen. a. It is due to decreased renal blood flow leading to neurohormonal activation and salt and water retention, similar to that seen in heart failure. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 b. However, in contrast to the low cardiac output seen in patients with heart failure, the cardiac output in patients with anemia is high. Page 1 / 2 Chapter 6­10: Hemolytic Anemias (framed using pathophysiology), Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility 6. Mild anemia is often asymptomatic. B. Symptoms of hypovolemia occur only in acute anemia caused by large volume blood loss. 4. Palpitations or tachycardia can occur. 5. Edema is sometimes seen. Universidad Peruana de Ciencias Aplicadas Access Provided by: a. It is due to decreased renal blood flow leading to neurohormonal activation and salt and water retention, similar to that seen in heart failure. b. However, in contrast to the low cardiac output seen in patients with heart failure, the cardiac output in patients with anemia is high. 6. Mild anemia is often asymptomatic. B. Symptoms of hypovolemia occur only in acute anemia caused by large volume blood loss. C. Conjunctival rim pallor 1. Present when the anterior rim of the inferior palpebral conjunctiva is the same pale pink color as the deeper posterior aspect, rather than the normal bright red color of the anterior rim. 2. The presence of conjunctival rim pallor strongly suggests the patient is anemic (LR+ 16.7). 3. However, the absence of pallor does not rule out anemia. D. Palmar crease pallor has an LR+ of 7.9. E. Pallor elsewhere (facial, nail bed) is not as useful, with LR+ < 5. F. No physical sign rules out anemia. G. The overall sensitivity and specificity of the physical exam for anemia is about 70%. Order a CBC if patients have symptoms that suggest anemia, even without physical exam signs, or if you observe conjunctival rim or palmar crease pallor. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­10: Hemolytic Anemias (framed using pathophysiology), Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 2 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­9: Hemolysis Jeremy Smith TEXTBOOK PRESENTATION A classic presentation of hemolytic anemia is a previously healthy patient presenting with relatively acute onset of mild jaundice associated with fatigue, exertional dyspnea, and dizziness, and a moderate to severe degree of anemia. DISEASE HIGHLIGHTS A. In macroangiopathic and microangiopathic hemolytic anemia and some complement­induced lysis, RBCs are destroyed in the intravascular space. 1. Completely destroyed cells release free Hb into the plasma, which then binds to haptoglobin, reducing the plasma haptoglobin level. 2. Some Hb is filtered by the glomerulus, causing hemoglobinuria, which darkens the urine. 3. Some filtered Hb is taken up by renal tubular cells, stored as hemosiderin; hemosiderinuria occurs about a week later, when the tubular cells are sloughed into the urine. 4. Damaged but incompletely hemolyzed cells are destroyed in the spleen. B. Deformed RBCs and those coated with complement are usually destroyed in the extravascular space, in the liver or spleen. 1. Most of the Hb is degraded into biliverdin, iron, and carbon monoxide. 2. Biliverdin is converted to unconjugated bilirubin and released into the plasma, increasing the unconjugated bilirubin level. 3. Some free Hb is released, which then binds to haptoglobin, again reducing the plasma haptoglobin level. EVIDENCE­BASED DIAGNOSIS A. The reticulocyte count is usually at least 4–5%; in 1 study of autoimmune hemolytic anemia, the median was 9%. B. The serum haptoglobin should be < 25 mg/dL. 1. Sensitivity = 83%, specificity = 96% for hemolysis; LR+ = 21, LR– = 0.18 2. Haptoglobin is an acute phase reactant. C. The LD is often increased. 1. Finding an increased LD and a decreased haptoglobin is 90% specific for the diagnosis of hemolysis. 2. Finding a normal LD and a normal serum haptoglobin (> 25 mg/dL) is 92% sensitive for the absence of hemolysis. D. The unconjugated bilirubin may be increased. E. Plasma and urine Hb should be elevated if the hemolysis is intravascular. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­9: Hemolysis, Jeremy Smith TREATMENT ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 1 / 2 Treatment depends on the underlying cause. In an autoimmune condition, immunosuppressive therapy, especially prednisone, is used. Rituximab and splenectomy are options in refractory cases. If hemolysis is associated with TTP and HUS, the treatment is plasmapheresis and immunosuppressive Universidad Peruana de Ciencias Aplicadas 2. Finding a normal LD and a normal serum haptoglobin (> 25 mg/dL) is 92% sensitive for the absence of hemolysis. Access Provided by: D. The unconjugated bilirubin may be increased. E. Plasma and urine Hb should be elevated if the hemolysis is intravascular. TREATMENT Treatment depends on the underlying cause. In an autoimmune condition, immunosuppressive therapy, especially prednisone, is used. Rituximab and splenectomy are options in refractory cases. If hemolysis is associated with TTP and HUS, the treatment is plasmapheresis and immunosuppressive therapy. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­9: Hemolysis, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 2 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­8: Folate Deficiency Jeremy Smith TEXTBOOK PRESENTATION The classic presentation is an alcoholic patient with malnutrition and anemia. DISEASE HIGHLIGHTS A. Anemia and macrocytosis are the most common manifestations; whether neurologic symptoms can occur is controversial. B. Most often caused by inadequate intake (especially in alcoholic patients) or increased demand due to pregnancy, chronic hemolysis, leukemia. C. Since absorption occurs in the jejunum, malabsorption is rare in the absence of bariatric surgery, short bowel syndrome, or bacterial overgrowth syndromes. D. Some drugs can cause folate deficiency, including methotrexate, phenytoin, sulfasalazine, and alcohol. E. Along with B12, folate is a cofactor for the conversion of homocysteine to methionine, so homocysteine levels (but not MMA levels) increase in folate deficiency. EVIDENCE­BASED DIAGNOSIS A. The sensitivity and specificity of serum folate measurements for the diagnosis of folate deficiency are not clear. B. Levels can decrease within a few days of dietary folate restriction, or with alcohol use, even though tissue stores can be normal; levels increase with feeding. C. Recent evidence suggests that RBC folate is not superior to serum folate for diagnosis of folate deficiency. Do not order red cell (RBC) folate to evaluate folate deficiency. D. Elevated homocysteine is about 80% sensitive for the diagnosis of folate deficiency; the specificity is unknown. E. A positive response to therapy is diagnostic. F. A patient with a normal serum folate and no response to folate replacement does not have folate deficiency. TREATMENT A. In patients with an acute deficiency, treat with 1 mg of folic acid daily for 1–4 months, or until there is complete hematologic recovery. 1. Never treat folate deficiency without determining whether the patient is B12 deficient. 2. Folate replacement can correct hematologic abnormalities while worsening the neurologic symptoms specific to B12 deficiency. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­8: Folate Deficiency, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Always check for B12 deficiency in a patient with folate deficiency. Page 1 / 2 TREATMENT Universidad Peruana de Ciencias Aplicadas A. In patients with an acute deficiency, treat with 1 mg of folic acid daily for 1–4 months, or until there is complete hematologic recovery. Access Provided by: 1. Never treat folate deficiency without determining whether the patient is B12 deficient. 2. Folate replacement can correct hematologic abnormalities while worsening the neurologic symptoms specific to B12 deficiency. Always check for B12 deficiency in a patient with folate deficiency. B. Patients with long­term increased demand, such as those with sickle cell anemia, should take 1 mg of folic acid daily indefinitely. C. Women who are trying to conceive and pregnant women should take a prenatal vitamin containing at least 0.4 mg of folic acid daily to prevent anencephaly. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­8: Folate Deficiency, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 2 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­7: Beta­Thalassemia Jeremy Smith TEXTBOOK PRESENTATION Beta­thalassemia major (homozygotes) presents in infancy with severe, transfusion­dependent anemia. Some homozygotes have residual beta chain synthesis resulting in an intermediate phenotype called thalassemia intermedia. Heterozygotes are usually anemic but asymptomatic. DISEASE HIGHLIGHTS A. Impaired production of beta globin chains. B. Common in the Mediterranean area and Southeast Asia. C. Beta­thalassemia minor: heterozygotes with 1 normal beta globin allele and 1 beta thalassemic allele. 1. Anemia is generally mild (Hb 9–10 g/dL), and microcytosis is severe (MCV 65–75 mcm3). 2. In pregnancy, anemia can be more severe than usual. 3. Asymptomatic splenomegaly occurs in 15–20% of patients. EVIDENCE­BASED DIAGNOSIS A. Iron studies should be normal; RDW usually normal; target cells abundant; RBCs may be normal or high. B. On Hb electrophoresis, the Hb A2 can be elevated, but a normal A2 does not rule out beta­thalassemia minor. TREATMENT OF BETA­THALASSEMIA MINOR None. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­7: Beta­Thalassemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 1 / 1 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­6: B 12 Deficiency Jeremy Smith TEXTBOOK PRESENTATION The classic presentation is an elderly woman with marked anemia and neurologic symptoms such as paresthesias, sensory loss (especially vibration and position), and ataxia. DISEASE HIGHLIGHTS A. It takes years to develop this deficiency because of extensive stores of vitamin B12 in the liver. B. Anemia and macrocytosis are not always present. 1. In 1 study, 28% of patients with neurologic symptoms due to B12 deficiency had no anemia or macrocytosis; another study found that up to 84% of patients with B12 deficiency may be missed if B12 levels are checked only in patients with macrocytosis. 2. In another study, the following clinical characteristics were found in patients with B12 deficiency: a. 28% were not anemic b. 17% had a normal MCV c. 17% had leukopenia, 35% thrombocytopenia, 12.5% pancytopenia d. 25% of patients had glossitis e. 36% had neuropsychiatric symptoms 1. Paresthesias occur initially, followed by ataxia with loss of vibration and position sense. 2. Neuropsychiatric symptoms can progress to severe weakness, spasticity, clonus, paraplegia, fecal and urinary incontinence. 3. Delirium and dementia can occur. The CBC can be normal in B12 deficiency. C. Intramedullary hemolysis can occur, leading to an increased lactate dehydrogenase (LD) and decreased haptoglobin. D. B12 absorption requires normal gastric and intestinal function. 1. Dietary B12 is protein bound and is released by acid peptic digestion in the stomach. 2. Although intrinsic factor is made by the parietal cells of the gastric body and fundus, it does not bind to B12 until both reach the jejunum. Downloaded 12:6 A Your IP is 52.36.32.128 3. The B122023­12­1 ­intrinsic factor complex binds to receptors in the terminal ileum, where B12 is absorbed. Page 1 / 4 Chapter 6­6: B12 Deficiency, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility E. The most common causes of B12 deficiency are food­cobalamin malabsorption, lack of intrinsic factor, and dietary deficiency; other causes of malabsorption are less common. D. B12 absorption requires normal gastric and intestinal function. Universidad Peruana de Ciencias Aplicadas 1. Dietary B12 is protein bound and is released by acid peptic digestion in the stomach. Access Provided by: 2. Although intrinsic factor is made by the parietal cells of the gastric body and fundus, it does not bind to B12 until both reach the jejunum. 3. The B12­intrinsic factor complex binds to receptors in the terminal ileum, where B12 is absorbed. E. The most common causes of B12 deficiency are food­cobalamin malabsorption, lack of intrinsic factor, and dietary deficiency; other causes of malabsorption are less common. 1. Dietary deficiency is rare unless the patient follows a vegan diet. 2. Food­cobalamin malabsorption occurs when B12 is not released from food proteins due to impaired acid peptic digestion. a. The B12 deficiency in this condition is often subclinical and affects up to 20% of older adults. b. It is caused by atrophic gastritis and achlorhydria, which can be seen with chronic H pylori infection, gastric surgery, and long­term use of acid­suppressing drugs. 3. Lack of intrinsic factor is caused by a. Gastrectomy (all patients with total gastrectomy and 5% of patients with partial gastrectomy will become B12 deficient) b. Pernicious anemia 1. An immunologically mediated gastric atrophy that leads to loss of parietal cells and a marked reduction in secretion of intrinsic factor 2. Uncommon before age 30 3. Seen most often in patients over age 50, with a median age at diagnosis of 70–80 years 4. 25% of patients have a family history of pernicious anemia and 10% have autoimmune thyroid disease. 4. B12 deficiency can also be caused by malabsorption in the terminal ileum due to surgical removal or bypass, Crohn disease, celiac disease, or bacterial overgrowth 5. Sometimes drugs interfere with B12 absorption, most notably metformin, proton pump inhibitors, colchicine, ethanol, and neomycin. 6. Blind loop syndrome can cause B12 deficiency due to utilization of B12 by the bacteria. 7. Malabsorption may rarely be due to congenital disorders, such as transcobalamin II deficiency. EVIDENCE­BASED DIAGNOSIS A. Determining whether a patient is B12 deficient is more complicated than it seems. 1. B12 levels can be falsely low in folate deficiency, pregnancy, and oral contraceptive use. 2. B12 levels can be falsely normal in myeloproliferative disorders, liver disease, and bacterial overgrowth syndromes. 3. The sensitivity of a B12 level < 200 pg/mL for proven clinical B12 deficiency is 65–95%; the specificity is 60–80%. B. B12 is a cofactor in the conversion of homocysteine to methionine, and of methmalonyl CoA (MMA) to succinyl CoA. 1. Consequently, in B12 deficiency, the levels of homocysteine and MMA increase. 2. Therefore, another way to diagnosis B12 deficiency is to measure homocysteine and MMA levels. a. In addition to B12 deficiency, MMA can be elevated in chronic kidney disease and hypovolemia. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Page 2 / 4 Chapter 6­6: B12 Deficiency, Jeremy Smith b. The sensitivity of MMA > 400 nmol/L for the diagnosis of BPolicy is 98%; modest elevations in the 300–700 nmol/L range can be seen in ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy • Notice • Accessibility 12 deficiency chronic kidney disease. MMA > 1000 nmol/L is highly specific for B12 deficiency. 1. Consequently, in B12 deficiency, the levels of homocysteine and MMA increase. Universidad Peruana de Ciencias Aplicadas Access Provided by: 2. Therefore, another way to diagnosis B12 deficiency is to measure homocysteine and MMA levels. a. In addition to B12 deficiency, MMA can be elevated in chronic kidney disease and hypovolemia. b. The sensitivity of MMA > 400 nmol/L for the diagnosis of B12 deficiency is 98%; modest elevations in the 300–700 nmol/L range can be seen in chronic kidney disease. MMA > 1000 nmol/L is highly specific for B12 deficiency. c. Homocysteine can be elevated in folate or pyridoxine deficiency, chronic kidney disease, hypovolemia, and hypothyroidism. d. The sensitivity of homocysteine ranges from 85% to 96%; an elevated homocysteine is less specific than an elevated MMA. C. Response to therapy is another way to establish the presence of B12 deficiency. 1. MMA and homocysteine normalize 7–14 days after the start of replacement therapy. 2. The reticulocyte count increases in 7–10 days, and the hemoglobin increases in 30 days. D. An algorithm for diagnosing B12 deficiency in patients with macrocytic anemia 1. B12 level < 100 pg/mL: deficiency present 2. B12 level 100–350 pg/mL: check MMA and homocysteine levels a. If both normal, deficiency unlikely b. If both elevated, deficiency present c. If MMA alone elevated, deficiency present d. If homocysteine alone elevated, possible deficiency 3. B12 > 350 pg/mL: deficiency unlikely Very low or very high B12 levels are usually diagnostic. Patients with neurologic symptoms consistent with B12 deficiency should have MMA and homocysteine levels checked even if the B12 level is low normal. TREATMENT A. IM cobalamin, 1000 mcg weekly for 6–8 weeks, and then monthly B. Can also use oral cobalamin, 1000–2000 mcg daily 1. Oral cobalamin is absorbed by a second, nonintrinsic factor­dependent mechanism that is relatively inefficient. 2. Patients with dietary deficiency and food­cobalamin malabsorption can be treated with lower doses of oral B12. 3. Randomized trials have shown that oral and intramuscular replacement are equally effective, even in patients with pernicious anemia or gastrectomies. C. Sublingual2023­12­1 and intranasal available but have not been extensively studied. Downloaded 12:6 formulations A Your IP isare 52.36.32.128 Chapter 6­6: B12 Deficiency, Jeremy Smith D. Lifelong treatment needed, unless the Terms cause of can be corrected. ©2023 McGraw Hill. AllisRights Reserved. ofdeficiency Use • Privacy Policy • Notice • Accessibility Page 3 / 4 2. Patients with dietary deficiency and food­cobalamin malabsorption can be treated with lower doses of oral B12.Peruana de Ciencias Aplicadas Universidad Access Provided by: 3. Randomized trials have shown that oral and intramuscular replacement are equally effective, even in patients with pernicious anemia or gastrectomies. C. Sublingual and intranasal formulations are available but have not been extensively studied. D. Lifelong treatment is needed, unless the cause of deficiency can be corrected. Downloaded 2023­12­1 12:6 A Your IP is 52.36.32.128 Chapter 6­6: B12 Deficiency, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 4 / 4 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­5: Anemia of Inflammation Jeremy Smith TEXTBOOK PRESENTATION A classic presentation is a person with a chronic inflammatory condition (eg, rheumatoid arthritis, osteomyelitis, inflammatory bowel disease) with a chronic, stable, normocytic anemia in the range of 8.5–9.5 g/dL. DISEASE HIGHLIGHTS A. Occurs in patients with acute or chronic immune activation B. Cytokines (interferons, interleukins, tumor necrosis factor) induce changes in iron homeostasis. 1. Dysregulation of iron homeostasis a. Increased uptake and retention of iron in reticuloendothelial system cells b. Limited availability of iron for erythropoiesis 2. Impaired proliferation and differentiation of erythroid progenitor cells 3. Blunted erythropoietin response a. Production of erythropoietin inadequate for degree of anemia b. Progenitor cells do not respond normally 4. Increased erythrophagocytosis leads to decreased RBC half­life C. Underlying causes of anemia of inflammation include 1. Chronic kidney disease a. In patients with end­stage renal disease who undergo dialysis, the anemia is due to lack of erythropoietin and marked inflammation. b. In patients with lesser degrees of chronic kidney disease, the anemia is caused primarily by lack of erythropoietin and anti­proliferative effects of uremic toxins. 2. Autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, vasculitis, sarcoidosis, and inflammatory bowel disease 3. Acute infections caused by viruses, bacteria, fungi, or parasites a. Can occur within 24–48 hours in acute bacterial infections, with Hb usually in the 10–12 g/dL range b. Occurs in as many as 90% of ICU patients, accompanied by inappropriately mild elevations of serum erythropoietin levels and blunted bone marrow response to endogenous erythropoietin, sometimes called “anemia of critical illness” 4. Chronic infections caused by viruses, bacteria, fungi, or parasites 5. Cancer,2023­12­1 either hematologic or solid Downloaded 12:5 A Your IP istumor 52.36.32.128 Chapter 6­5: Anemia of Inflammation, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. of Use • Privacy D. Some noninflammatory chronic diseasesTerms can also cause anemias.Policy • Notice • Accessibility 1. Endocrinopathies, such as Addison disease, thyroid disease, and panhypopituitarism can lead to mild chronic anemia. Page 1 / 2 Universidad Peruanalevels de Ciencias Aplicadas b. Occurs in as many as 90% of ICU patients, accompanied by inappropriately mild elevations of serum erythropoietin and blunted bone Access Provided by: marrow response to endogenous erythropoietin, sometimes called “anemia of critical illness” 4. Chronic infections caused by viruses, bacteria, fungi, or parasites 5. Cancer, either hematologic or solid tumor D. Some noninflammatory chronic diseases can also cause anemias. 1. Endocrinopathies, such as Addison disease, thyroid disease, and panhypopituitarism can lead to mild chronic anemia. 2. Liver disease can cause anemia. EVIDENCE­BASED DIAGNOSIS A. There is not a single test that proves or disproves a patient’s anemia is from anemia of inflammation. B. Instead, there are several diagnostic tests that can possibly be done, sometimes simultaneously and sometimes sequentially. An Hb of < 8 g/dL suggests there is an additional cause for the anemia, beyond the anemia of inflammation. 1. Even in the presence of a disease known to cause anemia, it is important to rule out iron, B12, and folate deficiencies. 2. The typical pattern of iron studies in anemia of inflammation is a low serum iron, low TIBC, low normal to normal transferrin saturation, and elevated serum ferritin. 3. MCV is usually normal but can be mildly microcytic. 4. Erythropoietin levels will be low in chronic kidney disease and not appropriately elevated for the degree of anemia in inflammatory conditions; interpretation is difficult and measurement of the erythropoietin level is generally not useful diagnostically. 5. Pancytopenia suggests there is bone marrow infiltration or a disease that suppresses the production of all cell lines. 6. When you see pancytopenia, think about bone marrow infiltration, B12 deficiency, viral infection, drug toxicity, hypersplenism, overwhelming infection, systemic lupus erythematosus, myelodysplastic syndrome, or acute alcohol intoxication. Bone marrow examination is necessary to establish the diagnosis when pancytopenia is present, serum tests are not diagnostic, the anemia progresses, or there is not an appropriate response to empiric therapy. TREATMENT A. Treat the underlying chronic disease, if possible. B. Indications for erythropoietin therapy and appropriate target Hb levels are evolving; iron should be given to all patients being treated with erythropoietin. Downloaded 2023­12­1 12:5 A Your IP is 52.36.32.128 Chapter 6­5: Anemia of Inflammation, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 2 / 2 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­4: Alpha­Thalassemia Jeremy Smith TEXTBOOK PRESENTATION Loss of 3 or 4 alpha globin genes causes severe disease that presents at birth or is fatal in utero. Patients with loss of 2 genes have alpha thalassemia minor with mild abnormalities and are usually anemic but asymptomatic. The loss of 1 gene is alpha thalassemia minima; the CBC is totally normal. DISEASE HIGHLIGHTS A. Impaired production of alpha globin chains. B. Common in Africa, the Mediterranean area and Southeast Asia. C. The genetics of alpha thalassemia minor vary 1. Alpha­thalassemia trait 1: Hb, 12–14 g/dL; MCV, 80–85 mcm3; Hb electrophoresis, normal 2. Alpha­thalassemia trait 2: Hb, 12–13 g/dL; MCV, 65–75 mcm3; Hb electrophoresis, normal EVIDENCE­BASED DIAGNOSIS Alpha­thalassemia is diagnosed by polymerase chain reaction genetic analysis. TREATMENT OF ALPHA­THALASSEMIA TRAIT None. Downloaded 2023­12­1 12:5 A Your IP is 52.36.32.128 Chapter 6­4: Alpha­Thalassemia, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 1 / 1 Universidad Peruana de Ciencias Aplicadas Access Provided by: Symptom to Diagnosis: An Evidence­Based Guide, 4e Chapter 6­3: Patient with Anemia ­ Case 3 Jeremy Smith CHIEF COMPLAINT PATIENT Mr. J is a 77­year­old African American man with a history of an aortic valve replacement about 2 years ago. He brought in results of tests done at another hospital: Hb, 9.0 g/dL; HCT, 27.4%; MCV, 90 mcm3; reticulocyte count, 7%; The RPI is 2.1. At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered? RANKING THE DIFFERENTIAL DIAGNOSIS The leading hypothesis is hemolysis, with the pivotal point being the elevated reticulocyte count and RPI. The only potential active alternative would be active bleeding, which is also associated with an elevated RPI; however, that diagnosis should be clinically obvious. The pretest probability of hemolysis is high, and so all other causes of anemia are alternative diagnoses to be considered only if the diagnosis of hemolysis is not supported by further testing. Table 6­4 lists the differential diagnosis. Table 6­4. Diagnostic hypotheses for Mr. J. Diagnostic Hypotheses Demographics, Risk Factors, Symptoms and Signs Important Tests Mechanical valve Reticulocyte count Known hereditary condition Haptoglobin Family history of anemia Indirect bilirubin Sepsis Lactate dehydrogenase Fever Examination of peripheral smear Autoimmune disease Direct antiglobulin (Coombs) test Leading Hypothesis Hemolysis Active Alternative—Must Not Miss Active bleeding Melena History Hematochezia Rectal exam for gross blood or positive fecal occult blood test Hematemesis Menorrhagia Downloaded 2023­12­1 12:5 A Your IP is 52.36.32.128 Chapter 6­3: Patient with Anemia ­ Case 3, Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility Page 1 / 3 The leading hypothesis is hemolysis, with the pivotal point being the elevated reticulocyte count and RPI. The only potential active alternative would be Universidad Peruana de Ciencias Aplicadas active bleeding, which is also associated with an elevated RPI; however, that diagnosis should be clinically obvious. The pretest probability of Access Provided by: hemolysis is high, and so all other causes of anemia are alternative diagnoses to be considered only if the diagnosis of hemolysis is not supported by further testing. Table 6­4 lists the differential diagnosis. Table 6­4. Diagnostic hypotheses for Mr. J. Diagnostic Hypotheses Demographics, Risk Factors, Symptoms and Signs Important Tests Mechanical valve Reticulocyte count Known hereditary condition Haptoglobin Family history of anemia Indirect bilirubin Sepsis Lactate dehydrogenase Fever Examination of peripheral smear Autoimmune disease Direct antiglobulin (Coombs) test Leading Hypothesis Hemolysis Active Alternative—Must Not Miss Active bleeding Melena History Hematochezia Rectal exam for gross blood or positive fecal occult blood test Hematemesis Menorrhagia Mr. J has no history of hematemesis, melena, hematochezia, or abdominal pain. His abdominal exam is normal, and rectal exam shows brown, hemoccult­negative stool. Is the clinical information sufficient to make a diagnosis? If not, what other information do you need? MAKING A DIAGNOSIS Mr. J’s serum haptoglobin is < 20 mg/dL, his serum bilirubin is normal, and his LD is elevated at 359 units/L. Have you crossed a diagnostic threshold for the leading hypothesis, hemolysis? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses? The combination of the high pretest probability and the large LR+ for this level of haptoglobin confirms the diagnosis of hemolysis. Active bleeding has been ruled out by history and physical exam. At this point, any further testing should be aimed at determining the cause of the hemolysis. A. The direct antiglobulin test (DAT), also known as the Coombs test, should be done in all patients to distinguish immune­mediated from non– immune­mediated hemolytic anemia. Downloaded 2023­12­1 12:5 A Your IP is 52.36.32.128 1. Detects antibody complement on3,the surface of the RBC Chapter 6­3: Patient withorAnemia ­ Case Jeremy Smith ©2023 McGraw Hill. All Rights Reserved. Terms of Use • Privacy Policy • Notice • Accessibility a. The DAT is positive for IgG in patients with warm autoimmune hemolytic anemia. Page 2 / 3 Universidad Peruana de Ciencias Aplicadas The combination of the high pretest probability and the large LR+ for this level of haptoglobin confirms the diagnosis of hemolysis. Active bleeding has Access Provided by: been ruled out by history and physical exam. At this point, any further testing should be aimed at determining the cause of the hemolysis. A. The direct antiglobulin test (DAT), also known as the Coombs test, should be done in all patients to distinguish immune­mediated from non– immune­mediated hemolytic anemia. 1. Detects antibody or complement on the surface of the RBC a. The DAT is positive for IgG in patients with warm autoimmune hemolytic anemia. b. The DAT is positive for complement in patients with cold autoimmune hemolytic anemia. c. It is also positive in paroxysmal cold hemoglobinuria, transfusion­related hemolytic anemia, and some drug­induced hemolytic anemias. 2. The indirect Coombs test detects antibodies to RBC antigens in the patient’s serum and is sometimes positive in drug­induced hemolytic anemias. B. The smear should be examined for schistocytes, seen in macroangiopathic and microangiopathic hemolytic anemias. 1. Concomitant thrombocytopenia and coagulopathy are seen in DIC (See Chapter 8­4: Disseminated Intravascular Coagulation (DIC)). 2. Concomitant thrombocytopenia, chronic kidney disease, or neurologic symptoms are seen in TTP and HUS (See Chapter 8­8: Thrombotic Thrombocytopenic Purpura (TTP)). C. Look for other causes of hemolytic anemia through history and physical exam and test selectively. 1. Does the patient have a mechanical valve? 2. Has the patient traveled to an area where malaria is endemic? 3. Has the patient been exposed to a toxin? 4. Does the patient have splenomegaly on exam or ultrasound? 5. Is there an undiagnosed hereditary cause (especially G6PD deficiency)? CASE RESOLUTION His WBC and platelet count as well as his kidney function are all normal; the Coombs test is negative. He does have a few schistocytes on his peripheral smear. The negative Coombs tests make autoimmune etiologies unlikely and the schistocytes suggest microangiopathic or macroangiopathic hemolysis. Given his history, the most likely etiology is hemolysis due to his mechanical valve. Since he is asymptomatic, it is not necessary to consider the removal of the valve. Downloaded 2023­12­1 12:5 A Your IP is