Anemia: Production Defects

In document Board Review From Medscape (Page 171-176)

9. A 30-year-old African-American woman presents to your office with a chief complaint of weakness. She states that she has been feeling “run down” for several weeks now. Further questioning reveals that she is diffusely weak. She is without focal deficits. She has experienced dyspnea on exertion, and she has a new rash. Physical examination is notable for mild tachycardia, pale conjunctiva, petechiae on her mucus membranes and lower extremities, and an absence of hepatomegaly or splenomegaly. Results of a complete blood cell count (CBC) are as follows: hematocrit, 21%; white blood cell count (WBC), 1,200 cells/mm3; and platelet count, 12,000 cells/mm3. The results of a bone marrow biopsy with aspirate are consistent with aplastic anemia.

Which of the following statements regarding aplastic anemia is false?

❑ A. Aplasia can be a prodrome to hairy-cell leukemia, acute lymphoblastic leukemia, or acute myeloblastic leukemia

❑ B. Viral infections remain one of the major causes of aplastic anemia

❑ C. Ionizing irradiation and chemotherapeutic drugs that can be used to treat malignant or immunologic disorders can cause aplastic anemia

❑ D. Approximately 20% of patients with hepatitis can experience aplastic anemia 2 to 3 weeks after they experience a typical case of acute hepatitis Key Concept/Objective: To understand the etiologies of aplastic anemia

Pancytopenia (i.e., anemia, neutropenia, and thrombocytopenia) and a finding of aplastic marrow on biopsy establish a working diagnosis of aplastic anemia. Aplastic anemia has a number of causes, although in many cases the exact cause cannot be determined. Ionizing irradiation and chemotherapeutic drugs used in the management of malignant and immunologic disorders have the capacity to destroy hematopoietic stem cells. With care-ful dosing and scheduling, recovery is expected. Certain drugs, such as chloramphenicol, produce marrow aplasia that is not dose dependent. Gold therapy and the inhalation of organic solvent vapors (e.g., benzene or glue) can also cause fatal marrow failure. In 2% to 10% of hepatitis patients, severe aplasia occurs 2 to 3 months after a seemingly typical case of acute disease. Often, the hepatitis has no obvious cause, and tests for hepatitis A, B, and C are negative. Aplasia can also be part of a prodrome to hairy-cell leukemia, acute lym-phoblastic leukemia, or, in rare cases, acute myeloid leukemia, or it can develop in the course of myelodysplasia. Parvovirus infection is the cause of the transient aplastic crises that occur in patients who have severe hemolytic disorders. The marrow in patients with such disorders must compensate for the peripheral hemolysis by increasing its production up to sevenfold. Although parvovirus can affect all precursor cells, the red cell precursors are the most profoundly affected. Anemia causes fatigue and shortness of breath; throm-bocytopenia causes petechiae, oral blood blisters, gingival bleeding, and hematuria, depending on the level of the platelet count. By far the major problem is the recurrent bac-terial infections caused by the profound neutropenia. The diagnosis of aplastic anemia requires a marrow aspirate and biopsy, as well as a thorough history of drug exposures, infections, and especially symptoms suggesting viral illnesses and serologic test results for hepatitis, infectious mononucleosis, HIV, and parvovirus. Measurement of red cell CD59 is helpful in the diagnosis of paroxysmal nocturnal hemoglobinuria. (Answer: D—

Approximately 20% of patients with hepatitis can experience aplastic anemia 2 to 3 weeks after they experience a typical case of acute hepatitis)

10. A 43-year-old white man presents to your clinic complaining of fatigue and paresthesias. He is a vegetar-ian and does not take a multivitamin. His examination reveals pallor, an absence of hepatosplenomegaly, normal muscle strength throughout, and loss of position sensation and vibratory sensation distally. A CBC reveals anemia, with a mean corpuscular volume (MCV) of 106 fl. His WBC, platelet count, and serum chemistries are normal. He has had no toxic exposures and is taking no medications.

Which of the following statements about megaloblastic anemia is false?

❑ A. Absorption of cobalamin in the small intestine is dependent on pro-teins produced in the mouth and stomach

❑ B. Megaloblastic erythropoiesis is characterized by defective DNA synthe-sis and arrest at the G2 phase, with impaired maturation and a

buildup of cells that do not synthesize DNA and that contain anom-alous DNA

❑ C. In most patients with severe cobalamin deficiency, the neurologic examination is normal

❑ D. Cobalamin deficiency is treated with parenteral cobalamin therapy

Key Concept/Objective: To understand the etiology, diagnosis, and treatment of pernicious anemia Megaloblastic erythropoiesis is characterized by defective DNA synthesis and arrest at the G2 phase, with impaired maturation and a buildup of cells that do not synthesize DNA and that contain anomalous DNA. This condition leads to asynchronous maturation between the nucleus and cytoplasm. RNA production and protein synthesis continue; thus, larger cells, or megaloblasts, are produced. In addition to macrocytic and megaloblastic anemia, the patient with cobalamin deficiency may have weakness, lethargy, or dementia, as well as atrophy of the lingual papillae and glossitis. Neuropathy is the presenting fea-ture in about 12% of patients with cobalamin (vitamin B12) deficiency without concomi-tant anemia. Patients with severe cobalamin deficiency initially complain of paresthesia.

The sense of touch and temperature sensitivity may be minimally impaired. Memory impairment and depression may be prominent. The disease may progress, involving the dorsal columns, causing ataxia and weakness. The physical examination reveals a broad-based gait, the Romberg sign, slowed reflexes, and a loss of sense of position and feeling of

vibration (especially when tested with a 256 Hz tuning fork). (Answer: C—In most patients with severe cobalamin deficiency, the neurologic examination is normal)

11. A 53-year-old woman is referred to your office by her gynecologist for management of anemia. She expe-rienced menopause at 48 years of age and has had no further vaginal bleeding. Two years ago, her hema-tocrit was 36%. During her last office visit, her hemahema-tocrit was 29%, and her MCV was 107 fl. The patient is dependent on alcohol. She admits to drinking a pint of wine daily, and she engages in occasional binge drinking on weekends. She denies any other sources of blood loss or icterus. She is apparently only mild-ly symptomatic with some fatigue.

Which of the following statements regarding megaloblastic anemia caused by folic acid deficiency is false?

❑ A. Serum folic acid levels more accurately reflect tissue stores than do red blood cell folic acid levels

❑ B. Folic acid deficiency can be differentiated from cobalamin deficiency by measuring methylmalonic acid and homocysteine levels; both are elevated in cobalamin deficiency, but only homocysteine is elevated in folic acid deficiency

❑ C. Megaloblastic anemia caused by folic acid deficiency can be masked by concurrent iron deficiency anemia, but hypersegmented polymor-phonuclear cells (PMNs) should still be present on the peripheral smear

❑ D. Folinic acid can be used to treat patients with megaloblastosis and bone marrow suppression associated with the use of methotrexate

Key Concept/Objective: To understand the diagnosis and treatment of megaloblastic anemia caused by folic acid deficiency

Patients with megaloblastic anemia who do not have glossitis, a family history of perni-cious anemia, or the neurologic features described for cobalamin deficiency may have folic acid deficiency. Tests to determine folic acid deficiency vary in their accuracy. Serum folic acid levels are less reliable than red blood cell folic acid levels. A serum folic acid level of less than 2 ng/ml is consistent with folic acid deficiency, as is a red blood cell folic acid level of less than 150 ng/ml. Because the combination of folic acid and iron deficiency is common, full expression of megaloblastosis is often blocked, and the patient will have a dimorphic anemia rather than the easily identifiable macro-ovalocytosis. Hypersegmen-tation of PMNs persists. The serum folic acid level decreases within 2 weeks after dietary folic acid ingestion completely ceases. Therefore, many hospitalized patients have low serum folic acid levels without real tissue folic acid deprivation. In evaluating patients for folic acid deficiency, values for the levels of serum folic acid, serum cobalamin, and red blood cell folic acid must be obtained. The red blood cell folic acid level reflects tissue stores. When it is difficult but necessary to distinguish the megaloblastosis of cobalamin deficiency from that of folic acid deficiency, measurements of the serum methylmalonic acid and homocysteine levels are helpful. (Answer: A—Serum folic acid levels more accurately reflect tissue stores than do red blood cell folic acid levels)

12. A 47-year-old man with a 10-year history of type 2 diabetes presents for a routine physical examination.

His diabetes is poorly controlled, and there is evidence of retinopathy and neuropathy. He is currently receiving maximum doses of oral glipizide and metformin. His ROS is negative for cardiorespiratory symptoms. His examination reveals a blood pressure of 148/92 mm Hg and retinal changes consistent with diabetic background retinopathy. He also has decreased sensation in his feet, as evidenced by his results on monofilament neuropathy testing. Laboratory studies reveal a hemoglobin A1Clevel of 10.6%, a microalbumin excretion rate of 300 µg/min, and a serum creatinine level of 1.4 mg/dl. His CBC reveals normal levels of leukocytes and platelets and a hemoglobin level of 9.1 g/dl, with a mean cell volume of 85. Three follow-up examinations for the presence of fecal occult blood were negative. On repeat test-ing, the hemoglobin level is 9.4 g/dl; the serum iron level is 35 µg/dl; total iron-binding capacity is 230;

and the ferritin level is 170 ng/L.

Which of the following is the most likely cause of this patient’s anemia?

❑ A. Bone marrow suppression

❑ B. Sequestration of iron in the reticuloendothelial system

❑ C. Lack of erythropoietin

❑ D. Inhibition of folate metabolism

❑ E. A hemolytic process

Key Concept/Objective: To understand the mechanism by which chronic disease can cause anemia Anemia of chronic disease is generally associated with conditions that release cytokines (tumor necrosis factor–α, interleukin-1, and other inflammatory cytokines). These cytokines decrease erythropoietin production, decrease the levels of iron released from the reticuloendothelial system, and increase serum ferritin levels. Administration of erythro-poietin in pharmacologic doses corrects the anemia of chronic disease by compensating for the decreased production of erythropoietin. (Answer: B—Sequestration of iron in the reticu-loendothelial system)

13. A 75-year-old man is brought to the clinic for evaluation of forgetfulness that has developed slowly over the past 6 months. His wife indicates that he has occasionally become lost while out shopping and sever-al times a day demonstrates forgetfulness in the course of attempting to complete a task. He has a history of controlled hypertension and is receiving lisinopril, 10 mg daily. He denies using alcohol, and review of systems is otherwise negative. His examination reveals a well-groomed man who appears to be as old as his stated age. His vital signs are normal, as is the rest of his examination. His Folstein Mini-Mental State Examination score is 24/30, with deficits noted in short-term memory. Thyroid-stimulating hormone test results and serum chemistries are normal. His CBC reveals a hemoglobin of 11.8 g/dl, with normal leuko-cyte and platelet counts. The differential reveals several granuloleuko-cytes with 5 nuclear segments.

What should be the next step in the treatment of this patient?

❑ A. Order T4and T3resin uptake tests

❑ B. Start donepezil, 10 mg daily

❑ C. Refer for a neuropsychiatric evaluation

❑ D. Obtain an MRI of the brain

❑ E. Determine the vitamin B12serum level

Key Concept/Objective: To understand that neuropsychiatric symptoms may occur in patients with vitamin B12deficiency before many of the typical hematologic changes of vitamin B12 defi-ciency occur

Memory impairment in the absence of hematologic changes can be a presenting symptom of vitamin B12deficiency. Studies have shown that in 20% to 30% of patients who are defi-cient in vitamin B12, anemia and macrocytosis are absent. A diagnosis of vitamin B12 defi-ciency should be entertained in patients with neurologic disturbances in the absence of anemia and macrocytosis. The indications for vitamin B12deficiency have broadened to include nonspecific forms of cerebral dysfunction. The finding of hypersegmented neu-trophils remains a sensitive indicator of vitamin B12deficiency. (Answer: E—Determine the vitamin B12serum level)

14. A 27-year-old African-American man presents to the hospital with increased fatigue, which he has been experiencing for the past several months. He has been treated for sickle cell anemia in the past and has received many blood transfusions. He has been hospitalized multiple times in the past for apparent crises. He currently has no fever, and his general ROS is negative. On physical examination, his vital signs are normal. His cardiothoracic examination is normal, as is his extremity examination. His abdominal examination reveals diffuse tenderness without guarding or organomegaly. Laboratory studies reveal a hemoglobin level of 8.0 g/dl, with a mean cell volume of 90 and a reticulocyte count of 0.8%.

Hemoglobin electrophoresis reveals 96% hemoglobin A and 4% hemoglobin A2. Serum chemistries reveal an LDH level of 600.

What should be the next step in the treatment of this patient?

❑ A. CT scan of the abdomen

❑ B. Bone marrow aspiration and biopsy

❑ C. Direct Coombs test

❑ D. Serum folate level test

❑ E. Administration of 2 units of packed RBCs

Key Concept/Objective: To understand the importance of a bone marrow examination in evalu-ating anemia of unclear etiology

A bone marrow examination is necessary to identify several of the different types of ane-mia associated with impaired production of RBCs. This patient presents with a history of sickle cell disease, but his current clinical symptoms are not consistent with either a hemolytic crisis (low reticulocyte count) or a pain crisis. An aplastic crisis should be enter-tained but is not likely, given his normal WBC and platelet counts. Although parvovirus B19 infection should be considered because it can produce pure red cell aplasia in patients with sickle cell anemia, the normal results on hemoglobin electrophoresis rule out sickle cell disease in this patient. Therefore, the specific diagnosis of his anemia is in doubt.

(Answer: B—Bone marrow aspiration and biopsy)

15. A previously healthy 66-year-old man presents with a 1-month history of increasing fatigue and easy bruising. He is on no medications and consumes no alcohol. He has been retired for the past 2 years from an accounting job. His examination reveals mild pallor of the palpebral conjunctiva, brisk carotid upstrokes, and a grade 2/6 systolic ejection murmur at the left sternal border, without radiation. His abdominal examination is normal. Examination of his extremities reveals many ecchymoses in various stages of healing and a few nonpalpable petechaie on his lower extremities. A CBC reveals a WBC count of 2.4, with 20% PMNs; hemoglobin of 9.7 g/dl; a reticulocyte count of 0.5%; and a platelet count of 20,000. Bone marrow aspiration and biopsy reveal 25% normal cellularity. A diagnosis of aplastic ane-mia is made.

Which of the following statements is true regarding this patient’s prognosis?

❑ A. Prognosis is relatively good, with a 70% rate of spontaneous remission within 1 year

❑ B. Prognosis is poor, with a 70% mortality within 1 year

❑ C. A complete cure can be expected with immunosuppressive treatment

❑ D. Allogeneic bone marrow transplantation is associated with an 80%

5-year survival rate

Key Concept/Objective: To understand the poor prognosis for patients with severe aplastic anemia

Severe aplastic anemia is defined by a bone marrow cellularity of less than 25% normal or a cellularity of less than 50% normal with fewer than 30% hematopoeitic cells and low peripheral cell lines. The likelihood of spontaneous remission is very low, and mortality within 1 year is 70%. For mild cases, supportive treatment with blood product replacement and hematopoietic growth factor treatment is indicated; in severe cases, either immuno-suppresive treatment—which would not be curative—or bone marrow transplantation may be indicated. The 5-year survival rate after bone marrow transplantation is excellent in patients younger than 49 years (86%) but drops to 54% in patients older than 60 years.

(Answer: B—Prognosis is poor, with a 70% mortality within 1 year)

16. A 30-year-old woman presents for evaluation. Over the past month, she has been experiencing increas-ing dyspnea with exertion. She has otherwise been in good health and has no known cardiorespiratory problems. She has been consuming three or four alcoholic drinks an evening for the past 6 years. She is on no medications. In giving her family history, she reports having a sibling with anemia. Her exami-nation reveals normal vital signs and mild pallor in the conjunctiva. Her cardiorespiratory examiexami-nation is normal. A CBC reveals a WBC count of 3.5 × 103, a platelet count of 144,000, and a hemoglobin level of 8.4 g/dl, with a mean cell volume of 84 and a reticulocyte count of 0.8%.

What would be the most likely finding on this bone marrow examination?

❑ A. Ringed sideroblasts and ineffective erythropoiesis

❑ B. Hypercellularity of RBC precursors

❑ C. Hypocellularity of the marrow blood-forming elements

❑ D. Normal cellularity

❑ E. Marrow fibrosis

Key Concept/Objective: To understand the acquired form of sideroblastic anemia

Sideroblastic anemias are a heterogeneous group of disorders characterized by anemia and the presence of ringed sideroblasts in the marrow. There are hereditary forms and acquired forms, which are further subdivided into benign and malignant variants. Abnormalities of heme synthesis are the usual causes. Iron enters the RBC precursor but cannot be incorpo-rated and accumulates to form ringed sideroblasts. The diagnosis is established by the pres-ence of reticulcytopenia and ringed sideroblasts in the bone marrow. Cytogenetic studies of the bone marrow may reveal changes seen in myelodysplastic syndromes. Alcohol abuse can cause a reversible form of sideroblastic anemia, and stopping alcohol is an important aspect of patient care. (Answer: A—Ringed sideroblasts and ineffective erythropoiesis)

For more information, see Schrier SL: 5 Hematology: III Anemia: Production Defects. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, June 2004

In document Board Review From Medscape (Page 171-176)