Macrocytic Anemias

A patient presents with ataxia, leg weakness, sphincÂter disturbances, and peripheral neuropathy affecting both sensory and motor components. A vitamin B12 deficiency is suspected, but lab values show coba-lamin levels to be within the normal range. What is the most likely environmental cause of these findings? (A) Chronic cyanide exposure (B) Prolonged carbon monoxide exposure (C) Hexachlorophene toxicity (D) Nitrous oxide toxicity (E) Amphotericin B ingestion

(D) Nitrous oxide toxicity Chronic Nitrous oxide is associated with megaloblastic anemia and subacute combined degeneration

What are the two major fates of homocysteine?

1) Homocysteine can accept a methyl group from N5-methyl-THF, regenerating Methionine 2) Homocysteine condenses with serine, forming Cystathione and eventually Cysteine 1) Requires B12 and Folate 2) Requires B6

A 5-year-old boy presents for examination to his pediatrician. His mother explains that he is not growing at the expected rate. You observe the physical exam findings depicted in Figure A. Results of his complete blood count are reported as follow: WBC 3,500/microliter; Hb 9.8 g/dL; MCV 95 fL; platelets 98,000 /microliter. What is the most likely underlying explanation of these findings? 1. Red cell aplasia 2. Iron deficiency 3. DNA repair disorder 4. Hemoglobinopathy 5. Infection

3. DNA repair disorder

A special pediatric hematology department receives a twenty two month old who has Microcephaly, Microphthalmia. Skeletal survey reveals absent radii and thumbs. Blood investigation reveals aplastic anemia. The doctor informs that the child is at risk for developing AML. The boy is most likely suffering from: 1. Simple Aplastic Anemia 2. Myelofibrosis 3. Myelosclerosis 4. Congenital Pure Red Cell Aplasia 5. TAR syndrome 6. Fanconi's Anemia

6. Fanconi's Anemia

Which neoplastic disorders are children with fanconi anemia especially prone to developing?

Acute myelogenous leukemia (AML) Myelodysplastic syndrome Squamous cell carcinoma of the head, neck, or vulva

Name 12 chemical agents (drugs & toxins) that can cause aplastic anemia?

Alkylating Agents Antimetabolites Arsenicals Benzene Chloramphenicol Chlorpromazine Carbamazepine Penicillamine Gold Salts Weed killers/insecticide Whole body irradiation

Describe the clinical presentation of Aplastic Anemia

Combination of findings associated with deficiencies of all 3 cell lines (pancytopenia) *Thrombocytopenia: Bleeding, Petechiae *Neutropenia: Infections, fever, *Anemia: Fatigue, pallor *Lymphocyte count is usually preserved (not part of the myeloid lineage)

A 3 year old Caucasian boy is brought by his parents to the clinic because they think he looks "pale" and "weak". On examination the boy is lethargic and has pale conjunctivae. Blood analysis denotes megaloblastic anemia. Urine analysis shows excess carbamoyl phosphate derivative in the urine. There are no other abnormalities. The most likely cause for this boy's condition is: A. Vitamin B12 deficiency B. Folic acid excess C. Ornithine transcarbamoylase deficiency D. Orotidine 5'-phosphate decarboxylase deficiency E. Carbamoyl phosphate synthetase I deficiency

D. Orotidine 5'-phosphate decarboxylase deficiency

Is the reticulocyte count increased or decreased in a patient with Diamond-Blackfan anemia?

Diamond-Blackfan anemia is an anemia of decreased production. Thus, the CBC will show a low reticulocyte count.

What are 2 sequelae of elevated levels of homocysteine seen in folate and vitamin B12 deficiency?

Elevated levels of homocysteine can cause endothelial cell damage and can result in atherosclerosis and thrombosis.

List six drugs that can cause folate deficiency

Ethanol Oral contraceptives Phenytoin Trimethoprim/sulfonamides Methotrexate

People who have Aplastic Anemia have an increased reticulocyte count T/F?

F! Reticulocytopenia is a characteristic finding of Aplastic Anemia Despite elevated EPO levels, reticulocytosis is absent

What is the most common inherited cause of aplastic anemia?

Fanconi Anemia

In what type of food is vitamin B12 found?

Fish, meat, poultry, eggs, milk, and milk products. Vitamin B12 is generally not present in plant foods, therefore vegans are at risk of Vitamin B12 deficiency.

What is the function of folate?

Folate is converted to tetrahydrafolate (THF), the active form, which is a carbon carrier critical for synthesis of nitrogenous bases (particularly thymine, adenine, and guanine) in nucleic acids, especially in states of rapid cell division (pregnancy, erythropoiesis).

Because B vitamins are water soluble, body stores of B vitamins are quickly depleted. What are the two exceptions?

Folic acid and B12

Deficiencies of which two vitamins lead to megaloblastic anemia?

Folic acid and B12

A physician misdiagnoses a vitamin B12 deficient patient with folate deficiency and instructs the patient to take folate supplements. Will the patient's symptoms be relieved?

Hematologic symptoms can be corrected Neurologic symptoms will not be corrected Hematologic symptoms are due to defects in dTMP production. Notice that folate (THF) is required to methylate dUMP to DTMP. B12 is only required to reqenerate THF However the neruologic symptoms are due to increased methylmalonic acid. Folate is not involved here

Name 5 viral agents that can cause aplastic anemia?

Hepatitis HIV CMV EBV Parvovirus

What are the absorption sites for the following nutrients? Iron B12 Folate?

Iron: Duodenum Folate: Jejunum B12: Ileum Dude, I Just Feel Ill Bro....

Macrocytic anemias can be further subdivided into megaloblastic and non-megaloblastic causes. Give examples of each

Megaloblastic -Folic acid deficiency -B12 deficiency -Orotic aciduria Non-Megaloblastic - - -

What is seen on bone marrow biopsy of a patient with Diamond-Blackfan anemia?

Normal marrow cellularity with a decreased amount of RBC precursors.

Orotic aciduria is an inability to form ___________ Folate deficiency is an inability to form ___________ Orotic aciduria can be treated with supplementation of ____________ Folate deficiency can be treated with supplementation of ____________

Orotic: UMP Folate: DTMP Orotic: Uridine Folate: Thymidine

In what type of food is Folate found?

Primarily found in leafy green vegetables and can be destroyed by overcooking

In fanconi anemia, levels of which serum protein are elevated in most cases?

Serum a-fetoprotein (>50% of cases).

Which spinal cord tracts are characteristically damaged and what are the pertaining symptoms in Vitamin B12 deficiency?

Spinocerebellar tracts (ataxia) Dorsal columns (loss of position and vibratory sense) Lateral corticospinal (UMN lesions/spasticity) *Dementia may also be present

Folate is necessary for the synthesis of which nitrogenous bases?

Thymine Purines (Adenine,guanine)f

Propionyl-Coa is an intermediate in the catabolism of many molecules. Name 5 of them

Valine, Isoleucine, Methionine, Threonine (Amino acids) Odd chain fatty acids

Neurologic symptoms of Vitamin B12 deficiency closely resemble what two disorders?

Vitamin E and Freidrich's Ataxia

How can we differentiate B12 deficiency from Folate deficiency based on the peripheral blood smear?

We can't. The peripheral blood smears will be identical Macrocytosis with hypersegmented neutrophils

Lab animals deprived of folic acid experience a marked increase in erythroid precursor cell production. Subsequently, many of these erythroid precursor cells undergo apoptosis without further maturation. Provision of which of the following supplements would reduce erythroid precursor cell apoptosis in these animals? a) Homocysteine b) Cytosine c) Thymidine d) Cobalamin e) Glutamate

c) Thymidine

decreased cd34 and aplastic anemia?

cd34 is expressed on homatopieotic precursors?

Stem cells of what hematopoietic lineage are often injured/deficient in aplastic anemia?

Myeloid Presents with pancytopenia - decreased numbers of erythrocytes, neutrophils, and platelets in the peripheral blood.

Which form of DNA repair is defective in Fanconi Anemia?

Non-homologous end joining

What is the characteristic neuropathy of Vitamin B12 deficiency called? What is the mechanism?

Subacute Combined Degeneration SCD is a deymyelinating disorder -Increased methylmalonic acid is toxic to myelin -increased propionyl coA replaces acetyl coa in neuronal membranes => demyelination -incorporation of abnormal fatty acids into neuronal lipids

Orotic aciduria is an AR disorder resulting from a defect in the bifunctional enzyme UMP synthase. What reaction does this enzyme catalyze? What are the two components of this enzyme?

UMP Synthase catalyzes the formation of UMP from orotate (one of the last steps of De NOVO Pyrimidine synthesis) UMP Synthase includes orotate phosphoribosyltransferase and orotidine 5'-phosphate decarboxylase

How does the time frame for the development of a vitamin B12 deficiency compare to that of a vitamin B9 (folate) deficiency?

While the liver stores a 3-4 *year* supply of vitamin *B12*, it only stores a 3-4 *month* supply of vitamin *B9 (folate)* Thus, while it can take years for a patient to become B12 deficient, it only takes months for a patient to develop a folate deficiency.

Synthesis of which DNA precursor is impaired in B12 and folate deficiency

dTMP Vitamin B12 is involved in the conversion of 5M-THF to THF THF is required for the methylation of dUMP to dTMP

Aplastic Anemia

* *A diagnosis of exclusion *Can occur at any age or in any race **Most common etiology is idiopathic (50-70% of cases have no identifiable etiology* *Other causes include drugs, chemicals, or viruses which cause damage to the marrow *May also be inherited (MC = Fanconi) *Diagnosis is based on pancytopenia on CBC and presence of hypocellularity on bone marrow biopsy **Splenomegaly is characteristically absent; if present, rethink diagnosis* **Reticulocytopenia* *Tx: Withdraw causative agent. Bone Marrow Transplant. If transplant is not possible, immunosuppressive agents such as Antithymocyte globulin, cyclosporine, and prednisone

Diamond-Blackfan Anemia

*AKA congenital hypoplastic anemia *Intrinsic defect of RBC progenitor cells which results in increased apoptosis (Pure RBC aplasia) *Primary defect appears to be faulty ribosomal biogenesis resulting in defective ribosomal function *Usually sporadic but when familial, it is inherited AD **Rapid onset within 1st year of life* *Elevated erythrocyte adenosine deaminase enzyme (eADA) activity **Low Reticulocyte count* *Associated with structural congenital malformations **Associated with elevated HbF but decreased total hemoglobin *Patients have a higher risk of malignancy than the general population. *Tx: Corticosteroids are the mainstay; Blood Transfusions may be important to correct Hb levels

Orotic Aciduria

*AR *Inability to convert orotic acid to UMP (De NOVO Pyrimidine synthesis pathway) *Defect in uridine monophosphate (UMP) synthase *Increased orotic acid crystals in urine *Results in a megaloblastic anemia **Does not improve with administration of vitamin B12 or folic acid* *Not enough thymidine to sustain normal erythropoiesis *Presents as failure to thrive, developmental delay **No hyperammonemia (distinguishes between ornithine transcarbamylase (OTC) deficiency (high orotic acid in urine with hyperammonemia *Tx: oral Uridine administration (bypasses need for UMP synthase )

Fanconi Anemia

*AR/XLR *Most common form of inherited aplastic anemia *Due to a DNA crosslink repair defect *Cellular hypersensitivity to DNA cross-linking agents (i.e DEB (diepoxybutane) and MMC (mitomycin C)) *Increased risk for development of AML *In addition to hematologic cancers, solid tumors, particularly epithelial squamous cell cancers (SCCs) of the head and neck and cervical/gynecological cancers, occur at markedly higher rates in FA patients *Tx: Hematopoietic stem cell transplantation is treatment of choice. Androgen therapy may be helpful

Absorption of Vitamin B12

*Dietary vitamin B12 is normally bound to proteins in food **Pepsin frees vitamin B12 from ingested proteins* * Free vitamin B12 binds to R-binders (haptocorrins) synthesized in salivary glands which protect against acid destruction *Pancreatic enzymes in the duodenum cleave off the R-binders *Vitamin B12 binds to intrinsic factor (secreted by parietal cells) *B12-IF complex is absorbed in the terminal ileum* *Vitamin B12 binds to transcobalamin 2 and enters the portal system *Delivered to metabolically active cells or stored in the liver (6-9 year supply)

In fanconi anemia, lymphocytes exhibit what feature when cultured in the presence of DNA cross-linking agents?

*Extensive chromosomal breakage* in the presence of DNA cross-linking agents (i.e. mitomycin).

Describe the appearance of a bone marrow biopsy in patients with Aplastic Anemia

*Hypocellular bone marrow that is largely devoid of hematopoietic cells *Contain mainly fat cells *Lymphocytes and plasma cells may be present

List 6 causes of Folate deficiency. Which is the most common?

*Malnutrition (eg, alcoholics, elderly ('tea and toast diet)) *Malabsorption *Drugs (eg, methotrexate, trimethoprim, phenytoin) *Increased equirement (eg, hemolytic anemia, pregnancy) *Infants being fet goat milk exclusively

SAM Pathway

*Methionine + ATP => SAM *SAM methylates precursor molecules and is turned to SAH *SAH is hydrolyzed to Adenosine and Homocysteine *Homocysteine can accept a methyl group from N5-methyl THF and be converted to methionine (requires B12 and folate) *Or Homocysteine can combine with serine and form cystathione which will form cysteine (requires B6)

Ornithine transcarbamylase (OTC) deficiency

*Most common urea cycle disorder. *X-LR (vs other urea cycle enzyme deficiencies, which are AR) *Interferes with the body's ability to eliminate ammonia *Often evident in the first few days of life, but may present later. *Excess carbamoyl phosphate is converted to orotic acid (part of the pyrimidine synthesis pathway). *Findings: Increased orotic acid in blood and urine, Increased BUN, symptoms of hyperammonemia. **No megaloblastic anemia (vs orotic aciduria).*

List 6 causes of B12 deficiency. Which is the most common?

*Pernicious Anemia (MC) *Insufficient intake (eg. veganism) *Malabsorption (sprue, enteritis) *Diphyllobothrium latum (fsh tapeworm) *Gastrectomy *Resection of terminal ileum (Crohn's) *Low gastric acid (due to PPI use)

Despite normal intake of folic acid, a relative deficiency can arise when requirements are increased. Name five conditions in which this is seen

*Pregnancy *Infancy *Conditions associated with increased hematopoiesis (hemolytic anemias, beta thalassemia) *Disseminated Cancer

How is Aplastic Anemia treated?

*Withdrawal pf causative agent if applicable *Bone marrow transplant if the patient is young and a compatible donor is found *Immunosuppressive therapy: Antithymocyte globulin plus cyclosporine *Hematopoietic growth factors (G-CSF and GM-CSF) *RBC/Platelet transfusion *Androgens may be helpful?

A 64-year-old woman is seen by a hematologist for evaluation of a macrocytic anemia. The woman was severely malnourished. Both homocysteine and methylmalonate were elevated in her blood and urine, and the transketolase level in her erythrocytes was below normal. 1. What is the best evidence cited that the anemia is due to a primary deficiency of cyanocobalamin (B12)? A. Macrocytic anemia B. Elevated methylmalonate C. Low transketolase activity D. Elevated homocysteine. E. Severe malnutrition 2. In response to a B12 deficiency, which of the additional conditions may develop in this patient if she is not treated? A. Progressive peripheral neuropathy B. Gout C. Wernicke-Korsakoff D. Destruction of parietal cells E. Bleeding gums and loose teeth

1. B. Elevated methylmalonate 2. A. Progressive peripheral neuropathy

What are the two essential functions of Vitamin B12?

1. The remethylation of homocysteine to methionine 2. The isomerization of methylmalonyl coenzyme A (CoA) that is produced during the degradation of some amino acids (isoleucine, valine, threonine, and methionine), and fatty acids with odd numbers of carbon atoms to succinyl CoA

A 23-year-old primigravid woman at 10 weeks gestation comes to the physician for her first prenatal visit She follows a vegetarian diet and eats no meat or fish Examination shows a uterus consistent in size with a 10-week gestation She intends to breast-teed her newborn Which of the following is the most appropriate additional supplemental vitamin for this patient during pregnancy and lactation? A) B12 (cyanocobalamin) B) C C) D D) E E)K

A) B12 (cyanocobalamin) *B12 is only found in animal products* Similar to Folate, B12 deficiencies during early pregnancy can also increase risk of NTDs

A 3-year-old boy who is HIV positive is brought for a routine examination. His diet is appropriate for age. His medications include three antiretroviral drugs and trimethoprim-sulfamethoxazole for Pneumocystis carinii prophylaxis. Laboratory studies show: Hemoglobin 8.6 g/dL Mean corpuscular hemoglobin 38 pg/cell Mean corpuscular hemoglobin concentration 30% Hb/cell Mean corpuscular volume 101 μm3 Leukocyte count 5600/mm3 Segmented neutrophils 60% (many hypersegmented) Bands 3% Lymphocytes 37% Red cell distribution width 21% (N=10-16) Which of the following is most likely to have prevented this patient's anemia? A) Folic acid supplementation B) Iron supplementation C) Thyroid supplementation D) Vitamin B12 (cyanocobalamin) supplementation E) Monthly intravenous immune globulin therapy

A) Folic acid supplementation trimethoprim-sulfamethoxazole -> folate deficiency folate deficiency -> megaloblastic macrocytic anemia+ hypersegmented neutrophils

Which of the following statements regarding Diamond-Blackfan anemia is false? A. Diamond Blackfan Anemia is usually microcytic B. Reticulocyte count in patients with Diamond Blackfan Anemia is low C. Patients with Diamond Blackfan Anemia have abnormalities of their thumbs D. Diamond Blackfan anemia is diagnosed in patients before their first birthday

A. Diamond Blackfan Anemia is usually microcytic

A woman 7 months pregnant with her first child develops anemia. Laboratory evaluation indicates an increased mean cell volume (MCV), hypersegmented neutrophils, and altered morphology of several other cell types. The most likely underlying cause of this woman's anemia is A. Folate deficiency B. Iron deficiency C. Glucose 6-phosphate dehydrogenase deficiency D. Cyanocobalamin (B12) deficiency E. Lead poisoning

A. Folate deficiency Pregnant woman with megaloblastic anemia and elevated serum homocysteine strongly suggests folate deficiency. Iron deficiency presents as microcytic, hypochromic anemia and would not elevate homocysteine. B12 deficiency is not most likely in this presentation.

Pathophysiology of Aplastic Anemia

Aplastic anemia is a condition of chronic bone marrow failure that is caused by damage of myeloid stem cells Possible causes of damage -May be autoimmune mediated (activated T cells my suppress and kill stem cells; evidence of this is the efficacy of immunosuppressive drugs in the tx of Aplastic anemia) -May be an inherited intrinsic abnormality of stem cells (abnormally short telomerases (TERT gene mutation) or a DNA repair defect)

What finding is characteristic upon bone marrow aspiration in patients with Aplastic Anemia?

Aspiration of the marrow space often produces no sample (dry tap) A dry tap is not pathognomonic for Aplastic Anemia and therefore bone marrow biopsy should be obtained as well

A 27-year-old mother brings her 4-year-old son to the pediatric outpatient clinic for evaluation. She is concerned because he has been more fatigued than usual over the last week. Two weeks ago, the child was taken to the emergency room for marked fatigue. He was later discharged with a diagnosis of a viral upper respiratory tract infection. At that time, the child was treated with diphenhydramine. When further questioned about the patient's past medical history, the mother comments that her son has fallen sick more frequently than usual this past year and that he seems to bruise more easily than other children. On exam, vital signs are: temperature 37.6° C, pulse 110/min, respirations 30/min, and blood pressure 107/70 mmHg. The child is pallorous and noticeably lethargic. Height and head circumference are at the 5th percentile for his age. Conjunctival pallor is present. On musculoskeletal exam, both thumbs appear significantly hypoplastic. Skin exam reveals multiple petechiae on patient's trunk and extremities. A complete blood count reveals a WBC count of 2,100/mm3, hemoglobin 6.7 g/dL, and platelets of 87,000/mm3. A peripheral blood smear reveals normocytic, normochromic erythrocytes. What is the most likely mechanism underlying this disease? A. Viral destruction of bone marrow progenitors B. A defect in DNA repair C. Peripheral destruction of erythrocytes D. Decreased hemoglobin production E. Autoimmune

B. A defect in DNA repair This patient is most likely ill from Fanconi anemia (FA). FA is a rare, autosomal recessive aplastic anemia. It is characterized by bone marrow failure, various congenital anomalies, and a greatly increased risk (up to 4000 times) for developing hematologic and solid malignancies. Some 13 genes have been implicated in the pathogenesis of FA. Mutations in these genes result in defective DNA repair, making chromosomes particularly susceptible to damage by DNA cross-linking agents such as mitomycin C. Patients with FA typically demonstrate café-aulait spots, short stature, radial and/or thumb malformations, and genitourinary abnormalities. Cardiopulmonary and gastrointestinal abnormalities can also be seen. Signs and symptoms of pancytopenia such as petechiae and easy bruising due to thrombocytopenia, pallor and fatigue due to anemia, and recurrent infections due to leukopenia are also associated with FA. Chromosome breakage analysis in the presence of DNA cross-linking agents is helpful in diagnosing FA. CBC shows pancytopenia with macrocytosis, which is reflected in an elevated erythrocyte mean corpuscular volume. A skeletal survey, abdominal ultrasound, and echocardiography should be performed to evaluate the presence and extent of any skeletal, renal, and/or cardiac abnormalities.Stem cell transplantation is the treatment of choice for FA. In cases where transplantation is not feasible, androgen administration has been found to be an effective therapy in a majority of patients. Treatment for pancytopenia may involve transfusion of red blood cells and platelets, as well as administration of granulocyte colony-stimulating-factor (G-CSF) for neutropenia.

How can we differentiate the lab findings of B12 deficiency from Folate deficiency?

B12: Increased Homocysteine, Increased Methylmalonic acid Folate: Increased Homocysteine, Normal Methylmalonic acid *Slide 10 shows us that both B12 and folate are required to regenerate methionine from homocysteine (def => increased homocysteine) *Slide 11 shows us that B12 is required to convert methylmalonyl coA into succinyl coA (def => increased methylmalonic acid)

What laboratory test would help in distinguishing an orotic aciduria caused by ornithine transcarbamylase deficiency from that caused by UMP synthase deficiency?

Blood ammonia level would expected to be elevated in ornithine transcarbamylase deficiency but not in UMP synthase deficiency.

How can we differentiate the clinical findings of B12 deficiency from Folate deficiency?

Both will present with signs and symptoms of anemia + glossitis B12 deficiency presetns with neurological symptoms

A newborn becomes lethargic and drowsy 24 hour after birth. Blood analysis shows hyperammonemia, coupled with Orotic aciduria. This individual has an enzyme deficiency that leads to an inability to directly produce which of the following? A. Carbamoyl phosphate B. Ornithine C. Citrulline D. Argininosuccinate E. Arginine

C. Citrulline Orotic aciduria = an excessive excretion of Orotic acid in urine. Can be due to a disorder in pyrimidine biosynthesis, which is inherited in an autosomal recessive manner. It can also be caused by a deficiency in liver mitochondrial ornithine transcarbamylase (OTC), an enzyme of the urea cycle that catalyzes the conversion of ornithine to citrulline There is no direct link between the urea cycle and pyrimidine biosynthetic pathway, but channeling of metabolites of the urea cycle to the pyrimidine biosynthetic pathway can occur due to a block at the level of Ornithine Transcarbamylase There are two isoforms of the enzyme Carbamoyl phosphate synthetase; I and II. Carbamoyl phosphate synthetase (mitochondrial) catalyzes the first step of urea formation. The resultant carbamoyl-P condenses with ornithine to form citrulline in the presence of OTC The cytosolic Carbamoyl phosphate synthetase-II catalyzes the first step of pyrimidine biosynthesis and the resultant carbamoyl-P, condenses with Aspartate to form Carbamoyl Aspartate (catalyzed by Aspartate transcarbamoylase) In OTC deficiency, excess carbamoyl phosphate exits to the cytosol,where it acts as a substrate for aspartate transcarbamylase and stimulates pyrimidine nucleotide biosynthesis causing orotic aciduria

A 55-year-old man presents with pancytopenia. He notes an occupational exposure to benzene. A bone marrow examination is performed and reveals a hypocellular marrow. Cytogenic analysis does show an abnormality (monosomy 7). Which of the following statements best summarizes the patient's condition? A. The patient most likely has aplastic anemia because he has a hypocellular bone marrow B. The patient most likely has aplastic anemia because he has a cytogenic abnormality consistent with this diagnosis C. The patient most likely has myelodysplastic syndrome because he has a hypocellular marrow D. The patient most likely has myelodysplastic syndrome because he has a cytogenic abnormality consistent with the diagnosis

D. The patient most likely has myelodysplastic syndrome because he has a cytogenic abnormality consistent with the diagnosis Most cases of myelodysplastic syndrome present with a hypercellular bone marrow; however, in 20% of cases, a hypocellular bone marrow is seen, making it difficult to distinguish from aplastic anemia. Both aplastic anemia and myelodysplastic syndrome have been associated with exposure to benzene. Cytogenetic abnormalities are present in about 50% of patients with myelodysplastic syndrome but are not seen with aplastic anemia.

16-year-old girl with cystic fibrosis with 3-week history of generalized weakness, numbness and tingling of her arms and legs, and difficulty walking. Not adhered to medications. Bilateral weakness and decreased deep tendon reflexes in the upper and lower extremities. Walks with an ataxic gait. Cause is deficiency of which? A) Folic Acid B) Vitamin A C) Vitamin B6 D) Vitamin D E) Vitamin E

E) Vitamin E CF (deficiency of ADEK) + decreased DTR + numbness and tingling in extremities (peripheral neuropathy) + ataxic gait (spinocerebellar damage)

A 4-month-old male infant is brought to you by his parents complaining that, for the past four weeks, he has been progressively lethargic, feeds poorly, tires easily and has increasing pallor. His antenatal and birth histories are unremarkable. His diet consists mainly of breast milk and his immunizations are up-to-date. The mother's blood type is O+. On examination, you note pallor of the mucous membranes and conjunctivae. He is mildly tachycardic. You also note that he has a webbed neck, cleft lip, shielded chest and triphalangeal thumbs. Cardiac auscultation reveals a systolic ejection murmur over the left upper sternal border. Initial investigations reveal the following: Hb 8 g/dL Ht 32 % MCV 100 fL Blood type A - Platelets 300,000 /cmm WBCs 10,000/cmm Reticulocytes 0.4% Bilirubin direct 0.1 mg/dL Bilirubin total 1.0 mg/dL Which of the following is the most likely diagnosis? A. Wiskott-Aldrich syndrome B. Transient erythroblastopenia of childhood C. Idiopathic aplastic anemia D. Fanconi's anemia E. Diamond-Blackfan anemia F. Rhesus incompatibility

E. Diamond-Blackfan anemia Triphalangeal thumbs + congenital defects (shielded chest/cleft lip/webbed neck) + macrocytic anemia + decreased reticulocyte = DBA

A 1-year-old female patient is lethargic, weak, and anemic. Her height and weight are both low for her age. Her urine contains an elevated level of orotic acid. The administration of which of the following compounds is most likely to alleviate her symptoms? A. Adenine. B. Guanine. C. Hypoxanthine. D. Thymidine. E. Uridine.

E. Uridine. The elevated excretion of orotic acid indicates that the patient has orotic aciduria, a rare genetic disorder affecting the de novo pyrimidine biosynthetic pathway. Deficiencies in the enzyme activities OMP decarboxylase and/or orotate phosphoribosyltransferase (both of which are domains of the enzyme UMP synthase) leave the patient unable to synthesize pyrimidines. Uridine, a pyrimidine nucleoside, is useful in treating this disorder because it bypasses the missing enzymes and can be salvaged to UMP, which can be converted to all the other pyrimidines. Although thymidine is a pyrimidine nucleoside, it cannot be converted to other pyrimidines. Hypo -xanthine, guanine, and adenine are all purine bases that have no value in helping to replace the missing pyrimidines.

In patients with aplastic anemia, what are the relative levels (reduced/elevated) of the reticulocyte count and EPO?

Elevated EPO Reduced reticulocyte count

Describe the clinical presentation of Fanconi Anemia

Fanconi Anemia is *Hypopigmented skin (>50%) *Short Stature (50%) *Café au lait spots (>50%) *Thumb or thumb and radial anomalies (absent or hypoplastic) (40%) *Abnormal Male gonads (30%) *Microcephaly (25%) *Structural Renal Defects (20%) *Abnormal Ears or hearing (10%) Individuals with FA display several congenital defects, but approximately 25%-40% of FA patients are physically normal FIND PICS

Fanconi Anemia is associated with _________________Thumbs Diamond Blackfield Anemia is associated with _________________Thumbs

Fanconi Anemia: Hypoplastic Thumbs Diamond Blackfield Anemia: Hypophalangeal thumb FIND PICS

Fanconi Anemia is associated with _________________Thumbs Diamond Blackfield Anemia is associated with _________________Thumbs

Fanconi Anemia: Hypoplastic Thumbs Diamond Blackfield Anemia: Triphalangeal thumb FIND PICS

What is the most common etiology of Aplastic Anemia?

Idiopathic In 50%-70% of cases, there is no identifiable etiology

What is the common mechanism by which B12/Cobalamin and Folate Deficiency results in Megaloblastic Anemia?

Impaired DNA synthesis

Describe the mechanism behind the macrocytosis seen in Megaloblastic Anemias

Impairment in DNA synthesis delays nuclear maturation and cell division. Because RNA and cytoplasmic elements are synthesized at a constant rate despite the cells impaired DNA synthesis the cells show *nuclear-cytoplasmic asynchrony* (cytoplasmic enlargement not matched by DNA enlargement)

A 35-year-old male presents to his physician complaining of two weeks of fatigue and easy bruising. He also reports recently having had an upper respiratory tract infection. Physical examination reveals no lymphadenopathy or hepatosplenomegaly. Laboratory studies show: Complete blood count Hemoglobin....................... 7.0 g/L Erythrocyte count..............1.8 min/mm3 Mean corpuscular volume...90 fl Reticulocytes..................... 0.1% Platelet count.................... 88000/mm3 Leukocyte count................ 2500/mm3 A peripheral blood smear shows normocytic, normochromic red blood cells. The other cell types are morphologically normal as well. Bone marrow biopsy in this patient would most likely show which of the following patterns? A. Hypocellular marrow filled with fat cells and fibrotic stroma B. Hypercellular marrow with megaloblastic hematopoiesis C. Hyper granular promyelocytes with multiple Auer rods D. Hypercellular marrow filled with numerous blast forms

A. Hypocellular marrow filled with fat cells and fibrotic stroma

A previously healthy 18 year old primigravid African American woman at 18 weeks gestation is brought to the emergency department because of a 2-day history of fever and a 12-hour history of severe left-sided back pain. She has had no prenatal care. Her family history is unknown because she was adopted. Her temperature is 102.4 deg F, pulse is 110, blood pressure is 100/62. Exam shows left costovertebral angle tenderness. The uterus is consistent in size with an 18-week gestation. Lab shows: Hemoglobin 7.9 Hemoglobin Electrophoresis: Hb A1 14%, Hb A2 4%, Hb F 7%, Hb S 75% MCV 90 Platelet count 159,000 Urine bacteria 3+, Urine WBC 3+ In addition to antibiotic therapy treatment, which of the following is the most appropriate pharmacotherapy? A) EPO B) Folic Acid C) Iron D) Vitamin B12 E) Vitamin C

B) Folic Acid African american + HbS of 75% = Sickle cell Anemia Sickle Cell (increased erythropoiesis) + Pregnancy both increase demand for folic acid

A 10-year-old girl has fever, fatigue, and easy bruising. Laboratory studies show: Hemoglobin 6.6 g/dL (N=11.8-15) Hematocrit 20% (N=36-45%) Leukocyte count 1300/mm3 Platelet count 12,000/mm3 A photomicrograph of bone marrow obtained on biopsy is shown. The most likely diagnosis is A) aleukemic leukemia B) aplastic anemia C) immune thrombocytopenic purpura D) myelofibrosis E) vitamin B12 (cyanocobalamin) deficiency

B) aplastic anemia

A 6-month-old boy becomes progressively lethargic and pale and shows delayed motor development. Laboratory evaluation reveals normal blood urea nitrogen (BUN), low serum iron, hemoglobin 4.6 g/dL,and leukopenia. His bone marrow shows marked megaloblastosis,which did not respond to treatment with iron, folic acid, vitamin B12'or pyridoxine. His urine developed abundant white precipitate identified as orotic acid. The underlying defect causing the megaloblastic anemia in this child is most likely in which of the following pathways? A. Homocysteine metabolism B. Pyrimidine synthesis C. Urea synthesis D. Uric acid synthesis E. Heme synthesis

B. Pyrimidine synthesis Orotic aciduria with normal BUN and symptoms of anemia = due to defect in UMP Synthase OTC Deficiency = increased BUN, increased ammonia, and no megaloblastic anemia

A 20-year-old African American man with sickle cell disease comes to the physician because of a 1-week history of shortness of breath on exertion, fatigue, and generalized weakness. He has had no fever, chills, night sweats, or cough productive of sputum. His only medication is oxycodone for joint pain. He weighs 68 kg (150 lb) and is 168 cm (66 in) tall. His temperature is 36.7 C (98 F), blood pressure is 120/70 mm Hg, pulse is 76/min, and respirations are 18/min. Examination shows no abnormalities. Laboratory studies show: Hematocrit 20% Mean corpuscular volume 110 μm3 Leukocyte count 2300/mm3 Reticulocyte count 1.8% Which of the following is the most likely mechanism for these findings? A) Adverse drug reaction B) Atrophy of gastric mucosa C) Bacterial overgrowth in the small intestine D) Increased demand for folic acid E) Increased demand for vitamin B12 (cyanocobalamin) F) Malabsorption G) Vitamin B1 (thiamine) deficiency

D) Increased demand for folic acid Conditions associated with increased hematopoiesis such as Sickle cell disease cause an increased demand for folic acid