Case 1
A 55 year-old white female with a history of hypothyroidism and pernicious anemia, had lost follow-up for 10 years. She presented with lethargy, confusion, exertional dyspnea, difficulty with ambulation, and cold intolerance. Abnormal physical findings included vitiligo, moderate lower extremity edema and a mid-systolic click. Laboratory findings revealed a hemoglobin (Hb) of 5.0 g/dL (normal 12–16) with a mean corpuscular volume (MCV) of 134 fL (normal 80–100); white cell count (WBC) 3,100/mm3 (normal 3,500–11,000); platelet 123,000/mm3 (normal 140,000–450,000); and reticulocyte count 6.3% (normal 0.5–2). Further study revealed vitamin B12 level 167 pg/mL (normal 211–946), homocysteine level 62.4 μmol/L (normal 5.0–13.9), methylmalonic acid level 13.53 μmol/L (normal 0 – 0.40), haptoglobin levels < 6 mg/dL (normal 16–200) and lactate dehydrogenase (LDH) 3152 U/L (normal 100–190). Thyroid studies revealed a thyroid-stimulating hormone (TSH) of 8.26 mlU/L (normal 0.37 – 4.42) with a thyroxin level of 0.71 ng/dL (normal 0.75 – 2.00). Other chemistry studies, including bilirubin levels, were normal. She was heterozygous for methylene tetrahydrofolate reductase (MTHFR) A1298C mutation. Peripheral smear was remarkable for schistocytes and hypersegmented neutrophils (Figure 1).
Patient was transfused with 2 units of packed red blood cells (RBC) and initiated on intramuscular vitamin B12 injections and daily levothyroxine supplement. Six weeks later the Hb was 12.1 g/dL, MCV at 91.2 fL, homocysteine level 14.6 μmol/L, TSH 4.27 and free T4 1.08 with resolved WBC and platelet counts.
Case 2
A 58 year-old white male with a history of essential hypertension and tobacco use was admitted with complaints of progressively increasing fatigue over the past three to four months. The patient denied hematochezia, hemoptysis, or hematuria. However, the patient did report slight paresthesias in both soles, without significant alterations of reflexes. Further history revealed a relatively recent change in patient's dietary habits as he had adopted a strict vegetarian diet over the past fifteen months due to personal experiences and convictions. His only medication was rimipril.
Positive physical findings at the time of admission included a slight conjunctival jaundice with pale skin and weakness in the limbs. The patient was found to have a macrocytic anemia with a slight increase in serum bilirubin levels (2.1 mg/dL) in a screening blood test two weeks prior to admission. Blood count on admission showed a WBC 3,400/mm3, Hb 7.7 g/dL (MCV 115 fl), and platelet 99,000/mm3. Serum vitamin B12 level was 100 pg/mL, whereas serum folate level, iron study, and thyroid function tests were within normal range. Reticulocyte count resulted 6% (normal range 2–6). Chemistry results were remarkable for serum bilirubin 2.3 mg/dL (1.9 mg/dL as unconjugated), elevated LDH (788 U/L) and serum haptoglobin < 7 mg/dL. Plasma homocysteine level was significantly increased at 88.8 μmol/L with an elevated methylmalonic acid level at 12.1 μmol/L. Serum creatinine, direct and indirect Coombs tests, and glucose-6-phosphate dehydrogenase activity in red blood cells were all normal. The patient resulted homozygous for MTHFR C677T mutation. Peripheral blood smear and marrow biopsy revealed a megaloblastic anemia with megaloblastic erythroid hyperplasia with granulopoiesis and megakaryocytosis (Figures 2 and 3).
During the one-week hospital stay, the patient was transfused with 1 unit of packed RBC and started on intramuscular injections of cobalamin and oral supplementation of folic acid. Meat was re-introduced in the patient's diet. The patient underwent an esophago-gastroduodenoscopy with gastric biopsy which exhibited evidence of atrophic gastritis. Studies for antibodies to intrinsic factor and gastric parietal cells were negative.
The patient was completely asymptomatic 4 months later with the following blood test results: WBC 5,400/mm3, Hb 11.8 g/dL with MCV 99 fL, platelet 250,000/mm3; serum vitamin B12 level 611 pg/mL, folate level 11.2 ng/mL, and homocysteine level at 11.2 μmol/L. Bilirubin, LDH and haptoglobin were all within the normal range.
Case 3
A 91 year-old white man with a history of atrial fibrillation, diabetes mellitus type 2 and atherosclerosis presented to the Emergency Department with complaints of increasing fatigue, exertional dyspnea, progressively worsening right upper quadrant pain and mild elevation of serum bilirubin over the past 6 weeks. Mild elevation of total bilirubin (ranging from 1.6 to 1.7 mg/dL) was noticed in a screening blood test three months prior to this presentation and no further work-up was initiated at that time. The patient also had a mild macrocytic anemia (hemoglobin at baseline 11.1 gm/dL with MCV 115 fL). The patient denied hemopytsis, hematochezia, or hematuria. Medications included a glipizide, hydrochlorothiazide, furosemide, and warfarin.
Abnormal physical findings included pale skin, an irregular heart rhythm and right upper quadrant tenderness with slight hepatomegaly, peripheral edema, varicosities and symmetrical weakness in both lower extremities. Thoracic and abdominal computed tomography scans revealed cardiomegaly and pleural effusion. Blood tests revealed WBC 3,100/mm3, Hb 6.6 g/dL with MCV 146 fL and platelet 97,000/mm3. The serum vitamin B12 level was 162 pg/mL with a normal folate level (16.8 ng/mL) and normal iron study. The homocysteine level was markedly elevated at 129.7 μmol/L, and haptoglobin was < 7 mg/dL. Bone marrow aspirate revealed a cellular bone marrow with 30% nucleated red blood cells with nuclear to cytoplasmic dyssynchrony within the red cell series and dyspoietic changes.
The patient was transfused with 2 units of packed RBC and initiated on intramuscular cobalamin injections, and was discharged in stable condition. Complete blood counts 4 months later revealed WBC 4,400/mm3, Hb 11.3 g/dL with MCV 102 fL, and platelet 202,000/mm3. Eight months later, vitamin B12 level was 586 pg/mL and his CBC as follows: WBC 5,300, Hb 12.2, and platelet 206,000, which were all within normal ranges. His bilirubin levels were normalized on the follow-up tests after discharge from hospital. Unfortunately, follow up homocysteine levels after cobalamin treatment were not measured and the patient died three years later. However, one of the patient's sons tested positive for homozygous MTHFR C677T mutation.