A 52-year-old male with no significant past medical history reports increasing generalized fatigue and weakness for the past 2 weeks. Physical examination reveals jaundice and pallor without organomegaly or lymphadenopathy. His hemoglobin was 5.9 g/dL with a mean corpuscular volume of 87.1 fL and elevated red blood cell distribution width of 30.7%. His liver function test was normal except for elevated total bilirubin of 3.7 mg/dL. Serum LDH was 701 IU/L, and serum haptoglobin was undetectable. Further investigation revealed serum vitamin B12 of <30 pg/mL with elevated methylmalonic acid and homocysteine level. In addition, serum ferritin and transferrin saturation were low. The patient was diagnosed with hemolytic anemia secondary to vitamin B12 deficiency with concomitant iron deficiency anemia.
Vitamin B12 (also known as cobalamin) deficiency can cause reversible bone marrow failure and demyelinating disease due to its inherent function in erythropoiesis and myelination of the central nervous system [
A 52-year-old male was initially presented in an ambulatory clinic complaining of fatigue and weakness for 2 weeks. The patient also complained of frequent epistaxis secondary to nose picking for 1 month. His fatigue was accompanied by dyspnea on exertion and lightheadedness which have increased in frequency in the last 4-5 days prior to the presentation. He denied similar symptoms in the past. He reported poor appetite but no weight loss or strange craving. Other than the symptoms reported previously, the review of symptoms was negative, including neurological complaints. Complete blood count (CBC) was taken in the clinic and he was found to have hemoglobin (Hb) of 6.2 g/dL. The patient was subsequently admitted to the hospital for further workup.
Further history revealed recent upper respiratory tract infection 1 month prior to the admission. The patient’s symptoms at that time consisted of sore throat, runny nose, and low grade fever. The symptoms resolved on thier own after 5 days. There was no rash or joint pain related to the recent upper respiratory tract infection. He denied any history of bleeding disorder or any past medical history including blood transfusion. The only medication reported was Metamucil to relieve occasional constipation.
The patient was originally from Mexico. He has been living in the United Stated for the last 14 years and has not recently visited his home country. He is married and has 2 children, age 16 and 14 years, which are healthy. The patient reported that his sister and his niece may have had history of anemia but he does not know the diagnosis. He denied any history of tobacco or drug use. He admitted to drink alcohol about 6 beers per week. He works in a pastry shop as a box assembler.
On admission, the patient was alert, oriented, and not in any distress. Physically, he looked thin and pale. Jaundice was also noted. His vital signs were blood pressure 107/59 mmHg, pulse 76/min, temperature 98.9 F, respiratory rate 18 min, oxygen saturation 100% on room air, height 165 cm, and weight 56 kg. His cardiopulmonary examination was normal. There was no lymphadenopathy. His abdomen was soft and nontender, with no organomegaly. There was no apparent rash, skin lesion, or joint swelling. Neurological exam was unremarkable. Rectal examination revealed normal prostate and no mass palpable. Brown stool was observed and bedside hemoccult test was negative.
Repeat CBC revealed Hb of 5.9 g/dL and hematocrit (Hct) of 18.6% with normal white blood cell (WBC) and platelet count. Red cell indices were normal except for red blood cell distribution width (RDW) which was abnormally high. Review of peripheral blood smear (Figure
Laboratory results on admission and during followup.
Lab | Reference | Admission | 4 weeks |
---|---|---|---|
WBC (/mm3) | 4.2–11.0 k/mm cu | 4.7 | 5.9 |
Hb (g/dL) | 13.5–17.0 g/dL | 5.9 | 10.1 |
Hct (%) | 41.0–52.0% | 18.6 | 32.3 |
Plt (/mm3) | 140–400 k/mm cu | 161 | 241 |
MCV (fL) | 80.0–100.0 fL | 87.1 | 85.8 |
MCH (pg/red cell) | 26.0–33.0 pg | 27.4 | 26.9 |
MCHC (g/dL) | 32.0–37.0% | 31.4 | 31.4 |
RDW (%) | 11.0–14.5% | 30.7 | 21.6 |
Differential count (%) | |||
Neutrophil | 40.0–72.0% | 59.3 | 53.2 |
Eosinophil | 0.0–10.0% | 1.1 | 1.4 |
Monocyte | 4.0–12.0% | 4.2 | 7.8 |
Lymphocyte | 17.0–45.0% | 35.1 | 36.6 |
Reticulocytes (%) | 0.5–2.8% | 2.4 | 1.2 |
Reticulocyte index | 1.0–2.0% | 0.4 | 0.6 |
PT (sec)/INR | 8.9–11.9 sec/0.9–1.1 | 15.2/1.4 | 11.9/1.1 |
PTT (sec) | 23–33 sec | 27 | NA |
Total/direct bilirubin | 0.0–1.0 mg/dL/0.0–0.3 mg/dL | 3.7/0.4 | 1.4/NA |
LDH (U/L) | 135–225 IU/L | 701 | 189 |
Haptoglobin (mg/dL) | 36–195 mg/dL | <6 | 98 |
Vitamin B12 (pg/mL) | 211–946 pg/mL | <30 | >2000 |
RBC folate (ng/mL) | >280 NG/ML RBC | 697 | 591 |
Homocysteine (Umol/L) | 3.7–13.9 Umol/L | 100 | NA |
Methylmalonic acid (nmol/L) | 87–318 nmol/L | 22708 | NA |
Iron (ug/dL) | 45–160 ug/dL | 36 | 107 |
Ferritin (ng/mL) | 30–400 ng/mL | 7 | 19 |
Iron saturation (%) | 20–55% | 9 | 23 |
TIBC (ug/dL) | 228.0–428.0 ug/dL | 403 | 456 |
IgA | 50–400 mg/dL | 612 | NA |
TTG IgA | <20.0 Units | 10.8 | NA |
Endomysial Ab | Negative | Negative | NA |
Intrinsic factor Ab | Negative | Negative | NA |
Examination of peripheral smear on admission showed marked anisocytosis and poikilocytosis. Microcytosis (red arrows) was predominant with interspersed large cells (yellow arrows) noted. Tear drop cells (white arrows), elliptocytes, and multiple fragmented red blood cells were also noted.
Based on initial results, additional workup was sent including lactate dehydrogenase (LDH), haptoglobin, Coombs test, iron study, serum B12, serum folic acid, cold agglutinin, fibrinogen level, homocysteine level, methylmalonic acid (MMA) level, glucose-6-phosphate dehydrogenase level, chest radiograph, urine analysis, anti-nuclear antibody level, anti-phospholipid antibodies, ADAMTS-13 level, CD55/59, mycoplasma titer, and viral titer including HIV, viral hepatitis panel, EBV, CMV, and parvovirus. All results are summarized in Table
Elevated LDH and low haptoglobin level were consistent with hemolytic anemia. Other test results were negative except for low serum vitamin B12 and abnormal iron study which was consistent with iron deficiency anemia. Serum homocysteine and methylmalonic acid were elevated which also confirmed the presence of vitamin B12 deficiency as the cause of hemolytic anemia.
Once diagnosed, the patient was started on vitamin B12 supplement, 1000 mcg intramuscular injection daily, folic acid 1 mg daily, and ferrous sulfate 325 mg three times daily on hospital day 3. He also received 2 units of packed red cell transfusion prior to discharge. The patient was discharged on hospital day 4. Prior to transfusion, celiac disease antibodies and intrinsic factor antibody were also sent to further elucidate the cause of vitamin B12 deficiency. However, all antibodies were negative. Esophagogastroduodenoscopy (EGD) was not performed because the patient declined. His nutrition was later assessed after the diagnosis of vitamin B12 and iron deficiency and revealed that his diet was mostly consistent with vegetables and legumes. He does not eat a lot of meat, although he may have fish occasionally.
Upon followup, 5 days after discharge, the patient reported improvement of his symptoms. His Hb was at 9.3 g/dL and hematocrit of 29.7%. Hemolysis was improving with total bilirubin and LDH, and haptoglobin level normalized. Vitamin B12 injection was then reduced to once weekly, and it was later converted to oral form. Subsequent visits showed resolution of all symptoms with improvement of CBC, iron study, and serum B12 level.
Anemia can be categorized into three pathophysiologic states: (1) blood loss, (2) defective erythropoiesis, and (3) destruction of erythrocytes [
Our patient presented with symptoms of increasing fatigue and weakness associated with dyspnea on exertion with extremely low Hb which confirmed the presence of anemia. Coexisting jaundice with elevated direct bilirubin and LDH, low haptoglobin level, and multiple fragmented red blood cell noted on peripheral smear indicate erythrocyte destruction or hemolytic anemia as the cause.
Hemolytic anemia represents a diverse group of diseases which can be divided in to congenital or acquired. Since the patient did not have history of anemia in the past, and no history of transfusion, no previous symptoms consistent with anemia or gallstone, no evidence of hepatosplenomegaly, it is unlikely that this is due to inherited conditions despite having suspected family history of anemia. Other confirmatory tests reported in Table
Commonly, vitamin B12 deficiency is associated with macrocytic anemia. However, the patient’s mean corpuscular volume (MCV) was normal which suggested the presence of concomitant iron deficiency anemia. Increased RDW was consistent with poikilocytosis and anisocytosis picture in the peripheral blood smear. Also, low reticulocyte index (<2) indicates defective erythropoiesis which can be explained by severe vitamin B12 deficiency and iron deficiency anemia. Low serum ferritin, iron level, and transferrin saturation (TSAT) confirmed the diagnosis.
Vitamin B12 or cobalamin deficiency is common in elderly population [
Vitamin B12 functions as a cofactor or coenzyme that participates in various biochemical reactions, including DNA synthesis [
Pernicious anemia is the most common cause of cobalamin deficiency worldwide [
The diagnosis of vitamin B12 deficiency can be done with initial testing of vitamin B12 assay [
In our patient, after the diagnoses of vitamin B12 deficiency and iron deficiency anemia were confirmed, further investigations were pursued to explain the cause. Celiac disease antibodies and intrinsic factor antibody were found to be negative which reduced the possibility of celiac disease and pernicious anemia. Since the patient never had history of abdominal pain, indigestion, acid reflux symptoms, or use of acid reducing medication, it is less likely that atrophic gastritis or
The treatment of cobalamin deficiency required replacement of vitamin B12. Daily high dose oral therapy (1000 to 2000 mcg per day) is as effective as parenteral formula in several randomized studies [
This case displayed the complexity of vitamin B12 deficiency where clinicians should be familiar. Once the diagnosis is confirmed, further investigation is warranted to explain the etiology. Life-long therapy is necessary in disease such as pernicious anemia and malabsorptive conditions. Individuals who are on strict vegetarian diet should be advised to take supplement as recommended by national guidelines in order to prevent harmful hematologic and neurological sequelae.
The authors have no Conflict interests.