The patient and his story
A 70-year-old pensioner with several comorbidities presented to his general practitioner’s office because of a sudden decline in his cognitive abilities and the onset of hallucinations. Subject had the following medical history: advanced renal failure, chronic obstructive pulmonary disease (COPD), peripheral arterial disease, insulin-dependent diabetes, and hypertension.
Over the previous six months, his wife had noticed a change in personality and a steady decline in cognitive abilities. In addition, her husband claimed to have seen rats on the floor and strangers in their apartment, the wife described.
Four weeks earlier, the patient had been hospitalized for anemia with exertional dyspnea.
Here are the results of the tests and exams:
Biological tests:
– Serum iron level 25 ug/dl
– Ferritin level 670 ng/ml
– Serum vitamin B12 level 247pg/ml
– Homocysteine level 29.3 umol/l (reference <15 umol/l)
– Level of methylmalonic acid 937nmol/l (reference 0-378 nmol/l) and folates of 6.7 ng/ml (reference ≥4.7 ng/ml).
During the hospitalization, the man received 400 mg of iron by injection, vitamin B12 and folic acid by mouth. The hemoglobin level at discharge from hospital treatment was 80 g/l.
The patient was on regular treatment with daily pantoprazole due to gastritis, but was not on metformin therapy.
Diet: unremarkable, neither vegetarian nor vegan.
Other results:
No hemolysis, endoscopy of the colon with demonstration of a non-hemorrhagic polyp, contrast CT scan of the head, thorax, abdomen and pelvis without particularities.
– Blood pressure 160/75 mmHg, heart rate 81 beats per minute.
– 9% oxygen saturation with known COPD.
– Neurologically awake, but only partially oriented.
– Motor operation and sensitivity not remarkable.
– Unsteady gait with short steps.
– No hallucinations at the time of the examination.
– Mini mental state test: 25.
– The score of the Patient Health Questionnaire-2 was 0 (no signs of major depression).
Other serological tests revealed:
– Vitamin B12 level: 482 pg/ml (normal range: 232-1245 pg/ml).
– Taux de folates : 6,7 ng/ml (minimum 4,7 ng/ml).
– Homocysteine level: 29.3 umol/l (<15 umol/l).
– Methylmalonic acid level: 460 nmol/l (0 – 378 nmol/l)
Other results:
- Unremarkable EEG.
- Carotid duplex ultrasound: slight bilateral atherosclerosis.
- Cranial MRI showed age-consistent volume loss and signs of microvascular disease.
Diagnosis is reversible dementia in the setting of symptomatic macrocytic anemia with low to normal serum B12 levels but elevated serum methylmalonic acid and homocysteine levels.
Treatment and evolution
While further investigations, including fluorodeoxyglucose (FDG-PET) positron emission tomography, were performed to rule out neurodegenerative causes, the patient continued to receive vitamin B12.
At the one-month follow-up, the MMST (Mini Mental Status Test) was 29, and the patient had no more hallucinations. According to his wife, mood and cognition have improved. The hemoglobin level was 113 g/l. Methylmalonic acid and homocysteine were increased with existing end-stage renal disease (hemodialysis) to 580nmol/l and 25umol/l, respectively.
Discussion and further information
According to Dr. Robert Haußmann and his colleagues, vitamin B12 and folic acid are elemental, water-soluble vitamins. Vitamin B12 must therefore be provided by food.
Particularly high concentrations of vitamin B12 are found in meat and dairy products and especially in animal liver, eggs and mussels, explain the authors. Folic acid is present in a variety of animal and plant products, especially in green leafy vegetables and also in animal liver.
Homocysteine and methylmalonic acid are intermediate metabolites that accumulate in vitamin B12 and folic acid deficiency, respectively. While homocysteine levels are elevated in both folic acid and vitamin B12 deficiency, elevated methylmalonic acid occurs specifically in vitamin B12 deficiency, Haußmann and colleagues explain.
Unlike vitamin B12, the body’s stores of folic acid can be depleted much more quickly, but despite this, folic acid deficiency is relatively rare outside of developing countries. On the other hand, vitamin B12 deficiency is a very common phenomenon in Germany, especially among the elderly.
Typical clinical manifestations of vitamin B12 or folic acid deficiency are hematological changes and various neuropsychiatric symptoms.
In addition to unclear macrocytic anemias, hypersegmented neutrophilic granulocytes and pancytopenias should also suggest possible vitamin B12 or folic acid deficiency.
Characteristic neurological symptoms include symmetrical paresthesias and numbness of the legs, peripheral sensory deficits, ataxia, extrapyramidal motor symptoms, and an abnormal reflex state with gait disturbances and possible symptoms of restless legs.
Psychiatric manifestations including “forgetfulness, slowing tendencies and dementia-like symptoms are multiple and include affective disturbances, irritability, sleep disturbances and psychotic phenomena.” In up to 40% of patients, these symptoms occur independently of hematological changes.
According to the authors, a possible cause is an insufficient intake of vitamin B12, especially as part of a vegetarian or vegan diet; the use of certain medications, for example proton pump inhibitors or metformin, might also be associated with vitamin B12 deficiency.
Vitamin B12 levels above 300 pg/ml are normal. At such levels, vitamin B12 deficiency is unlikely. Levels between 200 and 300 pg/ml, which should be considered borderline, and at levels <200 pg/ml, la détermination de paramètres supplémentaires est indiquée pour confirmer le diagnostic. Pour la détermination de l'acide folique, des valeurs >4.1 ng/ml was considered normal, and values of 2-4 ng/ml were considered borderline.
In patients with borderline vitamin B12 and folic acid levels, the intermediate metabolites methylmalonic acid and homocysteine should be determined. Normal levels of methylmalonic acid and homocysteine rule out vitamin B12 and folic acid deficiency, the authors say.
This article was written by Dr. Thomas Kron.
