History
A 75-year-old man has been found on the ground by his neighbour and brought to the emergency department. The man appears unkept, confused and agitated. His only com-plaint is of numb feet and he appears unsteady. Once a week his neighbour checks on him but generally he likes to be left alone. The neighbour has noticed that the man’s memory has been worsening lately. It is unclear what medications he might be taking, but the neighbour recalls he is a diabetic and takes ‘a tablet’ for this. He is not known to drink alcohol but does smoke. He is known to be a vegetarian.
Examination
This elderly man appears pale and is now unable to stand. There are several petechiae. He has glossitis and angular cheilitis. Cardiovascular, respiratory and abdominal examina-tions are unremarkable. Assessment of cognitive function shows a reduced abbreviated mental test score of 5/10. There is distal weakness affecting all limbs. Plantar responses are extensor. Knee and ankle jerks are absent. He is too confused to undergo testing of vibration sense and joint position sense. He refuses ophthalmoscopy. Observations: tem-perature 37.0°C, blood pressure 125/62 mmHg, heart rate 62/min, respiratory rate 20/min, SaO2 96 per cent on room air.
INVESTIGATIONS
Normal range
White cells 4.0 4–11 ¥ 109/L
Haemoglobin 6.5 13–18 g/dL
Mean cell volume 115 78–100 fL
Platelets 130 150–400 ¥ 109/L
Sodium 138 135–145 mmol/L
Potassium 3.8 3.5–5.0 mmol/L
Urea 4.0 3.0–7.0 mmol/L
Creatinine 48 60–110 mmol/L
C-reactive protein 300 <5 mg/L
Bilirubin 52 5–25 mmol/L
Alanine aminotransferase 24 8–55 IU/L Alkaline phosphatase 150 42–98 IU/L
Albumin 32 35–50 g/L
Glucose 10.9 3.5–5.5 mmol/L
Intrinsic factor antibody Positive Antiparietal cell antibody Positive
Questions:
• What do these findings suggest, and how would you confirm the diagnosis?
• How would you manage this patient?
This patient has a low haemoglobin and an elevated mean cell volume (MCV), making this a macrocytic anaemia. There are many causes of an elevated MCV, including haemolytic anaemia (large numbers of reticulocytes), as well as any cause of B12 or folate deficiency.
He has a distal weakness and absent knee and ankle reflexes, suggesting a peripheral motor neuropathy. It is unclear whether he has prominent sensory symptoms also, but he does complain of numb feet. The combination of a severe macrocytic anaemia and neurological signs suggests vitamin B12 deficiency.
Several differentials do exist in this case particularly as he is confused and unable to give a complete history. Alcoholic liver disease can present with macrocytic anaemia and nutritional deficiencies. Hypothyroidism can be excluded by a normal thyroid- stimulating hormone (TSH) level. He has a history of diabetes and his peripheral neuropathy may be caused by this; but it does not explain the worsening confusion and anaemia. Other causes of a macrocytic anaemia include folate deficiency, drugs (methotrexate, azathio-prine) and myelodysplastic syndromes.
B12 deficiency is diagnosed by measuring the level of serum B12. Less than 200 pg/mL is significant. Levels between 201 and 350 pg/mL require further testing. A peripheral blood film will show megalocytes (red blood cell precursors) with hypersegmented polymorpho-nuclear cells. The reticulocyte count will be low which suggests decreased production of red blood cells. Severe B12 deficiency can give rise to cognitive impairment or dementia, subacute combined degeneration of the spinal cord and optic atrophy. Other symptoms and signs are related to the degree of anaemia.
The acute management is to ensure haemodynamic stability and identify any signs to indicate that blood tranfusion is required (presence of heart failure, shortness of breath, chest pain). Patients who have severe anaemia are likely to need a blood transfusion but this has to be done cautiously due to the risk of precipitating heart failure. There are no signs of active bleeding and his blood pressure and heart rate are stable. There is no fever or raised inflammatory markers. Identifying the cause of his macrocytic anaemia is cru-cial to enable appropriate treatment. It is important to try to gain collateral history from the GP as past medical history and medications may help diagnose the cause.
Once a low vitamin B12 is established he should be given immediate intramuscular hydroxycobalamin as he has severe haematological and neurological features (peripheral neuropathy and pyramidal tract weakness with confusion). The usual dose is 1000 mg intramuscularly three times per week for two weeks, followed by once every three months.
Identifying the cause of vitamin B12 deficiency is the next step after urgently replacing it. In this case both intrinsic factor (IF) and antiparietal cell (APC) antibodies are positive.
IF antibody is highly specific but only present in 50 per cent of cases. APC antibody is highly sensitive but not specific. Thus pernicious anaemia is the likely cause of vitamin B12 deficiency. Pernicious anaemia is an autoimmune condition where there is destruction of the gastric parietal cells that make IF. Other causes to know about are:
• reduced dietary intake (vegan diets, gastric/intestinal surgery);
• malabsorption from the GI tract (Crohn’s, coeliac, bacterial overgrowth);
• proton pump inhibitors (reduce breakdown of vitamin B12 from food);
• metformin (decreases absorption of vitamin B12);
• atrophic gastritis.
111 KEY POINTS
• Early recognition and treatment of vitamin B12 deficiency is vital as it can lead to severe neurological disease that in many cases is not reversible.
• An underlying cause for vitamin B12 deficiency should be sought.
• It is important also to check folic acid levels in this setting. If the patient is deficient in both vitamin B12 and folic acid the B12 deficiency should be corrected first to avoid precipitating subacute combined degeneration of the cord.
113