Examination Her conjunctivae are pale and sclerae are yellow

A 63-year-old woman goes to her general practitioner (GP) complaining of extreme tiredness. She has been increasingly fatigued over the past year but in recent weeks she has become breathless on exertion, light-headed and complained of headaches. Her feet have become numb and she has started to become unsteady on her feet. She has had no significant previous medical illnesses. She is a retired teacher and lives alone. Until the last 2 years she was active, walking 3 or 4 miles a day. She is a non-smoker and drinks about 15 units of alcohol per week. She is taking no regular medication. Her mother and one of her two sisters have thyroid problems.

Examination Her conjunctivae are pale and sclerae are yellow. Her temperature is 37.8°C. Her pulse rate is 96/min regular, and blood pressure 142/72mmHg. Examination of her cardiovascular, respiratory and abdominal systems is normal. She has a symmetrical distal weakness affecting her arms and legs. Knee and ankle jerks are absent and she has extensor plantar responses. She has sensory loss in a glove and stocking distribution with a particularly severe loss of joint position sense.

Normal Haemoglobin 4.2g/dL 11.7–15.7g/dL Mean corpuscular volume (MCV) 112fL 80–99fL White cell count 3.3 109/L 3.5–11.0 109/L Platelets 102 109/L 150–440 109/L Sodium 136mmol/L 135–145mmol/L Potassium 4.4mmol/L 3.5–5.0mmol/L Urea 5.2mmol/L 2.5–6.7mmol/L Creatinine 92amol/L 70–120amol/L Glucose 4.4mmol/L 4.0–6.0mmol/L Bilirubin 45mmol/L 3–17mmol/L Alanine transaminase 33IU/L 5–35IU/L Alkaline phosphatase 263IU/L 30–300IU/L INVESTIGATIONS
Questions • What is the diagnosis? • How would you investigate and manage this patient?

ANSWER
This patient has a severe macrocytic anaemia and neurological signs due to vitamin B12 deficiency. There is a family history of thyroid disease. This can cause a macrocytic anaemia but not to this degree, and hypothyroidism would not explain the other features. Anaemia reduces tissue oxygenation and therefore can affect most organ systems. The symptoms and signs of anaemia depend on its rapidity of onset. Chronic anaemia causes fatigue and pallor of the mucous membranes. Cardiorespiratory symptoms and signs include breathlessness, chest pain, claudication, tachycardia, oedema and other signs of cardiac failure. Gastrointestinal symptoms include anorexia, weight loss, nausea and constipation. There may be menstrual irregularities and loss of libido. Neurological symptoms include headache, dizziness and cramps. There may be a low-grade fever. In pernicious anaemia, the MCV can rise to 100–140fL, and oval macrocytes are seen on the blood film. The reticulocyte count is inappropriately low for the degree of anaemia. The white cell count is usually moderately reduced. There is often a mild rise in serum bilirubin giving the patient a ‘lemon-yellow’ complexion. As in this patient, profound vitamin B12 deficiency also causes a peripheral neuropathy and subacute degeneration of the posterior columns and pyramidal tracts in the spinal cord, causing a sensory loss and increased difficulty walking. The peripheral neuropathy and pyramidal tract involvement produce the combination of absent ankle jerks and upgoing plantars. In its most extreme form it can lead to paraplegia, optic atrophy and dementia. Vitamin B12 is synthesized by microorganisms and is obtained by ingesting animal or vegetable products contaminated by bacteria. After ingestion, it is bound by intrinsic factor, synthesized by gastric parietal cells, and this complex is then absorbed in the terminal ileum. Vitamin B12 deficiency is most commonly of a gastric cause (pernicious anaemia due to an autoimmune atrophic gastritis; total gastrectomy), bacterial overgrowth in the small intestine destroying intrinsic factor, or a malabsorption from the terminal ileum (surgical resection; Crohn’s disease).
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• Folate deficiency • Excessive alcohol consumption • Hypothyroidism • Certain drugs, e.g. azathioprine, methotrexate • Primary acquired sideroblastic anaemia and myelodysplastic syndromes Differential diagnoses of macrocytic anaemia
• Vitamin B12 deficiency may occur in strict vegetarians who eat no dairy produce. • Typical neurological signs are position and vibration sense impairment in the legs, absent reflexes and extensor plantars. • Overenthusiastic blood transfusion should be avoided since it can provoke cardiac failure in vitamin B12 deficiency. KEY POINTS
A full dietary history should be taken. Vegans who omit all animal products from their diet often have subclinical vitamin B12 deficiency. Serum vitamin B12 and folate levels should be measured and antibodies to intrinsic factor and parietal cells should be assayed. Intrinsic factor antibodies are virtually specific for pernicious anaemia but are only present in about 50 per cent of cases. Parietal cell antibody is present in 85–90 per cent of patients with pernicious anaemia but can also occur in patients with other causes of atrophic gastritis. A radioactive B12absorption test (Schilling test) distinguishes gastric from intestinal causes of deficiency. Rapid correction of vitamin B12 is essential using intramuscular hydroxycobalamin to prevent cardiac failure and further neurological damage.