RESUMEN

A6

On the assumption that menstrual loss is the underlying cause of this anaemia, the outcome should be excellent.

CASE 3.2 – A 58-year-old woman is referred with a 12-month history of increasing difficulty in walking.

Q1: What is the likely diagnosis and possible differential diagnoses?

A1

The patient’s neurological examination reveals a combination of peripheral neuropathy and an upper motor neuron lesion in the lower limbs. In addition, there are symptoms and signs of anaemia, pancytopenia (i.e. all three cell lineages are reduced) and macrocytosis. All these point to vitamin B₁₂deficiency and a diagnosis of pernicious anaemia (PA) with subacute combined degeneration of the spinal cord and peripheral neuropathy. All dividing cells require vitamin B₁₂and the bone marrow, as one of the tissues with the fastest turnover, is often affected first. The raised bilirubin and LDH are a result of ineffective erythropoiesis within the bone marrow (so-called intramedullary haemolysis). Folate deficiency can give rise to a similar blood picture but neurological deficit does not occur.

Q2: What are the relevant points to elicit from the history?

A2

Pernicious anaemia is an autoimmune disease and so a personal and/or family history of other autoimmune diseases should be sought (e.g. type 1 diabetes, thyroid disease, Addison’s disease and vitiligo). Has the patient ever undergone any gastric surgery? Rarely there is associated subfertility (but this would not apply in this age group) and visual loss. Vitamin B₁₂is present in foods of animal origin. Daily requirements of vitamin B₁₂are very low so it is very unusual for vegans to develop clinical vitamin B₁₂deficiency but a dietary history should always be taken.

Q3: What are the possible clinical signs?

A3

The tongue is said to be ‘big and beefy’ in contrast to the atrophic tongue seen in iron deficiency. The skin has a lemon tinge (caused by the mildly elevated bilirubin). Optic atrophy can also occur and anecdotally patients are often said to be white haired.

Q4: What additional investigations are indicated?

A4

Measuring the serum vitamin B₁₂levels easily makes the diagnosis. Other useful tests are anti-parietal and intrinsic factor antibodies, which are present in 90 per cent and 60 per cent respectively. It may also be prudent to look for evidence of the other autoimmune disorders that are associated with PA. Historically, a Schilling test was performed to confirm vitamin B₁₂ malabsorption but this is rarely performed today because it exposes patients to irradiation and does not usually alter clinical management.

A bone marrow examination would confirm a megaloblastic anaemia but does not distinguish between vitamin B₁₂and folate deficiency, and hence is not routinely performed.

Q5: What is the treatment?

A5

Management is vitamin B₁₂usually given as 1 mg intramuscular injections for six doses over 2 weeks and then every 3 months for life. If required, the response to therapy can be assessed by the rise in reticulocytes and Hb and the fall in LDH.

Q6: What is the long-term outcome?

A6

The blood/marrow changes will improve over the following few weeks, but the neurological deficit may take many, many months and if severe at diagnosis may not resolve completely.

CASE 3.3 – A 78-year-old woman is referred with a 6-month history of general deterioration.

Q1: What is the likely diagnosis and possible differential diagnoses?

A1

The blood count shows mild pancytopenia and this, taken together with bony pain and hypercalcaemia, could indicate secondary cancer in the bone or possibly a primary haematological cancer of the bone marrow. The total protein is very

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high and the albumin low, meaning that the globulin level (total protein minus albumin) is very high. Supported by the presence of renal impairment, the diagnosis is likely to be multiple myeloma. When a very high globulin level occurs, a low sodium level is often seen (so-called pseudo-hyponatraemia).

Q2: What are the relevant points to elicit from the history?

A2

Multiple myeloma is a disease of elderly people and symptoms are often non-specific and attributed to old age. Symptoms caused by anaemia and bony pain (especially back) are typical and myeloma should always be considered with this combination. There are relatively few causes of thirst but the most common are diabetes (mellitus and insipidus), dehydration and hypercalcaemia. Hypercalcaemia also causes the confusion and polyuria that lead to dehydration (this will contribute to the raised creatinine in this patient). Renal impairment in myeloma is caused by dehydration, hypercalcaemia and paraprotein deposition in the kidney.

Q3: What are the possible clinical signs?

A3

Back pain is common as a result of pressure on spinal nerve roots or pathological fractures. Vertebral collapse can lead to paraplegia. Note that there is usually no enlargement of the liver, spleen or lymph nodes unless secondary amyloidosis has occurred.

Q4: What additional investigations are indicated?

A4

Multiple myeloma is a cancer of plasma cells. Immunoglobulins are normally produced by plasma cells and therefore a malignant proliferation of plasma cells leads to uncontrolled production of a single type of immunoglobulin (Ig) – so-called paraprotein. The plasma cells proliferate within the bone marrow, damaging normal bone marrow cells and bone and leading to anaemia and other blood cell cytopenias, hypercalcaemia and lytic lesions on radiographs.

The diagnosis of multiple myeloma depends on four tests:

1. Serum Ig estimation and protein electrophoresis.

2. Urinary sample for Bence Jones protein (light chain) analysis.

3. A skeletal survey looking for lytic lesions.

4. Bone marrow examination to assess malignant plasma cell infiltration.

Q5: What is the treatment?

A5

In this case, treatment of the hypercalcaemia would be of most immediate priority because this may reduce the confusion and alleviate symptoms of dehydration. Local irradiation may be indicated for bony pain. The anaemia can be treated with

blood transfusion in the short term, possibly with erythropoietin therapy thereafter. Treatment for myeloma consists of chemotherapy with autologous stem cell transplantation for younger patients. Steroids and anti-angiogenic agents also have a role as either upfront or palliative therapy. Regular bisphosphonate therapy reduces the risk of bony fracture and hypercalcaemia.

Q6: What is the long-term outcome?

A6

The prognosis is poor, with death usually within 2–3 years of diagnosis for patients not fit enough for autologous stem cell transplantation and around 5 years for those who are.

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