ANAEMIA
Case vignette
An 81-year-old female is admitted to the coronary care unit with crescendo angina. She also complains of early satiety, nocturia and pedal oedema. She reports a 10 kg weight loss over 3 months. She has a background history of rheumatoid arthritis. She is currently managed on a non-steroidal antiinflammatory agent and aspirin. On examination she is hypertensive with a pulse rate of 100 bpm. She has significant conjunctival and palmar crease pallor. The ECG shows evidence of left ventricular hypertrophy and diffuse ST segment depression, together with T wave inversion in the inferior leads. Her blood tests reveal an Hb level of 7 g/dL.
Approach to the patient
An Hb level of < 13 g/dL in men and < 12 g/dL in women is considered anaemic in common practice.
History
Ask about:
• the symptoms at presentation—patients may present with constitutional symptoms such as lethargy, malaise, exertional dyspnoea, fatigue or gastrointestinal blood loss in the form of haematemesis or melaena
• easy bruising, uncontrolled blood loss, large joint arthropathy and excessive bleeding post-surgery—features suggesting a coagulation disorder/bleeding diathesis
• other symptoms that would help identify the aetiology, such as change in bowel habits or weight loss suggesting colonic cancer, abdominal discomfort, bloating, anorexia and weight loss of gastric carcinoma, abdominal pain suggesting peptic ulcer disease, night sweats, weight loss and fevers suggesting lymphoma.
Take a detailed medication history, looking for evidence of therapy with non-steroidal antiinflammatory agents, sulfur-containing medications (haemolysis) and myelosuppressive agents. Enquire about alcoholism and general nutrition. Check whether the patient has had any transfusions and whether there have been any adverse transfusion reactions or transmission of blood-borne infections such as hepatitis C and HIV. It is also useful to know the patient’s blood group.
Examination
Look for features of anaemia such as palmar crease pallor, conjunctival pallor, tachypnoea, tachycardia and evidence of high-output cardiac failure. Look for signs that suggest the likely aetiology (see box): characteristic copper-hue pigmentation (the combined effect of melanin deposition, icterus and pallor) of the thalassaemia patient with malar hyperplasia and often stunted growth, pigmented lesions in the mouth (Peutz-Jeghers syndrome), scleral icterus (haemolysis), epigastric tenderness (peptic ulcer disease), abdominal distension or mass lesions, splenomegaly, hepatomegaly, bony tenderness (malignancy), lymphadenopathy (lymphoma), impaired cognition, peripheral neuropathy and dorsal column signs (vitamin B12 deficiency), arthropathy (anaemia of chronic disease or gastrointestinal blood loss secondary to NSAID use), slate-grey pigmentation, peripheral arteriovenous fistula, vascular access device or abdominal Tenckhoff catheter (renal anaemia).
Causes of anaemia
1. Bleeding (acute/chronic)
2. Haematinic deficiency (iron, vitamin B12, folate, vitamin C)
3. Haemolysis (immune/mechanical/toxic/paroxysmal nocturnal haemoglobinuria)
4. Chronic inflammation
5. Chronic renal failure
6. Bone marrow infiltration
7. Bone marrow suppression (e.g. cytotoxics, carbimazole, gold, irradiation)
8. Sepsis (e.g. malaria, Clostridium welchii)
9. Marrow aplasia
10. Myelodysplasia
11. Myelofibrosis
12. Haemoglobinopathies (sickle cell disease, thalassaemia)
13. Sideroblastic anaemia
Anaemia in the long case patient is often multifactorial. The diagnostic work-up should include a comprehensive battery of tests as guided by the clinical setting. Iron deficiency secondary to chronic blood loss, commonly from the gastrointestinal tract, is the most common cause of anaemia in this group of patients. Other differential diagnoses encountered commonly include anaemia of chronic disease, vitamin B12 and folate deficiency, myelodysplasia, aplastic anaemia, sideroblastic anaemia, myelosuppression, chronic renal failure, myelofibrosis and chronic alcoholism (due to a combination of bone marrow toxicity of alcohol, iron and folate deficiency and gastrointestinal bleeding).
Investigations
Investigation of anaemia should be guided by the clinical picture. The more common conditions should be excluded first. Relevant investigations in the anaemic patient include:
Blood picture: Patients with anaemia of chronic disease usually have normocytic, normochromic anaemia. Those with iron deficiency, thallasaemia or sideroblastic anaemia have microcytic, hypochromic anaemia. Microcytic, hypochromic anaemia is also seen in myelodysplastic syndrome.
2. Coagulation profile—international normalised ratio (INR), activated partial thromboplastin time (APTT), bleeding time and clotting time, to exclude a bleeding diathesis
3. Haematinics—iron studies in the form of serum ferritin, serum iron and transferrin saturation, to exclude iron deficiency
4. Serum vitamin B12 and serum and red cell folate levels
5. Haemolytic screen—including blood film, serum haptoglobin level, serum lactate dehydrogenase (LDH) level, serum bilirubin level, the direct Coombs’ test, haemoglobin electrophoresis, Heinz body preparation and, if indicated, the cold agglutinin test
6. Erythrocyte sedimentation rate (ESR)—looking for evidence of chronic inflammation and paraproteinaemia
7. Electrolyte profile and the renal function indices—to exclude renal failure as a cause
8. Erythropoietin levels
9. Thyroid function tests—to exclude hypothyroidism, which can cause a macrocytic anaemia
10. Chest X-ray—to exclude chronic pulmonary disease and pulmonary malignancies
11. Serum protein electrophoresis and immunoelectrophoresis—to exclude any paraproteinaemia
12. If all non-invasive and minimally invasive tests do not help in the correct diagnosis, the next investigation is a bone marrow biopsy with both aspiration and trephine.
Management
Management depends on severity (level of Hb) and the patient’s cardiopulmonary status. Initial steps include identification and correction of reversible, causative factors and replacement of blood with packed cell transfusions and/or the supplementation of haematinics as indicated.
As a general rule, blood transfusion is indicated if Hb is < 7 g/dL. If Hb remains > 10 g/dL, transfusion should be considered only if there is a compelling clinical indication such as precipitation of coronary ischaemia or heart failure.
Gastrointestinal bleeding warrants endoscopy (colonoscopy or gastroscopy) to identify the exact location of the bleeding and for possible therapy or biopsy of suspicious lesions. If gastroscopy and colonoscopy fail to identify the source of bleeding, capsule endoscopy may be warranted, to look for a small intestinal focus.
Patients with chronic renal failure need iron supplementation and at times may need IV iron infusion. Patients with kidney disease may benefit from therapy with erythropoietin or darbapoietin.
It is recommended that patients with chronic kidney disease be maintained at an Hb level of 11 g/dL or more.
Patients with anaemia of chronic disease improve when the underlying disease is well treated. Haematinic replacement and therapy with erythropoietin or darbapoietin is also indicated in this group.
Management of anaemia due to cytotoxic chemotherapy in patients with non-myeloid malignancies is similar to the management of anaemia of chronic disease.
HAEMATOLOGICAL MALIGNANCIES
Haematological malignancies are commonly encountered in the long case. History taking should enquire into the events surrounding the diagnosis, such as presenting symptoms of fatigue, lethargy, weight loss, fever, night sweats, bone pain, how the diagnosis was made, the various investigations that have been carried out, including bone marrow biopsy and/or excision biopsy of lymph nodes, and the treatment given so far, including blood transfusions, chemotherapy and bone marrow or stem cell transplantation. Ask about the side effects of chemotherapy and any episodes of febrile neutropenia, life-threatening sepsis etc. Ask how the patient is coping with the disease, what knowledge they have about the prognosis of the condition, what expectations they have for the future, and the level of social support available.
Following is a discussion of the salient points relevant to the commonly encountered haematological malignancies. The candidate is expected to have an up-to-date knowledge of each disease and to be able to handle wisely the complicated clinical issues associated with the management of these conditions.
MULTIPLE MYELOMA
Case vignette
A 56-year-old man presents with significant lethargy, severe back pain, loss of sensation in the lower extremities and dizziness. He also complains of bleeding gums and frequent blurring of vision. Physical examination reveals mucosal and conjunctival pallor and bony tenderness of the lower back. There are signs of peripheral neuropathy. His blood tests reveal anaemia, renal impairment and hypercalcaemia.
Approach to the patient
Multiple myeloma is a common malignant condition encountered in the long case setting, because patients with multiple myeloma can have many secondary medical complications. Multiple myeloma is due to disordered proliferation of a clone of plasma cells secreting monoclonal immunoglobulins. The clinical presentation of multiple myeloma is variable.
History
Ask about pain, bony fractures, lethargy, fatigue, dyspnoea, mucosal bleeding, fevers and rigors. Enquire about loss of sensation, limb weakness, visual problems and dizziness.
Some common presentations are intractable bone pain, pathological fracture, symptomatic anaemia, pancytopenia, sepsis, renal failure or acute symptomatic hypercalcaemia. Some may present with the hyperviscosity syndrome, with associated neuropathy and coagulopathy (oral and nasal bleeding, blurred vision, headache and vertigo) or amyloidosis. Hyperviscosity syndrome is more common in Waldenström’s macroglobulinaemia, where the paraprotein is IgM. The most common presenting symptom, however, is bone pain, particularly in the vertebral column. Multiple myeloma should be suspected in any patient over the age of 40 years presenting with bone pain, pathological fracture, osteoporosis, lethargy, anaemia and recurrent infections. Incidental discovery of proteinuria, hypercalcaemia, acute renal failure, high ESR or rouleaux formation should alert the clinician to look for multiple myeloma.
Examination
Look for evidence of anaemia and sepsis. Do not forget to look at the temperature chart. Check the mucosa for bleeding. Perform a thorough neurological examination. Look for bony fractures and assess for bone tenderness.
Investigations
1. Full blood count—looking for anaemia or pancytopenia
2. Blood film—looking for a normocytic normochromic picture and rouleaux formation
4. Serum electrolyte profile
5. Renal function indices—looking for renal failure due to light-chain toxicity, sepsis, amyloidosis and hypercalcaemia
6. Serum calcium level and serum albumin level—looking for hypercalcaemia and hypoalbuminaemia
8. Serum uric acid level—can be elevated
9. Serum and urine protein electrophoresis and immunoelectrophoresis—looking for a paraprotein band
10. Skeletal survey—looking for lytic bone lesions
11. Bone marrow biopsy (both aspirate and trephine)—looking for plasma cell infiltration. Bone marrow immunoperoxidase staining will identify kappa or lambda light chains in the plasma cells, confirming its monoclonal nature.
12. Cytogenetic analysis by interphase fluorescence in situ hybridisation (FISH)
Figure 8.1 Lytic bone lesions: anteroposterior (A) and lateral (B) radiographs of the distal forearm demonstrate an expansile destructive lytic lesion with its epicentre in the diametaphysis of the distal radius which abuts the epiphyseal plate
(reprinted from Kai B, Ryan A, Munk P L et al 2006 Gorham disease of bone: three cases and review of radiological features. Clinical Radiology 61:7).
Figure 8.2 Axial CT image of the head in bone window, revealing irregular lytic lesions of the cranial vault in the occipital and left temporal regions
(reprinted from Dinkar A D, Spadigam A, Sahai S 2007 Oral radiographic and clinico-pathologic presentation of Erdheim-Chester disease: a case report. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 103:5)
Figure 8.3 Bone marrow film of a myeloma patient
(reprinted from Kumar V, Abbas A K, Fausto N 2005 Robbins and Cotran Pathologic Basis of Disease, 7th edn. Elsevier, Philadelphia, p 679, fig 14.16)
Diagnostic criteria for multiple myeloma
For the diagnosis of multiple myeloma there should be one major criterion together with one minor criterion or three minor criteria present—these should be clinically manifest.
(Adapted from Grogan T M 2001 Plasma cell neoplasms. In: Jaffe E S, Harris N L, Stein H et al (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, p 142)
(Adapted from Grogan T M 2001 Plasma cell neoplasms. In: Jaffe E S, Harris N L, Stein H et al (eds) World Health Organization classification of tumours. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. IARC Press, Lyon, p 142)
(From Greipp P R, San Miguel J, Durie B J et al 2005 International staging system for multiple myeloma. Journal of Clinical Oncology 23(15):3412–3420)
(From Greipp P R, San Miguel J, Durie B J et al 2005 International staging system for multiple myeloma. Journal of Clinical Oncology 23(15):3412–3420)
Management
Emergent management of acute complications:
General management strategy:
1. If the patient is suitable for autologous bone marrow transplantation (patients aged less than 70 years and with good prognostic features)—initial cytoreduction with combination chemotherapy such as VAD (vincristine, doxorubicin, dexamethasone)/stem cell collection at maximal response/high-dose melphalan followed by stem cell rescue.
2. A second autologous bone marrow transplantation may be indicated if there is less than very good partial response (VGPR; a response less than 90%).
3. Maintenance therapy with thalidomide with or without steroids if in remission.
4. If the patient is not suitable for autologous bone marrow transplantation—thalidomide-based therapy with melphalan and prednisone or dexamethasone.
