Oxford Medical Publications Oxford Handbook of Geriatric Medicine

Chapter 16 Haematology

Investigating anaemia in older people

A low Hb is a frequently encountered abnormality in geriatric practice. It is worth remembering the following:

• Other parameters, usually documented in the FBC report (e.g. MCV), will greatly assist in characterizing the anaemia and should be scrutinized

• Looking up old FBC results will often reveal a pattern, e.g. a frail older person may run a chronically low Hb because of chronic disease or marrow failure. If there is a recent change, this should prompt more urgent investigation

• Unwell older patients may have low Hb as a result of fluid overload or marrow suppression. Repeat FBC as they recover, and see if it persists

• Multiple aetiology is common, so check a full range of blood tests in all anaemic older patients

• It is very important to check that the laboratory has received the correct blood specimens for these tests before arranging blind replacement therapy or a transfusion—subsequent samples will be invalid for haematinics

Most anaemic patients will require:

• Blood film

• Ferritin, serum iron and total iron-binding capacity (TIBC), or transferrin saturation

• B₁₂, folate

• Renal, liver, and thyroid function testing

• Blood and urine electrophoresis, serum free light chains and look for Bence–Jones proteins in the urine if the ESR is raised

If the anaemia has been characterized (e.g. iron-deficient, macrocytic, etc.), then decisions can be made about the nature and extent of further testing (see ‘Iron deficiency anaemia: diagnosis’, pp. 454–455 for details).

If the picture is mixed, then there may be multiple contributing factors (e.g. CKD, minor gastritis, early myelodysplasia)—list these and address each in turn.

Iron deficiency anaemia: diagnosis

This is the most common cause of microcytosis (but beware the occasional patient with lifelong microcytosis who has an inherited thalassaemia or sideroblastic anaemia).

Causes

• The most common is occult blood loss in the gut, especially in patients taking NSAIDs (even 75mg aspirin)

• Malabsorption (e.g. coeliac disease, gastrectomy, achlorhydria due to atrophic gastritis, or use of PPIs)

• Malnutrition as a sole cause is very unusual

► Multifactorial aetiology is common, e.g. mild chronic blood loss, borderline dietary intake, and mild malabsorption syndromes.

Diagnosis

History is vital (ask about weight loss and gut, kidney, urogenital, or ENT blood loss). Pallor (conjunctivae, nail beds) may be found. The emphasis of examination should be to find rectal or abdominal masses, hepatomegaly, and lymphadenopathy.

Investigations

• Microcytosis usual, but not in combined deficiency or acute blood loss

• Low serum ferritin levels (<12 micrograms/L) are diagnostic. Moderately low levels (12–45 micrograms/L) may also point to the diagnosis, as ferritin levels rise with age. Ferritin is an acute phase reactant, so normal/high levels do not rule out deficiency

• Serum iron levels will be low with high iron-binding capacity, i.e. the ratio of iron/iron binding (transferrin saturation) will be low (<15%). This is a useful way of distinguishing anaemia of chronic disorder where both iron and iron binding are low (and the ratio will be normal) (see also Table 16.1)

• Low iron stores on a bone marrow trephine are diagnostic, but this investigation is painful and rarely required

• Faecal occult blood is of limited value in cases of established iron deficiency—it is usually positive and you may feel that further gastrointestinal tests are needed anyhow

• Haematuria sufficient to cause anaemia is rare, and usually severe. Urinalysis may be indicated in patients with poor vision or cognition to look for renal tract blood loss

• Iron deficiency without anaemia should still be investigated, but the lower the Hb, the higher the likelihood of finding attributable pathology

Table 16.1 Characteristic findings in iron deficiency and chronic disease

Test	Iron deficiency	Chronic disease
MCV	Microcytic	Normocytic
Iron	Low	Often low
Transferrin or TIBC	Normal or high	Low
Iron:TIBC ratio (transferrin saturation)	Low (<15%)	Normal
Ferritin	Low is diagnostic	Normal or high

HOW TO . . . Investigate iron deficiency anaemia

The main dilemma is deciding how far to take investigations.

A fit patient, who would be a candidate for surgery, should have a minimum of an OGD and colon imaging (see ‘How to . . . Image the older colon’, p. 371). These should proceed, regardless of the degree of anaemia and whether there are symptoms. The finding of oesophagitis or an upper gastrointestinal ulcer should not stop a screening test for the colon to rule out a coexisting neoplasm. If these tests are negative, screen for coeliac disease and haematuria. Small bowel barium studies or capsule endoscopy are sometimes helpful. If there is intermittent overt gastrointestinal blood loss, mesenteric angiograms can demonstrate small angiodysplastic lesions if there is active haemorrhage.

At the other extreme, a frail, bedbound nursing home patient with dementia will probably merit empirical iron and PPI therapy without further investigations.

In between these extremes, physicians often adopt a ‘halfway house’. Some examples of this compromise include:

• Not proceeding to lower gastrointestinal tests if upper gastrointestinal pathology is found

• Where NSAIDs are the likely problem, stop the drug, give iron and a PPI, and only investigate if anaemia or evidence of bleeding continues after a suitable therapeutic trial

• Not performing lower gastrointestinal tests if the patient is not fit for, or not consenting to, surgical intervention

• Performing a flexible sigmoidoscopy, rather than a full colonoscopy (80% of tumours can be excluded this way without complete bowel preparation and with less risk and discomfort)

• Using oral contrast-enhanced CT colonography to image the colon (better tolerated) will miss small lesions but excludes large tumours

• Assuming that very long-standing and stable iron deficiency (several years) presents low risk for a malignant source

There are no hard rules about making these decisions, but it is advisable that any risk-taking is shared with the patient and/or relative and that you record your discussions in the notes. Remember that:

• Investigations are often better tolerated than you would expect, e.g. OGD remains a very safe test, even in very old people

• Sometimes it is worth doing tests, even if definitive treatment is not available, e.g. for a frail patient with bloody diarrhoea, a sigmoidoscopy may yield an alternative diagnosis or guide future palliative therapy

• A second medical opinion may help

Most patients are highly persuadable—if you do want them to take an active part in decisions, you will need to give an unbiased view of their options—‘You don’t want one of those unpleasant dangerous endoscopies, do you?’ does not present the patient with a fair choice.

Iron deficiency anaemia: treatment

Treatment is often simple. Treat the underlying cause, and replenish iron stores. The underlying marrow is usually healthy. Hb should rise by about 5g/L/week.

Blood transfusion is expensive and usually unnecessary, and can be dangerous. It should be used only for severe symptoms (e.g. unstable angina) or where ongoing acute bleeding is present.

Enteral iron

• Oral supplements (ferrous sulfate) are very effective, but compliance is often poor due to gastrointestinal side effects (constipation, nausea, diarrhoea)

• Sometimes a different preparation (i.e. ferrous gluconate or fumarate) is better tolerated

• Start with a low dose and ↑ as tolerated. It is better to take a lower dose for longer than abandon treatment after a few days due to side effects. Alternate day supplementation is often sufficient

• If stool is not greeny-black, adherence is poor

• Avoid slow-release preparations, as they are often poorly absorbed

• Remember that achlorhydria (atrophic gastritis or PPI administration) significantly reduces iron absorption

• Vitamin C may enhance absorption

Failure to respond to enteral iron

This should prompt consideration of the following:

• Is there ongoing haemorrhage?

• Is the patient adherent with therapy?

• Are there other contributory factors (e.g. kidney disease)?

• Is the iron being absorbed?

Parenteral iron therapy

• Use is ↑ with the development of safer preparations

• Consider if blood loss exceeds the ability of the gut to absorb oral iron (e.g. with angiodysplasia), the patient does not tolerate oral iron, or the oral iron is not adequately absorbed (e.g. with atrophic gastritis)

• Also used in renal patients on dialysis and those with inflammatory bowel disease (often intolerant of oral iron)

• iv infusions of iron sucrose, ferric carboxymaltose, or iron dextran can be given

• Risk of anaphylaxis, so test dose recommended, and there should be resuscitation facilities available

• Ferric carboxymaltose has a lower risk of anaphylaxis and can be infused quite quickly (over 15min) so is often preferred

• im preparations are rarely used

Duration of iron therapy

Continue iron for 3 months after the Hb concentration has normalized (to replenish the iron stores), but do not leave the patient on life-long treatment, unless you are unable to trace or treat the cause of ongoing blood loss. Monitoring Hb off iron can guide management by telling you whether blood loss continues; iron overload is not without risk.

Macrocytic anaemia

Causes

• B₁₂ deficiency—usually malabsorption

• Folate deficiency—often dietary, but also consider coeliac disease

• Liver failure and alcohol excess

• Drugs, e.g. methotrexate, phenytoin, azathioprine, metformin

• Reticulocytosis

Megaloblastic anaemia

• Caused by vitamin B₁₂ and folate deficiency

• Bone marrow shows big erythroblasts with immature nuclei due to defective DNA synthesis, while blood film may show hypersegmented neutrophils

• Can also cause suppression of white cell and platelet production (pancytopenia) and a mild jaundice with raised LDH due to low-grade haemolysis

• Lack of B₁₂ and/or folate also affects the brain (rare cause of reversible dementia) and nerve function (peripheral neuropathy and subacute combined degeneration of the cord). There is a poor correlation between the degree of anaemia and the presence of neurological sequelae which are often irreversible

Pernicious anaemia

An autoimmune gastritis is present in 80% of B₁₂ deficiency cases, resulting in achlorhydria, the absence of intrinsic factor, and therefore B₁₂ malabsorption. It is more common in elderly ♀ with a history of autoimmune disease. Proving the diagnosis (gastric biopsy, Schilling’s test to look for malabsorption and autoantibodies for intrinsic factor, and parietal cells) is fiddly and rarely undertaken. Treatment is empirical and pragmatic.

Treatment

• In combined deficiency or blind treatment, always correct both deficiencies simultaneously, as treating one can precipitate acute deficiency of the other and worsen neurology (especially subacute degeneration)

• Folic acid 5mg od is very well tolerated

• Hydroxocobalamin loading is 1mg by im injection three times a week for six doses, then 1mg every 3 months indefinitely

• Those with low B₁₂ levels without anaemia can go straight to the 3-monthly regimen

Anaemia of chronic disease

This is the most common cause of anaemia in older people. Illnesses such as infection, malignant disease, or connective tissue disorder may be accompanied by a moderate anaemia (90–100g/L). Frequent acute illness may have a similar effect.

Diagnosis

Often a diagnosis of exclusion. Normocytic and normochromic. There is low serum iron and iron binding capacity (normal transferrin saturation) with a normal or raised serum ferritin concentration. Bone marrow aspiration is rarely indicated but will usually demonstrate ↑ iron stores.

This underlying condition may not always be apparent, even after a careful history and examination, and screening tests should include:

• Blood film, ESR, CRP, and immunoglobulins

• Liver and renal function tests

• CXR

• Autoantibody screen

• Urine analysis

• TFTs

• PSA

If no diagnosis is made at this stage, symptomatic treatment should be given and the patient should be kept under regular review.

Treatment

• Hb will improve only after treatment of the underlying condition

• Patients should not be placed on long-term iron and/or folate supplements without evidence of deficiency (iron overload can occur and has theoretical risks)

• Symptomatic blood transfusion may be warranted

• Chronic disease often coexists with renal impairment; consider a trial of an erythropoiesis-stimulating agent (see ‘Chronic kidney disease: complications’, p. 392)

Unexplained anaemia

It is common to find mild anaemia (usually <20g below threshold) in older patients, that is not readily explained by any single process.

It is likely that there are several subtle factors at play, e.g.:

• Mild kidney impairment

• Low-level chronic inflammation

• Serial acute events

• Androgen reduction

• Erythropoietin reduction

• In some cases low level marrow failure

Approach by excluding other causes and listing possible contributing factors. It is probably not unexplained—just complex.

Paraproteinaemias

Abnormal expansion of a single line of plasma cells, which produce a monoclonal immunoglobulin. This is a malignant, or potentially malignant, condition that ↑ in prevalence with advancing age.

► A polyclonal hyperglobulinaemia is a common benign reaction to many illnesses and infection and is not related to paraproteinaemias.

It is important to exclude paraproteinaemias in any older patient with an unexplained anaemia or raised ESR. This is easily done with:

• Serum immunoglobulin level

• Serum free light chain assay (kappa:lambda ratio). An abnormal ratio suggests more sinister pathology

• Serum and urine electrophoresis, including quantification of a monoclonal immunoglobulin

• Bone marrow aspirate/trephine if one is found

Monoclonal gammopathy of undetermined significance (MGUS)

• This is the most common paraproteinaemia, occurring in 3% of over 70-year olds

• It is benign and usually has no clinical manifestations, although a minority may develop renal disease (known as monoclonal gammopathy of renal significance)

• There is a small/moderate monoclonal band (<20g/L), a low level of plasma cell expansion in the marrow (<10%), and a raised ESR, but no other clinical or laboratory features of multiple myeloma (MM)

• The paraprotein level should remain stable over time

• ‘Smouldering myeloma’ is sometimes diagnosed where the monoclonal band or plasma cell levels are higher than the thresholds listed here, but there are no other features of MM—this is treated in the same way as MGUS

• The importance of MGUS is that up to a quarter of the patients will eventually develop another haematological disease (usually MM). The median transformation time is 10 years and many patients die of unrelated illness during follow-up. There is no test which can predict which remain stable and which transform, so all should receive an annual clinical and laboratory review (FBC, serum electrophoresis with quantification of paraprotein level, kidney function, and calcium)

Multiple myeloma

Incidence in people over 80 is 30 per 100,000 per year. The marrow plasma cell expansion is malignant and causes bone erosion and marrow failure. Bence–Jones proteins (light chains excreted in urine) may contribute to kidney failure. Plasma hyperviscosity syndrome can occur.

► Exclude MM in anyone with an unexplained high ESR or anaemia.

Clinical features

• Malaise/fatigue (anaemia)

• Bone pain, pathological fracture, and cord compression (bone erosion)

• Thirst, confusion, and renal impairment (hypercalcaemia)

• Infections/fever (immunoparesis and neutropenia)

• Bleeding (thrombocytopenia)

• Hepatomegaly (20%) and splenomegaly (5%)

• Rarely neuropathy or amyloidosis can occur

Investigations

• Serum immunoglobulins and electrophoresis show a monoclonal band (sometimes two), usually quantified as over 30g/L with suppression ‘immunoparesis’ of other immunoglobulins. Immunoglobulin G (IgG) paraprotein most common, then IgA and light chains

• Serum free light chain assay with kappa:lambda ratio

• Other blood tests:

• High ESR—usually above 100

• Normochromic normocytic anaemia

• Neutropenia and thrombocytopenia occur late

• Hypercalcaemia

• Renal impairment

• ALP—may be normal despite bone lesions and hypercalcaemia

• Hypoalbuminaemia

• High β2-microglobulin levels

• Urine immunoglobulins—light chains occur as Bence–Jones protein in 75%.

• Plain X-rays—show lytic lesions or generalized osteopenia

• Isotope bone scans may be negative and are not recommended

• MRI may show non-specific, patchy high-signal marrow replacement

• Bone marrow aspirate and trephine—30% plasma cells

A confident diagnosis can be made with at least two of:

• >30% plasma cells in marrow

• Evidence of bone involvement

• A myeloma protein present in serum or urine, or both

Unfortunately, many cases are not this straightforward and cases are found with a normal ESR, no serum protein band (just Bence–Jones), or <30% plasma cells (where marrow expansion is patchy or occurring in a single plasmacytoma deposit).

Management

Should involve a haematologist.

Most patients will receive symptomatic treatment:

• Blood product transfusion

• Analgesia for bone pain

• Radiotherapy for localized bone pain/pathological fracture and for spinal cord compression

• Treatment of hypercalcaemia—see ‘HOW TO . . . Manage symptomatic hypercalcaemia’, p. 633

• Social and psychological support

Disease-modifying options include:

• A regimen containing melphalan, prednisolone, and thalidomide (MPT) chemotherapy is often used as first line for those >65

• Treatment is given in cycles (4-day courses of melphalan and prednisolone every 6 weeks, with daily thalidomide)

• Treatment continues in cycles until a plateau phase is reached (monitor M-protein in blood and urine)

• In younger (usually under 65), fitter patients, a bone marrow transplant is often recommended after initial chemotherapy

Prognosis

This is improving. Nonetheless, 5-year survival for patients aged 70–79 is 38%, dropping to 18% for those aged over 80, and palliative care should not be neglected at the end.

Severe anaemia (Hb <90g/L), kidney impairment, and hypercalcaemia are all associated with a poor prognosis.

Myelodysplasia and myelodysplastic syndrome

A group of neoplastic disorders of the haematopoietic stem cell, characterized by ↑ bone marrow failure with qualitative and quantitative abnormalities of all three cell lines, resulting in varying degrees of:

• Anaemia (macrocytic or normocytic)

• Neutropenia (sometimes with a monocytosis)

• Thrombocytopenia

A single cell line may be affected, especially at presentation. The qualitative abnormalities mean that function may be poor, even with normal counts (e.g. susceptibility to infection without neutropenia).

Common and under-diagnosed, with peak incidence at age 80. Cause unknown (except a tiny proportion who have myelodysplasia 2° to previous cytotoxic therapy).

Usually a hypercellular bone marrow (some normocellular/hypocellular) with dysplastic changes and up to 20% of blast cells. Some patients have ring sideroblasts (iron deposits in a ring shape around the nucleus). Transformation to acute myeloid leukaemia where blasts >20% occurs in a significant proportion (up to 30% eventually)—especially those with a high blast count at diagnosis.

Diagnosis

Around half of patients are asymptomatic at diagnosis (incidental finding on blood test). The rest present with anaemia, infections, or bleeding and may have splenomegaly (10%), hepatomegaly, and skin purpura.

First exclude B₁₂ and folate deficiency, alcohol excess, cytotoxics, and thyroid/liver/kidney failure. If characteristic features on blood film and mild disease, bone marrow examination may be unnecessary, but confident diagnosis/staging will usually require trephine and aspirate. Subclassification based on bone marrow morphology and karyotyping can be done by haematologists and aids prognostic precision.

Management

• Asymptomatic patients require nothing more than monitoring with regular blood counts—often stable for many years

• Mainstay of symptomatic treatment is blood transfusions

• Recurrent infections and bleeding complications should be treated with antibiotics and platelet transfusions, respectively

• Younger patients (age <70) with poor-risk disease are sometimes suitable for bone marrow transplantation or cytotoxic treatment, but these have a very high morbidity and mortality in older patients

• Growth factors, such as erythropoiesis-stimulating agents or granulocyte colony-stimulating factor, are occasionally used

• Average survival ranges from 6 months (high risk) to 12 years (very low risk), and around one-third die of unrelated causes

• Transformation to acute myeloid leukaemia has a very poor prognosis—palliative treatment only

HOW TO . . . Transfuse an older person

Acute transfusions

For example: haematemesis, post-operative blood loss.

• Speed of transfusion should be determined by the haemodynamic status (postural BP useful, remember elderly patients—especially those on β-blockers and with pacemakers—may not be able to mount an appropriate tachycardia)

• Furosemide not required in a volume-depleted patient

• Reassess fluid balance and repeat Hb frequently—it is very easy to under- or overestimate blood requirements, and older patients do not tolerate this as well

When not to transfuse

• Older people admitted acutely may have an alarmingly low Hb (often an unexpected finding on a screening blood test), but this should not automatically trigger urgent, fast, or large transfusion

• Most of these patients have a newly diagnosed chronic anaemia and can come to harm if transfused overenthusiastically—indeed many of these patients are better managed as an outpatient

• First assess the patient’s haemodynamic status and symptoms (fainting, very breathless, new confusion, unstable angina, or severe peripheral ischaemia are indications to transfuse; simple tiredness/malaise are not)

• B₁₂ injections or oral iron therapy can cause Hb to rise by 5–10g/L per week and may avoid inpatient care and the risks of transfusion

• If you do elect to transfuse, 1U may be sufficient (even for an Hb of 60) to tide the patient over until other treatments work

Routine/planned symptomatic transfusions

For example, myelodysplasia.

• In general, transfuse only when Hb drops to below 80 (unless symptoms, e.g. angina, occur at higher levels)

• Outpatient transfusion is now frequently done in DHs, with the patient sitting in a chair, rather than bed-bound

• Some units now give up to 4U/day (2h), unless the patient has heart failure or previous reactions

• Usually with oral furosemide cover (20–40mg/bag of blood)

• A careful system for cross-matching in 1° care (e.g. some units send out a pack containing pre-labelled bottles, request cards, and patient bands to district nurses to collect at home or in the GP surgery) can minimize traumatic journeys to hospital

Chronic lymphocytic leukaemia

Chronic lymphocytic leukaemia is the most common of the lymphoid leukaemias. Malignant proliferation of mature B-lymphocytes causes persistent lymphocytosis. Peak incidence age 60–80. ♀:♂ = 1:2.

Clinical features

• Often picked up incidentally on blood film when asymptomatic

• Symmetrical, non-tender lymphadenopathy (also tonsillar enlargement)

• Splenomegaly and/or hepatomegaly (in later stages)

• ↑ susceptibility to infections (e.g. thrush, herpes zoster, bacterial) due to low immunoglobulins and/or neutropenia

• Bruising/purpura due to thrombocytopenia

Investigations

Abnormal findings include:

• Lymphocytosis (>5 × 10⁹/L)—may be >100 × 10⁹/L

• Normocytic, normochromic anaemia and thrombocytopenia can occur

• Marrow trephine/aspiration replaced by lymphocytes (20–95% of cells)

• Reduced immunoglobulins develop with advanced disease

• LDH raised in some (indicating poor prognosis)

Staging systems use blood and marrow counts, chromosomal analysis, and degree of lymphadenopathy and organ involvement to predict survival and therefore guide management.