urine if the ESR is raised If the anemia has been characterized (eg iron de \201 cient, macrocytic etc.), then decisi ons can be made about the nature and extent of further testing. See b \200\230Iron deficie ncy anemia: diagnosis \200\231, p.454 for details. If the picture is mixed, then there may be multiple contributing factors (eg chronic kidney disease, minor gastritis, early myelodysplasia) \200\224 list these and address each in t urn. 454 CHAPTER 16 Hematology Iron de \201 ciency anemia: diagnosis This is the most common cause of microcytosis (but b eware the occa- sional patient with lifelong microcytosis who has an inherited thalassaemia or sideroblastic anemia). Causes \200 Most common is occult blood loss in the gut especially in patients taking NSAIDs (even 75mg aspirin) Malabsorption (eg coeliac disease, gastrectomy, achlorhydria due to atrophic gastritis or use of PPIs) Malnutrition as a sole cause is very unusual 2Multifactorial etiology is common \200\224 e g mild chronic blood loss, border- line 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 b e to \201 nd rectal or abdominal masses, hepatome- galy, and lymphadenopathy. Investigations \200 Microcytosis usual but not in combined de \201 ciency or acute blood loss \200 Low serum ferritin levels (<12micrograms/L) are diagnostic. Moderately low levels (12 \200\22345micrograms/L) may also point to the diagnosis as ferrit in levels rise with age. Ferritin is an acute phase reactant so normal/high levels don \200 \231t rule out de \201 ciency Serum iron levels will be low with high iron binding capacity, ie the ratio of iron/iron bi nding will be low (<15 % ). This is a useful way of distinguishing the anemia of chronic di sorder where both iron and iron binding are low (and the ratio will be normal) (see also Ta ble 16.1 ) Low iron stores on a bone marrow trephine are diagnostic but this investigation is painful and rarely required Fecal occult blood is of limited value in cases of established iron de \201 ciency \200 \224 it is usually positive and you may feel that further gastrointestinal tests are needed anyhow Table 16.1 Characteristic \201 ndings in iron de \201 ciency and chronic disease Test Iron de \201 ciency Chronic disease MCV Microcytic Normocytic Iron Low Often low Transferrin or total iron binding capacity (TIBC) Normal or high Low Iron: TIBC ratio Low (<15 % ) Normal Ferritin Low is diagnostic Normal or high IRON DEFICIENCY anemia: DIAGNOSIS 455 Haematuria suf \201 cient to cause anemia is rare, and usually severe. Urinalysis may be indicated in patients with poor vision or cognition to look for renal tra ct blood loss Iron de \201 ciency without anemia should still be investigated but the lower the Hb the higher the likelihood of \201 nding attributable pathology HOW TO Investigate iron de \201 ciency anemia The main dilemma is deciding how far t o take investigations. A \201 t patient , who would be a candidate for surgery, should have a minimum of OGD and colon imaging ( see b \200\230HOW TO Image the older colon \200\231, p.373). These should proceed regardless of the degree of anemia and whether there are symptoms. The \201 nding of oesophagitis or an upper gastrointestinal ulcer should not stop a screening t est for the colon to rule out a coexisting neoplasm. If these tests are negative, screen fo r coeliac disease (eg endomysial antibody) and haematuria. Small bowel barium studies or ca psule endoscopy are sometimes helpful. If there is intermittent overt gastrointestinal bloo d loss mesenteric angiograms can demonstrate small angiodysplastic lesions if there is acti ve hemorrhage. At the other extreme a frail, bed-bound nursing home patient with dementia will probably me rit empirical iron and PPI therapy without further investigations. In between these extremes physicians often adopt a \200\230half way house \200\231. Some examples of this compromise include: \200 Not proceeding to lower ga strointestinal tests if upper gastrointestinal pathology is found Where NSAIDs are the likely problem, stop the drug, give iron, and a PPI, and only investig ate if the anemia or evidence of bleeding continues after a suitable therapeutic trial Not performing lower gastrointestinal tests if the patient is not \201 t for, or not consenting to surgical intervention Performing a \202 exible sigmoidoscopy rather than a full colonoscopy (80 % of tumors can be excluded this way without complete bowel preparation and with less risk and discomfort) Using oral contrast-enhanced CT colography to image the colon (better tolerated) will miss small lesions but excludes large tumors \200 Assuming that v ery longstanding and stable iron de \201 ciency (several years) presents low risk for a malignant source There are no hard rules about making these decisions but it is advis- able that any risk-ta king is shared with the patient and/or relative and that you record your discussions in the notes. Remember that: \200 Investigations are often better tolerated than you would expe ct, eg OGD remains a very safe test even in very old people Sometimes it is worth doing tests even if de \201 nitive treatment is not available, eg for a frail patient with bloody diarrhea a sigmoidoscopy may yield an alterna tive diagnosis or guide future palliative therapy A second medical opinion may help Most patients are highly persuadable \200\224 if you do want them to take an active part in decisions you will need to give an unbiased view of the ir options \200\224 \200\230You don \200\231t want one of those unpleasant dangerous endo - scopies do you? \200\231 does not present the patient with a fair choice. 456 CHAPTER 16 Hematology Iron de \201 ciency anemia: treatment Treatment is often simple. Treat the underlying caus e, and replenish iron stores. The underlying marrow is usually healthy. Hb should rise by a bout 0.5g/dL/week. Blood transfusion is expensive, usually unnecessary and can be dangerous. It should be used only for severe symptoms (eg unstable angina) or where ongoing acute bleeding is present. Enteral iron \200 Oral supplements (ferrous sulfate 200mg od to tds) are very effective but compliance is often poor due to gastrointestinal side effects (constipation, nausea, di arrhea) Sometimes a different preparation (ie ferrous gluconate or fumarate) is better tolerated Start with low dose and increase as tolerated. It is better to take a lower dose for longer than abandon treatment after a few days due to side effects. Alternat e day supplementation is often suf \201 cient If stool is not greeny-black, concordance is poor \200 Avoid slow-release preparations, a s they are often poorly absorbed \200 Remember that achlorhydria (atrophic gastritis or P PI administration) signi \201 cantly reduces iron absorption Failure to respond to enteral iron This should prompt consideration of the following: \200 Is there ongoing hemorrhage? \200 Is the patient concordant with therapy? \200 Are th ere other contributory factors (eg kidney disease) \200 Is the iron being absorbed? Parenteral iron therapy \200 Use is increasing with the development of safer preparations \200 Consider if blood loss exceeds ability of gut to absorb oral iron (eg with angiodysplasia), the patient does not tolerate oral iron, or the oral iron is not adequately absorbed (eg with atrophic gastritis) Also used in renal patients on erythropoietin (need adequate iron for response) and those with in \202 ammatory bowel disease (often intolerant of oral iron) Iv infusions of iron sucrose (Venofer ), ferric carboxymaltose (Ferinject ) or iron dextran (CosmoFer ) 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 hemoglobin concentration has nor- malized (to replenish the iron stores) but don \200\231t leave the patient on life- lo ng treatment unless you are unable to trace or treat the cause of ongoing blood loss. Monit oring hemoglobin off iron can guide management by telling you whether blood loss continues; iron overload is not without risk. MACROCYTIC anemia 457 Macrocytic anemia Causes \200 B12 de \201 ciency \200\224 usually malabsorption \200 Folate de \201 ciency \200\224 often dietary but also consider coeliac disease \200 Mye lodysplasia \200 Aplastic anemia \200 Hypothyroidism \200 Myeloma \200 Liver failur e and alcohol excess \200 Drugs, eg methotrexate, phenytoin, azathioprine, hydroxycarbami de \200 Reticulocytosis Megaloblastic anemia \200 Caused by vitamin B12 and folate de \201 ciency \200 Bone ma rrow shows big erythroblasts with immature nuclei due to defective DNA synthesis while blood \201 lm 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 effects 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 anemia and the presence of neurological sequelae wh ich are often irreversible Pernicious anemia An autoimmune gastritis is present in 80 % of B12 de \201 ciency cases, resulting in achlorhydria, the absence of intrinsic factor, and therefore B12 malabsorption . It is more common in elderly females with a history of autoimmune disease. Proving the di agnosis (gastric biopsy, Schilling \200\231s test to look for malabsorption and autoantibod ies for intrinsic factor, and parietal cells) is \201 ddly and rarely undertaken. Treatme nt is empirical and pragmatic. Treatment \200 In combined de \201 ciency or blind treatment always correct both de \201 ciencies simultaneously as treating one can precipitate acute de \201 ciency of the o ther and worsen neurology (especially subacute degeneration) Folic acid 5mg od is very well tolerated \200 Hydroxocobalamin loading is 1mg by intramus cular injection three times a week for 6 doses then 1mg every 3 months inde \201 nitely \200 Those with low B12 levels without anemia can go straight to the 3-monthly regimen 458 CHAPTER 16 Hematology Anemia of chronic disease This is the most common cause of anemia in older people. Illnesse s such as infection, malignant disease, or connective tissue disorder may be accompanied by a moderate anemia (9 \200\22310g/dL). Frequent acute illness may have a similar effect. Diagnosis Often a diagnosis of exclusion. Normocytic and normochromic. There is a low serum iron and iron binding capacity with a normal or raised serum ferritin concentration. Bone marrow aspiration is rarely indicated but will usually demonstrate increased iron stores. This underlying condition may not always be apparent even after a careful history and examination and screening tests should include: \200 Blood \201 lm, ESR, CRP, and immunoglobulins \200 Liver and renal function tests \200 CXR \200 Auto antibody screen \200 Urine analysis \200 TFTs \200 Prostrate-speci \201 c antigen (P SA) If no diagnosis is made at this stage symptomatic treatment should be given and the pat ient should be kept under regular review. Treatment \200 Hemoglobin 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 de \201 ciency (iron overload can occur and has theoretica l risks) Symptomatic blood transfusion may be warranted \200 Chronic disease often coexists with r enal impairment; consider a trial of erythropoietin therapy ( see b \200\230Chronic kidney disease: complications \200\231, p.394) Unexplained anemia It is common to \201 nd a mild anemia (usually <2g 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, for example: Mild kidney impairment \200 Low level chronic in \202 ammation \200 Serial acute event s \200 Androgen reduction \200 Erythropoietin reduction \200 In some cases an \200 \230anemia of ageing \200\231 Approach by excluding other causes, and listing possible cont ributing factors. It is probably not unexplained \200\224 just complex. PARAPROTEINAEMIAS 459 Paraproteinaemias Abnormal expansion of a single line of plasma cells, which produce a mono clonal immunoglobulin. This is a malignant, or potentially malignant condition that increas es in prevalence with advancing age 2A polyclonal hyperglobulinaemia is a common benign rea ction to many illnesses and infection and is not related to the paraproteinaemias. It is important to exclude paraproteinaemias in any older patient with an unexplained anemia or raised ESR. This is easily done with: \200 Serum immunoglobulin levels \200 Serum and urine electrophoresis including quanti \201 cation of a monoclonal immunoglobulin Bone marrow aspirate/trephine if one is found Monoclonal gammopathy of undetermined signi \201 cance (MGUS) \200 This is the most comm on paraproteinaemia, occurring in 3 % of over 70 year olds It is benign and has no clinical manifestations \200 There is a small/moderate monoclonal band (<20g/L), a low level of plasma cell expansion in the marrow (<10 % ), and a raised E SR but no other clinical or laboratory features of multiple myeloma (MM) The paraprotein level should remain stable over time \200 \200\230Smoldering myeloma \200\231 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 \200\224 this is tre ated in the same way as MGUS The importance of MGUS is that up to a fourth of the patients will eventually develop anoth er hematological 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 whic h remain stable and which transform so all should receive an annual clinical and laboratory review (FBC, serum electrophoresis with quanti \201 cation of paraprotein level, kidney f unction, and calcium) 460 CHAPTER 16 Hematology 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 protein s (light chains excreted in urine) may contribute to kidney failure. Plasma hyperviscosity syndrome can occur. 2Exclude MM in anyone with an unexplained high ESR or anemia Clinical features \200 Malaise/fatigue (anemia) \200 Bone pain, pathological fracture a nd cord compression (bone erosion) \200 Thirst, confusion and renal impairment (hypercalc aemia) \200 Infections/fever (immunoparesis and neutropenia) \200 Bleeding (thrombocyto penia) \200 Hepatomegaly (20 % ) and splenomegaly (5 % ) \200 Rarely neuropathy or amyl oidosis can occur Investigation \200 Serum immunoglobulins and electrophoresis show a monoclonal band (some times two), usually quanti \201 ed as over 30g/L with suppression \200\230immunoparesis \200\231 of other immunoglobulins. IgG paraprotein most common, then IgA and light chains. Other blood tests High ESR \200\224 usually above 100 \200 Normochromic normocytic anemia \200 Neutropen ia and thrombocytopenia occur late \200 Hypercalcaemia \200 Renal impairment \200 ALP \200\224 may be normal despite bone lesions and hypercalcaemia \200 Hypoalbuminaemia \200 High B 2-microglobulin levels Urine immunoglobulins \200\224 light chains occur as Bence Jones protein in 75 % Plain X-rays \200\224 show lytic lesions or generalized osteopenia \200 Isotope bone sca ns may be negative and are not recommended \200 MRI may show non-speci \201 c patchy hig h signal marrow replacement \200 Bone marrow aspirate and trephine l 30 % plasma cells A con \201 dent diagnosis can be made with at least two of: > 30 % plasma cells in marrow \200 Evidence of bone involvement \200 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 % plasm a cells (where marrow expansion is patchy or occurring in a single plasmacytoma deposit). MULTIPLE MYELOMA 461 Management Should usually involve a hematologist. Most patients will receive symptomatic treatment : Blood product transfusion \200 Analgesia for bone pain \200 Radiotherapy for localized bone pain/pathological fracture and for spinal cord compression Treatment of hypercalcaemia \200\224 see b \200\230HOW TO Manage symptomatic hypercalcaemia \200\231, p.633 Social and psychological support Disease-modifying options include: \200 In younger (usua lly under 65), \201 tter patients a bone marrow transplant is often recommended after initial chemotherapy A regimen containing melphalan, prednisolone and thalidomide (MPT) chemotherapy is often used as \201 rst line for those > 65 Treatment is given in cycles (four-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) Higher risk MM, or those who progress on standard chemotherapy may be given regimens includ ing bortezomib (an iv proteasome inhibitor) or lenalidomide (an immunomodulating drug given orally along with dexamethasone) Prognosis Median survival even with treatment is 4 years and palliative care should not be neglected at the end. Severe anemia (Hb<9g/dL), kidney impairment, and hypercalcaemia are all associated with a poor prognosis. 462 CHAPTER 16 Hematology Myelodysplasia and myelodysplastic syndrome A group of neoplastic disorders of the haemopoi etic stem cell character- ized by increasing bone marrow failure with qualitative and quant itative abnormalities of all three cell lines resulting in varying degrees of: \200 Anemi a (macrocytic or normocytic) \200 Neutropenia (sometimes with a monocytosis) \200 Throm bocytopenia A single cell line may be affected, especially at presentation. The quali- tati ve abnormalities mean that function may be poor even with normal counts (eg susceptibility to infection without neutropenia). Common and underdiagnosed with peak incidence age 80. Cause unknown (except a tiny proporti on who have myelodysplasia secondary to previous cytotoxic therapy). Usually a hypercellular bone marrow (some normocellular/hypocellular) with dysplastic chang es and up to 20 % blast cells. Some patients have ring sideroblasts (iron deposits in ring shape around nucleus). Transformation to acute myeloid leukemia where blasts > 20 % occurs in a signi \201 cant proportion (up to 30 % eventually) \200\224 especially those with a high blast count at diagnosis. Diagnosis Around half of patients are asymptomatic at diagnosis (incidental \201 nding on blood test). The rest present with anemia, infections, or bleeding and may have splenomega ly (10 % ), hepatomegaly and skin purpura. First exclude B12 and folate de \201 ciency, alcohol excess, cytotoxics and thyroid/liver/ kidney failure. If characteristic features on blood \201 lm and mild disease, bone marrow examination may be unnecessary but con \201 dent diagnosis/staging will usually require t rephine and aspirate. Subclassi \201 cation based on bone marrow morphology and karyotypin g can be done by hematologists and aids prognostic precision. Management \200 Asymptomatic patients require nothing more than monitoring with regular blood counts \200\224 often stable for many years Mainstay of symptomatic treatment is blood transfusions \200 Recurrent infections and ble eding 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 erythropoietin or granulocyte colony stimulating factor are occasionally used Average survival ranges from 6 months (high risk) to 4 years (low risk) and around one-third die of unrelated causes Transformation to acute myeloid leukemia has a very poor prognosis \200\224 palliative treatment only MYELODYSPLASIA AND MYELODYSPLASTIC SYNDROME 463 HOW TO Transfuse an older person Acute transfusions For example: haematemesis, postop erative blood loss \200 Speed of transfusion should be determined by the haemodynamic sta tus (postural BP useful, remember elderly patients \200\224 especially those on B -blocker s and with pacemakers \200\224 may not be able to mount an appropriate tachycardia) Furosemide not required in a volume-depleted patient \200 Reassess \202 uid balance and repeat Hb frequently \200\224 it is very easy to under or overestimate blood requirements and older patients do not tolerate this as well When not to transfuse \200 Older people admitted acutely may have an alarmingly low hemoglobin (often an unexpected \201 nding 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 anemia and can come to harm if transf used overenthusiastically \200\224 indeed many of these patients are better managed as an outpatient First assess patient \200\231s haemodynamic status and symptoms (fainting, very breathless, new confusion, unstable angina or severe peripheral ischaemia are indicati ons to transfuse; simple tiredness/malaise is not) B12 injections or oral iron therapy can cause hemoglobin to rise by 0.5 \200\2231g/dL per week and may avoid inpatient care and the risks of transfusion If you do elect to transfuse, two units may be suf \201 cient (even for an Hb of 6) to tide the patient over until other treatments work Routine/planned symptomatic transfusions eg myelodysplasia \200 In general transfuse only when hemoglobin drops to below 8 (unless symptoms, eg 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 4 units/day (2hr) unless patient has heart failure or previous reactions Usually with oral furosemide cover (20 \200\22340mg/bag of blood) \200 A careful system f or cross-matching in primary care (eg some units send out a pack containing pre-labeled bot tles, request cards, and patient bands to district nurses to collect at home or in GP surge ry) can minimize traumatic journeys to hospital 464 CHAPTER 16 Hematology Chronic lymphocytic leukemia Chronic lymphocytic leukemia is the most common of the lymphoi d leukaemias. Malignant proliferation of mature B-lymphocytes causes per- sistent lymphocyt osis. Peak incidence age 60 \200\22380. Female:male 1:2. Clinical features \200 Often picked up incidentally on blood \201 lm when asymptomatic \200 Symmetrical non-tender lymphadenopathy (also tonsillar enlargement) \200 Splenomeg aly and/or hepatomegaly (in later stages) \200 Increased susceptibility to infections (eg thrush, herpes zoster, bacterial) due to low immunoglobulins and/or neutropenia Bruising/purpura due to thrombocytopenia Investigations Abnormal \201 ndings include: \200 Lymphocytosis ( > 5 \227 10 9 /L) \200\224 may be > 100 \227 10 9 /L \200 Normocytic, normochromic anemia and thrombocytop enia can occur \200 Marrow trephine/aspiration replaced by lymphocytes (20 \200\22395 % o f cells) \200 Reduced immunoglobulins develop with advanced disease \200 LDH raised in some (indicating poor prognosis) Staging systems use blood and marrow counts and degree of lymphad- enopathy and organ involvement to predict survival and therefore guide management. Treatment \200 Asymptomatic patients with non-progressive early stage disease are just observed/reviewed in hematology clinics In later stages and progressive disease aim for symptom control (not correction of the lymphocytosis) with: \200 Short courses of oral chemotherapy using chlo rambucil or \202 udarabine-based regimens (eg with rituximab and cyclophosphamide) Prednisolone \200\224 can help with anemia, neutropenia or thrombocytopenia and reduces he patosplenomegaly Radiotherapy \200\224 useful for bulky lymph nodes Most patients respond to treatment initially but relapse after time. Prognosis \200 Varies according to stage and prognostic factors but in most patients is a chronic, non-aggressive disease Many elderly patients are likely to die with, rather than of, the disease (as in myelo \201 brosis and prostate cancer) However, patients with aggressive disease have a life expectancy of 2 \200\2233 years. 465 Chapter 17 Musculoskeletal system Osteoarthritis 466 Osteoarthritis: management 467 Osteoporosis 468 Osteoporosis: management 470 HOW TO Manage non-operative fractures 471 Polymyalgia rheumatica 472 Giant cell arteritis 474 HOW TO Manage steroid therapy in giant cell arteritis 476 Muscle symptoms 478 HOW TO Grade muscle strength 479 Paget \200\231s disease 480 Gout 482 Pseudogout 484 Contractures 485 Cervical spondylosis a nd myelopathy 486 Osteomyelitis 488 The elderly foot 490 HOW TO Care for the elderly foot 491 The elderly hand 492 The painful hip 494 The painful back 496 The painful shoulder 498