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The blood in systemic disorders
HAEMATOLOGY
Haematology
The blood in systemic disorders Jerry L Spivak The high rate of proliferation required of the bone marrow renders it highly susceptible to the influence of external factors. ● Anaemia is the most common haematological abnormality seen in systemic disorders. ● In the anaemia of chronic disease, erythropoietin production is reduced and proliferation of erythroid progenitor cells is also impaired; this anaemia can generally be alleviated by correction of the underlying disease process. ● The status of the endocrine system must always be considered in evaluation of a normocytic, normochromic anaemia. ● Anaemia in infection can be due to host or parasite factors or to the treatment administered. ● Anaemia due to malignant disease responds to erythropoietin therapy in many cases; failure to respond is a poor prognostic sign. ●
When confronted with a disturbance of haemopoiesis, the physician must find out whether it is due to a disorder primarily involving the haemopoietic system or is secondary to an underlying systemic disease or treatment. This distinction is critical for decisions on appropriate management. When the haematological abnormality is secondary, correction of the underlying disorder or withdrawal of the offending treatment suffices in most cases to alleviate the blood abnormality. A systematic approach to the diagnosis will always be rewarded; blind haematinic therapy will not. Haemopoiesis is the orderly continuous process by which primitive progenitor cells give rise to the mature circulating blood cells. To ensure an adequate quantity of cells for oxygen transport, host defence, and haemostasis, the bone marrow must produce 1011 red cells, 1011 white cells, and 1011 platelets every day to replace those lost through senescence or use. Given this high rate of proliferation, the bone marrow is susceptible to agents or diseases that interfere with the supply of haemopoietic growth factors, disturb the anatomical integrity of the tissue, or provoke the production of antiproliferative, proinflammatory cytokines. Disorders of the blood may first become manifest by dysfunction of a particular organ because the blood has an essential role in the body’s economy and the circulation is ubiquitous. More commonly, however, systemic disorders or diseases involving a particular organ or tissue first become manifest by an abnormality of the blood. The mechanisms involved include suppression or stimulation of bone-marrow function, increased destruction or sequestration of blood cells, haemodilution, and bleeding. Since the causes are many and often correctable, whereas the blood abnormalities are generally not amenable to blind haematinic therapy, the diagnostic approach must be thorough. The presence of a systemic disease, of course, does not exclude another cause for a blood abnormality. For example, rheumatological disorders and myelodysplasia are well known to coexist,1 as are mediastinal germ-cell tumours and haematological malignant disease.2 Furthermore, because Lancet 2000; 355: 1707–12 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (J Spivak MD) (e-mail: [email protected])
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there is no correlation between the severity of an anaemia and its cause, that cause must be diligently sought. A careful medical history including previous blood counts, assessment of exposure to alcohol, drugs and toxins, and travel history, as well as physical findings such as jaundice, telangiectasia, purpurpa, lymphadenopathy, splenomegaly, and sternal tenderness can focus the diagnostic approach. Careful scrutiny of a blood smear is essential; a normal smear is as helpful as one showing distinctive morphological abnormalities of the red cells, white cells, or platelets. A reticulocyte count is important for distinguishing decreased red-cell production from increased destruction unless both conditions are present. Bone-marrow aspiration may be necessary to distinguish an intrinsic marrow disorder from the non-specific marrow suppression caused by a systemic illness. A bonemarrow biopsy must be done with pancytopenia or when marrow cannot be aspirated. Since anaemia is the most common haematological abnormality associated with systemic diseases, it is the focus of this review, with consideration of leucocyte, platelet, and coagulation abnormalities when they are distinctive.
The anaemia of chronic disease Owing to the high turnover rate of erythroid progenitor cells and the unique hormonal regulation required for their proliferation and survival, impairment of erythropoiesis is the commonest adverse effect of systemic disorders on haemopoiesis. The resultant hypoproliferative anaemia, designated the anaemia of chronic disease, was originally defined as an anaemia occurring in diverse conditions such as infection, inflammation, and neoplasia, with the unifying features of a low serum iron and iron-binding capacity, decreased transferrin saturation, and adequate storage iron, in the absence of bleeding, haemolysis, renal disease, or exposure to drugs or toxins.3 Another characteristic is a slightly shorter than normal red-cell life-span. This definition is now recognised to be incomplete because anaemia associated with the same abnormalities of iron distribution can occur in disorders without overt inflammation, infection, or neoplasia,4 and because when this form of anaemia was first recognised the hormonal regulation of erythropoiesis was not fully understood. We now know that the distinctive iron abnormalities of the anaemia of chronic disease are not central to its pathogenesis.
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HAEMATOLOGY
Hormonal regulation of erythropoiesis in health and disease
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500 400 300 Serum erythropoietin (U/L)
Erythropoietin Under normal circumstances, erythropoiesis is regulated by erythropoietin. The main role of this hormone is to couple blood oxygen-carrying capacity with long-term tissue oxygen requirements. Hypoxia is the only physiological stimulus for erythropoietin production, and there is normally an inverse linear correlation between the concentrations of erythropoietin and haemoglobin (figure 1). Produced primarily in the kidneys in adults and only to a small extent in the liver, erythropoietin interacts with committed erythroid progenitor cells in the bone marrow to promote their proliferation and maintain their viability as they differentiate.5,6 Because erythropoietin is a survival factor for erythroid progenitor cells, its production is constitutive and it is always present in the plasma.7 Steady-state maintenance of plasma erythropoietin involves not only constitutive production of the hormone, but also marrow-cell uptake—arrest of erythropoiesis results in an increase in plasma erythropoietin beyond what might be expected for the resulting degree of anaemia.8 Normally, in a given individual the plasma erythropoietin concentration is constant, just as the redcell mass is constant, although the absolute values of both vary among individuals. However, within the normal range of haemoglobin, erythropoietin is not the only growth factor that regulates erythropoiesis. Men have a larger red-cell mass than women, but the sexes do not differ in terms of their plasma erythropoietin concentration. The difference in red-cell mass is due to androgen production; androgen deprivation equalises the haemoglobin concentrations of men and women without a change in plasma erythropoietin.7 Erythropoietin production is tightly regulated, presumably to prevent inappropriate increases in the redcell mass. Thus, an increase in red-cell mass or plasma viscosity suppresses erythropoietin production independently of tissue hypoxia.9 Furthermore, although small increments in plasma erythropoietin occur with slight decreases in haemoglobin, until the haemoglobin concentration falls below 10·5 g/dL (105 g/L) the erythropoietin concentration does not rise outside the normal range. When there is significant anaemia, an erythropoietin measurement provides a useful gauge of erythropoietin production because there is only one form of circulating hormone, there are no preformed stores, production is controlled at the gene level, and both production and plasma clearance are independent of the plasma concentration.7 Most importantly, the plasma or serum erythropoietin concentration cannot be thought of as simply a surrogate measure of tissue oxygenation because various conditions (eg, renal parenchymal disease, hyperviscosity, cancer, infection, inflammation, chronic liver disease, surgery, pregnancy, and prematurity) suppress erythropoietin production without regard to tissue oxygenation. The mechanism for the blunted erythropoietin response to anaemia with systemic disorders is thought to be through inhibition of erythropoietin gene transcription by inflammatory cytokines such as interleukin 1 and tumour necrosis factor (TNF).10 Such suppression, of course, is never absolute and cannot be appreciated without comparison with the expected physiological response for the degree of anaemia (figure 1). As a general
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Figure 1: Relation between plasma erythropoietin and haemoglobin concentrations A=uncomplicated iron-deficiency anaemia; outer curves are 95% CI. B=effect of a slight increase in serum creatinine on the plasma erythropoietin-haemoglobin relation; bar on erythropoietin axis shows the normal range.
rule, an inappropriately low erythropoietin concentration in an anaemic patient suggests an inadequate response of the kidneys to tissue hypoxia but is not predictive of marrow responsiveness to the hormone. As a corollary, since erythroid progenitor cells normally metabolise erythropoietin, an inappropriately high plasma erythropoietin concentration in the absence of acute hepatocellular damage or certain drugs (eg, zidovudine) suggests a marrow failure state. Erythroid progenitor cells Suppression of erythropoietin production, low blood iron concentration, low transferrin saturation, and a slight decrease in red-cell life-span alone or together are not sufficient to cause anaemia if bone-marrow function is normal. However, extensive studies in vitro and in vivo suggest that proliferation of erythroid progenitor cells is impaired in the anaemia of chronic disease as a consequence of the same inflammatory cytokines as suppress erythropoietin production.11 This observation accords with the demonstration that plasma concentrations of TNF and interleukin 1, both of which inhibit erythropoiesis in vitro and in vivo, are high when there is inflammation, infection, or neoplasia. Interleukin 1 seems to exert its effects indirectly through TNF and interferon-gamma, whereas the effect of TNF may be mediated partly by interferon-beta.11 Since these inflammatory cytokines can induce hypoferraemia, the anaemia of chronic disease seems to be a non-specific
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HAEMATOLOGY
MCV (fL)
Haemoglobin (g/dL)
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Platelet count (109/L)
important factor in the causation of the anaemia of chronic renal disease, and a significant role for 120 700 120 uraemic toxins is unlikely. This contention is Platelets supported by the temporary amelioration of 110 110 600 Haemoglobin anaemia in an anephric man with acute viral 10 100 500 hepatitis,17 and the high response rate of the anaemia of chronic renal disease to the 9 90 400 administration of recombinant erythropoietin.18 8 80 300 There are, of course, other causes of anaemia in 7 70 200 uraemic patients. Platelets are dysfunctional in MCV this setting, predisposing to bleeding; red-cell 6 60 100 life-span is shortened for unknown reasons; 0 5 50 haemodialysis can introduce red-cell toxins such 1 2 3 4 5 as copper, formaldehyde, chlorine, nitrates, and Time (months) chloramines while removing folic acid; both dialysis and phosphate binders can introduce excessive aluminum; iron depletion through Figure 2: Haemoglobin, mean corpuscular volume (MCV), and platelet count dialyser blood loss and diagnostic phlebotomy before and after administration of prednisone to a 74-year-old woman with can reach 2 g per year; and parathyroidpolymyalgia rheumatica hormone-induced osteitis fibrosa can cause Furthermore, the anaemia and leucopenia.16 consequence of activation of the inflammatory cytokine concentrations of the inflammatory cytokines, TNF and network with simultaneous suppression of both interleukin 1, are increased in haemodialysis patients. erythropoietin production and the ability of erythroid Finally, renal insufficiency can mask the red-cell progenitor cells to proliferate in response to the hormone. morphological abnormalities associated with vitamin B12 The idea that the distinctive abnormalities of iron or folic acid deficiency.19 distribution are not the primary cause of anaemia is supported by the observations that iron therapy did not Acute renal failure correct anaemia in patients with rheumatoid arthritis Anaemia in the setting of acute renal failure is also whereas administration of recombinant erythropoietin did associated with impaired erythopoietin production,20 but correct the anaemia, even though low blood iron and low this anaemia is primarily the consequence of the drug or transferrin saturation persisted.12 Similar observations disorder causing the renal failure. Haemolysis is the most have been made in anaemic patients with inflammatory common mechanism. The underlying causes include bowel disease, cancer, or AIDS.13–15 Thus, suppression of acute and delayed haemolytic transfusion reactions, erythropoietin production and lowered responsiveness oxidant haemolysis due to deficiency of glucose-6of the hormone’s target cells seem to be central to phosphate dehydrogenase, clostridial sepsis, haemolyticthe pathogenesis of the anaemia associated with a uraemic syndrome, thrombotic thrombocytopenic systemic illness. Furthermore, although pharmacological purpura, disseminated intravascular coagulation due to concentrations of erythropoietin can correct anaemia in sepsis or pregnancy, malaria, eclampsia, malignant this situation, the effect is not absolute nor does it address hypertension, systemic vasculitis, Goodpasture’s the underlying cause. The concept that the anaemia syndrome, and certain drugs (mitomycin, cyclosporin, associated with a chronic disease is mild and normocytic and cisplatin). Red-cell fragmentation, readily identified must also be abandoned, since this anaemia can be severe on a peripheral-blood smear, is a prominent feature of and microcytic (figure 2). many of these disorders and an important clue to the mechanism of the anaemia. Unless renal parenchymal Systemic disorders affecting the blood damage is severe, correction of the causative disorder Chronic renal failure results in restoration of the red-cell mass. Since the kidneys are the main site of erythropoietin production in adults, intrinsic renal disease is inevitably Endocrine disease associated with impairment of erythropoietin production. Erythropoietin is the only hormone obligatory for An increase in serum creatinine above 133 mol/L is erythropoiesis but this process is normally influenced associated with loss of the normal inverse linear relation directly or indirectly by many other hormones. In general, between plasma erythropoietin and haemoglobin the haematological abnormalities associated with concentration. In this setting, the degree of hypoxia endocrine-gland insufficiency reflect the function of the required to induce erythropoietin production is greatly involved gland. In most cases, the development of the increased. There is no direct correlation between the endocrine abnormality is so insidious and the anaemia so severity of impairment of renal excretory function and the bland that in this situation the best haematologist is a impairment of renal erythropoietin production. Diabetes good internal medicine specialist. mellitus is one disorder in which the degree of anaemia Pituitary—The anaemia associated with anterior can be out of proportion to the apparent reduction in pituitary failure is normocytic and normochromic, mild in renal excretory function. With some forms of renal degree, and puzzling unless the relation between tissue oxygen consumption and red-cell production is disease, such as focal sclerosing glomerulonephritis and considered. With Sheehan’s syndrome, the onset of the renal tumours, or after renal transplantation, endocrine failure may be remote from the causal event, erythropoietin production may be inappropriately and pancytopenia or a coagulation abnormality may be increased and can occasionally cause erythrocytosis.16 the presenting feature.21 Impaired erythropoietin production is the single most
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HAEMATOLOGY
Gonads—Androgen insufficiency results in a 1–2 g/dL (10–20 g/L) decrease in the haemoglobin concentration and macrocytosis, but the other symptoms of gonadal insufficiency are more obvious. As a corollary, androgen excess, commonly the result of self-medication, causes erythrocytosis. Abnormalities of the oestrogenprogesterone axis are not associated with anaemia, although oral contraceptives can interfere with metabolism of folic acid and have rarely been implicated in acquired sideroblastic anaemia. Adrenal—The anaemia associated with chronic adrenal insufficiency is partly masked by a concomitant reduction in plasma volume. Lymphocytosis, neutropenia, and eosinophilia are important clues to the cause of the anaemia in this setting. Chronic adrenal insufficiency may also be complicated by pernicious anaemia. Parathyroid—Although uncommon in primary hyperparathyroidism, anaemia in this disorder has the classic characteristics of the anaemia of chronic disease but is usually the consequence of the myelosclerosis associated with advanced disease. Blood abnormalities in the setting of hypoparathyroidism may be due to pernicious anaemia or even red-cell aplasia, usually in the setting of a type I polyendocrinopathy syndrome. Thyroid—Haematological abnormalities are associated with both hypothyroidism and hyperthyroidism but in a reciprocal relation.22,23 With hypothyroidism, anaemia may be masked by a decrease in plasma volume, and a relative macrocytosis is common even in the absence of anaemia or deficiency of folic acid or vitamin B12. With thyroid replacement, the mean corpuscular volume (MCV) falls. If microcytosis occurs, it is usually in the setting of menorrhagia, which in some cases is associated with acquired type 1 von Willebrand’s disease.24 Acanthocytosis, although not severe in most cases, is another haematological feature of hypothyroidism. In hyperthyroidism, microcytosis is common even in the absence of anaemia, and an increase in the plasma volume can mask a slight increase in red-cell mass. In some patients, hypothyroid or hyperthyroid, iron distribution abnormalities typical of the anaemia of chronic disease have been documented. Hypothyroidism commonly occurs in the setting of pernicious anaemia whereas hyperthyroidism typically predates this type of anaemia.25 Leucopenia and immune thrombocytopenia can occur with hyperthyroidism, as can generalised lymphadenopathy and lymphocytosis. Hyperthyroid patients are also at risk of agranulocytosis with propylthiouracil or thiamazole therapy Gastrointestinal disease The alimentary tract is the point of entry for both the nutrients essential for haemopoiesis and the substances that suppress it. Compromise of intestinal integrity by disease, drugs, or surgery can result in malabsorption of minerals such as iron and copper and vitamins such as folic acid and vitamin B12. Occult bleeding with resultant iron deficiency is commonly the earliest sign of a gastrointestinal cancer, and macrocytosis is the earliest sign of deficiency of folic acid or vitamin B12. Simple inanition, whether involuntary or voluntary as with anorexia nervosa, causes serous fat atrophy of the marrow, anaemia, leucopenia, and occasionally pancytopenia. Protein deprivation decreases erythropoietin production, and caloric deprivation from any cause is associated with red-cell acanthocytosis.
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Intoxication with heavy metals such as copper, lead, or arsenic, which might occur with iron-deficiency-induced geophagia, can cause haemolysis, marrow suppression, and neutropenia; coarse red-cell stippling is a clue to heavy-metal poisoning. Zinc ingested in excess can cause sideroblastic anaemia. Iron deficiency due to occult bleeding is common in inflammatory bowel disease, which can also cause anaemia through malabsorption of vitamin B12 when the terminal ileum is involved, or suppression of erythropoiesis through stimulation of inflammatory cytokine production.13 As in other situations with significant inflammation, thrombocytosis can occur. Substantial absorption of the “nonabsorbable” sulphonamides used in the treatment of inflammatory bowel disease causes oxidant haemolysis with the characteristic blistered red cells in slow acetylators or when there is dehydration and hypoalbuminaemia.26 Malabsorption syndromes may first be manifest by bleeding due to deficiency of vitamin K; protein-losing enteropathies cause lymphopenia and bowel disorders such as coeliac disease and ulcerative colitis cause immune-complex formation and hyposplenism. Liver disease Blood abnormalities are a common complication of liver disease. The underlying cause depends on the nature of the hepatic dysfunction. Haemoglobin oxygen affinity is decreased in patients with cirrhosis but, independently of this abnormality, erythropoietin production and erythropoiesis are depressed with a resultant increase in marrow iron stores characteristic of the anaemia of chronic disease.27,28 With cirrhosis and portal hypertension, iron deficiency is caused by blood loss from oesophageal varices, peptic ulceration, or gastritis, potentiated in some cases by impaired synthesis of coagulation factors or thrombocytopenia. The synthesis of fibrinogen and factors II, V, VII, IX, and X is impaired by hepatocellular failure. Alcohol abuse lowers nutritional intake and disrupts the enterohepatic cycling of folic acid, leading to megaloblastic and eventually sideroblastic anaemia.29 Erythroblast vacuolation and high blood iron are other consequences of acute alcohol poisoning. Alcohol-induced chronic pancreatitis can lead to malasorption of vitamin B12, and portal hypertension expands the plasma volume and causes splenomegaly with sequestration of red cells, white cells, and platelets. Ethanol and its metabolite acetaldehyde directly suppress production of platelets as well as red cells, resulting in the characteristic rebound thrombocytosis after ethanol withdrawal. Granulocyte progenitor cells are resistant to the toxic effects of ethanol, and depression of leucocyte production is uncommon with alcohol abuse in the absence of splenomegaly or another cause. Ethanol can, however, impair granulocyte function. Alcohol abuse alone in the absence of folic acid deficiency also causes macrocytosis, and the increase in plasma free cholesterol in obstructive jaundice produces macrocytes and target cells. Severe hepatocellular damage is associated with acanthocytosis, and a leucoerythroblastic reaction in rare cases. Viral hepatitis is associated with an increase in atypical lymphocytes, haemolysis in patients with deficiency of red-cell glucose-6-phosphate dehydrogenase, and pure red-cell aplasia or aplastic anaemia in occasional cases. Wilson’s disease causes haemolytic anaemia.
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HAEMATOLOGY
Rheumatological disease Inflammation is a prototypical cause of the anaemia of chronic disease; the anaemia can be severe and microcytic with prominent thrombocytosis (figure 2). Anaemia may be an important clue to an underlying disorder such as polymyalgia rheumatica, which if unrecognised can progress to sudden blindness. At the same time, certain types of anaemia in the setting of a rheumatological disorder, such as salicylate-induced deficiency of folic acid or concomitant pernicious anaemia, can be easily remedied but the overt signs of megaloblastic erythropoiesis can be masked by concomitant iron deficiency or inflammation.19 Autoimmune haemolytic anaemia, neutropenia, thrombocytopenia, or red-cell aplasia can develop and overshadow the underlying rheumatological disorder, particularly when it is systemic lupus erythematosus. With lupus, anaemia is the most common complication, followed by leucopenia (more commonly due to lymphopenia than neutropenia) and thrombocytopenia.30 The anaemia can be due to marrow suppression by inflammatory mediators or renal disease, vasculitis, thrombotic thrombocytopenia purpura, or warm-antibody-mediated haemolysis (IgG and/or complement); autoantibodies also bring about the neutropenia and thrombocytopenia in this disorder. Neutropenia in rheumatoid arthritis is generally associated with splenomegaly and occasionally leg ulcers (Felty’s syndrome); the mechanism can involve autoantibodies, immune complexes, or proliferation of large granular lymphocytes. The antiphospholipid syndrome is an autoimmune disorder in which both thrombocytopenia and thrombosis may be prominent in the presence or absence of a rheumatological disorder.31 Immune-complex disease can produce hyposplenism, and haematophagic histiocytosis and myelofibrosis can complicate systemic lupus erythematosus. Immunosuppressive therapy with methotrexate or azathioprine can lead to myelodysplasia. Infection Infectious processes can adversely affect haemopoiesis by many mechanisms in addition to non-specific suppression of erythropoietin production and erythropoiesis through the production of inflammatory cytokines.32 For erythropoiesis, these mechanisms include iron deficiency due to hookworm infestation, deficiency of vitamin B12 due to the presence of a fish tapeworm, haemolysis, nonimmune (malaria, bartonellosis, clostridial infection, babesiosis, or deficency of glucose-6-phosphate dehydrogenase) or immune (malaria, syphilis, EpsteinBarr virus, mycoplasma, and certain antibiotics), and direct infection of erythroid progenitor cells (parvovirus B19) Mild anaemia can be the consequence of a significant underlying disorder such as bacterial endocarditis. Furthermore, the status of the host profoundly influences the clinical manifestations of the particular infection. Thus, patients with chronic haemolytic anaemia are particularly susceptible to red-cell aplasia induced by parvoviris B19, salmonella sepsis, or deep-seated fungal infections when being treated with corticosteroids. In asplenic patients, infection with encapsulated organisms can lead to overwhelming sepsis, intravascular coagulation, and death; these patients are also susceptible to babesiosis. Infections can trigger oxidant haemolysis of red cells deficient in glucose-6-
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phosphate dehydrogenase; such red cells are also at risk of haemolysis from drugs such as sulphamethoxazole, nitrofurantoin, and primaquine. Immune haemolysis of normal red cells has been caused by penicillin, cephalothin, stibophen, quinine, and sulphonamides, and by syphilis (paroxymal cold haemoglobinuria) and Epstein-Barr virus and mycoplasma (cold agglutinin disease) infections. Other side-effects of antibiotic therapy include marrow suppression or aplasia (chloramphenicol, sulphonamides), neutropenia (sulphonamides, penicillin derivatives), thrombocytopenia or impairment of platelet function (penicillin derivatives), and coagulation abnormalities (moxalactam, cefamandole). Infection with Epstein-Barr or hepatitis virus can cause aplastic anaemia, and Epstein-Barr virus and cytomegalovirus can cause an infectious mononucleosis syndrome. Lymphocytosis can also be caused by pertussis or toxoplasma infection, and eosinophilia is seen with tissue invasion by parasites such as ascaris, strongyloides, schistosomes, trichina, and toxocara. Thrombocytopenia may the consequence of infection-induced disseminated intravascular coagulation, sepsis, or the antibiotics used to treat the infection. Rarely, infection causes pancytopenia due to marrow necrosis. Anaemia in malaria has multiple causes.33 The impact of the disease on erythropoiesis depends on the host’s immune and general health status and on the virulence and target cells of the parasite involved; Plasmodium vivax invades reticulocytes only whereas P falciparum invades red cells of all ages, producing a greater degree of parasitaemia. In addition to mechanical lysis of parasitised red cells, there is immune haemolysis of parasitised and non-parasitised red cells, suppression of erythropoiesis by inflammatory cytokines such as TNF, and plasma volume expansion. Black-water fever seems to be consequence of quinine toxicity. Thrombocytopenia is also common with acute malaria but leucopenia is not. Perhaps no other infectious agent has a more global impact on haemopoiesis than HIV-1.34 An acute and easily overlooked viral syndrome with atypical lymphocytes is the first manifestation of HIV-1 infection in many cases. Leucopenia (both lymphopenia and neutropenia, usually with an increase in band forms) or thrombocytopenia with or without generalised lymphadenopathy, are also common presenting manifestations. Anaemia is a frequent complication of HIV-1 infection, and its severity increases with disease progression. Indeed, anaemia is a negative prognostic indicator in HIV-1-infected patients,35 and an isolated severe anaemia is an important manifestation of disseminated Mycobacterium avium intracellulare (MAI) infection. Erythropoietin production is also suppressed in HIV-1 infection but is restored with zidovudine therapy, although the anaemia does not generally improve.36 The severe immunodeficiency state induced by HIV-1 allows microorganisms to proliferate. Bone-marrow aspiration or biopsy is an efficient way to diagnose infections caused by histoplasma, candida, cryptococcus, pneumocystis, toxoplasma, MAI, and leishmania or an infection-associated haematophagic syndrome. Red-cell aplasia due to parvovirus B19, Kaposi’s sarcoma, and lymphoma, as well as bone-marrow necrosis, myelofibrosis, and serous fat atrophy can also be recognised in this way. Some drugs used in treatment of HIV-1 and its infectious complications (eg, zidovudine, ganciclovir, and trimethoprim-sulphamethoxazole) are
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HAEMATOLOGY
myelotoxic; zidovudine causes severe anaemia and leucopenia and the other two drugs cause severe neutropenia. Cancer The causes of anaemia with non-haematological malignant disorders are multiple and diverse, ranging from simple haemodilution to haematophagic histiocytosis. The most common cause of anaemia is suppression of erythropoietin production and erythropoiesis; in many cases these abnormalities are reversible with recombinant erythropoietin therapy.14 Other remediable or non-remediable causes of anaemia must be excluded before the institution of such therapy. Although recombinant erythropoietin therapy is effective even with concomitant chemotherapy or if the marrow is affected by tumour, identification of the tumours for which chemotherapy alone will alleviate the associated anaemia is important. As a corollary, failure of the anaemia of cancer to respond to recombinant erythropoietin is in itself a poor prognostic sign.37 A microangiopathic haemolytic anaemia is also a poor prognostic sign, because it suggests pulmonary metastases. Immune haemolytic anaemia, thrombocytopenia, and red-cell aplasia can occur with non-haematological malignant disorders and with lymphomas or Hodgkin’s disease. A leucoerythroblastic reaction due to extramedullary haemopoiesis is a clue to the presence of marrow tumour metastases or myelofibrosis. Marrow necrosis is common in acute leukaemia. Thrombocytosis, generally mild, is another haematological manifestation of malignant disease. Leucocytosis without evidence of infection occurs in association with certain tumours. Erythrocytosis can be caused by renal, hepatic, adrenal, and cerebellar tumours. Disseminated intravascular coagulation with marantic endocarditis (Trousseau’s syndrome) may also be the first sign of an occult cancer but the identity of the tumour can be difficult to establish in this situation.38 Some anticancer drugs such as mitomycin and cyclosporin can cause a haemolytic-uraemic syndrome. Others such as cisplatin, melphalan, and methotrexate can cause haemolysis or renal damage. Doxorubicin causes oxidant haemolysis of glucose-6-phosphate-dehydrogenase-deficient red cells.39
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Singh A, Eckardt KE, Zimmermann AG. Increased plasma viscosity as a reason for inappropriate erythropoietin formation. J Clin Invest 1993; 91: 251–56. Jelkman W, Pagel H, Wolff M, et al. Monokines inhibiting erythropoietin production in human hepatoma cultures and in isolated perfused rat kidneys. Life Sci 1991; 50: 301–08. Means RT, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood 1992; 80: 1639–47. Pincus T, Olsen N, Russel IJ. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990; 89: 161–68. Schreiber S, Howaldt S, Schnoor M. Recombinant erythropoietin for the treatment of anemia in inflammatory bowel disease. N Engl J Med 1996; 334: 619–23. Oster W, Herrman F, Gamm H. Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 1990; 8: 956–62. Fischl M, Galpin JE, Levine JD, et al. Recombinant human erythropoietin for patients with AIDS treated with zidovudine. N Engl J Med 1990; 322: 1488–93. Spivak JL, Watson AF. Hematopoiesis and the kidney. In: Seldin D, Glebisch G, eds. The kidney, 2nd edn. New York: Raven Press, 1991: 1553–93. Klassen DK, Spivak JL. Hepatitis-related hepatic erythropoietin production. Am J Med 1990; 89: 684–86. Eschbach JW, Abdulhadi MD, Browne JK. Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase III multicenter clinical trial. Ann Intern Med 1989; 111: 992–1000. Spivak JL. Masked megaloblastic anemia. Arch Intern Med 1982; 142: 2111–14. Lipkin GW, Kendall RG, Russon LH. Erythropoietin deficiency in acute renal failure. Nephrol Dial Transplant 1990; 5: 920–22. Brown CH, Kvols LK, Hsu TH. Factor IX deficiency and bleeding in a patient with Sheehan’s syndrome. Blood 1972; 39: 650–57. Horton L, Coburn RJ, England JM. The haematology of hypothyroidism. QJM 1975; 177: 101–24. Nightingale S, Vitek PJ, Himsworth RL. The haematology of hyperthyroidism. QJM 1978; 185: 35–47. Dalton RG, Savidge GF, Matthews KB. Hypothyroidism as a cause of aquired von Willebrand’s disease Lancet 1987; i: 1007–09. Carmel R, Spencer CA. Clinical and subclinical thyroid disorders associated with pernicious anemia. Arch Intern Med 1982; 142: 1465–69. Pounder RE, Craven ER, Henthorn JS. Red cell abnormalities associated with sulphasalazine maintenance therapy for ulcerative colitis. Gut 1975; 16: 181–86. Siciliano M, Tomasello D, Milanti A. Reduced serum levels of immunoractive erythropoietin in patients with cirrhosis and chronic anemia. Hepatology 1995; 22: 1132–35. Savage D, Lindenbaum J. Anemia in alcoholics. Medicine 1986; 65: 322–38. Eichner ER. The hematologic disorders of alcoholism. Am J Med 1973; 54: 621–30. Budman DR, Steinberg AD. Hematologic aspects of systemic lupus erythematosus. Ann Intern Med 1977; 86: 220–29. Asherson RA, Khamashta M, Ordi-Ros J, et al. The primary antiphospholipid syndrome: major clinical and serological features. Medicine 1989; 68: 366–74. Barrett-Connor E. Anemia and infection. Am J Med 1972; 52: 242–53. Perrin LH, Mackey LJ, Miescher PA. The hematology of malaria in man. Semin Hematol 1982; 19: 70–82. Spivak JL. Bender BS, Quinn TC. Hematologic abnormalities in the acquired immunodeficiency syndrome. Am J Med 1984; 77: 224–28. Moore RD, Keruly JC, Chaisson RE. Anemia and survival in HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 29–33. Spivak JL, Barnes DC, Fuchs E, et al. Serum immunoreactive erythropoietin in HIV-infected patients. JAMA 1989; 261: 3104–07. Ludwig,H, Fritz E, Leitgeb C, et al. Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 1994; 84: 1056–63. Sack GH, Levin J, Bell WR. Trousseau’s syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, pathophysiologic, and therapeutic features. Medicine 1977; 56: 1–37. Doll D, Weiss RB. Chemotherapeutic agents and the erythron. Cancer Treat Rev 1983; 10: 185–200.
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Haematology
The blood in systemic disorders Jerry L Spivak The high rate of proliferation required of the bone marrow renders it highly susceptible to the influence of external factors. ● Anaemia is the most common haematological abnormality seen in systemic disorders. ● In the anaemia of chronic disease, erythropoietin production is reduced and proliferation of erythroid progenitor cells is also impaired; this anaemia can generally be alleviated by correction of the underlying disease process. ● The status of the endocrine system must always be considered in evaluation of a normocytic, normochromic anaemia. ● Anaemia in infection can be due to host or parasite factors or to the treatment administered. ● Anaemia due to malignant disease responds to erythropoietin therapy in many cases; failure to respond is a poor prognostic sign. ●
When confronted with a disturbance of haemopoiesis, the physician must find out whether it is due to a disorder primarily involving the haemopoietic system or is secondary to an underlying systemic disease or treatment. This distinction is critical for decisions on appropriate management. When the haematological abnormality is secondary, correction of the underlying disorder or withdrawal of the offending treatment suffices in most cases to alleviate the blood abnormality. A systematic approach to the diagnosis will always be rewarded; blind haematinic therapy will not. Haemopoiesis is the orderly continuous process by which primitive progenitor cells give rise to the mature circulating blood cells. To ensure an adequate quantity of cells for oxygen transport, host defence, and haemostasis, the bone marrow must produce 1011 red cells, 1011 white cells, and 1011 platelets every day to replace those lost through senescence or use. Given this high rate of proliferation, the bone marrow is susceptible to agents or diseases that interfere with the supply of haemopoietic growth factors, disturb the anatomical integrity of the tissue, or provoke the production of antiproliferative, proinflammatory cytokines. Disorders of the blood may first become manifest by dysfunction of a particular organ because the blood has an essential role in the body’s economy and the circulation is ubiquitous. More commonly, however, systemic disorders or diseases involving a particular organ or tissue first become manifest by an abnormality of the blood. The mechanisms involved include suppression or stimulation of bone-marrow function, increased destruction or sequestration of blood cells, haemodilution, and bleeding. Since the causes are many and often correctable, whereas the blood abnormalities are generally not amenable to blind haematinic therapy, the diagnostic approach must be thorough. The presence of a systemic disease, of course, does not exclude another cause for a blood abnormality. For example, rheumatological disorders and myelodysplasia are well known to coexist,1 as are mediastinal germ-cell tumours and haematological malignant disease.2 Furthermore, because Lancet 2000; 355: 1707–12 Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA (J Spivak MD) (e-mail: [email protected])
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there is no correlation between the severity of an anaemia and its cause, that cause must be diligently sought. A careful medical history including previous blood counts, assessment of exposure to alcohol, drugs and toxins, and travel history, as well as physical findings such as jaundice, telangiectasia, purpurpa, lymphadenopathy, splenomegaly, and sternal tenderness can focus the diagnostic approach. Careful scrutiny of a blood smear is essential; a normal smear is as helpful as one showing distinctive morphological abnormalities of the red cells, white cells, or platelets. A reticulocyte count is important for distinguishing decreased red-cell production from increased destruction unless both conditions are present. Bone-marrow aspiration may be necessary to distinguish an intrinsic marrow disorder from the non-specific marrow suppression caused by a systemic illness. A bonemarrow biopsy must be done with pancytopenia or when marrow cannot be aspirated. Since anaemia is the most common haematological abnormality associated with systemic diseases, it is the focus of this review, with consideration of leucocyte, platelet, and coagulation abnormalities when they are distinctive.
The anaemia of chronic disease Owing to the high turnover rate of erythroid progenitor cells and the unique hormonal regulation required for their proliferation and survival, impairment of erythropoiesis is the commonest adverse effect of systemic disorders on haemopoiesis. The resultant hypoproliferative anaemia, designated the anaemia of chronic disease, was originally defined as an anaemia occurring in diverse conditions such as infection, inflammation, and neoplasia, with the unifying features of a low serum iron and iron-binding capacity, decreased transferrin saturation, and adequate storage iron, in the absence of bleeding, haemolysis, renal disease, or exposure to drugs or toxins.3 Another characteristic is a slightly shorter than normal red-cell life-span. This definition is now recognised to be incomplete because anaemia associated with the same abnormalities of iron distribution can occur in disorders without overt inflammation, infection, or neoplasia,4 and because when this form of anaemia was first recognised the hormonal regulation of erythropoiesis was not fully understood. We now know that the distinctive iron abnormalities of the anaemia of chronic disease are not central to its pathogenesis.
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HAEMATOLOGY
Hormonal regulation of erythropoiesis in health and disease
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500 400 300 Serum erythropoietin (U/L)
Erythropoietin Under normal circumstances, erythropoiesis is regulated by erythropoietin. The main role of this hormone is to couple blood oxygen-carrying capacity with long-term tissue oxygen requirements. Hypoxia is the only physiological stimulus for erythropoietin production, and there is normally an inverse linear correlation between the concentrations of erythropoietin and haemoglobin (figure 1). Produced primarily in the kidneys in adults and only to a small extent in the liver, erythropoietin interacts with committed erythroid progenitor cells in the bone marrow to promote their proliferation and maintain their viability as they differentiate.5,6 Because erythropoietin is a survival factor for erythroid progenitor cells, its production is constitutive and it is always present in the plasma.7 Steady-state maintenance of plasma erythropoietin involves not only constitutive production of the hormone, but also marrow-cell uptake—arrest of erythropoiesis results in an increase in plasma erythropoietin beyond what might be expected for the resulting degree of anaemia.8 Normally, in a given individual the plasma erythropoietin concentration is constant, just as the redcell mass is constant, although the absolute values of both vary among individuals. However, within the normal range of haemoglobin, erythropoietin is not the only growth factor that regulates erythropoiesis. Men have a larger red-cell mass than women, but the sexes do not differ in terms of their plasma erythropoietin concentration. The difference in red-cell mass is due to androgen production; androgen deprivation equalises the haemoglobin concentrations of men and women without a change in plasma erythropoietin.7 Erythropoietin production is tightly regulated, presumably to prevent inappropriate increases in the redcell mass. Thus, an increase in red-cell mass or plasma viscosity suppresses erythropoietin production independently of tissue hypoxia.9 Furthermore, although small increments in plasma erythropoietin occur with slight decreases in haemoglobin, until the haemoglobin concentration falls below 10·5 g/dL (105 g/L) the erythropoietin concentration does not rise outside the normal range. When there is significant anaemia, an erythropoietin measurement provides a useful gauge of erythropoietin production because there is only one form of circulating hormone, there are no preformed stores, production is controlled at the gene level, and both production and plasma clearance are independent of the plasma concentration.7 Most importantly, the plasma or serum erythropoietin concentration cannot be thought of as simply a surrogate measure of tissue oxygenation because various conditions (eg, renal parenchymal disease, hyperviscosity, cancer, infection, inflammation, chronic liver disease, surgery, pregnancy, and prematurity) suppress erythropoietin production without regard to tissue oxygenation. The mechanism for the blunted erythropoietin response to anaemia with systemic disorders is thought to be through inhibition of erythropoietin gene transcription by inflammatory cytokines such as interleukin 1 and tumour necrosis factor (TNF).10 Such suppression, of course, is never absolute and cannot be appreciated without comparison with the expected physiological response for the degree of anaemia (figure 1). As a general
A
200 100 0 5
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9
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r=0·32
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9 10 11 12 13 14 15 Haemoglobin (g/dL)
Figure 1: Relation between plasma erythropoietin and haemoglobin concentrations A=uncomplicated iron-deficiency anaemia; outer curves are 95% CI. B=effect of a slight increase in serum creatinine on the plasma erythropoietin-haemoglobin relation; bar on erythropoietin axis shows the normal range.
rule, an inappropriately low erythropoietin concentration in an anaemic patient suggests an inadequate response of the kidneys to tissue hypoxia but is not predictive of marrow responsiveness to the hormone. As a corollary, since erythroid progenitor cells normally metabolise erythropoietin, an inappropriately high plasma erythropoietin concentration in the absence of acute hepatocellular damage or certain drugs (eg, zidovudine) suggests a marrow failure state. Erythroid progenitor cells Suppression of erythropoietin production, low blood iron concentration, low transferrin saturation, and a slight decrease in red-cell life-span alone or together are not sufficient to cause anaemia if bone-marrow function is normal. However, extensive studies in vitro and in vivo suggest that proliferation of erythroid progenitor cells is impaired in the anaemia of chronic disease as a consequence of the same inflammatory cytokines as suppress erythropoietin production.11 This observation accords with the demonstration that plasma concentrations of TNF and interleukin 1, both of which inhibit erythropoiesis in vitro and in vivo, are high when there is inflammation, infection, or neoplasia. Interleukin 1 seems to exert its effects indirectly through TNF and interferon-gamma, whereas the effect of TNF may be mediated partly by interferon-beta.11 Since these inflammatory cytokines can induce hypoferraemia, the anaemia of chronic disease seems to be a non-specific
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HAEMATOLOGY
MCV (fL)
Haemoglobin (g/dL)
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Platelet count (109/L)
important factor in the causation of the anaemia of chronic renal disease, and a significant role for 120 700 120 uraemic toxins is unlikely. This contention is Platelets supported by the temporary amelioration of 110 110 600 Haemoglobin anaemia in an anephric man with acute viral 10 100 500 hepatitis,17 and the high response rate of the anaemia of chronic renal disease to the 9 90 400 administration of recombinant erythropoietin.18 8 80 300 There are, of course, other causes of anaemia in 7 70 200 uraemic patients. Platelets are dysfunctional in MCV this setting, predisposing to bleeding; red-cell 6 60 100 life-span is shortened for unknown reasons; 0 5 50 haemodialysis can introduce red-cell toxins such 1 2 3 4 5 as copper, formaldehyde, chlorine, nitrates, and Time (months) chloramines while removing folic acid; both dialysis and phosphate binders can introduce excessive aluminum; iron depletion through Figure 2: Haemoglobin, mean corpuscular volume (MCV), and platelet count dialyser blood loss and diagnostic phlebotomy before and after administration of prednisone to a 74-year-old woman with can reach 2 g per year; and parathyroidpolymyalgia rheumatica hormone-induced osteitis fibrosa can cause Furthermore, the anaemia and leucopenia.16 consequence of activation of the inflammatory cytokine concentrations of the inflammatory cytokines, TNF and network with simultaneous suppression of both interleukin 1, are increased in haemodialysis patients. erythropoietin production and the ability of erythroid Finally, renal insufficiency can mask the red-cell progenitor cells to proliferate in response to the hormone. morphological abnormalities associated with vitamin B12 The idea that the distinctive abnormalities of iron or folic acid deficiency.19 distribution are not the primary cause of anaemia is supported by the observations that iron therapy did not Acute renal failure correct anaemia in patients with rheumatoid arthritis Anaemia in the setting of acute renal failure is also whereas administration of recombinant erythropoietin did associated with impaired erythopoietin production,20 but correct the anaemia, even though low blood iron and low this anaemia is primarily the consequence of the drug or transferrin saturation persisted.12 Similar observations disorder causing the renal failure. Haemolysis is the most have been made in anaemic patients with inflammatory common mechanism. The underlying causes include bowel disease, cancer, or AIDS.13–15 Thus, suppression of acute and delayed haemolytic transfusion reactions, erythropoietin production and lowered responsiveness oxidant haemolysis due to deficiency of glucose-6of the hormone’s target cells seem to be central to phosphate dehydrogenase, clostridial sepsis, haemolyticthe pathogenesis of the anaemia associated with a uraemic syndrome, thrombotic thrombocytopenic systemic illness. Furthermore, although pharmacological purpura, disseminated intravascular coagulation due to concentrations of erythropoietin can correct anaemia in sepsis or pregnancy, malaria, eclampsia, malignant this situation, the effect is not absolute nor does it address hypertension, systemic vasculitis, Goodpasture’s the underlying cause. The concept that the anaemia syndrome, and certain drugs (mitomycin, cyclosporin, associated with a chronic disease is mild and normocytic and cisplatin). Red-cell fragmentation, readily identified must also be abandoned, since this anaemia can be severe on a peripheral-blood smear, is a prominent feature of and microcytic (figure 2). many of these disorders and an important clue to the mechanism of the anaemia. Unless renal parenchymal Systemic disorders affecting the blood damage is severe, correction of the causative disorder Chronic renal failure results in restoration of the red-cell mass. Since the kidneys are the main site of erythropoietin production in adults, intrinsic renal disease is inevitably Endocrine disease associated with impairment of erythropoietin production. Erythropoietin is the only hormone obligatory for An increase in serum creatinine above 133 mol/L is erythropoiesis but this process is normally influenced associated with loss of the normal inverse linear relation directly or indirectly by many other hormones. In general, between plasma erythropoietin and haemoglobin the haematological abnormalities associated with concentration. In this setting, the degree of hypoxia endocrine-gland insufficiency reflect the function of the required to induce erythropoietin production is greatly involved gland. In most cases, the development of the increased. There is no direct correlation between the endocrine abnormality is so insidious and the anaemia so severity of impairment of renal excretory function and the bland that in this situation the best haematologist is a impairment of renal erythropoietin production. Diabetes good internal medicine specialist. mellitus is one disorder in which the degree of anaemia Pituitary—The anaemia associated with anterior can be out of proportion to the apparent reduction in pituitary failure is normocytic and normochromic, mild in renal excretory function. With some forms of renal degree, and puzzling unless the relation between tissue oxygen consumption and red-cell production is disease, such as focal sclerosing glomerulonephritis and considered. With Sheehan’s syndrome, the onset of the renal tumours, or after renal transplantation, endocrine failure may be remote from the causal event, erythropoietin production may be inappropriately and pancytopenia or a coagulation abnormality may be increased and can occasionally cause erythrocytosis.16 the presenting feature.21 Impaired erythropoietin production is the single most
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HAEMATOLOGY
Gonads—Androgen insufficiency results in a 1–2 g/dL (10–20 g/L) decrease in the haemoglobin concentration and macrocytosis, but the other symptoms of gonadal insufficiency are more obvious. As a corollary, androgen excess, commonly the result of self-medication, causes erythrocytosis. Abnormalities of the oestrogenprogesterone axis are not associated with anaemia, although oral contraceptives can interfere with metabolism of folic acid and have rarely been implicated in acquired sideroblastic anaemia. Adrenal—The anaemia associated with chronic adrenal insufficiency is partly masked by a concomitant reduction in plasma volume. Lymphocytosis, neutropenia, and eosinophilia are important clues to the cause of the anaemia in this setting. Chronic adrenal insufficiency may also be complicated by pernicious anaemia. Parathyroid—Although uncommon in primary hyperparathyroidism, anaemia in this disorder has the classic characteristics of the anaemia of chronic disease but is usually the consequence of the myelosclerosis associated with advanced disease. Blood abnormalities in the setting of hypoparathyroidism may be due to pernicious anaemia or even red-cell aplasia, usually in the setting of a type I polyendocrinopathy syndrome. Thyroid—Haematological abnormalities are associated with both hypothyroidism and hyperthyroidism but in a reciprocal relation.22,23 With hypothyroidism, anaemia may be masked by a decrease in plasma volume, and a relative macrocytosis is common even in the absence of anaemia or deficiency of folic acid or vitamin B12. With thyroid replacement, the mean corpuscular volume (MCV) falls. If microcytosis occurs, it is usually in the setting of menorrhagia, which in some cases is associated with acquired type 1 von Willebrand’s disease.24 Acanthocytosis, although not severe in most cases, is another haematological feature of hypothyroidism. In hyperthyroidism, microcytosis is common even in the absence of anaemia, and an increase in the plasma volume can mask a slight increase in red-cell mass. In some patients, hypothyroid or hyperthyroid, iron distribution abnormalities typical of the anaemia of chronic disease have been documented. Hypothyroidism commonly occurs in the setting of pernicious anaemia whereas hyperthyroidism typically predates this type of anaemia.25 Leucopenia and immune thrombocytopenia can occur with hyperthyroidism, as can generalised lymphadenopathy and lymphocytosis. Hyperthyroid patients are also at risk of agranulocytosis with propylthiouracil or thiamazole therapy Gastrointestinal disease The alimentary tract is the point of entry for both the nutrients essential for haemopoiesis and the substances that suppress it. Compromise of intestinal integrity by disease, drugs, or surgery can result in malabsorption of minerals such as iron and copper and vitamins such as folic acid and vitamin B12. Occult bleeding with resultant iron deficiency is commonly the earliest sign of a gastrointestinal cancer, and macrocytosis is the earliest sign of deficiency of folic acid or vitamin B12. Simple inanition, whether involuntary or voluntary as with anorexia nervosa, causes serous fat atrophy of the marrow, anaemia, leucopenia, and occasionally pancytopenia. Protein deprivation decreases erythropoietin production, and caloric deprivation from any cause is associated with red-cell acanthocytosis.
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Intoxication with heavy metals such as copper, lead, or arsenic, which might occur with iron-deficiency-induced geophagia, can cause haemolysis, marrow suppression, and neutropenia; coarse red-cell stippling is a clue to heavy-metal poisoning. Zinc ingested in excess can cause sideroblastic anaemia. Iron deficiency due to occult bleeding is common in inflammatory bowel disease, which can also cause anaemia through malabsorption of vitamin B12 when the terminal ileum is involved, or suppression of erythropoiesis through stimulation of inflammatory cytokine production.13 As in other situations with significant inflammation, thrombocytosis can occur. Substantial absorption of the “nonabsorbable” sulphonamides used in the treatment of inflammatory bowel disease causes oxidant haemolysis with the characteristic blistered red cells in slow acetylators or when there is dehydration and hypoalbuminaemia.26 Malabsorption syndromes may first be manifest by bleeding due to deficiency of vitamin K; protein-losing enteropathies cause lymphopenia and bowel disorders such as coeliac disease and ulcerative colitis cause immune-complex formation and hyposplenism. Liver disease Blood abnormalities are a common complication of liver disease. The underlying cause depends on the nature of the hepatic dysfunction. Haemoglobin oxygen affinity is decreased in patients with cirrhosis but, independently of this abnormality, erythropoietin production and erythropoiesis are depressed with a resultant increase in marrow iron stores characteristic of the anaemia of chronic disease.27,28 With cirrhosis and portal hypertension, iron deficiency is caused by blood loss from oesophageal varices, peptic ulceration, or gastritis, potentiated in some cases by impaired synthesis of coagulation factors or thrombocytopenia. The synthesis of fibrinogen and factors II, V, VII, IX, and X is impaired by hepatocellular failure. Alcohol abuse lowers nutritional intake and disrupts the enterohepatic cycling of folic acid, leading to megaloblastic and eventually sideroblastic anaemia.29 Erythroblast vacuolation and high blood iron are other consequences of acute alcohol poisoning. Alcohol-induced chronic pancreatitis can lead to malasorption of vitamin B12, and portal hypertension expands the plasma volume and causes splenomegaly with sequestration of red cells, white cells, and platelets. Ethanol and its metabolite acetaldehyde directly suppress production of platelets as well as red cells, resulting in the characteristic rebound thrombocytosis after ethanol withdrawal. Granulocyte progenitor cells are resistant to the toxic effects of ethanol, and depression of leucocyte production is uncommon with alcohol abuse in the absence of splenomegaly or another cause. Ethanol can, however, impair granulocyte function. Alcohol abuse alone in the absence of folic acid deficiency also causes macrocytosis, and the increase in plasma free cholesterol in obstructive jaundice produces macrocytes and target cells. Severe hepatocellular damage is associated with acanthocytosis, and a leucoerythroblastic reaction in rare cases. Viral hepatitis is associated with an increase in atypical lymphocytes, haemolysis in patients with deficiency of red-cell glucose-6-phosphate dehydrogenase, and pure red-cell aplasia or aplastic anaemia in occasional cases. Wilson’s disease causes haemolytic anaemia.
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HAEMATOLOGY
Rheumatological disease Inflammation is a prototypical cause of the anaemia of chronic disease; the anaemia can be severe and microcytic with prominent thrombocytosis (figure 2). Anaemia may be an important clue to an underlying disorder such as polymyalgia rheumatica, which if unrecognised can progress to sudden blindness. At the same time, certain types of anaemia in the setting of a rheumatological disorder, such as salicylate-induced deficiency of folic acid or concomitant pernicious anaemia, can be easily remedied but the overt signs of megaloblastic erythropoiesis can be masked by concomitant iron deficiency or inflammation.19 Autoimmune haemolytic anaemia, neutropenia, thrombocytopenia, or red-cell aplasia can develop and overshadow the underlying rheumatological disorder, particularly when it is systemic lupus erythematosus. With lupus, anaemia is the most common complication, followed by leucopenia (more commonly due to lymphopenia than neutropenia) and thrombocytopenia.30 The anaemia can be due to marrow suppression by inflammatory mediators or renal disease, vasculitis, thrombotic thrombocytopenia purpura, or warm-antibody-mediated haemolysis (IgG and/or complement); autoantibodies also bring about the neutropenia and thrombocytopenia in this disorder. Neutropenia in rheumatoid arthritis is generally associated with splenomegaly and occasionally leg ulcers (Felty’s syndrome); the mechanism can involve autoantibodies, immune complexes, or proliferation of large granular lymphocytes. The antiphospholipid syndrome is an autoimmune disorder in which both thrombocytopenia and thrombosis may be prominent in the presence or absence of a rheumatological disorder.31 Immune-complex disease can produce hyposplenism, and haematophagic histiocytosis and myelofibrosis can complicate systemic lupus erythematosus. Immunosuppressive therapy with methotrexate or azathioprine can lead to myelodysplasia. Infection Infectious processes can adversely affect haemopoiesis by many mechanisms in addition to non-specific suppression of erythropoietin production and erythropoiesis through the production of inflammatory cytokines.32 For erythropoiesis, these mechanisms include iron deficiency due to hookworm infestation, deficiency of vitamin B12 due to the presence of a fish tapeworm, haemolysis, nonimmune (malaria, bartonellosis, clostridial infection, babesiosis, or deficency of glucose-6-phosphate dehydrogenase) or immune (malaria, syphilis, EpsteinBarr virus, mycoplasma, and certain antibiotics), and direct infection of erythroid progenitor cells (parvovirus B19) Mild anaemia can be the consequence of a significant underlying disorder such as bacterial endocarditis. Furthermore, the status of the host profoundly influences the clinical manifestations of the particular infection. Thus, patients with chronic haemolytic anaemia are particularly susceptible to red-cell aplasia induced by parvoviris B19, salmonella sepsis, or deep-seated fungal infections when being treated with corticosteroids. In asplenic patients, infection with encapsulated organisms can lead to overwhelming sepsis, intravascular coagulation, and death; these patients are also susceptible to babesiosis. Infections can trigger oxidant haemolysis of red cells deficient in glucose-6-
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phosphate dehydrogenase; such red cells are also at risk of haemolysis from drugs such as sulphamethoxazole, nitrofurantoin, and primaquine. Immune haemolysis of normal red cells has been caused by penicillin, cephalothin, stibophen, quinine, and sulphonamides, and by syphilis (paroxymal cold haemoglobinuria) and Epstein-Barr virus and mycoplasma (cold agglutinin disease) infections. Other side-effects of antibiotic therapy include marrow suppression or aplasia (chloramphenicol, sulphonamides), neutropenia (sulphonamides, penicillin derivatives), thrombocytopenia or impairment of platelet function (penicillin derivatives), and coagulation abnormalities (moxalactam, cefamandole). Infection with Epstein-Barr or hepatitis virus can cause aplastic anaemia, and Epstein-Barr virus and cytomegalovirus can cause an infectious mononucleosis syndrome. Lymphocytosis can also be caused by pertussis or toxoplasma infection, and eosinophilia is seen with tissue invasion by parasites such as ascaris, strongyloides, schistosomes, trichina, and toxocara. Thrombocytopenia may the consequence of infection-induced disseminated intravascular coagulation, sepsis, or the antibiotics used to treat the infection. Rarely, infection causes pancytopenia due to marrow necrosis. Anaemia in malaria has multiple causes.33 The impact of the disease on erythropoiesis depends on the host’s immune and general health status and on the virulence and target cells of the parasite involved; Plasmodium vivax invades reticulocytes only whereas P falciparum invades red cells of all ages, producing a greater degree of parasitaemia. In addition to mechanical lysis of parasitised red cells, there is immune haemolysis of parasitised and non-parasitised red cells, suppression of erythropoiesis by inflammatory cytokines such as TNF, and plasma volume expansion. Black-water fever seems to be consequence of quinine toxicity. Thrombocytopenia is also common with acute malaria but leucopenia is not. Perhaps no other infectious agent has a more global impact on haemopoiesis than HIV-1.34 An acute and easily overlooked viral syndrome with atypical lymphocytes is the first manifestation of HIV-1 infection in many cases. Leucopenia (both lymphopenia and neutropenia, usually with an increase in band forms) or thrombocytopenia with or without generalised lymphadenopathy, are also common presenting manifestations. Anaemia is a frequent complication of HIV-1 infection, and its severity increases with disease progression. Indeed, anaemia is a negative prognostic indicator in HIV-1-infected patients,35 and an isolated severe anaemia is an important manifestation of disseminated Mycobacterium avium intracellulare (MAI) infection. Erythropoietin production is also suppressed in HIV-1 infection but is restored with zidovudine therapy, although the anaemia does not generally improve.36 The severe immunodeficiency state induced by HIV-1 allows microorganisms to proliferate. Bone-marrow aspiration or biopsy is an efficient way to diagnose infections caused by histoplasma, candida, cryptococcus, pneumocystis, toxoplasma, MAI, and leishmania or an infection-associated haematophagic syndrome. Red-cell aplasia due to parvovirus B19, Kaposi’s sarcoma, and lymphoma, as well as bone-marrow necrosis, myelofibrosis, and serous fat atrophy can also be recognised in this way. Some drugs used in treatment of HIV-1 and its infectious complications (eg, zidovudine, ganciclovir, and trimethoprim-sulphamethoxazole) are
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HAEMATOLOGY
myelotoxic; zidovudine causes severe anaemia and leucopenia and the other two drugs cause severe neutropenia. Cancer The causes of anaemia with non-haematological malignant disorders are multiple and diverse, ranging from simple haemodilution to haematophagic histiocytosis. The most common cause of anaemia is suppression of erythropoietin production and erythropoiesis; in many cases these abnormalities are reversible with recombinant erythropoietin therapy.14 Other remediable or non-remediable causes of anaemia must be excluded before the institution of such therapy. Although recombinant erythropoietin therapy is effective even with concomitant chemotherapy or if the marrow is affected by tumour, identification of the tumours for which chemotherapy alone will alleviate the associated anaemia is important. As a corollary, failure of the anaemia of cancer to respond to recombinant erythropoietin is in itself a poor prognostic sign.37 A microangiopathic haemolytic anaemia is also a poor prognostic sign, because it suggests pulmonary metastases. Immune haemolytic anaemia, thrombocytopenia, and red-cell aplasia can occur with non-haematological malignant disorders and with lymphomas or Hodgkin’s disease. A leucoerythroblastic reaction due to extramedullary haemopoiesis is a clue to the presence of marrow tumour metastases or myelofibrosis. Marrow necrosis is common in acute leukaemia. Thrombocytosis, generally mild, is another haematological manifestation of malignant disease. Leucocytosis without evidence of infection occurs in association with certain tumours. Erythrocytosis can be caused by renal, hepatic, adrenal, and cerebellar tumours. Disseminated intravascular coagulation with marantic endocarditis (Trousseau’s syndrome) may also be the first sign of an occult cancer but the identity of the tumour can be difficult to establish in this situation.38 Some anticancer drugs such as mitomycin and cyclosporin can cause a haemolytic-uraemic syndrome. Others such as cisplatin, melphalan, and methotrexate can cause haemolysis or renal damage. Doxorubicin causes oxidant haemolysis of glucose-6-phosphate-dehydrogenase-deficient red cells.39
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THE LANCET • Vol 355 • May 13, 2000
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