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The blood in systemic disease
THE BLOOD IN SYSTEMIC DISEASE
The blood in systemic disease
Key points C
Anaemia of chronic disease can result from infection, inflammation or cancer
C
Haematinic deficiency can result from a systemic disease or its treatment
C
Hepatic and renal diseases are often lead to haematological abnormalities of diverse types
C
Eosinophilia is more often a feature of a systemic disease than of a haematological disorder
Barbara Bain
Abstract Systemic disease has protean manifestations. Most frequently observed is anaemia of chronic disease, anaemia can also be autoimmune, microangiopathic, mechanical or caused by haematinic deficiency, bone marrow replacement or pure red cell aplasia. The platelet count can be increased or decreased. The number of neutrophils, eosinophils, monocytes and lymphocytes can be increased, but neutropenia, eosinopenia and lymphopenia can also occur. Leucocytes can appear activated. Systemic disease can lead to thromboembolism, haemorrhage or disseminated intravascular coagulation. Lymphoma can occur as a result of viral infection, immune deficiency or the treatment of systemic disease.
for the cellularity as a result of increased intramedullary death of precursors; the two often occur together. It has been postulated that anaemia of chronic disease is a defence mechanism in infection as bacteria can be deprived of iron. The anaemia that occurs is initially normocytic and normochromic, but when the condition is more severe it becomes microcytic and hypochromic. The low serum iron is associated with a reduced transferrin concentration and saturation. This is in contrast to iron deficiency anaemia, when transferrin concentration is increased. Serum ferritin is high in the normal range or increased, this being mediated by IL-1, IL-6, IL-10 and TNF-a. Concomitant features often include an increased erythrocyte sedimentation rate and increased rouleaux formation. When anaemia of chronic disease and iron deficiency coexist, the situation is more complex; transferrin may be neither reduced nor increased, and ferritin tends to be in the low-normal range. Treatment is ideally directed at the underlying disease. When this is not sufficiently effective, recombinant erythropoietin with supplementary oral or intravenous iron can be of benefit. Tocilizumab, an antibody to the IL-6 receptor, can improve the haemoglobin concentration.
Keywords Anaemia of chronic disease; autoimmune disease; cancer; eosinophilia; haematinic deficiency; haemolysis; heart failure; infection; liver disease; renal disease
Introduction Non-haematological diseases can have prominent haematological manifestations affecting all lineages. Haematological features can be cytokine-mediated in chronic infection, inflammation or malignancy, or can result from haematinic deficiency or bone marrow or splenic infiltration. In addition, in the case of autoimmune disorders, the blood and bone marrow can be one target of more generalized disease.
Anaemia of chronic disease The anaemia of chronic disease, sometimes called the anaemia of inflammation, is a common feature of infection, inflammation and malignant disease.1 It is mediated by cytokines, particularly interleukin (IL) 6. There is resultant increased hepatocyte synthesis of hepcidin, which binds and internalizes ferroportin in macrophages and enterocytes, leading to its ubiquitination and degradation; iron export from enterocytes and macrophages is thus reduced (Figure 1). The plasma iron concentration falls, and there is reduced availability of iron for haemoglobin synthesis. There is a concomitant blunted erythropoietin response, mediated by IL-1 and tumour necrosis factor-a (TNF-a). There is some degree of dyserythropoiesis, ineffectiveness of erythropoiesis and shortening of red cell lifespan. The term ‘dyserythropoiesis’ indicates cytologically abnormal or dysplastic erythropoiesis, while ‘ineffective erythropoiesis’ indicates that the production of mature cells is less than expected
Haematinic deficiency Haematinic deficiencies can be the direct result of a disease process or be attributable to the treatment of a systemic disease. Iron deficiency anaemia can result from malabsorption (atrophic gastritis, gastric atrophy, Helicobacter pylori infection, pancreatic insufficiency, coeliac disease), blood loss (use of corticosteroids or non-steroidal anti-inflammatory drugs, ulcerative colitis, Crohn’s disease, diverticulitis), chronic urinary loss of iron (mechanical haemolytic anaemia caused by a defective prosthetic valve) or sequestration of iron in pulmonary macrophages (idiopathic pulmonary haemosiderosis). Folic acid deficiency can result from malabsorption (coeliac disease, tropical sprue) or increased need (extensive skin disease). Vitamin B12 deficiency can result from malabsorption (occasionally coeliac disease but typically total gastrectomy or, in pernicious anaemia, autoimmune gastric atrophy; also H. pylori infection). Rarely, vitamin B12 deficiency results from Crohn’s disease, but more often it is a feature of treatment of this condition by resection of the terminal ileum. Vitamin B12 deficiency can result from tropical sprue.
Barbara Bain MB BS FRACP FRCPath is Professor of Diagnostic Haematology, Imperial College London Faculty of Medicine and Honorary Consultant Haematologist, St Mary’s Hospital London, UK. Competing interests: none declared.
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
Hepcidin in anaemia of chronic disease
Interleukin 6 secreted by macrophage Hepcidin synthesis by hepatocyte upregulated
acting on macrophage Reduced release of iron from macrophage as ferroportin is internalized and degraded
Plasma iron reduced Iron export from enterocyte and plasma iron reduced
Hepcidin binds to ferroportin, which is internalized and degraded
Enteral absorption of iron reduced
Figure 1 Role of hepcidin and disturbed iron metabolism in anaemia of chronic disease. Reproduced with permission from Bain BJ, Interactive haematology image bank, 2nd edn (DVD). Oxford: Wiley-Blackwell, 2014.
common cause of death after the cancer itself. The rate of arterial thrombosis is also increased. When the bone marrow is infiltrated, there can be a leucoerythroblastic anaemia and other cytopenias. Rarely, the spleen is infiltrated, leading to hyposplenism, or there are circulating tumour cells (carcinocythaemia).2
Bariatric surgery can cause haematinic deficiency if suitable supplementation is not given. In particular, it can cause iron deficiency and also copper deficiency, the latter leading to anaemia, neutropenia and vacuolation of haemopoietic cells in the bone marrow. Autoimmune disease Systemic lupus erythematosus serves as an archetypal autoimmune disease that often affects the blood and bone marrow. Possible haematological features are shown in Table 1. Autoimmune diseases can have specific haematological associations. Rheumatoid arthritis can be associated with Felty’s syndrome e splenomegaly and autoimmune neutropenia e which is often the result of an associated large granular lymphocyte leukaemia. Thymoma can also be associated with autoimmune haematological complications, specifically pure red cell aplasia, pure white cell aplasia, amegakaryocytic thrombocytopenia and aplastic anaemia.
Renal disease Acute kidney injury can be the result of a microangiopathy, and thus have microangiopathic haemolytic anaemia and thrombocytopenia as features. Responsible conditions include haemolytic euraemic syndrome, atypical haemolyticeuraemic syndrome (caused by defects of complement components), thrombotic thrombocytopenic purpura and drug-induced microangiopathy. Various renal conditions cause inappropriate secretion of erythropoietin with consequent polycythaemia. These include renal carcinoma (hypernephroma), Wilms’ tumour, renal adenoma, renal haemangioma, renal sarcoma, renal cysts including polycystic disease of the kidney, renal artery stenosis, renal vein thrombosis, post-transplant polycythaemia, hydronephrosis, horseshoe kidney, nephrocalcinosis (including that caused by hyperparathyroidism), Bartter’s syndrome, renal lymphangiectasis and perinephric lymphangioma.3 Chronic kidney disease is associated with a normocytic normochromic anaemia attributable to reduced erythropoietin secretion and reduced red cell survival. Hepcidin is excreted by the kidney and plasma hepcidin may be increased, with ensuing
Cancer Carcinoma and other cancers can be associated with anaemia of chronic disease, iron deficiency anaemia resulting from blood loss, microangiopathic haemolytic anaemia and disseminated intravascular coagulation. Reactive changes can include neutrophilia, monocytosis and thrombocytosis. There is an increased incidence of venous thromboembolism, this being the most
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
Possible haematological features of bacterial and viral infections
Possible haematological features of systemic lupus erythematosus C C C C C C C C
Bacterial infection Neutrophilia Left shift Toxic granulation and vacuolation €hle bodies Do Neutropenia (brucellosis, typhoid fever) Lymphopenia Eosinopenia Lymphocytosis (pertussis) Monocytosis Red cell agglutination and cold antibody-mediated haemolysis (Mycoplasma pneumoniae) Haemolyticeuraemic syndrome (Escherichia coli, Shigella) Toxin-mediated haemolysis (Clostridium perfringens) Bacteria-induced haemolysis (Oroya fever Bartonella bacilliformis) Paroxysmal cold haemoglobinuria (although this more often follows viral infection) Pseudopolycythaemia capillary leak syndrome (meningococcal septicaemia) Anaemia of chronic disease Increased rouleaux formation Increased erythrocyte sedimentation rate Thrombocytosis Thrombocytopenia Haemophagocytic lymphohistiocytosis (tuberculosis, other mycobacterial infections) Bone marrow granulomas (tuberculosis, other mycobacterial infections) Viral infection Lymphocytosis Atypical lymphocytes (EBV, CMV) Neutropenia (dengue fever, HIV) Neutrophilia Thrombocytopenia (viral haemorrhagic fevers, autoimmune thrombocytopenia, thrombotic thrombocytopenic purpura in HIV infection) Pseudopolycythaemia capillary leak syndrome (viral haemorrhagic fevers) Neutrophil dysplasia and giant metamyelocytes (HIV) Red cell agglutination and cold antibody-mediated haemolysis (EBV) Paroxysmal cold haemoglobinuria (measles, mumps, chicken pox, EBV, CMV) Triggering of autoimmune haemolytic anaemia Cryoglobulinaemia (hepatitis C) Haemophagocytic lymphohistiocytosis (EBV, CMV) Pure red cell aplasia (parvovirus B19 infection) Anaemia of chronic disease Pancytopenia (HIV infection)
Autoimmune haemolytic anaemia Autoimmune thrombocytopenic purpura Pure red cell aplasia Autoimmune neutropenia Lupus anticoagulant leading to thrombophilia Acquired haemophilia caused by factor VIII antibodies Bone marrow fibrosis Rarely the presence of lupus erythematosus (LE) cells in a bone marrow aspirate
Table 1
features of anaemia of chronic disease. When the anaemia of chronic kidney disease is treated with erythropoiesis-stimulating agents, functional iron deficiency can occur; it is responsive to intravenous iron.4 Renal insufficiency can cause red cells to become echinocytic, and platelet function is impaired. Liver disease Liver disease is characterized by anaemia, macrocytosis and target cells. When there is associated hypersplenism, there may be pancytopenia. Coagulation is disordered, with deficiency of most coagulation factors, with the exception of factor VIII. There is a concomitant decrease in the naturally occurring anticoagulants protein S, protein C and antithrombin. There is a decrease in plasminogen and in antifibrinolytic proteins thrombinactivatable fibrinolysis inhibitor (TAFI), antiplasmin and plasminogen activator inhibitor 1. There is dysfibrinogenaemia as a result of increased sialylation of fibrinogen leading to ineffective polymerization and prolongation of the thrombin time and reptilase time. In Zieve’s syndrome, there is an acute fatty liver associated with irregularly contracted cells, hyperlipidaemia and haemolysis. In liver failure, there may be acanthocytosis with haemolysis (‘spur cell haemolytic anaemia’). Wilson’s disease can cause haemolytic anaemia without any specific morphological features, but can also be complicated by acute oxidantinduced haemolytic anaemia when copper is released from dying liver cells; the blood film then shows irregularly contracted cells, and Heinz bodies can be detected. Infection Bacterial and viral infections frequently have haematological manifestations (Table 2). Human immunodeficiency virus (HIV) infection predisposes to Hodgkin lymphoma and various types of non-Hodgkin lymphoma. EpsteineBarr virus infection is an aetiological factor in Hodgkin lymphoma and various types of non-Hodgkin lymphoma including Burkitt lymphoma and diffuse large cell lymphoma. Infection by the human T cell lymphotropic virus 1 is a prerequisite for the development of adult T cell leukaemia/lymphoma. Certain parasitic infections (malaria, babesiosis) cause haemolytic anaemia, and Plasmodium falciparum infection can also cause disseminated intravascular coagulation. Malaria is also an
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CMV, cytomegalovirus; EBV, EpsteineBarr virus; HIV, human immunodeficiency virus.
Table 2
aetiological factor in endemic Burkitt lymphoma. Helminth infection is usually associated with eosinophilia. Roundworm infection of the bowel often leads to iron deficiency. Leishmaniasis can cause pancytopenia.
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
with a hypercoagulable state, which can lead to left ventricular thrombus and cerebral embolism.
Examples of systemic diseases that can cause eosinophilia
Splenic atrophy The spleen can atrophy in coeliac disease, dermatitis herpetiformis and other autoimmune disease. Less often, hyposplenism results from embolism or thrombosis of the splenic arteries, antiphospholipid syndrome, idiopathic splenic calcification or splenic replacement in sarcoidosis, metastatic carcinoma or amyloidosis. The blood film in hyposplenism shows target cells, Howell Jolly bodies, acanthocytes, thrombocytosis and sometimes lymphocytosis. The detection of such features by the haematology laboratory, in any circumstance, can be important as the patient is at risk of various infections (bacterial and unicellular parasites), and prophylaxis is indicated.
Connective tissue diseases Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome), systemic necrotizing vasculitis (variant of polyarteritis nodosa), eosinophilic cellulitis Parasitic infections Hookworm infection, ascariasis, strongyloidiasis, trichinosis, filariasis, loiasis, onchocerciasis, visceral larva migrans, fascioliasis, fasciolopsiasis, paragonimiasis, schistosomiasis (acute phase), toxocariasis, ankylostomiasis Skin diseases Pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, herpes gestationalis, eosinophilic pustular folliculitis, familial peeling skin syndrome, acute generalized exanthematous pustulosis Allergies Atopic eczema, asthma, allergic rhinitis (hay fever), acute urticaria, allergic bronchopulmonary fungal infections Drug hypersensitivity including drug rash with eosinophilia and systemic symptoms (DRESS syndrome) Cyclical angio-oedema with eosinophilia Fungal infections Coccidioidomycosis, disseminated histoplasmosis
Eosinophilia Eosinophilia uncommonly represents a primary haematological disease. Much more often, it is reactive to a systemic disease (Table 3).3 A KEY REFERENCES 1 Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol 2011; 154: 289e300. 2 Brace W, Bain B, Walker M, Catovsky D. Teaching cases from the Royal Marsden Hospital Case 9: an elderly patient with unusual circulating cells. Leuk Lymphoma 1995; 18: 529e30. 3 Bain BJ. Blood cells. 5th edn. 2015. Oxford: Wiley‒Blackwell, 2015. 4 Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2012; 161: 639e48. 5 Silverberg DS, Wexler D, Palazzuoli A, et al. The anemia of heart failure. Acta Haematol 2009; 122: 109e19.
Table 3
Heart failure Heart failure can lead to anaemia. This can be the result of associated impaired renal function and reduced erythropoietin synthesis plus increased cytokine production; this depresses marrow function, contributes to depression of erythropoietin synthesis and increases hepcidin synthesis (leading to actual or functional iron deficiency/anaemia of chronic disease).5 Iron therapy, particularly intravenous iron, can be of benefit, as can erythropoiesis-stimulating agents. Heart failure is also associated
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most likely diagnosis? A. b-Thalassaemia B. Anaemia of chronic disease C. Felty’s syndrome D. Iron deficiency anaemia E. Iron deficiency plus anaemia of chronic disease
A 44-year-old Greek woman was attending outpatients. She was taking a non-steroidal anti-inflammatory drug for rheumatoid arthritis. Investigations Haemoglobin 98 g/litre (115e165) Mean cell volume 75 fl (80e96) Serum ferritin 78 micromol/litre (15e300) Erythrocyte sedimentation rate 65 mm/hour (<20)
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Question 2 A 34-year-old white British woman presented with fatigue and pallor. She had a history of dermatitis herpetiformis for which she was taking dapsone.
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THE BLOOD IN SYSTEMIC DISEASE
Investigations Haemoglobin 98 g/litre (115e165) Mean cell volume 105 fl (80e96) White cell count 13.4 109/litre (4.0e11.0) Neutrophils 5.9 109/litre (1.5e7.0) Lymphocytes 6.2 109/litre (1.5e4.0) Platelets 340 109/litre (150e400) Reticulocytes 180 109/litre (0.5e2.4) A blood film showed red cell agglutinates and atypical lymphocytes, some of which were plasmacytoid Chest X-ray showed consolidation in the right upper zone
Investigations Haemoglobin 78 g/litre (115e165) Mean cell volume 107 fl (80e96) A blood film showed macrocytosis, oval macrocytes and hypersegmented neutrophils What is the most likely diagnosis? A. Excess alcohol consumption B. Folic acid deficiency C. Hypothyroidism D. Oxidant-induced haemolysis E. Vitamin B12 deficiency
Question 3
What is the most likely diagnosis? A. EpsteineBarr virus infection B. Cytomegalovirus infection C. Dengue fever D. Mycoplasma pneumoniae infection E. Primary infection with human immunodeficiency virus
A 34-year-old woman Italian woman who lives in the UK presented with cough and fever. On examination, she showed bronchial breathing and increased vocal resonance over the right upper lobe. The tip of the spleen was felt. There was no lymphadenopathy.
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
The blood in systemic disease
Key points C
Anaemia of chronic disease can result from infection, inflammation or cancer
C
Haematinic deficiency can result from a systemic disease or its treatment
C
Hepatic and renal diseases are often lead to haematological abnormalities of diverse types
C
Eosinophilia is more often a feature of a systemic disease than of a haematological disorder
Barbara Bain
Abstract Systemic disease has protean manifestations. Most frequently observed is anaemia of chronic disease, anaemia can also be autoimmune, microangiopathic, mechanical or caused by haematinic deficiency, bone marrow replacement or pure red cell aplasia. The platelet count can be increased or decreased. The number of neutrophils, eosinophils, monocytes and lymphocytes can be increased, but neutropenia, eosinopenia and lymphopenia can also occur. Leucocytes can appear activated. Systemic disease can lead to thromboembolism, haemorrhage or disseminated intravascular coagulation. Lymphoma can occur as a result of viral infection, immune deficiency or the treatment of systemic disease.
for the cellularity as a result of increased intramedullary death of precursors; the two often occur together. It has been postulated that anaemia of chronic disease is a defence mechanism in infection as bacteria can be deprived of iron. The anaemia that occurs is initially normocytic and normochromic, but when the condition is more severe it becomes microcytic and hypochromic. The low serum iron is associated with a reduced transferrin concentration and saturation. This is in contrast to iron deficiency anaemia, when transferrin concentration is increased. Serum ferritin is high in the normal range or increased, this being mediated by IL-1, IL-6, IL-10 and TNF-a. Concomitant features often include an increased erythrocyte sedimentation rate and increased rouleaux formation. When anaemia of chronic disease and iron deficiency coexist, the situation is more complex; transferrin may be neither reduced nor increased, and ferritin tends to be in the low-normal range. Treatment is ideally directed at the underlying disease. When this is not sufficiently effective, recombinant erythropoietin with supplementary oral or intravenous iron can be of benefit. Tocilizumab, an antibody to the IL-6 receptor, can improve the haemoglobin concentration.
Keywords Anaemia of chronic disease; autoimmune disease; cancer; eosinophilia; haematinic deficiency; haemolysis; heart failure; infection; liver disease; renal disease
Introduction Non-haematological diseases can have prominent haematological manifestations affecting all lineages. Haematological features can be cytokine-mediated in chronic infection, inflammation or malignancy, or can result from haematinic deficiency or bone marrow or splenic infiltration. In addition, in the case of autoimmune disorders, the blood and bone marrow can be one target of more generalized disease.
Anaemia of chronic disease The anaemia of chronic disease, sometimes called the anaemia of inflammation, is a common feature of infection, inflammation and malignant disease.1 It is mediated by cytokines, particularly interleukin (IL) 6. There is resultant increased hepatocyte synthesis of hepcidin, which binds and internalizes ferroportin in macrophages and enterocytes, leading to its ubiquitination and degradation; iron export from enterocytes and macrophages is thus reduced (Figure 1). The plasma iron concentration falls, and there is reduced availability of iron for haemoglobin synthesis. There is a concomitant blunted erythropoietin response, mediated by IL-1 and tumour necrosis factor-a (TNF-a). There is some degree of dyserythropoiesis, ineffectiveness of erythropoiesis and shortening of red cell lifespan. The term ‘dyserythropoiesis’ indicates cytologically abnormal or dysplastic erythropoiesis, while ‘ineffective erythropoiesis’ indicates that the production of mature cells is less than expected
Haematinic deficiency Haematinic deficiencies can be the direct result of a disease process or be attributable to the treatment of a systemic disease. Iron deficiency anaemia can result from malabsorption (atrophic gastritis, gastric atrophy, Helicobacter pylori infection, pancreatic insufficiency, coeliac disease), blood loss (use of corticosteroids or non-steroidal anti-inflammatory drugs, ulcerative colitis, Crohn’s disease, diverticulitis), chronic urinary loss of iron (mechanical haemolytic anaemia caused by a defective prosthetic valve) or sequestration of iron in pulmonary macrophages (idiopathic pulmonary haemosiderosis). Folic acid deficiency can result from malabsorption (coeliac disease, tropical sprue) or increased need (extensive skin disease). Vitamin B12 deficiency can result from malabsorption (occasionally coeliac disease but typically total gastrectomy or, in pernicious anaemia, autoimmune gastric atrophy; also H. pylori infection). Rarely, vitamin B12 deficiency results from Crohn’s disease, but more often it is a feature of treatment of this condition by resection of the terminal ileum. Vitamin B12 deficiency can result from tropical sprue.
Barbara Bain MB BS FRACP FRCPath is Professor of Diagnostic Haematology, Imperial College London Faculty of Medicine and Honorary Consultant Haematologist, St Mary’s Hospital London, UK. Competing interests: none declared.
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1
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
Hepcidin in anaemia of chronic disease
Interleukin 6 secreted by macrophage Hepcidin synthesis by hepatocyte upregulated
acting on macrophage Reduced release of iron from macrophage as ferroportin is internalized and degraded
Plasma iron reduced Iron export from enterocyte and plasma iron reduced
Hepcidin binds to ferroportin, which is internalized and degraded
Enteral absorption of iron reduced
Figure 1 Role of hepcidin and disturbed iron metabolism in anaemia of chronic disease. Reproduced with permission from Bain BJ, Interactive haematology image bank, 2nd edn (DVD). Oxford: Wiley-Blackwell, 2014.
common cause of death after the cancer itself. The rate of arterial thrombosis is also increased. When the bone marrow is infiltrated, there can be a leucoerythroblastic anaemia and other cytopenias. Rarely, the spleen is infiltrated, leading to hyposplenism, or there are circulating tumour cells (carcinocythaemia).2
Bariatric surgery can cause haematinic deficiency if suitable supplementation is not given. In particular, it can cause iron deficiency and also copper deficiency, the latter leading to anaemia, neutropenia and vacuolation of haemopoietic cells in the bone marrow. Autoimmune disease Systemic lupus erythematosus serves as an archetypal autoimmune disease that often affects the blood and bone marrow. Possible haematological features are shown in Table 1. Autoimmune diseases can have specific haematological associations. Rheumatoid arthritis can be associated with Felty’s syndrome e splenomegaly and autoimmune neutropenia e which is often the result of an associated large granular lymphocyte leukaemia. Thymoma can also be associated with autoimmune haematological complications, specifically pure red cell aplasia, pure white cell aplasia, amegakaryocytic thrombocytopenia and aplastic anaemia.
Renal disease Acute kidney injury can be the result of a microangiopathy, and thus have microangiopathic haemolytic anaemia and thrombocytopenia as features. Responsible conditions include haemolytic euraemic syndrome, atypical haemolyticeuraemic syndrome (caused by defects of complement components), thrombotic thrombocytopenic purpura and drug-induced microangiopathy. Various renal conditions cause inappropriate secretion of erythropoietin with consequent polycythaemia. These include renal carcinoma (hypernephroma), Wilms’ tumour, renal adenoma, renal haemangioma, renal sarcoma, renal cysts including polycystic disease of the kidney, renal artery stenosis, renal vein thrombosis, post-transplant polycythaemia, hydronephrosis, horseshoe kidney, nephrocalcinosis (including that caused by hyperparathyroidism), Bartter’s syndrome, renal lymphangiectasis and perinephric lymphangioma.3 Chronic kidney disease is associated with a normocytic normochromic anaemia attributable to reduced erythropoietin secretion and reduced red cell survival. Hepcidin is excreted by the kidney and plasma hepcidin may be increased, with ensuing
Cancer Carcinoma and other cancers can be associated with anaemia of chronic disease, iron deficiency anaemia resulting from blood loss, microangiopathic haemolytic anaemia and disseminated intravascular coagulation. Reactive changes can include neutrophilia, monocytosis and thrombocytosis. There is an increased incidence of venous thromboembolism, this being the most
MEDICINE --:-
2
Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
Possible haematological features of bacterial and viral infections
Possible haematological features of systemic lupus erythematosus C C C C C C C C
Bacterial infection Neutrophilia Left shift Toxic granulation and vacuolation €hle bodies Do Neutropenia (brucellosis, typhoid fever) Lymphopenia Eosinopenia Lymphocytosis (pertussis) Monocytosis Red cell agglutination and cold antibody-mediated haemolysis (Mycoplasma pneumoniae) Haemolyticeuraemic syndrome (Escherichia coli, Shigella) Toxin-mediated haemolysis (Clostridium perfringens) Bacteria-induced haemolysis (Oroya fever Bartonella bacilliformis) Paroxysmal cold haemoglobinuria (although this more often follows viral infection) Pseudopolycythaemia capillary leak syndrome (meningococcal septicaemia) Anaemia of chronic disease Increased rouleaux formation Increased erythrocyte sedimentation rate Thrombocytosis Thrombocytopenia Haemophagocytic lymphohistiocytosis (tuberculosis, other mycobacterial infections) Bone marrow granulomas (tuberculosis, other mycobacterial infections) Viral infection Lymphocytosis Atypical lymphocytes (EBV, CMV) Neutropenia (dengue fever, HIV) Neutrophilia Thrombocytopenia (viral haemorrhagic fevers, autoimmune thrombocytopenia, thrombotic thrombocytopenic purpura in HIV infection) Pseudopolycythaemia capillary leak syndrome (viral haemorrhagic fevers) Neutrophil dysplasia and giant metamyelocytes (HIV) Red cell agglutination and cold antibody-mediated haemolysis (EBV) Paroxysmal cold haemoglobinuria (measles, mumps, chicken pox, EBV, CMV) Triggering of autoimmune haemolytic anaemia Cryoglobulinaemia (hepatitis C) Haemophagocytic lymphohistiocytosis (EBV, CMV) Pure red cell aplasia (parvovirus B19 infection) Anaemia of chronic disease Pancytopenia (HIV infection)
Autoimmune haemolytic anaemia Autoimmune thrombocytopenic purpura Pure red cell aplasia Autoimmune neutropenia Lupus anticoagulant leading to thrombophilia Acquired haemophilia caused by factor VIII antibodies Bone marrow fibrosis Rarely the presence of lupus erythematosus (LE) cells in a bone marrow aspirate
Table 1
features of anaemia of chronic disease. When the anaemia of chronic kidney disease is treated with erythropoiesis-stimulating agents, functional iron deficiency can occur; it is responsive to intravenous iron.4 Renal insufficiency can cause red cells to become echinocytic, and platelet function is impaired. Liver disease Liver disease is characterized by anaemia, macrocytosis and target cells. When there is associated hypersplenism, there may be pancytopenia. Coagulation is disordered, with deficiency of most coagulation factors, with the exception of factor VIII. There is a concomitant decrease in the naturally occurring anticoagulants protein S, protein C and antithrombin. There is a decrease in plasminogen and in antifibrinolytic proteins thrombinactivatable fibrinolysis inhibitor (TAFI), antiplasmin and plasminogen activator inhibitor 1. There is dysfibrinogenaemia as a result of increased sialylation of fibrinogen leading to ineffective polymerization and prolongation of the thrombin time and reptilase time. In Zieve’s syndrome, there is an acute fatty liver associated with irregularly contracted cells, hyperlipidaemia and haemolysis. In liver failure, there may be acanthocytosis with haemolysis (‘spur cell haemolytic anaemia’). Wilson’s disease can cause haemolytic anaemia without any specific morphological features, but can also be complicated by acute oxidantinduced haemolytic anaemia when copper is released from dying liver cells; the blood film then shows irregularly contracted cells, and Heinz bodies can be detected. Infection Bacterial and viral infections frequently have haematological manifestations (Table 2). Human immunodeficiency virus (HIV) infection predisposes to Hodgkin lymphoma and various types of non-Hodgkin lymphoma. EpsteineBarr virus infection is an aetiological factor in Hodgkin lymphoma and various types of non-Hodgkin lymphoma including Burkitt lymphoma and diffuse large cell lymphoma. Infection by the human T cell lymphotropic virus 1 is a prerequisite for the development of adult T cell leukaemia/lymphoma. Certain parasitic infections (malaria, babesiosis) cause haemolytic anaemia, and Plasmodium falciparum infection can also cause disseminated intravascular coagulation. Malaria is also an
MEDICINE --:-
CMV, cytomegalovirus; EBV, EpsteineBarr virus; HIV, human immunodeficiency virus.
Table 2
aetiological factor in endemic Burkitt lymphoma. Helminth infection is usually associated with eosinophilia. Roundworm infection of the bowel often leads to iron deficiency. Leishmaniasis can cause pancytopenia.
3
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
with a hypercoagulable state, which can lead to left ventricular thrombus and cerebral embolism.
Examples of systemic diseases that can cause eosinophilia
Splenic atrophy The spleen can atrophy in coeliac disease, dermatitis herpetiformis and other autoimmune disease. Less often, hyposplenism results from embolism or thrombosis of the splenic arteries, antiphospholipid syndrome, idiopathic splenic calcification or splenic replacement in sarcoidosis, metastatic carcinoma or amyloidosis. The blood film in hyposplenism shows target cells, Howell Jolly bodies, acanthocytes, thrombocytosis and sometimes lymphocytosis. The detection of such features by the haematology laboratory, in any circumstance, can be important as the patient is at risk of various infections (bacterial and unicellular parasites), and prophylaxis is indicated.
Connective tissue diseases Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome), systemic necrotizing vasculitis (variant of polyarteritis nodosa), eosinophilic cellulitis Parasitic infections Hookworm infection, ascariasis, strongyloidiasis, trichinosis, filariasis, loiasis, onchocerciasis, visceral larva migrans, fascioliasis, fasciolopsiasis, paragonimiasis, schistosomiasis (acute phase), toxocariasis, ankylostomiasis Skin diseases Pemphigus vulgaris, bullous pemphigoid, dermatitis herpetiformis, herpes gestationalis, eosinophilic pustular folliculitis, familial peeling skin syndrome, acute generalized exanthematous pustulosis Allergies Atopic eczema, asthma, allergic rhinitis (hay fever), acute urticaria, allergic bronchopulmonary fungal infections Drug hypersensitivity including drug rash with eosinophilia and systemic symptoms (DRESS syndrome) Cyclical angio-oedema with eosinophilia Fungal infections Coccidioidomycosis, disseminated histoplasmosis
Eosinophilia Eosinophilia uncommonly represents a primary haematological disease. Much more often, it is reactive to a systemic disease (Table 3).3 A KEY REFERENCES 1 Cullis JO. Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol 2011; 154: 289e300. 2 Brace W, Bain B, Walker M, Catovsky D. Teaching cases from the Royal Marsden Hospital Case 9: an elderly patient with unusual circulating cells. Leuk Lymphoma 1995; 18: 529e30. 3 Bain BJ. Blood cells. 5th edn. 2015. Oxford: Wiley‒Blackwell, 2015. 4 Thomas DW, Hinchliffe RF, Briggs C, et al. Guideline for the laboratory diagnosis of functional iron deficiency. Br J Haematol 2012; 161: 639e48. 5 Silverberg DS, Wexler D, Palazzuoli A, et al. The anemia of heart failure. Acta Haematol 2009; 122: 109e19.
Table 3
Heart failure Heart failure can lead to anaemia. This can be the result of associated impaired renal function and reduced erythropoietin synthesis plus increased cytokine production; this depresses marrow function, contributes to depression of erythropoietin synthesis and increases hepcidin synthesis (leading to actual or functional iron deficiency/anaemia of chronic disease).5 Iron therapy, particularly intravenous iron, can be of benefit, as can erythropoiesis-stimulating agents. Heart failure is also associated
TEST YOURSELF To test your knowledge based on the article you have just read, please complete the questions below. The answers can be found at the end of the issue or online here.
Question 1
What is the most likely diagnosis? A. b-Thalassaemia B. Anaemia of chronic disease C. Felty’s syndrome D. Iron deficiency anaemia E. Iron deficiency plus anaemia of chronic disease
A 44-year-old Greek woman was attending outpatients. She was taking a non-steroidal anti-inflammatory drug for rheumatoid arthritis. Investigations Haemoglobin 98 g/litre (115e165) Mean cell volume 75 fl (80e96) Serum ferritin 78 micromol/litre (15e300) Erythrocyte sedimentation rate 65 mm/hour (<20)
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Question 2 A 34-year-old white British woman presented with fatigue and pallor. She had a history of dermatitis herpetiformis for which she was taking dapsone.
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Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002
THE BLOOD IN SYSTEMIC DISEASE
Investigations Haemoglobin 98 g/litre (115e165) Mean cell volume 105 fl (80e96) White cell count 13.4 109/litre (4.0e11.0) Neutrophils 5.9 109/litre (1.5e7.0) Lymphocytes 6.2 109/litre (1.5e4.0) Platelets 340 109/litre (150e400) Reticulocytes 180 109/litre (0.5e2.4) A blood film showed red cell agglutinates and atypical lymphocytes, some of which were plasmacytoid Chest X-ray showed consolidation in the right upper zone
Investigations Haemoglobin 78 g/litre (115e165) Mean cell volume 107 fl (80e96) A blood film showed macrocytosis, oval macrocytes and hypersegmented neutrophils What is the most likely diagnosis? A. Excess alcohol consumption B. Folic acid deficiency C. Hypothyroidism D. Oxidant-induced haemolysis E. Vitamin B12 deficiency
Question 3
What is the most likely diagnosis? A. EpsteineBarr virus infection B. Cytomegalovirus infection C. Dengue fever D. Mycoplasma pneumoniae infection E. Primary infection with human immunodeficiency virus
A 34-year-old woman Italian woman who lives in the UK presented with cough and fever. On examination, she showed bronchial breathing and increased vocal resonance over the right upper lobe. The tip of the spleen was felt. There was no lymphadenopathy.
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Ó 2017 Published by Elsevier Ltd.
Please cite this article in press as: Bain B, The blood in systemic disease, Medicine (2017), http://dx.doi.org/10.1016/j.mpmed.2017.02.002