Haematology in Systemic Disease

1. Anaemia of Chronic Disease
2. Anaemia of Renal Failure
3. Rheumatoid Arthritis
4. Liver Disease
5. Alcohol
6. Post-Operative Changes
7. Infection
8. Cancer
9. Quiz

• Chronic diseases such as rheumatoid arthritis have an effect on the different components of blood. These diseases can eventually result in anaemia of chronic disease.
• Chronic diseases cause the production of cytokines (signalling proteins released during inflammation). Cytokines stimulate hepcidin, a hormone made in the liver that controls iron. Hepcidin blocks iron absorption in the gut and traps iron inside macrophages. The iron is still in the body but cannot be used. This is called a functional iron deficiency, and it leads to anaemia.
• Cytokines also inhibit the production of erythropoietin (EPO), a hormone made by the kidney that stimulates red cell production. This reduces erythropoiesis (the making of red blood cells).
• Macrophage activity in chronic disease is increased which means red blood cells are broken down more quickly, so there are fewer red cells in circulation resulting in anaemia. 
• Chronic conditions that can cause anaemia in these ways include chronic kidney disease and rheumatoid arthritis. The anaemia of chronic liver disease has other causes, described in the liver disease section.

Haematology is often used as a method of diagnosis for diseases of many different types, normally through analysing blood from the patient. An abnormal blood result may be caused by a systemic disease (a disease that affects the whole body). An abnormal result does not have to come from a primary blood disorder (a disease that starts in the blood or bone marrow). Abnormal results come about when one or more of the following is compromised: the production of blood cells, their time in circulation or the removal mechanisms for the blood cells.

The causes of the abnormal results are often multifactorial (there are many contributing causes), because systemic diseases influence the blood in many ways. These influences may come from the disease itself, its complications or its treatment.

Anaemia of Chronic Disease

Anaemia of chronic disease is also known as anaemia of inflammation. It is a very common condition (the commonest anaemia in hospital patients). It is associated with chronic inflammatory conditions (e.g. rheumatoid arthritis and systemic lupus erythematosus, an autoimmune disease that can affect many organs), chronic infections (e.g. tuberculosis) and malignancy (cancer).

In any inflammatory response, cytokines (e.g. interleukin-6, IL-6) are released from immune cells. This release of cytokines has 3 key effects:

1. Firstly, cytokines stimulate the production of hepcidin in the liver. Hepcidin causes ferroportin (the protein that lets iron out of cells and into the blood) to be broken down (see the article on iron metabolism). This has two effects. It decreases the amount of iron absorbed in the gut, and it reduces the release of iron stored in macrophages as ferritin (the iron storage protein). Together these lead to a functional iron deficiency. The deficiency is functional in nature because the iron stores in the body are normal or even raised, but the iron is inaccessible.
2. Secondly, cytokines inhibit erythropoietin (EPO) production by the kidney. This issue is compounded by the fact that cytokines reduce the bone marrow’s responsiveness to the already limited EPO. Overall, erythropoiesis (production of red blood cells) is inhibited.
3. Finally, the inflammation from the disease increases the activity of the macrophages in the reticuloendothelial (RE) system. These are the macrophages in the spleen, liver and bone marrow that remove old cells. This shortens the lives of the red blood cells (erythrocytes). These factors together cause the anaemia.

The MCV (mean cell volume, the average size of the red cells) is usually normal, so the anaemia is normocytic (normal-sized red cells) and normochromic (normal colour). It becomes microcytic (smaller than normal red cells) if iron deficiency also develops.

Anaemia of Renal Failure

The severity of kidney failure in chronic kidney disease (CKD) is usually proportional to the severity of anaemia experienced. Renal function and dysfunction can affect erythropoiesis through several mechanisms:

• Clearance of Hepcidin: the failing kidneys clear less hepcidin. Its level in the blood rises, so its effects on iron (described above) are greater.
• Erythropoietin Production: damage to the kidneys decreases the amount of erythropoietin produced. With less EPO produced there is less stimulation of the bone marrow, so reduced proliferation (multiplication) of the erythrocytes.
• Raised Cytokines: chronic inflammation in the kidneys increases cytokine release from the immune cells. As stated above, this decreases the bone marrow’s response to EPO.
• Uraemia: if the kidneys are failing they are ineffective at filtering and removing urea (a waste product) from the blood, leading to uraemia. This causes inflammation of the blood vessels and so raises the number of cytokines. Uraemia also impairs platelet function, so platelets stick together and to the vessel wall poorly, which increases the risk of bleeding. Finally, uraemia directly reduces the erythrocyte lifespan.
• Dialysis (treatment that does some of the work of failed kidneys): this can cause damage to the erythrocytes as they pass through the dialysis machine. Note there is also the possibility of bleeding with haemodialysis (dialysis that filters the blood through a machine).

Renal anaemia is typically normocytic (normal-sized red cells) and normochromic (normal colour) on investigation, and becomes microcytic (small red cells) if iron deficiency is also present. It is hypoproliferative: the bone marrow makes too few new red cells, so the reticulocyte count (reticulocytes are immature red blood cells) is low, not high. Ferritin (the iron storage protein) can be normal or raised because inflammation increases it, so NICE advises against using ferritin alone to assess iron deficiency in CKD. Note that CRP (C-reactive protein, a blood marker of inflammation) is often raised due to inflammation. The anaemia is treated alongside the CKD, not after it. Check the haematinics (substances needed to make red cells: B12, folate and iron) and optimise iron status. Do this before, or at the same time as, starting an erythropoiesis-stimulating agent (ESA, a drug that works like EPO). ESAs are offered to people who are likely to benefit. The usual target is a haemoglobin of 100 to 120 g/litre rather than a normal level. Iron is usually given IV (into a vein) in people on haemodialysis and in adults who are receiving an ESA. This is because absorption of oral iron is reduced by the action of hepcidin. In people who are not having haemodialysis and are not receiving an ESA, NICE advises considering a trial of oral iron before IV iron. Blood transfusion is not routine treatment for this anaemia. NICE advises avoiding transfusion if possible in people who may have a kidney transplant, and using it only when it is clinically indicated.

Abnormal blood results in a patient with CKD can be caused by a wide range of factors. Here are a few suggested causes to consider:

• Erythrocyte count:
  
  • Anaemia (low):
    
    • Diabetes is a common cause of chronic kidney disease. Chronic kidney disease in turn leads to anaemia through the mechanisms described above.
    • Other haematinic causes include iron deficiency.
  • Polycythaemia (high red cell count):
    
    • Erythropoietin-secreting renal tumours can increase haematopoiesis (the making of blood cells).
• White cell count:
  
  • Neutropenia (low neutrophil count):
    
    • The patient could be on immunosuppression medication (drugs that dampen the immune system) after a kidney transplant to prevent rejection.
    • Bone marrow inflammation can reduce the production of white cells.
  • Neutrophilia (high neutrophil count):
    
    • Inflammation leads to increased white cell activation.
    • Steroids, which can be given to reduce immune causes of kidney failure, can themselves raise the neutrophil count.
    • Any infection in the kidney could raise the white cell count.
• Platelet count:
  
  • Thrombocytopenia (low platelet count):
    
    • If present, uraemia may reduce platelet production by the megakaryocytes (the bone marrow cells that make platelets), although the exact mechanism is not settled.
    • Some drugs used to treat renal failure can cause a low platelet count.
  • Thrombocytosis (high platelet count):
    
    • If the patient is iron deficient this can lead to an increased count.

Rheumatoid Arthritis

Image - A hand with rheumatoid arthritis

Creative commons source by James Heilman, MD [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory condition which primarily targets the small joints in the hand causing pain and joint stiffness. Firm swellings known as rheumatoid nodules can develop under the skin around the affected joints in the later stages of disease. These nodules are made up of fibrous tissue surrounding a central area of fibrinoid necrosis. Fibrinoid necrosis is a form of tissue death. In a typical nodule the area of fibrinoid necrosis is surrounded by palisading epithelioid macrophages (macrophages lined up around the dead tissue).

RA is treated with disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate (a drug that dampens the immune system). NICE advises starting a DMARD as soon as possible, ideally within 3 months of the start of persistent symptoms, to control inflammation and slow disease progression. Corticosteroids (steroid anti-inflammatory drugs, such as prednisolone) can be given for a short time while a new DMARD takes effect. Non-steroidal anti-inflammatory drugs (NSAIDs, such as ibuprofen) can be considered when pain or stiffness is not controlled. NICE advises the lowest effective dose for the shortest possible time, together with a proton pump inhibitor (PPI, a drug that reduces stomach acid) to protect the stomach.

There is a correlation between the severity of the rheumatoid arthritis and the severity of the anaemia of chronic disease resulting from the inflammation.

Abnormal blood results in a patient with RA can be caused by a wide range of factors. Here are a few suggested causes to consider:

• Erythrocyte count:
  
  • Anaemia
    
    • Anaemia of chronic disease.
    • Long-term NSAID use can cause peptic ulcers (sores in the lining of the stomach or duodenum). This can cause blood loss leading to iron deficiency and anaemia.
    • A haematinic deficiency (a lack of vitamin B12, folate or iron) is always a possibility, so consider it when other causes have been excluded.
    • Methotrexate compromises the folate pathway: it inhibits the enzyme dihydrofolate reductase, which is essential for making purines and pyrimidines (building blocks of DNA). Patients on methotrexate are therefore given folic acid as a supplement to reduce side-effects such as mouth ulcers and nausea, usually once a week on a different day from the methotrexate. There is no evidence that folic acid reduces the harmful effects of methotrexate on the blood (such as low blood counts), so patients on methotrexate need regular full blood counts.
• White cell count:
  
  • Neutrophilia
    
    • Patients being treated with corticosteroids can have a high white cell count, because corticosteroids can cause a neutrophilia.
    • Patients are susceptible to infections if on steroids. Any infection could raise the white cell count. The exception is a patient who is already neutropenic, for example because of methotrexate, which can reduce blood counts. Infection in a neutropenic patient can become neutropenic sepsis (sepsis with a very low neutrophil count), which needs immediate assessment in hospital.
• Platelet count:
  
  • Thrombocytopenia
    
    • Immune dysfunction is often related to RA. When it is present, platelets may be destroyed faster.
    • If present, splenomegaly (an enlarged spleen) will increase the rate of platelet destruction.
  • Thrombocytosis
    
    • Inflammation can cause a reactive thrombocytosis (a raised platelet count caused by another condition rather than a bone marrow disorder). Cytokines such as interleukin-6 stimulate thrombopoietin (the hormone that stimulates platelet production), which raises the platelet count. Iron deficiency, for example from blood loss from a peptic ulcer caused by NSAIDs, can also raise the platelet count.

Diagram - Felty's syndrome triad

SimpleMed original by Dr. Tom Bradley

Felty’s syndrome is a triad of rheumatoid arthritis, splenomegaly and neutropenia. Thrombocytopenia and anaemia are also associated with the syndrome. The neutropenia has more than one cause. White cells are destroyed faster by the reticuloendothelial system, and they are trapped (sequestered) in the spleen. The bone marrow also produces fewer neutrophils. Possible causes include suppression by large granular lymphocytes (lymphocytes with visible granules) and antibodies against G-CSF (granulocyte colony-stimulating factor, the cytokine that stimulates neutrophil production). The immune processes in rheumatoid arthritis can also lead to the destruction of white cells in the peripheral circulation.

Liver Disease

Chronic liver disease (cirrhosis) will lead to portal hypertension (raised pressure in the portal vein, which carries blood from the gut to the liver). This happens because the scarring of the liver restricts blood flow through it. This causes a backup of blood into the portal system and therefore an increased pressure within. This portal hypertension causes a pooling of blood within the spleen and so leads to splenomegaly. The splenomegaly causes excess sequestration and removal of cells within the spleen, reducing the red and white cell count.

The portal hypertension can also cause oesophageal and gastric varices (swollen, enlarged veins). Varices occur at points where the portal system and systemic circulation meet. Because pressure in the portal system is high, blood is shunted through small surface veins into the lower-pressure systemic circulation. This increased blood flow through these small veins leads to them becoming enlarged and at risk of bursting and leading to bleeding which can be very severe. The bleeding can be made worse by the deficiency of vitamin K dependent clotting factors II (prothrombin), VII, IX and X which accompanies liver disease. This happens because the liver normally makes all of these factors, and in cirrhosis it makes less of them. Levels of various other clotting proteins also fall. However, clotting is not simply impaired. Changes that favour bleeding and changes that favour clotting happen together, so haemostasis (the balance between bleeding and clotting) is rebalanced rather than lost. Patients with cirrhosis can therefore have clotting complications as well as bleeding. A prolonged prothrombin time (PT, a blood test that measures how long the blood takes to clot) is common in liver disease, but by itself it does not show a high risk of bleeding. The balance is relatively unstable, so a patient can still bleed or form clots. Blood loss in this way can lead to anaemia in patients with liver disease and can cause iron deficiency.

Patients with advanced liver disease can develop a haemolytic anaemia (anaemia caused by red cells breaking down early) called spur cell anaemia. Changes in the lipids of the erythrocyte membrane lead to abnormally shaped erythrocytes called acanthocytes, which have irregularly spaced spikes. These rigid cells are more prone to damage during circulation and are destroyed early in the spleen, which contributes to the haemolytic anaemia. Zieve’s syndrome is a separate and rare cause of haemolytic anaemia. It is classically defined by haemolytic anaemia, hyperbilirubinaemia (a high bilirubin level, which causes jaundice) and transient hyperlipidaemia (raised blood lipids) after recent heavy alcohol use.

Thrombocytopenia is common in chronic liver disease as levels of thrombopoietin, synthesised mainly in the liver, are reduced. Thrombopoietin’s function is to stimulate the production of platelets by the megakaryocytes in the bone marrow. Due to splenomegaly, patients will also pool and destroy platelets in the spleen. (Some immune causes of liver disease also produce antibodies against platelets.) Platelet function is also altered in liver disease, as part of complex changes in the clotting system. A low platelet count is therefore only one factor in the risk of bleeding.

Acute hepatitis (inflammation of the liver) can rarely be followed, weeks to months later, by bone marrow failure. This is called hepatitis-associated aplastic anaemia. Most cases follow hepatitis in which no virus can be found. In aplastic anaemia there is marked loss of haematopoietic (blood-forming) stem cells and the marrow is replaced with fat.

Preview the Haematology in Systemic Disease quiz