Session 6 Flashcards
How does anaemia of chronic disease / anaemia of inflammation cause anaemia?
Anaemia of chronic disease (also called anaemia of inflammation) is a common cause of anaemia (2nd worldwide after iron deficiency) associated with chronic inflammatory conditions such as rheumatoid arthritis, chronic infections (e.g. tuberculosis) and malignancy. The chronic release of cytokines such as IL-6 in such inflammatory conditions increases the production of hepcidin by the liver. Increased hepcidin results in less iron absorption from the gut and less release of iron from stores by decreasing ferroportin expression and promoting internalisation of ferroportin molecules. Anaemia of chronic disease can therefore be thought of as a functional loss of iron (total iron stores in the body may be normal, it’s just that the iron is not being made available for erythropoiesis in the bone marrow). Similar to iron deficiency anaemia, in the early stages of the disease MCV is normal but as the disease progresses microcytic anaemia results. Increased activity of macrophages in the underlying chronic inflammatory condition also reduces the lifespan of red blood cells. Furthermore cytokines released due to the underlying inflammation also exert inhibitory effects on erythropoiesis by limiting proliferation and differentiation of red cell progenitors and blunting the response to erythropoietin. (Bone marrow becomes less responsive to erythropoietin).
The primary treatment for anaemia of chronic disease is to treat the underlying disorder
How does chronic kidney disease cause anaemia?
Patients with chronic kidney disease typically develop normochromic normocytic anaemia with the severity of anaemia being proportional to the severity kidney disease i.e. the lower the GFR (glomerular filtration rate) the higher the severity of the anaemia. There are a number of factors underlying the development of anaemia in chronic kidney disease with a deficiency of erythropoietin production by the damaged kidneys usually the most dominant. Lower levels of erythropoietin in the circulation results in a lower level of erythropoiesis in bone marrow leading to insufficient red cell production and anaemia. Damaged kidneys also result in a reduced renal clearance of hepcidin from blood and, together with an associated inflammatory mediated increase in hepcidin production by the liver, the same mechanisms that come into play in anaemia of chronic disease (see above) also act to reduce erythropoiesis due to a functional lack of iron in chronic kidney disease. Kidney dysfunction can result in uraemia and this increase in urea concentration in blood acts to inhibit erythropoiesis and reduces the lifespan of existing red blood cells as well as inhibiting platelet function, which can cause chronic bleeding from the gastrointestinal tract. Furthermore, anaemia can be worsened in patients requiring regular haemodialysis due to loss and mechanical destruction of red blood cells.
Erythropoietin (recombinant human forms) are commonly used in the management of renal anaemia. However, care needs to be taken as adverse effects such as hypertension, seizures, and blood clotting during dialysis can occur. Furthermore, erythropoietin will only be effective in patients with sufficient iron, folate and B12 to support an increase in erythropoiesis.
How does rheumatoid arthritis cause abnormalities in blood?
The anaemia of chronic disease is often proportional to the severity of disease. Co-existing iron-deficiency can be difficult to diagnose but also occurs more commonly in this disease due to the need for NSAIDs and corticosteroids which can cause gastrointestinal blood loss.
In flares of this disease neutrophilia and thrombocytosis may be present, whereas some of the disease-modifying anti-rheumatic drugs (DMARDs) cause thrombocytopenia and/or neutropenia through marrow suppression, immune causes or folate-inhibition. Felty’s syndrome is the triad of Rheumatoid arthritis, splenomegaly and neutropenia.
How does alcoholism cause blood abnormalities?
Chronic excessive alcohol consumption has a range of adverse effects on the marrow, spleen and blood cells. Heavy alcohol consumption results in a generalised toxic effect on bone marrow leading to the suppression of haematopoiesis and resulting in the production of structurally abnormal blood cell precursors that cannot mature into functional cells. Red cells become macrocytic and thrombocytopenia is common. Acetaldehyde produced from ethanol metabolism can produce protein-acetaldehyde adducts on red blood cells leading to an immune response against these modified proteins. Cirrhosis of the liver can also result in abnormal production of some of the clotting factors and this contribute to gastrointestinal bleeding contributing to anaemia. Furthermore, portal hypertension may lead to congestive splenomegaly and splenic trapping of red cells, white cells and platelets resulting in progressive pancytopaenia. Alcohol abuse is also a common cause of folic acid deficiency leading to a megaloblastic anaemia.
Give an example for what might cause each of the following: Neutrophila Neutropenia Lymphocytosis Lymphopenia Eosinophilia DIC MAHA Splenomegaly Aplastic anaemia
Neutrophila - Bacterial infection Neutropenia - Post-viral infection Lymphocytosis - Viral infection in children e.g. Bordatella Pertussis Lymphopenia - HIV Eosinophilia - Parasitic infection DIC - Sepsis MAHA - E. coli diarrhoea in children Splenomegaly - Malaria, glandular fever Aplastic anaemia - Viral hepatitis
What kind of changes in the blood may you see in a patient post operation?
Following major surgery patients often have a mild thrombocytosis or neutrophilia which should settle. Anaemia can be present due to blood loss or dilution (by peri-operative intravenous fluid) and, in the context of a normal bone marrow and normal reserves / dietary content of iron, folate and B12 will resolve spontaneously. Worsening neutrophilia or thrombocytosis could represent the development of an infective complication, as would DIC. Immobile patients post-operatively are at increased risk of deep vein thrombosis, particularly in the context of cancer, dehydration and/or pelvic or orthopaedic surgery.
Immediately post-splenectomy there is often a very high rebound thrombocytosis and lymphocytosis and this can persist in some patients long-term. Howell-Jolly bodies will be seen in the red cells.
What type of changes in the blood may you see in a patient with cancer?
Patients with non-haematological cancer e.g. lung, breast can have many manifestations in the blood.
A fall in Hb can occur as an anaemia of chronic disease or due to blood loss, haemolytic anaemia, infiltration of the bone marrow or due to chemotherapy interrupting blood cell production.
Patients receiving chemotherapy may need blood product support (donor red cells or platelets) and are at risk of neutropenic sepsis.
If the bone marrow is infiltrated by metastatic cancer a leucoerythroblastic blood film may be seen (immature white cells and nucleated red blood cells seen in the blood, often in the context of a pancytopenia)
People with active cancer are at a much greater risk of venous thrombo-embolism (deep vein thrombosis and pulmonary embolism)
What is the purpose of homeostatic mechanisms?
Homeostatic mechanisms act to counteract changes in the internal environment
•Variables are regulated so that internal conditions remain stable and relatively constant
Give an example for homeostasis at each cellular level
- Cell (e.g. regulation of intracellular Ca2+concentration)
- Tissue (e.g. balance between cell proliferation and cell death (apoptosis)
- Organ (e.g. Kidney regulates water and ion concentrations in blood)
- Organism (e.g. constant body temperature)
Describe how a negative feedback system works
First there is a stimulus.
This is then detected by a receptor e.g
•Chemoreceptors
•Thermoreceptors
•Proprioceptors
•Nociceptors
Then the receptor communicates via the nervous or endocrine system as part of the afferent pathway to a control centre.
The control centre determines the set point, analyses the afferent input and then determines the set response.
It then communicates to an effector via the efferent pathway through the nervous and endocrine system.
The effector causes the change for example in sweat glands, muscle, kidney.
How does the body follow a biological clock?
- Set point of control centre can vary
- Circadian(or diurnal) rhythm
- “Biological clock” in brain in small group of neurones in suprachiasmatic nucleus
- Cues from the environment (Zeitgebers) keep body on a 24 hour cycle.
- Light
- Temperature
- Social interaction
- Exercise
- Eating/drinking pattern
- Long haul flights crossing time zones can result in mismatch between environmental cues and body clock causing jet lag
- Hormone melatonin from pineal gland involved in setting biological clock
What is an erythroid island and when might we see it?
Macrophage “nursing” immature erythrocytes and providing them with recycled iron from phagocytosed old RBCs. the immature erythrocytes surround the macrophage forming a type of island.
How does iron leave macrophages?
Through ferroportin
What is uraemia and how can it cause anaemia?
Higher than normal urea which can reduce lifespan of RBCs. Uraemia also inhibits megakaryocytes leading to low platelet counts
What would the investigations look like for someone of anaemia of chronic disease?
Often normocytic normochromic or microcytic anaemia
Normal or high ferritin
Normal or high Reticulocyte Haemoglobin content (CHr)
CRP often elevated
What is the management for anaemia of chronic renal failure?
Use Reticulocyte Haemoglobin Content (CHr) (or % hypochromic cells) to assess for functional iron deficiency
Give iron if ferritin <200μg/L (normal range 15-400μg/L ) or CHr low
Iron given in intravenous form as absorption is impaired (….Hepcidin)
Why might you get haematological abnormalities in renal disease?
Erythrocytes Low •ARF/ACD •Blood loss •Haematinic causes High •Post renal transplant •Renal tumour
Neutrophils •immunosuppression due to post renal transplant drugs •marrow infiltration egin myeloma High •inflammation •connective tissue disease •Infection •drugs: steroids cause neutrophilia
Platelets •direct effect of uraemia on platelet production •Many drugs •Haemolytic uraemic syndrome High •reactive to cytokines •bleeding •iron deficiency
What is rheumatoid arthritis and how is it treated?
Chronic immune mediated inflammatory condition
Treated with
◦Analgesis often NSAIDs
◦Corticosteroids
◦Chemotherapy eg methotrexate
◦Biological agents –monoclonal antibodies
Why might you get haematological abnormalities in rheumatoid arthritis?
Erythrocytes Low •Anaemia of chronic disease •blood loss eg due to NSAIDs/corticosteroids •Haematinic from loss of appetite •Immune cytopenia
Neutrophils High •Associated inflammation •infection •drug reactions….. Low •drugs eg methotrexate •immune
Platelets High •reactive •bleeding •iron deficiency Low •drugs, autoimmune splenomegaly (Felty’s)
What is Felty’s syndrome?
Rheumatoid arthritis, splenomegaly and neutropenia.
Neutropenia
◦ Secondary to splenomegaly, peripheral destruction of neutrophils, and failure of bone marrow to produce neutrophils
◦ high level of G-CSF, insensitivity of myeloid cells to cytokines
How can liver cirrhosis cause splenomegaly?
Portal Hypertension causes
splenomegaly from the back pressure, which leads to:
•Splenic sequestration of cells
•Overactive removal of cells
What are the haematological features of liver disease?
Portal hypertension also leads to oesophageal and gastric varices (dilated veins prone to bleeding
due to higher than normal pressure), so regular endoscopies.
Blood loss from varices or lack of platelets and clotting factors causing other bleeding
Deficiencies of coagulation factors
Endothelial dysfunction
Thrombocytopenia
Defective platelet function
