Haematology
A 65 year old man is brought to the Emergency Department after collapsing at home. His full blood count shows a microcytic anaemia. Which of the following does NOT typically cause a microcytic anaemia?
Answer:
- Microcytic anaemia (MCV < 80 fl)
- Iron deficiency
- Thalassaemia
- Sideroblastic anaemia
- Anaemia of chronic disease (some cases)
- Lead poisoning
Anaemia
Haematology
Last Updated: 12th February 2021
Definition
Anaemia is defined as a haemoglobin (Hb) level two standard deviations below the normal for age and sex:
- In men aged over 15 years — Hb below 130 g/L
- In non-pregnant women aged over 15 years — Hb below 120 g/L
- In children aged 12–14 years — Hb below 120 g/L
- In pregnant women — Hb below 110 g/L throughout pregnancy
- Postpartum — below 100 g/L
Pathophysiology
Anaemia may occur from an actual reduction in total circulating haemoglobin mass, or with an increase in plasma volume e.g. in pregnancy, causing a dilutional anaemia. Likewise, a reduction in plasma volume may mask anaemia or even cause an apparent polycythaemia. After acute major blood loss, anaemia is not immediately apparent because total blood volume is reduced and it takes up to a day for plasma volume to be replaced and hence the degree of anaemia to become apparent. The initial clinical features in acute haemorrhage are therefore a result of reduction in blood volume rather than that of anaemia.
Clinical Features
When anaemia develops slowly, the associated symptoms are often very mild as the body has time to adapt to the fall in haemoglobin. This involves mechanisms such as an increase in red cell 2,3 -diphosphoglycerate (2,3 - DPG), which shifts the oxygen dissociation curve to the right, allowing enhanced delivery of O2 to the tissues, and an increase in stroke volume and heart rate. In acute onset anaemia, a lack of physiological adaptation leads to more marked symptoms and signs. Significant symptoms may also occur in more mild anaemia in older patients with impaired cardiovascular reserve.
Non-specific symptoms of anaemia include:
- Dyspnoea
- Fatigue
- Headache
- Dizziness
- Weakness
- Palpitations
- Tinnitus
- Cognitive changes
- Worsening of angina, congestive heart failure or intermittent claudication
Non-specific signs of anaemia include:
- Pallor of mucous membranes or nail beds (if Hb < 90 g/L)
- Tachycardia, murmurs, cardiac enlargement, and heart failure may occur if anaemia is severe (Hb < 80 g/L)
Causes
Anaemia can be classified according to the red cell size or mean cell volume (MCV), into microcytic, normocytic and macrocytic anaemia. This classification is not perfect, as some conditions can straddle two categories e.g. anaemia of chronic disease is usually normocytic, but may be microcytic or there may be combined macrocytic and microcytic causes cancelling each other out to produce an apparent normocytic anaemia.
- Microcytic anaemia (MCV < 80 fl)
- Iron deficiency
- Thalassaemia
- Sideroblastic anaemia
- Anaemia of chronic disease (some cases)
- Lead poisoning
- Normocytic anaemia (MCV 80 -96 fl)
- Most haemolytic anaemias
- Anaemia of chronic disease (most cases)
- Mixed cases
- Macrocytic anaemia (MCV > 96 fl)
- Megaloblastic anaemia
- Vitamin B12 deficiency
- Folate deficiency
- Other non-megaloblastic causes
- Alcohol - may cause macrocytosis with neither anaemia nor a change in liver function
- Drugs — antimetabolites, such as hydroxycarbamide, methotrexate and azathioprine
- Haematological abnormalities - myelodysplasia, aplastic anaemia, pure red cell aplasia, myeloma, reticulocytosis
- Liver disease — chronic liver disease is associated with anaemia that is mildly macrocytic
- Pregnancy and the neonatal period
- Severe thyroid deficiency — anaemia caused by hypothyroidism is often macrocytic
- Smoking
- Megaloblastic anaemia
Iron Deficiency Anaemia
Iron deficiency anaemia is the most common cause of microcytic anaemia and of any anaemia worldwide.
Causes
- Inadequate intake:
- Dietary iron deficiency is fairly uncommon in the UK
- Growing children and elderly people with iron-poor diets may become deficient
- Excessive requirements:
- Pregnancy, menstruation, lactation
- Times of rapid growth in children
- Exfoliative skin disease
- Malabsorption:
- Drugs e.g. tetracyclines, quinolones, antacids and proton pump inhibitors
- Partial or total gastrectomy
- Coeliac disease, inflammatory bowel disease (IBD), Helicobacter pylori infection
- Excessive loss:
- Blood loss from the gastrointestinal (GI) tract is the most common cause of iron deficiency anaemia in adult men and postmenopausal women. It can be caused by aspirin or nonsteroidal anti-inflammatory drug use, colonic carcinoma, gastric carcinoma, benign gastric ulceration, or angiodysplasia.
- Blood loss due to menstruation is the most common cause of iron deficiency anaemia in pre-menopausal women.
- In tropical countries, infestation of the gut is a common cause of iron deficiency, especially with hookworm and schistosomiasis.
Clinical Features
- General features of anaemia
- Specific features of iron deficiency:
- Koilonychia (spoon-shaped nails with longitudinal ridging)
- Angular cheilitis (ulceration at the corners of the mouth)
- Atrophic glossitis (painful smooth red tongue)
- Pica (unusual dietary cravings)
- Dry and rough skin, dry and damaged hair
- Diffuse and moderate alopecia
Laboratory Findings
- Hypochromic microcytic anaemia
- Blood film appearances:
- Increased percentage of hypochromic red cells
- Anisocytosis (variation in the size of red blood cells)
- Poikilocytosis (presence of irregular shaped red blood cells)
- Characteristic 'pencil cells'
- Iron status:
- ↓ Serum ferritin (serum ferritin level of less than 15 micrograms/L confirms iron deficiency)
- ↓ Serum iron
- ↑ Transferrin
- ↓Transferrin saturation
- ↑ Total iron binding capacity (TIBC)
Megaloblastic Anaemia
Megaloblastic anaemia is characterised by an abnormal appearance of the bone marrow erythroblasts in which nuclear development is delayed and nuclear chromatin has a lacy open appearance.
Pathophysiology
Megaloblastic anemia results from inhibition of DNA synthesis during red blood cell production. When DNA synthesis is impaired, the cell cycle cannot progress from the growth stage to the mitosis stage. This leads to continuing cell growth without division, which presents as macrocytosis. The defect in red cell DNA synthesis is most often due to hypovitaminosis, specifically vitamin B12 deficiency or folate deficiency.
Causes of Vitamin B12 and Folate Deficiency
Causes of vitamin B12 deficiency:
- Pernicious anaemia (most common cause of severe B12 deficiency)
- Normally, vitamin B12 combines with IF, which is produced by parietal cells in the stomach, to form an IF–B12 complex. The complex binds to surface receptors for IF in the distal ileum, which then allows absorption of vitamin B12 to take place. Pernicious anaemia is caused by an autoimmune process which affects the gastric mucosa, leading to atrophy. This atrophy reduces the number of parietal cells which secrete intrinsic factor (IF).
- Drugs — colchicine, metformin, nitrous oxide, proton pump inhibitors, H2-receptor antagonists
- Gastric — total or partial gastrectomy, congenital intrinsic factor deficiency or abnormality, Zollinger-Ellison syndrome
- Inherited — intrinsic factor receptor deficiency (Imerslund Gräsback syndrome), congenital intrinsic factor deficiency (juvenile pernicious anaemia), cobalamin mutation, transcobalamin deficiency
- Intestinal — malabsorption (for example gluten-induced enteropathy), ileal resection, Crohn's disease, blind loop syndrome, parasites (for example, giardiasis, fish tapeworm)
- Nutritional — malnutrition, vegan diet
Causes of folate deficiency:
- Drugs — alcohol, anticonvulsants, nitrofurantoin, sulfasalazine, methotrexate, trimethoprim
- Increased requirements, for example, due to:
- Pregnancy and lactation, prematurity
- Malignancy (for example leukaemia, carcinoma, or lymphoma)
- Blood disorders (for example haemolytic anaemias, sickle cell anaemia, myelofibrosis)
- Inflammatory diseases (for example tuberculosis, Crohn's disease, or malaria)
- Exfoliative skin diseases
- Excessive urinary excretion (for example due to congestive heart failure, acute liver damage, or chronic dialysis)
- Liver disease
- Malabsorption — due to coeliac disease, tropical sprue, congenital specific malabsorption, jejunal resection, or inflammatory bowel disease
- Nutrition — alcoholism or dietary fads
Clinical Features
- General features of anaemia
- Specific features of B12/folate deficiency:
- Increased incidence of foetal neural tube defects in pregnancy
- Lemon yellow tinge (combination of pallor and jaundice)
- Atrophic glossitis
- Angular cheilitis
- Specific features of B12 deficiency:
- Neurological symptoms — for example, paraesthesia, ataxia, progressive symmetrical neuropathy which affects the legs more than the arms, numbness, poor motor coordination, memory lapses, and age-related cognitive impairment
Laboratory Features
- Macrocytic anaemia
- Blood film appearances:
- Oval macrocytes
- Hypersegmented neutrophils
- Circulating megaloblasts
- Low B12 or folate
Haemolytic Anaemia
Haemolytic anaemias are caused by a shortened red cell lifespan. Because of erythropoietic hyperplasia and anatomical extension of bone marrow, red cell destruction may be increased several-fold before the patient becomes anaemic.
Causes
Hereditary causes:
- Red cell membrane e.g. hereditary spherocytosis, hereditary elliptocytosis
- Red cell metabolism e.g. glucose-6-phosphate dehydrogenase (G6PD) deficiency, pyruvate kinase deficiency
- Haemoglobin synthesis e.g. thalassaemia, sickle cell disease
Acquired causes:
- Autoimmune e.g. warm or cold antibody type (characterised by a positive direct Coombs test and divided into 'warm' and 'cold' types according to whether the antibody reacts more strongly with red cells at 37 degrees Celsius or 4 degrees Celsius)
- Alloimmune e.g. haemolytic disease of the newborn or haemolytic transfusion reactions
- Red cell fragmentation syndromes e.g. DIC, TTP, HUS
- Infections e.g. malaria
- Drug or chemical-associated
- Secondary to liver or renal disease
- Paroxysmal nocturnal haemoglobinuria
Pathophysiology
Physiological red cell destruction is normally extravascular in the macrophages of the reticuloendothelial system. Globin is degraded to amino acids, haem to protoporphyrin, carbon monoxide and iron. Protoporphyrin is metabolised to biliverdin, and then bilirubin, conjugated to a glucuronide in the liver, excreted in faeces as stercobilinogen and, after reabsorption, in urine as urobilinogen.
Pathological red cell destruction is also usually extravascular. However it may also be intravascular. Some haemoglobin may then appear in plasma, where it is toxic and may cause fever, rigors and tissue damage. It is excreted unchanged in the urine and may cause renal damage. It is also partly reabsorbed by the renal tubules and broken down in the tubular cells to haemosiderin which appears in the urine.
Causes of intravascular haemolysis:
- Haemolytic transfusion reactions
- G6PD deficiency
- Red cell fragmentation syndromes
- Some severe autoimmune haemolytic anaemias
- Some drug-and infection-induced haemolytic anaemias
- Paroxysmal nocturnal haemoglobinuria
Clinical Features
- Anaemia
- Jaundice (caused by unconjugated bilirubin in plasma, bilirubin is absent from urine)
- Pigment gallstones
- Splenomegaly
- Ankle ulcers
- Expansion of marrow with, in children, bone expansion e.g. frontal bossing in beta-thalassaemia major
- Aplastic crisis caused by parvovirus
- Megaloblastic anaemia caused by folate deficiency
Laboratory Features
- Haemoglobin may be normal or reduced
- Reticulocyte count is raised
- Blood film shows polychromasia and altered red cell shape
- Bone marrow shows increased erythropoiesis
- Serum indirect (unconjugated) bilirubin is raised
- Urine urobilinogen is raised
- Serum haptoglobin is absent
- Lactate dehydrogenase is raised
- +/- Features of intravascular haemolysis
- Haemoglobinaemia
- Methaemalbuminaemia
- Haemoglobinuria (dark urine)
- Haemosiderinuria
Anaemia of Chronic Disease
Anaemia of chronic disease is a common normochromic or mildly hypochromic anaemia, occurring in patients with inflammatory and malignant diseases.
Causes
- Chronic infections
- Especially osteomyelitis, bacterial endocarditis, TB, chronic abscesses, bronchiectasis, chronic UTI, HIV, AIDs, malaria
- Chronic inflammatory disorders
- Rheumatoid arthritis, polymyalgia rheumatica, systemic lupus erythematosus, scleroderma, inflammatory bowel disease, thrombophlebitis
- Malignancy
- Especially metastatic, lymphoma
- Other
- Congestive heart failure
Pathophysiology
Hepcidin, released by the liver in response to inflammatory cytokines, reduces iron absorption and iron release by macrophages into plasma. Increased level of cytokines also interact directly with accessory marrow stromal cells, macrophages and erythroid progenitors to reduce erythropoiesis, iron utilisation and response to erythropoietin.
Laboratory Features
- Normocytic or mildly microcytic anaemia
- Moderate anaemia (> 90 g/L), severity correlates to severity of underlying disease
- Reduced serum iron
- Reduced total iron binding capacity (TIBC)
- Reduced transferrin saturation
- Normal or raised ferritin (adequate iron stores in bone marrow but stainable iron absent from erythroblasts)
- Raised ESR and CRP
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
