Anaemia

Anaemia is a quantitative deficiency of haemoglobin (Hb). Haemoglobin is the oxygen-carrying component of RBCs.

The WHO defines anaemia as:

• Hb <130g/L in men aged >15 years.
• Hb <120g/L in women aged >15 years.
• Hb <110g/L in pregnant women.

🏃🏻‍♀️ Physiology

First, let’s recap what haemoglobin does and how it works:

Haemoglobin is made of four subunits, 2 alpha subunits and 2 beta subunits. Each of these subunits contains a haem group with iron. This allows it to bind to oxygen (4 molecules of oxygen per haemoglobin).

Hb is able to change shape (i.e. affinity) depending on the number of oxygen molecules bound to it. As more molecules bind to Hb, its affinity increases. This is known as cooperativity. If no oxygen is bound, Hb is in a tense state (T-state) and when the first oxygen binds, it changes to a relaxed state (R-state) with more affinity.

Oxyhaemoglobin reaching tissues with low pO2 causes a dissociation of oxygen → increasing local pO2.

When there is a higher pO2 concentration (as in the pulmonary circuit), Hb will bind to oxygen and will dissociate from CO2 (carbaminohaemoglobin).

2,3-DPG, temperature, pH, pCO2 all affect oxygen affinity.

Let’s recap erythropoiesis quickly:

Our body produces approximately 2.5 billion erythrocytes per kg per day.

Erythropoiesis occurs in the yolk sac within the early foetus, before changing to the liver and spleen between 2-5 months. At 5 months it finally moves to bone marrow. In children, most bones’ bone marrow can produce RBCs, however, in adults it is mostly in the vertebrae, ribs, sternum, sacrum, pelvis and proximal femur.

Extramedullary haemotopoiesis may be triggered when there is insufficient bone marrow production (it is triggered by erythropoietin which is produced by the kidneys in response to hypoxia) which can be seen in thalassemias, myelofibrosis and other haemoglobinopathies.

A multipotent haematopoietic stem cell (MHSC) known as a haemocytoblast is the origin of all blood cells. They differentiate into a common myeloid progenitor which will go on to produce RBCs, mast cells, megakaryocytes (which then form thrombocytes) and myeloblasts (which then form myeloid WBCs).

Let’s look at the steps between our common myeloid progenitor and our mature erythrocyte:

We progress from a CMP to a megakaryocyte erythroid progenitor (which makes erythrocytes and megakaryocytes). It then forms into a proethryoblast which is the earliest identifiable morphological precursor of an RBC. As our erythroid cells mature, they shrink and lose their nuclei. The reticulocyte is the first erythroid cell to be anucleate. It retains some RNA to produce haemoglobin in the bone marrow and then enters peripheral blood where its RNA is lost → mature RBC.

RBCs are cleared via the spleen when they are senescent (age-related), rigid or abnormally shaped. This is because they are unable to squeeze through the splenic slits and are retained in the spleen before being cleared. A normal RBC lifespan lasts from 110-120 days.

Pathophysiology

There are numerous causes of anaemia, but simply put we can break it down into 3 causes:

1. Blood loss
2. Decreased RBC production
3. Increased RBC destruction - haemolytic causes of anaemia will be discussed separately in its own CCC on haemolytic anaemia.

🔢 Classification

We can classify anaemias based in the size of the RBC which is reflected as the MCV (mean corpuscular/cell volume).

A normal MCV lies between 80-100fL.

We can therefore classify anaemias as:

1. Microcytic - <80fL
2. Normocytic - 80-100fL
3. Macrocytic - >100fL

🐈

TAILS for microcytic anaemias:

T - Thalassaemia

A - Anaemia of chronic disease

I - Iron deficiency anaemia

L - Lead poisoning

S - Sideroblastic anaemia

3 A’s and 2 H’s for normocytic anaemias:

A - Acute blood loss

A - Anaemia of chronic disease

A - Aplastic anaemia

H - Haemolytic anaemia

H - Hypothyroidism

In this CCC we will look at some microcytic anaemias* (iron deficiency, sideroblastic, lead poisoning, anaemia of chronic disease) and aplastic anaemia.

The other anaemias will be covered in vitamin B12/folate deficiency, haemolytic anaemia, and anaemia of renal disease CCCs.

Although thalassemia may be a cause of microcytic anaemia, we will cover it in haemolytic anaemias as it is more relevant within that topic.

IRON DEFICIENCY ANAEMIA

Iron deficiency anaemia (IDA) is the most common cause of anaemia globally.

🏘 Epidemiology

Anaemia is present in approximately 1/3rd of the worlds population, and IDA is the most common cause of anaemia.

It is more common in women (3% of men in the UK and 8% of women in the UK have IDA).

Pathophysiology

Iron is used in the formation of haemoglobin. There is no mechanism for the body to regulate iron levels. It can only remove it physiologically with menstrual bleeding, sweating, skin desquamination, urinary/faecal excretion.

Menstruating women lose about 2mg of iron everyday. Men and post-menopausal women lose about 1mg of iron daily. Menorrhagia is the most common cause in pre-menopausal women, while GI bleeding ins the most common in men and post-menopausal women.

Pregnancy causes 580mg of iron loss approximately during the gestation period as we expand maternal RBC mass and need to supply iron to the foetus and placenta too (most iron loss occurs in the 3rd trimester).

Children have the highest iron demands due to their rapid growth.

We are able to gain iron through meat and dark green leafy vegetables. Vegans and vegetarians are more likely to develop IDA due to the lack of dietary iron intake.

Intestinal malabsorption also may affect iron absorption which can lead to iron deficiency (for example in coeliac disease).

So to summarise, 5 mechanisms for IDA are:

1. Inadequate intake
2. Impaired absorption
3. Increased iron loss due to bleeding
4. Increased iron requirements due to infancy, pregnancy or lactation
5. Idiopathic

Iron physiology and interpreting iron studies:

Iron is absorbed from the duodenum. It is converted from ferric (Fe3+) → ferrous (Fe2+) iron. It is then absorbed through DMT1 channels into the enterocytes and then from the enterocytes into the circulation through ferroportin 1.

When iron is in the plasma it is then oxidised by haephestin and bound to transferrin.

Transferrin (transporter of ferric iron) transports iron in the blood and is also able to enter cells (mainly RBCs, hepatocytes and immune cells) by binding to the transferrin receptor (TfR).

Most serum iron is converted into haem in erythroid cells (precursor erythrocytes) which then combines with globin to form haemoglobin. When the RBC dies, the iron is saved by macrophages with erythrophagocytosis and the iron re-enters circulation

Iron is mainly stored as ferritin and a small portion is stored as haemosiderin.

Now let’s look at the different iron studies and what they are actually measuring:

• Serum iron - measures the ferric iron (Fe3+) that is bound to transferrin. It is a poor marker of iron levels as this level can vary greatly with many factors.
• Ferritin - as mentioned this is an intracellular storage protein of iron that indicates the total iron stores in the body.
• Elevated ferritin - is a marker of iron overload but as mentioned before, ferritin is also an acute phase reactant and can be elevated with liver disease and inflammation.
• Reduced ferritin is the most specific measure of IDA as nothing else will cause low ferritin levels. How
• Transferrin/total iron binding capacity (TIBC) - transferrin is the transporter protein of iron in the blood. The TIBC is proportionate to this. It is essentially the reverse of ferritin.
• Elevated transferrin/TIBC - marker of IDA.
• Reduced transferrin/TIBC - may indicate an acute phase reaction, liver disease or iron overload.
• Transferrin saturation - the percentage of transferrin bound to iron. It is more accurate at determining the total body iron than measuring serum iron.
• Elevated transferrin saturation - iron overload (haemochromatosis, multiple transfusions, iron-loading anaemias).
• Reduced transferrin saturation - IDA or chronic disease.

⚠️ Risk factors

😷 Presentation

• Fatigue is the most common presentation by far.
• Shortness of breath upon exertion due to decreased oxygen carrying capacity.
• Palpitations
• Pallor
• Koilonychia - spooning of the nails. Supposedly it is rare, but some nail changes of sorts occur in 1/4 patients.
• Hair loss - but evidence is unclear if this is true or not.

• Restless leg syndrome
• Atrophic glossitis - glossitis with atrophy of papillae.
• Angular stomatitis
• Post-cricoid web or oesophageal web which causes dysphagia - this is known as Plummer-Vinson syndrome which is a triad of IDA, dysphagia and oesophageal webs. It most typically affects middle-aged women.

🔍 Investigations

The history is the most important aspect to elicit relevant information about their symptoms and any recent changes that could have caused their anaemia to start.

🧰 Management

Management first and foremost involves treatment of underlying cause.

• Iron supplementation - oral iron replacement therapy is the first-line option. If they are not responsive they can be considered for IV, this may be if related to malignancy, IBD, or heart failure. Transfusion can even be considered in patients with cardiac compromise, but this is rare.
• Oral ferrous sulfate - this should be continued up until 3 months after correction of IDA to replenish stores.
• Adverse effects include: nausea, abdominal pain, constipation, diarrhoea.
• Iron rich diet - including meat and dark-green leafy vegetables.

SIDEROBLASTIC ANAEMIA

Sideroblastic anaemia is a rarer cause of microcytic anaemia, that commonly gets misdiagnosed for IDA. Sideroblasts are deposits of iron in mitochondria of red cells that form a ring around the nucleus.

Pathophysiology

There is a disordered incorporation of iron into haem within the mitochondria of developing late erythroblasts. This then leads to a toxic accumulation of iron in the mitochondria that form a perinuclear ring known as a ring sideroblast around the erythroblast.

There are both congenital and acquired causes of sideroblastic anaemia:

Congenital

• Delta-aminolevulinate synthase-2 (delta-ALA synthase 2) deficiency - delta-ALA is a precursor of protoporhyrin which is one of the 2 components of haem. The other component being iron. A deficiency therefore results in iron accumulation.

Acquired (MALI 🇲🇱)

😷 Presentation

• Microcytic anaemia refractory to intensive iron therapy
• Atypically raised serum ferritin and serum iron

🔍 Investigations

🔬

Sideroblastic anaemia investigations:

• FBC
• Hypochromic microcytic anaemia
• Iron studies
• Elevated ferritin
• Elevated iron
• Elevated transferrin saturation
• Blood film
• Basophilic stippling of RBCs

• Bone marrow biopsy
• Ring sideroblasts with Prussian blue staining

🧰 Management

1. Supportive treatment
2. If acquired → treat underlying cause.
3. Pyridoxine (vitamin B6) may prove useful but its efficacy remains questionable still.

LEAD POISONING

Lead poisoning occurs after inhalation or ingestion of lead from the environment, food, or water.

Pathophysiology

Smaller lead particles are better absorbed. This often occurs through inhalation in the lungs. In the GI tract it is not absorbed as well, but if there is existing IDA and mineral deficiencies then it increases the absorption of lead.

Lead competes with certain minerals such as calcium and zinc in certain cellular processes. Some of these processes that it inhibits include:

1. Mitochondrial calcium uptake
2. Protein kinase C - a calcium dependant enzyme necessary for brain function → neurotoxicity.
3. Presynaptic terminals - calcium-dependant neurotransmitter release → peripheral neuropathy.
4. ALA dehydretase - also involved in protoporphoryin synthesis (and therefore haem synthesis) → anaemia.

Some sources of exposure of lead may include:

• Older housing - pre-1950 housing has the most cases of home lead exposure. Deteriorating paint surfaces also has a strong association with lead poisoning in such homes.
• Bullet firing ranges - bullets are often made with lead and as a result this can lead to inhalation of airborne lead particles.
• Lead-contaminated water - piping made out of or soldered with lead of course provides a significant risk, especially when acidic water and stagnant water comes into contact with the lead. This has most famously lead to lead poisoning in Flint, Michigan in recent times.
• Leaded petrol - leaded petrol has been banned worldwide for road use. The last country to stop using it was Algeria, in 2021. However, it is still used in some cases such as in aviation and motorsport. Its production was ceased in September, 2021 though.
• Toys - children aged 9-36 months are at increased risk due to their hand-to-mouth activity. Household objects and toys that contain lead are of great concern at this stage.

😷 Presentation

• Abdominal pain
• Peripheral neuropathy - mainly presenting with motor weakness.
• Cognitive impairment, neuropsychiatric features and behavioural changes - due to the neurotoxicity.
• Fatigue
• Constipation
• Blue lines on the gum margin - a rare finding, especially rare in children. These are known as Burton’s lines.

🚨 The greatest risk of a complication is neurodevelopmental delay in children.

🔍 Investigations

1. ⭐️ Whole-blood lead levels - venous blood which is then anticoagulated with heparin is tested. There is no normal level, however, a level above 10mcg/dL is considered significant and places great risk of IQ loss.
2. ⭐️ FBC - IDA may also be co-existing due to lead exposure, so we may see basophilic stippling and other features consistent with microcytic anaemia. Iron studies may be done as well for this same reason.
3. Serum and urine delta-ALA levels - may be raised.
4. Urinary coproporphyrin - raised.
5. X-ray of long bones - as lead can accumulate in the metaphyses of long bones in children.

🧰 Management

Chelation therapy is the first-line management (other than separation from the exposure source of course).

Some chelating agents being used include:

1. Dimercaptosuccinic acid (DMSA)
2. D-penicillamine
3. EDTA
4. Dimercaprol

ANAEMIA OF CHRONIC DISEASE

Anaemia of chronic disease (ACD) is characterised by anaemia and evidence of immune system activation.

Pathophysiology

It is predominantly caused by inflammation. Inflammatory cytokines such as IL-1 and IL-6 (especially IL-6) stimulates hepcidin release from the liver which disables ferroportin on the basolateral surface of enterocytes which allows iron to pass from enterocytes → bloodstream.

This decrease in iron reduces haem production and thus RBC production and RBC survival.

A decrease in hypoxia inducible factor then causes a decrease in erythropoietin which subsequently reduces erythropoiesis. It is this increased RBC destruction coupled with reduced RBC production that leads to ACD.

Causes of ACD include:

1. Malignancy
2. Chronic infections - such as TB, hepatitis, HIV, osteomyelitis.
3. Connective tissue disorders and autoimmune disorders - such a rheumatoid arthritis, SLE, IBD,
4. Chronic diseases - CKD, CHF, COPD.

😷 Presentation

• Fatigue and lethargy
• Dysponoea
• Anorexia
• Pallor
• Absent history of bleeding, alcoholism, chemical exposure
• Presence or physical findings suggestive infection, neoplasm, autoimmune disorder or chronic disease

🔍 Investigations

Investigations to order depend on clinical history and examination findings.

However, it is of course important to order the usual FBC and iron studies, peripheral blood smear.

🧰 Management

🥇 Treatment of underlying cause is the primary target of treatment.

However, if the underlying disorder is not responsive and the anaemia poses additional risks, we can consider:

1. RBC transfusion
2. Erythropoietin-stimulating agents
1. Epoetin alfa
2. Darbepoeitin alfa
3. Iron supplementation