What is anaemia?

The World Health Organisation (WHO) defines anaemia as a condition where the number of red blood cells or the concentration of haemoglobin, a protein in the red blood cells essential for the carrying of oxygen, is lower than normal and insufficient to meet an individual’s physiological needs.¹ In figures, that is a haemoglobin (Hb) level of <12g/dL in women and <13g/dL in men, although higher levels have recently been proposed on the basis of sex, age and race.⁸ Haemoglobin is required to carry oxygen around the body so when an individual suffers with anaemia there is a decreased capacity of the blood to carry oxygen to the bodies tissues and organs, causing fatigue, dizziness and shortness of breath.¹ Affecting one third of the world’s population, anaemia can have varying and complex causes which are important to understand and differentiate to deliver suitable treatment.²

What is Pernicious Anaemia (PA)?

Pernicious anemia is a rare autoimmune condition which prohibits your body from absorbing vitamin B12 from the diet, therefore leading to vitamin B12 deficiency.³ Without sufficient vitamin B12, the volume of red blood cells carrying oxygen throughout the body is reduced, which can subsequently present as megaloblastic anaemia. The condition usually presents itself in people over the age of 60, however, it can affect people of all ages worldwide.⁴

What is Iron Deficiency Anaemia (IDA)?

Recognised by the WHO as the most common nutritional deficiency in the world, 30% of the world’s population is affected by the condition of iron deficiency anaemia with people assigned female at birth and children from resource-poor countries affected most.⁵ Most commonly caused by gastrointestinal bleeding and menstruation in people assigned female at birth, other causes include decreased levels of dietary iron and decreased iron absorption.⁶

Can pernicious anaemia and iron deficiency anaemia coexist?

As PA and IDA affect different aspects of red blood cell production, they can co-exist, however, on a diagnostic blood smear, both macrocytic (large) and microcytic (small) red blood cells can be seen. This leads to difficulties in diagnosis, as no clear answer is given from the smear. In cases of malnutrition, both B12 and iron intake may be insufficient, vegan diets without supplements can also result in both conditions.

How does pernicious anaemia cause illness?

Vitamin B12 has two main roles: it is involved in making DNA through red blood cell production and it helps to keep nerves healthy as it is involved in the process of nerve myelination (nerve insulation). In pernicious anaemia, a cascade of events leads to megaloblastic anaemia.⁴

• B12 is released from food carrier proteins in the acidic gastric stomach and binds to haptocorrin, protecting B12 from degradation
• Pancreatic proteases (enzymes for protein breakdown) release B12 from haptocorrin in the small intestine and binds to intrinsic factor (IF) from gastric parietal cells reducing stomach acid
• The IF-B12 complex binds to receptors and transcobalamin and is absorbed in the terminal ileum, it then enters the bloodstream. From here it is transported to cells via transcobalamin receptors
• B12 is converted to adenosylcobalamin and methylcobalamin in the cells and these work as cofactors for two important B12-dependent enzymatic reactions

• B12 or Adenosylcobalamin deficiency causes an increase in levels of methylmalonic acid (MMA)
• A Methylcobalamin deficiency leads to increased homocysteine levels
• This reduces S-adenosylmethionine (SAM) and methionine production⁴

Overall, the body lacks an intrinsic factor, which is needed to absorb B12 in the intestines. Therefore, even if an individual eats enough B12, it cannot be correctly taken up leading to Vitamin B12 malabsorption impairing DNA synthesis.⁴

How does iron deficiency anaemia cause illness?

Iron is available in two forms: haem iron from animal sources (meat, poultry, fish, which is easily absorbed, and non-haem iron from plant sources which is not easy to absorb.

Iron deficiency anaemia is more straightforward than PA and occurs when iron levels are insufficient to support normal red blood cell (RBC) production. These iron levels are controlled by dietary intake, impaired intestinal absorption, and cellular recycling.⁵ Insufficient iron supplies impair haemoglobin synthesis, leading to smaller (microcytic), pale (hypochromic) RBCs and reducing oxygen-carrying capacity. Phytates, polyphenols and tannins can inhibit iron absorption however, Vitamin C, citrates and gastric acid can enhance iron absorption. Other causes include increased demand for iron (e.g., pregnancy), or chronic blood loss (e.g., menstruation, GI bleeding), which cause a depletion in iron stores.⁵ For every 5–15 mg elemental iron or 1–5 mg haem iron ingested per day only 1–2 mg is absorbed.¹⁰ 

What are the shared clinical features of PA and IDA?

Non-specific symptoms with are often demonstrated in a case of anaemia however, some common symptoms for both PA and Iron deficient anaemia include fatigue, pallor, shortness of breath and weakness all due to poor oxygen delivery.⁷

What are the distinct clinical features of PA and IDA?

PA:

• Neurological issues:damaged myelin can lead to numbness, tingling, memory issues, balance problems, poor muscle control⁷
• Memory loss/issues
• Weight loss
• Tongue inflammation (glossitis)

 IDA:

• Pica (eating objects that are not intended to be eaten)
• Koilonychia (nail plate becomes thin and concave)
• Angular cheilitis (fissures at the corners of the mouth)⁸

How can PA and IDA Coexist?

The coexistence is an interesting clinical situation because these are two very different types of anaemia with seemingly opposing causes. The following mechanisms allow this coexistence to occur:

• Gastric parietal cell loss decreases the production of IF and Hydrochloric acid. Due to its requirement for an acidic environment, a decrease in HCI availability impairs absorption of both B12 and iron. Therefore, B12 deficiency itself can indirectly lead to iron deficiency
• Bariatric surgery or patients who suffer afrom utoimmune gastritis in PA can cause GI bleeding issues, leading to chronic blood loss and therefore iron deficiency.
• Iron and B12 absorption can be impaired in patients suffering from other malabsorptive or nutritional disorders most commonly Coeliac disease and H. pylori infection
• Use of Proton Pump inhibitors over a long period of time can become a medication-related cause of coexistence⁹

How is PA and IDA Diagnosed?

 Despite the progress made in understanding anaemia, there are diagnostic challenges in determining the primary cause due to the complexity and overlap of symptoms.¹¹ Diagnosis usually involves a combination of clinical evaluation and blood tests.⁴ The table below demonstrates the diagnostic tests and there corresponding results in each diagnostic picture.

If there is a co-existence of both pernicious and iron-deficient anaemia, some findings may be masked and this complicates diagnosis. In pernicious anaemia, iron deficiency may normalise MCV and, in iron deficiency anaemia, B12 deficiency may mask microcytosis of RBC. If a mixed picture is demonstrated on laboratory analysis, then investigation for cause can be carried out including endoscopy/colonoscopy to determine GI bleeding, gastric biopsy to confirm atrophic gastritis (thinning of the stomach lining) in pernicious anaemia and a dietary assessment to determine iron intake.^2,5

How is PA and IDA Treated?

PA treatment

Lifelong B12 treatment is required. This starts with an intense course of intramuscular B12 administered daily for up to 2 weeks. Then weekly injection up to 2 months, then monthly or every 2 to 3 weeks. After the initial intense course, the patient can continue with intramuscular injections or can move to high dose daily oral B12 supplements.⁴

IDA treatment

Patients with IDA should be treated with the aim of supplementing iron stores and returning the haemoglobin to a normal level.⁵ Iron replenishment can be delivered via three routes: oral iron, parenteral iron or transfusion of packed red cells each of which has different benefits to the patient.

• Oral: Ferrous Sulphate, it is a cheap option, however,side effects include constipation, nausea and diarrhea. The proper dosing of ferrous iron preparations is, however, a debated topic among clinicians. Daily doses of elemental iron should not be greater than 100 mg/day, of which the body can only absorb 10-20mg of iron per day. It should be noted that 200 mg of ferrous sulphate is equivalent to 65 mg of elemental iron⁵
• Intravenous/ Subcutaneous: Preferred route of administration due to its rapid correction of Hb, few side effects, safer product⁵ and bypasses the GI tract avoiding further aggravation
• Transfusion: Reserved for patients with extreme anaemia, however, patients may need additional iron supplementation. Side effects include GI bleeding or transfusion reactions⁵

What is the prognosis and long-term management for PA and IDA?

Prognosis of IDA is favourable if the underlying cause is identified and treated early. The treatment aims to replenish iron stores and return the Hb to a normal level. Haemoglobin begins to normalise within 2 months of treatment. This has been shown to improve quality of life, morbidity statistics, prognosis in secondary chronic disease and outcomes in pregnancy.⁵ IDA may reoccur if the underlying cause is not addressed.

Prognosis in pernicious anaemia is good. Normalisation of red blood cell count should occur within weeks from beginning B12 treatment. Neurological symptoms are slower to improve than blood count improvement, and the level of neurological recovery is conversely comparable to the severity and duration of symptoms before treatment. Psychiatric symptoms may improve rapidly.⁴ B12 supplementation has been demonstrated to stop the progression of pernicious anaemia and improve neurological function in most patients with subacute combined degeneration (SCD), however, very few completely recover from B12 deficiency.⁴ Patients with pernicious anaemia are at an increased risk of gastric cancer therefore a lifelong dedication to treatment and monitoring is very important.

Summary

Pernicious anaemia is a type of vitamin B12 deficiency caused by the lack of intrinsic factor, leading to poor B12 absorption. Iron deficiency anaemia results from insufficient iron, leading to reduced haemoglobin production. Both are conditions in which their oxygen carrying capacity is insufficient to meet human physiologic needs. Both having different causes and usually presenting with distinct red blood cell appearance they can co-exist. This is most commonly seen in patients with poor nutrition, chronic illnesses, or GI disorders. Coexistence complicates diagnosis, as one condition can hide the features of the other. To reach an accurate diagnosis, emphasis lies on comprehensive evaluation through laboratory blood tests assessing both B12 and iron levels. Individualized treatment is recommended depending on patient history and prognosis for both conditions is mostly good.