Overview

What Is Pernicious Anemia?

Pernicious anemia is an autoimmune disorder that is caused by the body’s inability to absorb an adequate amount of dietary vitamin B12, which in turn leads to the development of a B12 deficiency. B12, often found in animal-derived foods such as dairy products, meat and eggs, is vital for the production of healthy red blood cells, and its absorption is facilitated by a protein produced by the stomach, known as intrinsic factor.^1,2 In individuals with Pernicious anemia, intrinsic factor is not produced, thus preventing B12 absorption, which in turn impairs red blood cell production, causing those with the disorder to feel anemia symptoms such as fatigue as well as cardiopulmonary, neurological and gastric symptoms.^1,3 It’s considered relatively rare, with most cases occurring after the age of 30, with diagnosis often around the age of 60.⁶

Pathophysiology Of Pernicious Anemia

Vitamin B12 absorption is facilitated by Intrinsic Factor (IF), a protein produced by the parietal cells in the stomach. In healthy individuals, IF binds to vitamin B12 within the small intestine, forming a complex that keeps B12 stable and prevents degradation throughout transport. Following absorption in the ileum—the last segment of the small intestine that joins the large intestine—it is subsequently released into the bloodstream for utilisation. Once absorbed, B12 is essential for erythropoiesis, or the process by which blood cells are made.¹

In pernicious anemia, IF is not produced or it’s blocked by anti-IF antibodies, which prevent binding of B12, making it unable to produce a complex. As a result, B12 absorption is halted. Without B12, DNA synthesis, which is required in erythropoiesis (the process by which new red blood cells are made in the body), is disrupted; thus, the cells divide, but the nuclei remain immature, resulting in misshapen blood cells called megaloblasts. These are often destroyed at the site of cell division, such as in the bone marrow, but some do mature and become large blood cells known as macrocytes, which are unable to carry enough, or any, haemoglobin. Without haemoglobin, they cannot carry oxygen and therefore do not function as they should, resulting in a reduced blood count and anemia.⁷

Signs And Symptoms

Due to the lack of B12, the body is unable to produce enough healthy red blood cells, thus causing anemia and its associated symptoms. It's important to note that the symptoms caused by the anemia are not necessarily specific to the B12 deficiency and are associated with all types of anemia.

These include:⁵

• Fatigue/Tiredness
• Dizziness
• Shortness of breath
• Cold hands and feet
• Arrhythmias (irregular heartbeat) 

Vitamin B12 deficiency, if left untreated, can damage the nervous system, causing a myriad of symptoms such as:⁵

• Muscle weakness
• Trouble walking
• Weakened bones 
• Numbing of hands and feet 

Additionally, it can cause gastrointestinal issues such as diarrhoea and a decreased appetite, as well as cardiopulmonary symptoms such as heart palpitations.¹

Causes Of Pernicious Anemia

For the most part, pernicious anemia is thought to be caused by an autoimmune response by the body, so essentially, antibodies are being produced which can attack healthy tissues, in this case, the parietal cells or the IF itself. 

It can also be caused by the presence of another autoimmune condition, such as Addison's disease or type 1 diabetes, which can increase its risk.⁸ In rare cases, children are born with a congenital form of the disease; therefore, there can be a genetic cause.

Another potential cause is damage or weakening of the stomach lining, for example, from conditions such as atrophic gastritis, which can cause problems with producing IF or from surgeries where parts of the stomach are removed, which means the parietal cells that produce IF are no longer present.⁹

Other non-autoimmune linked causes include small intestine bacterial overgrowth (SIBO), where there is an overgrowth of the wrong bacteria, which can use up the B12 before it has a chance to be absorbed.²

Diagnosis

Diagnosis for pernicious anemia is often difficult, especially since many symptoms also align with regular anemia as well as other illnesses. Therefore, diagnosis relies on clinical evaluation in combination with medical testing. 

Commonly used tests

• Full blood count—checks the size of the blood cells. Since B12 causes enlarged cells (macrocytosis), it’s used as an indicator for pernicious anemia. However only around 60% of patients with the condition actually have macrocytosis so further testing would be required
• Anti-Intrinsic factor antibody test—Those with the condition typically have these antibodies present. The test is highly specific so if positive, then it indicates that the patient has auto-immune pernicious anemia
• Parietal antibody test—Similarly to the anti-intrinsic factor antibody test, almost all patients with the condition have parietal antibodies and thus will test positive³
• Methylmalonic acid levels (MMA) test—B12 deficiency is associated with high MMA levels
• Upper endoscopy—More invasive. Provides a view of the stomach lining, therefore, it can be used to check for degradation or damage²

Treatment And Disease Progression

Once diagnosed, the condition is usually treated initially using intramuscular B12 injections. Eventually, this is exchanged for a high dose of oral B12 replacement instead. If it was caused as a result of bacterial overgrowth, then antibiotics may be administered.

Once treatment is given, symptoms usually stop, but it's important to note that the condition is not curable, so though symptoms have stopped, lifelong supplementation is required.

It can cause nerve damage and an increased risk of stomach cancer, among other consequences, if treatment is not received.²

Chronic Atrophic Gastritis And Its Connection To Pernicious Anemia

Atrophic gastritis is a condition which causes chronic inflammation and degeneration of the stomach lining. There are two forms, classified based on the underlying cause of inflammation. Environmental metaplastic atrophic gastritis (EMAG) typically results from external factors, such as bacterial infections. The bacteria H.pylori  can cause a chronic infection that can destroy the gastric mucosal layer, which is required to protect the stomach lining from digestive acids. Long-term exposure to these acidic conditions without a mucus layer leads to this form of atrophic gastritis. 

Another type, known as autoimmune atrophic gastritis (AAG), as the name suggests, is caused by the body’s unwarranted autoimmune response, which causes it to attack the cells of the stomach lining. This works similarly to autoimmune pernicious anemia, where the body's immune system is damaging the healthy cells in the stomach, which in turn stops production of important products from these cells, leading to disease symptoms.¹¹ In fact. Pernicious anemia and atrophic gastritis are heavily linked, as either form of atrophic gastritis can cause progressive loss of parietal cells, which in turn blocks IF production and eventually B12 absorption, leading to anemia.¹⁴ In addition to this, both are considered risk factors for gastric cancer, with atrophic gastritis being considered a precursor lesion.¹⁰

Pernicious Anemia And Gastric Cancer Risk

Gastric cancer, like all cancers, is defined as uncontrolled or abnormal cell growth. In this case, it  can form anywhere in the stomach, but most often starts at the stomach lining from the epithelial cells and can continue to develop and form tumours called adenocarcinomas.¹⁵

It’s the 5th most common cancer in the world and can develop at any age, with risk increasing with age.  

There are various risk factors that can also determine where in the stomach the cancer forms. 

H.pyloi can significantly increase the risk of gastric cancer in the middle as well as the lower regions of the stomach, as it can cause atrophic gastritis, which subsequently leads to changes and damage to the stomach lining and can then lead to the development of gastric cancer.¹³ For example, the degradation of the stomach lining leads to a low acid environment as cells that are responsible for producing stomach acid are damaged. This environment provides optimum conditions for tumour formation and is thought to be a precursor.

Another risk factor, though not as common due to the rarity of the condition, is pernicious anemia. According to case studies, there was an 11-fold increase in risk of developing gastric carcinoid tumours (also known as neuroendocrine tumours) in patients with pernicious anemia, but it’s also important to note that despite there being a strong correlation, this type of tumour is very rare, so overall risk is low. Since atrophic gastritis is usually associated with pernicious anemia, both are considered to increase the overall risk of cancer.¹⁶

Summary

Overall, it’s clear that pernicious anemia, chronic atrophic gastritis and gastric cancer are interconnected, with both of the former conditions mentioned resulting in loss of vital cells within the stomach lining and degradation of gastric mucosa. Therefore, it’s impossible to say for definite that pernicious anemia by itself is a cause for increased cancer risk, as it’s often followed by or resulting from chronic atrophic gastritis. Thus, further studies to understand the mechanism of action and how it increases conditions for cancer formation would have to be investigated for both conditions.