Introduction

Pernicious anaemia (PA) is a type of megaloblastic anaemia that can occur due to a rare autoimmune disorder, leading to a decline in the absorption of vitamin B12 (cobalamin) and resulting in B12 deficiency in the blood. When DNA, the building blocks of our body, cannot be formed properly because of the absence of sufficient vitamin B12 or vitamin B9 (folate), megaloblastic anaemia occurs. This deficiency causes abnormally red blood cell precursors to be abnormally big(megaloblasts), they can be found in the bone marrow and the blood. Anaemia is the reduction in normal red blood cells, causing a lack of energy and shortness of breath. Pernicious anaemia particularly affects elderly individuals over the age of 60. 

It is important to study anaemia in elderly populations because anaemia is a significant factor in morbidity, mortality, and frailty in the elderly. Anaemia leads to a reduction in quality of life as it causes fatigue due to insufficient oxygen delivery to the body’s cells, preventing individuals from partaking in normal activities. When cells lack oxygen, they become dysfunctional and cannot perform their normal functions adequately. Moreover, older adults are more affected by the causes of anaemia because their bodies are less capable of producing new red blood cells.
Furthermore, as we age, there is a higher likelihood of developing autoimmune diseases and chronic conditions, making them more susceptible to pernicious anaemia, which is an autoimmune condition. Pernicious anaemia is difficult to diagnose because its symptoms are similar to those of other conditions. There are several diagnostic challenges. However, it is crucial to diagnose it as early as possible because it can lead to the development of irreversible neurological symptoms. 

Background on pernicious anaemia

Pernicious anaemia is a type of anaemia that results from inadequate intake of vitamin B12 in the body. This can be through your diet lacking vitamin B12-rich foods or a lack of digestive problem where it is not absorbed from the small intestine. Foods such as meat (liver and beef), eggs and dairy are rich in B12 and essential for red blood cell and nerve production; therefore, their deficiency can lead to megaloblastic anaemia due to disrupted DNA synthesis and improper nerve development. B12 deficiency causes megaloblastic changes in all formed blood elements, but red blood cells show the most significant changes, with the degree of anaemia corresponding to the severity of red blood cell physical changes.

Vitamin B12 or cobalamin is an essential vitamin that cannot be made by the human body and must be obtained through diet. However, even with adequate intake of vitamin B12 in the diet, the condition of the stomach lining and the presence of intrinsic factors determine whether the body can absorb the nutrient from food. 

Pernicious anaemia can develop through a reduction in B12 absorption in the small intestine, due to intrinsic factor (IF) deficiency. In the stomach, parietal cells are acid-producing cells that also secrete intrinsic factors. IF binds to vitamin B12 from foods, and the B12/IF complex is transported to the small intestine, where it is absorbed into the bloodstream. Anti-IF antibodies prevent B12 from binding to IF, B12/IF complex is not formed, halting intestinal absorption.

Symptoms of pernicious anaemia can be classified into: 

• Common symptoms of anaemia: fatigue, shortness of breath, dry, pale skin, and dizziness.
• Neurological symptoms: muscle weakness, tingling in hands and feet, numbness, dementia, depression, and personality changes.
• Gastrointestinal symptoms: changes in appetite, bloating, nausea, heartburn, swollen, irritated, bleeding gums.
• Heart problems: irregular heartbeat, palpitations( feeling like your heart is beating too fast) 

Complications of PA may also include an enlarged spleen or liver, subacute combined degeneration (SCD) of the spinal cord due to neurological degeneration. 

Age-related risk factors

Decreased gastric acid production (atrophic gastritis)

Atrophic gastritis is a chronic condition where the stomach lining thins and weakens due to inflammation. It can have various causes, such as bacterial infections and autoimmune attacks in the stomach. This leads to decreased stomach cell functionality and lower acid ( hydrochloric acid) levels, causing a decline in the release of cobalamin (B12). Also, less parietal cells are available to produce the IF needed for dietary B12 absorption.

Changes in diet and nutrient absorption

As people age, dietary needs and the body's ability to absorb nutrients change significantly, impacting overall health and well-being. It can lead to deficiencies in vitamin B12, calcium, and iron. 

Use of medications (e.g., proton pump inhibitors, metformin)

PPIS are used to reduce stomach acid, can impair the release of B12 from food and may affect B12 absorption. Metformin, a diabetes medication, can reduce the absorption of B12 in the small intestine. 

Autoimmune factors become more common with age

These autoimmune factors may affect the stomach lining, damaging it and preventing the absorption of stomach acid. Pernicious anaemia is more common in older adults, partly due to age-related changes in the stomach lining that may make them more susceptible to autoimmune gastritis. Additionally, some elderly individuals may have other autoimmune diseases, such as Hashimoto's thyroiditis or vitiligo, which can increase their risk of developing pernicious anaemia.

Co-existing chronic conditions (e.g., diabetes, thyroid disease)

Pernicious anaemia in the elderly is frequently associated with co-existing chronic conditions, particularly autoimmune diseases and those affecting the digestive system or the immune system. These conditions can impair B12 absorption, leading to pernicious anaemia. These diseases usually come with the natural ageing process. 

Diagnostic challenges in the elderly

Non-specific and overlapping symptoms: Symptoms like fatigue, memory loss and weakness are non-specific and may overlap with other diseases or ageing in general. In particular, it may mimic some blood conditions like myelodysplastic syndrome, acute leukaemia, sideroblastic anemia, bone marrow failure states, thrombotic microangiopathy, and thromboembolism. 

Cognitive decline and misdiagnosis: As we age, there is usually some kind of cognitive decline and B12 deficiency is also associated with neurological symptoms. Therefore, the elderly can be misdiagnosed with dementia or depression with ageing instead of pernicious anemia.

Delayed presentation due to slow disease progression:

The onset and progression of PA is often gradual. This is because your body stores B12 from the food you eat. Your body keeps these stores for a long time (up to 2- 5 years), and you only present with symptoms after these stores have been exhausted. Alternatively, patients may have no anaemic symptoms since they become acclimated to the subtle nature of the disease. 

Limitations of standard tests: 

Diagnostic challenges remain tangible for many practising clinicians, since there is a lack of reliable cobalamin (B12) assays. Also, there may be normal B12 levels seen in the blood of patients with a B12 deficiency even if the body isn't utilising B12 effectively. Functional deficiency arises when the body struggles to transport B12 into cells or utilise it for metabolism, despite adequate levels in the blood. 

Normal B12 levels do not help us conclude a normal B12 status. In these cases, other tests, such as homocysteine and methylmalonic acid (MMA) levels, may reveal deficiencies even with normal B12

Under-recognition by healthcare providers:

Pernicious anaemia is also under-recognised by healthcare providers. It is not the first disease that is looked into when these symptoms present.

Diagnostic tools and approaches

To diagnose pernicious anaemia, the following are needed

Blood tests

Blood tests can be taken to check B12, methylmalonic acid (MMA), and homocysteine levels to diagnose pernicious anaemia. Elevated levels of homocysteine and MMA may be a sign of vitamin B12 deficiency. CBC (complete blood count) will also reveal anaemia with the red blood cell count, haematocrit and haemoglobin levels. Also, a blood smear and bone marrow biopsy will show the shape of blood cells and indicate where there are abnormal red blood cells, like megaloblasts. 

Upper GI endoscopy

This procedure allows the stomach to be visualised with a camera down your throat. If there is atrophy, pernicious anaemia can be concluded. 

Intrinsic factor antibody test (IF Ab) and Schilling test:PA can be diagnosed without Schilling tests in patients with megaloblastic anaemia, vitamin B12 deficiency and with a positive IF Antibody test. In some patients, if IF Ab is negative, Schilling tests still need to be performed to confirm pernicious anaemia. In more recent times, Schillings' tests are no longer performed. It is no longer preferred due to advancements in technology.

Importance of full clinical history and physical examination

A physician must take your full history to determine whether you are susceptible to pernicious anemia. They can determine this based on your diet, lifestyle, and medical history. Also, by examining a patient, they can tell if there are any stomach issues. 

Role of neurological and cognitive assessment

A decline in B12 will cause some neurological issues that can be assessed by a physician.

Management and treatment

Vitamin B12 will be supplemented where deficient. It can be taken by mouth or with injections of hydroxocobalamin, depending on whether or not it is caused by diet or stomach-related issues.

It is important to monitor vitamin B12 levels long-term to ensure levels of supplementation are adequate. If B12 deficiency is caused by a lack of B12 in your diet, you may be advised to take B12 supplements between meals. If you find it difficult to get enough vitamin B12 in your diet, because you follow a plant-based diet, you may need vitamin B12 tablets for life. Follow-up appointments are necessary to prevent the onset of complications like dementia, depression. etc

Summary

Pernicious anaemia is a type of anaemia caused by a deficiency in vitamin B12 (cobalamin), and it is most common in people above the age of 60. This is because it is comorbid with other chronic conditions that come with age. Early detection and good care are important with pernicious anaemia because it poses risks to the quality of life of the individual affected. Its symptoms are usually non-specific, therefore clinicians and caregivers must look out for symptoms in patients.