Introduction

A brief explanation of pernicious anaemia (PA)

Pernicious anaemia is a rare autoimmune disorder that prevents the absorption of vitamin B12 (cobalamin) in the diet, which promotes a deficiency of B12 and subsequently triggers megaloblastic anaemia. It can occur in individuals of any age, but frequently among people older than 60, and has been described among individuals worldwide. Despite the growth of medical knowledge, the diagnosis of pernicious anaemia still challenges healthcare providers, considering its multifaceted nature and broad range of symptoms, as well as the shortcomings of available diagnostic tests. Once pernicious anaemia has been diagnosed, it should usually be treated with B12 supplementation, and treatment typically will lead to an improvement in the anaemia; however, lifelong B12 supplementation and subsequent monitoring are required.¹

Overview of the etiology of pernicious anaemia

Pernicious anaemia occurs in the context of autoimmune gastritis, in which the immune system attacks gastric parietal cells, resulting in the absence of intrinsic factor (IF) that is fundamental for vitamin B12 absorption. The immune system produces antibodies, including intrinsic factor antibodies (IFA) and parietal cell antibodies (PCA). PCA antibodies specifically target the proton pump's subunits (alpha and beta) in the parietal cells, leading to their demise. The gradual degeneration of these cells induces atrophic gastritis, and eventually, the absence of intrinsic factors with significant impairment in vitamin B12 absorption. Pernicious anaemia also may occur in association with various other autoimmune disorders, commonly type 1 diabetes, vitiligo, and autoimmune thyroid disease, with some studies proposing genetic factors for these associations. Some HLA alleles, such as HLA-DRB1/03 and HLA-DRB1/04, could contribute to an individual's susceptibility to autoimmune gastritis and pernicious anaemia. There are also congenital and juvenile forms of pernicious anaemia that follow an autosomal recessive inheritance pattern and exhibit defective or ineffective intrinsic factors engendering malabsorption of vitamin B12.²

Importance of timely treatment for PA

Once treated appropriately, pernicious anaemia (PA) can be successfully maintained,  and the anaemia will typically subside, and the prognosis is good. However, some persistent neurological symptoms may remain, particularly if neurological symptoms manifested before diagnosis. Delays in therapy run the risk of longer-term or permanent neurological injury. Nonetheless, significant improvement in neurological function can be expected in the likely vast majority of patients after starting therapy. If pernicious anaemia is not treated seriously, then complications of haemoglobin, such as congestive heart failure, can occur. In summary, even after successful treatment of PA, there is a higher risk of gastric cancer at some point in the patient's lifetime. Additionally, even if fulminantly treated, non-compliance with treatment can recur symptoms and subsequently include anaemia and neurological symptoms.²

Pathophysiology of pernicious anaemia

Pernicious anaemia is the result of an intrinsic factor (IF) deficiency, which prevents the absorption of vitamin B12. Vitamin B12 is vital for producing red blood cells and for the physiological function of the neural and cerebral systems.. Vitamin B12 deficiency leads to impaired DNA synthesis and ultimately to megaloblastic anaemia, along with nerve dysfunction that affects especially the erythrocytes. After binding with IF, vitamin B12 is absorbed in the small intestine and converted to active forms within the cells to facilitate essential enzymatic actions. Deficiency causes the accumulation of methylmalonic acid (MMA) and homocysteine, which leads to cellular and overall bodily stress, irreparable damage to proteins, and neurologic manifestations, including cognitive decline. It also affects the synthesis of S-adenosylmethionine (SAM), a major methyl group donor. In the case of deficiency, prompt initiation of treatment is crucial.¹

Neurological complications of untreated pernicious anaemia

Diagnosing pernicious anaemia (PA) can be complicated, and patients may wait as long as ten years for a valid diagnosis. If untreated, pernicious anaemia can lead to irreversible nerve damage; Sub-Acute Combined Degeneration of the Cord (last commonly misdiagnosed as MS/multiple sclerosis), for example, can be misdiagnosed, which can lead to unnecessary testing. Symptoms of SACD, such as problems with balance and numbness, overlap with MS, leading to incorrect conclusions.³

Pernicious anaemia (PA) is an autoimmune condition that impairs the absorption of vitamin B12, ultimately resulting in a multitude of associated morbidities if untreated. Neurologic injury is perhaps the most worrisome, as it may present as peripheral neuropathy, characterised by tingling, numbness, and loss of vibratory and proprioceptive sensations in the distal extremities. Subacute combined degeneration (SCD) is associated with demyelination of the posterior and lateral columns of the spinal cord, which presents as weakness, ataxia, and gait abnormalities. Cognitive deficits, such as memory loss, disorientation, and dementia (in advanced cases), have been reported regarding vitamin B12 deficiency. Psychological issues, like depression, anxiety, irritability, and, rarely, psychosis, have also been reported in patients with vitamin B12 deficiency. Notably, neurologic manifestations can occur in patients who have normocytic anaemia, making it difficult to detect and treat vitamin B12 deficiency early. It is clear that vitamin B12 therapy is crucial and can lead to a significant neurological recovery if commenced early. Any delay in the treatment contributes to worse outcomes.^4,5

Cardiovascular complications of untreated pernicious anaemia

Untreated pernicious anaemia (PA) can lead to serious cardiovascular events. A reduction in haemoglobin decreases the blood's capacity to carry oxygen, which causes compensation, primarily in the form of increased cardiac output. This includes an increase in heart rate and stroke volume to supply the body with oxygen. Studies show that cardiac output can increase by 200% or 300% when haemoglobin reaches 30% or 40% of normal, respectively.⁶ There have also been reports of acute cardiac presentations of PA, such as non-ST-elevation myocardial infarction (NSTEMI), relating to the cardiac complications caused by vitamin B12 deficiency. Also, hyperhomocysteinaemia, frequently found in patients with PA, is a risk for vascular diseases, which include ischaemic stroke.^6,7

Diagnosis and detection

The diagnosis of PA relies on a combination of clinical findings and specific blood tests since there is no definitive test. Generally, the serum B12 is sufficient but can have sensitivities and specificity limitations, as the threshold for deficiency is frequently too high, and inaccuracies exist in some cases in determining deficiency. The serum holotranscobalamin (HoloTC) gives more accurate B12 levels, as it assesses active B12 but has limitations of its own. Testing for methylmalonic acid (MMA) and homocysteine is a fundamental indicator of B12 deficiency, even though several factors can alter results. The Full Blood Count (FBC) is associated with macrocytosis (enlarged red blood cells) to announce  B12 deficiency, but not all patients demonstrate this sign. Diagnosis for PA includes testing for anti-intrinsic factor antibodies and parietal cell antibodies, which have limited sensitivity. Finally, a serum gastrin test can also be pursued when the tests mentioned previously give inconclusive results.⁸

Treatment

The lifelong management of pernicious anaemia starts with an initial course of intramuscular (IM) B12 (1000 micrograms) injections. During the first 1 to 2 weeks, injections should be administered daily or on alternating days, which will then shift to injections every week for 1 or 2 months, followed by monthly (cyanocobalamin) or injections every 2-3 months (hydroxocobalamin) for maintenance therapy. A high-dose oral B12 (1000-2000 micrograms per day) can also be used for lifelong management. However, IM injections are generally preferred in patients with pernicious anaemia, especially when symptoms are severe, and there is neurologic involvement. Patients should be counselled about the ongoing lifelong nature of therapy, the implications of ongoing B12 therapy, such as gastric cancer, and the importance of monitoring for red flag symptoms, including dyspepsia (indigestion), blood in stools, unexplained weight loss, and appetite loss. Patients wishing to self-administer IM injections will need to be counselled on the safest injection techniques and site rotation. Follow-up visits are required in order to monitor the efficacy of anaemia treatment and to make changes to therapy.^1,2

Summary

Pernicious anaemia (PA) is an autoimmune disease that impedes the absorption of vitamin B12, ultimately contributing to megaloblastic anaemia, along with progressive neurological impairment. Mostly, it is diagnosed in older adults. Because there are so many symptoms of PA and limited methods to test for the disease, diagnosing it often might be delayed. The cause of PA is from the immune system targeting stomach cells that produce intrinsic factor (IF), an explained substance necessary for absorption of B12, which leads to a failure in the body to absorb vitamin B12. If pernicious anaemia is left untreated, serious complications can arise, resulting in neurological deficits (e.g., memory loss, numbness or tingling, difficulty walking), cardiovascular incidents, or gastric cancer. With treatment, repeated lifelong replacement of vitamin B12 is critical, and continued compliance in outpatient therapy is also essential. Vitamin B12 is administered by health professionals as intramuscular (IM) injections or high-dose oral tablets; however, if a patient has significant symptoms, IM is recommended over oral dosage. The earlier a patient is treated, the greater the improvement in symptoms, mainly improved neurological outcomes; prompt retention of treatment will also lessen your chance of permanent neurological injury. Education about treatment, treatment compliance, recognised risks, such as gastric cancer, and warning signs like weight loss, lack of appetite, or gastrointestinal complications is important for patients. Patients should regularly see their doctor following diagnosis to continue the treatment of pernicious anaemia and to monitor for potential complications.