Pathophysiology Underlying Pernicious Anaemia Biology Essay

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The following essay explores the pathophysiology underlying pernicious anaemia, with reference to primary sources. In order to fully understand the pathophysiology of pernicious anaemia, normal physiology is also discussed. With this in mind, contemporary treatments and management strategies that are currently in place are then critically appraised using the latest literature.

Pernicious anaemia, typically seen in the over 60's, is the most common type of megalobastic anaemia and is usually attributed to the end stage of type A chronic atrophic (autoimmune) gastritis, which in turn leads to Vitamin B12 (cobalamin) deficiency (Toh et al., 1997). Autoimmune gastritis and pernicious anemia are common autoimmune diseases with respective prevalences of 2 and 0.15-1% in the general population (De block et al, 2008). It only manifests once all cobalamin stores (from the liver) have been depleted. Fundamentally, pernicious anaemia results from a lack of intrinsic factor (IF), which is a glycoprotein required for the absorption in the gastrointestinal tract of dietary sources of cobalamin (Toh and Alderuccio, 2004).

Pernicious anaemia presents with a vast spectrum of signs and symptoms, including glossitis, generalised weakness, parasthesia, weight loss, infections, nausea, confusion and an unsteady gait. On a long term basis, patients are predisposed to gastric cancer. Haematologically, erythrocytes are normochromic and megalobastic (mean corpuscular volume is increased above 80-95fl in adults (Hoffbrand and Proven, 1997)). The condition is more common in females and is also thought to be more common in people with blood group A. In addition, those with a family history of pernicious anaemia are at an increased risk, along with people suffering from other autoimmune diseases such as Addison's disease (Hoffbrand and Proven, 1997). A more thorough understanding into the pathophysiology of the disease will enable contemporary treatment and management of the disease to be critically appraised.

Martens et al., (2002) explain that under normal circumstances, cobalamin is vital for nuclear maturation and DNA synthesis in erythrocytes by means of catalysing the action of methionine synthase and R-methylmalonyl-CoA mutase. Vitamin B12 cannot be synthesised by the body therefore dietary intake is essential. It is stored in the liver (2-5mg), and recommended daily amounts are 2-5μg (Malouf and Areosa, 2003). The pathway for absorption of dietary cobalamin is vital in maintaining hepatic stores. According to Berne et al. (2004), it takes four hours for cobalamin to appear in the blood following ingestion and peak plasma levels occur 6-8 hours after a meal.

Andres et al., (2004) describe the metabolic pathway of cobalamin following ingestion. In short, cobalamin ingested in the diet is bound to animal protein which is released upon contact with pepsin and hydrochloric acid. Meanwhile, parietal and salivary cells release R-Protein which binds to the free cobalamin. Intrinsic factor is also released by parietal cells but this has a weaker affinity to cobalamin than R-Protein. The release of intrinsic factor by parietal cells is mediated by histamine, acetylcholine and gastrin which are physiological agonists of hydrochloric acid secretion (Berne et al., 2004). Pancreatic enzymes degrade both biliary and dietary cobalamin-R protein complexes. This releases free cobalamin, allowing it to bind with intrinsic factor. In the brush border of the ileum the intrinsic factor cobalamin complex attaches to mucosal cell receptors (cubilin) (Andres et al., 2004). Free intrinsic factor does not compete for binding, whilst free cobalamin is not recognised by cubilin (Berne et al., 2004). This highlights the importance of intrinsic factor. The cobalamin binds to transport proteins (transcobalamin I, II and III). Attached to the transcobalamin, the cobalamin is then transported systemically via the portal system. Absorption into the ileal cells occurs by means of receptor mediated endocytosis of the transcobalamin-cobalamin complex. The cobalamin is then separated from the transport protein and converted into one of two coenzymes, methylcobalamin and adenosylcobalamin. It should also be noted that passive diffusion of cobalamin occurs at a rate of 1.2% of that absorbed, across the small bowel (Nyholm et al., 2003). Once metabolised it then acts as a cofactor and coenzyme for DNA synthesis, methione synthesis from homocysteine and conversion of propionyl into succinyl coenzyme A from methylmalonate (Andres et al., 2004).

As discussed above, cobalamin is essential for DNA synthesis. Inhibition of DNA synthesis in red blood cells results in the formation of fragile megaloblastic erythrocytes. In addition to this, symptoms involving the nervous system, such as parasthesia occur as a result of demyelination of neurones (Malouf and Areosa, 2003). In order to analyse treatments in place, the pathophysiology of pernicious anaemia will now be discussed.

Much of the evidence surrounding pernicious anaemia connects it to autoimmune chronic gastritis. Later symtoms such as parasthesia are directly as a result of cobalamin deficiency. The lack of intrinsic factor required for the absorption of cobalamin is as a result of loss of parietal cells and antibodies towards both intrinsic factor and the parietal cells (Toh et al., 1997). In order to further understand the development of pernicious anaemia, the early stages of atrophic gastritis must first be understood. Alderuccio and Toh (2000) explain that in its early stages, atrophic gastritis begins with infiltration of the gastric submucosa with inflammatory cells. Over time, this extends into the lamina propria, which ultimately leads to the destruction of parietal and zymogenic cells. These are then replaced by mucus containing cells.

Bergman et al., (2003) state that autoimmune gastritis, which underlies pernicious anaemia occurs due to autoantibodies to gastric parietal cells. Specifically, the H+/K+ ATPase part of parietal cells, which is responsible for the secretion of hydrogen by parietal cells, which are recognised by CD4+ T cells. Subsequently, achlorhydria, low serum levels of pepsinogen I and increased gastrin levels also results. In patients with pernicious anaemia, these autoantibodies, along with autoantibodies towards intrinsic factor can usually be detected in patient serum and gastric fluid, with levels being directly proportional to the concentration of parietal cells (Toh and Alderuccio, 2004). Toh and Alderuccio (2004) also explain that two types of intrinsic factor autoantibodies have been identified. Type I bind to the cobalamin binding site of the intrinsic factor, whilst type II bind to a remote site. Berne et al., (2004) state that these autoantibodies act by preventing the binding of cobalamin to the intrinsic factor.

Toh and Alderuccio (2004) suggest that parietal cell antibodies are a marker of autoimmune gastritis, whilst intrinsic factor antibodies are actually a marked feature of pernicious anaemia. This is because the presence of only the antibodies to the H+/K+ ATPase of the parietal cell suggests that the gastric lesion is likely to remain at its preliminary stages. In contrast, when intrinsic factor antibodies are present the gastric atrophy is at its end stage, which is associated with pernicious anaemia. In patients with pernicious anaemia, 90% have intrinsic factor autoantibodies. However, as the parietal cell mass reduces, the number of antibodies reduces as a result of the loss of "antigenic drive". Therefore the presence of parietal cell antibodies alone are not diagnostic of the progression to pernicious anaemia. Toh and Alderuccio (2004) also explain that as a result of limited research in the field over the past 30 years combined with a 20-30 year developmental timescale of pernicious anaemia, it is currently unknown whether or not all patients positive for parietal cell antibodies will develop pernicious anaemia. Therefore, more research is required to confirm the developmental process of the antibodies.

Genetic factors play a significant role in the development of chronic gastritis and therefore subsequently pernicious anaemia, demonstrated by the presence of autoantibodies and clustering of the disease within families and amongst those with underlying autoimmune diseases. Gorden et al., (2004) state that a lack of intrinsic factor secretion can be attributed to the destruction of parietal cells as a result of adult onset gastric atrophy, or it may be congenital. They claim that the congenital deficiency is thought to be autosomal recessive. Lahner and Annibale (2009) also suggest genetic susceptibility as a result of human leucocyte antigen- DR genotypes. In addition, they also provide a crucial link between pernicious anaemia and the development of intestinal type gastric adenocarcinoma and gastric carcinoid type I.

De Block et al., (2008) suggest that in patients with type one diabetes the risk of autoimmune gastritis, in turn leading to pernicious anaemia is increased by three to five times. With this in mind, they suggest that this provides a strong rationale for the implementation of a screening programme with early diagnosis and periodic examination via gastroscopy. Toh and Gleeson (1997) also acknowledge that pernicious anaemia is associated with autoimmune conditions, especially those affecting the endocrine system such as autoimmune thyroiditis, type one diabetes and Addisons disease. However, they also recognise that chronic gastritis can also develop secondary to alcoholism, hot tea and smoking. In addition, partial or total gastrectomy causes intrinsic factor deficiency due to the loss of parietal cells.

Helicobacter Pylori infection has been identified as a potential causative factor in the development of cobalamin deficiency (Kaptan et al, 2000). This is consistent with Hersko et al., (2006) who question previous claims that pernicious anaemia is a disease of the elderly. They agree that the autoimmune cascade is triggered by Helicobacter Pylori infection, occurring decades prior to the presentation of cobalamin deficiency. Toh and Alderuccio (2004) also state that Helicobacter Pylori is likely to induce autoreactive T cells, cause epitope spreading and bystander activation, although they do recognise that its involvement remains controversial. This should therefore be considered in the development of novel treatments, focusing on the screening and eradication of Helicobacter Pylori infection. Current recommendations for patients with autoimmune gastritis include testing and treatment (Toh and Alderuccio, 2004).

Berne et al., (2004) discuss pernicious anaemia in childhood, which whilst is rare, should not be disregarded since this also challenges the idea of pernicious anaemia being exclusively a disease of the elderly. They claim that there are three forms in childhood which are autoimmune, congenital intrinsic factor deficiency (with normal pepsin and hydrochloric acid) and congenital Vitamin B12 malabsorption syndrome, where there are reduced ileal intrinsic factor cobalamin receptors.

Ardill et al., (1998) proposed that in addition to intrinsic factor and parietal cells, there may also be an autoantibody to gastrin. They state that autoantibodies arise when there is a break down in immunological tolerance. In pernicious anaemia, gastrin levels are normally, but not always elevated due to achlorhydria at the end stage of autoimmune gastritis. This leads to failure of the negative feedback mechanism. However the recognition of potential gastrin autoantibodies may obscure plasma gastrin levels, giving lower results than would be the case without the presence of the autoantibodies. This suggests another potential line of treatment where more research is required to determine how effective it may be.

Having discussed the pathophysiology of pernicious anaemia, current treatment and management of the disease will now be appraised. As discussed, cobalamin is essential for DNA synthesis. Pernicious anaemia is as a result of a lack of intrinsic factor leading to an inability to absorb cobalamin from the diet. With this in mind, current treatment in the UK involves regular intramuscular injections (monthly to three monthly), which bypass the gastrointestinal system, therefore avoiding any requirement for intrinsic factor (Nyholm et al., 2003). There is currently no long term cure of the disease with more focus on management as opposed to cure (Oh and Brown, 2003).

Vidal et al., (2004) studied the effectiveness of oral versus intramuscular injections of Vitamin B12 in the knowledge that regular injections cost the health service time and money. Contrary to the UK, Canada and Sweden already use oral supplementation at doses high enough for passive absorption to take effect. Vidal et al., (2004) state that the passive diffusion of cobalamin across the ileum, without the requirement for intrinsic factor, accounts for 1.2% of the total absorbed. Therefore they propose through their own research, that a dose of 2000μg of oral vitamin B12 daily, reduced to 1000μg daily, then weekly, then monthly, is likely to be as successful as intramuscular injections at replacing hepatic stores and reversing short term haematological and neurological effects. Andres et al., (2008) state that in order to manage pernicious anaemia, 1000μg per day of oral cyanocobalamin is required. With a total storage in the liver of 2-5mg, and 1.2% of absorption occurring passively, hepatic stores should be replenished at this dose.

Nyholm et al., (2003) also found oral to be equally effective whilst reducing costs of nurse visits and enabling patients to have the choice. They studied 89 patients over 18 months and found no haematological differences to intramuscular administration. Walraven et al., (2001) also agree and found that there would be substantial savings if guidelines were implemented on a national level to change the standard practice to oral versus intramuscular. More recently, Butler et al., (2006) carried out a systematic review comparing oral and intramuscular administration in Vitamin B12 deficient patients. Once again, they agreed with the above evidence. Lederle (1991) initially proposed oral supplementation as "medicine's best kept secret". Therefore, 19 years on, further research is still required for medics to use oral tablets preferentially with appropriate guidelines in place, or indeed to rule this out as an option.

In order to ensure that patients are receiving the best possible treatment, effective tests must be performed to enable accurate diagnosis. Oh and Brown (2003) discuss the use of the measurement of methylmalonic acid and homocysteine levels which are raised in even the early stages of pernicious anaemia. The traditionally used "Schilling Test" is less sensitive and works by measuring urinary excretion of Vitamin B12, therefore estimating its absorption. Testing for Helicobacter Pylori would also dramatically improve outcomes by means of eradication of the infection (Alderuccio and Toh, 2004). Alderuccio and Toh (2004) also concluded that more research is required into the field of autoantibodies specific to pernicious anaemia. Further research would enable novel treatments to be considered. In addition, genetic testing may prove useful, since there is a confirmed link within families. Also, it has been suggested that regular screening should occur for those with other autoimmune conditions (De Block et al., 2008).

It should be questioned that with so much evidence to suggest that pernicious anaemia is directly associated with autoimmune gastritis, why is there not more screening in place to prevent its effects taking place. In addition, clear associations have been made within families and in individuals with other autoimmune diseases. In terms of the prevention of the autoimmune process, no cures have been found. However, more research should be implemented into the replacement of intrinsic factor. This would perhaps be an option since according to Berne et al., (2004) free intrinsic factor does not compete for binding at the mucosal cell receptors of the ileum. In addition, the eradication and treatment of Helicobacter Pylori should be addressed.

In the meantime, the vast research that suggests that oral therapy may be just as effective as parenteral with large enough doses to take advantage of the passive diffusion of cobalamin across the small bowel. However, it is extremely important not to disregard the potential long term effects of pernicious anaemia, such as the predisposition to gastric carcinoma. This highlights the need to treat each patient on an individual basis, taking effective measures to monitor for changes.

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