Continuing Education Activity
Pernicious anemia (PA) is megaloblastic anemia resulting from a deficiency of cobalamin (vitamin B12), which in turn is caused by a lack of intrinsic factor (IF). Intrinsic factor is a glycoprotein that binds cobalamin and thereby enables its absorption in the terminal ileum. Pernicious anemia is often described as an autoimmune disorder due to the findings of gastric autoantibodies directed against both IF and parietal cells and the increased frequency of other autoimmune diseases seen in patients with pernicious anemia. This activity reviews the clinical presentation, evaluation, and treatment of pernicious anemia and highlights the interprofessional team's role in the management of patients with this condition.
- Review the steps in the diagnosis of pernicious anemia.
- Summarize the pathophysiology of pernicious anemia.
- Outline the treatment strategy for pernicious anemia.
- Describe how the interprofessional team can work collaboratively to prevent the potentially profound complications of pernicious anemia by applying knowledge about the presentation, evaluation, and management of this disease.
Pernicious anemia (PA) is megaloblastic anemia that results from a deficiency in cobalamin (vitamin B12) due to a deficit of intrinsic factor (IF). Intrinsic factor is a glycoprotein that binds cobalamin and therefore enables its absorption at the terminal ileum. The disease is often described as an autoimmune disorder due to the findings of gastric autoantibodies directed against both IF and parietal cells. Pernicious anemia also correlates with other autoimmune diseases and as well as genetic diseases.
The clinical presentation of pernicious anemia is multifarious and insidious in onset. Symptoms may include fatigue, pallor, paresthesia, incontinence, psychosis, and generalized weakness. The diagnosis is problematic secondary to the restricted availability of diagnostic tools. Treatment aims at the repletion of therapeutic doses of vitamin B12 either through intramuscular injections or oral supplementation. When the disease remains undiagnosed and untreated for an extended period, it may lead to neurological complications and even fatal anemia. This activity covers the epidemiology, pathogenesis, clinical presentation, evaluation, and treatment of pernicious anemia.
Research has identified two etiologies for pernicious anemia:
Autoimmune gastritis is characterized by the destruction of gastric parietal cells and the resulting lack of the glycoprotein intrinsic factor secreted by these cells. The antibodies identified with autoimmunity are intrinsic factor antibodies (IFA) and parietal cell antibodies (PCA).
Parietal cell antibodies work against the parietal cell proton pump ATPase. The primary targets of parietal cell antibodies are the alpha and beta proton pump subunits. Research has determined that parietal cell antibodies are immunoglobulins from the M, G, and A isotypes, which operate against both subunits.
Intrinsic factor antibodies are immunoglobulin G isotype, and they can be either type 1 or type 2 antibodies. Type 1 conducts against the cobalamin binding site. Type 2 acts against the ileal mucosa receptor.
Other autoimmune diseases include pernicious anemia, which can be associated with autoimmune diseases, such as type 1 diabetes (3% to 4%), vitiligo (2% to 8%), and autoimmune thyroid disease (3% to 32%). This association has led to studies exposing that HLA alleles may be related to autoimmune gastritis. HLA-DRB1/03 and HLA-DRB1/04 alleles may predispose to autoimmune gastritis.
Researchers have also identified congenital and juvenile forms of pernicious anemia, which are thought to follow an autosomal recessive inheritance pattern.
Other causes of cobalamin deficiency include:
- Vegetarian diet
- Loss of gastric mucosa (gastrectomy, use of H2 blockers)
- Insufficient pancreatic enzymes (ZES, chronic pancreatitis)
- Tapeworm infestation
- Bacterial overgrowth
- Defects in the ileal mucosa leading to poor uptake of cobalamin
Some studies state that the prevalence of pernicious anemia is 0.1% in the general population, which increases to 1.9% in patients aged older than 60 years. It affects all age groups but is most frequently associated as a disease of adults greater than 60 years of age with the median age being 70 to 80 years. Estimates of prevalence in the U.S.A. are 151 per 100000. The prevalence in persons of European and African ancestry is more common in older adults (4.0% and 4.3% prevalence, respectively) than in people of Asian descent.
There are two types of autoantibodies identified in pernicious anemia: intrinsic factor antibodies (IFA) and parietal cell antibodies (PCA).
Parietal cell antibodies conduct their activity against the parietal cell proton pump ATPase. Autoimmunity begins with the activation of gastric dendritic cells, which in turn trigger CD4+ T cell lymphocytes in perigastric lymph nodes. These triggered CD4+ T cells to identify the proton pump ATPase, which leads to their immune destruction. The mechanism by which the dendritic cells become activated is not known. Some research studies suggest H. pylori infection as a trigger. The studies propose molecular mimicry and immune cross-reactivity between the proton pump ATPase and the H. pylori organisms. The anti parietal antibodies are present in the majority of patients with pernicious anemia.
Intrinsic factor antibodies are immunoglobulin G isotype, and they can be either type 1 or type 2 antibodies. Type 1 operates against the cobalamin binding site, whereas type 2 directs its activity against the ileal mucosa receptor. B12 and intrinsic factor bind to receptors on the ileum, which allows for absorption. Vitamin B12, once absorbed, is a cofactor for the enzyme methionine synthase, which takes part in the conversion of homocysteine to methionine. If this process cannot occur due to pernicious anemia, homocysteine levels accumulate, and pyrimidine bases cannot form, which interferes with DNA synthesis and causes megaloblastic anemia. Vitamin B12 is also a cofactor for the enzyme methylmalonyl-CoA mutase, which converts methylmalonyl-CoA to succinyl-CoA. In patients with pernicious anemia, methylmalonic acid (MMA) levels accumulate. Elevated levels of MMA and homocysteine contribute to myelin damage, which causes neurologic deficits, such as neuropathy and ataxia. When there is cobalamin deficiency, patients can develop severe neurological impairment, including peripheral neuropathy, psychosis, or leukoencephalopathy.
Common dietary source of cobalamin includes milk and meat. Because the body stores of cobalamin are limited, strict adherence to a vegetarian diet can lead to pernicious anemia.
It is important to note that the coexistence of iron deficiency anemia is also common because, in the absence of acid, the dietary ferric iron cannot be absorbed from the stomach. Finally, patients with pernicious anemia may also have thyroid disease and are prone to gastric cancers.
History and Physical
The clinical presentation of pernicious anemia is often insidious, and symptoms may vary during its course. Patients often lack awareness of their symptoms, or they may have become used to them. A clinician should perform a complete history, including a detailed past medical history and family history, which focuses on autoimmune disease. The clinician should also conduct a complete physical exam emphasizing hematological, gastrointestinal, and neurological findings.
- Hematological manifestations: pallor, fatigue, shortness of breath, dizziness, tachycardia, lightheadedness, and decreased cognitive and physical function
- Gastrointestinal manifestations: abdominal bloating, loss of appetite, weight loss, and diarrhea
- Neurological manifestations: Peripheral neuropathy, paresthesia, weakness, ataxia, forgetfulness, and psychosis
- Cardiac symptoms may include dyspnea, palpitations, and edema.
- Urinary retention as a result of spinal cord damage can also occur.
Pernicious anemia, if left untreated, may be fatal. The physical findings may include:
- Low-grade fever
- Beefy red tongue
- Blotchy skin pigmentation
- Altered mental status
- Visual deficits
- Enlarged liver if heart failure is present
Initial lab tests include:
Complete blood count (CBC), serum B12 levels, and a peripheral smear. The CBC should demonstrate anemia, as shown by decreased hemoglobin and hematocrit (hemoglobin concentration less than 13 g/dL for men and less than 12 g/dL for women). The mean corpuscular volume (MCV) would be greater than or equal to 100 fL, an expected finding in macrocytic anemia. The peripheral blood smear may demonstrate hyper-segmented neutrophils (neutrophils with five lobes or greater). B12 levels of under 200 pg/mL are considered deficient. Indirect bilirubin and lactate dehydrogenase levels are usually elevated due to the rapid breakdown of red blood cells.
After initial lab tests confirm B12 deficiency, the diagnosis of pernicious anemia will depend on further testing, such as the presence of atrophic body gastritis (ABG) and intrinsic factor deficiency. One must rule out folic acid deficiency. Many patients with pernicious anemia will have elevated serum homocysteine and methylmalonic acid levels. Methylmalonic aciduria in the absence of an inborn error of methylmalonic acid metabolism confirms cobalamin deficiency. Diagnostic criteria for ABG require a histological sampling of gastric body mucosa. Findings associated with PA are the presence of corpus-restricted atrophy with a spared antrum, as well as the presence of hyperplasia of ECL cells. Serological markers can also help identify ABG; for example, increased levels of fasting gastrin and decreased levels of pepsinogen I suggest the presence of mucosal damage. Anti-intrinsic factor antibodies and anti-parietal cell antibodies should be evaluated in patients with a high probability of disease, even if B12 levels are normal. Some patients can have severe neurologic symptoms with falsely normal B12 levels.
Intrinsic factor deficiency can be evaluated by the Shilling test, which is now being replaced by other diagnostic strategies such as detecting intrinsic factor antibodies. Antibodies to intrinsic factor can be of two types. One is the blocking type against the B12 binding site present in 70% of patients, and the other is antibodies to parietal cells present in 90% of patients, but it is less specific.
Alternative and new approaches to the diagnosis of PA are under evaluation. One of these is a newer propriety cobalamin absorption test, which has its basis in measuring the change in holoTC following oral ingestion of non-radiolabeled cobalamin. Another approach has been described using accelerator mass spectrometry to quantify 14C in the blood following an orally administered dose of [14C]-cyanocobalamin. One may empirically administer vitamin B12 intramuscularly and assess the response if cobalamin deficiency is suspected. Most patients will feel clinically better within 24 hours. Additionally, marked reticulocytosis will appear within 5 to 7 days.
It is important to know that falsely low levels of cobalamin may occur in the following situations:
- Multiple myeloma
- Use of hormonal therapy or oral contraceptives
- Severe folic acid deficiency
- High levels of ascorbic acid
Treatment / Management
Patients generally receive an intramuscular injection of 1000 mcg B12 every day or every other day during the first week of treatment. The next month, they receive injections every week, subsequently followed by monthly injections. The alternative to intramuscular injection B12 is high-dose oral B12. A 1000 to 2000 mcg/day has been demonstrated to be effective, although recommendations are to always use the parenteral route in severe neurological manifestations. Approved sublingual and intranasal formulations of B12 are also available. Oral dosage is recommended for patients unable to take IM injections, but cobalamin levels must be measured frequently to ensure absorption. Finally, oral therapy is not recommended for patients with CNS symptoms.
The earliest sign of treatment response is an increase in reticulocyte count, usually within three days of treatment. Following changes in the decrease of biochemical markers such as MMA and plasma homocysteine levels have been observed in the first five days of treatment. Sustained normalization of serum cobalamin usually occurs following two weeks of therapy. The macrocytosis correction takes place during the first month of treatment. A clinical interview should be considered every year to monitor for new symptoms. These may include epigastric pain, dysphagia, iron deficiency, and/or others that can require gastroscopic investigation.
The key management principle is the importance of routine follow-up. Patients with underlying causes like chronic pancreatitis, bacterial overgrowth, or tapeworm will require additional treatments. Blood transfusions are not required in most patients. With treatment, the symptoms of heart failure resolve, but some patients may require concomitant diuretic therapy.
- Increased erythropoiesis: response to hemorrhage, hemolytic anemia
- Hypoplastic anemia
- Myelodysplastic syndrome
- Ileal disease or resection
- Liver disease
- Chronic obstructive pulmonary disease
- Proton pump inhibitor therapy
- Fish tapeworm
- Pancreatic insufficiency
- Corpus-predominant H. pylori gastritis
- Drugs (phenobarbital, azathioprine, methotrexate, 6-mercaptopurine, 5-fluorouracil, acyclovir)
Prognosis is variable, and most pernicious anemia patients have a subtle progression that can take 20 to 30 years, or even more, to become clinically significant. Even with a relatively benign prognosis, pernicious anemia can have fatal consequences if left undiagnosed. These consequences can be secondary to severe anemia and its complications, neurological compromise, and susceptibility to all types of gastric tumors. Delayed treatment may not always reverse neurological deficits. In addition, if the anemia is severe, it may lead to heart failure.
The risk of gastric cancer is present for life in patients with atrophic gastritis.
The complications associated with pernicious anemia are extensive, varying from mild symptoms such as fatigue to life-threatening pancytopenias.
- Anemia is the most frequent clinical sign. Other hematological manifestations such as neutropenia, thrombocytopenia, pancytopenia due to ineffective erythropoiesis, and pseudothrombotic microangiopathy may be present. Thromboembolic events are also a complication.
- Glossitis (inflammation of the tongue) may occur secondary to papillary atrophy resulting in a bald tongue and a burning sensation upon contact with different types of food.
- Neurological signs are usually present due to subacute combined degeneration of the spinal cord. Manifestations are predominantly in the lower limbs. The damage to myelin is responsible for ataxia, areflexia, and paresthesias with positive Romberg signs.
- The development of gastric carcinoid tumors is also a possible complication.
Postoperative and Rehabilitation Care
Long term monitoring is vital to ensure that the patient is not developing worsening of the CNS symptoms.
Deterrence and Patient Education
Pernicious anemia is an often silent and insidious autoimmune disease. Patients may become acclimated to their complaints. Health care providers should increase their awareness of this disorder to provide the best patient outcomes.
Enhancing Healthcare Team Outcomes
Pernicious anemia is often an insidious and under-diagnosed autoimmune disorder, which can lead to fatal complications.
The most appropriate way to supervise this disorder is through interprofessional and interprofessional teams that include primary care physicians, internists, gastroenterologists, neurologists, oncologists, pharmacists, and nurses. The healthcare team should strive to increase awareness of the disease and promptly test for it when appropriate. The nurse can intervene in a primary screening during triage by asking for signs and symptoms suggestive of underlying anemia, neurological or gastroenteric manifestations. The most at-risk population includes people over 60 years of age. These older individuals should receive prospective screening for possible vitamin B12 deficiency. The patient's siblings and children should be monitored as many cases of pernicious anemia are familial. Only with open communication between the clinicians can the outcomes of patients with pernicious anemia be improved. [Level 5]
The dietitian should educate patients about their dietary habits. Vegetarians should be told that they may develop pernicious anemia if they do not consume milk, eggs, or meat. These patients may be provided with supplements. Once treated, the patients should be supervised routinely by their clinician, in tandem with other interprofessional healthcare team members.