Elsevier

Autoimmunity Reviews

Volume 13, Issues 4–5, April–May 2014, Pages 565-568
Autoimmunity Reviews

Review
Diagnosis and classification of pernicious anemia

https://doi.org/10.1016/j.autrev.2014.01.042Get rights and content

Highlights

  • Pernicious anemia (PA) is a complex disorder consisting of hematological, gastric and immunological alterations.

  • Diagnosis of PA relies on atrophic body gastritis, megaloblastic anemia, cobalamin deficiency and antibodies to intrinsic factor (IFA) and to gastric parietal cells (PCA).

  • PCA are present at a high frequency in PA (80%–90%), especially in early stages of the disease, but are not completely specific.

  • IFA are considered specific markers for diagnosing PA and are detected in 40%–60% of patients with PA.

Abstract

Pernicious anemia (PA) is a complex disorder consisting of hematological, gastric and immunological alterations. Diagnosis of PA relies on histologically proven atrophic body gastritis, peripheral blood examination showing megaloblastic anemia with hypersegmented neutrophils, cobalamin deficiency and antibodies to intrinsic factor and to gastric parietal cells. Anti-parietal cell antibodies are found in 90% of patients with PA, but have low specificity and are seen in atrophic gastritis without megaloblastic anemia as well as in various autoimmune disorders. Anti-intrinsic factor antibodies are less sensitive, being found in only 60% of patients with PA, but are considered highly specific for PA. The incidence of PA increases with age and is rare in persons younger than 30 years of age. The highest prevalence is seen in Northern Europeans, especially those in the United Kingdom and Scandinavia, although PA has been reported in virtually every ethnic group. Because of the complexity of the diagnosis, PA prevalence is probably underestimated and no reliable data are available on the risk of gastric cancer as the end-stage evolution of atrophic gastritis in these patients.

Introduction

Pernicious anemia (PA) is a disease of autoimmune origin in which atrophy of the gastric mucosa which involves the body and fundus of the stomach, reduces the number of parietal cells that produce the intrinsic factor necessary for absorption of vitamin B12, which, in turn, is indispensible for erythropoiesis and myelin synthesis. This condition is progressive over a span of years, from a mild chronic inflammation of the stomach body to an advanced state associated with a lack of vitamin B12.

The symptomatology is dominated by a profound megaloblastic-type anemia and, in the most serious cases, by neurological alterations, which can precede the diagnosis of gastric atrophy by several decades.

The autoimmune nature of the process that brings on gastric atrophy and PA is documented by the presence of autoantibodies against intrinsic factor secreted by the stomach and the gastric parietal cells, and by the frequent coexistence in these patients of other disorders of autoimmune origin. Recent epidemiological studies support the evidence that autoimmune gastritis and PA are found across all continents [1], [2] and probably are underdiagnosed [3], [4], given that most patients with microcytic or macrocytic anemia are treated with iron, folates, and cobalamin, without any more thorough investigation into the cause of the anemia; a biopsy of the gastric mucosa in many cases is not undertaken; even if a biopsy is performed, the pathologists often describe a generic histological pattern of chronic gastritis with intestinal metaplasia [5], [6].

Section snippets

Historical notes

1860: Austin Flint, connects observations made by Thomas Addison in 1849, describing an important form of anemia associated with a degenerative disease of the tubular glands of the stomach.

1872: Anton Biermer designates this condition ‘pernicious anemia’.

1900: Faber and Bloch document for the first time in a patient with PA the presence of a histological pattern of gastric atrophy.

1953: William B. Castle demonstrates that anemia is caused by a concomitant lack of an ‘extrinsic factor’

Genetics

A genetic susceptibility for PA is suggested by a specific HLA-DR pattern and by blocking experiments with anti-DR and anti-DQ antibodies that have shown that DR antigen represents the HLA restriction element in atrophic body gastritis [8]. By using a DNA-based, sequence-specific oligonucleotide technology, it has been observed that the genotypes HLA-DRB1*03 and DRB1*04, which are known to be associated with other autoimmune disease (such as type1 diabetes and autoimmune thyroid disease) [9],

Clinical features

Pernicious anemia usually manifests itself in persons over age 30 and strikes both sexes equally. It is particularly frequent in northern Europeans, especially Scandinavians. Nevertheless, it is present in other populations but is relatively infrequent in subjects of the oriental races.

Patients usually exhibit symptoms of anemia with pallor, fatigue, lightheadedness, or tachycardia. Often the anemia is of such insidious onset that the severity is not suspected clinically. Inhibition of DNA

Autoantibodies

Patients with PA have been shown to have two types of antibodies, one to parietal cells (PCA) and the other to intrinsic factor (IFA) or its binding site in the small bowel.

Diagnostic criteria

The diagnosis of PA relies on demonstration of megaloblastic anemia, low serum vitamin B12 levels, gastric atrophia, and the presence of antibodies to gastric parietal cell or intrinsic factor (Table 1).

The anemia is macrocytic and normochromic with reduction in the absolute number of reticulocytes. The hemoglogin level may be seriously reduced, even down to 3 g/dL. The patient's red blood cells (RBCs) exhibit marked anisopoikilocytosis and numerous oval macrocytes (megalocytes).

Hypersegmented

Detection of autoantibodies

PCA are usually detected by indirect immunofluorescence (IIF) performed on cryostat sections of rodent stomach; positivity is characterized by a homogeneous and diffuse cytoplasmic staining of only the parietal cells. However, since IIF is not very sensitive, provides only semi-quantitative values, and interpretation of results is highly subjective and depends on the expertise of the observer, ELISA methods, using highly purified H+/K+ ATPase antigens from human or porcine stomach have been

Histopathological features

From the histological point of view, the mucosa of the cardia and fundus is thinned and atrophied, with shrunken glands and containing few principal and parietal cells, while usually the mucosa of the antrum is spared. However, in about 50% of PA patients, antral mucosa is not spared, and in about 27% of PA patients, a concomitant antral atrophic gastritis may be observed. These data strongly suggest that an extension of gastritis to the gastric antrum does not necessarily exclude the diagnosis

Treatment

Pernicious anemia is caused by inadequate secretion of gastric intrinsic factor necessary for vitamin B12 absorption and thus cannot be treated with oral vitamin B12 supplements; rather, vitamin B12 must be administered parenterally. An intramuscular injection of 1 mg of vitamin B12 is generally given every day for 1 week, followed by 1 mg every week for 4 weeks and then 1 mg every month thereafter. PA requires lifelong treatment. Symptoms of vitamin B12 deficiency may be improved after just a few

References (29)

  • R. Carmel

    Prevalence of undiagnosed pernicious anemia in the elderly

    Arch Intern Med

    (1996)
  • C. Herscko et al.

    Variable hematologic presentation of autoimmune gastritis: age-related progression from iron deficiency to cobalamin depletion

    Blood

    (2006)
  • J.C. Chan et al.

    Longitudinal study of Chinese patients with pernicious anaemia

    Postgrad Med J

    (2008)
  • W.J. Irvine et al.

    Immunological relationship between pernicious anemia and thyroid disease

    Br Med J

    (1962)
  • Cited by (117)

    • Rare case of pernicious anaemia from a university hospital of Nepal: A case report

      2022, Annals of Medicine and Surgery
      Citation Excerpt :

      Pernicious Anaemia is a complex disorder with haematological, gastric, immunological and neurological alterations characterised by cobalamin deficiency [1,2].

    • Neurosurgical Mimics

      2022, Neurologic Clinics
      Citation Excerpt :

      Some medications and therapeutic agents such as the diabetic medication metformin and the anesthetic nitrous oxide gas are known to interfere with absorption and metabolism of vitamin B12.35 Symptomatic cobalamin deficiency is most common in the elderly population and most frequently due to malabsorption and pernicious anemia.36 Neurologic symptoms are often the presenting feature of B12 deficiency, given that the onset is insidious, and often at a later stage by the time of diagnosis.

    View all citing articles on Scopus
    View full text