PERNICIOUS ANEMIA AND OTHER MEGALOBLASTIC ANEMIAS

PERNICIOUS ANEMIA AND OTHER MEGALOBLASTIC ANEMIAS

Current Diagnosis

• Megaloblastic anemia is a macrocytic anemia characterized by macroovalocytes and hypersegmented neutrophils on the peripheral smear.

• In adults, many underlying conditions lead to megaloblastic anemia, but the most common ones are folate (folic acid, vitamin B9) deficiency, vitamin B12  (cobalamin) deficiency, and pernicious anemia.

• In the adult population, folate deficiency usually develops as a result of inadequate dietary intake or as an adverse effect of several drugs (methotrexate [Trexall], cotrimoxazole [Bactrim], sulfasalazine [Azulfidine], anticonvulsants) or alcohol intake.

• In adults and the elderly, vitamin B12  deficiency is mainly due to cobalamin malabsorption from food and to pernicious anemia.

Current Therapy

• Recognition of the condition causing megaloblastic anemia is a prerequisite of successful therapy.

• Treatment of nutrient-deficiency megaloblastic anemia is easy with nutrient replacement.

• Vitamin B12  deficiency can be treated with both oral and parenteral therapy.

• If vitamin B12  deficiency is untreated, folate repletion will correct the megaloblastic anemia but not the associated neuropathic changes that occur with B12  deficiency.

Anemia is a common condition, especially in adults, and its prevalence increases with age. It affects quality of life, physical function, and even cognitive function in elderly patients. Anemia is a comorbid condition that affects other diseases (e.g., heart disease, cerebrovascular insufficiency) and is associated with a risk of death. Thus, anemia should not be accepted as a benign condition or a consequence of aging. In adults, many underlying conditions lead to megaloblastic anemia, but the most common ones are nutrient deficiencies, especially folate (folic acid, vitamin B9) deficiency, vitamin B12  (cobalamin) deficiency, and pernicious anemia.

Recognition of these conditions is a prerequisite of successful therapy. Although low hemoglobin levels are often seen with advancing age, anemia should not be assumed to be a normal consequence of aging. Age may be associated with compromised hematopoietic reserve, and the elderly can be more susceptible to anemia in the presence of hematopoietic stress induced by an underlying disorder.

Consequently, it is important to identify the underlying disorder. In practice, a hemoglobin (Hb) level less than 10 g/dL is considered a trigger for the investigation of the cause of anemia.

Definition

The World Health Organization (WHO) defines anemia as a hemoglobin concentration less than 12 g/dL for nonpregnant women and less than 13 g/dL for men. Megaloblastic anemia is characterized by many large immature and dysfunctional red blood cells (megaloblasts) in the bone marrow and by hypersegmented or multisegmented neutrophils. Megaloblastic anemia includes nutrient deficiencies related to folate and vitamin B12 and pernicious anemia. Megaloblastic anemia is included in the group of macrocytic anemias (mean corpuscular volume [MCV] >100 fL). Macrocytic anemia also includes anemia related to chronic alcohol use (with or without liver disease), thyroid failure, and myelodysplastic syndromes.

Epidemiology

In adults, the prevalence of anemia varies by country, ethnic group, and the health status of the patients. Living conditions can also influence this prevalence. Nevertheless, the prevalence of anemia increases with advancing age, especially after age 60 to 65 years, and rises sharply after the age of 80 years. Results from the third National Health and Nutrition Examination Survey (NHANES III) carried out in the United States indicates that the prevalence of anemia was 11% in community-dwelling men and 10.2% among women 65 years or older. Survey findings also indicate that most anemia among the elderly is mild; only 2.8% of women and 1.6% of men have a hemoglobin less than 11 g/dL.

Results from the Framingham cohort indicate a slightly lower prevalence of anemia among older people living in the United States compared to the NHANES IIII survey. In the Framingham group of 1016 subjects 67 to 96 years of age, the prevalence of anemia in men and women is 6.1% and 10.5%, respectively.

In adults, causes of anemia are divided into three broad groups: nutrient-deficiency anemia, including iron deficiency, folate deficiency, and B12 deficiency anemia; anemia of chronic disease, perhaps better termed anemia of chronic inflammation; and unexplained anemia. Table 1 presents the cause of anemia in 300 consecutive patients hospitalized in an internal medicine department.

Table 1

Etiology of Anemia in 300 Consecutive Patients Older than 65 Years Hospitalized in a Department of Internal Medicine in a Tertiary Reference Center

 

Etiology  Prevalence (%)
Chronic inflammation (chronic disease) 23.0
Iron deficiency 18
Renal failure 9
Liver disease and endocrine disease (chronic disease) 7
Posthemorrhagic 7
Folate deficiency 6*
Myelodysplasia 5
Vitamin B12  deficiency 4†
Unexplained causes 21

Adapted from Andrès E, Federici L, Serraj K, Kaltenbach G: Update of nutrient-deficiency anemia in elderly patients. Eur J Intern Med  2008;19:488–93.

*  10% of these patients have megaloblastic  anemia.

†  Vitamin B 12 deficiency is defined as a serum cobalamin level <200 pg/mL (<150 pmol/L) in  2 samples.

In the NHANES III study, 34% of all anemia in elderly patients is caused by deficiencies of nutrients including folate, vitamin B12, and iron, alone or in combination. About 60% of nutrient-deficiency anemia is associated with iron deficiency, and most of those cases are the result of chronic blood loss from gastrointestinal lesions. The remaining cases of nutritient-deficiency anemia are usually associated with vitamin B12 or folate deficiency (or both) and are easily treated.

Twelve percent of anemias were associated with renal insufficiency, 20% were due to chronic diseases, and in 34% the cause remained unexplained.

Etiology

Folate Deficiency Anemia in Adults

A balanced diet contains 500 to 700 µg of folate. On average, 50% to 60% of dietary folate is absorbed in the duodenum and jejunum.

Folate deficiency usually develops as a result of inadequate dietary intake. The body stores very little folate, only enough to last 4 to 6 months. Patients usually have a history of weight loss, poor weight gain, and weakness. In addition, several drugs (methotrexate [Trexall], cotrimoxazole [Bactrim], sulfasalazine [Azulfidine], and anticonvulsants) and alcohol can cause deficiency of folate by inhibiting absorption or by affecting folate metabolism.

Vitamin B12  Deficiency Anemia in Adults

Deficiency of vitamin B12 and folate are common, especially among the elderly, each occurring in at least 5% of patients. In these patients, the etiologies of cobalamin deficiency are represented primarily by food- cobalamin malabsorption, other causes of malabsorption such as surgical resection of the stomach or ileum, pernicious anemia, and, more rarely, by intake deficiency. In our work, in which we followed more than 200 elderly patients with a proven deficiency, food- cobalamin malabsorption accounted for about 60% to 70% of the etiologies of cobalamin deficiency, and pernicious anemia accounted for 15% to 25%. Figure 1 presents the principal causes of cobalamin deficiency in 172 patients hospitalized in an internal medicine department.

FIGURE 1    Etiologies of cobalamin deficiency in 172 elderly  patients hospitalized in the university hospital of Strasbourg, France. (Adapted from Andrès E, Loukili NH, Noel E, et al: Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J 2004;171:251-260; and Andrès E, Vidal-Alaball J, Federici L, et al: Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, treatment with special focus on oral cobalamin therapy. Eur J Intern Med 2007;18:456–62.)

Food-Cobalamin Malabsorption

Initially described by Carmel in the 1990s, food-cobalamin malabsorption is characterized by the inability to release bound cobalamin from food or intestinal transport proteins, particularly in the setting of hypochlorhydria, where the absorption of unbound cobalamin is normal. This syndrome is defined by cobalamin deficiency despite sufficient food-cobalamin intake and a normal Schilling test. The normal Schilling test rules out pernicious anemia and other causes of malabsorption. The principal characteristics of this syndrome are listed in Box 1.

Box 1
Food-Cobalamin Malabsorption Syndrome
Criteria for Food-Cobalamin Malabsorption

Low serum cobalamin (vitamin B12) levels

Normal results of Schilling test using free cyanocobalamin labeled with cobalt-58, or abnormal results of derived Schilling test*

No anti-intrinsic factor antibodies

No dietary cobalamin deficiency

Associated Conditions or Agents

Gastric disease

•  Atrophic gastritis

•   Type A atrophic gastritis

•   Gastric disease associated with Helicobacter pylori infection

•   Partial gastrectomy

•   Gastric bypass

•   Vagotomy

Pancreatic insufficiency

•   Alcohol abuse

Gastric or intestinal bacterial overgrowth

•   Achlorhydria

•   Tropical sprue

•   Ogylvie’s syndrome

•  HIV

Drugs

•  Antacids (H2-receptor antagonists and proton-pump inhibitors)

•  Biguanides (metformin [Glucophage])

Alcohol abuse

Sjögren’s syndrome, systemic sclerosis

Haptocorrin deficiency

Aging or idiopathic

Adapted from Andrès E, Affenberger S, Vinzio S, et al: Food-cobalamin malabsorption in elderly patients: Clinical manifestations and treatment. Am J Med   2005;118:1154-1159.
* Derived Schilling tests use food-bound cobalamin (e.g., egg yolk, chicken, and fish proteins).

Food-cobalamin malabsorption is caused primarily by atrophic gastritis. More than 40% of patients older than 80 years have gastric atrophy. Factors that commonly contribute to food-cobalamin malabsorption include Helicobacter pylori infection, chronic carriage of H.pylori, intestinal microbial proliferation (in which case, cobalamin deficiency can be corrected by antibiotic treatment); long-term ingestion of antacids, H2-receptor antagonists and proton-pump inhibitors, and biguanides (metformin [Glucophage]); chronic alcoholism; surgery or gastric reconstruction (e.g., bypass surgery for obesity); and complete or partial pancreatic exocrine

Pernicious Anemia

Pernicious anemia, also known as Biermer’s anemia or Addison’s anemia, is caused by impaired absorption of vitamin B12 owing to the neutralization of intrinsic factor action in the setting of immune atrophic gastritis. In elderly patients, this form of megaloblastic anemia is one of the leading causes of cobalamin deficiency.

Pernicious anemia has a genetic component. In practice, the diagnosis of pernicious anemia is based on the presence of intrinsic factor antibodies in serum (specificity, >98%; sensitivity, around 50%) or biopsy-proven autoimmune atrophic gastritis. The presence of H. pylori infection in gastric biopsies is an exclusion factor. Pernicious anemia is associated with other immunologic diseases such as Sjögren’s syndrome, Hashimoto’s disease, type 1 diabetes mellitus, and celiac disease.

Other Causes of Cobalamin Deficiency

Cobalamin deficiency caused by dietary deficiency or malabsorption is rare. Dietary causes of deficiency are limited to elderly people who are already malnourished. This mainly concerns elderly patients living in institutions or in psychiatric hospitals. Since the 1980s, the malabsorption of cobalamin has become rare, owing mainly to the decreasing frequency of gastrectomy and surgical resection of the terminal small intestine. Other disorders associated with cobalamin malabsorption include deficiency in the exocrine function of the pancreas after chronic pancreatitis (usually alcoholic), lymphomas or tuberculosis of the intestine, Crohn’s disease, Whipple’s disease, and celiac disease. Uncommon etiology also includes nitrous oxide anesthesia and abuse.

Clinical Features

Box 2 presents features related to vitamin B12 deficiency. It should be noted that vitamin B12 deficiency may be present in the absence of anemia. The symptoms of folate deficiency are nearly indistinguishable from those of cobalamin deficiency. Box 3 presents the other hematologic manifestations of cobalamin deficiency.

Box 2
Nonhematologic Manifestations of Vitamin B1 2  Deficiency
Neuropsychiatric Common

Polyneuritis (especially sensitive ones)

Ataxia

Babinski’s phenomenon

Classic

Combined sclerosis of the spinal cord

Rare

Cerebellar syndromes affecting the cranial nerves including optic neuritis, optic atrophy

Urinary incontinence

Fecal incontinence

Under Study

Changes in higher cognitive functions, including dementia Stroke and atherosclerosis (hyperhomocysteinemia) Parkinsonian syndromes

Depression

Multiple sclerosis

Digestive

Classic

Hunter’s glossitis

Jaundice

Lactate dehydrogenase and bilirubin elevation (intramedullary destruction)

Debatable

Abdominal pain

Dyspepsia Nausea, vomiting

Diarrhea

Disturbances in intestinal functioning

Rare

Resistant and recurring mucocutaneous ulcers

Other

Under Study

Atrophy of the vaginal mucosa

Chronic vaginal and urinary infections (especially mycosis)

Venous thromboembolic disease

Angina (hyperhomocysteinemia)

Adapted from Andrès E, Loukili NH, Noel E, et al: Vitamin B12 (cobalamin) deficiency in  elderly patients. Can Med Assoc J 2004;171:251–260; and Andrès E, Vidal-Alaball J, Federici L, et al: Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology,   causes, clinical manifestations, treatment with special focus on oral cobalamin therapy. Eur J Intern Med 2007;18:456–462.

Box 3
Hematologic Manifestations of  Vitamin B1 2 Deficiency
Common

Macrocytosis

Hypersegmentation of neutrophils

Aregenerative macrocytic anemia

Megaloblastic anemia

Rare

Isolated thrombocytopenia and neutropenia

Pancytopenia

Uncommon

Hemolytic anemia

Pseudothrombotic microangiopathy

Adapted from Andrès E, Loukili NH, Noel E, et al: Vitamin B12 (cobalamin) deficiency in  elderly patients. Can Med Assoc J 2004;171:251-260; and Andrès E, Vidal-Alaball J, Federici L, et al: Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, treatment with special focus on oral cobalamin therapy. Eur J Intern Med 2007;18:456–462.

Diagnosis

Patients with nutrient-deficiency anemia often have mild to moderate anemia with hemoglobin levels between 8 and 10 g/dL. In anemia of exclusive folate and/or vitamin B12 deficiency, the erythrocytes are usually macrocytic (MCV >100 fL). Megaloblastic processes are characterized on the peripheral smear by macroovalocytes and hypersegmented neutrophils. Bone marrow aspiration, which is rarely required for diagnosis, demonstrates large immature and dysfunctional red blood cells (megaloblasts) and hypersegmented or multisegmented neutrophils. In cobalamin deficiency (<150 pmol/L), serum vitamin B12 level is low (<200 pg/mL), serum methylmalonic acid is increased, and homocysteine levels are increased. In folate deficiency, testing the red cell folate concentration is more reliable than the serum level.

Prevention

Providing food sources of nutrients is best for preventing megaloblastic anemia. Food source supplementation may be necessary, especially for the very old. The National Academy of Sciences recommends that folate and vitamin B12 be supplemented for the elderly in the form of fortified cereal.

Treatment

Treatment of megaloblastic anemia requires particular attention to discerning the cause. In adult patients, vitamin B12 deficiency anemia may be treated by vitamin B12 supplementation, parenterally or orally. Our working group has developed an effective oral treatment regimen for food-cobalamin malabsorption and pernicious anemia using crystalline cobalamin (cyanocobalamin)1 (Figure 2). The effect of oral cobalamin treatment in patients presenting with severe neurologic manifestations has not yet been adequately documented.

FIGURE 2    Therapeutic schema for vitamin B12 deficiency.  (Adapted from Andrès E, Affenberger S, Vinzio S, et al: Food-cobalamin malabsorption in elderly

patients: Clinical manifestations and treatment. Am J Med 2005;118: 1154–1159; Andrès E, Federici L, Serraj K, Kaltenbach G: Update of nutrient-deficiency anemia in elderly patients. Eur J Intern Med 2008;19:488–493; Andrès E, Loukili NH, Noel E, et al: Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J 2004;171: 251–260; and Andrès E, Vidal-Alaball J, Federici L, et al: Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, treatment with special focus on oral cobalamin therapy. Eur J Intern Med 2007;18:456–462.)

For folate deficiency anemia, therapeutic doses of folic acid vary between 1 and 5 mg/day. Usually, these various therapies are continued for at least 3 to 6 months, provided that the underlying causes of the deficiency have been corrected.

If vitamin B12 deficiency is present but undiagnosed, folate repletion will correct the megaloblastic anemia, but not the possible neuropathic changes that occur with B12 deficiency.

References

1.     Andrès E., Affenberger S., Vinzio S., et al. Food-cobalamin malabsorption in elderly patients: Clinical manifestations and treatment. Am J Med. 2005;118:1154–1159.

2.    Andrès E., Federici L., Serraj K., Kaltenbach G. Update of nutrient-deficiency anemia in elderly patients. Eur J Intern Med. 2008;19:488–493.

3.     Andrès E., Loukili N.H., Noel E., et al. Vitamin B12 (cobalamin) deficiency in elderly patients. Can Med Assoc J. 2004;171:251– 260.

4.    Andrès E., Vidal-Alaball J., Federici L., et al. Clinical aspects of cobalamin deficiency in elderly patients. Epidemiology, causes, clinical manifestations, treatment with special focus on oral cobalamin therapy. Eur J Intern Med. 2007;18:456–462.

5.     Carmel R. Malabsorption of food-cobalamin. Baillieres Clin Haematol. 1995;8:639–655.

6      McDowell M.A., Fryar C.D., Ogden C.L. Anthropometric reference data for children and adults: United States, 1988– 1994. Vital Health Stat. 2009;11(249):1–68.

7.    Vidal-Alaball J., Butler C.C., Cannings-John R., et al. Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency. Cochrane Database Syst Rev. (20):2005 CD004655.

8.    Wickramasinghe S.N. Diagnosis of megaloblastic anaemias. Blood Rev. 2006;20:299–318.

1  Not FDA approved for this  indication.

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