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Pernicious Anemia Clinical Presentation

  • Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD  more...
 
Updated: Aug 05, 2015
 

History

The onset of pernicious anemia usually is insidious and vague. The classic triad of weakness, sore tongue, and paresthesias may be elicited but usually is not the chief symptom complex. Typically, medical attention is sought because of symptoms suggestive of cardiac, renal, genitourinary, gastrointestinal, infectious, mental, or neurological disorders, and the patient is found to be anemic with macrocytic cellular indices.

General symptoms

Weight loss of 10-15 lb occurs in about 50% of patients and probably is due to anorexia, which is observed in most patients. Low-grade fever occurs in one third of newly diagnosed patients and promptly disappears with treatment.

Cardiac symptoms

The anemia often is well tolerated in pernicious anemia, and many patients are ambulatory with hematocrit levels in the mid-teens. However, the cardiac output is usually increased with hematocrits less than 20%, and the heart rate accelerates. Congestive heart failure and coronary insufficiency can occur, most particularly in patients with preexisting heart disease.

Gastrointestinal symptoms

Approximately 50% of patients have a smooth tongue with loss of papillae. This is usually most marked along the edges of the tongue. The tongue may be painful and beefy red. Occasionally, red patches are observed on the edges of the dorsum of the tongue. Patients may report burning or soreness, most particularly on the anterior third of the tongue. These symptoms may be associated with changes in taste and loss of appetite.

Patients may report either constipation or having several semisolid bowel movements daily. These symptoms have been attributed to megaloblastic changes of the cells of the intestinal mucosa.

Nonspecific gastrointestinal (GI) symptoms are not unusual and include anorexia, nausea, vomiting, heartburn, pyrosis, flatulence, and a sense of fullness. Rarely, patients present with severe abdominal pain associated with abdominal rigidity; this has been attributed to spinal cord pathology. Venkatesh and colleagues report the case of a patient who presented with epigastric pain, diarrhea, and vomiting and was found to have thrombosis of the portal, superior mesenteric, and splenic veins due to hyperhomocysteinemia secondary to pernicious anemia.[7]

Neurologic symptoms

Neurologic symptoms can be elicited in patients with pernicious anemia. The most common of these are paresthesias, weakness, clumsiness, and an unsteady gait. The last two symptoms become worse in darkness because they reflect the loss of proprioception in a patient who is unable to rely upon vision for compensation. These neurologic symptoms are due to myelin degeneration and loss of nerve fibers in the dorsal and lateral columns of the spinal cord and cerebral cortex.

Neurologic symptoms and findings may be present in the absence of anemia. This is more common in patients taking folic acid or on a high-folate diet.

Older patients may present with symptoms suggesting senile dementia or Alzheimer disease; memory loss, irritability, and personality changes are commonplace. Megaloblastic madness is less common and can be manifested by delusions, hallucinations, outbursts, and paranoid schizophrenic ideation. Identifying the cause is important because significant reversal of these symptoms and findings can occur with vitamin B12 administration.

Kocaoglu et al reported a case of vitamin B12 deficiency and cerebral atrophy in a 12-month-old infant whose development had slowed since 6 months of age; the infant was exclusively breastfed and his mother was a long-time vegetarian. Neurologic recovery began within days after the infant received an intramuscular cobalamin injection.[8]

Genitourinary symptoms

Urinary retention and impaired micturition may occur because of spinal cord damage. This can predispose patients to urinary tract infections.

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Physical Examination

The finding of severe anemia in an adult patient whose constitutional symptoms are relatively mild and in whom weight loss is not a major symptom should arouse suspicion of pernicious anemia.

Typically, patients with pernicious anemia are described as having a stereotypic appearance: they have a lemon-yellow waxy pallor with premature whitening of the hair, and they appear flabby, with a bulky frame that is generally incongruent with the severe anemia and weakness. It should be remembered, however, that whereas this characterization is useful in patients of northern European descent, it is less helpful among patients of other ethnic groups (who, as noted, are more commonly affected than was once believed).

The following signs may be noted:

  • Low-grade fever and mild icterus are commonplace but are usually mild and easily missed
  • A beefy, red, smooth tongue may be observed
  • In patients with dark complexions, blotchy skin pigmentation may be observed
  • Tachycardia often is present and may be accompanied by flow murmurs
  • Abnormal mentation and deterioration of vision and hearing may be observed
  • With severe anemia, dyspnea, tachypnea, and evidence of congestive heart failure may be present
  • Retinal hemorrhages and exudates may accompany severe anemia
  • The liver may be enlarged in association with congestive heart failure
  • A splenic tip is palpable in about 20% of patients

Neurologic assessment

A careful neurologic assessment is important. All megaloblastic disorders can give rise to hematologic and epithelial manifestations, but only cobalamin deficiency causes neurologic deficits. Neurologic findings may occur in the absence of anemia and epithelial manifestations of pernicious anemia, making it more difficult to identify the etiology. If left untreated, they can become irreversible.

Suspect pernicious anemia in all patients with recent loss of mental capacities. Somnolence, dementia, psychotic depression, and frank psychosis may be observed, which can be reversed or improved by treatment with cobalamin. Perversion of taste and smell and visual disturbances, which can progress to optic atrophy, can likewise result from central nervous system (CNS) cobalamin deficiency.

A history of either paresthesias in the fingers and toes or difficulty with gait and balance should prompt a careful neurologic examination. Loss of position sense in the second toe and loss of vibratory sense for a 256-Hz tuning fork, but not for a 128-Hz fork, are the earliest signs of posterolateral column disease. If untreated, this can progress to spastic ataxia from demyelinization of the dorsal and lateral columns of the spinal cord.

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Contributor Information and Disclosures
Author

Paul Schick, MD Emeritus Professor, Department of Internal Medicine, Jefferson Medical College of Thomas Jefferson University; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital

Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Coauthor(s)

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.

Acknowledgements

David Aboulafia, MD Medical Director, Bailey-Boushay House, Clinical Professor, Department of Medicine, Division of Hematology, Attending Physician, Section of Hematology/Oncology, Virginia Mason Clinic; Investigator, Virginia Mason Community Clinic Oncology Program/SWOG

David Aboulafia, MD is a member of the following medical societies: American College of Physicians, American Medical Association, American Medical Directors Association, American Society of Hematology, Infectious Diseases Society of America, and Phi Beta Kappa

Disclosure: Nothing to disclose.

Troy H Guthrie, Jr, MD Director of Cancer Institute, Baptist Medical Center

Troy H Guthrie, Jr, MD is a member of the following medical societies: American Federation for Medical Research, American Medical Association, American Society of Hematology, Florida Medical Association, Medical Association of Georgia, and Southern Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

References
  1. Hoffman R, Benz EJ, Furie B, Shattil SJ. Hematology: Basic Principles and Practice. Philadelphia, Pa: Churchill Livingstone; 2009.

  2. Elmadfa I, Singer I. Vitamin B-12 and homocysteine status among vegetarians: a global perspective. Am J Clin Nutr. 2009 May. 89(5):1693S-1698S. [Medline].

  3. Andrès E, Vogel T, Federici L, Zimmer J, Ciobanu E, Kaltenbach G. Cobalamin deficiency in elderly patients: a personal view. Curr Gerontol Geriatr Res. 2008. 848267. [Medline]. [Full Text].

  4. Bizzaro N, Antico A. Diagnosis and classification of pernicious anemia. Autoimmun Rev. 2014 Apr-May. 13(4-5):565-8. [Medline].

  5. Murphy G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A, et al. Cancer Risk After Pernicious Anemia in the US Elderly Population. Clin Gastroenterol Hepatol. 2015 Jun 14. [Medline].

  6. Chan JC, Liu HS, Kho BC, Lau TK, Li VL, Chan FH, et al. Longitudinal study of Chinese patients with pernicious anaemia. Postgrad Med J. 2008 Dec. 84(998):644-50. [Medline].

  7. Venkatesh P, Shaikh N, Malmstrom MF, Kumar VR, Nour B. Portal, superior mesenteric and splenic vein thrombosis secondary to hyperhomocysteinemia with pernicious anemia: a case report. J Med Case Rep. 2014 Aug 25. 8:286. [Medline]. [Full Text].

  8. Kocaoglu C, Akin F, Caksen H, Böke SB, Arslan S, Aygün S. Cerebral atrophy in a vitamin B12-deficient infant of a vegetarian mother. J Health Popul Nutr. 2014 Jun. 32(2):367-71. [Medline]. [Full Text].

  9. Centers for Disease Control and Prevention. Vitamin B12 Deficiency: Detection and Diagnosis. CDC. Available at http://www.cdc.gov/ncbddd/b12/detection.html. June 29, 2009; Accessed: August 5, 2015.

  10. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med. 2013 Jan 10. 368(2):149-60. [Medline].

  11. Graber JJ, Sherman FT, Kaufmann H, Kolodny EH, Sathe S. Vitamin B12-responsive severe leukoencephalopathy and autonomic dysfunction in a patient with "normal" serum B12 levels. J Neurol Neurosurg Psychiatry. 2010 Dec. 81(12):1369-71. [Medline].

  12. Erkurt MA, Aydogdu I, Dikilitas M, Kuku I, Kaya E, Bayraktar N, et al. Effects of cyanocobalamin on immunity in patients with pernicious anemia. Med Princ Pract. 2008. 17(2):131-5. [Medline].

  13. Zhang J, Field CJ, Vine D, Chen L. Intestinal Uptake and Transport of Vitamin B12-loaded Soy Protein Nanoparticles. Pharm Res. 2014 Oct 16. [Medline].

  14. Andres E, Serraj K. Optimal management of pernicious anemia. J Blood Med. 2012. 3:97-103. [Medline]. [Full Text].

  15. Favrat B, Vaucher P, Herzig L, et al. Oral vitamin B12 for patients suspected of subtle cobalamin deficiency: a multicentre pragmatic randomised controlled trial. BMC Fam Pract. 2011 Jan 13. 12:2. [Medline]. [Full Text].

 
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Pernicious anemia. The structure of cyanocobalamin is depicted. The cyanide (Cn) is in green. Other forms of cobalamin (Cbl) include hydroxocobalamin (OHCbl), methylcobalamin (MeCbl), and deoxyadenosylcobalamin (AdoCbl). In these forms, the beta-group is substituted for Cn. The corrin ring with a central cobalt atom is shown in red and the benzimidazole unit in blue. The corrin ring has 4 pyrroles, which bind to the cobalt atom. The fifth substituent is a derivative of dimethylbenzimidazole. The sixth substituent can be Cn, CC3, hydroxycorticosteroid (OH), or deoxyadenosyl. The cobalt atom can be in a +1, +2, or +3 oxidation state. In hydroxocobalamin, it is in the +3 state. The cobalt atom is reduced in a nicotinamide adenine dinucleotide (NADH)–dependent reaction to yield the active coenzyme. It catalyzes 2 types of reactions, which involve either rearrangements (conversion of l methylmalonyl coenzyme A [CoA] to succinyl CoA) or methylation (synthesis of methionine).
Pernicious anemia. Inherited disorders of cobalamin (Cbl) metabolism are depicted. The numbers and letters correspond to the sites at which abnormalities have been identified, as follows: (1) absence of intrinsic factor (IF); (2) abnormal Cbl intestinal adsorption; and (3) abnormal transcobalamin II (TC II), (a) mitochondrial Cbl reduction (Cbl A), (b) cobalamin adenosyl transferase (Cbl B), (c and d) cytosolic Cbl metabolism (Cbl C and D), (e and g) methyl transferase Cbl utilization (Cbl E and G), and (f) lysosomal Cbl efflux (Cbl F).
Pernicious anemia. Cobalamin (Cbl) is freed from meat in the acidic milieu of the stomach where it binds R factors in competition with intrinsic factor (IF). Cbl is freed from R factors in the duodenum by proteolytic digestion of the R factors by pancreatic enzymes. The IF-Cbl complex transits to the ileum where it is bound to ileal receptors. The IF-Cbl enters the ileal absorptive cell, and the Cbl is released and enters the plasma. In the plasma, the Cbl is bound to transcobalamin II (TC II), which delivers the complex to nonintestinal cells. In these cells, Cbl is freed from the transport protein.
Peripheral smear of blood from a patient with pernicious anemia. Macrocytes are observed, and some of the red blood cells show ovalocytosis. A 6-lobed polymorphonuclear leucocyte is present.
Bone marrow aspirate from a patient with untreated pernicious anemia. Megaloblastic maturation of erythroid precursors is shown. Two megaloblasts occupy the center of the slide with a megaloblastic normoblast above.
Response to therapy with cobalamin (Cbl) in a previously untreated patient with pernicious anemia. A reticulocytosis occurs within 5 days after an injection of 1000 mcg of Cbl and lasts for about 2 weeks. The hemoglobin (Hgb) concentration increases at a slower rate because many of the reticulocytes are abnormal and do not survive as mature erythrocytes. After 1 or 2 weeks, the Hgb concentration increases about 1 g/dL per week.
Table 1. Serum Methylmalonic Acid and Homocysteine Values Used in Differentiating Between Cobalamin and Folic Acid Deficiency
Patient Condition Methylmalonic Acid Homocysteine
Healthy Normal Normal
Vitamin B12 deficiency Elevated Elevated
Folate deficiency Normal Elevated
Table 2. Schilling test results
Patient Condition Stage I



No Intrinsic Factor



Stage II



Intrinsic Factor



Stage III



Antibiotic



Stage IV



Pancreatic Extract



Healthy Normal
Pernicious anemia Low Normal
Bacterial overgrowth Low Low Normal
Pancreatic insufficiency Low Low Low Normal
Defect in ileum Low Low Low Low
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