Also Known As
Cobalamin Deficiency
Folic Acid or B9 Deficiency
This article was last reviewed on
This article waslast modified on
October 10, 2017.
What are vitamin B12 and folate deficiencies?

Vitamin B12 and folate deficiencies are a lack of these two B complex vitamins that the body needs for several important functions. They are required to make normal red blood cells (RBCs), repair tissues and cells, synthesize DNA (the genetic material in cells). B12 is also important for normal nerve cell function. B12 and folate (also known as folic acid or vitamin B9) are nutrients that cannot be produced in the body and must be supplied by the diet. The body stores 3 to 6 years worth of B12 and about a 3 months' supply of folate in the liver. So a B12 and/or folate deficiency reflects a chronic shortage of one or both of these vitamins.

In the U.S., B12 and folate deficiencies are not common in healthy adults because the body can store sufficient amounts and most adults eat enough foods or take supplements that contain these vitamins to meet their daily requirements. There are, however, people at risk of deficiency, such as the elderly, people with intestinal problems that prevent them from absorbing enough of the vitamins, heavy alcohol drinkers, and pregnant women, who need increased amounts of these vitamins.

B12 and folate deficiencies and their associated signs and symptoms can take months to years to manifest in adults. Infants and children will show signs of deficiency more rapidly because they have not yet had time to store sufficient amounts.

Over time, a deficiency in either B12 or folate can lead to macrocytic anemia, a condition in which red blood cells are enlarged. This production of fewer but larger red blood cells decreases the blood's ability to carry oxygen. People with anemia may be weak, light-headed, and short of breath. Megaloblastic anemia, a type of macrocytic anemia, is characterized by the production of fewer but larger RBCs in addition to some cellular changes in the bone marrow. Other laboratory findings associated with megaloblastic anemia include decreased white blood cell (WBC) count and platelet count.

A deficiency in B12 can also result in varying degrees of neuropathy or nerve damage that can cause tingling and numbness in the person's hands and feet. In severe cases, mental changes that range from confusion and irritability to dementia may occur.

Pregnant women need increased folate for proper fetal development because of the added stress of rapidly growing fetal cells. A folate deficiency during pregnancy, especially in the early weeks when a woman might not know she is pregnant, may lead to premature birth and neural tube birth defects (NTDs) such as spina bifida in the child. To help prevent NTDs, the Food and Drug Administration mandated increased folate supplementation of grain products a number of years ago, which led to about a 50% decrease in neural tube defects in the U.S. Even so, it can be difficult sometimes to get enough folate from foods, so it is recommended that all women who may become pregnant take 400 micrograms of folate every day.

Accordion Title
About Vitamin B and Folate Deficiencies
  • Signs and Symptoms

    The initial signs and symptoms associated with B12 and folate deficiencies may be subtle and nonspecific. They may be related to the resulting megaloblastic anemia, nerve damage, and/or gastrointestinal changes. People with an early deficiency may be diagnosed before they experience any noticeable symptoms. Other affected people may experience a variety of mild to severe signs and symptoms that can include:

    • Diarrhea
    • Dizziness
    • Fatigue, muscle weakness
    • Loss of appetite
    • Pale skin
    • Rapid heart rate, irregular heartbeats
    • Shortness of breath
    • Sore tongue and mouth
    • Tingling, numbness, and/or burning in the feet, hands, arms, and legs (with B12 deficiency)
    • Confusion or forgetfulness
    • Paranoia
  • Causes

    There are a variety of causes of B12 and/or folate deficiencies. They include:

    Insufficient dietary intake
    B12 is found in animal products such as red meat, fish, poultry, milk, and eggs. Folate, also called folic acid or vitamin B9, is found in leafy green vegetables, citrus fruits, dry beans, yeast, and fortified cereals.

    The human body stores several years' worth of B12 in the liver. Since a variety of foods consumed by Americans contain B12, a dietary deficiency of this vitamin is extremely rare in the U.S. It may be seen, for example, in people with generally poor nutrition or malnutrition, in vegans who do not consume any animal products, including milk and eggs, and in breastfed infants of vegans. In adults, dietary deficiencies do not usually cause symptoms until stores of the vitamins within the body have been depleted. Deficiencies in children and infants, however, show up fairly quickly since they have not had time to store as much of the vitamins as adults.

    Folate deficiency used to be a common, but in 1997 the U.S. government mandated supplementation of cereals, breads, and other grain products with folic acid. Because folate is stored in tissue in smaller quantities than B12, folate must be consumed more regularly than B12.

    Malabsorption
    Both B12 and folate deficiencies may be seen in people who have conditions that interfere with absorption of the vitamins in the small intestine. Vitamin B12 absorption occurs in a series of steps. B12 is normally released from food by stomach acid and then, in the small intestine, is bound to intrinsic factor (IF), a protein made by parietal cells in the stomach. This B12-IF complex is then absorbed by the small intestine, bound by carrier proteins (transcobalamins), and enters the circulation. If a disease or condition interferes with any of these steps, then B12 absorption is impaired.

    Some examples of these conditions include:

    • Pernicious anemia is the most common cause of B12 deficiency. A protein called intrinsic factor, made by parietal cells that line the stomach, is needed for B12 absorption. In pernicious anemia, inflammation damages the parietal cells, leading to little or no intrinsic factor, thus preventing the intestines from absorbing B12. With insufficient B12, the body produces enlarged but fewer RBCs. Because of the larger than normal RBCs, this is often referred to as megaloblastic or macrocytic anemia.
    • Celiac disease
    • Inflammatory bowel disease, including Crohns disease and ulcerative colitis
    • Bacterial overgrowth or the presence of parasites in the intestines
    • Reduced stomach acid production; stomach acid is necessary to separate B12 from the protein in food. This is the most common cause of B12 deficiency in the elderly and in individuals on drugs that suppress gastric acid production.
    • Surgery that removes part of the stomach (and the parietal cells) or the intestines may greatly reduce absorption of nutrients. This is a concern that is considered when gastric by-pass procedures are performed.
    • Chronic pancreatitis


    Increased need
    All pregnant women need increased amounts of folate for proper fetal development. If a woman has a folate deficiency prior to pregnancy, it will be intensified during the pregnancy and may lead to premature birth and neural tube defects in the child. It is recommended that women with any chance of becoming pregnant take folic acid supplements because neural tube defects can develop in the first few weeks of pregnancy, before many women realize they are pregnant. (For more details, read the article on Neural Tube Defects.)

    People with cancer that has spread (metastasized) or with a chronic hemolytic anemia such as due to sickle cell disease have an increased need for folate.


    Other causes:

    • Heavy alcohol drinking and chronic alcoholism can cause B12 and/or folate deficiency through a combination of poor nutrition and a decrease in the amount of B12 released from dietary proteins.
    • Some drugs can cause B12 deficiency. For example, the diabetes drug metformin prevents B12 from being absorbed, while omeprazole (an acid reflux drug also known as Prilosec) reduces gastric acids and prevents B12 release from food.
    • Anti-seizure medications such as phenytoin can decrease folate by blocking folate absorption.
    • Methotrexate, an anti-cancer drug, affects body metabolism and use of folate.
  • Tests

    Laboratory testing is used to detect a vitamin deficiency, determine its severity, establish it as the underlying cause of someone's symptoms, and to monitor the effectiveness of treatment. The anemia and large red blood cells (RBCs) associated with a vitamin B12 or folate deficiency are often initially detected during a routine complete blood count (CBC). Additional laboratory testing is performed as follow up to identify the specific deficiency.

    Laboratory Tests

    Ordered to diagnose or monitor B12 and folate deficiencies:

    • B12 blood level. If low, a deficiency is indicated, but it does not identify the cause. A low level of intrinsic factor may be a cause, for example. This test also may be ordered to monitor the effectiveness of treatment.
    • Folate level. Either serum or RBC folate levels may be tested; if either is low, it indicates a deficiency. The tests may also be ordered to monitor the effectiveness of treatment. Pregnant women may be given this test at prenatal checkups.
    • CBC. This group of tests is ordered routinely to evaluate the health of blood cells. It determines the number of cell types and can give an indication of the physical characteristics of some of the cells. With both B12 and folate deficiencies, the amount of hemoglobin and the red blood cell count may be low and the RBCs are abnormally large (macrocytic or megaloblastic), resulting in an anemia. White blood cells and platelets also may be decreased.
    • Methylmalonic acid (MMA). This test may be ordered to help detect mild or early B12 deficiency.
    • Homocysteine. This test is seldom ordered but may be elevated in both B12 and folate deficiency.


    Ordered to help determine the cause of a B12 deficiency:

    • Intrinsic factor antibody. The antibody prevents intrinsic factor from carrying out its function, that is, to carry vitamin B12 and allow B12 to be absorbed at a specific segment of the small intestine.
    • Parietal cell antibody. An antibody against the parietal cells that produce intrinsic factor. This antibody can disrupt the production of intrinsic factor and is present in a large percentage of those with pernicious anemia, but it may also be seen in other autoimmune disorders.
    • Gastrin. A hormone that regulates the production of acid in the stomach during the digestive process. Increased gastrin is sometimes seen in pernicious anemia.
    • Schilling test. Once frequently ordered to confirm a diagnosis of pernicious anemia, this test is generally no longer available.
  • Treatment

    Treatment for B12 and folate deficiencies frequently involves supplementation, which may be long-term or lifetime, depending on the underlying cause. People who lack intrinsic factor or have conditions causing general malabsorption require injections of B12. Folate is given as an oral supplement.

    It is generally recommended that all women contemplating having a child or who may become pregnant take folic acid supplements to ensure that they have a sufficient store for normal fetal development and to prevent neural tube defects.

    Individuals deficient in both B12 and folate will require replenishment of both. If someone with a B12 deficiency only takes folic acid supplements, the macrocytic anemia may be resolved but the underlying neuropathy caused by the B12 deficiency will persist. Appropriate treatment should resolve symptoms but may not reverse all of the nerve damage.

View Sources

NOTE: This article is based on research that utilizes the sources cited here as well as the collective experience of the Lab Tests Online Editorial Review Board. This article is periodically reviewed by the Editorial Board and may be updated as a result of the review.

Sources Used for Current Review

(Reviewed 2014 September 9). Vitamin B12. MedlinePlus Drug. Available online at http://www.nlm.nih.gov/medlineplus/druginfo/natural/926.html through http://www.nlm.nih.gov. Accessed February 2015.

Mayo Clinic Staff (2014 January 2). Vitamin Deficiency Anemia. MayoClinic. Available online at http://www.mayoclinic.org/diseases-conditions/vitamin-deficiency-anemia/basics/symptoms/con-20019550 through http://www.mayoclinic.com. Accessed February 2015.

Hulisz, Darrell (2013 November 21). Should All Antiepileptic Drugs Be Given With Folic Acid? Medscape Multispecialty. Available online at http://www.medscape.com/viewarticle/814588 through http://www.medscape.com. Accessed February 2015.

(Reviewed 2012 September). Take folic acid before you're pregnant. March of Dimes, Available online at http://www.marchofdimes.org/pregnancy/take-folic-acid-before-youre-pregnant.aspx# through http://www.marchofdimes.org. Accessed February 2015.

(Revised 2011 April). Pernicious Anemia. National Heart Lung and Blood Institute. Available online at http://www.nhlbi.nih.gov/health/dci/Diseases/prnanmia/prnanmia_what.html through http://www.nhlbi.nih.gov. Accessed February 2015.

Chen, Y. (Updated 2014 February 24). Anemia – B12 deficiency. MedlinePlus Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000574.htm through http://www.nlm.nih.gov. Accessed February 2015.

Horowitz, D. (Updated 2014 February 25). Intrinsic Factor. MedlinePlus Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/002381.htm through http://www.nlm.nih.gov. Accessed February 2015.

Gersten, T. (Reviewed 2013 September 20). Folate Deficiency. Pubmed Health. Available online at http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001394/ through http://www.ncbi.nlm.nih.gov. Accessed February 2015.

(Updated 2014 January 16). Devkota, B.P. Methylmalonic Acid. Medscape. Available online at http://emedicine.medscape.com/article/2108967-overview#a30 through http://emedicine.medscape.com. Accessed February 2015.

(2014 August). Vitamin B12 Deficiency Evaluation. Mayo Medical Laboratories. Available online at http://www.mayomedicallaboratories.com/it-mmfiles/Vitamin_B12_Deficiency_Evaluation.pdf through http://www.mayomedicallaboratories.com. Accessed February 2015.

Test 83632 : Pernicious Anemia Cascade. Mayo Medical Laboratories. Available online at www.mayomedicallaboratories.com/interpretive-guide/?alpha=P&unit_code=83632 through http://www.mayomedicallaboratories.com. Accessed February 2015.

Gersten, T. (Updated 2014 February 24). Antiparietal cell antibody test. MedlinePlus Medical Encyclopedia. http://www.nlm.nih.gov/medlineplus/ency/article/003351.htm through http://www.nlm.nih.gov. Accessed February 2015.

Parietal Cell Antibodies, IgG, Serum. Mayo Medical Laboratories. Available online at http://www.mayomedicallaboratories.com/test-catalog/Clinical+and+Interpretive/83728 through http://www.mayomedicallaboratories.com. Accessed February 2015.

Schick, P. (Updated 2014 December 2). Pernicious Anemia. Medscape Reference. Available online at http://emedicine.medscape.com/article/204930-overview through http://emedicine.medscape.com. Accessed February 2015.

Maakaron, J.E. (Updated 2014 March 20). Macrocytosis Treatment and Management. Medscape Reference. Available online at http://emedicine.medscape.com/article/203858-treatment through http://emedicine.medscape.com. Accessed February 2015.

(©2015) Linus Pauling Institute. Vitamin B12. Available online at http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/ through http://lpi.oregonstate.edu. Accessed March 2015.

(©2015) Linus Pauling Institute. Folate. Available online at http://lpi.oregonstate.edu/infocenter/vitamins/fa/ through http://lpi.oregonstate.edu. Accessed March 2015.

Singh, N. (Updated 2014 September 23). Vitamin B-12 Associated Neurological Diseases Treatment & Management. Medscape Reference. Available online at http://emedicine.medscape.com/article/1152670-treatment through http://emedicine.medscape.com. Accessed February 2015.

Johnson, L. (Updated 2014 October). Folate. Merck Manual. Available online at http://www.merckmanuals.com/professional/nutritional_disorders/vitamin_deficiency_dependency_and_toxicity/folate.html through http://www.merckmanuals.com. Accessed February 2015.

Policy Statement: Folic Acid for the Prevention of Neural Tube Defects. Pediatrics. 1999;104(2):325–327. Reaffirmed May 2012. Pp. 325 -327. Available online at http://pediatrics.aappublications.org/content/104/2/325.full through http://pediatrics.aappublications.org. Accessed March 2015.

Sources Used for Previous Reviews
Thomas, Clayton L., Editor (1997). Taber's Cyclopedic Medical Dictionary. F.A. Davis Company, Philadelphia, PA [18th Edition].

Cohen, E. (1003 June 05). Medical Encyclopedia: Anemia - B12 deficiency. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000574.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Webner, D. (2003 April 26). Medical Encyclopedia: Folate deficiency. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000354.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Cohen, E. (2003 April 25). Medical Encyclopedia: Folate-deficiency anemia. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000551.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Brose, M. (2003 June 1). Medical Encyclopedia: Folic acid - test. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/003686.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Angelo, S. (2003 January 19). Medical Encyclopedia: Folic acid (folate). MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/002408.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Cohen, E. (2002 November 7). Medical Encyclopedia: Pernicious anemia. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000569.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

Angelo, S. (2003 January 18). Medical Encyclopedia: Vitamin B12. MedlinePlus Health Information, Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/002403.htm through http://www.nlm.nih.gov/medlineplus/encyclopedia.html

(© 2004). Folate, RBC and Serum. ARUP's Guide to Clinical Laboratory Testing. Available online at http://www.aruplab.com/guides/clt/tests/clt_a237.jsp#1149156 through http://www.aruplab.com

(© 2004). Intrinsic Factor Blocking Antibody. ARUP's Guide to Clinical Laboratory Testing. Available online at http://www.aruplab.com/guides/clt/tests/clt_a23b.jsp#1152989 through http://www.aruplab.com

(© 2004). Vitamin B12. ARUP's Guide to Clinical Laboratory Testing. Available online at http://www.aruplab.com/guides/clt/tests/clt_270c.jsp#1150535 through http://www.aruplab.com

(© 2004). Vitamin B12 Binding Capacity. ARUP's Guide to Clinical Laboratory Testing. Available online at http://www.aruplab.com/guides/clt/tests/clt_271c.jsp#1150556 through http://www.aruplab.com

Stevenson, R. (© 2004). Spina bifida. AccessMed Health Information Library, Hendrick Health System. Available online at http://www.ehendrick.org/healthy/001258.htm through http://www.ehendrick.org

Carson-DeWitt, R. (© 2004). Pernicious anemia. AccessMed Health Information Library, Hendrick Health System. Available online at http://www.ehendrick.org/healthy/001049.htm through http://www.ehendrick.org

Haggerty, M. (© 2004). Folic acid deficiency anemia. AccessMed Health Information Library, Hendrick Health System. Available online at http://www.ehendrick.org/healthy/000541.htm through http://www.ehendrick.org

Patience Paradox, (© 2004). Folic acid. AccessMed Health Information Library, Hendrick Health System. Available online at http://www.ehendrick.org/healthy/001540.htm through http://www.ehendrick.org

Haggerty, M. (© 2004). Anemias. AccessMed Health Information Library, Hendrick Health System. Available online at http://www.ehendrick.org/healthy/ through http://www.ehendrick.org

(2002 December 9, Updated). Vitamin B12. NIH Clinical Center, Facts About Dietary Supplements. Available online at http://ods.od.nih.gov through http://ods.od.nih.gov

(2002 December 9, Updated). Folate. NIH Clinical Center, Facts About Dietary Supplements. Available online at http://ods.od.nih.gov/factsheets/cc/folate.html through http://ods.od.nih.gov

Johnson, L. (©1995-2004). Vitamin B12. Merck Manual – Second Home Edition, Section 12. Disorders of Nutrition and metabolism, Chapter 154. Vitamins. Available online at http://www.merck.com/pubs/mmanual_home2/sec12/ch154/ch154j.htm through http://www.merck.com

Johnson, L. ((©1995-2004). Folic Acid. Merck Manual – Second Home Edition, Section 12. Disorders of Nutrition and metabolism, Chapter 154. Vitamins. Available online at http://www.merck.com/pubs/mmanual_home2/sec12/ch154/ch154k.htm through http://www.merck.com

(2003 October). Vitamin B-12. Available online at http://familydoctor.org/765.xml through http://www.familydoctor.org.

Pagana, Kathleen D. & Pagana, Timothy J. (© 2007). Mosby's Diagnostic and Laboratory Test Reference 8th Edition: Mosby, Inc., Saint Louis, MO. Pp 460-461, 834-836, and 999-1000.

Clarke, W. and Dufour, D. R., Editors (2006). Contemporary Practice in Clinical Chemistry, AACC Press, Washington, DC. Pp 403-406.

Wu, A. (2006). Tietz Clinical Guide to Laboratory Tests, Fourth Edition. Saunders Elsevier, St. Louis, Missouri.410-413, 1124-1127.

Grund, S. (2007 August 27, Updated). Pernicious anemia. MedlinePlus Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000569.htm throughhttp://www.nlm.nih.gov/medlineplus/encyclopedia.html. Accessed on 4/12/08.

Matsui, W. (2007 February 14). Anemia - B12 deficiency. Medical Encyclopedia. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000574.htm throughhttp://www.nlm.nih.gov/medlineplus/encyclopedia.html. Accessed on 4/12/08.

Kasper, D.L., et al, Editors (2005). Harrison's Principles of Internal Medicine 16th Edition: McGraw-Hill. Pp 602-604, and 2404.

McClatchey, K.D., Editor (2002), Clinical Laboratory Medicine 2nd Edition: Lippincott Williams & Wilkins, Philadelphia, PA. Pp 842-844.

(Reviewed 2011 April 4). Vitamin B12. MedlinePlus Drug Information [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/druginfo/natural/926.html through http://www.nlm.nih.gov. Accessed August 2011.

(Reviewed 2011 June 24). Dietary Supplement Fact Sheet: Vitamin B12. NIH Office of Dietary Supplements [On-line information]. Available online at http://ods.od.nih.gov/factsheets/VitaminB12-QuickFacts/ through http://ods.od.nih.gov. Accessed August 2011.

Mayo Clinic Staff (2011 March 4). Vitamin Deficiency Anemia. MayoClinic.com [On-line information]. Available online at http://www.mayoclinic.com/health/vitamin-deficiency-anemia/DS00325/METHOD=print through http://www.mayoclinic.com. Accessed July 2011.

(Revised 2011 April). Pernicious Anemia. National Heart Lung and Blood Institute [On-line information]. Available online at http://www.nhlbi.nih.gov/health/dci/Diseases/prnanmia/prnanmia_what.html through http://www.nhlbi.nih.gov. Accessed August 2011.

Chen, Y. (Updated 2010 January 31). Anemia – B12 deficiency. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000574.htm through http://www.nlm.nih.gov. Accessed August 2011.

Schick, P. (Updated 2011 May 26). Megaloblastic Anemia. Medscape Reference [On-line information]. Available online at http://emedicine.medscape.com/article/204066-overview through http://emedicine.medscape.com. Accessed August 2011.

Frank, E. et. al. (Updated 2010 September). Megaloblastic Anemia. ARUP Consult [On-line information]. Available online at http://www.arupconsult.com/Topics/MegaloblasticAnemia.html through http://www.arupconsult.com. Accessed July 2011.

Conrad, M. (Updated 2011 May 26). Pernicious Anemia. Medscape Reference [On-line information]. Available online at http://emedicine.medscape.com/article/204930-overview through http://emedicine.medscape.com. Accessed August 2011.

Dugdale, D. (Updated 2008 November 23). Pernicious anemia. MedlinePlus Medical Encyclopedia [On-line information]. Available online at http://www.nlm.nih.gov/medlineplus/ency/article/000569.htm through http://www.nlm.nih.gov. Accessed August 2011.

OH, R. and Brown, D. (2003 March 1). Vitamin B12 Deficiency. Am Fam Physician. 2003 Mar 1;67(5):979-986. [On-line information]. Available online at http://www.aafp.org/afp/2003/0301/p979.html through http://www.aafp.org. Accessed August 2011.

Pagana, K. D. & Pagana, T. J. (© 2011). Mosby's Diagnostic and Laboratory Test Reference 10th Edition: Mosby, Inc., Saint Louis, MO. Pp 468-470, 1038-1039.

Tietz Textbook of Clinical Chemistry and Molecular Diagnostics. Burtis CA, Ashwood ER, Bruns DE, eds. St. Louis: Elsevier Saunders; 2006, Pp 1100-1103.

Kasper DL, Braunwald E, Fauci AS, Hauser SL, Longo DL, Jameson JL eds. (2005) Harrison's Principles of Internal Medicine, 16th Edition, McGraw Hill, Pp 601-604.