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Clinical Chemistry and Laboratory Medicine (CCLM)

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Volume 43, Issue 10


Hyperhomocysteinemia and arteriosclerosis: historical perspectives

Kilmer S. McCully
  • Pathology and Laboratory Medicine Service, Veterans Affairs Medical Center, West Roxbury, MA, and Harvard Medical School, Boston, MA, United States of America
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2005-09-30 | DOI: https://doi.org/10.1515/CCLM.2005.172


Early concepts of the origin of arteriosclerosis were introduced in the 19th century by Rokitansky and Virchow, who described mural thrombosis, inflammatory damage to arterial intima, increased intimal permeability to plasma, mucoid degeneration of arterial wall, deposition of plasma lipids in plaques, and fibrosis and calcification of plaques. Experimental production of arteriosclerosis by feeding animal foods to rabbits was attributed to protein intoxication by Ignatowsky in 1908 and to dietary cholesterol by Anitschkow in 1913. Newburgh confirmed the protein hypothesis in 1915–1925 but failed to identify which amino acid produced plaques because methionine (1922) and homocysteine (1932) had not yet been discovered. Cases of homocystinuria from inherited deficiency of cystathionine synthase were found to be associated with thrombosis and vascular disease in 1964. The index case of methionine synthase deficiency (cobalamin C disease) was found by McCully in 1969 to be associated with arteriosclerosis, leading to the homocysteine theory of arteriosclerosis. The theory explains experimental arteriosclerosis by deficiency of vitamin B6 in monkeys, choline deficiency in rats, thyroid deficiency in rats, and methionine deficiency in monkeys. The thrombogenic and atherogenic effects of homocysteine were demonstrated in rabbits, baboons and other species, reproducing the pathological findings found in homocystinuria. Clinical and epidemiological studies in the past two decades have demonstrated that elevated plasma homocysteine is a potent independent risk factor for arteriosclerosis in the general population, supporting the validity of the theory.

Keywords: arteriosclerosis; atherogenesis; homocysteine; homocystinuria; methionine


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About the article

Corresponding author: Kilmer S. McCully, MD, Chief, Pathology and Laboratory Medicine Service, VA Boston Healthcare System, 1400 Veterans of Foreign Wars Parkway, West Roxbury, MA 02132, USA Phone: +1-857-203-5990, Fax: +1-857-203-5623,

Published Online: 2005-09-30

Published in Print: 2005-10-01

Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 43, Issue 10, Pages 980–986, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/CCLM.2005.172.

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©2005 by Walter de Gruyter Berlin New York. Copyright Clearance Center

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