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  • Updated 07.21.2021
  • Released 04.13.1998
  • Expires For CME 07.21.2024

Hyperhomocysteinemia

Introduction

Overview

In this article, the author discusses hyperhomocysteinemia and reviews developments in the understanding of its relationship with cerebrovascular disease and dementia. Although folic acid, vitamin B12, and vitamin B6 lower homocysteine levels, many recent randomized, controlled trials suggest that treatment with these vitamins does not clearly lower the risk of vascular disease.

Key points

• Severe hyperhomocysteinemia (homocysteine level > 100 µM, also reported as homocysteinuria) is associated with congenital manifestation of ectopia lentis, myopia, marfanoid features, livedo reticularis, malar rash, intellectual disability, seizures, and also with arterial and venous vascular occlusions/thromboembolism.

• Homocystinuria occurs as the result of inborn errors of metabolism that impair enzyme systems important for methionine metabolism, including cystathionine beta-synthase (CBS).

• Moderate hyperhomocysteinemia (homocysteine level 15 µM - 100 µM) is associated with increased risk of cerebrovascular disease and cognitive dysfunction.

• Vitamin B complex (folic acid, pyridoxine, cobalamin) can lower homocysteine levels and has been a main treatment for severe hyperhomocysteinemia.

• In moderate hyperhomocysteinemia, the effectiveness of vitamin B complex therapy in order to prevent stroke or dementia is not well established.

Historical note and terminology

Hyperhomocysteinemia is defined as elevation, typically 20-fold or higher, of plasma total concentration of homocysteine and disulfide addition products of homocysteine (homocystine, cysteine-homocysteine), collectively termed "homocyst(e)ine" (Hcy) or "total homocysteine."

The hypothesis that hyperhomocysteinemia is a risk factor for vascular disease was proposed in 1969 by Dr. Kilmer S McCully, who observed advanced atherosclerosis in children with rare inherited disorders causing markedly elevated levels of total plasma homocysteine (35). The persons homozygous for cystathionine beta-synthase deficiency, leading to homozygous homocystinuria, frequently develop premature atherosclerosis and thrombotic complications as stroke (40). There has been a resurgence of interest in hyperhomocysteinemia because of the recognition that even moderately elevated concentrations of total plasma homocysteine are associated with increased risk of stroke, cardiovascular disease, and venous thrombosis (07; 46; 11).

Categorizing homocysteine levels into severe, moderate, and normal ranges is useful. Severe hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration greater than 100 µM. Moderate hyperhomocysteinemia is defined as a fasting total plasma homocysteine concentration between 15 µM and 100 µM. Mean fasting concentrations of total plasma homocysteine are usually less than or equal to 10 µM, with the 95th percentile at approximately 15 µM.

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