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Homocysteine and "Buerger’s disease"

• Autoimmune diseases including vasculitis and scleroderma.
  
• Hypercoagulable states.
  
• Diabetes mellitus.
  
• Proximal source of emboli.
  

Q2: What are the caused of a raised serum homocysteine?
Box 1 lists the causes of raised homocysteine.

Box 1: Causes of raised plasma homocysteine Genetic Cystathionine ß-synthetase deficiency (classical homocystinuria). MTHFR polymorphism. Vitamin deficiency Folate. B12. B6. Physiological and lifestyle Smoking. Excess coffee consumption. Ageing. Pathological diseases Renal failure. Carcinoma of the breast and ovary. Hypothyroidism. Drugs Methotrexate. Phenytoin. Theophylline.

 

Q3: What is the appropriate treatment for this patient?
The appropriate treatment for this patient is folic acid and vitamin B12. Homocysteine is metabolised by remethylation and transsulphuration as shown in fig 1. MTHFR homozygosity typically responds to folate but vitamin B12 is often added to further stimulate the remethylation pathway.

View larger version (20K): [in this window] [in a new window]   Figure 1 Homocysteine metabolism (CBS, cystathionine ß-synthetase; MTHFR, methylenetetrahydrofolate reductase; THF, tetrahydrofolate).

Discussion
Increased serum homocysteine is a risk factor for atherosclerotic disease.² The raised level of homocysteine and the history of smoking are likely to be implicated in premature atherosclerotic disease, as in this case. The arteriogram and histology were not typical of Buerger’s disease, which is a non-atherosclerotic, segmental inflammatory disease that most commonly affects medium sized arteries.¹ Although this patient did not have Buerger’s disease, modestly increased levels of serum homocysteine have been reported in patients with Buerger’s disease,³ and it has been suggested that this may be a contributory factor in the pathogenesis.

Learning points Raised levels of serum homocysteine are an independent risk factor for atherosclerotic vascular disease. Homozygosity for the C677T polymorphism of MTHFR can cause a marked elevation in serum homocysteine when folate is low. Simple treatment with folic acid and vitamins B6 and B12 is effective in reducing serum homocysteine. Serum homocysteine should be added to the screening investigations before making a diagnosis of Buerger’s disease.

 

The enzyme MTHFR is required for remethylation of homocysteine to methionine. The most common alteration in the MTHFR gene is a point mutation (C677T) that causes an alanine-to-valine substitution.⁴ The allele frequency of the MTHFR C677T mutation is 35%, with a homozygous rate of 12%.⁴ Homozygosity is associated with modest elevations in plasma homocysteine but low levels of folate or vitamin B12 lead to a relatively large increase.⁵ Under these circumstances simple treatment with folic acid and vitamin B12 supplementation may be extremely effective in reducing serum homocysteine. As well as reducing the serum homocysteine, folic acid and B vitamins may prove protective in hyperhomocysteinaemia induced atherosclerosis, and lowering homocysteine levels has been shown to reduce restenosis rates after coronary angioplasty.⁶ Vitamin B6 is a cofactor for the transsulphuration of homocysteine metabolism (fig 1), and depleted vitamin B6 levels may also contribute to raised homocysteine.

We believe that this is a case of hyperhomocysteinaemia, initially misdiagnosed as Buerger’s disease. We suggest that if Buerger’s disease, a diagnosis of exclusion, is to be sustained then serum homocysteine should be added to the list of screening investigations.¹ This is of particular importance since, as this case demonstrates, simple vitamin and folic acid supplementation can normalise homocysteine levels.

Final diagnosis
Hyperhomocysteinaemia.

ACKNOWLEDGEMENTS
The authors thank Dr IFW McDowell, Department of Medical Biochemistry, University Hospital of Wales, Cardiff for performing the genetic analysis.

References

1. Olin JW. Thromboangiitis obliterans (Buerger’s disease). N Engl J Med 2000;343:864–9.[Free Full Text]
2. Graham IM, Daly LE, Refsum HM, et al. Plasma homocysteine as a risk factor for vascular disease. JAMA 1997;277:1775–81.[Abstract]
3. Stammler F, Diehm C, Hsu E, et al. The prevalence of hyperhomocysteinemia in thromboangiitis obliterans. Dtsch Med Wochenschr 1996;121:1417–23.[Medline]
4. Rozen R. Genetic predisposition to hyperhomocysteinaemia: deficiency of methylenetetrahydrofolate reductase (MTHFR). Thromb Haemost 1997;78:523–6.[Medline]
5. Verhoeff BJ, Trip MD, Prins M, et al. The effect of a common methylene tetrahydrofolate reductase mutation on levels of homocysteine, folate, vitamin B12 and on the risk of premature atherosclerosis. Atherosclerosis 1998;141:161–6.[Medline]
6. Schynder G, Roffi M, Pin R, et al. Decreased rate of coronary restenosis after lowering of plasma homocysteine levels. N Engl J Med 2001;345:1593–600.[Abstract/Free Full Text]

This article has been cited by other articles:

				U Umasankar and F Huwez Homocysteine and Buerger's disease * Authors' reply Postgrad. Med. J., December 1, 2002; 78(926): 764 - 764. [Full Text] [PDF]

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