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Q1: Which conditions should be excluded before making a diagnosis of Buerger’s disease?
The diagnoses that should be excluded before making the diagnosis of Buerger’s disease are as follows.1
Autoimmune diseases including vasculitis and scleroderma.
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
Cystathionine β-synthetase deficiency (classical homocystinuria).
Physiological and lifestyle
Excess coffee consumption.
Carcinoma of the breast and ovary.
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.
The patient was advised to stop smoking, and was prescribed folic acid 5 mg and cyanocobalamin 0.5 mg daily. She defaulted from follow up. Six months later the patient was hospitalised with acute abdominal pain due to small bowel infarction. The small bowel histopathology revealed non-specific features of ischaemia and infarction. There was fresh thrombus with no evidence of organisation and a non-specific intimal proliferation. Typical features of Buerger’s disease (microabscesses, vein and nerve involvement) were absent. She had continued to smoke and admitted non-compliance with drug therapy. Serum homocysteine was still raised at 69.2 μmol/l. Folic acid supplementation (5 mg/day) was given in total parenteral nutrition and after two weeks serum homocysteine was normal (11.7 μmol/l). However, her condition deteriorated due to breakdown of the small bowel anastomosis, and she died from septicaemia.
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.
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.
The authors thank Dr IFW McDowell, Department of Medical Biochemistry, University Hospital of Wales, Cardiff for performing the genetic analysis.
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