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Livedoid vasculopathy The role of hyperhomocysteinemia and its simple therapeutic consequences

European Journal of Dermatology. Volume 16, Number 2, 159-62, March-April 2006, Therapy

Summary

Author(s) : Frank Meiss, Wolfgang Christian Marsch, Matthias Fischer , Department of Dermatology and Venerology, Martin-Luther-University Halle-Wittenberg, Ernst-Kromayer-Str. 5, D-06097 Halle (Saale), Germany.

Summary : Livedoid vasculopathy (LV) is characterized by localized painful ulcers, livedo reticularis and atrophie blanche. LV is considered as an occlusive vasculopathy due to a hypercoagulable state. Hyperhomocysteinemia is a prothrombotic condition, which has as yet received little attention in this context. We report a 49-year-old woman with livedoid vasculopathy. The patient presented with an elevated homocysteine level caused by renal insufficiency, vitamin-B6 deficiency and reduced vitamin-B12 concentration. We treated her with low-molecular heparin and pentoxifylline. Folic acid, vitamin B6 and B12 were substituted for therapy of hyperhomocysteinemia. Substitution therapy led to a reduction of homocysteine levels. Under the complex therapy the ulcers healed without recurrence within 16 months. Thrombophilia is of pathogenetic importance in LV. Hyperhomocysteinemia may be another cause of hypercoagulability. Substitution of folic acid, vitamins B12 and B6 (cofactors of homocysteine metabolism) is an effective treatment of hyperhomocysteinemia and thus hypercoagulability can be causally treated.

Keywords : hypercoagulability, hyperhomocysteinemia, livedoid vasculopathy, thrombophilia

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ARTICLE

Auteur(s) : Frank Meiss, Wolfgang Christian Marsch, Matthias Fischer

Department of Dermatology and Venerology, Martin-Luther-University Halle-Wittenberg, Ernst-Kromayer-Str. 5, D-06097 Halle (Saale), Germany

accepté le 26 Novembre 2005

Livedoid vasculopathy (LV) is a clinical diagnosis characterized by livedo reticularis, painful chronic-recurrent ulcers and atrophie blanche. Most commonly affected are the calves, and especially the malleolar area [1, 2]. LV is a thrombotic (occlusive) vasculopathy of the small vessels of the lower extremities [1, 3]. Frequently, microthromboses and/or segmental hyalinization of the subendothelial intima of blood vessels of the middle and lower dermis are found, as histological correlates [2, 4]. Even though some aspects of the etiology and pathogenesis have not been elucidated up to now, LV, is considered to have an underlying defect in the coagulation system [1, 2]. In some patients with LV, the molecular basis of hypercoagulability has been well characterized in the past (table 1) while in others it is still unknown. On this basis LV can be basically differentiated into “symptomatic” and “idiopathic” [1].Homocysteine is a non-protein-forming sulphydryl amino acid deriving from the demethylation of dietary methionine [5]. Remethylation- and transsulphuration-pathways are responsible for homocysteine plasma concentration [5]. These pathways can be influenced by inherited and acquired conditions thus leading to hyperhomocysteinemia (table 2). Hyperhomocysteinemia is considered to be a systemic prothrombotic condition. The exact mechanism by which hyperhomocysteinemia contributes to vascular disease is uncertain [5]. It has been proposed that formation of reactive oxygen species, LDL oxidation, reduced production and availability of nitric oxide contribute to endothelial toxicity in hyperhomocysteinemia [6]. Moreover procoagulant effects of increased thromboxane-mediated platelet aggregation, inhibition of cell surface thrombomodulin expression and protein C activation, enhancement of lipoprotein(a)-fibrin binding, and activation of factors V, X, and XII have been described as potential mechanisms of homocysteine-induced thrombosis [7]. There is a positive correlation between elevated homocysteine plasma concentration and premature onset of artherosclerosis and deep vein thromboses [5]. Although moderate and intermediate hyperhomocysteinemia is by no means rare and is present in 12%-47% of patients with coronary, cerebral or peripheral arterial occlusive disease [8], it has received little attention to date in dermatological literature.

Clinical observations

( Table 1 )( Table 2 )We report a 49-year-old woman in whom livido reticularis occurred on both calves 3 months prior to hospitalization. During the course, multiple, very painful ulcers had rapidly developed. The patient was a renal transplant recipient (first transplantation 1980, second transplantation 2000) due to end stage renal failure caused by chronic pyelonephritis.

Examination on admission revealed non-thermoreactive (persistence despite rewarming) irregular livedo reticularis and several ulcers of bizarre configuration up to 5 × 3 cm in size on both calves (( figure 1 )). These were covered with purulent-fibrinous necroses. Periulcerous erythema and hemorrhages were evident (( figure 2A )).

Results of a skin biopsy showed a flat ulcer with purulent demarcation. Adjacent to the ulcer ground and within the upper and middle dermis, thrombosis within the blood vessels was present (( figure 3 )). There was no evidence of leucocytoclasia. In the middle and lower dermis sparse perivascular inflammatory fibrosis and minimal calcifications were evident.

The results of intensive laboratory diagnostics on admission were within normal ranges or negative for: autoantibodies (antinuclear-, ds-DNA-, histon-, antineutrophile cytoplasmatic-, cardiolipin-antibodies); coagulation and thrombophilia parameters (lupus anticoagulant, circulating immune complexes, cryoproteins, APC-ratio, protein-C-activity, protein-S-activity, antithrombin-III-activity, prothrombin- and methylenetetrahydrofolate-reductase-mutation, prothrombin time, partial thromboplastin time); routine parameters (folic acid, transaminases, calcium, phosphate, calcium-phosphate product).

Whereas the following parameters were out of normal range: renal parameters (creatinine 201 μmol L^–1 (< 88), urea 11,8 μmol L^–1 (3.6-8.0), creatinine clearance 0.47 mL sec^–1 BSA^–1 (1.09-2.57), parat hormone 209 pg mL^–1 (10-65)); full blood count (hemoglobin 6.8 mmol L^–1 (7.3-9.9), MCV 104 fl (85-95)); homocysteine concentration (pre-treament) 28.8 μmol L^–1 (< 9 μmol L^–1); vitamin B6 3.5 μg L^–1 (5-30); vitamin B12 166 pmol L^–1 (165-835). Arterial macroangiopathy and varicosis cruris were clinically not evident and results of doppler sonography were without pathological findings.

In addition to local ulcer treatment with hydrocolloid and calcium alginate dressings, we administered anticoagulatory therapy with low-molecular heparin (Enoxaparin 40 mg/die) and to promote rheology, pentoxifylline (1,200 mg/die) was used. For specific therapy of the hyperhomocysteinemia [9], we substituted vitamin B6 (50 mg/die), vitamin B12 (300 μg/die) and folic acid (1 mg/die). Under the therapy scheme, the earlier rapid increase in ulcer size could be stopped. Livedoid discoloration decreased and was no longer visible after about 2 months. Within 6 months the ulcers completely healed, leaving typical atrophic, hyperpigmented scars (( figure 2B )). The homocysteine level on discharge, 2 months after hospital admission, was 13.2 μmol L^–1, well below that on admission. On a follow up examination after 16 months the patient was still without recurrence of LV, laboratory diagnostics revealed a homocysteine plasma concentration of 11.9 μmol L^–1. Vitamin B12-, vitamin B6 and folic acid levels were within normal range during continuous vitamin supplementation.
Table 1 Causes of hypercoagulability in livedoid vasculopathy [1, 3, 10-17]

Causes of hypercoagulability

Antithrombin-III-Deficiency

Protein C-Deficiency

Factor-V- Leiden Mutation

Prothrombin G20210A Gene Mutation

Plasminogen-Activator-Inhibitor activity increased

Plasminogen-Activator activity reduced

Fibrinopeptide A concentration elevated

Antiphospholipid-Syndrome

Hyperhomocysteinemia

Table 2 Causes of hyperhomocysteinemia [5, 8, 9, 18, 19]

Genetically determined

Acquired

1. Defect of

- Cystathione-β-Synthase
- Methylene tetrahydrofolate-Reductase (MTHFR)
- Methionine-Synthase

2. Sex (m > f)

1. Vitamin deficiency

- Folic acid
- Vitamin B12
- Vitamin B6

2. Diseases

- Chronic renal failure
- Pernicious anemia

3. Medications

- Folic acid antagonists
- Vitamin B6-antagonists

4. Age

Discussion

LV is currently considered as a cutaneous arteriolar thrombotic (occlusive) vasculopathy [1]. Numerous reports have confirmed that a systemic hypercoagulability (table 1) is a “conditio sine qua non” in LV and appears to play a predominant role in the pathogenesis [1, 3, 10-17]. Hyperhomocysteinemia, a systemic hyercoagulable state, has apparently been overlooked in the context of LV. Gibson and coworkers [17] found significantly higher homocysteine concentrations in patients with LV than in a control group. However, these results must be critically interpreted, since the mean value cited for the serum homocysteine concentrations (mean ± SD: 8.7 ± 3.1 μmol L^–1) in the group of patients with LV reflects only mild hyperhomocysteinemia. The homocysteine concentration cited for the normal population by the American Heart Association ranges between 5-15 μmol L^–1 and a basal homocysteine level < 10 μmol L^–1 is considered to be a reasonable therapeutic goal for subjects at increased cardiovascular risk [8].

Basically, differentiation can be made between genetically-determined and acquired causes of impaired homocysteine metabolism with consecutive hyperhomocysteinemia (table 2) [5, 8, 9, 18, 19]. In our patient, we found a complex combination of acquired causes of hyperhomocysteinemia (chronic renal failure, vitamin-B6 deficiency, vitamin-B12 concentration at the lower normal range). Alterations of the remethylation pathways have been demonstrated in chronic renal failure, and homocysteine concentration is increased, with decreasing levels of renal function. Vitamin-B12 is an essential cofactor of homocysteine remethylation via methionine synthase whereas vitamin-B6 is an essential cofactor of cystathionine β-synthase in the transsulphuration pathway [5]. A mutation of the methylenetetrahydrofolate reductase-(MTHFR)-gene could be ruled out (C677T and A1298C MTHFR-polymorphism).

Therapy of hyperhomocysteinemia in patients with LV by vitamin substitution has been suggested [17]. The present case report thus shows the validity of the theory put forth by Gibson and colleagues [17]: long-term reduction of an elevated homocysteine concentration by means of vitamin substitution leads via induction of ulcer healing to recurrence-free healing of the LV.

Our data make it seem plausible that a search for hereditary or acquired hyperhomocysteinemia should be included in the screening of patients with LV for procoagulatory factors. The increasing illumination of prothrombotic conditions in the onset and maintenance of LV make induction of specific therapy possible in addition to the generally-recognized recommendations (improvement of rheology, antithrombotic therapy) [1]. In the case of LV based on hyperhomocysteinemia, normalization of elevated homocysteine plasma concentrations can be achieved by economical and low side-effect substitution of folic acid, vitamin B12 and vitamin B6.

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