Livedo reticularis: a rare manifestation of Graves hyperthyroidism associated with anticardiolipin antibodies.

Abstract: Livedo reticularis is a common presentation of the anticardiolipin syndrome. Although the presence of anticardiolipin (aCL) antibodies was previously reported in association with both Graves disease and Hashimoto thyroiditis, I am aware of no previous report of livedo reticularis in patients with Graves disease. A 29-year-old woman presented with very active Graves thyrotoxicosis. Physical examination revealed, in addition to signs of very active hyperthyroidism, marked livedo reticularis on both her legs. Laboratory tests confirmed the clinical impression regarding her thyroid activity and revealed prolonged prothrombin time (and partial thromboplastin time) and elevated levels of both immunoglobulin G and immunoglobulin M aCL antibodies. After methimazole-induced remission, livedo reticularis completely disappeared and the levels of aCL antibodies decreased to within the low range of normal. The literature on aCL antibodies and autoimmune thyroid diseases is reviewed and the interaction between the occurrence of aCL antibodies, disease activity, and drug therapy in Graves disease is discussed.

Key Words: anticardiolipin antibodies, Graves disease, hyperthyroidism, livedo reticularis, thyroid

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The case of a patient who developed livedo reticularis during uncontrolled Graves hyperthyroidism is described. This presentation proved to be a manifestation of a coexistent anticardiolipin antibodies syndrome. Livedo reticularis and anticardiolipin (aCL) antibodies disappeared when her hyper-thyroidism was controlled. To the best of my knowledge, this is the first description of livedo reticularis in association with Graves disease or hyperthyroidism.

Case Report

A 29-year-old Bedouin woman was referred for evaluation of hyperthyroidism. There was no known history of thyroid disease or recent exposure to iodine. There was a history of autoimmune thyroid disease in her extended family but no other autoimmune diseases. Physical examination was characteristic of very active hyperthyroidism with a diffusely enlarged goiter, two to three times the normal size, and no evidence of active orbitopathy. Laboratory results showed that her thyroid-stimulating hormone (TSH) was < 0.05 mIU/mL (normal, 0.4-4 mIU/mL), her free tri-iodothyronine (T3) was > 20 pg/mL (normal, 2.3-4.2 pg/mL), and her free thyroxine (T4) was > 16 ng/mL (normal, 0.8-1.5 ng/mL). The clinical and laboratory findings were consistent with very active thyrotoxicosis, most likely Graves disease. The patient proved noncompliant with the prescribed medication and was lost to follow-up.

One year later, the patient was hospitalized for signs and symptoms of very active thyrotoxicosis and bilateral leg swelling. Physical examination revealed characteristic signs of hyperthyroidism, no active orbitopathy, moderate bilateral pitting leg edema, and marked livedo reticularis. Laboratory results showed that her TSH was < 0.05 mIU/mL, her free T3 was > 20 pg/mL, her free T4 was > 10.1 ng/mL, her prothrombin time was 18.7 seconds (control, 13.1 seconds), her international normalized ratio was 1.58, and her activated partial thromboplastin time was 29 seconds (control, 25 seconds). Her anticardiolipin antibodies were as follows: IgM, 26 U/mL (normal, < 7 U/mL); and IgG, 24.6 U/mL (normal, <10 U/mL). An echocardiographic examination was normal. Treatment with methimazole and atenolol was resumed.

Five months after her hospitalization, the patient returned to the outpatient clinic while on 40 mg/d methimazole. Physical examination suggested hypothyroidism, and her goiter was approximately five times the normal size. There was no evidence for livedo reticularis. Laboratory results showed that her TSH was 61.8 mIU/mL, her free T3 was < 0.2 pg/mL, and her free T4 was 0.1 ng/mL. Anticardiolipin antibodies were as follows: IgM, 0.6 U/mL; and IgG, 1.6 U/mL.

Discussion

Livedo reticularis is a weblike pattern of cyanosed skin surrounding pale areas, seen most often on the leg, which is persistent and does not disappear after warming. Livedo reticularis is often associated with elevated levels of aCL antibodies or lupus anticoagulant (11-22%). (1) Previously livedo reticularis was rarely reported in patients with hypothyroidism but, to the best of our knowledge, was never before reported in association with hyperthyroidism. (2) The detection of aCL antibodies in this case was prompted by the appearance of livedo reticularis on both her legs during a very active phase of hyperthyroidism and disturbed coagulation functions. There was no indication of systemic lupus erythematosus (SLE) in this patient.

The association of aCL antibodies with Graves disease was first noted more than a decade ago. (3) Nevertheless, the data regarding this association and its clinical significance are still limited and controversial. In their initial observation, Marongiu et al (3) detected increased IgG aCL antibodies in 38% and IgM aCL antibodies in 33% of 65 Graves disease patients, whereas none of their 58 control subjects demonstrated elevated IgG aCL antibodies and only one (2%) had elevated IgM aCL antibodies. Nevertheless, it should be noted that other studies failed to detect aCL antibodies and others detected a much lower prevalence rate of aCL antibodies in patients with Graves disease or other autoimmune thyroid diseases (Table). The difference between the studies may reflect the lack of aCL antibodies in association with Graves disease in the particular populations that were examined, or could be related to the specific time points at which blood samples were obtained (active disease versus posttreatment; see below).

Antithyroid drugs are known to produce lupus-like syndromes (SLE) in humans. (4) SLE and drug-related lupus are major predisposing factors for aCL antibodies. (1) However, I am not aware of any report linking aCL antibodies with antithyroid drug treatment. In the present case, aCL antibodies were clearly unrelated to antithyroid drug therapy, because the patient did not receive antithyroid treatment when aCL antibodies were detected, and aCL antibody levels markedly decreased after methimazole administration.

Despite the apparent increased prevalence of elevated aCL antibodies in patients with autoimmune thyroid diseases, clinical manifestations of the antiphospholipid syndrome are very rare, and although embolic events have repeatedly been reported in patients with hyperthyroidism, the reports usually represent small series, are almost exclusively limited to patients with atrial fibrillation, and are not necessarily related to aCL antibodies. In fact, other than a frequently cited study by Parker and Lawson, (5) which suggested an increased thromboembolic event rate as an important cause of death in patients with hyperthyroidism, there seem to be no epidemiologic data pertaining to the risk of thromboembolism in hyperthyroid patients. It should be noted that Parker and Lawson reported on 33 fatalities attributed to hyperthyroidism in a cohort of exceptionally complicated patients, who are unlike the characteristic hyperthyroid patients currently seen in the practice. I am aware of only two reports on symptomatic antiphospholipid syndrome in patients with Graves disease: a 48-year-old woman with recurrent deep vein thrombosis (6) and a 33-year-old woman with massive ischemic cerebral infarction. (7) Livedo reticularis, the result of cutaneous capillary insufficiency, may also be considered a mild symptomatic presentation of the aCL syndrome. The apparent discrepancy between the relatively increased prevalence of aCL antibodies among patients with autoimmune thyroid diseases and the low occurrence of clinical manifestations is somewhat not surprising given that a large proportion of carriers of aCL and lupus anticoagulant antibodies in the general population, as well as among patients with SLE, do not develop clinical manifestations during prolonged periods of follow-up. (1)

The precise relationship between the appearance of aCL antibodies and the intensity of Graves disease activity is not yet clear. Although Diez et al (8) reported no such correlation, in several reports, (6,9) including the present study, the level of aCL antibodies seemed to decrease with achievement of drug-induced control of thyroid function. It should be noted that in animal models, both methimazole and propylthiouracil were found to attenuate levels of autoantibodies and manifestations of experimental SLE. (10) Whether changes of aCL antibody levels with disease activity was related to thyroid activity per se, to the known immunosuppressive effect of antithyroid drugs, or to some other factor remains to be determined.

Table. Prevalence of anticardiolipin or lupus anticoagulant
Antibodies (a)

                    % Elevated anticardiolipin antibodies or lupus
                                 anticoagulant (b)
Study               Graves    Hasimoto   Non-ATD  Normal controls

Marongiu et al,
  1991 (3)          33-38     --         --               0
Petri et al,
  1991 (11)          0         0         --               --
Diez et al,
  1993 (8)           7.1-7.3   2.3-14.2  11.6             2.7-4.1
Paggi et al,
  1994 (9)          36        40         --               --
Tani et al,
  1997 (12)          3.2 (Graves and Hashimoto combined)  0.5
Evangelopoulou
  et al, 1999 (13)   3.4      11.4        0               0

(a) Non-ATD, nonautoimmune thyroid diseases.
(b) Range represents differences in prevalence between different types
of anticardiolipin antibody assays in the same study.

Accepted June 30, 2003.

Copyright [c] 2004 by The Southern Medical Association

0038-4348/04/9706-0601

References

1. Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002;346:752-763.

2. Picascia DD, Pellegrini JR. Livedo reticularis. Cutis 1987;39:429-432.

3. Marongiu F, Conti M, Murtas ML, et al. Anticardiolipin antibodies in Graves disease: Relationship with thrombin activity in vivo. Thromb Res 1991;64:745-749.

4. Mathieu E, Fain O, Sitbon M, et al. Systemic adverse effect of antithyroid drugs. Clin Rheumatol 1999;18:66-68.

5. Parker JL, Lawson DH. Death from thyrotoxicosis. Lancet 1973;2:894-895.

6. Hofbauer LC, Spitzweg C, Heufelder AE. Graves disease associated with the primary antiphospholipid syndrome. J Rheumatol 1996;23:1435-1437.

7. Mayaudon H, Crozes P, Riveline JP, et al. Antiphospholipid antibodies in Basedow disease [in French]. Presse Med 1994;23:1496 (letter).

8. Diez JJ, Doforno RA, Iglesias P, et al. Anticardiolipin antibodies in autoimmune thyroid disease. J Clin Lab Immunol 1993;40:125-134.

9. Paggi A, Caccavo D, Ferri GM, et al. Anti-cardiolipin antibodies in autoimmune thyroid diseases. Clin Endocrinol (Oxf) 1994;40:329-333.

10. Shoenfeld Y, Krause I. Immunosuppression and immunomodulation of experimental models of systemic lupus erythematosus and antiphospholipid syndrome. Transplant Proc 1996;28:3096-3098.

11. Petri M, Nelson L, Weimer F, et al. The automated modified Russell viper venom time test for the lupus anticoagulant. J Rheumatol 1991;18:1823-1825.

12. Tani Y, Morita M, Noguchi S. Prevalence of prolonged APTT and lupus anticoagulant in autoimmune thyroid disease [in Japanese]. Rinsho Byori 1997;45:899-902.

13. Evangelopoulou ME, Alevizaki M, Toumanidis S, et al. Mitral valve prolapse in autoimmune thyroid disease: An index of systemic autoimmunity? Thyroid 1999;9:973-977.

RELATED ARTICLE: Key Points

* Anticardiolipin antibodies were detected, in different studies, in 0 to 38% of Graves disease patients and in up to 14% of patients with Hashimoto thyroiditis.

* The occurrence of anticardiolipin antibodies in patients with autoimmune thyroid disorders is usually asymptomatic, and they may disappear as thyroid activity is controlled.

* The patient described in this article is unique because she presented both anticardiolipin antibodies and livedo reticularis, a characteristic feature of the anticardiolipin syndrome, both of which disappeared simultaneously when thyroid activity subsided.

Yair Liel, MD

From the Endocrine Unit, Soroka University Medical Center, and the Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel.

Reprint requests to Yair Liel, MD, Department of Medicine "C," Soroka Medical Center, P.O. Box 151, Beer-Sheva 84101, Israel. Email: [e-mail]