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Original Article |
Division of Endocrinology, Diabetes, Metabolism, Nutrition, and Internal Medicine (V.F.), and Department of Dermatology (D.D.F.A.), Mayo Clinic, Rochester, Minnesota 55905
Address all correspondence and requests for reprints to: Vahab Fatourechi, M.D., Mayo Clinic, 200 First Street SW, Rochester, Minnesota 55905. E-mail: fatourechi.vahab{at}mayo.edu.
Abstract
Thyroid acropachy is an extreme manifestation of autoimmune thyroid disease. It presents with digital clubbing, swelling of digits and toes, and periosteal reaction of extremity bones. It is almost always associated with ophthalmopathy and thyroid dermopathy. During a 26-yr period at our institution, of 178 patients with thyroid dermopathy, 40 had acropachy. Clubbing associated with thyroid dermopathy (pretibial myxedema) was seen in 35 patients. Clubbing usually was not a patient complaint and was noted only by clinical observers. Four of eight patients with hand and extremity radiographs had periosteal reaction. Seven had associated extremity and joint pain; this pain was absent at long-term follow-up. Half of the patients required systemic corticosteroid therapy, 53% required transantral or transfrontal orbital decompression for severe ophthalmopathy, and 18% had the elephantiasic form of dermopathy. Cigarette-smoking rates were 81% for women and 75% for men (mean, 28 pack-years). All 13 patients who had thyroid-stimulating Ig measurement had high titers. Long-term follow-up (median, 12.5 yr) revealed that acropachy was not a complaint in follow-up visits or questionnaires. The data suggest that thyroid acropachy is an indicator of severity of ophthalmopathy and dermopathy. It is a source of clinical concern only if dermopathy is persistent and severe.
THYROID-ASSOCIATED OPHTHALMOPATHY, thyroid dermopathy, and thyroid acropachy are extrathyroidal manifestations of autoimmune thyroid disease. Previously, we reported on the community prevalence (1) and clinical features (2) of thyroid dermopathy. On the basis of community studies, thyroid dermopathy (pretibial myxedema) and acropachy occur in 4% and 1%, respectively, of patients with Graves’ ophthalmopathy (1). Among patients with severe ophthalmopathy, the prevalence of dermopathy is as high as 12% (3). Ophthalmopathy is almost always present with dermopathy. Acropachy is present in extreme forms of dermopathy and may present with clubbing and swelling of the fingers and toes, with or without periosteal reaction of the distal bones; more rarely, acropachy may present with articular manifestation of distal joints. Many isolated reports of acropachy have appeared in the medical literature (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23), but large series and outcome studies are lacking.
In this report, we provide data on 40 patients treated at our institution in a 26-yr period. We focus on long-term outcome, the relationship between acropachy and associated eye disease and dermopathy, and its association with tobacco use.
Patients and Methods
We retrospectively reviewed the medical records of all patients who had a dismissal diagnosis of thyroid dermopathy or pretibial myxedema between January 29, 1969, and November 15, 1995, at Mayo Clinic (Rochester, MN). All of the charts were abstracted, and a questionnaire was sent to patients in September 2000 to obtain current disease status and outcome information.
Previously, we reported long-term outcome results for 178 patients with dermopathy (24). For the present study, we selected all patients from that series with a diagnosis of thyroid acropachy or clubbing associated with dermopathy. One author (V.F.) reviewed all of the medical records in detail, excluding cases of questionable diagnosis. Inclusion criteria were clubbing of the fingers or dermal thickening of the upper-extremity digits associated with clubbing and documented by a staff endocrinologist or dermatologist. Excluded were patients with other causes of clubbing and patients in whom clubbing of the toenails with dermopathy of the feet was unassociated with clubbing of the fingers. These patients were not included because dermopathy of the toes and the dorsum of the foot occasionally was associated with clubbing of one or two toes, depending on the involvement of the toes with dermopathy, and was unassociated with clubbing of the fingernails. Five cases without clubbing also were included because of typical skin changes of fingers and atypical changes of fingernails. These five patients had thickening of the skin of the digits and changes of the nails. The nail changes were not typical for clubbing. There was no other condition to explain the changes of the nails and fingers.
Diagnosis was made, and classification of dermopathy and ophthalmopathy was performed according to previously described criteria (25). Clinical forms of dermopathy were defined as previously reported (2, 24). All cases of elephantiasis were in the acropachy group; the review process identified two cases not among the previously reported five cases (24). Periosteal bone reaction on radiography of the hand was confirmatory, but was not necessary for diagnosis. Histological confirmation of dermopathy was present in 60% of patients.
Of 45 patients with a diagnosis of thyroid acropachy associated with dermopathy at a visit or in a dismissal diagnosis, 40 patients met the inclusion criteria. In the five excluded patients, clubbing or changes of the nails and digits could not be confirmed in three and was questionable in two; typical changes of digits were absent in all five patients.
Six patients (15%) were lost to follow-up, and 21 patients (53%) completed the follow-up questionnaire. The mean length of follow-up from diagnosis of acropachy was 12.2 yr (median, 9.7 yr; SD, 9.4 yr; maximum, 35.3 yr).
Data related to tobacco use, severity of ophthalmopathy, treatment of ophthalmopathy and dermopathy, and response to questionnaire in the year 2000 were analyzed. In this retrospective analysis, clinical definitions and objective findings were used to define the degree of severity of eye disease. Optic neuropathy, disfiguring proptosis, constant diplopia, and treatment with immunomodulation or orbital decompression were considered indicative of severe eye disease. Patients with symptomatic ophthalmopathy were considered to have mild to moderate Graves’ ophthalmopathy.
Results
Demographics
A total of 31 women and 9 men met the inclusion criteria (ratio of women to men, 3.4:1). The average age was 50 yr (range, 32–82 yr).
Thyroid function status
Hyperthyroidism was present in 35 patients (88%). One patient remained euthyroid, and four were hypothyroid when ophthalmopathy, dermopathy, or acropachy developed. Radioactive iodine therapy was given to 32 patients (80%), and subtotal thyroidectomy was performed on four patients (10%); all of these patients were receiving T4 therapy at last follow-up. Antithyroid oral medication was given to six patients (15%). For 13 patients, data on thyroid-stimulating Ig were available; all 13 patients had high levels, with a mean and median thyroid-stimulating Ig index of 12 (normal, less than 1.3). Another patient who was evaluated earlier had a high level of long-acting thyroid stimulator. At last follow-up, 80% were euthyroid and receiving T4 therapy, and 7.5% were euthyroid and receiving no therapy; the thyroid function status of the other patients was unknown.
Ophthalmopathy
All 40 patients had ophthalmopathy. Twenty-four patients (60%) had severe eye disease, and 16 patients (40%) had mild to moderate disease; 6 patients (15%) had optic neuropathy. Table 1
summarizes the treatment given to these patients. Twenty-five patients (63%) required systemic corticosteroid therapy or an eye operation.
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Because all patients were selected from a group of 178 patients with thyroid dermopathy, all patients had dermopathy. All had lower extremity involvement (in one patient, in a lower-extremity skin graft from the upper thorax), and all had pretibial myxedema. The dermopathy was severe, with the advanced elephantiasis form occurring in seven patients (18%). Table 2 lists the various types of dermopathy and treatment given.
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Three types of acropachy were recognized: clubbing of the fingernails (Fig. 1) and toenails in 35 patients (88%); swelling and tightness of the skin of fingers and toes (Fig. 2) with or without clubbing, in 8 patients (20%); and the complete picture, with pain in distal small joints, clubbing, soft tissue swelling, and subperiosteal reaction seen on a radiograph (Fig. 3) or bone scan (Fig. 4) in 4 patients (10%). When substantial dermopathy of the toes was present, clubbing of the affected toe occasionally was present; however, if there was no clubbing of the upper extremity, the diagnosis of acropachy was not made.
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shows characteristics of patients with thyroid acropachy. Five patients (12%) did not have clubbing but had skin changes in the hands or atypical nail changes adequate for diagnosis of acropachy. Of the eight patients with clubbing who had radiography of the hand, four (50%) had typical periosteal reactions in the phalangeal bones (Fig. 3
). In one patient with lower extremity pain, the results of radiography were negative (Fig. 4A), but the bone scan showed irregularly increased uptake in the cortical areas of both femurs and the distal halves of the tibiae, suggesting osteoarthropathy (Fig. 4B). This patient was a 43-yr-old nonsmoker, and there was no indication of malignancy or a pulmonary disorder causing pulmonary osteoarthropathy. The extremity pain had completely resolved by the year 2000 follow-up.
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Table 4 shows the time relationship between the diagnosis of acropachy and the appearance of other manifestations of autoimmune thyroid disease. Only two patients had a diagnosis of acropachy before they had a diagnosis of thyroid dysfunction; in only five patients did the diagnosis of acropachy precede the diagnosis of ophthalmopathy or dermopathy. In most patients with acropachy, the diagnosis of acropachy was made after the appearance of other manifestations. Acropachy was diagnosed 1–2 yr after the diagnosis of dermopathy in 42%, more than 1 yr after the diagnosis of ophthalmopathy in 58%, and 1–2 yr after the diagnosis of thyroid dysfunction in 68% of the patients.
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Among 39 patients for whom tobacco history was available and accurate, 31 (79%) were smokers; 25 (81%) of the women and 6 (75%) of the men were smokers. All of these patients were smokers at the time of symptom development except one patient who had stopped smoking tobacco 3 yr before symptom onset. The mean cigarette use was 28 pack-years.
Associated medical conditions
Chronic obstructive lung disease was present in three patients who also were heavy smokers (13, 35, and 45 pack-years). However, clubbing in these three patients chronologically matched severe dermopathy rather than pulmonary osteoarthropathy. In one of these patients, hand radiographs at first were negative but later were typical for thyroid acropachy.
Although three patients developed malignancies (one uterine, two breast), none had disease at the time of acropachy. A patient in whom lung cancer developed many years after diagnosis of acropachy died 14 yr later. Two patients had rheumatic heart disease, and two had ischemic heart disease, but these conditions were not severe enough to cause clubbing. Associated autoimmune diseases were present in two patients: one patient with seronegative rheumatoid arthritis and one with scleroderma. Two patients had type 2 diabetes mellitus.
Outcome of ophthalmopathy and dermopathy
Table 5 shows the outcome for patients with dermopathy and ophthalmopathy, according to the results of the last examination or the patient follow-up questionnaire. These results were achieved after several eye operations for ophthalmopathy in 22 patients (55%) and in many cases after local and systemic corticosteroid therapy for the dermopathy.
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Table 6 shows the outcome for patients with thyroid acropachy, according to the results of the last examination or the follow-up questionnaire. In most patients, clubbing or acropachy was not symptomatic. In all who had joint pain, the pain had resolved at last follow-up. Patients who were symptomatic at last follow-up had symptoms related to massive dermopathy, preventing them from wearing shoes and causing substantial cosmetic concern. In response to the follow-up questionnaire, no patient complained of clubbing, and in the follow-up examination, medical examiners rarely commented on clubbing or acropachy. In this retrospective study, the rate of resolution of clubbing is unclear.
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Thyroid acropachy is the least common manifestation of autoimmune thyroid disease. Previous reports indicated that 7% of patients with pretibial myxedema have thyroid acropachy (2). An epidemiological community study showed that 4% of patients with ophthalmopathy have dermopathy, and that one of five patients with dermopathy has acropachy (1). The latter findings are similar to the finding in the present study that 23% of patients with dermopathy who are evaluated in referral practice have acropachy. Our data show that if the criterion of clubbing alone is applied to the diagnosis of thyroid acropachy and a meticulous clinical examination is performed, more patients with acropachy will be diagnosed. Acropachy almost always is associated with dermopathy and ophthalmopathy, although an isolated case of acropachy without dermopathy has been reported (11).
Previous reports have indicated that women and men are affected in equal proportions (11). This is not supported by the present study, which found a female-to-male ratio of 3.4:1. In a typical case with full-blown manifestations, there was soft tissue swelling of the hands and feet in association with clubbing of the fingers and toes. The skin was commonly pigmented and hyperkeratotic. Although local warmth over the joints (characteristic of pulmonary osteoarthropathy) was absent, 10% of our patients reported extremity pain and arthralgia, which eventually resolved. In our patients and in those reported by others (11, 21), the upper extremity almost always was involved. The disease process often is asymmetric, and involvement of a single digit has been reported (6). Some of our patients also had asymmetric involvement. Although acropachy often was painless and was diagnosed when the main feature was ophthalmopathy or dermopathy, some patients, like previously reported patients (26), had lymphatic obstruction, extreme swelling, loss of function, and pain. One patient had extremity pain, with the bone scan showing periosteal reaction in the long bones of the lower extremity.
Our data show that thyroid acropachy can occur in euthyroid and hypothyroid patients, a finding consistent with the findings of other reports (2, 11). The present study also confirms previous observations regarding the chronological sequence of presentations of extrathyroidal manifestations of autoimmune thyroid disease, namely, that thyroid dysfunction develops first, followed by ophthalmopathy, then dermopathy, and finally, acropachy (2, 11, 21).
There are some differences between clubbing and periostitis (27, 28) seen in thyroid acropachy and clubbing and pulmonary osteoarthropathy seen in lung and other systemic (29, 30, 31, 32) and paraneoplastic conditions. Thyroid acropachy is distinguished by the uniform presence of thyroid dermopathy and ophthalmopathy. Radiological features are also somewhat different; in patients with thyroid acropachy, there is less involvement of the long bones, although one of the patients in our study did have long-bone involvement. In pulmonary osteoarthropathy, periosteal reaction usually is symmetric; in acropachy, it can be asymmetric. In acropachy, radiographs show a characteristic subperiosteal spiculated, frothy, or lacy appearance (9, 21), quite different from the laminal periosteal proliferation of classic pulmonary osteoarthropathy. There may even be a pathogenic difference. Megakaryocytes and platelet clumps not trapped in the lungs and entering the systemic circulation have been proposed as a cause in lung disease (33). A right-to-left shunt also allows bypass of the pulmonary vascular bed. Platelets contain and release platelet-derived growth factor, whose known effects could explain all of the pathological changes observed in patients with clubbing. In thyroid acropachy, however, other mechanisms (such as autoimmune phenomena and increased glycosaminoglycan and fibroblast proliferation similar to changes in thyroid ophthalmopathy and dermopathy) may be at work (34, 35, 36, 37).
In the cases we studied, radiological findings were present in 50% of the patients who had lower and upper extremity radiographs. There was fusiform soft tissue swelling of the digits and periosteal bone formation, which usually involved the metacarpals, the proximal and middle phalanges of the fingers, and the metatarsal and proximal phalanges of the toes. It is usually believed that the periosteal reaction in thyroid acropachy, unlike that in pulmonary osteoarthropathy, does not occur in the long bones of the forearms or the legs (38). However, in a case that we studied, the patient had extremity pain, a negative conventional radiograph, and a bone scan showing a subperiosteal reaction in the femur and tibia similar to that in pulmonary osteoarthropathy (Fig. 4). This observation is consistent with a previous report that, in the early stages of acropachy, when bone radiographs are normal, technetium-99m pyrophosphate bone scans show focal accumulation of the radionuclide in the affected areas (39). A recent report has characterized the magnetic resonance imaging finding in a case of thyroid acropachy (40).
Dermopathy is indicative of a severe autoimmune thyroid disease; acropachy is likely to indicate an even more severe form. Dermopathy is present in 4% of unselected cases of ophthalmopathy (1) but occurs in 13% of cases of ophthalmopathy severe enough to require orbital decompression (3, 41, 42). In the cases of acropachy that we studied, there was clear immunological evidence of active severe autoimmune disease. Consistent with previous reports (43, 44, 45), each of the 13 patients in whom thyroid-stimulating Ig was measured had a high index level.
Among the cases studied, there was clinical evidence of the extreme forms of ophthalmopathy in patients with acropachy. Most patients required orbital decompression, and 63% had either systemic corticosteroid therapy or some type of eye operation. Also, there were extreme forms of dermopathy; 18% of patients had the elephantiasic form. However, referral to our center for orbital decompression may have introduced bias for more severe cases of ophthalmopathy and dermopathy and hence acropachy.
In patients with thyroid acropachy, skin biopsy demonstrates typical findings of pretibial myxedema, including fibroblast activation and glycosaminoglycan deposition. Similar findings have been noted in skin overlying periosteal changes of acropachy (10). Little is known about the pathological characteristics and pathogenesis of thyroid acropachy. One histological study of bone revealed nodular fibrosis of the periosteal area, subperiosteal bone formation, and fibrosis of the marrow space (46). In our study, we had no biopsy specimens other than those from areas of dermopathy.
The very high rate of smokers among the patients we studied is of interest; 81% of the women and 75% of the men were heavy current smokers. Compared with smoking rates in the U.S. population, these rates are 3.7 times higher for women and 2.6 times higher for men (47). Tobacco use as a risk factor for Graves’ ophthalmopathy is an established fact (48, 49, 50, 51). However, a report from our institution did not find significant differences between tobacco smokers and nonsmokers in the cumulative probabilities of having an operation for severe eye disease in Olmsted County (52). The very high rate of tobacco use among the patients we studied adds to the evidence that tobacco is an important risk factor for severe manifestations of Graves’ disease. The question can be raised whether tobacco dependency and associated obstructive lung disease contribute to clubbing. Only three of the patients in our study had chronic obstructive lung disease; in all three patients, severe dermopathy, radiological images, and chronology of disease were typical for thyroid acropachy. It is unclear whether subclinical pulmonary dysfunction associated with tobacco use contributes to the development of severe dermopathy and acropachy.
No specific treatment for acropachy of thyroid disease is available, other than systemic immunosuppressive therapy and local corticosteroid therapy. These treatments usually are directed at associated ophthalmopathy and dermopathy. For persistent pulmonary osteoarthropathy, local octreotide injection and local radiotherapy have been tried (53, 54, 55). Whether these measures would help patients with thyroid acropachy is unclear. In most of the patients we studied, clubbing was asymptomatic. In the few symptomatic patients with joint and extremity pain, therapy of dermopathy was the only treatment given, and acropachy symptoms resolved. Mechanical effects of elephantiasis and bulky dermopathy were the main complaints in symptomatic patients.
In the patients we studied, no therapy specific for acropachy was given, but most patients received local therapy for dermopathy and systemic corticosteroid therapy for ophthalmopathy. Specific beneficial effects of such therapies in patients with acropachy are possible but remain unclear.
In summary, the present study shows that thyroid acropachy in its more common form presents with asymptomatic digital clubbing associated with severe ophthalmopathy and symptomatic dermopathy. Often, the physician makes the diagnosis, and patients do not have specific acropachy-related symptoms. In advanced cases, when periosteal involvement is present, pain and arthralgia also may be present. After long-term follow-up, remission of acropachy may occur. The present study does not clarify the percentage of patients with digital clubbing in whom remission of clubbing occurs. Long-term follow-up shows that dermopathy and ophthalmopathy, not acropachy, usually are the sources of the complaint and functional problem.
Acknowledgments
Footnotes
This work was supported by the Richard Emslander Clinical Investigator Award and a Scholarly Clinician Award of the Mayo Foundation.
K.M.S. is a student at the Mayo Medical School.
Received May 13, 2002.
Accepted August 21, 2002.
References
in cultured human retroocular fibroblasts. J Clin Endocrinol Metab 72:1169–1171
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