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Corticosteroid-Induced Juxta-articular Adiposis Dolorosa

By Steven S. Greenbaum, MD, John Varga, MD

From the Departments of Dermatology (Dr Greenbaum) and Medicine (Dr Varga),
Jefferson Medical College, Philadelphia, Pa.

Reprinted from the Archives of Dermatology

February 1991, Volume 127, pages 231-233
Copyright 1991, American Medical Association


Adiposis dolorosa is an uncommon disorder of subcutaneous tissue that was first described by Dercum1 in 1892 at Jefferson Medical College, Philadelphia, Pa. The understanding of this disease has not progressed very much in the past 98 years. It remains better understood as a clinical entity than as a physiologic or metabolic process.

Characteristically, adiposis dolorosa is usually seen in postmenopausal women, although younger women and, rarely, men may be affected.2 There are multiple painful, symmetrically distributed, fatty deposits that may be either diffuse or localized. The pain varies from discomfort on palpation to excruciating, paroxysmal spontaneous attacks.3 Adiposis dolorosa is commonly localized to the lower extremities (especially around the knees), where it has been termed juxta-articular adiposis dolorosa.4 However, the painful fatty tumors of this disease have been reported to occur in almost any location except the head and neck.5

The search for the most effective therapy for adiposis dolorosa has been frustrating. Proposed treatments have included prostigmine and aminoacetic acid,6 non-steroidal anti-inflammatory agents,4 compression bandages,6 intravenous lidocaine,7 systemic corticosteroids, surgical excision, and liposuction.8

We describe a patient treated with prednisone who presented with juxta-articular adiposis dolorosa. The temporal association of high-dose corticosteroid use and the development of the lesions, and their resolution after reduction of corticosteroid dose, suggest a causal relationship in this case. To our knowledge, this possible adverse effect of corticosteroids has not been previously reported.

REPORT OF A CASE

A 67-year-old white woman was referred for evaluation of painful masses on her knees. She had been in good health until August 1989, when she noted the onset of diarrhea, abdominal discomfort, and marked fatigue. Two weeks later she developed numbness and swelling of her lower extremities, accompanied by weakness, tenderness, and myalgias. She became unable to climb stairs or continue with her daily activities and was hospitalized. She had been taking L-tryptophan (4 g/d) for 3 months for treatment of insomnia. Her physical examination was notable for proximal muscle weakness and cutaneous induration of the arms and legs; the hands were spared. Laboratory examination showed striking eosinophilia (white blood cells, 3.6 x 109/L). A full-thickness skin biopsy demonstrated findings consistent with eosinophilic fasciitis (Fig 1). The L-tryptophan therapy was discontinued, and treatment with prednisone (60 mg/d) was started. Six weeks later, because of the lack of response, the dosage of prednisone was increased to 80 mg/d. During the following two weeks, the patient reported improvement of myalgias, diminished swelling, and a 14-kg weight loss. Four weeks later, however, she developed severe pain around her knees. She was referred to Thomas Jefferson University Hospital in January 1990.

On physical examination she had full facies, oral candidiasis, a "buffalo hump," marked truncal obesity, and grade 3/5 proximal muscle weakness. Diffuse subcutaneous induration was present in all her extremities. Markedly tender, well-circumscribed, fist-sized subcutaneous masses superior to both knees were noted (Fig 2). There was no effusion in the knees. Laboratory investigation showed hyperglycemia (glucose, 26.4) but a normal blood cell count and erythrocyte sedimentation rate. Her serum cholesterol level was 7.75 mmol/L, and her triglyceride level was 6.42 mmol/L. A chest roentgenogram showed a widened superior mediastinum and tracheal narrowing (Fig 3). A computed tomographic scan of the chest confirmed mediastinal widening, suggestive of mediastinal lipomatosis. Histopathologic examination of a deep biopsy specimen from one of the periarticular masses showed normal subcutaneous adipose tissue with a moderate increase in vascularity. There was no evidence of inflammation, necrosis, or fibrosis within the dermis or the septa.

During the following months, a progressive reduction of the prednisone dose was associated with a gradual increase in muscle strength and improvement of the pain in the knees, as well as a progressive decrease in the size of the peripatellar fatty tumors. Four months after the patient's initial evaluation, when she was taking 30 mg of prednisone on alternate days, these lesions had disappeared completely. A subsequent chest roentgenogram showed a normal-sized mediastinum.


gb-fig1r.gif (12232 bytes)gb-fig2r.gif (48905 bytes)Fig 1. --Histopathologic findings in full-thickness skin biopsy specimen of clinically involved skin show markedly thickened fascia. There is a mixed inflammatory cell infiltrate composed of lymphocytes, plasma cells, and eosinophils (hematoxylin-eosin, original magnification x 100).

 

Fig 2.--Suprapatellar juxta-articular fatty masses. A biopsy specimen was obtained from the mass on the right side.

 


Fig 3.--Chest roentgenogram demonstrating widening of the mediastinum

gb-fig3r.gif (38332 bytes).COMMENT

Our patient developed juxta-articular adiposis dolorosa while being treated with high doses of prednisone for eosinophilia-myalgia syndrome (EMS). Eosinophilia-myalgia syndrome is a recently described illness occurring in an epidemic form, which develops in a proportion of individuals using L-tryptophan for the treatment of insomnia, as well as for a wide variety of somatic complaints.9 Case control studies from the Centers for Disease Control have firmly established an association between L-tryptophan use and the development of EMS10 and have traced the illness to L-tryptophan preparations produced by a single manufacturer.11 Patients with EMS have an abrupt onset of illness that is characterized by skin rash, swelling of extremities, and severe myalgias and frequently accompanied by fever, arthalgia, and cutaneous hypersensitivity, as well as respiratory symptoms.12 Following the stereotypic acute phase of the illness, a subset of patients with EMS develop chronic symptoms, including muscle weakness, sclerodermalike or fasciitislike skin changes, and neuropathy. Although cutaneous and sub-cutaneous induration is a feature of chronic EMS, lipomas and adiposis dolorosa have not been described in these patients. No satisfactory treatment is available for the prevention or management of the chronic syndrome, but the use of corticosteroids in the early stages of EMS frequently results in improvement of myalgias, tissue swelling, fever, and respiratory symptoms and resolution of the eosinophilia.13 The role of L-tryptophan in the development of the EMS epidemic is not well understood. This amino acid, which is available without a physician's prescription, has been enthusiastically advocated for the management of insomnia, depression, obesity, and premenstrual syndrome,14 and has been widely used in the United States. No systemic illness was associated with L-tryptophan ingestion prior to 1989, but abnormalities in tryptophan metabolism have been implicated in the pathogenesis of scleroderma15 and diffuse fasciitis.16 Adiposis dolorosa has not been reported in association with the use of L-tryptophan.

Since the original description of adiposis dolorosa by Dercum,1 the clinical spectrum of this unusual entity has changed little. In addition to the painful nodular depositions of fat, there are other typical components of adiposis dolorosa. General obesity, fatigability, weakness, and a wide variety of emotional disturbances have all been described in this syndrome. The pathogenesis of adiposis dolorosa remains unknown. An early study suggested that a defect in the synthesis of monounsaturated fatty acids may play a role in its development.3 Further studies are needed to substantiate this hypothesis and to identify a specific biochemical defect.

Long-term exposure to corticosteroids leads to gross obesity and affects the regulation of localized fat metabolism in patients with Cushing's disease as well as those receiving corticosteroids for disease states.17,18 Characteristically, in corticosteroid excess, increased deposits of adipose tissue are seen along the central body axis: truncally (usually as increased intraabdominal fit), episternally, supraclavicularly, and in the posterior cervical area (buffalo hump). 19 The facial fullness, termed moon facies, is due to increased buccal fat. 20 Recently, the ability of computed tomographic scanning to detect adipose tissue with great sensitivity has led to the recognition of steroid-induced increased fat deposition in the cavernous sinus,21 mediastinum, 20 temporal region,22 and epidurally.23

It is sometimes difficult to determine whether fat accumulation in corticosteroid excess is caused by in-creased localized fatty deposition or by a relative atrophy of surrounding tissue such as muscle. It has been shown, for example, that in many cushingoid patients there is marked thigh muscle atrophy, which tends to accentuate truncal obesity. In addition, paraspinal and shoulder muscle atrophy makes the buffalo hump more apparent.20

The mechanism by which steroids alter fat metabolism remains poorly understood. Patients with Cushing's syndrome, or those who become cushingoid be-cause of medication, display typically altered lipid metabolism, including increased levels of very-low-, low-, and high-density lipoproteins.17,18,24,25 There are other theories to account for the unusual distribution of fat in states of corticosteroid excess, e.g., that it is induced by different hormones.26 Furthermore, there appear to be regional differences in the ability of cellular receptors to bind corticosteroids.26

To our knowledge, there are no previous reports of an association between corticosteroid ingestion and the development of adiposis dolorosa. Our patient developed gross truncal obesity, moon facies, and mediastinal widening due to epicardial fat deposition, as well as markedly painful periarticular localized fatty deposits, after taking high doses of prednisone for the treatment of EMS. These changes were suggestive of a wide-spread dyslipoproteinemia induced by corticosteroids. She also developed diabetes mellitus. As the dosage of prednisone was gradually lowered, dramatic improvement of adiposis dolorosa, as well as a return to more normal blood glucose levels, occurred. We suggest that alterations induced by high-dose prednisone therapy and clinically manifested by truncal obesity, moon facies, and mediastinal lipomatosis contributed to the development of juxta-articular adiposis dolorosa in this patient.

This study was supported in part by grant AR 01817 from the National Institutes of Health, Bethesda, Md.  
The authors thank Sergio A. Jimenez, MD, for helpful discussion and Helene Cohen for secretarial assistance in preparing this manuscript.

References

  1. Dercum FX. Three cases of a hitherto unclassified affection resembling in its grosser aspects obesity, but associated with special symptoms: adiposis dolorosa. Am J Med Sci. 1982;104:521-535.

  2. Bonatus T J, Alexander AH. Dercum's disease (adiposis dolorosa): a case report and review of the literature. Clin Octhop Rel Res. 1986;205:251-253.

  3. Blomstrand R, Juhlin L, Nordenstare H, Ohlsson R, Werner B, Engstrom J. Adiposis dolorosa associated with defects oflipid metabolism. Acta Derm Venereol (Stockh). 1971;51:243-250.

  4. Eisman J, Swezey RL. Juxta-articular adiposis dolorosa: what is it? report of two cases. Ann Rheum Dis. 1979;38:479-482.

  5. Steiger WA, Litvin H, Lasche EM, Durant TM. Adiposis dolorosa (Dercum's disease). N Engl J Med. 1952;247:393-396.

  6. Stallworth JM, Hennigar GR, Jonsson HT, Rodriguez O. The chronically swollen painful extremity. JAMA. 1974;228:1656-1659.

  7. Peterson P, Kastrup J. Dercum's disease (adiposis dolorosa): treatment of the severe pain with intravenous lidocaine. Pain. 1987;28:77-80.

  8. Scheinberg MA, Diniz R, Diamant J. Improvement of juxta-articular adiposis dolorosa by fat suction. Arthritis Rheum. 1987;30:1435-1437.

  9. Varga J, Peltonen J, Uitto J, Jimenez SA. Development of diffuse fasciitis with eosinophilia during L-tryptophan treatment: demonstration of elevated type 1 collagen gene expression in affected tissues: a clinicopathological study of four patients. Ann Intern Med. 1990;112:344-351.

  10. Centers for Disease Control. Eosinophilia-myalgia syndrome and L-tryptophan-containing products--New Mexico, Minnesota, Oregon, and New York. MMWR. 1989;38:785-788.

  11. Slutsker L, Hoesly FC, Miller LM, Williams LP, Watson JC, Fleming DW. Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer. JAMA. 1990;264: 213-217.

  12. Silver R, Heyes P, Maize J, Quem~ B, Vionnet-Fuasset M, Sternberg E. Scleroderma, fasciitis, and eosinophilia associated with the ingestion of tryptophan. N Engl J Med. 1990;322:874-888.

  13. Varga J, Helmart-Patterson D, Emery D, et al. Clinical spec-trum of the systemic manifestations of the eosinophilia-myalgia syndrome. Semin Arthritis Rheum. 1990;19:313-328.

  14. L-tryptophan: a 'natural' sedative? Med Lett Drugs Ther. 1977;19:108.

  15. Fries JF, Lindgren JA, Bull JM. Scleroderma-like lesions and the carcinoid syndrome. Arch Intern Med. 1973;131:550-553.

  16. Stachow A, JablonskaS, KenckaD. Tryptophan metabolism in scleroderma and eosinophilic fasciitis. In: Black CM, Myers AR, eds. Current Topics in Rheumatology: Systemic Sclerosis (Scleroderma). New York, NY: Gower Medical Publishers; 1985:130-134.

  17. Cushing H. Basophiladenomas of the pituitary body and their clinical manifestations. Bull Johns Hopkins Hosp. 1932;50:137-195.

  18. Scale PS, Compton MR. Side-effects of corticosteroid agents. Med J Aust. 1986;144:139-142.

  19. Mayo-Smith W, Hayes CW, Biller BM, Klibanski A, Rosenthal H, Rosenthal D. Body fat distribution measured with CT: correlations in healthy subjects, patients with anorexia nervosa, and patients with Cushing's syndrome. Radiology. 1989;170:515-518.

  20. Horber HH, Xurcher RM, Herren H, Crivelli MA, Robotti G, Frey FJ. Altered body fat distribution in patients with glucocorticoid treatment and in patients on long-term dialysis. Am J Clin Nutr. 1986;43:758-769.

  21. Bachow TB, Hesselink JR, Aaron JO, Davis KR, Taveras JM. Fat deposition in the cavernous sinus in Cushing's disease. Radiolo-gy. 1984;153:135-136.

  22. Gottlieb NL. Temporal fat pad sign during corticosteroid treatment. Arch Intern Med. 1980;140:1507-1508.

  23. Brythian D, Piette C, Ducervean MN, Robert G, Godeau P, Heitz F. Steroid induced spinal epidural lipomatosis: CT survey. J Cornput Assist Tomogr. 1988;12:501-503.

  24. Ettinger WH, Goldberg AP, Appelbaum-Bowden D, Hazzard WR. Dyslipoproteinemia in systemic lupus erythematosus: effect of corticosteroids. Am J Med. 1987;83:503-508.

  25. Zimmerman F, Fainura M, Eisenberg S. The effect of prednisone therapy on plasma lipoproteins and apoproteins: a prospective study. Metabolism. 1984;33:521-526.

  26. Rebuffe-Scrive M. Steroid hormones and distribution of adipose tissue. Acta Med Scand Suppl. 1988;723:143-146.

Thanks to Dr. Greenbaum for permission to display this article.   Reprint requests to Department of Dermatology, Thomas Jefferson University, Suite 4019, 111 S 11th St, Philadelphia, PA 19107 (Dr Greenbaum).


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