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The Journal of Clinical Endocrinology & Metabolism Vol. 84, No. 9 3010-3012
Copyright © 1999 by The Endocrine Society

Special Articles

Cushing’s Disease Presenting with Avascular Necrosis of the Hip: An Orthopedic Emergency

Christian A. Koch, Constantine Tsigos, Nicholas J. Patronas and Dimitris A. Papanicolaou

Developmental Endocrinology Branch, National Institutes of Child Health and Human Development (C.A.K., D.A.P.); Department of Radiology, Clinical Center (N.J.P.); National Institutes of Health, Bethesda, Maryland 20892; and National Diabetes Center (C.T.), Athens, Greece

Address all correspondence and requests for reprints to: Dimitris A. Papanicolaou, M.D., Developmental Endocrinology Branch, National Institutes of Child Health and Human Development, National Institutes of Health, Building 10, Room 10N262, 10 Center Drive MSC 1862, Bethesda, Maryland 20892-1862. E-mail: papanicd{at}mail.nih.gov


   Abstract
Top
 Abstract
Case Report
 Discussion
 References
 
Nontraumatic avascular necrosis (AVN) of the hip is commonly caused by exogenous glucocorticoid administration, whereas it has rarely been associated with endogenous hypercortisolism. We report a 30-yr-old woman with Cushing’s disease whose presenting manifestation was early AVN of the hip. Although plain x-ray was negative, magnetic resonance imaging (MRI) of the hip showed stage 2 AVN. Her orthopedic disease was considered an emergency, and thus, it was treated with core decompression before the diagnosis of Cushing’s syndrome (CS) was pursued further. The femur recovered fully, as demonstrated by her improved clinical picture and a subsequent MRI. AVN carries a poor prognosis, if not treated early. The diagnostic procedure of choice is MRI, because plain radiographs are falsely negative in early stages. This case illustrates that AVN can be the presenting manifestation of CS; to prevent irreversible effects on the femoral head, core decompression should not be delayed for the purpose of evaluation and treatment of CS.


   Case Report
Top
 Abstract
 Case Report
Discussion
 References
 
A 30-yr-old, previously healthy Greek woman presented with severe left hip pain of sudden onset. She had had no history of trauma. Apart from bromazepam at bedtime, she was on no other medications. She had never been treated with oral, inhaled, or locally applied corticosteroids. She did not smoke or drink alcohol. Review of systems revealed weight gain, hypertension, hirsutism, amenorrhea, easy bruising, insomnia, and mood swings over the previous year. On physical examination, she was afebrile and had a blood pressure of 157/110 mm Hg, centripetal obesity, a small buffalo hump and supraclavicular fat pads, mild acne, and hirsutism. Range of motion of her left hip joint was decreased, compared with the right hip joint. Though the plain radiograph of the hip was negative, magnetic resonance imaging (MRI) of the left femur showed a stage 2 avascular necrosis (AVN) of the femoral head, with stage 1 being the earliest and stage 6 the most advanced (1) (Fig. 1Go). Cushing’s syndrome (CS) was suspected, based on her clinical presentation. Urinary free cortisol excretion was 1258 nmol/day = 456 µg/day (normal range, 55–331 nmol/day = 20–120 µg/day). At that time, it was felt that, to avoid further deterioration of her AVN, she should have hip surgery before addressing her CS. Therefore, she underwent immediate core decompression surgery with decongestion of the left femoral head. She had good wound healing, with an uneventful postoperative course.



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  		Figure 1. Two consecutive axial inversion recovery MRI images of both hips. Abnormal high intensity signal changes are noted in the bone marrow of the left femoral head. Joint effusion is also noted in the left hip (arrows). These findings are most consistent with the diagnosis of early AVN (stage 2).

 
Four months after hip surgery, she was referred to the National Institutes of Health Clinical Center for evaluation of her hypercortisolism. At that time, her hip examination was normal. In particular, there was no trochanteric tenderness or hip pain on inner or outer rotation. Twenty-four-hour urinary free cortisol levels ranged from 690-1504 nmol/day = 250–545 µg/day (normal range, 66–298 nmol/day = 24–108 µg/day), and there was absence of diurnal serum cortisol rhythm. A CRH stimulation test and an overnight 8-mg-dexamethasone suppression test were indicative of Cushing’s disease. An MRI of the pituitary gland showed no adenoma. Inferior petrosal sinus sampling showed lateralization to the right side, before and after stimulation with CRH. The patient underwent transsphenoidal surgery, with removal of a noninvasive 3-mm right-sided pituitary microadenoma that stained positively for ACTH. Postoperatively, both plasma and urinary cortisol concentrations became undetectable. The patient had also a repeat MRI of the pelvis, which demonstrated an increased signal intensity of the left femoral head, indicating significant improvement, compared with the original MRI (Fig. 2Go).



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  		Figure 2. Two consecutive MRI images of both hips, using a similar inversion recovery technique, 4 months after core decompression of the left femoral head and neck. There is complete reversal of the signal abnormality noted on the preoperative examination. The normal contour of the left femoral head is well preserved. There is no evidence of joint effusion.

 

   Discussion
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 Abstract
 Case Report
 Discussion
References
 
This case demonstrates that AVN of the hip can be the presenting manifestation of Cushing’s disease. AVN is mediated by interosseous hypertension followed by intramedullary venous stasis, edema, necrosis, fibrosis, and infarction that finally leads to collapse of the femoral head (2). The most common causes of nontraumatic AVN are exogenous glucocorticoid administration and alcoholism (3). Though AVN of the hip is a well-recognized complication of steroid treatment (4), it has rarely been reported in cases of endogenous hypercortisolism. To our knowledge, only 14 patients with AVN, associated with endogenous CS, have been documented in the medical literature (5, 6, 7, 8, 9, 10, 11, 12, 13). In one of the largest series of corticosteroid-induced AVN (7), 3 of 77 patients (4%) were found to suffer from endogenous CS. In the same series, exogenous glucocorticoid administration accounted for approximately 31% of nontraumatic AVN, whereas alcohol intake accounted for 33% of the cases. Interestingly, 32% of patients with glucocorticoid-induced AVN were alcoholic as well.

The pathogenesis of AVN in hypercortisolism is still unknown. One favored theory suggests that fat embolization from the liver, from bone marrow fat cells, or from destabilization and coalescence of plasma lipoproteins may be responsible. Another possibility is that corticosteroids and the associated insulin resistance favor the development of hypertension and arteriosclerosis, making AVN a so-called coronary disease of the hip (14). Finally, it has been suggested that osteoporosis caused by corticosteroid exposure increases the risk of AVN, because of glucocorticoid-induced microfractures in the susceptible bones. However, the incidence of AVN is not increased in noncorticosteroid-related osteoporosis, making the latter an unlikely explanation. The fact that even short-term exposure to corticosteroids can lead to AVN (15, 16, 17) suggests that additional mechanisms must be invoked besides the above, all of which would presume a longer exposure to glucocorticoids. Of all sites, the femoral head seems to be more susceptible to AVN, probably because of its limited blood supply through the delicate artery of the ligamentum teres, which is a terminal vessel arising from the obturator artery.

In the past, a number of features have been used to diagnose AVN by conventional radiography. These radiographic abnormalities, however, occur in advanced stages of the disease, when a therapeutic intervention would have little or no impact. Recent evidence shows that MRI allows diagnosis of AVN at the early stages of the disease (1). In our patient, MRI revealed stage 2 necrosis of the femoral head, whereas the plain radiographs were negative. Because AVN very rarely develops in the absence of trauma or other factors, such as exogenous glucocorticoids, alcoholism or liver disease, we concluded that the AVN diagnosed in our patient, without such predisposing risk factors, was attributable to endogenous hypercortisolism.

AVN carries a poor prognosis if not treated early. In a recent series, only 31% of patients with precollapse AVN had a satisfactory clinical result without an operative procedure (18). Thus, early surgical intervention would be necessary to avoid permanent abnormalities of the femoral head and hip. Surgical treatment options are dependent on the stage of the disease, and they include core decompression, bone grafting, various osteotomies, and total hip replacement (1). In precollapse stages, as in our case, core decompression is the most effective form of treatment (2). Core decompression decreases the pressure within the medulla of the head and neck of the femur and potentially leads to improved circulation to the femoral head (1).

In summary, this case illustrates that AVN, an orthopedic emergency, can be the presenting manifestation of Cushing’s disease. Thus, CS should be suspected in every patient that presents with AVN in the absence of other predisposing factors, such as alcohol abuse or exogenous glucocorticoid administration. On the other hand, AVN should be suspected in any patient with CS presenting with sudden hip pain. In such a case, an MRI must be obtained for confirmation because plain radiographs are falsely negative in early stages. Once the diagnosis is established, core decompression of the femoral head should be performed. Such surgical intervention in early AVN should generally precede treatment of CS, for the purpose of preventing irreversible effects on the femoral head. Nevertheless, this approach should be individualized, depending on the severity of CS.

Received March 22, 1999.

Accepted June 9, 1999.


   References
Top
 Abstract
 Case Report
 Discussion
 References
 

  1. Mazieres B. 1998 Regional and heritable bone and collagen diseases. Osteonecrosis. In: Klippel JH, Dieppe PA, eds. Rheumatology. 2nd ed. London: Mosby International; 8.47.1–8.47.10.
  2. Smith SW, Ferhing TK, Griffin WL, Beaver WB. 1995 Core decompression of the osteonecrotic femoral head. Am J Bone Joint Surg. 77:674–680.[Abstract/Free Full Text]
  3. Ninomiya S. 1989 An epidemiological survey of idiopathic avascular necrosis of the femoral head in Japan. Annual report of the Japanese Investigation Committee for Intractable Disease. Osaka: University Publisher.
  4. Thornton MJ, O’Sullivan G, Williams MP, Hughes PM. 1997 Avascular necrosis of bone following an intensified chemotherapy regimen including high dose steroids. Clin Radiol. 52:607–612.[CrossRef][Medline]
  5. Madell SH, Freeman LM. 1964 Avascular necrosis of bone in Cushing’s syndrome. Radiology. 83:1068–1070.
  6. Patterson RJ, Bickel WH, Dahlin DC. 1964 Idiopathic avascular necrosis of the head of the femur. Am J Bone Joint Surg. 46:267–282.[Free Full Text]
  7. Fisher DE, Bickel WH. 1971 Corticosteroid induced avascular necrosis. Am J Bone Joint Surg. 53:859–873.[Abstract/Free Full Text]
  8. Modlinger RS, Nicolis GL, Pertsemlidis D, Gabrilove JL. 1972 Cushing’s syndrome and avascular necrosis of bone associated with carcinoid-islet cell tumor of the pancreas. Cancer. 30:782–790.[CrossRef][Medline]
  9. Cerletty JM, Ziebert AP, Mueller KH. 1973 Avascular necrosis of the femoral head as the presenting manifestation of Cushing’s disease. Clin Orthop. 97:69–73.
  10. Sharon P, Kaplinsky N, Leiba S, Frankl O. 1977 Aseptic necrosis of head of femur: presenting manifestation in Cushing’s disease. J Rheumatol. 4:73–75.[Medline]
  11. Phillips KA, Nance Jr EP, Rodriguez RM, Kaye JJ. 1986 Avascular necrosis of bone: a manifestation of Cushing’s disease. South Med J. 79:825–829.[Medline]
  12. Wicks IP, Calligeros D, Kidson W, Bertouch JV. 1987 Cushing’s disease presenting with avascular necrosis of the femoral heads and complicated by pituitary apoplexy. Ann Rheum Dis. 46:783–786.[Abstract/Free Full Text]
  13. Kobayashi S, Terayama K. 1991 Osteoarthritis secondary to avascular necrosis of the femoral head as a manifestation of Cushing’s disease (French). Rev Chir Orthop Reparatrice Appar Mot. 77:362–365.[Medline]
  14. Hungerford DS, Zizic TM. 1983 Pathogenesis of ischemic necrosis of the femoral head. In: Hungerford DS, ed. The hip. Proc of the 11th Open Scientific Meeting of The Hip Society. St. Louis: CV Mosby; 249–256.
  15. Williams PL, Corbett M. 1983 Avascular necrosis of bone complicating corticosteroid replacement therapy. Ann Rheum Dis. 42:276–279.[Abstract/Free Full Text]
  16. Taylor LJ. 1984 Multifocal avascular necrosis after short-term high-dose steroid therapy. A report of three cases. Br J Bone Joint Surg. 66:431–433.
  17. Solomon L, Pearse MF. 1994 Osteonecrosis following low-dose, short-course corticosteroids. J Orthop Rheumatol. 7:203–205.
  18. Mont MA, Hungerford DS. 1995 Non-traumatic avascular necrosis of the femoral head. Am J Bone Joint Surg. 77:459–474.[Free Full Text]




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