Hypertrophic osteoarthropathy in cystic fibrosis - Semantic Scholar

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Mar 17, 1984 - reports of the syndrome are that vagotomy results in almost immediate symptomatic relief"l and radiological regression of the periostealĀ ...
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BRITISH MEDICAL JOURNAL

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17 MARCH 1984

References ' Kesson AM, Talbot JM, Gyory AZ. Microscopic examination of urine. Lancet 1978;ii:809-12. ' Mahajan SK, Ordonex NG, Feitelson PJ, et al. Lupus nephropathy without clinical renal involvement. Medicine (Baltimore) 1977 ;56: 493-501. 3 Appel GB, Silva FG, Pirani CL, et al. Renal involvement in systemic lupus erythematosus (SLE). Medicine (Baltimore) 1978 ;57 :371-410. Gyory AZ, Kesson AM, Talbot JM. Microscopy of urine now you see it, now you don't! Am HeartJ7 1980;99:537-8. 5 Gyory AZ, Edwards KDG, Stewart JH, et al. Comprehensive one-day renal function testing in man. J7 Clin Pathol 1974;27:382-91.

6 Fairley KF, Birch DF. Hematuria: a simple method for identifying glomerular bleeding. Kidney Int 1982 ;21:105-8. 7Addis T. The number of formed elements in the urinary sediment of normal individuals. J Clin Invest 1926;2:409-15. Triger DR, Smith JWG. Survival of urinary leucocytes. J Clin Pathol 1966 ;19 :443-7. Rosenbaum R, Hoffsten PE, Stanley RJ, et al. Use of computerized tomography to diagnose complications of percutaneous renal biopsy. Kidney Int 1978;14:87-92.

(Accepted 21 December 1983)

Hypertrophic osteoarthropathy in cystic fibrosis STANLEY BRAUDE, HARRY KENNEDY, MARGARET HODSON, JOHN BATTEN Abstract Seven adult patients with cystic fibrosis who had radiological evidence of hypertrophic osteoarthropathy were reviewed. In five of the patients symptoms were particularly pronounced at times of acute infective exacerbations; appropriate treatment of the infective episodes resulted in reduction or resolution of the bone pain and joint effusions. Despite this symptomatic relief periosteal changes persisted radiologically and their chronic nature was indicated by changes in the midshafts of long bones. Four of the seven patients had transient gynaecomastia or mastalgia related to infective exacerbations. It is hypothesised that a neuroendocrine mechanismnamely, release of vasoactive intestinal polypeptide might account for the osteoarthropathy.

Introduction Hypertrophic osteoarthropathy is said to be rare in cystic fibrosis and has a variable relation to the severity of the underlying pulmonary disease.'-3 We report on seven patients with cystic fibrosis who had radiologically proved hypertrophic osteoarthropathy. Although gynaecomastia and hypertrophic osteoarthropathy are well recognised in squamous bronchogenic carcinoma, we do not think that they have been reported previously in association with cystic fibrosis. Details of patients Seven patients (six men, one woman) with cystic fibrosis were investigated radiologically because of bone pain and were found to have hypertrophic osteoarthropathy. The table gives details of clinical and laboratory features. We report on one of the patients (case 1) in greater detail below. Case report-A 21 year old man known to have had cystic fibrosis for 15 years was admitted with a two week history of increasing dyspnoea and production of sputum. Over the week before admission Brompton Hospital and Cardiothoracic Institute, University of London STANLEY BRAUDE, MRCP, registrar in thoracic medicine HARRY KENNEDY, MRCP, senior house officer in thoracic medicine MARGARET HODSON, MD, FRcP, senior lecturer in thoracic medicine and honorary consultant physician JOHN BATTEN, MD, FRCP, consultant physician Correspondence to: Dr S Braude, Lower Medical Corridor, Hammersmith Hospital, London W12 OHS.

FIG 1-New bone seen in midshaft of fibula with no intervening band of radiolucence.

he had noted that his ankles and knees had become swollen and tender. He had a history of similar joint symptoms associated with exacerbation of his chest disease. On examination he had gross finger clubbing with swollen, hot ankle joints bilaterally and a left knee effusion. The wrists were not swollen, and all joint movements were full. Bilateral gynaecomastia was present. Clinical signs in the chest were unchanged from those at previous examinations, but there was clear evidence of physiological deterioration (forced expiratory volume in one second and vital capacity 800 and 1400 ml compared with 1250 and 1950 ml three months previously). Sputum culture grew mucoid, fully sensitive Pseudomonas aeruginosa, and he was treated with intravenous piperacillin and gentamicin. Radiographs of both tibias showed periosteal reactions. With treatment of his pulmonary disease the arthropathy and gynaecomastia resolved completely within 10 days, but radiological follow up two months after discharge showed that the

periosteal changes persisted. All seven patients had the characteristic radiological appearance of hypertrophic osteoarthropathy, with periosteal reaction separated from underlying cortex by a thin radiolucent line at the ends of long bones. In addition, all patients showed a characteristic abnormality of the midshaft to some extent: new bone was seen apparently fused with the cortex of the shaft with no intermediate band of radiolucency (fig 1). This has previously been described as a sign of the chronic nature of the periostitic process.4 In one patient the distribution of periosteal reaction was unusual, the proximal femur being affected (fig 2). No

BRITISH MEDICAL JOURNAL

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patients had biochemical evidence of osteomalacia, and there were no clinical findings to suggest scurvy, which may cause similar periosteal reactions.5 Joint effusions were noted in all seven patients at some time. In five of the patients arthropathy of the large joints with swelling of the knees, ankles, and occasionally the wrists was a consistent feature of acute exacerbation of the bronchopulmonary infection; the joint symptoms did not antedate the pseudomonas infection. In these five patients hypertrophic osteoarthropathy was diagnosed when they presented with an acute deterioration in their respiratory symptoms.

FIG 2-Unusual site of periosteal reaction with characteristic anoearance at Droximal and distal ends of femur.

Their physiological deterioration was considerable (mean drop in vital capacity 270 ; range 18-42%), and they needed treatment with intravenous antibiotics. Three patients with a longer history of joint symptoms (mean 2-8 years) each had at least two further similar exacerbations of respiratory symptoms accompanied by painful arthropathy. In three of the men (table) gynaecomastia was a dominant symptom and occurred simultaneously with the joint effusions at times of acute chest infections. The woman noted severe mastalgia in the same clinical setting. Treatment of the underlying infection with appropriate antibiotics resulted in resolution of the joint and breast symptoms in all four patients. Gynaecomastia could not be ascribed to any part of their treatment. No patient was taking drugs known to cause gynaecomastia,6 and none had clinical or biochemical evidence of liver disease.

Discussion

An episodic form of arthritis has been described in children with cystic fibrosis,7 and we have found that joint symptoms occur in up to 15%0 of patients attending the cystic fibrosis clinic at this hospital. As joint effusions are a recognised part of hypertrophic osteoarthropathy8 joint symptoms in patients with cystic fibrosis should prompt careful radiological examination of the long bones of the arms and legs, especially as the periosteal changes may be chronic and asymptomatic. Donnelly and Johnson suggested that radionuclide bone scans using 99mtechnetium pyrophosphate are more sensitive than plain radiographs in detecting early periosteal changes. 9 Radionuclide scintigraphy in patients with bone and joint symptoms but no radiological abnormality may increase the diagnostic yield. A recent review of the pathogenesis of hypertrophic osteoarthropathy drew attention to various immunological, endocrine, and neural mechanisms.10 The only consistent features in all

Details of patients (pseudomonas was predominant pathogen in all cases)

Case No

Age (years) and sex

1 2 3 4 5 6 7

21M 22 M 25 M 30 M 30 F 18 M 22 M

Painful Best vital capacity arthropathy as over past year consistent feature Gynaecomastia or mastalgia (absolute value of acute and Ā°' predicted bronchiectatic exacerbation 1-951(36) + + 3-1 1 (56) + + 1-61 (30) + + 1-81 (40) + 1-3 1 (45) + + 251 (45) 2-31 (47) -

reports of the syndrome are that vagotomy results in almost immediate symptomatic relief"l and radiological regression of the periosteal changes in six to 12 weeks10 and that blood flow in the calf and forearm is increased and decreases if the underlying cause is removed.12 It seems reasonable to regard the vagal stimulation as the "afferent" limb connecting centrally with a possible neurotransmitter that mediates the "efferent" limb. Vasoactive intestinal peptide is a non-adrenergic non-cholinergic neurotransmitter whose release from the porcine pancreas is mediated by electrical vagal stimulation.1' It is an extremely powerful peripheral vasodilator,'4 and its release by vagal stimulation might possibly account for the observed increase in blood flow in the calf and forearm. Clinically, the association of hypertrophic osteoarthropathy and cystic fibrosis is perhaps more common than was previously recognised as patients (as in our cases) tend to present with joint symptoms and signs at times of acute chest infection. This may lead to diagnostic difficulty as attention is focused on primary joint syndromes. Because of this all patients of this hospital with cystic fibrosis and joint symptoms are currently being investigated prospectively so that the incidence of hypertrophic osteoarthropathy and its relation to arthropathy may be more closely defined. The association in our patients between joint symptoms and pulmonary exacerbations raises important questions about the pathogenesis of hypertrophic osteoarthropathy in general. We thank Miss V Rawlinson for invaluable secretarial help.

References 1 Nathanson I, Riddlesberger MM Jr. Pulmonary hypertrophic osteoarthropathy in cystic fibrosis. Radiology 1980 ;135 :649-51. 2 Grossman H, Denning CR, Bailer DH. Hypertrophic osteoarthropathy in cystic fibrosis. Am J Dis Child 1964;107:1-6. 3 Matthay MA, Matthay RA, Mills DM, Lakshminarayan S. Hypertrophic osteoarthropathy in adults with cystic fibrosis. Thorax 1976;31:572-5. 4 Ginsburg J. Hypertrophic pulmonary osteoarthropathy. Postgrad Med J

1963;39:639-45. Salih SY, Halim MA. Idiopathic hypertrophic osteoarthropathy with severe recurrent arthritis in an African and a review of the literature. East Afr Med3' 1978;55:31-5. 6 Carlson HE. Gynecomastia. N EnglJ Med 1980;303:795-9. 7 Newman AJ, Answell BM. Episodic arthritis in children with cystic fibrosis. J Pediatr 1979 ;94 :594-6. 8 Reardon G, Collins AJ, Balon PA. The effect of adrenergic blockade in hypertrophic pulmonary osteoarthropathy. Postgrad Med J 1979;52: 170-3. 9 Donnelly B, Johnson PM. Detection of hypertrophic pulmonary osteoarthropathy by skeletal imaging with 99m Tc labelled diphosphonate. Radiology 1975;114:389-91. 10 Shneerson JM. Digital clubbing and hypertrophic osteoarthropathy: the underlying mechanisms. BrJ7 Dis Chest 1981;75:113-31. 11 Flavell G. Reversal of pulmonary hypertrophic osteoarthropathy by vagotomy. Lancet 1956 ;i :260-2. 12 Ginsburg J. Observations of the peripheral circulation in hypertrophic pulmonary osteoarthropathy. Q J Med 1958;27:335-40. 13 Fahrenkrug J, De Muckadell OBS, Holst JJ, Jensen SL. Vasoactive intestinal polypeptide in vagally mediated pancreatic secretion of fluid and HCO3. Am J Physiol 1979;237:535-40. 14 Williams TJ. Vasoactive intestinal polypeptide is more potent than prostaglandin E2 as a vasodilator and oedema potentiator in rabbit skin. Br 7 Pharmacol 1982;77:505-9. 5

(Accepted 4_7anuary 1984)