CURRENT STATUS
Lee E. Smith, M.D., Editor
Steroid Complications in Patients with Ulcerative Colitis Masato Kusunoki, M.D.,* Gabriela M6eslein, M.D.,* Yasutsugu Shoji, M.D.,* Shinsuke Fujita, M.D.,* Hidenori Yanagi, M.D.,* Youichirou Sakanoue, M.D.,* Naoaki Saito, M.D.,-~ Joji Utsunomiya, M.D.* From the *2nd Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan and the afDepartment of Pharmacology, Kobe University, School of Medicine, Kobe, Japan Physicians treating patients with ulcerative colitis are confronted with the difficult task of deciding whether medical or surgical treatment is best for their patients. There are no definitive criteria to indicate when medical therapy should be exchanged for definitive surgery. Even in patients who respond well to glucocorticoid treatment, the side effects of these drugs may necessitate surgery. We reviewed the steroid complications of our operative cases retrospectively. Although ulcerative colitis was usually in remission, severe steroid complications were no longer tolerable and definitive surgery was required. We also reviewed the literature regarding the adverse effects of steroid. Because of advances in sphincter-preserving surgery, re-evaluation of the treatment of ulcerative colitis is necessary. Although conservative treatment remains the first choice, tolerance of irreversible side effects (especially in children) no longer seems to be justified. In such patients, early definitive surgery may offer more than it appears to sacrifice. [Key words: Ulcerative colitis; Glucocorticoid side effects; Sphincter-preserving ileoanal anastomosis] Kusunoki M, M6eslein G, Shoji Y, Fujita S, Yanagi H, Sakanoue Y, Saito N, UtsunomiyaJ. Steroid complications in patients with ulcerative colitis. Dis Colon Rectum 1992;35:1003-1009.
everal authors have reported a rising incidence of ulcerative colitis (UC) in younger age groups)' 2 This may be partly due to more sophisticated methods of detection of the disease and to a wider knowledge of the symptoms of inflammatory bowel disease, but it may also represent a genuine shift toward the earlier onset of UC. Conservative therapy using various anti-inflammatory agents is generally initiated at first. Among a total of 4,484 cases of UC reviewed in Japan, 14.3 percent had been treated surgically. 3 Because of toxic dilatation, perforation, obstruction, massive bleed-
ing, carcinoma, chronic failure to respond to medications, and severe complications of glucocorticoid therapy, 4 it is often difficult to determine when definitive surgery should be performed in UC patients undergoing prolonged medical treatment. Some aspects of this disease deserve special consideration in younger patients; e.g., glucocorticoid side effects may be more severe after prolonged medication in younger patients than in adults. To offer patients with UC the best treatment possible and the optimum quality of life, the early detection of patients at high risk of drug complications is necessary. Accordingly, we analyzed the steroid-related complications occurring in our UC patients prior to surgery and reviewed the outcome of prolonged steroid therapy in an attempt to define when surgery should be performed, especially in young patients with glucocorticoid complications.
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Address reprint requests to Dr. Kusunoki: The 2nd Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho Nishinomiya, 663 Japan.
GLUCOCORTICOID SIDE EFFECTS IN OUR UC PATIENTS Sixty-one patients with UC underwent total proctocolectomy and ileal J-pouch-anal anastomosis between November 1983 and September 1991 at the Second Department of Surgery at Hyogo College of Medicine in Japan. Detailed data on the preoperative medical treatment were available in 54 cases. Their clinical profiles are shown in Table 1. All the patients were treated with glucocorticoids. We divided them into a group 30 years old (Table 1). The total dose of steroids was lower in the under-30 group. However, the postoperative management of steroid 1003
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Table 1,
Clinical Profile of the Patients Number M/F Age (yr) Duration (months) Total dosage of glucocorticoids (mg) Time required for postoperative weaning (days)
Total
Aged 30yr
54 23/31 30.4 _+ 1.7 (13-58) 39.3 _+ 5.0 (0.5-158) 22,775 + 3,825 (310-171,500) 46.8 _+ 5.1 (5-161)
29 12/17 21.2 _+ 0.9 (13-29) 28.1 + 4.4 (0.5-96) 17,936 +_ 3,622 (727-78,540) 45.2 _+ 5.6 (5-99)
25 11/14 41.4 _+ 1.8 (30-58) 52.2 _+ 9.1 (0.5-158) 28,389 __.7,136 (310-171,500) 39.1 _+ 6.3 (6-97)
Numbers in parentheses show the ranges. Data are given as the mean _+ SEM.
withdrawal was similar in both groups, as were the time required to withdraw glucocorticoid therapy and the incidence of withdrawal symptoms. The preoperative steroid-related complications are summarized in Table 2. The incidence of major complications was similar in both groups, although a higher incidence of cataract and growth retardation was noted in the under-30 patients. Minor steroid complications were also quite similar in both groups. There was no relationship between incidence of complications and the dose or duration of glucocorticoid therapy.
REVIEW OF STEROID-RELATED COMPLICATIONS The beneficial anti-inflammatory effect of glucocorticoid therapy is beyond dispute, but, since virtually every body tissue contains glucocorticoid receptors 5, 6 and is a potential target for these hormones, numerous unwanted toxic effects may also occur in patients taking these drugs. Two main categories of adverse reactions occur in relation to glucocorticoid therapy: those resulting from drug withdrawal and those due to high-dose treatment. There is a characteristic corticosteroid withdrawal syndrome that consists of fever, myalgia, arthralgia, and malaise, but this is sometimes difficult to diagnose and may be mistaken for rheumatoid disease or rheumatic fever.: Prolonged corticosteroid therapy may result in suppression of the pituitaryadrenal axis, and its recovery to normal may require up to nine months in some patients, s During this recovery period and even afterwards, the patient may need to be protected during stressful situations, such as surgery or severe infection by the prophylactic administration of corticosteroids. In
Table 2.
Steroid Side Effects Patients Aged Under 30 yr Major Side Effects
13 (44.8)
Osteoporosis Osteonecrosis Cataract Glaucoma
10 (34.4) 1 (3.4) 5 (17.2) 1 (3.4)
Growth retardation Hypertension Diabetes Myopathy Neuropathy Hearing disturbance
Minor Side Effects
25 (86.2)
Moon face Acne Striae cutis Other skin lesions 2 (6.9) Edema
22 (75.9) 17(58.6) 18 (62.1) 2 (6.9)
2 (6.9) Dysmenorrhea 0 (0.0) Hypertrichosis 3(10.3) Headache 2 (6.9)Insomnia 1 (3.4) Others
12 (70.6)
4 (13.8)
10 (34.5) 2 (6.9) 1 (3.4) 1 (3.4)
Patients Aged 30 yr or Older Major Side Effects
14 (56.0)
Minor Side Effects
Osteoporosis Osteonecrosis Cataract Glaucoma
8 (32.0) 2 (8.0) 1 (4.0) 0 (0.0)
Moon face Acne Striae cutis Other skin lesions Edema
Growth retardation Hypertension Diabetes Myopathy Neuropathy Hearing disturbance Thrombosis
--
1 (4.0) Dysmenorrhea 2 (8.0) Hypertrichosis 2 (8.0) Headache 1 (4.0) Insomnia 0 (0.0) Others 0 (0.0)
Numbers in parentheses show percentages.
20 (80.0) 20 10 12 0
(80.0) (40.0) (48.0) (0.0)
1 (4.0) 8(32.0) 8 (32.0) 5 (20.0) 1 (4.0) 1 (4.0)
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addition to pituitary-adrenal axis suppression, the principal complications resulting from prolonged corticosteroid therapy are hypertension, hyperglycemia, immunosuppression, peptic ulcer, osteoporosis, myopathy, behavioral disturbances, posterior subcapsular cataract, growth inhibition, and Cushing's syndrome. 6' 9 Young patients seem to be especially at risk of developing certain major complications such as growth inhibition, osteoporosis, and cataracts.
Growth Inhibition The stunting of growth in children with UC on steroid therapy is considerably more severe than would be expected owing to the underlying disease and occurs even in those on low-dose continuous regimens; it is apparently due to an adverse effect on epiphyseal growth. 1~ Modifications of growth hormone metabolism may play a role in the etiology of this problem, but several studies have failed to show any increase in growth when exogenous growth hormone was given to dwarfed children on glucocorticoid therapy. TM 12 Inhibition of growth is related to a rather widespread inhibitory effect of glucocorticoids on DNA synthesis and cell division, which can adversely affect the liver, gastric mucosa, brain, lungs, and epidermis. 9 Corticosteroids do not characteristically produce the bone marrow depression or enteritis that follows exposure to human-specific antimitotic agents. Growth inhibition caused by glucocorticoids may be lessened by an alternate-day schedule of administration, and withdrawal of the drug plus adequate dietary supplementation will induce a period of accelerated "catch-up" growth if the epiphyses have not yet closed. 13' 14 The importance of withdrawing steroids at a stage that will still enable the young patient to achieve normal somatic growth is self-evident.
Osteoporosis and Osteonecrosis Osteoporosis and vertebral compression fractures are frequent and serious complications, of corticosteroid therapy, with the ribs and vertebrae generally being the bones most severely affected. Growing children with their high bone turnover rate and postmenopausal women seem to be more susceptible to glucocorticoid-induced bone loss.15.16 The development of osteopenia seems to be the cumulative result of two major effects: a
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profound inhibition of osteoblast activity and proliferation as well as a reduction of intestinal calcium absorption. Glucocorticoids also cause an increase in the secretion of parathyroid hormone, which stimulates osteoclast activity, so that both decreased formation and increased bone resorption occur in patients on chronic steroid therapy.9,15 Corticosteroids also increase renal Ca 2+ excretion. 9 Administration of calcium or vitamin D has been attempted to counteract this, but the results have been controversial, 17 19 perhaps partly owing to the previous lack of accurate noninvasive methods for the measurement of cortical and trabecular bone density. The development of quantitative computed tomography for the i n v i v o measurement of bone density2~ may therefore contribute to a clarification of the effects of supplementation with vitamin D and calcium in these patients. The degree of reversibility of glucocorticoid-induced osteoporosis is also uncertain, and further investigations are necessary, but it seems that alternate-day drug administration may reduce the severity of the osteoporosis. It has been reported that deflazacort, a prednisolone derivative, may exert a bone-sparing action while maintaining a good anti-inflammatory effect,21 but studies in a larger population are needed to confirm this. Aseptic bone necrosis (osteonecrosis) may develop during long-term glucocorticoid therapy; the femoral head is most often involved, and the damage is permanent. = The mechanism of this adverse effect is not known at present. 9 Myopathy Steroid myopathy is characterized by weakness of the proximal musculature of the limbs and the trunk and has been comprehensively reviewed by Ellis 23and Knox e t al. 24 The maintenance of normal skeletal muscle function requires an adequate corticosteroid level, but excessive doses of either mineralocorticoids or glucocorticoids lead to adverse effects, which appear to be secondary to circulatory dysfunction. In contrast, abnormalities in plasma electrolytes and carbohydrate metabolism in adrenocortical insufficiency produce only a minor impairment of skeletal muscle function. 9 Steroid myopathy may occur soon after the start of treatment and may be sufficiently severe to prevent ambulation. It is a serious complication and is thought to be an indication for the withdrawal of therapy.
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Recovery from such myopathy is usually slow and incomplete.
Cataract In 1960, Black e t a / . 25 first reported the occurrence of posterior subcapsular cataract associated with long-term drug administration. They found that the dosage and duration of steroid therapy were directly related to the development of such cataracts. However, there has been disagreement in the subsequent literature on this subject. 26-3~ Interpretation of the reported data is often difficult, since even within patient groups there may be variations regarding the duration of treatment, the regimen used for glucocorticoid administration (intermittent or continuous), and the underlying disease. There does seem to be general agreement, however, on the fact that younger patients tend to develop posterior subcapsular cataracts at lower steroid doses and within a shorter time period than older individuals. Posterior subcapsular cataracts in children receiving steroid therapy have been reported by Levine and Leopold, 3I who found that the majority of rheumatoid arthritis patients treated with 20 mg/day of prednisone for four years developed cataracts. Serious visual impairment due to glucocorticoid-induced posterior subcapsular cataracts is rare because the opacity tends to progress slowly. Slitlamp examination at six-month intervals should detect the patients at risk, enabling a decision to be made on the continuation of glucocorticoid therapy. Reversal of Grade I cataracts has been reported after the discontinuation of glucocorticoid administration. 29
Dis Colon Rectum, October 1992
ing's syndrome and hypertension is frequently lacking.32 34 Glucocorticoids have been reported to antagonize hypertension due to mineralocorticold. 35 Mineralocorticoid-induced hypertension can be treated by using diuretics to reduce Na + retention. 9 Hypertension is observed in most patients with Cushing's syndrome < 9 and also occurs after administration of glucocorticoids, which lack mineralocorticoid activity.36 38 This glucocorticoidinduced hypertension has not been well explained, but both Na+ retention and changes in circulatory hemodynamics may play a role. Natriuresis is often not useful for treating hypertension in patients with primary aldosteronism, and the plasma renin activity has been reported to be normal or increased in glucocorticoid-induced hypertension. 34 Glucocorticoids are essential for maintaining the integrity and responses of the microcirculation.5 They also influence the handling of a number of electrolytes, such as potassium and calcium, and generally enhance the response to ~-adrenergic stimulation. 6 Hypertension is common in patients receiving glucocorticoid therapy and has been reported to occur in 20 percent of patients with iatrogenic Cushing's syndrome.39 We have found no reports mentioning a higher incidence of this complication in pediatric patients compared with adults. Etheridge and Hoch-Ligeti4~ reported that an eight-year-old child who had been treated with glucocorticoid had extensive lipid deposits in the intimal layer of the aorta. These findings suggested a relationship between glucocorticoids and atherosclerosis, which might also be a factor in the development of hypertension. N e u r o p s y c h i a t r i c Effects
Hypertension The most striking effects of corticosteroids on the cardiovascular system are the consequence of changes in the regulation of renal Na+ excretion. 9 These effects are actually observed more particularly in hypocorticoidism, where a reduction in blood volume accompanied by an increase in viscosity can lead to hypotension and cardiovascular collapse. 6 Corticosteroids exert important actions on various elements of the circulatory system, including the capillaries, the arterioles, and the myocardium. An excess of mineralocorticoids produces hypertension, hypopotassemia, and suppressed renin activity. However, evidence of mineralocorticoid excess in patients with spontaneous Cush-
Psychologic disturbance may be associated with both glucocorticoid excess and deficiency.6 Administration of glucocorticoids can cause mental disturbances ranging from agitation, insomnia, and mood changes to manic-depressive psychosis or schizophrenic type. 9 Depression is the most common manifestation seen in spontaneous Cushing's syndrome, whereas an elevation of mood or frank euphoria is common in iatrogenic Cushing's syndrome. 33 It is no longer believed that a previous history of psychiatric problems predisposes a patient to developing such disturbances during glucocorticoid therapy, and conversely the absence of a psychiatric history is no guarantee against the occurrence of glucocorticoid psychosis. 41 The brain appears to be a direct target of gluco-
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corticoids, and the concentration of specific receptors varies in different brain regions, with high concentrations being found in the hippocampus and to a lesser extent in the amygdala and cortex. 42 It is likely that the effects of corticosteroids on fluid and electrolyte balance and on other parameters may also influence the changes observed in the central nervous system. The effects of steroids on the brain have been reported to include depletion of 3,-aminobutyric acid, 5 inhibition of myelination, 6 and changes in the electroencephalogramY A classic glucocorticoid-related manifestation affecting the central nervous system in pediatric patients is pseudotumor cerebriY' 43 The pathogenesis of this rare condition is unknown, but it has been related to cerebral edema resulting from various other effects of glucocorticoid therapy.
Gastrointestinal Effects It is not clear why patients with Addison's disease almost always have nausea and rather vague gastrointestinal symptoms. They are not associated with gastrointestinal ulcers, and some investigators have suggested that chronic peptic ulcer is quite rare in patients with Addison's disease. 6 Trethewie 44 suggested an influence on gut smooth muscle contractility. Cushing's syndrome has been implicated as causing an increased incidence of peptic ulcer. 45 However, most studies have been performed on iatrogenic Cushing's syndrome, and in fact a review of the literature suggests that an increased association has not been substantiated. 6 Despite the lack of documentation of an increased incidence of gastric ulcer in humans, animal studies have convincingly shown an increase in acid secretion associated with peptic ulceration related to glucocorticoid therapy. 46'4v Loeb and Sternschein 4u reported that there was a marked suppression of thymidine incorporation into gastric mucosal DNA within 24 hours of glucocorticoid administration, whereas this decrease was not observed in the jejunal mucosa. It thus seems likely that glucocorticoids have a catabolic effect on the stomach, and this may explain the development of gastric ulcers in animals. It is also unknown whether there is an interaction between glucocorticoids and nonsteroidal anti-inflammatory drugs, such as aspirin, which can themselves cause ulcers. Messer e t a L 49 reported from a survey of the literature that steroid therapy approximately doubled the risk of ulceration.
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Glucocorticoid therapy has also rarely been associated with pancreatitis. 33 Whether this is due to obstruction of the outflow of pancreatic secretions or to catabolism of cells and the subsequent release of enzymes has not been established. 6 CONCLUSIONS For the past three decades, the clinical use of adrenal glucocorticoids has been a valuable method of symptomatic relief for many diseases, including UC. Steroid therapy influences so many metabolic processes that it is perhaps surprising that an adrenalectomized patient, who is given salt repletion and protected from stressful situations, usually only experiences vague symptoms and does not become acutely ill. 6 This fact implies that the role of the adrenal cortex in the fine-tuning of metabolic processes is less important under normal circumstances than that of some other hormones. Glucocorticoids generally require several hours to elicit a maximum response. 9 Physicians have traditionally thought in terms of too much or too little of a hormone and have categorized endocrine diseases as those with an excess or deficiency of a particular hormone. It may be possible that glucocorticoid hyperresponsiveness plays a more subtle role in various disease processes. The precise mechanisms of glucocorticoid activity are not yet known, but serious side effects secondary to its prolonged use may occur in various situations. The literature shows general agreement as to the higher incidence of osteoporosis and cataract in children. In our series, the younger patients also developed these complications. The severity of glucocorticoid side effects was the main indication for surgical treatment in our UC patients, since the underlying disease itself was in a state of remission. When treating children, though, we feel that it is also most important to give consideration to the poorer overall prognosis and the higher risk of future colonic malignancy when deciding on further therapy. Careful follow-up examinations for the early detection of patients at risk and more interdisciplinary consultation may help to determine the best treatment modality, which remains an individual decision for every UC patient. No definite criteria can be offered to indicate which patients are better managed medically, and many different aspects of the disease and therapy must be taken into account. The introduction of restorative proctocolectomy and ileoanal anastomosis allows the maintenance
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of satisfactory anorectal function and avoids a perm a n e n t stoma. 5~ 5~ T h e s e p r o c e d u r e s are u s e d with increasing f r e q u e n c y for UC patients, w h o can thus b e freed from steroid therapy and the risk of carcinoma. For s o m e y o u n g patients, early surgery m a y offer m o r e than it a p p a r e n t l y sacrifices t h r o u g h avoiding the complications of steroid therapy.
REFERENCES 1. Ehrenpreis T, Ericsson NA. Surgical treatment of ulcerative colitis in childhood. Surg Clin North Am 1964;44:1521-36. 2. Ein SH, Lynch MJ, Stephens CA. Ulcerative colitis in children under one year: a twenty-year review. J Pediatr Surg 1970;6:264-71. 3. Utsunomiya T, Shinohara H, Suzuki K, Kitahora T, Takanami I, Yokota A. Surgical treatment of ulcerative colitis in Japan: an epidemiological investigation. J Jpn Soc Colo-Proctol 1989;42:64-75. 4. Sachar DB. Colectomy in ulcerative colitis. In: Bayless TM, ed. Current management of inflammatory bowel disease. Philadelphia: BC Decker, 1983: 100-3. 5. David DS, Grieco MH, Cushman P Jr. Adrenal glucocorticoids after twenty years: a review of their clinically relevant consequences. J Chronic Dis 1970;22:637-711. 6. Baxter JD. Glucocorticoid hormone action. Pharmacol Ther 1976;2:605-59. 7. Amatruda TT Jr, Hollingsworth DR, D'Esopo ND, Upton GV, Bondy PK. A study of the mechanism of the steroid withdrawal syndrome. J Clin Endocrinol Metab 1960;20:339-54. 8. Graber AL, Ney RE, Nicholson WE, Island DP, Liddle GW. Natural history of pituitary adrenal recovery following long term suppression with corticosteroids. J Clin Endocrinol Metab 1965;25:11-6. 9. Haynes RC Jr. Adrenocorticotropic hormone; adrenocortical steroids and their synthetic analogs; inhibitors of the synthesis and actions of adrenocortical hormones. In: Gilman AG, Rail IW, Nies AS, Taylor P, eds. The pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:1431-62. 10. Falliers CJ, Tan LS, Szentivanyi J, Jorgensen JR, Bukantz SC. Childhood asthma and steroid therapy as influences on growth. Am J Dis Child 1963;105: 127-37. 11. Morris HG, Jorgenson JR, Elrich H, Goldsmith RE, Subryan VL. Metabolic effects of human growth hormone in corticosteroid treated children. J Clin Invest 1968;47:436-51. 12. Soyka LF, Zinskind A, Crawford JD. Treatment of short stature in children and adolescents with human
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pituitary growth hormone. N Engl J Med 1964;271: 754-64. Boldgett FM, Burgin L, Iezzoni D, Gribetz D, Talbot NB. Effects of prolonged cortisone therapy on the statural growth, skeletal maturation and metabolic status of children. N Engl J Med 1954;254:636-41. Prader A, Tanner JM, Von Harnack GA. Catch-up growth following illness or starvation: an example of developmental canalization in man. J Pediatr 1963;62:646-59. Feldman D, Krishman AV. Glucocorticoid effects on calcium metabolism and bone in the development of osteopenia. In: Christiansen C, Johansen JS, Riis BJ, eds. Osteoporosis 1987. Denmark: Osteopress ApS, 1987:1006-13. Saville PD, Kharmosh O. Osteoporosis of rheumatoid arthritis: influence of age, sex and corticosteroids. Arthritis Rheum 1967;10:423-30. Rickers H, Deding AA, Christiansen C, R~dbro P. Mineral loss in cortical and trabecular bone during high-dose prednisone treatment. Calcif Tissue Int 1984;36:269-73. Bianchi ML, Bardare M, Borzani M, Nogara A, Soldati L, Biondelli G. Bone derangement in juvenile rheumatoid arthritis. In: Christiansen C, Johansen JS, Riis BJ, eds. Osteoporosis 1987. Denmark: Osteopress ApS, 1987:1041-3. Van Berkum FN, Pols HA, Braun JJ, Heysteeg M, Kooij PP, Birkenh~iger JC. Glucocorticoid induced bone loss and treatment with 1-alpha-hydroxyvitamin D3: a placebo-controlled double blind trial. In: Christiansen C, Johansen JS, Riis BJ, eds. Osteoporosis 1987. Denmark: Osteopress ApS, 1987: 1033-6. Genant HR, Cann CE, Ettinger B, Gordan GS. Quantitative computed tomography of vertebral spongiosa, a" sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med 1982;97: 699-7O5. Devogelaer JP, Huaux JP, Dufour JP, Esselinckx W, Stasse P, Nagant de Deuxchaisnes C. Bone-sparing action of deflazacort versus equipotent doses of prednisone: a double-blind study in males with rheumatoid arthritis. In: Christiansen C, JohansenJS, Riis BJ, eds. Osteoporosis 1987. Denmark: Osteopress ApS, 1987:1014-5. Zizic TM, Marcoux C, Hungerford DS, Stevens MB. Corticosteroid therapy associated with ischemic necrosis of bone in systemic lupus erythmatosus. Am J Med 1985;79:576-604. Ellis EF. Steroid myopathy. J Allergy Clin Immunol 1985;76:431-2. Knox AJ, Mascie-Taylor BH, Muers MF. Acute hydrocortisone myopathy in severe asthma. Thorax 1986; 41:411-2.
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25. Black RC, Oglesby RB, Von Sallman L. Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis. JAMA 1960;174: 166-71. 26. Skarka HW, Prchal JT. Effect of corticosteroids on cataract formation. Arch Ophthalmol 1980;98: 1773-7. 27. Braver DA, Richards RD, Good TA. Posterior subcapsular cataracts in corticosteroid-treated children. J Pediatr 1966;69:735-8. 28. Sevel D, Weinberg EG, Van Neikerk CH. Lenticular complications of long term steroid therapy in children with asthma and eczema. J Allergy Clin Immunol 1977;60:215-7. 29. Forman AR, Loreto JA, Tina LU. Reversibility of corticosteroid-associated cataracts in children with the nephrotic syndrome. Am J Ophtha!mol 1977;84: 75-8. 30. Urban RC Jr, Cotlier E. Corticosteroid-induced cataracts. Surv Ophthalmol 1986;31:102-10. 31. Levine SB, Leopold IH. Advances in ocular corticosteroids. Med Clin North Am 1973;57:1191-201. 32. Crane MG, Harris JJ. Deoxycorticosterone secretion rates in hyperadrenocorticism. J Clin Endocrinol 1966;26:1135-44. 33. Christy NP. The human adrenal cortex. New York: Harper & Row, 1971:395-425. 34. Krakoff L, Nicolis G, Amsal B. Pathogenesis of hypertension in Cushing's syndrome. Am J Med 1975; 58:216-20. 35. Friedman SM, Friedman CL, Nakashima M. Action of cortisone on cardiovascular-renal effects of deoxycorticosterone acetate. Am J Physiol 1950;163: 319 25. 36. Mendlowitz M, Naftchi N, Weinreb H, Gitlow SE. Effect of prednisone on digital vascular reactivity in normotensive and hypertensive subjects. J Appl Physiol 1961;16:89-102. 37. Brunner HR, Chang P, Wallace R, Sealey JE, Laragh JH. Angiotensin II vascular receptors. J Clin Invest 1972;51:58-67. 38. Yard AC, Kadowitz PJ. Studies on the mechanism of hydrocortisone potentiation of vasoconstrictor responses to epinephrine in the anesthetized animal.
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EurJ Pharmacol 1972;20:1-9. 39. Treadwell BL, Sever ED, Savage O, Copeman WS. Side-effects of long term treatment with corticosteroids and corticotropin. Lancet 1964;1:1121-3. 40. Etheridge EM, Hock-Ligeti C. Lipid deposition in aortas in younger age groups following cortisone and adrenocorticotropic hormone. Am J Pathol 1951; 28:315-20. 41. Lewin DA, Smith RE. Steroid-induced psychiatric syndromes. J Affective Disord 1983;5:319-22. 42. McEwen BS, Denef CJ, Gerlach JH, et al. Chemical studies of the brain as a steroid hormone target tissue. In: Schmitt FO, Worren FG, eds. The neurosciences. Third study program. Hong Kong: Colonial Press, 1974:599-619. 43. Walker AE, Adamkiewicz JJ. Pseudotumor cerebri associated with prolonged corticosteroid therapy. JAMA 1964;188:779-84. 44. Trethewie ER. Cortisone and anaphylaxis. J Exp Biol Med Sci 1958;36:275-83. 45. Cooke AR. The stomach and duodenum. In: Sleidinger MM, Fordtran JS, eds. Gastrointestinal disease. Philadelphia: WB Saunders, 1973:644-56. 46. Nicholoff DM. Effect of cortisone and corticotropin on gastric secretion and peptic ulceration in the dog. Arch Surg 1969;98:640-4. 47. Okabe S, Saziki R, Takagi K. Cortisone acetate and stress on the healing process of chronic gastric ulcer in rats. J Appl Physiol 1971;30:793-6. 48. Loeb JN, Sternschein MJ. Suppression of thymidine incorporation into the gastric mucosa of cortisonetreated rats, possible relation to glucocorticoid-induced gastric ulceration. Endocrinology 1973;92: 1322-7. 49. Messer J, Reitman D, Sacks HS, Smith H Jr, Chalmers TC. Association of adrenocorticosteroid therapy and peptic ulcer disease. N Engl J Med 1983;309:21-4. 50. Utsunomiya J, Yamamura T, Kusunoki M, Iwama T. The current technique of ileoanal anastomosis. Dig Surg 1988;5:207-14. 51. Dozois RR, Kelly KA, Welling DR, et al. Ileal pouchanal anastomosis: comparison of results in familial adenomatous poIyposis and chronic ulcerative colitis. Ann Surg 1989;210:268 73.
Lee E. Smith, M.D., Editor
Steroid Complications in Patients with Ulcerative Colitis Masato Kusunoki, M.D.,* Gabriela M6eslein, M.D.,* Yasutsugu Shoji, M.D.,* Shinsuke Fujita, M.D.,* Hidenori Yanagi, M.D.,* Youichirou Sakanoue, M.D.,* Naoaki Saito, M.D.,-~ Joji Utsunomiya, M.D.* From the *2nd Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan and the afDepartment of Pharmacology, Kobe University, School of Medicine, Kobe, Japan Physicians treating patients with ulcerative colitis are confronted with the difficult task of deciding whether medical or surgical treatment is best for their patients. There are no definitive criteria to indicate when medical therapy should be exchanged for definitive surgery. Even in patients who respond well to glucocorticoid treatment, the side effects of these drugs may necessitate surgery. We reviewed the steroid complications of our operative cases retrospectively. Although ulcerative colitis was usually in remission, severe steroid complications were no longer tolerable and definitive surgery was required. We also reviewed the literature regarding the adverse effects of steroid. Because of advances in sphincter-preserving surgery, re-evaluation of the treatment of ulcerative colitis is necessary. Although conservative treatment remains the first choice, tolerance of irreversible side effects (especially in children) no longer seems to be justified. In such patients, early definitive surgery may offer more than it appears to sacrifice. [Key words: Ulcerative colitis; Glucocorticoid side effects; Sphincter-preserving ileoanal anastomosis] Kusunoki M, M6eslein G, Shoji Y, Fujita S, Yanagi H, Sakanoue Y, Saito N, UtsunomiyaJ. Steroid complications in patients with ulcerative colitis. Dis Colon Rectum 1992;35:1003-1009.
everal authors have reported a rising incidence of ulcerative colitis (UC) in younger age groups)' 2 This may be partly due to more sophisticated methods of detection of the disease and to a wider knowledge of the symptoms of inflammatory bowel disease, but it may also represent a genuine shift toward the earlier onset of UC. Conservative therapy using various anti-inflammatory agents is generally initiated at first. Among a total of 4,484 cases of UC reviewed in Japan, 14.3 percent had been treated surgically. 3 Because of toxic dilatation, perforation, obstruction, massive bleed-
ing, carcinoma, chronic failure to respond to medications, and severe complications of glucocorticoid therapy, 4 it is often difficult to determine when definitive surgery should be performed in UC patients undergoing prolonged medical treatment. Some aspects of this disease deserve special consideration in younger patients; e.g., glucocorticoid side effects may be more severe after prolonged medication in younger patients than in adults. To offer patients with UC the best treatment possible and the optimum quality of life, the early detection of patients at high risk of drug complications is necessary. Accordingly, we analyzed the steroid-related complications occurring in our UC patients prior to surgery and reviewed the outcome of prolonged steroid therapy in an attempt to define when surgery should be performed, especially in young patients with glucocorticoid complications.
S
Address reprint requests to Dr. Kusunoki: The 2nd Department of Surgery, Hyogo College of Medicine, 1-1 Mukogawa-cho Nishinomiya, 663 Japan.
GLUCOCORTICOID SIDE EFFECTS IN OUR UC PATIENTS Sixty-one patients with UC underwent total proctocolectomy and ileal J-pouch-anal anastomosis between November 1983 and September 1991 at the Second Department of Surgery at Hyogo College of Medicine in Japan. Detailed data on the preoperative medical treatment were available in 54 cases. Their clinical profiles are shown in Table 1. All the patients were treated with glucocorticoids. We divided them into a group 30 years old (Table 1). The total dose of steroids was lower in the under-30 group. However, the postoperative management of steroid 1003
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Table 1,
Clinical Profile of the Patients Number M/F Age (yr) Duration (months) Total dosage of glucocorticoids (mg) Time required for postoperative weaning (days)
Total
Aged 30yr
54 23/31 30.4 _+ 1.7 (13-58) 39.3 _+ 5.0 (0.5-158) 22,775 + 3,825 (310-171,500) 46.8 _+ 5.1 (5-161)
29 12/17 21.2 _+ 0.9 (13-29) 28.1 + 4.4 (0.5-96) 17,936 +_ 3,622 (727-78,540) 45.2 _+ 5.6 (5-99)
25 11/14 41.4 _+ 1.8 (30-58) 52.2 _+ 9.1 (0.5-158) 28,389 __.7,136 (310-171,500) 39.1 _+ 6.3 (6-97)
Numbers in parentheses show the ranges. Data are given as the mean _+ SEM.
withdrawal was similar in both groups, as were the time required to withdraw glucocorticoid therapy and the incidence of withdrawal symptoms. The preoperative steroid-related complications are summarized in Table 2. The incidence of major complications was similar in both groups, although a higher incidence of cataract and growth retardation was noted in the under-30 patients. Minor steroid complications were also quite similar in both groups. There was no relationship between incidence of complications and the dose or duration of glucocorticoid therapy.
REVIEW OF STEROID-RELATED COMPLICATIONS The beneficial anti-inflammatory effect of glucocorticoid therapy is beyond dispute, but, since virtually every body tissue contains glucocorticoid receptors 5, 6 and is a potential target for these hormones, numerous unwanted toxic effects may also occur in patients taking these drugs. Two main categories of adverse reactions occur in relation to glucocorticoid therapy: those resulting from drug withdrawal and those due to high-dose treatment. There is a characteristic corticosteroid withdrawal syndrome that consists of fever, myalgia, arthralgia, and malaise, but this is sometimes difficult to diagnose and may be mistaken for rheumatoid disease or rheumatic fever.: Prolonged corticosteroid therapy may result in suppression of the pituitaryadrenal axis, and its recovery to normal may require up to nine months in some patients, s During this recovery period and even afterwards, the patient may need to be protected during stressful situations, such as surgery or severe infection by the prophylactic administration of corticosteroids. In
Table 2.
Steroid Side Effects Patients Aged Under 30 yr Major Side Effects
13 (44.8)
Osteoporosis Osteonecrosis Cataract Glaucoma
10 (34.4) 1 (3.4) 5 (17.2) 1 (3.4)
Growth retardation Hypertension Diabetes Myopathy Neuropathy Hearing disturbance
Minor Side Effects
25 (86.2)
Moon face Acne Striae cutis Other skin lesions 2 (6.9) Edema
22 (75.9) 17(58.6) 18 (62.1) 2 (6.9)
2 (6.9) Dysmenorrhea 0 (0.0) Hypertrichosis 3(10.3) Headache 2 (6.9)Insomnia 1 (3.4) Others
12 (70.6)
4 (13.8)
10 (34.5) 2 (6.9) 1 (3.4) 1 (3.4)
Patients Aged 30 yr or Older Major Side Effects
14 (56.0)
Minor Side Effects
Osteoporosis Osteonecrosis Cataract Glaucoma
8 (32.0) 2 (8.0) 1 (4.0) 0 (0.0)
Moon face Acne Striae cutis Other skin lesions Edema
Growth retardation Hypertension Diabetes Myopathy Neuropathy Hearing disturbance Thrombosis
--
1 (4.0) Dysmenorrhea 2 (8.0) Hypertrichosis 2 (8.0) Headache 1 (4.0) Insomnia 0 (0.0) Others 0 (0.0)
Numbers in parentheses show percentages.
20 (80.0) 20 10 12 0
(80.0) (40.0) (48.0) (0.0)
1 (4.0) 8(32.0) 8 (32.0) 5 (20.0) 1 (4.0) 1 (4.0)
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addition to pituitary-adrenal axis suppression, the principal complications resulting from prolonged corticosteroid therapy are hypertension, hyperglycemia, immunosuppression, peptic ulcer, osteoporosis, myopathy, behavioral disturbances, posterior subcapsular cataract, growth inhibition, and Cushing's syndrome. 6' 9 Young patients seem to be especially at risk of developing certain major complications such as growth inhibition, osteoporosis, and cataracts.
Growth Inhibition The stunting of growth in children with UC on steroid therapy is considerably more severe than would be expected owing to the underlying disease and occurs even in those on low-dose continuous regimens; it is apparently due to an adverse effect on epiphyseal growth. 1~ Modifications of growth hormone metabolism may play a role in the etiology of this problem, but several studies have failed to show any increase in growth when exogenous growth hormone was given to dwarfed children on glucocorticoid therapy. TM 12 Inhibition of growth is related to a rather widespread inhibitory effect of glucocorticoids on DNA synthesis and cell division, which can adversely affect the liver, gastric mucosa, brain, lungs, and epidermis. 9 Corticosteroids do not characteristically produce the bone marrow depression or enteritis that follows exposure to human-specific antimitotic agents. Growth inhibition caused by glucocorticoids may be lessened by an alternate-day schedule of administration, and withdrawal of the drug plus adequate dietary supplementation will induce a period of accelerated "catch-up" growth if the epiphyses have not yet closed. 13' 14 The importance of withdrawing steroids at a stage that will still enable the young patient to achieve normal somatic growth is self-evident.
Osteoporosis and Osteonecrosis Osteoporosis and vertebral compression fractures are frequent and serious complications, of corticosteroid therapy, with the ribs and vertebrae generally being the bones most severely affected. Growing children with their high bone turnover rate and postmenopausal women seem to be more susceptible to glucocorticoid-induced bone loss.15.16 The development of osteopenia seems to be the cumulative result of two major effects: a
1005
profound inhibition of osteoblast activity and proliferation as well as a reduction of intestinal calcium absorption. Glucocorticoids also cause an increase in the secretion of parathyroid hormone, which stimulates osteoclast activity, so that both decreased formation and increased bone resorption occur in patients on chronic steroid therapy.9,15 Corticosteroids also increase renal Ca 2+ excretion. 9 Administration of calcium or vitamin D has been attempted to counteract this, but the results have been controversial, 17 19 perhaps partly owing to the previous lack of accurate noninvasive methods for the measurement of cortical and trabecular bone density. The development of quantitative computed tomography for the i n v i v o measurement of bone density2~ may therefore contribute to a clarification of the effects of supplementation with vitamin D and calcium in these patients. The degree of reversibility of glucocorticoid-induced osteoporosis is also uncertain, and further investigations are necessary, but it seems that alternate-day drug administration may reduce the severity of the osteoporosis. It has been reported that deflazacort, a prednisolone derivative, may exert a bone-sparing action while maintaining a good anti-inflammatory effect,21 but studies in a larger population are needed to confirm this. Aseptic bone necrosis (osteonecrosis) may develop during long-term glucocorticoid therapy; the femoral head is most often involved, and the damage is permanent. = The mechanism of this adverse effect is not known at present. 9 Myopathy Steroid myopathy is characterized by weakness of the proximal musculature of the limbs and the trunk and has been comprehensively reviewed by Ellis 23and Knox e t al. 24 The maintenance of normal skeletal muscle function requires an adequate corticosteroid level, but excessive doses of either mineralocorticoids or glucocorticoids lead to adverse effects, which appear to be secondary to circulatory dysfunction. In contrast, abnormalities in plasma electrolytes and carbohydrate metabolism in adrenocortical insufficiency produce only a minor impairment of skeletal muscle function. 9 Steroid myopathy may occur soon after the start of treatment and may be sufficiently severe to prevent ambulation. It is a serious complication and is thought to be an indication for the withdrawal of therapy.
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KUSUNOKI ET AL
Recovery from such myopathy is usually slow and incomplete.
Cataract In 1960, Black e t a / . 25 first reported the occurrence of posterior subcapsular cataract associated with long-term drug administration. They found that the dosage and duration of steroid therapy were directly related to the development of such cataracts. However, there has been disagreement in the subsequent literature on this subject. 26-3~ Interpretation of the reported data is often difficult, since even within patient groups there may be variations regarding the duration of treatment, the regimen used for glucocorticoid administration (intermittent or continuous), and the underlying disease. There does seem to be general agreement, however, on the fact that younger patients tend to develop posterior subcapsular cataracts at lower steroid doses and within a shorter time period than older individuals. Posterior subcapsular cataracts in children receiving steroid therapy have been reported by Levine and Leopold, 3I who found that the majority of rheumatoid arthritis patients treated with 20 mg/day of prednisone for four years developed cataracts. Serious visual impairment due to glucocorticoid-induced posterior subcapsular cataracts is rare because the opacity tends to progress slowly. Slitlamp examination at six-month intervals should detect the patients at risk, enabling a decision to be made on the continuation of glucocorticoid therapy. Reversal of Grade I cataracts has been reported after the discontinuation of glucocorticoid administration. 29
Dis Colon Rectum, October 1992
ing's syndrome and hypertension is frequently lacking.32 34 Glucocorticoids have been reported to antagonize hypertension due to mineralocorticold. 35 Mineralocorticoid-induced hypertension can be treated by using diuretics to reduce Na + retention. 9 Hypertension is observed in most patients with Cushing's syndrome < 9 and also occurs after administration of glucocorticoids, which lack mineralocorticoid activity.36 38 This glucocorticoidinduced hypertension has not been well explained, but both Na+ retention and changes in circulatory hemodynamics may play a role. Natriuresis is often not useful for treating hypertension in patients with primary aldosteronism, and the plasma renin activity has been reported to be normal or increased in glucocorticoid-induced hypertension. 34 Glucocorticoids are essential for maintaining the integrity and responses of the microcirculation.5 They also influence the handling of a number of electrolytes, such as potassium and calcium, and generally enhance the response to ~-adrenergic stimulation. 6 Hypertension is common in patients receiving glucocorticoid therapy and has been reported to occur in 20 percent of patients with iatrogenic Cushing's syndrome.39 We have found no reports mentioning a higher incidence of this complication in pediatric patients compared with adults. Etheridge and Hoch-Ligeti4~ reported that an eight-year-old child who had been treated with glucocorticoid had extensive lipid deposits in the intimal layer of the aorta. These findings suggested a relationship between glucocorticoids and atherosclerosis, which might also be a factor in the development of hypertension. N e u r o p s y c h i a t r i c Effects
Hypertension The most striking effects of corticosteroids on the cardiovascular system are the consequence of changes in the regulation of renal Na+ excretion. 9 These effects are actually observed more particularly in hypocorticoidism, where a reduction in blood volume accompanied by an increase in viscosity can lead to hypotension and cardiovascular collapse. 6 Corticosteroids exert important actions on various elements of the circulatory system, including the capillaries, the arterioles, and the myocardium. An excess of mineralocorticoids produces hypertension, hypopotassemia, and suppressed renin activity. However, evidence of mineralocorticoid excess in patients with spontaneous Cush-
Psychologic disturbance may be associated with both glucocorticoid excess and deficiency.6 Administration of glucocorticoids can cause mental disturbances ranging from agitation, insomnia, and mood changes to manic-depressive psychosis or schizophrenic type. 9 Depression is the most common manifestation seen in spontaneous Cushing's syndrome, whereas an elevation of mood or frank euphoria is common in iatrogenic Cushing's syndrome. 33 It is no longer believed that a previous history of psychiatric problems predisposes a patient to developing such disturbances during glucocorticoid therapy, and conversely the absence of a psychiatric history is no guarantee against the occurrence of glucocorticoid psychosis. 41 The brain appears to be a direct target of gluco-
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STEROID COMPLICATIONS IN UC
corticoids, and the concentration of specific receptors varies in different brain regions, with high concentrations being found in the hippocampus and to a lesser extent in the amygdala and cortex. 42 It is likely that the effects of corticosteroids on fluid and electrolyte balance and on other parameters may also influence the changes observed in the central nervous system. The effects of steroids on the brain have been reported to include depletion of 3,-aminobutyric acid, 5 inhibition of myelination, 6 and changes in the electroencephalogramY A classic glucocorticoid-related manifestation affecting the central nervous system in pediatric patients is pseudotumor cerebriY' 43 The pathogenesis of this rare condition is unknown, but it has been related to cerebral edema resulting from various other effects of glucocorticoid therapy.
Gastrointestinal Effects It is not clear why patients with Addison's disease almost always have nausea and rather vague gastrointestinal symptoms. They are not associated with gastrointestinal ulcers, and some investigators have suggested that chronic peptic ulcer is quite rare in patients with Addison's disease. 6 Trethewie 44 suggested an influence on gut smooth muscle contractility. Cushing's syndrome has been implicated as causing an increased incidence of peptic ulcer. 45 However, most studies have been performed on iatrogenic Cushing's syndrome, and in fact a review of the literature suggests that an increased association has not been substantiated. 6 Despite the lack of documentation of an increased incidence of gastric ulcer in humans, animal studies have convincingly shown an increase in acid secretion associated with peptic ulceration related to glucocorticoid therapy. 46'4v Loeb and Sternschein 4u reported that there was a marked suppression of thymidine incorporation into gastric mucosal DNA within 24 hours of glucocorticoid administration, whereas this decrease was not observed in the jejunal mucosa. It thus seems likely that glucocorticoids have a catabolic effect on the stomach, and this may explain the development of gastric ulcers in animals. It is also unknown whether there is an interaction between glucocorticoids and nonsteroidal anti-inflammatory drugs, such as aspirin, which can themselves cause ulcers. Messer e t a L 49 reported from a survey of the literature that steroid therapy approximately doubled the risk of ulceration.
1007
Glucocorticoid therapy has also rarely been associated with pancreatitis. 33 Whether this is due to obstruction of the outflow of pancreatic secretions or to catabolism of cells and the subsequent release of enzymes has not been established. 6 CONCLUSIONS For the past three decades, the clinical use of adrenal glucocorticoids has been a valuable method of symptomatic relief for many diseases, including UC. Steroid therapy influences so many metabolic processes that it is perhaps surprising that an adrenalectomized patient, who is given salt repletion and protected from stressful situations, usually only experiences vague symptoms and does not become acutely ill. 6 This fact implies that the role of the adrenal cortex in the fine-tuning of metabolic processes is less important under normal circumstances than that of some other hormones. Glucocorticoids generally require several hours to elicit a maximum response. 9 Physicians have traditionally thought in terms of too much or too little of a hormone and have categorized endocrine diseases as those with an excess or deficiency of a particular hormone. It may be possible that glucocorticoid hyperresponsiveness plays a more subtle role in various disease processes. The precise mechanisms of glucocorticoid activity are not yet known, but serious side effects secondary to its prolonged use may occur in various situations. The literature shows general agreement as to the higher incidence of osteoporosis and cataract in children. In our series, the younger patients also developed these complications. The severity of glucocorticoid side effects was the main indication for surgical treatment in our UC patients, since the underlying disease itself was in a state of remission. When treating children, though, we feel that it is also most important to give consideration to the poorer overall prognosis and the higher risk of future colonic malignancy when deciding on further therapy. Careful follow-up examinations for the early detection of patients at risk and more interdisciplinary consultation may help to determine the best treatment modality, which remains an individual decision for every UC patient. No definite criteria can be offered to indicate which patients are better managed medically, and many different aspects of the disease and therapy must be taken into account. The introduction of restorative proctocolectomy and ileoanal anastomosis allows the maintenance
KUSUNOKI E T AL
1008
of satisfactory anorectal function and avoids a perm a n e n t stoma. 5~ 5~ T h e s e p r o c e d u r e s are u s e d with increasing f r e q u e n c y for UC patients, w h o can thus b e freed from steroid therapy and the risk of carcinoma. For s o m e y o u n g patients, early surgery m a y offer m o r e than it a p p a r e n t l y sacrifices t h r o u g h avoiding the complications of steroid therapy.
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25. Black RC, Oglesby RB, Von Sallman L. Posterior subcapsular cataracts induced by corticosteroids in patients with rheumatoid arthritis. JAMA 1960;174: 166-71. 26. Skarka HW, Prchal JT. Effect of corticosteroids on cataract formation. Arch Ophthalmol 1980;98: 1773-7. 27. Braver DA, Richards RD, Good TA. Posterior subcapsular cataracts in corticosteroid-treated children. J Pediatr 1966;69:735-8. 28. Sevel D, Weinberg EG, Van Neikerk CH. Lenticular complications of long term steroid therapy in children with asthma and eczema. J Allergy Clin Immunol 1977;60:215-7. 29. Forman AR, Loreto JA, Tina LU. Reversibility of corticosteroid-associated cataracts in children with the nephrotic syndrome. Am J Ophtha!mol 1977;84: 75-8. 30. Urban RC Jr, Cotlier E. Corticosteroid-induced cataracts. Surv Ophthalmol 1986;31:102-10. 31. Levine SB, Leopold IH. Advances in ocular corticosteroids. Med Clin North Am 1973;57:1191-201. 32. Crane MG, Harris JJ. Deoxycorticosterone secretion rates in hyperadrenocorticism. J Clin Endocrinol 1966;26:1135-44. 33. Christy NP. The human adrenal cortex. New York: Harper & Row, 1971:395-425. 34. Krakoff L, Nicolis G, Amsal B. Pathogenesis of hypertension in Cushing's syndrome. Am J Med 1975; 58:216-20. 35. Friedman SM, Friedman CL, Nakashima M. Action of cortisone on cardiovascular-renal effects of deoxycorticosterone acetate. Am J Physiol 1950;163: 319 25. 36. Mendlowitz M, Naftchi N, Weinreb H, Gitlow SE. Effect of prednisone on digital vascular reactivity in normotensive and hypertensive subjects. J Appl Physiol 1961;16:89-102. 37. Brunner HR, Chang P, Wallace R, Sealey JE, Laragh JH. Angiotensin II vascular receptors. J Clin Invest 1972;51:58-67. 38. Yard AC, Kadowitz PJ. Studies on the mechanism of hydrocortisone potentiation of vasoconstrictor responses to epinephrine in the anesthetized animal.
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EurJ Pharmacol 1972;20:1-9. 39. Treadwell BL, Sever ED, Savage O, Copeman WS. Side-effects of long term treatment with corticosteroids and corticotropin. Lancet 1964;1:1121-3. 40. Etheridge EM, Hock-Ligeti C. Lipid deposition in aortas in younger age groups following cortisone and adrenocorticotropic hormone. Am J Pathol 1951; 28:315-20. 41. Lewin DA, Smith RE. Steroid-induced psychiatric syndromes. J Affective Disord 1983;5:319-22. 42. McEwen BS, Denef CJ, Gerlach JH, et al. Chemical studies of the brain as a steroid hormone target tissue. In: Schmitt FO, Worren FG, eds. The neurosciences. Third study program. Hong Kong: Colonial Press, 1974:599-619. 43. Walker AE, Adamkiewicz JJ. Pseudotumor cerebri associated with prolonged corticosteroid therapy. JAMA 1964;188:779-84. 44. Trethewie ER. Cortisone and anaphylaxis. J Exp Biol Med Sci 1958;36:275-83. 45. Cooke AR. The stomach and duodenum. In: Sleidinger MM, Fordtran JS, eds. Gastrointestinal disease. Philadelphia: WB Saunders, 1973:644-56. 46. Nicholoff DM. Effect of cortisone and corticotropin on gastric secretion and peptic ulceration in the dog. Arch Surg 1969;98:640-4. 47. Okabe S, Saziki R, Takagi K. Cortisone acetate and stress on the healing process of chronic gastric ulcer in rats. J Appl Physiol 1971;30:793-6. 48. Loeb JN, Sternschein MJ. Suppression of thymidine incorporation into the gastric mucosa of cortisonetreated rats, possible relation to glucocorticoid-induced gastric ulceration. Endocrinology 1973;92: 1322-7. 49. Messer J, Reitman D, Sacks HS, Smith H Jr, Chalmers TC. Association of adrenocorticosteroid therapy and peptic ulcer disease. N Engl J Med 1983;309:21-4. 50. Utsunomiya J, Yamamura T, Kusunoki M, Iwama T. The current technique of ileoanal anastomosis. Dig Surg 1988;5:207-14. 51. Dozois RR, Kelly KA, Welling DR, et al. Ileal pouchanal anastomosis: comparison of results in familial adenomatous poIyposis and chronic ulcerative colitis. Ann Surg 1989;210:268 73.
