Retroperitoneal fibrosis

Retroperitoneal Fibrosis Idiopathic retroperitoneal fibrosis was first described in 1905 by the French urologist Albarran. Retroperitoneal fibrosis became an established clinical entity in 1948 when Ormond reported two cases. [1] Since then, more than 500 cases have been reported in the literature. [2]

Various terms have been used to designate this disorder, including Ormond's disease, periureteritis fibrosa, periureteritis plastica, chronic periureteritis, sclerosing retroperitoneal granuloma and fibrous retroperitonitis. [3] In recent years, the condition has been known as retroperitoneal fibrosis, a term that more closely describes the actual pathologic process. Etiologically, retroperitoneal fibrosis is classified as a primary idiopathic disease or as a disease secondary to known causes. All identifiable causes of fibrosis must be excluded before the process can be considered idiopathic.

Sclerosing peritonitis, although not the same process as retroperitoneal fibrosis, was first identified in 1974 as a complication of treatment with the beta-adrenergic blocking agent practolol. [4] Subsequently, there have been additional reports, [5-10] primarily in European journals, of other beta-blocking agents causing retroperitoncal fibrosis.

Retroperitoneal fibrosis should be suspected in patients with unexplained abdominal pain and retroperitoneal lesions. The diagnosis is suggested by the history and physical examination, and the characteristic appearance of retroperitoneal fibrosis on excretory urography or retrograde pyelography.

Illustrative Case

A 34-year-old man was admitted to the hospital because of a three-week history of sharp low back pain radiating anteriorly in a girdle distribution. Nausea, vomiting and constipation were also present.

The patient's medical history was significant for hypertension of 16 years' duration. He had been taking metoprolol, 50 mg orally twice daily, for the past four years. He had smoked cigarettes (one and one-half packs per day) for 16 years, drank alcohol socially and denied the use of hallucinogenic drugs or methysergide.

Physical examination revealed a mildly obese man with a blood pressure of 120/96 mm Hg. Abdominal examination showed left-sided rigidity and tenderness on deep palpation, with no rebound tenderness. The straight-leg-raising test was negative. Bowel sounds were normoactive. The rest of the physical examination was unremarkable.

Laboratory studies showed a white blood cell count of 18,100 per [mm.sup.3] (18.1 X [10.sup.9] per L) with a normal differential. Blood chemistries, catecholamine studies and the 5-hydroxyindoleacetic acid level were within normal limits. Intravenous pyelography was unremarkable. Computed tomographic (CT) scanning of the abdomen revealed a retroperitoneal process involving the distal abdominal aorta (Figure 1). There were also well-Defined enlarged lymph nodes in the upper abdominal periaortic region. These findings were suggestive of lymphadenopathy, retroperitoneal fibrosis or a retroperitoneal inflammatory

process.

At laparotomy, a hard, well-vascularized mass was found around the abdominal aorta. The lesion was unresectable, but a biopsy specimen was obtained. There was no gross involvement of the ureters, and no other palpable mass was detected. Pathologically, the mass showed fragments of adipose tissue with interstitial fibroblastic proliferation and infiltration by lymphocytes and histiocytes (Figure 2). The lymph nodes showed reactive changes.

After a symptom-free postoperative intervl of one month, the patient was readmitted to the hospital because of recurrence of severe back and abdominal pain, vomiting and dehydration. The white blood cell count was 16,100 per [mm.sup.3] (16.1 X [10.sup.9] per L) with a normal differential; hemoglobin, 13.6 g per dL (136 g per L), and hematocrit, 40 percent (0.40). The erythrocyte sedimentation rate was 126 mm per hour.

Laboratory studies showed a blood urea nitrogen (BUN) level of 17 mg per dL (6.0 mmol per L) and creatinine of 3.6 mg per dL (320 [mu]mol per L). Intravenous pyelography revealed obstruction of the ureters with bilateral hydronephrosis (Figure 3).

Therapy with oral methylprednisolone, 1 mg per kg per day, was started, and bilateral stents were placed in the ureters. He responded dramatically, with the pain subsiding almost completely. Both the erythrocyte sedimentation rate and serum creatinine level gradually declined, to final values of 43 mm per hour and 1.1 mg per dL (100 [mu]mol per L), respectively. The patient was scheduled for a repeat laparotomy with possible ureterolysis, but moved from the area before surgery could be performed.

Pathology

Retroperitoneal fibrosis frequently envelopes the aorta, the vena cava and the ureters bilaterally. The process is usually located between the hilum of the kidney and the sacral promontory, with the center of the fibrotic plaque at the level of the fourth and fifth lumbar vertebrae, overlying the bifurcation of the abdominal aorta. The fibrotic process may extend along the common iliac arteries, may involve the root of the mesentery or may spread into the mediastinum through the diaphragm, causing mediastinal fibrosis. The psoas muscle may occasionally be involved. Encasement of the ureters tends to pull them toward the midline, with eventual progression to hydronephrosis and varying degrees of renal failure.

Grossly, retroperitoneal fibrosis appears as a glistening tan-to-gray, woody mass, predominantly dense-fibrous tissue consisting of collagen fibrils and fibroblasts. The earliest findings may include a subacute, nonspecific inflammatory reaction consisting of polymorphonuclear leukocytes, lymphocytes, plasma cells and eosinophils. Various forms of vasculitis, calcification and granuloma formation are frequent associated findings. [11]

Etilogy

In most instances, retroperitoneal fibrosis is idiophatic, with no etiologic factor found. Many causative agents have been identified, however, and it is necessary to exclude possible secondary causes of fibrosis (Table 1) before the process is considered idiopathic.

There is overwhelming evidence that long-term use of methysergide (Sansert), such as for migraine headache, causes retroperitoneal fibrosis. In 1966, Graham and colleagues [12] initially described the relationship between methysergide and retroperitoneal fibrosis. Other cases subsequently have been reported. The method by which ergot compounds induce retroperitoneal fibrosis is poorly understood. Methysergide and lysergic acid diethylamide (LSD), another ergot alkaloid, are strong competitive antagonists of serotonin and cause an increase in the amount of endogenous serotonin. Fibrosis is thought to be caused by serotonin nd its metabolites. There have also been reports of an association between retroperitoneal fibrosis and the use of methyldopa, analgesics (mainly phenacetin) nd amphetamines. [3]

The mechanism by which beta-adrenergic blocking agents induce fibrosis has not been identified. However, it is known that endogenous catecholamines reduce lysosomal leakage from phagocytes, thereby inhibiting inflammatory tissue damage. Beta-blocking agents may produce inflammatory changes that lead to fibrosis by interfering with the controlling role of endogenous catecholamines. [4]

Some investigators believe that any association between antihypertensive drugs and retroperitoneal fibrosis is coincidental rather than causal. [13] Retroperitoneal fibrosis may cause hypertension of renal origin. If retroperitoneal fibrosis remains undiagnosed, some patients with this disorder may be given beta-blocking agents to treat the hypertension. However, this did not appear to be the situation in the illustrative case. This patient's hypertension was present for 16 years before the diagnosis of retroperitoneal fibrosis was made, and the patient had been receiving metoprolol for four years. Moreover, at the time of the original work-up, there was no evidence of renal involvement. In the absence of another known causative agent, metoprolol may have been responsible for this patient's retroperitoneal fibrosis.

Diagnosis

Retroperitoneal fibrosis occurs most often in the fifth and sixth decades of life, but the condition has been described in patients as young as 15 years of age. [14] The male-to-female ratio is approximately 3:1. [15] Early symptoms are usually non-specific, and the correct diagnosis is often made only when obstructive uropathy leads to renal failure. Symptoms result from entrapment of the ureters, the gonadal blood vessels, aorta, vena cava and their branches, and the surrounding nerves. In the majority of patients, the presenting symptom is pain in the lumbosacral region and the lower aspect of the flanks. The pain radiates anteriorly to both lower quadrants of the abdomen, the periumbilical region or the testes. Insidious in onset, the pain is dull and noncolicky and is not altered by activity, body position or increasing intra-abdominal pressure. Pain becomes more severe as the disease progresses.

Later symptoms include oliguria and renal failure due to ureteral involvement; hydrocele and testicular pain due to gonadal vessel obstruction; hypertension due to renal artery occlusion; abdominal pain due to intestinal ischemia, and lower extremity edema from vena caval encasement. Aortic occlusion and insufficiency are rare, but they do occur. [16]

Laboratory tests are generally not diagnostic. An increased erythrocyte sedimentation rate and an elevated BUN level, with serum creatinine levels of varying degrees, are present either alone or in combination, depending on the stage of the fibrotic process. Polyclonal gammopathy with hypoalbuminemia and various thyroid autoantibodies, a positive Coombs' test and the presence of anti-smooth muscle antibodies are nonspecific laboratory findings. [15]

The most reliable diagnostic tests are radiologic examinations of the urinary tract. Intravenous pyelogram characteristically shows narrowing of the ureters at the L5 level, medial deviation of the ureters, and dilatation of the pelvicaliceal systems and ureters proximal to the obstruction. [17,18] However, these urographic findings are variable and nonspecific; asymmetric obstruction and medial positioning of the ureters at the level of L5 may be a normal variant. [18,19] Normal intravenous pyelography has also been reported [19,20] in patients with well-defined lesions (as in the illustrative case).

Ultrasonography and CT scanning of the abdomen have become valuable techniques for establishing the diagnosis of retroperitoneal fibrosis. However, neither the appearance of the mass nor localization permits definitive differentiation between benign lesions and malignancies such as lymphoma, sarcoma or metastatic adenopathy. [18,19,21] Thus, while the diagnosis of retroperitoneal fibrosis can be made on the basis of the history, physical examination and radiologic investigation, in many cases the diagnosis is not firmly established until surgical exploration is performed.

Treatment

Treatment of retroperitoneal fibrosis depends on the stage and the extent of the disease at the time of diagnosis. The goal of treatment is to conserve renal function by relieving renal obstruction and preventing further progression of fibrosis. If the patient has been taking any of the drugs listed in Table 1, the agent should be discontinued. This measure alone may result in gradual improvement if the patient has minimal renal impairment and obstruction. Sometimes, however, fibrosis continues to progress even after withdrawal of the offending agent. Patients with significant renal impairment benefit from placement of ureteral catheters and urinary decompression.

Exploratory laparotomy is indicated in all patients with suspected retroperitoneal fibrosis. After preliminary exploration, ureterolysis is performed, and the freed ureters may be transplanted to an intraperitoneal position. The ureters may also be transposed laterally, interposing retroperitoneal fat between them and the fibrous tissue, or they may be wrapped with omental fat. [22-24] If there is significant involvement of the great vessels, procedures to either free the vessels or bypass them should be performed. [22-24]

The use of corticosteroids in the treatment of retroperitoneal fibrosis is still a matter of controversy. Steroids are assumed to be effective in treating ureteral obstruction in the early edematous and inflammatory stage of the disease. Although reversal of established fibrosis cannot be achieved with steroids, further progression may be slowed.

Steroids are used with good results after ureterolysis and intraperitoneal transplantation. Oral or intravenous pulse therapy, such as methylprednisolone (Medrol, AmethaPred, Solu-Medrol, etc.) in a dosage of 40 mg per kg daily for three days (not to exceed 1 g per day), followed by 1 mg per kg per day for three months, has been used as primary treatment for retroperitoneal fibrosis in a few patients. [25] Medroxyprogesterone acetate (Provera), 1 g intramuscularly every two weeks for one year, followed by 1 g orally each month for 18 months, has been used to treat a female patient with recurrent retroperitoneal fibrosis, and the results were impressive. [26] In another instance, a six-week course of azathioprine (Imuran), 150 mg per day, has been used as an alternative therapy. [27]

Final Comment

Retroperitoneal fibrosis is an uncommon disorder that requires a high index of suspicion before the diagnosis can be made. In addition to various disorders and other drugs, beta-adrenergic blocking agents should be considered as a possible cause of retroperitoneal fibrosis once the diagnosis is made. The therapeutic goal is to preserve the function of the involved organs and prevent progression of the fibrotic process. In most cases, surgery is the treatment of choice. In mild cases, the outcome is good.

REFERENCES

[1] Ormond JK. Bilateral ureteral obstruction due to envelopment and compression by an inflammatory retroperitoneal process. J Urol 1948; 59:1072-9.

[2] van Niekerk JP. Diagnosis and management of retroperitoneal fibrosis. South Afr Med J 1982; 62(7):193-5.

[3] Persky L, Kursh ED, Feldman S, Resnick MI. Disease of retroperitoneum-retroperitoneal fibrosis. In: Walsh PC, ed. Campbell's Urology. 5th ed. Philadelphia: Saunders, 1986:595-601.

[4] Marshall AJ, Baddeley H, Barritt DW, et al. Practolol peritonitis. A study of 16 cases and a survey of small bowel function in patients taking beta adrenergic blockers. Q J Med 1977; 46:135-49.

[5] Johnson JN, McFarland J. Retroperitoneal fibrosis associated with atenolol [Letter]. Br Med J 1980; 280:864.

[6] Bullimore DW. Retroperitoneal fibrosis associated with atenolol [Letter]. Br Med J 1980; 281:59-60.

[7] Laakso M, Arvala I, Tervonen S, Sotarauta M. Retroperitoneal fibrosis associated with sotalol. Br Med J [Clin Res] 1982; 285:1085-6.

[8] Thompson J, Julian DG. Retroperitoneal fibrosis associated with metoprolol. Br Med J [Clin Res] 1982; 284:83-4.

[9] McClusky DR, Donaldson RA, McGeown MG. Oxprenolol and retroperitoneal fibrosis. Br Med J 1980; 281:1459-60.

[10] Pierce JR Jr, Trostle DC, Warner JJ. Propranolol and retroperitoneal fibrosis [Letter]. Ann Intern Med 1981; 95:244.

[11] Mitchinson MJ. The pathology of idiopathic retroperitoneal fibrosis. J Clin Pathol 1970; 23:681-9.

[12] Graham JR, Suby HI, LeCompte PR, Sadowsky NL. Fibrotic disorders associated with methysergide therapy for headache. N Engl J Med 1966; 274:359-68.

[13] Pryor JP, Castle WM, Dukes DC, Smith JC, Watson ME, Williams JL. Do beta-adrenoceptor blocking drugs cause retroperitoneal fibrosis? Br Med J [Clin Res] 1983; 287:639-41.

[14] Calder HL, McArthur JE, Allan DG, Prentice NG. Retroperitoneal fibrosis in childhood: case report and review. NZ Med J 1981; 94:213-5.

[15] Lepor H, Walsh PC. Idiopathic retroperitoneal fibrosis. J Urol 1979; 122:1-6.

[16] Shortland GJ, Archer TJ, Webster JH. Intermittent claudication caused by retroperitoneal fibrosis. Br J Surg 1986; 73:156-7.

[17] Arger PH, Stolz JL, Miller WT. Retroperitoneal fibrosis: an analysis of the clinical spectrum and roentgenographic signs. AJR 1973; 119:812-21.

[18] Fagan CJ, Larrieu AJ, Amparo EG. Retroperitoneal fibrosis: ultrasound and CT features. AJR 1979; 133:239-43.

[19] Brun B, Laursen K, Sorensen IN, Lorentzen JE, Kristensen JK. CT in retroperitoneal fibrosis. AJR 1981; 137:535-8.

[20] Creagh FM, Stone T, Stephenson TP, Lazarus JH. Retroperitoneal fibrosis with normal intravenous urogram. Postgrad Med J 1985; 61(712):183-4.

[21] Degesys GE, Dunnick NR, Silverman PM, Cohan RH, Illescas FF, Castagno A. Retroperitoneal fibrosis: use of CT in distinguishing among possible causes. AJR 1986; 146:57-60.

[22] Cooksey G, Powell PH, Singh M, Yeates WK. Idiopathic retroperitoneal fibrosis: a long-term review after surgical treatment. Br J Urol 1982; 54:628-31.

[23] Miles RM, Brock J, Martin C. Idiopathic retroperitoneal fibrosis. A sometime surgical problem. Am Surg 1984; 50(2):76-84.

[24] Tiptaft RC, Costello AJ, Paris AM, Blandy JP. The long-term follow-up of idiopathic retroperitoneal fibrosis. Br J Urol 1982; 54:620-4.

[25] Feild C, Arnold W, Gloster ES, Sharp G, Redman J. Steroid therapy as treatment for idiopathic fibrosis of the retroperitoneum and mediastinum. Pediatrics 1986; 78:936-8.

[26] Barnhill D, Hoskins W, Burke T, Weiser E, Heller P, Park R. The treatment of retroperitoneal fibromatosis with medroxyprogesterone acetate. Obstet Gynecol 1987; 70(3 Pt 2):502-4.

[27] Cogan E, Fastrez R. Azathioprine. An alternative treatment for recurrent idiopathic retroperitoneal fibrosis. Arch Intern Med 1985; 145:753-5.

NASIMULAHSAN, M.D. is a resident in family medicine at the Eastern Virginia Graduate School of Medicine, Norfolk, Va. After graduating from Chittagong Medical College, Chittagong, Bangladesh, Dr. Ahsan trained in pathology at the University of Maryland Hospitals in Baltimore and the Milton S. Hershey Medical Center, Hershey, Pa.

ALI A. CHOUDHURY, M.D. is director of the dialysis unit at Portsmouth (Va.) General Hospital and associate professor in the Department of Internal Medicine at Eastern Virginia Graduate School of Medicine. Dr. Choudhury is a graduate of Dhaka Medical College, Dhaka, Bangladesh. He received post-graduate training in Great Britain.

ALEXANDER BERGER, M.D. is director of the Portsmouth Family Medicine Center residency program at the Eastern Virginia Graduate School of Medicine and professor in the Department of Family and Community Medicine at Eastern Virginia Medical School, Norfolk. Dr. Berger graduated from the University of Zurich Medical School, Zurich, Switzerland, and received family practice training at District of Columbia General Hospital, Washington, D.C.

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