CORRESPONDENCETREATMENT OFMENSTRUATION-ASSOCIATEDRECURRENCE OFHEREDITARYPANCREATITIS WITHPHARMACOLOGICOVARIAN SUPPRESSION

To the Editor:Almost 30 years ago, it was recog-

nized that the exocrine pancreas is re-sponsive to estrogen. It has remainedunknown whether this observationhas clinical or pathophysiologic rele-vance beyond the occasional cases ofdrug-induced pancreatitis in womenwho take estrogen for hormone re-placement therapy or as oral contra-ceptives (1,2). We report a patientwho had a hereditary variety of thedisease, whose episodes of pancreati-tis closely paralleled her menstrualcycle over several years, and whose re-currence of pancreatitis dramaticallysubsided in response to pharmaco-logic ovarian suppression.

A 17-year-old girl was admitted toour outpatient department becauseof recurrent episodes of acute pancre-atitis that coincided with the onset ofher menstrual cycle. Over 4 years,these episodes of menstruation-asso-ciated pancreatitis (serum lipase level�3000 U/L) led to 14 hospital admis-sions, and they coincided with the 28-day menstrual cycle consistently dur-ing the last 5 months. The girl hadbeen adopted as an infant and was notrelated to her legal parents and sib-lings. Gynecological and ultrasoundexaminations revealed no abnormal-ities, and intra- or retroperitoneal en-dometriosis was excluded by diagnos-tic laparoscopy and computed to-mography. In the absence of otherrisk factors for pancreatitis and be-cause of her age, informed consentfor genetic testing was obtained. Amutation in the cationic trypsinogengene (PRSS1, R122H) that is com-monly associated with hereditarypancreatitis (3) was found. Because of

the strong association between theepisodes of pancreatitis and the onsetof menstruation, we sought to sup-press ovarian function with continu-ous pharmacological hormone ther-apy (0.03 mg of ethinylestradiol and 2mg of dienogest administered daily).

The patient reported no adverse ef-fects, and her menstrual cycles ceased.She continued hormone treatmentfor 3.5 months, which she thenstopped for personal reasons. Subse-quently, she experienced anothermild episode of pancreatitis (elevatedserum lipase level of 400 U/L) that didnot require hospitalization. After thisepisode, she resumed hormone treat-ment and has remained symptomfree.

Our patient suffers from hereditarypancreatitis, a genetically defined va-riety of the disease that is associatedwith germ line mutations in the cat-ionic trypsinogen gene (3,4). Due tothe mutation, trypsinogen is structur-ally altered, and pancreatitis attackscould be triggered in affected patientsby a stimulus that is physiologic forthe healthy pancreas but disease caus-ing in carriers of trypsinogen muta-tions (5). Estrogen, which is known toalter the response of the exocrinepancreas to physiologic and patho-logic stimuli (6), may explain theassociation between the onset ofmenstruation and the recurrence ofpancreatitis in our patient. A phar-macologic suppression of ovarianfunction, on the other hand, appearsto be a promising and safe treatmentstrategy in women with menstrua-tion-associated episodes of pancreati-tis.

Jorg Heinig, MDPeter Simon, MD

Frank Ulrich Weiss, PhDKlaus Peter Zimmer, MDWolfram Domschke, MD

Markus M. Lerch, MDWestfalische Wilhelms-Universitat

Munster, Germany

1. Pancreatitis from oral contraceptives [edi-torial]. BMJ. 1973;4:688 –689.

2. Parker WA. Estrogen-induced pancreatitis.Clin Pharm. 1983;2:75–79.

3. Whitcomb DC, Gorry MC, Preston RA, etal. Hereditary pancreatitis is caused by amutation in the cationic trypsinogen gene.Nat Genet. 1996;14:141–145.

4. Simon P, Weiss FU, Sahin-Toth M, et al.Hereditary pancreatitis caused by a novelPRSS1 mutation (Arg-122-Cys) that altersautoactivation and autodegradation of cat-ionic trypsinogen. J Biol Chem. 2002;277:5404 –5410.

5. Lerch MM, Gorelick FS. Trypsinogen acti-vation in acute pancreatitis. Med Clin NorthAm. 2000;84:549 –563.

6. Blevins GT Jr, McCullough SS, Wilbert TN,et al. Estradiol alters cholecystokinin stimu-lus-response coupling in rat pancreaticacini. Am J Physiol. 1998;275:G993–G998.

RETROPERITONEALFIBROSIS DUE TOWEGENER’SGRANULOMATOSIS: AMISDIAGNOSIS ASTUBERCULOSIS

To the Editor:Retroperitoneal fibrosis may occur

as an isolated finding or in associationwith drugs, medical conditions, suchas vasculitis (e.g., Wegener’s granulo-matosis), or infection (e.g., tubercu-losis). We report a case of retroperi-toneal fibrosis due to Wegener’sgranulomatosis that was mistaken fortuberculosis.

A 51-year-old man presented withabdominal pain, urinary symptoms,weight loss, and fever in October2000. Abdominal sonography and in-travenous urography showed a lefthydronephrosis with a nonsecretingkidney, and a compensating hyper-trophied right kidney. Retroperito-neal fibrosis sheathing the ureter wasdiscovered during a left nephrec-tomy. The pathological examinationshowed epithelioid granulomas withnecrosis, giant cells, and an infiltrateof lymphoepithelioid cells consistentwith a diagnosis of retroperitoneal fi-brosis–related tuberculosis. Serumcreatinine level was 106 �mol/L be-fore surgery and 95 �mol/L after sur-

164 ©2002 by Excerpta Medica, Inc. 0002-9343/02/$–see front matterAll rights reserved.

Table. Studies of Retroperitoneal Fibrosis in Wegener’s Granulomatosis

Study Author(Reference)

Age(years) Sex Symptoms

RetroperitonealFibrosis as First

Symptom Medical Therapy Urological Therapy Course

Middleton (2) 65 M Lower back pain, intermittentfever, urinary hesitancy,dribbling, nocturia, weightloss

No Cyclophosphamide Balloon dilatation,ureteral stent

Resolution of obstructivesyndrome within 4weeks; 9 months later,serum creatinine levelat 1.8 to 2 mg/dL;symptom free after 11months withouttherapy

Metselaar (3) 50 M Abdominal pain Yes Corticotherapy,cyclophosphamide

— Improvement of renalfunction; hemodialysisdiscontinued after 4months

Adelizzi (4) 30 M Pain in the right buttock and leg,nausea and vomiting,intermittent fevers, fatigue,weight loss

Yes Cyclophosphamide,corticotherapy

—

Leche (5) 37 F Anuria, intermittent fever,abdominal pain, fatigue

Yes Corticotherapy,cyclophosphamide

— Remission

ter Maaten (6) 49 M Persistent pain in the groin Yes Cyclophosphamide,corticotherapy

Ureterolysis Renal functiondeteriorated graduallyduring the following 7years; undergoingchronic intermittenthemodialysis

Baker (8) 60 F Fatigue, weakness, intermittentfever, sweats and chills

No Cyclophosphamide,corticotherapy

Transureteroureterostomy Remission

Le ThiHuong (9)

56 M Renal colic, hematuria No Corticotherapy,cyclophosphamide

— Alive, in remission 5 yearslater; persistentasymptomatic ureteralstenosis withouthydronephrosis

Le ThiHuong (9)

72 F Anuria No Corticotherapy,cyclophosphamide

Surgical therapy,double J stents

Stents removed after 2months; died 3 yearslater from acuterespiratory failure

F � female; M � male.

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gery. Antituberculous treatmentcomprising rifampicin, isoniazid,ethambutol, and pyrazinamid wasstarted. Three months later, he devel-oped a rapid, progressive oliguric re-nal insufficiency in his right kidney(serum creatinine, 500 �mol/L).Right percutaneous nephrostomyand ureteral catheterization usingdouble J stents were performed, with-out renal function improvement. Hewas then referred to the nephrologydepartment. Laboratory findingsshowed a C-reactive protein level of133 mg/L, a serum creatinine level of550 �mol/L, proteinuria of 2.5 g/d,and microscopic hematuria. A trans-jugular kidney biopsy specimen dis-closed a pauci-immune crescenticglomerulonephritis with necrotizingvasculitis. He had also developed ane-mia and dyspnea. Thoracic computedtomographic scan and bronchic en-doscopy evaluation showed an alveo-lar hemorrhage. A diagnosis of Wege-ner’s granulomatosis was made. Cy-toplasmic antineutrophil cytoplasmantibodies to proteinase 3 were de-tected in a titer of 1:320. The patientreceived methylprednisone (1 g/d)for 3 consecutive days and one cyclo-phosphamide pulse of 1000 mg, re-layed by prednisone (1 mg/kg/d) as-sociated with a monthly cyclophos-phamide pulse. One year later, renalfunction improved partially (serumcreatinine, 230 �mol/L; proteinuria,1 g/24 h, without hematuria).

Retroperitoneal fibrosis is uncom-mon, with a prevalence of 1 in100,000 persons. It leads to extensivefibrosis throughout the retroperito-neum, causing ureteric obstructionand hydronephrosis (1). Prostatitis isthe most common extrarenal uro-genital manifestation of Wegener’sgranulomatosis (2). Retroperitonealfibrosis may appear as the sole pre-liminary symptom of Wegener’sgranulomatosis (3– 6). In a report oftuberculosis associated with Wegen-er’s granulomatosis (7), tuberculosiswas localized in the lungs in one pa-tient and in the synovial fluid in an-other, but not in the retroperito-

neum. Urogenital complications ofWegener’s granulomatosis have beenshown to be sensitive to corticoste-roid and cyclophosphamide therapy(2– 6,8,9) (Table). However, a case ofWegener’s granulomatosis that re-sponded to antituberculous therapyhas been reported (10), suggestingthat antituberculous drugs such astrimethoprim-sulfamethoxazole mayeliminate causal or precipitatingagents in Wegener’s granulomatosis.

Awareness that retroperitoneal fi-brosis can be the sole preliminarysymptom of Wegener’s granuloma-tosis can prevent misdiagnosis, andhence improve therapeutic ap-proaches.

Hassane Izzedine, MDAude Servais, MD

Vincent Launay-Vacher, PharmDGilbert Deray, MD

Department of Nephrology,Pitie Salpetriere Hospital,

47-83 Boulevard de l’Hopital,75013 Paris, France

1. Amis ES. Retroperitoneal fibrosis. J Roent-genol. 1991;157:321–329.

2. Middleton G, Karp D, Lee E, Cush J. We-gener’s granulomatosis presenting aslower back pain with prostatitis and ure-teral obstruction. J Rheumatol. 1994;21:566 –569.

3. Metselaar HJ, ten Kate FJ, Weimar W.Ureter obstruction as a complication ofWegener’s granulomatosis. Eur Urol. 1985;11:63–64.

4. Adelizzi RA, Shockley FK, Pietras JR. We-gener’s granulomatosis with ureteric ob-struction. J Rheumatol. 1986;13:448 –451.

5. Leche J, Feuilhade C, Ferroir JP, et al. We-gener’s disease of urologic and neurologiconset in French. Ann Med Interne (Paris).1985;136:353.

6. ter Maaten JC, Franssen CFM, DaenekindtAA, Hoorntje SJ. Triple Wegener’s granu-lomatosis in the urogenital tract. Nephron.1993;63:358 –359.

7. Gordon C, Luqmani R, Fields P, et al. Twocases of “Wegener’s tuberculosis.” Br JRheumatol. 1993;32:143–149.

8. Baker SB, Robinson DR. Unusual renalmanifestations of Wegener’s granuloma-tosis. Report of two cases. Am J Med. 1978;64:883–889.

9. Le Thi Huong D, Papo T, Piette JC, et al.Monthly intravenous pulse cyclophospha-mide therapy in Wegener’s granulomato-sis. Clin Exp Rheumatol. 1996;14:9 –16.

10. Toyoshima M, Chida K, Suda T, et al. We-gener’s granulomatosis responding to an-tituberculous drugs. Chest. 2001;119:643–645.

RECENT-ONSETTUBERCULOUS PLEURISYPRESENTING ASPSEUDOCHYLOTHORAX

To the Editor:Pseudochylothorax is an uncom-

mon high-lipid pleural effusion thatusually arises from chronic pleurisyand requires several years to develop.Tuberculosis is the most frequent eti-ology. A rapid course is infrequentand has been described in associa-tion with rare infections. We reporta patient without a previous historyof tuberculosis who presented withpseudochylothorax of less than 8months’ development.

A 72-year-old man presented inJanuary 2000 with 4 months of pro-gressive dyspnea on exertion. Hesmoked, had a history of chronic ob-structive lung disease, and had under-gone laryngectomy in 1990. He de-nied having had tuberculosis or con-tact with Mycobacterium tuberculosis.A routine radiograph in January 1999had revealed a pseudonodular imagein the left thorax compatible withnipple shadow (Figure, left), and acontrol radiograph in April 1999 hadshowed minimal right pleural effu-sion (Figure, center).

On admission, diminished breath-ing sounds were apparent over theright lung. The purified protein de-rivative was negative. Blood chemicalvalues were normal, except for anerythrocyte sedimentation rate of 99mm/h. Chest radiograph (Figure,right) and computerized tomographyconfirmed the presence of a largepleural effusion without pleuralthickness. Thoracentesis resulted in aturbid fluid, with 600 x 106 leuko-cytes/L, 90% lymphocytes; total pro-tein 45 g/L; lactate dehydrogenase 346U/L; glucose 78 mg/dL; and adeno-sine deaminase 16.9 U/L (reference

Letters to the Editor

166 August 1, 2002 THE AMERICAN JOURNAL OF MEDICINE� Volume 113