An Unusual Cause of Abdominal Pain
Jeffrey H. Phillips, M.D., F.A.C.P. Internal Medicine Clinical Update March 24, 2004
History of illness
63 year old African American man presents June, 2003 with 3 weeks of nausea and periumbilical abdominal discomfort PMH: mild intermittent asthma; BPH; tonsillectomy MEDS: prn albuterol ALLERGIES: None FH: Father with Alzheimer’s. Brother with DM. SH: retired insurance exec.; nonsmoker x 40 years; no alcohol x 2 years; one coffee per day; exercises regularly ROS: weight down 10 pounds; otherwise neg.
Physical exam
VS: BP 130/70, HR 70, RR 14, T 98.3 No jaundice or rash Sclera anicteric; no oral ulcers; no adenopathy Normal cardiopulmonary exam Abdomen soft; mildly tender in the epigastric and periumbilical areas; bowel sounds normal No hernias; 1+ prostate; stool guaiac negative
Diagnostic work-up (June’03)
WBC 6100, Hb 11.8, platelets 411,000; BUN/Cr 20/1.1, LFTs, lipase, PSA normal; globulin slightly elevated at 4.5 UGI: moderate GE reflux; otherwise negative Sonogram: normal liver and pancreas; hypoechoic tissue encasing abdominal aorta; no adenopathy CT abdomen: 4 x 5 cm periaortic mass from SMA origin down to iliac arteries; compatible with matted nodes, probable lymphoma; no aorta aneurysm seen CT directed needle biopsies: abnormal but nondiagnostic
CT – June, 2003
Diagnostic work-up (July ’03)
Hospitalized in July for open biopsy Path consistent with idiopathic retroperitoneal fibrosis (special stains negative for lymphoma) Pertinent labs:
ESR 141 CRP 5.77 ANA, cANCA normal H/H 8.3/26.3; platelets 631,000 BUN/Cr 24/1.9
Who ya’ gonna call…?
Surgery? Gastroenterology? Rheumatology? Oncology? Urology? Chief of Medicine?
Idiopathic retroperitoneal fibrosis
First described by French urologist Albarran in 1905 Established as clinical entity by Ormond in 1948 with description of two cases Characterized by the extensive development of inflammatory fibrotic tissue in the retroperitoneum Often leading to compression and obstruction of ureters and adjacent organs
Idiopathic retroperitoneal fibrosis
Annual incidence: 0.2 to 0.5 per 100,000 Average age 50; M:F ratio 2:1 No ethnic differences Pathology: dense plaque in the RP, starting at aortic bifurcation, enveloping aorta, IVC, ureters Bilateral in two thirds of cases May involve gonadal, celiac, SM, renal arteries
Pathogenesis
Cause unknown; probably autoimmune response to an insoluble lipid called ceroid leaking through thinned arterial walls (circulating ceroid Abs in >90% patients) Increased production of cytokines (interleukins and Th2) mediates inflammation/fibrosis Early stage: plaque highly vascular with deposition of collagen and infiltrates of polyclonal B and CD4 T cells Inflammatory tissue is gradually replaced by fibrosis Most clinical features secondary to mass effect of fibrosis on adjacent structures
Clinical features
80% present with dull, poorly localized, noncolicky pain in back, flank, or abdomen Weight loss, nausea, malaise less frequent Increasing urinary obstruction with decreased volume or flank pain Impingement of the IVC or aorta may produce lower extremity edema, thrombophlebitis, claudication, or intestinal ischemia
Diagnosis
Elevated ESR in 80 to 90% Mild normochromic, normocytic anemia Elevated BUN/Cr Imaging depends on presentation: IVP vs. sonogram vs. CT abdomen; MRI may image best Biopsy necessary to exclude secondary causes May coexist with other immune-mediated diseases:
PBC, RA, SLE, PAN, GN, ankylosing spondylitis, fibrosing mediastinitis, Hashimoto’s thyroiditis, Wegener’s
Treatment - Surgical
Indicated in cases with severe ureteral or other organ involvement (ureterolysis) Cystoscopically placed ureteral stents may obviate need for open surgery Open biopsy also necessary to exclude lymphoma or metastaic cancer as cause of fibrotic process
Treatment - Medical
Corticosteroids
First used in 1958 Suppress inflammatory response Best if started in early stages Typical regimen is prednisone 40 to 60 mg daily tapered to 10 mg daily over 3 to 6 months and then continued several years at low dose Pulse dosing or alternate day dosing are options
Steroid Therapy for Idiopathic Retroperitoneal Fibrosis: Dose and Duration
Kardar, et al. Journal of Urology (2002) 168: 550-555
Prospective study of 12 patients with IPF over 10 year period treated with alternate day steroids 60 mg q.o.d. x 2 months, 40 mg q.o.d. x 2 weeks, 20 mg q.o.d. x 2 weeks, 10 mg q.o.d. x 2 weeks, and then 5 mg daily for 2 years Follow-up of 26 to 132 months (median 63) Only 2 patients failed (1 non-responder and 1 with recurrent symptoms and elevated ESR)
Treatment - Medical
Immunosuppressive agents
Azathioprine Cyclophosphamide Methotrexate Mycophenolate mofetil Typically given initially with steroids May serve as a steroid sparing agent May be first-line when surgery not an option
Immunosuppressive Therapy for Idiopathic Retroperitoneal Fibrosis: A Retrospective Analysis of 26 Cases Marcolongo, et al. AJM (2004) 116: 194-197
26 patients with IRF and ureteral obstruction over a 12 year period treated with ureteral stents or nephrostomy All patients received prednisone (1 to 1.5 mg/kg for 3 weeks, then tapered over 6 months) and
Azathioprine 2.5 mg/kg/d x 6 months then reduced to 1.5 mg/kg x 6 months or Cyclophosphamide 2 mg/kg/d x 3months and tapered and discontinued within 6 months
Treatment failure rate: 1 per 100 patient-years This study showed increased safety with azathioprine
Tamoxifen
Effective in pelvic desmoid tumors Thought to increase production of transforming growth factor-B, an immunosuppressive cytokine that modulates fibroblast activity Also inhibits protein kinase C, an obligatory mediator of cell proliferation Relatively safe though may increase risk of thromboembolism and ovarian cancer Several small series show effectiveness
Prognosis
Resolution is rare without treatment Over time, mass less likely to respond to medical therapy (less inflammation and more fibrosis) Renal insufficiency resolves or significantly improves with treatment Ureteral obstruction may recur in up to 50% treated with surgery alone, compared to 10% treated with steroids, and 1% with steroids plus immunosuppressive therapy
Office visit
Aug. 9 Aug. 15 Aug. 29 Sep. 24 Oct. 29 Dec. 16
Prednisone, mg
Imuran, mg
50
ESR, Hb
141, 8.3(Cr 1.9) 89, 9.4 11, 11.1 (Cr 1.1) 18, 12.2 12, 13.6 13, 13.2
60 60 60 40 35 30
Jan. 7 Jan. 27
Feb. 19 Mar. 16
25 20
15 10
50 50
50 50
13, 13.0 9, 13.3
8, 12.9 11, 13.0
CT images
June, 2003 September, 2003
CT images March 19, 2004
Conclusions
80% present with dull, poorly localized pain in back, flank, or abdomen; ESR elevated in 80% to 90% CT or MRI, and biopsy help exclude secondary causes Surgery often necessary for ureteral involvement Steroids with or without immunosuppresive therapy is mainstay of treatment and offers best prognosis Long-term follow-up is necessary
Early diagnosis and prompt treatment preserve organ function