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IgG4 Isolated Retroperitoneal Fibrosis and Aneurysmal Periaortitis

Published:September 04, 2017DOI:https://doi.org/10.1016/j.amjmed.2017.08.017

      Presentation

      Severe constipation was the presentation of an inflammatory disease. A 70-year-old-man with a past medical history of hypertension and prostate cancer in remission presented with 3 months of abdominal pain. His pain was generalized and dull, with an intensity of 8/10, radiating to the back, worse with food intake and lying down. The pain was interfering with sleep. Associated with this he had severe constipation for which he was taking polyethylene glycol on a daily basis in order to have bowel movements every other day. Prior to this he used to have regular bowel movements without the need of a medication. There was no weight loss, fever, chills, or arthralgias. A recent endoscopy had demonstrated mild gastritis and duodenitis, and a colonoscopy revealed moderate to severe diverticulosis. His past medical history was unremarkable.

      Assessment

      On examination he was afebrile, in no distress. His blood pressure was 161/95 mm Hg and heart rate 76 beats per minute. His physical examination revealed tenderness to palpation in the epigastrium and mesogastrium with no peritoneal signs. Rectal examination revealed a normal anal tone, no hemorrhoids, fissures, or skin tags, and there was no stool in the rectal vault. The rest of the physical examination was noncontributory.
      A complete blood work-up revealed mild normocytic anemia with a hemoglobin level of 12.9 mg/dL (normal range 13.5-17.5 mg/dL). Renal profile and serum protein electrophoresis were within normal limits. Sedimentation rate was 68 mm/h (normal range 0-22 mm/h) and C-reactive protein level was 18.5 mg/L (normal range ≤ 8.0 mg/L). Autoimmune panel was positive only for a rheumatoid factor of 19 IU/mL (normal range < 15 IU/mL).
      Computed tomography scan of the abdomen demonstrated a periaortic retroperitoneal enhancing density with peri-infiltrative changes surrounding the infrarenal abdominal aorta at the level of a fusiform, probably inflammatory 3-cm aneurysmal dilatation. This was accompanied by a mass-like component encasing the right ileocolic branches of the inferior mesenteric artery and the ileocolic branch of the superior mesenteric artery (Figure 1). Findings were confirmed by a magnetic resonance imaging (MRI) study (Figure 2). The imaging raised the concern for retroperitoneal fibrosis; however, serum immunoglobulin G4 (IgG4) levels were normal.
      Figure 1
      Figure 1Axial contrast-enhanced computed tomography images at the level just above the aortic bifurcation. Arterial phase image (A) demonstrates extensive retroperitoneal soft tissue encircling the abdominal aorta (Ao) by nearly 270° (gray block arrows). Abnormal soft tissue also encases the inferior mesenteric artery (black thin arrow) and an ileocolic branch of the superior mesenteric artery (white thin arrow). Fifteen-minute delayed image (B) demonstrates low-level enhancement in the retroperitoneal soft tissue. Mild inflammatory changes extend laterally to the right from the primary retroperitoneal process (white hatched arrows). The underlying aorta is ectatic with a calcified wall and mural plaque (black arrowheads).
      Figure 2
      Figure 2Axial contrast-enhanced magnetic resonance images with gadofosveset at the same level as in performed 1 month after the initial computed tomography (CT) scan. Similar to the earlier CT, portal venous phase image (A) demonstrates extensive retroperitoneal soft tissue encircling the abdominal aorta (gray block arrows). Abnormal soft tissue again encases the inferior mesenteric artery (black thin arrow) and an ileocolic branch of the superior mesenteric artery (white thin arrow). Motion-corrected subtraction image (B) demonstrates clear enhancement in the retroperitoneal soft tissue (white *). More conspicuous than on the prior CT is effacement of the inferior vena cava by the retroperitoneal tissue (gray curved arrow). Stable ectasia of the infrarenal abdominal aorta.

      Diagnosis

      The differential included malignancy (however, he had no weight loss or constitutional symptoms) and infection; but given the radiologic characteristics, lack of fever and normal white count, this was lower in the differential. Given the characteristics of the abdominal pain, chronic mesenteric ischemia was concerning. IgG4-related disease (IgG4-RD) was also in the differential, although he had a normal IgG4 level.
      A computed tomography-guided biopsy of the mass was performed and revealed sclerosing lymphoplasmacytic infiltrate with focal storiform fibrosis (Figure 3). Special stains were performed demonstrating plasmacytosis (Figure 4) and increased IgG4-stained plasma cells (>30 cells per high power field) compatible with retroperitoneal fibrosis (Figure 5). Age-appropriate screening was performed, ruling out an associated malignancy.
      Figure 3
      Figure 3Hematoxylin & eosin 100× demonstrating sclerosing lymphoplasmacytic infiltrate (black arrow) with focal storiform fibrosis (white arrow).
      Figure 4
      Figure 4CD138 400× demonstrating density of plasma cells (CD138); please see to compare.
      Figure 5
      Figure 5400×: Immunostaining for IgG-4 demonstrating >30 cells per high power field. In comparison with CD138 stain, there is evidence of IgG4 deposition in more than 40% of the totality of plasma cells.
      Retroperitoneal fibrosis (RPF), also known as Ormond's disease, is an infrequent fibroinflammatory disease of the retroperitoneum. Its incidence varies from 0.1-2/100,000.
      • Vaglio A.
      • Zwerina J.
      IgG4-related disease.
      • Yachoui R.
      • Sehgal R.
      • Carmichael B.
      Idiopathic retroperitoneal fibrosis: clinicopathologic features and outcome analysis.
      It occurs predominantly in males (2:1-3:1), and the mean age of presentation is 50-60 years.
      • Urban M.L.
      • Palmisano A.
      • Nicastro M.
      • Corradi D.
      • Buzio C.
      • Vaglio A.
      Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach.
      • Zhou H.-J.
      • Yan Y.
      • Zhou B.
      • Lan T.-F.
      • Wang X.-Y.
      • Li C.-S.
      Retroperitoneal fibrosis: a retrospective clinical data analysis of 30 patients in a 10-year period.
      • Fatima J.
      • Gota C.
      • Clair D.G.
      • Billings S.D.
      • Gornik H.L.
      Inflammatory abdominal aortic aneurysm with retroperitoneal fibrosis.
      The fibrosis characteristically surrounds the infrarenal part of the abdominal aorta and the iliac arteries.
      • Scheel P.J.
      • Feeley N.
      Retroperitoneal fibrosis.
      Its presentation includes dull and constant abdominal or back pain; a more severe presentation includes obstructive nephropathy and lower-extremity edema due to the compression of retroperitoneal structures.
      • Urban M.L.
      • Palmisano A.
      • Nicastro M.
      • Corradi D.
      • Buzio C.
      • Vaglio A.
      Idiopathic and secondary forms of retroperitoneal fibrosis: a diagnostic approach.
      The most common symptom is pain; it can be located in the lumbar, flank, and abdominal area. The pain is frequently poorly localized and dull. The pathophysiology of the pain depends on the affected organs and can be secondary to external compression of the mesenteric arteries causing mesenteric ischemia, secondary to obstructive uropathy and due to the inflammatory process itself. Pain is frequently accompanied by systemic symptoms such as weight loss, fever, and anorexia.
      • Scheel P.J.
      • Feeley N.
      Retroperitoneal fibrosis: the clinical, laboratory, and radiographic presentation.
      • van Bommel E.F.H.
      • Jansen I.
      • Hendriksz T.R.
      • Aarnoudse A.L.
      Idiopathic retroperitoneal fibrosis: prospective evaluation of incidence and clinicoradiologic presentation.
      The mechanism for constipation is poorly understood, but may be related to the inflammation and external compression. Abdominal computed tomography and MRI are the imaging modalities of choice for the diagnosis of RPF; however, biopsy is the definitive diagnosis. RPF can be secondary to neoplasia, surgical interventions, radiotherapy, infections, and medication.
      • Vaglio A.
      • Corradi D.
      • Manenti L.
      • Ferretti S.
      • Garini G.
      • Buzio C.
      Evidence of autoimmunity in chronic periaortitis: a prospective study.
      • Palmisano A.
      • Vaglio A.
      Chronic periaortitis: a fibro-inflammatory disorder.
      Sixty percent of the cases used to be idiopathic; however, since the discovery of IgG4-RD, a significant percentage has been found to be related to this entity.
      • Khosroshahi A.
      • Carruthers M.N.
      • Stone J.H.
      • et al.
      Rethinking Ormond's disease: “idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease.
      IgG4-RD is a fibroinflammatory condition that was first recognized in 2001 when the correlation of autoimmune pancreatitis and elevated IgG4 in the serum was found (currently called type 1 autoimmune pancreatitis).
      • Hamano H.
      • Kawa S.
      • Horiuchi A.
      • et al.
      High serum IgG4 concentrations in patients with sclerosing pancreatitis.
      This disease characteristically forms tumor-like lesions in any organ system. There is frequently elevated IgG4 serum concentration; however, 30%-40% of the patients have a normal IgG4 level.
      • Stone J.H.
      • Zen Y.
      • Deshpande V.
      IgG4-related disease.
      • Sah R.P.
      • Chari S.T.
      Serologic issues in IgG4-related systemic disease and autoimmune pancreatitis.
      IgG4-RD has typical histopathologic findings such as lymphoplasmacytic infiltrate with a predominance in IgG4-bearing plasma cells (in the IgG4-RD variant), storiform fibrosis, and obliterative phlebitis; tissue eosinophilia can often be found.
      • Deshpande V.
      • Zen Y.
      • Chan J.K.
      • et al.
      Consensus statement on the pathology of IgG4-related disease.
      • Umehara H.
      • Okazaki K.
      • Masaki Y.
      • et al.
      Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011.
      • Stone J.H.
      • Brito-Zerón P.
      • Bosch X.
      • Ramos-Casals M.
      Diagnostic approach to the complexity of IgG4-related disease.
      The diagnosis cannot be made without a pathologic evaluation. There are still some questions about the pathogenesis of this disease and whether IgG4 deposition is a primary or secondary response. IgG4-RD can also present as an IgG4-related aortitis, which is known to cause aortic aneurysms and aortic dissections, representing a differential diagnosis in the work-up of other large vessel vasculitis such as Takayasu arteritis.
      • Khosroshahi A.
      • Carruthers M.N.
      • Stone J.H.
      • et al.
      Rethinking Ormond's disease: “idiopathic” retroperitoneal fibrosis in the era of IgG4-related disease.

      Management

      The patient was placed on high-dose steroids (prednisone 60 mg/d) in combination with mycophenolic acid and pneumocystis pneumonia prophylaxis. The patient experienced significant improvement of his abdominal pain and constipation with the treatment. He continued following in the Rheumatology clinic, where serial abdominal MRI studies were performed demonstrating improvement of the periaortic soft tissue (Figure 6). Prednisone was slowly tapered down based on symptoms, and mycophenolic acid was continued.
      Figure 6
      Figure 6Axial contrast-enhanced, portal venous phase magnetic resonance images with gadofosveset at the same level as in Figure 1, Figure 2, performed prior to (A) and after treatment (B). (A) is the same image as in . (B) is from a study performed 3 months after the examination shown in (A). There has been marked reduction in retroperitoneal soft tissue post treatment. While the proximal inferior mesenteric artery remains encased (black thin arrow), the ileocolic branch of the superior mesenteric artery is now virtually free of disease (white thin arrow). Decreased mass effect on the IVC. Stable ectasia of the infrarenal abdominal aorta.
      Steroid therapy is the main treatment for symptomatic cases of IgG4-RD, the recommended initial dose is 0.6 mg/kg for 2-4 weeks and subsequently, the dose should be tapered down 10% every 14 days. The majority of patients will respond to corticosteroid treatment.
      • Yamamoto M.
      • Takahashi H.
      • Shinomura Y.
      Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist.
      Other immunosuppressive agents such as azathioprine, rituximab, and mycophenolic acid have also been reported for the treatment of this patients and are effective accomplishing steroid-sparing effects.
      • Yamamoto M.
      • Takahashi H.
      • Shinomura Y.
      Mechanisms and assessment of IgG4-related disease: lessons for the rheumatologist.
      The treatment should be initiated at the time of diagnosis to prevent progression and further complications. High-dose steroids are recommended in the acute phase, and other immunosuppressive agents may also be required. Our goal is to create awareness of the clinical presentation of IgG-4-related diseases and the importance of early diagnosis and treatment.

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