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Retroperitoneal Fibrosis

Ormond Disease

Patients suffering from retroperitoneal fibrosis show a pathological proliferation of connective tissue in the retroperitoneal space that may compromise different organs, e.g., kidneys, ureters and aorta.


Presentation

Symptoms associated with RPF are generally very unspecific. The most common symptom is lower back or abdominal pain and patients often report difficulties to localize its origin [11]. Due to inflammation, patients may present with fever. Loss of appetite, nausea and consecutive weight loss may be observed as well as anemia and jaundice. If blood flow to and from one of the lower limbs is restricted, the respective leg may swell and turn cyanotic. Movements may be impaired. Less frequently, intestinal hemorrhages occur.

Somewhat surprisingly, only 10% of RPF patients experience problems while urinating. Upon bilateral ureteral obstruction, however, such symptoms will develop rapidly. Oliguria but also polyuria may be observed and further examination will reveal hydronephrosis and hypertension [12]. If left untreated, these events result in kidney failure. Limited kidney function may aggravate nausea and provoke vomiting.

Abdominal or rectal examination may reveal the presence of a retroperitoneal mass in a smaller share of patients.

Fever of Unknown Origin
  • In the context of fever of unknown origin, an abdomen computed tomography was ordered. A temporal artery biopsy was also performed because during hospitalization she complained of a headache.[ncbi.nlm.nih.gov]
Hemoptysis
  • We report a 79-year-old man with multiple organs involvement of IgG4-RRPF, who developed right lower extremity edema, hemoptysis and fever. The abdomen computed tomography (CT) scan image showed lymph nodes enlargement.[ncbi.nlm.nih.gov]
Abdominal Pain
  • The clinical presentation often includes constitutional symptoms, abdominal pain, and signs of renal insufficiency or renal failure related to ureteral obstruction.[ncbi.nlm.nih.gov]
  • A 62-year-old man with abdominal pain and lumbago was admitted to our hospital. Blood examination revealed renal insufficiency, and CT revealed retroperitoneal fibrosis causing bilateral hydrocele and ureteral compression.[ncbi.nlm.nih.gov]
  • RPF was found predominantly in elderly men with atypical clinical manifestations of back pain, abdominal pain, and lower limb edemas.[ncbi.nlm.nih.gov]
  • We report a case of 69-year-old male with recurrent lower abdominal pain for 10 months.[ncbi.nlm.nih.gov]
  • pain for the past 30 days.[ncbi.nlm.nih.gov]
Dyspepsia
  • She underwent endoscopy for heartburn, melena, dyspepsia, and weight loss (7 kg/5 month), which revealed congestion of the mucosa of the fundus and body with fine linear erosion and decreased distensibility of the stomach suggesting linitis plastica.[ncbi.nlm.nih.gov]
Melena
  • She underwent endoscopy for heartburn, melena, dyspepsia, and weight loss (7 kg/5 month), which revealed congestion of the mucosa of the fundus and body with fine linear erosion and decreased distensibility of the stomach suggesting linitis plastica.[ncbi.nlm.nih.gov]
Anterior Uveitis
  • The authors describe a 55-year-old black female who presented with isolated recurrent anterior uveitis. Laboratory evaluations were notable for elevated inflammatory markers.[ncbi.nlm.nih.gov]
Back Pain
  • A 54-year-old lady being investigated at the medical clinic for back pain and weight loss, was diagnosed with idiopathic retroperitoneal fibrosis on the basis of CT imaging, biopsy findings and absence of known secondary causes.[ncbi.nlm.nih.gov]
  • We present the case of a male patient with post traumatic retroperitoneal fibrosis whose main clinical expression was low-back pain.[ncbi.nlm.nih.gov]
  • The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain.[ncbi.nlm.nih.gov]
  • We report a challenging and difficult to diagnose case of an older man with anasarca, back pain, and renal insufficiency secondary to idiopathic retroperitoneal fibrosis. The patient's symptoms responded well with steroid treatment.[doi.org]
Low Back Pain
  • We present the case of a male patient with post traumatic retroperitoneal fibrosis whose main clinical expression was low-back pain.[ncbi.nlm.nih.gov]
  • Abdominal, flank, and/or low back pain were the most common presenting symptoms. Four patients (15 %) had associated autoimmune or fibrosing disorders.[ncbi.nlm.nih.gov]
  • Clinically, IRPF is characterised by low back pain radiating to both flanks and intermittent claudication of lower limbs; advanced stages are associated with acute renal failure secondary to bilateral ureteral obstruction.[archivesofmedicine.com]
  • Retroperitoneal fibrosis: unusual cause of low back pain. South Med J. 2001;94:735-37. Dedeoglu F, et al. Successful treatment of retroperitoneal fibrosis with tamoxifen in a child. J Rheumatol. 2001;28:1693-95. Inoue T, et al.[rarediseases.org]
  • Idiopathic retroperitoneal fibrosis accounts for over 70% of cases. [1] The incidence of the idiopathic form was reported to be 0.1 per 100,000 person-years with its prevalence of 1.4 per 100,000 residents. [2] Symptoms may occur such as low back pain[doi.org]
Breast Mass
  • The left breast mass was proven as a malignancy on biopsy and surgical excisional biopsy of the mediastinal mass revealed metastasis from the breast cancer on histopathologic examination.[ncbi.nlm.nih.gov]
Encephalopathy
  • She was diagnosed with hypertensive emergency on physical examination, and brain magnetic resonance imaging showed posterior reversible encephalopathy syndrome (PRES) with bilateral thalamic haemorrhage.[ncbi.nlm.nih.gov]
Polyuria
  • However, polyuria from post-obstructive diuresis and unmasked central diabetes insipidus ensued.[ncbi.nlm.nih.gov]
  • Symptoms include low-back and abdominal pain; weakness; weight loss; fever; and, with urinary tract involvement, frequency of urination, hematuria, polyuria, or anuria.[medical-dictionary.thefreedictionary.com]
  • Urinary features include polyuria, polydipsia, anorexia, nocturia, oliguria, urinary frequency and haematuria. Children may present with hip or gluteal pain.[patient.info]
  • Oliguria but also polyuria may be observed and further examination will reveal hydronephrosis and hypertension. If left untreated, these events result in kidney failure. Limited kidney function may aggravate nausea and provoke vomiting.[symptoma.com]
Nocturia
  • Urinary features include polyuria, polydipsia, anorexia, nocturia, oliguria, urinary frequency and haematuria. Children may present with hip or gluteal pain.[patient.info]

Workup

While physical examination, laboratory analyses of blood and urine samples allow for an evaluation of the overall condition of the patient, definitive diagnosis of RFP can only be attained by histopathological analysis of a biopsy. Diagnostic imaging techniques have to be applied to assess the extend of tissue compromise.

With regards to hemogram and blood biochemistry, parameters indicating anemia, inflammation and renal problems will be altered. In detail, a normocytic normochromic anemia can often be observed. Increased levels of C-reactive protein and prolonged erythrocyte sedimentation rates point at tissue inflammation. Urea and creatinine levels are often enhanced. Hypergammaglobulinemia and the presence of antinuclear autoantibodies support the suspicion of an autoimmune process [13]. Alkaline phosphatase levels are frequently elevated and may even be considered a marker of RFP [14].

Urine analysis does usually not reveal any pathological findings. In some cases, hematuria or pyuria may result from damage to the urinary tract.

Further diagnostics are based on imaging techniques. Standard radiographic imaging may be helpful to detect  renal enlargement due to hydronephrosis or neoplasms, but is little sensitive towards RPF and ureteral obstruction. Computed tomography scans are superior to standard radiographic imaging, but should also be carried out utilizing contrast agents. Intravenous urography or retrograde pyeolography may be applied to visualize the urinary tract and significantly improve sensitivity of imaging diagnostics. A classic triad of delayed excretion of contrast agents due to hydronephrosis, medial deviation of the middle third of one or both ureters and their tapering at the level of the fourth and fifth lumbar vertebrae has been described for RPF [15]. These symptoms are, however, not specific and may be found in a significant share of healthy controls. Of note, catheterization for retrograde pyeolography is usually not hindered by RPF. Lymphatic vessels are more easily compressed by excess connective tissue than blood vessels and ureters. Thus, lymphangiography may be of help to identify RFP before any of the before mentioned structures are compromised. Such an examination may reveal delayed passage of contrast agents, obstruction of flow and possibly non-visualizability of lymphatic vessels in the lumbar area. If magnetic resonance imaging is conducted, findings vary with fluid contents of fibrotic tissue. In this context, early stages of RFP are associated with high fluid contents and thus appear with high T2 signal intensity while this is no longer the case in advanced RFP and diminished fluid content. Corticosteroid-induced reduction of edema also decreases T2 signal intensity. Inhomogeneities visible in any of the aforementioned imaging techniques may indicate the presence of malignant neoplasms.

Ultrasonographic exams are used to assess response to therapy in follow-ups rather than for diagnosis.

If analysis of blood samples and findings of diagnostic imaging support the diagnosis of RFP, a biopsy needs to be obtained. This is frequently done as part of a surgical intervention to relieve ureteral obstruction, but laparoscopic procedures should be preferred if the latter is not required. Here, morbidity and costs are significantly lower. Core needle biopsies do often not provide sufficient tissue for diagnosis.

Mediastinal Mass
  • The left breast mass was proven as a malignancy on biopsy and surgical excisional biopsy of the mediastinal mass revealed metastasis from the breast cancer on histopathologic examination.[ncbi.nlm.nih.gov]
Candida
  • Candida fungus ball is a rare presentation of urinary tract infections among adult patients and is associated with considerable morbidity. Because clinical signs are not specific, diagnosis is often delayed.[ncbi.nlm.nih.gov]
Actinomyces Israelii
  • The pathology report showed fibrosis and Actinomyces israelii infection. Parenteral and oral penicillins were administered.[ncbi.nlm.nih.gov]

Treatment

Spontaneous remission has been observed in rare cases.

Immunosuppressive therapy with corticosteroids has been proven very effective in treating RFP, particularly in early stages of the disease [16]. Furthermore, azathioprine has been administered to reduce the autoimmune response behind RFP [17]. Current research focuses on the employment of progesterone and estrogen-receptor modulator tamoxifen in RFP treatment.

Drug therapy may even replace surgery if such interventions are not feasible due to the overall condition of the patient. However, ureteral obstruction may require ureterolysis in order to fully regain functionality of this side's urinary tract. Ureteral stents may pose an alternative treatment option although they should not be considered long-term solutions.

Relapses are common and may occur until years after initial diagnosis. It has been reported that wrapping up the ureter in retroperitoneal fat after ureterolysis may delay recurrence of ureteral obstruction.

Prognosis

If RPF is not associated with malignancies and a possibly underlying disease can be treated, prognosis is good [10]. Full functionality of the urinary tract is usually regained. However, if RPF develops as a sequelae of malignant neoplasms, prognosis is poor.

Etiology

The majority of RPF cases is deemed idiopathic because no underlying pathological condition can be identified. However, the hypothesis of RPF being an IgG4-related disease, i.e., a disease characterized by fibrosis and infiltration of lymphocytes that produce antibodies of type IgG4, is gaining consent [4] [5]. It is supported by the fact that many RPF patients respond to immunosuppressive therapy.

An association between malignant neoplasms and RPF has been proven. Excess proliferation of retroperitoneal connective tissue may, however, also result from chemotherapy or irradiation applied to treat cancer. RPF seems to develop more frequently after abdominal aortic aneurysm and subsides after repair of the former. Moreover, iatrogenic RPF has been described. Here, the condition may be induced by use of beta-sympatholytics, methyldopa or methysergide and others. Abuse of illegal drugs like cocaine may trigger RPF as well as traumas and/or inflammation, e.g., glomerulonephritis, systemic vasculitis, mediastinitis, spondylitis. Additionally, a relation between RPF and hormonal disorders like hypopituitarism, hypothyroidism and Hashimoto's thyroiditis may exist. An association to autoimmune diseases like systemic lupus erythematosus has been proposed.

A genetic component seems likely [6].

Epidemiology

RPF is considered a rare disease. In a study realized in Northern Europe, an overall incidence of 1 per 1,000,000 person years and a prevalence of less than 2 per 100,000 individuals has been estimated [7]. Another study has been conducted several years later and reported an incidence of more than 1 per 100,000 person years [8].

RPF usually strikes adults aged 40 to 60 years. Men seem to be affected up to three times as often as women.

Sex distribution
Age distribution

Pathophysiology

The retroperitoneal space is delimited by diaphragm, parietal peritoneum, transverse fascia and pelvis. An anterior pararenal, perirenal and posterior pararenal section result from subdivision of the overall retroperitoneal space by the kidneys. While there is retroperitoneal fat in the latter, the kidneys themselves, adrenal glands and ureters and their respective vessels are located in the perirenal space. The anterior pararenal sector contains secondarily retroperitoneal organs, i.e., organs that did not develop retroperitoneally but that were relocated here at a later point in time. Thus, they once possessed mesenteries, but these have grown together with the parietal peritoneum. There position is a lot more fixed than those of the primarily retroperitoneal organs ubicated in the other sections. Secondarily retroperitoneal organs are pancreas, duodenum, ascending and descending colon. Also, aorta, inferior vena cava as well as additional blood and lymphatic vessels are located in the anterior pararenal space.

While still most cases of RPF are deemed idiopathic, this disease is increasingly recognized as an autoimmune disease. Epitopes located in atherosclerotic plaques have been proposed as triggering antigens. Indeed, diagnostic imaging as well as autopsies have shown that atherosclerotic plaques in the abdominal aorta often serve as point of origin of fibrosis. It has been hypothesized that lesions to the arterial wall may allow insoluble lipids such as ceroid to diffuse into the periaortic connective tissue. Here, it could provoke an immune response. The presence of anti-ceroid antibodies and ceroid-containing macrophages in local lymph nodes seem to confirm this theory. This pathogenetic mechanism accounts for the fact that this disease has also been termed chronic periaortitis [9].

While this hypothesis may be convincing, RPF may also occur in children whose abdominal aorta does not contain atherosclerotic plaques. Thus, additional factors have to be involved in RPF pathogenesis. As has been indicated above, certain drugs may trigger RPF, possibly by stimulating an autoimmune reaction in form of haptens.

Prevention

Avoidance of certain drugs that have been shown to trigger RFP may contribute to prevention of this disease. However, RFP is a rare disease and the benefit of ceasing such therapies may not outweigh its downsides.

Summary

The retroperitoneal space harbors kidneys, adrenal glands, ureters, aorta, inferior vena cava and other vessels. These organs are not covered by the peritoneum and do not possess mesenteries. With regards to the spine, the retroperitoneal space is located ventral of the inferior lumbar vertebrae.

The pathological condition of excess proliferation of connective tissue in the retroperitoneal space is called retroperitoneal fibrosis (RPF). This disease is also termed Ormond's disease in honor of the urologist who discovered the condition in the past century. The etiology of RPF is unclear, but many patients benefit from an immunosuppressive therapy with corticosteroids and this fact suggests an immune pathogenesis [1] [2]. About one out of ten RPF patients is also diagnosed with metastasizing malignant neoplasms and a pathogenetic association between both conditions is likely [3].

RPF may cause obstruction of the above mentioned organs, particularly of the thin ureters. Symptoms correspond to ureteral obstruction and are rather unspecific. The disease may also provoke hypertension and lower back pain. While urographic examination may reveal the former and further diagnostic imaging may support a tentative diagnosis of RPF, only a histopathologic analysis of a biopsy allows for confirming this diagnosis. Besides corticosteroids, cytostatic drugs may be administered to inhibit connective tissue proliferation. Many patients will require surgical intervention to relieve ureteral obstructions.

Due to the possible relation between RPF and malignant neoplasms, all patients diagnosed with RPF should undergo a thorough examination to rule out the presence of malignancies. If detected, they should be treated accordingly.

Patient Information

The retroperitoneal space is located in front of the lumbar spine. It is anatomically separated from the intra-abdominal area and harbors kidneys, ureters, abdominal aorta, important veins and lymphatic vessels. Connective tissue is also present in the retroperitoneal space. If this tissue starts to proliferate excessively, it may compress the aforementioned structures and provoke a pathological condition termed retroperitoneal fibrosis (RPF).

Causes

No specific cause can be identified for the majority of RPF cases. However, recent research results have supported the hypothesis of an autoimmune pathogenesis, i.e., an immune response against endogenous structures may cause inflammation and fibrosis. It has been speculated that atherosclerotic plaques present in the abdominal aorta may be the starting point of RPF.

In about 10% of RPF cases, the disease is related to the presence of malignant tumors.

Symptoms

Only unspecific symptoms are developed by RPF patients. The most common ones are lower back or abdominal pain, fever, loss of appetite, nausea and loss of weight. Patients may feel tired and weak and show yellowish discoloration of eyes and mucous membranes.

Legs may swell and turn bluish if blood flow to and from the lower limbs is restricted due to compression of blood vessels in the retroperitoneal space.

Some patients experience difficulties urinating.

Diagnosis

Physical examination, analysis of blood and urine samples may prompt a slight suspicion for RPF. This will be confirmed with diagnostic imaging approaches that allow visualization of the patient's urinary tract. Therefor, contrast agents will be passed through kidneys and ureters.

Definitive diagnosis requires histopathological analysis of biopsy samples. Such tissue samples are often obtained during surgical interventions.

Treatment

Due to the autoimmune mechanism behind RPF, a significant share of patients responds to immunosuppressive therapy with corticosteroids or azathioprine.

Surgery or laparoscopic ureterolysis may be necessary to relieve ureteral obstructions.

References

Article

  1. Carton RW, Wong R. Multifocal fibrosclerosis manifested by vena caval obstructions and associated with vasculitis. Ann Intern Med. 1969; 70(1):81-86.
  2. Martorana D, Vaglio A, Greco P, et al. Chronic periaortitis and HLA-DRB1*03: another clue to an autoimmune origin. Arthritis Rheum. 2006; 55(1):126-130.
  3. Lepor H, Walsh PC. Idiopathic retroperitoneal fibrosis. J Urol. 1979; 122(1):1-6.
  4. Chiba K, Kamisawa T, Tabata T, et al. Clinical features of 10 patients with IgG4-related retroperitoneal fibrosis. Intern Med. 2013; 52(14):1545-1551.
  5. Fujimori N, Ito T, Igarashi H, et al. Retroperitoneal fibrosis associated with immunoglobulin G4-related disease. World J Gastroenterol. 2013; 19(1):35-41.
  6. Astudillo L, Alric L, Jamard B, Laroche M. [Retroperitoneal fibrosis in an HLA-B27-positive patient]. Rev Med Interne. 1999; 20(12):1149-1150.
  7. Uibu T, Oksa P, Auvinen A, et al. Asbestos exposure as a risk factor for retroperitoneal fibrosis. Lancet. 2004; 363(9419):1422-1426.
  8. Vaglio A. Retroperitoneal fibrosis: new insights into clinical presentation and diagnosis. Medicine (Baltimore). 2009; 88(4):208-210.
  9. Mitchinson MJ. Chronic periaortitis and periarteritis. Histopathology. 1984; 8(4):589-600.
  10. Baker LR. Auto-allergic periaortitis (idiopathic retroperitoneal fibrosis). BJU Int. 2003; 92(7):663-665.
  11. Koep L, Zuidema GD. The clinical significance of retroperitoneal fibrosis. Surgery. 1977; 81(3):250-257.
  12. Hamano H, Kawa S, Ochi Y, et al. Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet. 2002; 359(9315):1403-1404.
  13. Vaglio A, Corradi D, Manenti L, Ferretti S, Garini G, Buzio C. Evidence of autoimmunity in chronic periaortitis: a prospective study. Am J Med. 2003; 114(6):454-462.
  14. Barrison IG, Walker JG, Jones C, Snell ME. Idiopathic retroperitoneal fibrosis--is serum alkaline phosphatase a marker of disease activity? Postgrad Med J. 1988; 64(749):239-241.
  15. Webb AJ, Dawson-Edwards P. Non-malignant retroperitoneal fibrosis. Br J Surg. 1967; 54(6):508-518.
  16. van Bommel EF. Retroperitoneal fibrosis. Neth J Med. 2002; 60(6):231-242.
  17. Cogan E, Fastrez R. Azathioprine. An alternative treatment for recurrent idiopathic retroperitoneal fibrosis. Arch Intern Med. 1985; 145(4):753-755.

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Last updated: 2019-07-11 20:37