Concomitant presentation of IgG₄-negative idiopathic retroperitoneal fibrosis and Addison’s disease

Abstract

We describe a patient who was admitted to our medical centre with acute renal failure, hyponatraemia and hyperkalaemia. CT of the abdomen and pelvis showed a retroperitoneal mass with bilateral ureteral obstruction. Biopsy revealed fibrosis with inflammatory infiltrate, but rare IgG₄-positive plasma cells. After placement of bilateral pigtail nephrostomy catheters, renal failure improved but metabolic derangements remained. Morning serum cortisol level was equivocal, but with blunted response on cosyntropin stimulation testing indicating adrenal insufficiency. Serology for 21-hydroxylase antibodies was strongly positive, supporting the diagnosis of Addison’s disease. In addition to nephrostomy catheters for obstructive uropathy, idiopathic retroperitoneal fibrosis was treated with mycophenolate mofetil. Physiological doses of hydrocortisone and fludrocortisone for Addison’s disease were also initiated. The patient continues to be monitored for regression of the mass. Based on review of the literature, this is the first reported case of IgG₄-negative idiopathic retroperitoneal fibrosis presenting with autoimmune primary adrenal insufficiency.

Background

Idiopathic retroperitoneal fibrosis (IRPF), also called chronic periaortitis, is a condition in which fibroinflammatory tissue develops in the retroperitoneal space. The estimated incidence of IRPF is 0.1–1.3 cases per 100 000 persons per year, with an estimated male to female predominance of 2-3:1.¹ IRPF often presents as a retroperitoneal mass surrounding the abdominal aorta, iliac arteries and inferior vena cava—frequently extending to the ureters. IRPF is associated with external compression of these structures with intraluminal sparing. Conversely, fibrosis may also result in dilatation of the aortic lumen, termed inflammatory aortic aneurysm.²

Patients with IRPF usually present with abdominal pain, back pain or flank pain. They may present in acute renal failure secondary to obstructive uropathy. Constitutional symptoms including fever, weight loss and fatigue are also common.² Scrotal swelling, hydrocele or varicocele may occur due to obstruction of gonadal vasculature. Laboratory findings may show elevated acute phase reactants including erythrocyte sedimentation rate and C-reactive protein.

Retroperitoneal fibrosis can be idiopathic or develop as part of the diffuse fibroinflammatory condition known as IgG₄-related disease (IgG₄-RD), medications, infection, abdominal surgery or radiation.^{3 4} The histology of IRPF is characterised by dense sclerosis with collagen deposition and an inflammatory infiltrate consisting of T and B lymphocytes, macrophages, plasma cells and eosinophils. Neutrophils are notably rare or absent.^{4 5} Immunosuppression is a mainstay of medical therapy for IRPF. The disease usually responds well to glucocorticoids, with prednisone at a dose of 0.5–1.0 mg/kg being first line. Successful treatment with rituximab, mycophenolate mofetil, methotrexate, azathioprine and cyclophosphamide for steroid-resistant disease has been reported.^{4 6} If ureteral compression is present, either nephrostomy catheter placement or stenting must be performed. Treatment of inflammatory aortic aneurysm involves either endovascular or open repair.⁷ Generally, IRPF has a favourable prognosis if recognised and treated appropriately.

The pathogenesis of IRPF remains poorly understood, however research indicates its aetiology is likely autoimmune.^{8 9} IRPF has been associated with other autoimmune diseases in the literature, most commonly Hashimoto’s thyroiditis.^{10 11} Graves’ disease and Reidel’s thyroiditis have also been reported although the latter is now considered as a manifestation of IgG₄-RD.^{12 13} There are case reports of IRPF associated with rheumatoid arthritis, ankylosing spondylitis, antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, systemic lupus erythematosus and psoriasis.^14–17 Concomitant autoimmune adrenalitis has not been previously reported.

Primary adrenal insufficiency, commonly known as Addison’s disease (AD), results from destruction of the glucocorticoid hormone-producing cells of the adrenal glands. Autoimmune adrenalitis is the most common cause of AD in developed countries, while tuberculous adrenalitis is more common in developing countries.¹⁸ Primary adrenal failure classically presents with hypotension, salt craving, and hyperpigmentation of the skin and mucous membranes. Other constitutional signs include fatigue, unintended weight loss and generalised abdominal pain. Laboratory studies may reveal hyponatraemia and hyperkalaemia, due to mineralocorticoid deficiency, low serum cortisol levels and elevated serum adrenocorticotropic hormone (ACTH). A blunted or absent cortisol response to ACTH (cosyntropin stimulation) is diagnostic. Serology is frequently positive for antibodies to 21-hydroxylase, an enzyme involved in the biosynthesis of aldosterone and cortisol.¹⁸ Treatment of AD includes glucocorticoids, usually in the form of hydrocortisone physiologically dosed two or three times per day and mineralocorticoids in the form of fludrocortisone. AD has been described in association with a variety of autoimmune disorders, most notably as part of the polyglandular autoimmune syndromes.¹⁹ In a study of 83 patients with autoimmune adrenalitis, 20.5% also had primary hypothyroidism and 9.6% had vitiligo.²⁰

Case presentation

The patient was a 49-year-old man with medical history of long-standing hypothyroidism (treated with levothyroxine), attention deficit hyperactivity disorder and depression (treated with paroxetine and olanzapine) who presented with profound weakness, nausea, vomiting, abdominal pain and 30-pound weight loss over the previous 3 months. The patient denied fever, chills, chest pain, shortness of breath, diarrhoea, constipation, dysuria or lower extremity oedema. Review of systems was also negative for symptoms of hypothyroidism and hyperthyroidism. On physical examination, the patient’s abdomen was non-tender to palpation, non-distended and without appreciable organomegaly or palpable masses. Musculoskeletal examination showed no evidence of muscle wasting, weakness or joint synovitis. Additionally, no abnormal skin or mucosal findings were noted.

Investigations

Complete blood count showed haemoglobin of 123 g/L, white cell count of 13.9×10⁹/L and platelets of 223×10³/µL. Serum chemistry was notable for sodium of 120 mEq/L, potassium of 5.1 mEq/L, urea nitrogen of 39 mg/dL and creatinine of 4.32 mg/dL.

CT of the abdomen and pelvis was performed which demonstrated a 5.9×2.2×9.8 cm retroperitoneal mass encasing the aorta, inferior vena cava and both ureters with moderate hydronephrosis bilaterally (figures 1 and 2). The patient subsequently underwent bilateral percutaneous pigtail nephrostomy catheter placement which improved renal function and urine output. However, hyponatraemia (Na+ 116–127 mEq/L) and hyperkalaemia (K+ 4.3–5.7 mEq/L) persisted and in fact worsened. Trials of both fluid resuscitation and fluid restriction had minimal effect on the serum sodium. Serum cortisol of 9.1 µg/dL at 08:00 was equivocal which prompted a cosyntropin stimulation test. Cortisol level remained unchanged at 9.5 µg/dL 60 min after cosyntropin administration. Plasma renin level was elevated at 105 ng/mL/hour (range 1.9–3.7 ng/mL/hour) and aldosterone was near the lower limit of normal at 3.4 ng/dL (range 3.0–39.0 ng/dL). These findings supported a diagnosis of adrenal insufficiency.

Figure 1.

Axial CT of the abdomen and pelvis demonstrating the retroperitoneal mass.

Figure 2.

Coronal view of the midline retroperitoneal mass.

Workup to determine primary versus secondary adrenal insufficiency revealed an elevated ACTH of 1109 pg/mL (range 10–50 pg/mL). 21-Hydroxylase antibody was strongly positive at 24 U/mL (normal <1.0 U/mL) and interferon gamma release assay for tuberculosis was negative. With these results, the diagnosis of primary autoimmune adrenalitis was made.

Biopsy of the retroperitoneal mass revealed fibrosis and scattered lymphoid aggregates with plasma cells, histiocytes and lymphocytes. Lymphocyte lineage showed a mixture of T and B lymphocytes without monoclonal proliferation. IgG-positive plasma cells were present, but with minimal IgG₄-positive plasma cells. There was no evidence of malignancy.

Evaluation of thyroid function showed thyroid stimulating hormone was 7.07 IU/mL (range 0.4–4.0 IU/mL) with free T4 1.27 ng/dL (range 0.6–1.3 ng/dL). Antibodies to thyroid peroxidase (1 IU/mL, normal <4) and thyroglobulin antibodies (2 IU/mL, normal <9) were present but at titers below what is considered positive. Pituitary hormone workup revealed elevated prolactin at 151.0 ng/mL (normal range for men 2.6–13.1 ng/mL), undetectable serum testosterone (normal range 300–1200 ng/dL), follicle-stimulating hormone 1.1 mIU/mL (normal range 1.3–19.3 mIU/mL), luteinizing hormone 1.7 mIU/mL (normal range 1.2–8.6 mIU/mL) and insulin-like growth factor 1 88 ng/mL (normal range 67–205 ng/mL). Given these findings of hyperprolactinaemia and hypogonadotropic hypogonadism, MRI of the brain was obtained to assess for abnormalities of the pituitary gland. The MRI showed no abnormal pituitary tissue or masses.

Serology was notable for a positive antinuclear antibody titer of 1:160 in a speckled pattern. Double stranded DNA antibody and ANCA were negative. Serum immunoglobulin levels were all within normal parameters. Serum IgG subclass analysis demonstrated mildly elevated IgG₁ with normal IgG₂, IgG₃ and IgG₄ (table 1).

Table 1.

Serum immunoglobulins

Serum immunoglobulins	Serum level (mg/dL)	Normal range (mg/dL)
IgM	287.3	46–216
IgA	281.5	63–391
IgE	8.5 U/mL	0–142
IgG total	1417	700–1600
IgG1	1001	240–810
IgG2	320	130–555
IgG3	23	15–102
IgG4	57	2–96

Differential diagnosis

The differential diagnosis for the retroperitoneal mass included retroperitoneal fibrosis (IgG₄-related or idiopathic) and lymphoma. Tissue biopsy findings helped to identify the cause. The lack of monoclonal proliferation went against the diagnosis of lymphoma. To differentiate between IgG₄-RD and IRPF, the diagnostic criteria for IgG₄-RD were used. None of the histopathological criteria, including dense lymphoplasmacytic infiltrate, storiform fibrosis and obliterative phlebitis were met. Tissue eosinophilia and increased number of IgG₄-positive plasma cells, which are often seen in IgG₄-RD, were absent. Diagnosis of IgG₄-RD is also supported by increased number of IgG₄-positive plasma cells per high powered field (HPF) on microscopy.²¹ In the retroperitoneum, 10 IgG₄-positive plasma cells/HPF are required. The biopsy in this case showed fewer than 10 IgG₄-positive plasma cells/HPF. Furthermore, serum IgG₄ levels, which are frequently elevated in IgG₄-RD, were normal. These factors all support the diagnosis of IRPF over IgG₄-RD.

In regards to the electrolyte abnormalities, hypovolaemic hyponatraemia due to poor oral intake and postobstructive diuresis was initially considered in the differential diagnosis. Despite fluid resuscitation, serum sodium remained low. The syndrome of inappropriate antidiuretic hormone (SIADH) was then considered, given the lack of response to fluids. However, the serum sodium did not improve with 1 L of daily fluid restriction. Additionally, hypovolaemia and SIADH did not explain the hyperkalaemia. It was at this point that the diagnosis of adrenal insufficiency was entertained.

Due to the patient’s hypogonadotropic hypogonadism, autoimmune hypophysitis was considered in the differential diagnosis. MRI of the brain was negative for pituitary abnormalities. Additionally, hyperprolactinaemia in the setting of olanzapine, elevation of serum ACTH on presentation and normal serum IGF-1 were more suggestive of a possible drug-induced hypogonadotropic hypogonadism.

Treatment

For management of IRPF, mycophenolate mofetil was initiated at a goal dose of 1000 mg two times per day. Corticosteroids were not used as first-line treatment to allow reliable interpretation of simultaneous workup for adrenal insufficiency.

Pigtail nephrostomy catheters were placed bilaterally for temporary relief of obstructive uropathy and to monitor response to therapy. For AD, the patient started taking hydrocortisone 10 mg in the morning, 5 mg at 24:00, 5 mg at 17:00 for glucocorticoid replacement and fludrocortisone 0.1 mg daily for mineralocorticoid replacement. The patient continues to follow with endocrinology for management of AD. Levothyroxine dose was increased for subclinical hypothyroidism. Testosterone replacement therapy was offered for hypogonadotropic hypogonadism but the patient declined treatment.

Outcome and follow-up

The patient continues to be followed as an outpatient for regression of the retroperitoneal mass with serial abdominal CT scans. Once the mass has sufficiently regressed, the pigtail nephrostomy catheters will be removed.

Discussion

Based on review of the literature, this is the first reported case of associated IRPF and AD. It is particularly notable that these conditions presented simultaneously, as patients with multiple autoimmune comorbidities often have each disease present over time. A similar case was reported by Guarda et al who described a patient with retroperitoneal fibrosis and hypophysitis resulting in secondary adrenal insufficiency.²² However, that case was shown to be IgG₄-related.

One of the most common autoimmune endocrine disorder associated with IRPF is Hashimoto’s thyroiditis.^10–12 The patient described in this case had long-standing hypothyroidism prior to this presentation. Thyroid antibodies were present, although in low titers. It is possible this represents an autoimmune polyendocrine syndrome associated with IRPF. IRPF has been associated with other autoimmune conditions, suggesting that it too may have an autoimmune aetiology.

IRPF was previously thought to develop as a result of inflammatory reaction to antigens in aortic atherosclerotic plaques. Aortic histopathology generally demonstrated thinning of the tunica media with pronounced thickening, inflammation and fibrosis of the tunica adventitia.⁵ The theory was that thinning of the media resulted in presentation of oxidised low-density lipoproteins by plaque macrophages to T and B lymphocytes causing localised inflammation. Another common histological finding is vasculitis of the aortic vasa vasorum.²³

Recent research, however, has indicated that IRPF may be the result of a systemic inflammatory response or autoimmune phenomenon. One large genetic analysis study showed an association of IRPF with human leucocyte antigen (HLA) DRB1*03, an allele associated with type 1 diabetes mellitus, systemic lupus erythematosus and myasthenia gravis.⁸ Similarly, AD has been shown to have an association with the HLA-DRB1 gene locus. In a study of Norwegian patients, Skinningsrud et al demonstrated increased susceptibility to the development of AD with the presence of HLA-DRB1*03:01 and HLA-DRB1*04:04 alleles.²⁴

The association with autoimmune endocrinopathies has been observed with IgG₄-RD including autoimmune pancreatitis, Reidel’s thyroiditis and autoimmune hypophysitis. The growing body of evidence associating IRPF with autoimmune endocrine disease may support the notion that IRPF is on the same disease spectrum as IgG₄-RD. IRPF may represent a ‘seronegative’ form on the spectrum of fibroinflammatory disease.

The concomitant presentation of these two conditions also raises the question, did these diseases occur simultaneously or did one trigger the other? Cases reporting association between IRPF and other autoimmune diseases demonstrate that either IRPF occurs before the other autoimmune disease but also vice versa. Further research is needed to determine the connection between these two entities.

Learning points.

• Idiopathic retroperitoneal fibrosis (IRPF) presents with symptoms of back and/or flank pain, but can also present as obstructive uropathy from ureteral compression.

• Current research suggests that IRPF has an autoimmune aetiology.

• Addison’s disease (AD) should be suspected in patients with persistent hyponatraemia and hyperkalaemia, particularly in the setting of hypotension.

• Both IRPF and AD are associated with a variety of other autoimmune disorders. Providers should maintain a high index of suspicion for the coexistence or development of other autoimmune diseases in patients with these conditions.