Jay Simhan, MD
Michael A. Pontari, MD
BASICS
DESCRIPTION
• Sarcoidosis is a systemic granulomatous disease with unknown etiology; it is characterized by the formation of noncaseating granulomas, primarily in the lungs, but also throughout the rest of the body.
• Hypercalcuria is more common than hypercalcemia.
– Renal stones secondary to hypercalcuria can be associated in up to 14% of patients. Occasionally, this can be the presenting complaint that leads to the diagnosis of sarcoidosis.
• Other urologic manifestations of sarcoidosis are rare. These include acute interstitial nephritis, neurogenic bladder dysfunction secondary to neurosarcoidosis, renal pseudotumors, bladder sarcoidosis with gross hematuria, and ureteral obstruction due to retroperitoneal adenopathy or fibrosis.
EPIDEMIOLOGY
Incidence
• In US, sarcoidosis is 10 times more common in African Americans than in whites (AA: 35–64/100,000; whites: 10–14/100,000)
– African Americans have a 2.4% lifetime risk of developing the disease, whereas in Caucasian Americans and Europeans, the incidence is lower
• Female > Male
• Onset is most often before age 50. Peak is age 20–39 (1)[A]
• Sarcoidosis affects both men and women, but it seems to be most prevalent among African American women
Prevalence
1–40 cases per 100,000 population
RISK FACTORS
• Many organisms have been linked, including Mycoplasma sp., fungi, Histoplasma and Cryptococcus spp.; viruses, and Propionibacterium (2)[B].
• Environmental exposures to noninfectious agents, such as aluminum, zirconium, talc, pine tree pollen, and clay, have also been implicated.
Genetics
• Familial clustering of cases has been reported. Monozygotic twins who have sarcoidosis are 2–4 times as likely to have the disease as dizygotic twins.
• Most common allele found in sarcoidosis is HLA-B8. Other associated alleles include HLA-A1 and HLA-DR3.
PATHOPHYSIOLOGY
• The cause of sarcoidosis is unknown. Symptoms are extensive and can involve pulmonary, arthritic, skin lesions, and manifestations relative to specific organ involvement.
• It is suspected that the granulomas of sarcoidosis are caused by an abnormal immunologic response to a stimulus.
• The most common presentation is pulmonary: Bilateral hilar adenopathy (50%). Less common is bilateral hilar adenopathy and pulmonary infiltrate (25%) and pulmonary infiltrate alone (15%). Other presenting manifestations include cough, wheezing, fever, malaise, fatigue, hepatomegaly, splenomegaly, night sweats, and uveitis.
• Hypercalcemia:
– Present in at least 20–30% of patients with sarcoidosis.
– Sarcoidosis may cause resorptive hypercalciuria and urolithiasis.
– The sarcoid granuloma produces 1,25 (OH)2D3 (calcitriol), causing increased intestinal absorption of calcium, hypercalcemia. 60% develop hypercalciuria (3)[A].
– Pulmonary alveolar cells and lymph node in patients with sarcoidosis are capable of synthesizing vitamin D; this is usually a function limited to the kidney.
– Most patients with sarcoidosis have a suppressed level of PTH secondary to hypercalcemia.
– Secondary hyperoxaluria can be seen.
– Most sarcoidosis stones are calcium oxalate.
• Glomerular involvement is very rare and may include:
– Membranous nephropathy, IgA nephropathy, minimal-change disease, proliferative or crescentic glomerulonephritis, and focal glomerulosclerosis.
– Interstitial nephritis with granuloma formation is relatively common in sarcoidosis.
• Tubulointerstitial nephritis and uveitis (TINU) syndrome is idiopathic; these patients should be evaluated for sarcoidosis and Sjögren syndrome.
• Prostatic involvement has been reported.
ALERT
A diagnosis of sarcoidosis should always be considered when patients present with renal calculi of unknown origin.
ASSOCIATED CONDITIONS
Erythema nodosum
GENERAL PREVENTION
N/A
DIAGNOSIS
HISTORY
• Sarcoidosis can involve any organ system; the clinical presentation is variable and insidious.
• Patients most commonly present in winter and early spring, which suggests a possible environmental trigger.
• Cutaneous involvement is seen in 25% of patients with sarcoidosis. It may accompany systemic involvement.
• Fever, anorexia, and polyarthralgias.
• Dyspnea on exertion, cough, chest pain, and occasionally hemoptysis.
PHYSICAL EXAM
• Cutaneous involvement may be present (lupus pernio, erythema nodosum)
– Most common sites are face, upper back, trunk, or extremities (3)[A]
• Wheezing
• Adenopathy
• Some cases of involvement of testis and epididymis, range from induration to painless mass
• Neurologic symptoms
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Sterile pyuria and mild proteinuria
• Leukopenia and/or thrombocytopenia are common.
• Eosinophilia: 24%
• Anemia: 5%
• Hypercalciuria: 49%
• Hypercalcemia: 13%
• Elevated calcitriol levels
• Serum ACE level is elevated in 60% of patients; therefore, this test is not sensitive in diagnosing sarcoidosis.
• BUN and Cr may be elevated if there is renal involvement.
Imaging
• Chest imaging may demonstrate hilar adenopathy or pulmonary infiltrate present in 90% of sarcoidosis patients.
• Abdominal imaging may show hepatomegaly, retroperitoneal adenopathy, and retroperitoneal fibrosis.
• Stones and nephrocalcinosis secondary to hypercalcemia can be seen on CT.
• Sarcoid renal pseudotumors can mimic renal cell carcinoma, and more diffuse enlargement may mimic lymphoma. Retroperitoneal lymph nodes may enlarge sufficiently in sarcoidosis to cause obstruction.
• In rare cases of urinary involvement, ureterohydronephrosis may be seen from urolithiasis or obstruction.
Diagnostic Procedures/Surgery
• Many physicians prefer a biopsy to confirm the diagnosis of sarcoidosis.
– Mediastinoscopy is utilized to assess hilar adenopathy.
– Fiberoptic bronchoscopy with transbronchial biopsy is used for biopsy documentation of pulmonary sarcoidosis.
– Biopsy of renal mass (especially atypical in appearance) in patient with sarcoid to distinguish from RCC.
• Bladder involvement confirmation requires transurethral bladder resection.
• Sarcoidosis can also be differentiated from other diagnoses by the rapid resolution of hypercalcemia with initiation of corticosteroid therapy.
• In cases of bilateral testicular masses in man with sarcoid and negative markers, consider testes sparing approach (3)[C].
Pathologic Findings
Typical sarcoid lesions are characterized by the presence of circumscribed granulomas of epithelioid cells with little or no necrosis (noncaseating granuloma).
DIFFERENTIAL DIAGNOSIS
• Interstitial lung diseases:
– Medications (nitrofurantoin, methotrexate), idiopathic pulmonary fibrosis, collagen vascular diseases, amyloidosis, hypersensitivity pneumonitis, granulomatous vasculitis, collagen vascular diseases
– Other granulomatous diseases: TB, brucellosis, Q fever, biliary cirrhosis, Wegener granulomatosis, Hodgkin disease
• Other skin and arthritic disorders
• Other causes of hypercalcemia/hypercalcuria:
– PTH-related malignancy, vitamin D-related mediations (eg, lithium), endocrine disorders, immobilization
• Causes of interstitial nephritis:
– Sjögren syndrome
– Systemic lupus erythematosus
– Wegener granulomatosis
– Behçet disease
TREATMENT
GENERAL MEASURES
• Sarcoidosis remains a diagnosis of exclusion. Before a definitive diagnosis can be made, multiple other conditions that can share similar symptomatology and pathologic findings must be ruled out (See “Differential diagnosis” above).
• Coordination of care is suggested with experts in the management of the systemic and pulmonary manifestations of the disease.
• Corticosteroids are the mainstay of therapy for most manifestations of sarcoidosis.
• For sarcoidosis-related renal disease, the primary management is steroid therapy. Although many have poor renal function on presentation, patients may respond dramatically to steroid therapy. The steroids are given at high dose for 1–2 mo then reduced for the remainder of the course, which should be at least 1 yr.
• Hydration and limiting sodium intake can reduce hypercalcuria.
MEDICATION
First Line
• Oral corticosteroids are the treatment of choice for patients with hypercalcemia and systemic involvement.
– Initial prednisone 40 mg/d, PO which is tapered to every other day over several weeks for long-term therapy; typically 10–15 mg PO every other day
• Nephropathy due to sarcoidosis appears to respond to steroid therapy.
Second Line
• Inhaled steroids
• Methotrexate
• Chloroquine
SURGERY/OTHER PROCEDURES
• Biopsy is necessary for diagnosis.
• Obstruction may require diversion.
• Surgical management of urolithiasis
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
N/A
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• The course of the disease is variable.
• Spontaneous remission occurs in 50% of patients.
• 1/3 of patients have eventual improvement.
• 10–30% of patients have chronic or progressive disease.
COMPLICATIONS
• Renal lithiasis, gross hematuria, ureteral obstruction, neurogenic bladder dysfunction
• Renal failure is rare and is due to hypercalcemic nephropathy.
FOLLOW-UP
Patient Monitoring
History, physical exam, chest x-ray, pulmonary function tests, and serum chemistry
Patient Resources
• National Heart Lung and Blood Institute. http://www.nhlbi.nih.gov/health/health-topics/topics/sarc/
• UpToDate. http://www.uptodate.com/contents/sarcoidosis-beyond-the-basics
REFERENCES
1. Rybicki BA, Major M, Popovich J Jr, et al. Racial differences in sarcoidosis incidence: A 5 year study in a health maintenance organization. Am J Epidemiol. 1997;145:234–241.
2. Culver DA. Sarcoidosis. Immunol Allergy Clin N Am. 2012;32:487–511.
3. La Rochelle JC, Coogan CL. Urological manifestations of sarcoidosis. J Urol. 2012;187:18–24.
ADDITIONAL READING
• Fitzpatrick KJ, Chancellor MB, Rivas DA, et al. Urologic manifestations of spinal cord sarcoidosis. J Spinal Cord Med. 1996;19(3):201–203.
• Koyama T, et al. Radiologic manifestations of sarcoidosis in various organs. Radiographics. 2004;24:87–104.
• Rao PK. Sabanegh ES. Genitoruinary sarcoidosis. Rev Urol. 2009;11:108–113.
• Rehman J, Rizkala ER, Chughtai B, et al. Hypoechoic testicular mass: A case of testicular and epididymal sarcoidosis. Urology. 2005;66(3):657.
See Also (Topic, Algorithm, Media)
• Hypercalcemia, Urologic Considerations
• Urolithiasis, Adult, General
CODES
ICD9
• 135 Sarcoidosis
• 275.40 Unspecified disorder of calcium metabolism
• 592.0 Calculus of kidney
ICD10
• D86.9 Sarcoidosis, unspecified
• E83.52 Hypercalcemia
• N20.0 Calculus of kidney
CLINICAL/SURGICAL PEARLS
• Sarcoidosis may cause resorptive hypercalciuria and urolithiasis.
• Retroperitoneal lymph nodes may enlarge sufficiently in sarcoidosis to cause obstruction..
• Consider a diagnosis of sarcoidosis in patients presenting with nephrolithiasis of unknown etiology, especially in an African American female.
• For sarcoidosis-related renal disease, oral corticosteroids is the mainstay of treatment.+