Sarcoidosis

  • Diagnosis
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Lymphadenopathy on chest x-ray or other appropriate clinical signs and symptoms consistent with diagnosis of sarcoidosis

Criteria for Diagnosis

  • Clinical and radiological presentation
    • Noncaseating granulomas
    • No evidence of other disease

Laboratory Testing

  • Diagnosis of exclusion
    • Rule out other granulomatous diseases – consider stains and cultures for fungi and tuberculosis (TB test)
  • Chemistry panel – nonspecific test; may demonstrate hypercalcemia (~10%), hypercalcuria (~30%), or liver transaminase elevations (~20%)
  • Angiotensin converting enzyme (ACE) – may have elevated level (2x normal), but this is not diagnostic for disease
  • Pulmonary sarcoidosis
    • Fiber optic bronchoscopy with BAL, transbronchial biopsy, or endobronchial biopsy
    • Bronchoalveolar lavage (BAL)
      • Winterbauer criteria – CD4/CD8 >2; ≤1% neutrophils; ≤1% eosinophils
      • Triad has 59% sensitivity, 94% specificity
        • Positive predictive value 73%; negative predictive value 90%
        • Most centers use >3.5 as definitive (Costabel, 2010)
    • Transbronchial biopsy
      • Has better yield if 4-5 specimens are obtained – yield increased when endobronchial biopsy combined with transbronchial biopsy
      • If Winterbauer criteria are met and clinical presentation is consistent with sarcoidosis, absence of granulomas on biopsy does not negate the diagnosis of sarcoidosis
      • If results are negative and high suspicion remains, consider surgical biopsy with mediastinoscopy procedure of choice
  • Neurosarcoidosis
    • CSF studies
    • Rule out meningitis first
    • Nonspecific – lymphocyte pleocytosis, increased protein, decreased glucose, increased opening pressure
    • ACE – elevated level supports diagnosis of neurosarcoidosis but is not diagnostic
      • Specific (94-95%) but not sensitive (<60%)
    • ~30% have no abnormalities
    • Elevated CD4/CD8 frequent
  • Ocular sarcoidosis
    • Histology positive or ACE positive with ocular signs and symptoms

Histology

  • Presence of noncaseating granulomas
    • Tissue obtained by bronchoscopy if pulmonary signs and symptoms
    • May be obtained from other organ sites – skin, lymph node, parotid are most common
    • Special stains for acid fast and fungi should be performed to rule out other diseases

Imaging Studies

  • Pulmonary disease – high resolution CT produces better diagnostic yield than a chest x-ray; classically shows widespread micronodules with perilymphangitic distribution in middle and upper lobes (unnecessary test for most patients)
    • Justified when there are atypical chest x-rays or normal chest x-rays with suspicion of disease
    • Useful for detection of lung disease complications
  • Central nervous system (CNS) disease
    • Gadolinium-enhanced MRI
      • Involvement of leptomeninges in ~40%
    • CT – not as accurate as MRI but can be used if MRI is contraindicated
  • Gallium 67 scan
    • Classic uptake – parotid and lacrimal glands (Panda sign), paratracheal and bilateral hilar uptake (Lambda sign)

Other Testing

  • Cardiac MRI – test of choice for diagnosis of cardiac sarcoidosis
  • Pulmonary function testing – full function testing with diffusing capacity of the lung for carbon monoxide demonstrates decreased volumes and diffusion capacity
  • EKG – if patient develops dilated heart or new arrhythmia
    • May proceed with echo, then perfusion scans (thallium, gallium, or technetium) to assess for cardiac involvement

Differential Diagnosis

  • Serial ACE – may be useful in monitoring disease activity
  • Serial pulmonary function tests – useful in monitoring pulmonary disease

Sarcoidosis is a multisystemic disorder of unknown etiology, characterized by granuloma formation.

Epidemiology

  • Incidence – 10-20/100,000 in U.S. (Heinle, 2014)
    • 40/100,000 among African Americans and in some North European countries
  • Age – peak incidence in 20s-40s; rare in children <15 years
  • Sex – M<F
  • Ethnicity – most prevalent in Swedish, Danish, and African-Americans

Genetics

  • HLA-DRB1*03 – disease usually spontaneously resolves
  • HLA-DRB1*14/*15 – disease tends to be chronic

Risk Factors

  • Family member with sarcoidosis (fivefold increased risk)
  • HLA-DRB1*1101, HLA-DPB1*0101 alleles

Pathophysiology

  • Result of chronic immunological response associated with a genetic susceptibility and exposure to specific infections or environmental factors
    • Exaggerated immune response to so far unidentified antigens
  • Accumulation of activated T-cells and macrophages at site of disease activity
  • Lymphocytes are CD4 type
  • Macrophages release cytokines that drive inflammation, granuloma formation, and eventual fibrosis

Disease Stages

  • Stage 0 – normal
  • Stage I – isolated bilateral thoracic lymphadenopathy
  • Stage II – bilateral hilar without adenopathy; lymphadenopathy plus lung infiltration
  • Stage III – parenchymal infiltration
  • Stage IV – advanced parenchymal disease, including overt pulmonary fibrosis

Clinical Presentation

  • Asymptomatic (30-50%) routine chest x-ray with abnormalities of hilar adenopathy typically leads to diagnosis
  • Nonspecific (30%) – fever, weight loss, fatigue
  • Pulmonary (30%)
    • Löfgren syndrome – bilateral hilar adenopathy, ankle arthritis, fever, myalgia, weight loss, and erythema nodosum
    • Dyspnea, wheezing
  • Dermatologic – maculopapular rashes, plaques and nodules (lupus pernio), erythema nodosum, and lupus pernio
  • Renal – nephrolithiasis, nephrocalcinosis, renal failure
  • Cardiac – conduction disorders, infiltrative cardiomyopathy with heart failure, pericarditis
  • Ophthalmic – anterior uveitis
  • Hepatic/splenic – granulomas, but dysfunction is rare
  • Endocrine – hypercalcemia with nephrolithiasis
  • Central nervous system – neurosarcoidosis is an uncommon but serious manifestation of sarcoidosis, affecting about 5-10% of patients
    • Most common manifestations include myelopathy, cranial neuropathy, and encephalopathy
      • Most common nerves are cranial nerves (CN) VII and II
    • Untreated patients may develop acute neurologic emergencies, including seizures, cord compression, and increased intracranial pressure
    • Heerfordt syndrome – uveitis, parotid gland enlargement, fever, and cranial neuropathy (usually CN VII)
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry

Alkaline Phosphatase, Serum or Plasma 0020005
Method: Quantitative Enzymatic

Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Angiotensin Converting Enzyme, Serum 0080001
Method: Quantitative Enzymatic

Limitations 

Antihypertensive medications such as ACE inhibitors, ACE receptor blockers, and diuretics may interfere with test results

Test is a nonspecific indicator of response to treatment; not specific for diagnosis

In neurosarcoidosis, serum ACE concentrations are less likely to be elevated than CSF ACE concentrations; CSF ACE levels are increased in about 55% of patients with neurosarcoidosis, 5% of those with sarcoidosis (without neurologic abnormality), and 13% of those with other neurological diseases

Measurement of ACE activity for the evaluation of sarcoidosis is not reliable when ACE inhibitors are present; serum ACE activity is reduced in patients on ACE inhibitor therapy

Follow-up 

Further tissue biopsy and evaluation for granulomas is necessary to confirm the diagnosis 

Angiotensin Converting Enzyme, CSF 0098974
Method: Quantitative Spectrophotometry

Limitations 

Antihypertensive medications such as ACE inhibitors, ACE receptor blockers, and diuretics may interfere with test results

Test is a nonspecific indicator of response to treatment and is not specific for sarcoidosis

Lymphocyte Subset Panel 4 - T-Cell Subsets Percent and Ratio, Bronchoalveolar Lavage 0093420
Method: Flow Cytometry

QuantiFERON-TB Gold In-Tube 0051729
Method: Cell Culture/Semi-Quantitative Enzyme-Linked Immunosorbent Assay

Limitations 

Negative result does not completely rule out TB infection; positive result does not differentiate active from latent TB

General References

Bargagli E, Mazzi A, Rottoli P. Markers of inflammation in sarcoidosis: blood, urine, BAL, sputum, and exhaled gas. Clin Chest Med. 2008; 29(3): 445-58, viii. PubMed

Costabel U, Bonella F, Ohshimo S, Guzman J. Diagnostic modalities in sarcoidosis: BAL, EBUS, and PET. Semin Respir Crit Care Med. 2010; 31(4): 404-8. PubMed

Hamzeh N. Sarcoidosis. Med Clin North Am. 2011; 95(6): 1223-34. PubMed

Heinle R, Chang C. Diagnostic criteria for sarcoidosis. Autoimmun Rev. 2014; 13(4-5): 383-7. PubMed

Keir G, Wells AU. Assessing pulmonary disease and response to therapy: which test? Semin Respir Crit Care Med. 2010; 31(4): 409-18. PubMed

Nunes H, Bouvry D, Soler P, Valeyre D. Sarcoidosis. Orphanet J Rare Dis. 2007; 2: 46. PubMed

O'Regan A, Berman JS. Sarcoidosis. Ann Intern Med. 2012; 156(9): ITC5-1, ITC5-2, ITC5-3, ITC5-4, ITC5-5, ITC5-6, ITC5-7, ITC5-8, ITC5-9, ITC5-10, ITC5-11, ITC5-12, ITC5-13, ITC5-14, ITC5-15; . PubMed

Rose AS, Tielker MA, Knox KS. Hepatic, ocular, and cutaneous sarcoidosis. Clin Chest Med. 2008; 29(3): 509-24, ix. PubMed

Valeyre D, Prasse A, Nunes H, Uzunhan Y, Brillet P, Müller-Quernheim J. Sarcoidosis. Lancet. 2014; 383(9923): 1155-67. PubMed

Wells AU. The clinical utility of bronchoalveolar lavage in diffuse parenchymal lung disease. Eur Respir Rev. 2010; 19(117): 237-41. PubMed

Winterbauer RH, Lammert J, Selland M, Wu R, Corley D, Springmeyer SC. Bronchoalveolar lavage cell populations in the diagnosis of sarcoidosis. Chest. 1993; 104(2): 352-61. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Erickson A, Cousin R, Wu JT, Ashwood ER. Quantitative spectrophotometric microplate assay for angiotensin-converting enzyme in cerebrospinal fluid. Clin Chem. 2003; 49(6 Pt 1): 970-2. PubMed

Krasowski MD, Savage J, Ehlers A, Maakestad J, Schmidt GA, La'ulu SL, Rasmussen NN, Strathmann FG, Genzen JR. Ordering of the Serum Angiotensin-Converting Enzyme Test in Patients Receiving Angiotensin-Converting Enzyme Inhibitor Therapy: An Avoidable but Common Error Chest. 2015; 148(6): 1447-53. PubMed

Medical Reviewers

Last Update: August 2016