Sarcoidosis

Diagnosis

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

Monitoring

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

Clinical Background

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)

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
Calcium, Serum or Plasma 0020027
Method: Quantitative Spectrophotometry

Evaluate for hypercalcemia

   
Alkaline Phosphatase, Serum or Plasma 0020005
Method: Quantitative Enzymatic

Evaluate hepatic involvement

   
Hepatic Function Panel 0020416
Method: Quantitative Enzymatic/Quantitative Spectrophotometry

Evaluate hepatic involvement

   
Angiotensin Converting Enzyme, Serum 0080001
Method: Quantitative Enzymatic

Support diagnosis of sarcoidosis or neurosarcoidosis via ACE levels in serum

May be used to evaluate treatment response

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

Further tissue biopsy and evaluation for granulomas is necessary to confirm the diagnosis
Angiotensin Converting Enzyme, CSF 0098974
Method: Quantitative Spectrophotometry

Support diagnosis of neurosarcoidosis

May be used to evaluate treatment response

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

Diagnosis sarcoidosis

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

Rule out tuberculosis as etiology of other granulomas

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

 
Additional Tests Available
 
Click the plus sign to expand the table of additional tests.
Test Name and NumberComments
CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology

Electrolyte Panel 0020410
Method: Quantitative Ion-Selective Electrode/Enzymatic

Rule out meningitis

Useful in assessing metabolic derangement as cause of altered consciousness

Cerebrospinal Fluid (CSF) Culture and Gram Stain 0060106
Method: Stain/Culture/Identification

Rule out meningitis

Glucose, Plasma or Serum 0020024
Method: Quantitative Enzymatic

Rule out meningitis

Useful in assessing metabolic derangement as cause of altered consciousness

Cell Count, CSF 0095018
Method: Cell Count/Differential

Rule out meningitis

Aids in differentiating bacterial from viral meningitis

Glucose, CSF 0020515
Method: Enzymatic

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology

Usually low (<10mg/dL) in bacterial meningitis and tuberculous disease

Protein, Total, CSF 0020514
Method: Reflectance Spectrophotometry

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology