Sarcoidosis

Sarcoidosis is a multisystemic disorder of unknown etiology, characterized by granuloma formation. Tissue biopsy is the primary test used to diagnose sarcoidosis; other laboratory tests, including CBC and chemistry panels, are not specific for the diagnosis but may be useful in assessing disease severity.

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

  • General testing
    • Diagnosis of exclusion
      • Rule out other granulomatous diseases – consider stains, cultures, and serologies for fungi, acid fast bacteria, and tuberculosis
    • Nonspecific testing
      • Chemistry panel – nonspecific test; may demonstrate
      • CBC – also nonspecific but may show leukopenia with lymphopenia
    • Angiotensin converting enzyme (ACE) – may have elevated level (2x normal), but this is not diagnostic for disease
  • Type specific testing
    • Pulmonary sarcoidosis
      • Fiber optic bronchoscopy with bronchoalveolar lavage (BAL), transbronchial biopsy, or endobronchial biopsy
      • 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
      • Cerebrospinal fluid (CSF) findings are nonspecific – lymphocyte pleocytosis, increased protein, decreased glucose, increased opening pressure
      • Rule out meningitis first
      • ACE – elevated level supports diagnosis of neurosarcoidosis but is not diagnostic
        • Specific (~90%) 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
    • Chest x-ray – hilar lymphadenopathy or parenchymal disease (nodules or fibrosis)
      • Necessary for staging
    • High resolution computed tomography (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)
  • Central nervous system (CNS) disease
    • Gadolinium-enhanced magnetic resonance imaging (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

  • Pulmonary function testing
    • May show restriction abnormalities, airflow obstruction, and/or reduced diffusing capacity of the lung for carbon monoxide (DLCO)
  • Electrocardiogram (ECG)
    • Obtained at baseline, with further testing (eg, echocardiogram) for abnormal result
  • Cardiac MRI
    • Test of choice for diagnosis of cardiac sarcoidosis

Differential Diagnosis

Monitoring

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

Background

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 Swedes, Danes, and African Americans

Genetics

  • Certain alleles have been noted to be associated with sarcoidosis presentations, although not with enough consistency to be considered in the clinical workup
    • HLA-DRB1*03 – higher rate of spontaneous resolution at 2 years if positive
    • HLA-DRB1*14/*15 – disease tends to be chronic
    • HLA-DRB1*0401 – associated with ocular involvement
    • HLA-DRB1*0101 – associated with abnormal calcium metabolism
    • HLA-DRB1*0301, HLA-DRB1*0101 – associated with T-cell expansion
    • HLA- DQB1*0601 – associated with cardiac sarcoidosis

Risk Factors

  • Family member with sarcoidosis (5-fold 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 antigens not yet identified
  • 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 – bilateral hilar lymphadenopathy
  • Stage II – bilateral hilar lymphadenopathy with 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
  • Musculoskeletal – arthralgias
  • 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)

ARUP Lab Tests

Evaluate for hypercalcemia

Evaluate hepatic involvement

Panel includes albumin; alkaline phosphatase (ALP); aspartate aminotransferase (AST); alanine aminotransferase (ALT); bilirubin, direct; protein, total; and bilirubin, total

Support diagnosis of sarcoidosis or neurosarcoidosis via angiotensin converting enzyme (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 cerebrospinal fluid (CSF) ACE concentrations

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

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

Support the diagnosis of sarcoidosis

Related Tests

Aid in the detection of latent disease among persons at increased risk for tuberculosis (TB)

Positive predictive value is less in low-risk populations

Test may be used in persons who have received BCG vaccine

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology

Rule out meningitis

Useful in assessing metabolic derangement as cause of altered consciousness

Panel includes sodium, serum or plasma; potassium, serum or plasma; chloride, serum or plasma; carbon dioxide, serum or plasma; anion gap

Identify bacteria in cerebrospinal fluid (CSF)

Gold standard test for diagnosing the presence of mycobacteria organisms

Monitor respiratory specimens in previously diagnosed patients

Should NOT be ordered without culture in previously undiagnosed patients

For panel test that includes culture and stain, refer to acid-fast bacillus (AFB) culture and AFB stain

Rule out meningitis

Useful in assessing metabolic derangement as cause of altered consciousness

Rule out meningitis

Aid in differentiating bacterial from viral meningitis

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology

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

Rule out meningitis

May be helpful in differentiating bacterial from viral etiology

Medical Experts

Contributor

Genzen

Jonathan R. Genzen, MD, PhD

Associate Professor of Clinical Pathology, University of Utah

Chief Operations Officer, Medical Director of Automated Core Laboratory and Farmington Health Center Clinical Laboratory, at ARUP Laboratories

Contributor

References

Additional Resources
  • 22547486

    O'Regan A
    Berman JS
    Ann Intern Med
    May 2012
    156
    9
    ITC5-1 through ITC5-15; quiz ITC5-16
    PubMed
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