Sarcoidosis

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Epidemiology
 Peak incidence: 25–35 years old with a second peak for females 50–65 years old  [1]

 Sex: ♀ > ♂ (2:1)
 Prevalence: ∼ 10 times higher among African Americans than whites  [2]

Sarcoidosis most frequently affects young African American women in the US.

Epidemiological data refers to the US, unless otherwise specified.

Etiology
The cause of sarcoidosis is still unknown. Current hypotheses suggest that the etiology is
multifactorial. [3]

 Genetic 
 Environmental agent exposure (e.g., beryllium and its salts may cause granulomas)
 Infectious agents (e.g., mycobacteria are seen as potential etiologic agents)

Pathophysiology
Sarcoidosis is a systemic disorder characterized by widespread, immune-mediated formation
of noncaseating granulomas.

 T-cell dysfunctionand increased B-cell activity result in local immune

hyperactivity and inflammation.
 Formation of noncaseating granulomas within the lungs and the lymphatic system (see
“Granulomatous inflammation” for details)
o Macrophages activate Th1 cells. 
o Th1 cells stimulate the formation of epithelioid cells and multinucleated giant
cells by releasing IFN-γ.
o Epithelioid cells produce angiotensin-converting enzyme (ACE) and
release cytokines, which recruit more immune cells.
o A mature granuloma is composed of epithelioid cells and macrophages in the
center, which are surrounded by lymphocytes and fibroblasts.
  Fibrosis and subsequent damage of organs and tissue: Epithelioid cells secrete cytokines to
recruit fibroblasts, which cause fibrosis.
 Calcium dysregulation: activated macrophages produce 1-alpha hydroxylase → ↑ 1,25-
dihydroxyvitamin D (hypervitaminosis D) → hyperphosphatemia, hypercalcemia, and
possibly renal failure 

Clinical features
Acute sarcoidosis and chronic sarcoidosis are two distinct manifestations of the disease,
where acute sarcoidosis does not necessarily precede chronic sarcoidosis.

Acute sarcoidosis (approx. ⅓ of cases)  [6]

 Typically has a sudden onset and remits spontaneously within approx. 2 years

 Progression to chronic sarcoidosis is rare.
 General: fever, malaise, lack of appetite, weight loss
 Pulmonary: dyspnea, cough, chest pain
 Extrapulmonary: arthritis, anterior uveitis, erythema nodosum 
Chronic sarcoidosis (approx. ⅔ of cases)  [6]

 Inrare cases, preceded by acute sarcoidosis

 Gradual disease course; may be recurrent or progressive

Pulmonary (most common)  [7]

 Often asymptomatic in the early stages

 Interstitial fibrosis
o Cough, exertional dyspnea
o Mild rales on pulmonary auscultation

Extrapulmonary   [8]

 Peripheral lymph nodes involvement: the most frequent site of extrapulmonary

manifestation (∼ 40%) 
 Ocular findings (∼ 25%)
o Granulomatous uveitis = ‫חלק בעין‬
o Blurred vision (ocular sarcoidosis) 
 Skin findings (∼25%)    
[9]

o Lupus pernio
 Pathognomonic, extensive, purple skin lesions (violaceous skin plaques)
on the nose, cheeks, chin, and/or ears; also referred to as epithelioid
granulomas of the dermis   
 Facial rash similar to that seen in lupus
o Scar sarcoidosis: inflamed, purple skin infiltration and elevation of old scars or
tattoos 
 Other manifestations
 o Musculoskeletal
Arthralgias/arthritis: resembles rheumatoid arthritis; usually bilateral

involvement of the ankle joints
 Bone lesions
o Nervous system (neurosarcoidosis)
Cranial nerve palsy (facial nerve palsy is the most common)

 Diabetes insipidus
 Meningitis
 Hypopituitarism
 Peripheral neuropathy
 Myopathy
o Heart: restrictive cardiomyopathy, pericardial effusion, AV block, or even sudden
cardiac death
o Liver: hepatic granulomas; hepatomegaly in ∼ 30% of cases
o Kidneys: most commonly related to calcium metabolism
(e.g., nephrocalcinosis, nephrolithiasis)
o Spleen: splenomegaly in ∼ 30% of cases
Features of sarcoidosis are GRUELING: Granulomas, aRthritis, Uveitis, Erythema
nodosum, Lymphadenopathy, Interstitial fibrosis, Negative TB test, and Gammaglobulinemia.

Subtypes and variants

Lofgren syndrome  [10]

 Highly acute clinical presentation with fever and the following triad of symptoms

o Migratory polyarthritis: symmetrical arthritis that primarily affects the ankles
o Erythema nodosum: primarily affects the extensor surface of the lower legs
o Bilateral hilar lymphadenopathy

Heerfordt syndrome  [11]

 An atypical clinical presentation with fever and the following triad of symptoms

o Parotitis
o Uveitis (iridocyclitis)
o Facial palsy

Jungling disease  [12]

A special form of chronic sarcoidosis

 Cystic bone lesions of the acral regions (fingers)
Stages

Stages of chronic sarcoidosis

Chronic
Chest x-ray findings
sarcoidosis

Stage 0  Normal findings 

Stage I  Bilateral hilar lymphadenopathy (reversible)*

 Bilateral reticular or ground-glass opacities with hilar lymphadenopathy;

Stage II
disseminated, reticulonodular infiltrates

Stage III  Bilateral reticular or ground-glass opacities without hilar lymphadenopathy

Stage IV  Lung fibrosis 

* In most cases, the disease resolves spontaneously at this stage.

Diagnostics
 A chest x-ray (which may reveal parenchymal disease with hilar lymphadenopathy) is the
most appropriate initial test for a patient with suspected sarcoidosis.
 Laboratory tests may support the diagnosis of sarcoidosis, but a biopsy is the gold standard.
 Additional tests can help determine the severity of the disease, possible complications, and
prognosis.

Chest x-ray
 Best initialtest
 Sarcoidosis is frequently an incidental finding detected on chest x-ray
 Findings: hilar lymphadenopathy with or without bilateral reticular opacities 
 Chronic sarcoidosis is categorized according to chest x-ray findings (see “Stages” above).

Patients with chronic sarcoidosis often have moderate clinical manifestations but radiographic
findings of extensive disease.

High-resolution CT (HRCT)  [14]

 Nextdiagnostic test if chest x-ray is suspicious or normal

 HRCT can detect parenchymal and mediastinal abnormalities such as:
 o Extensive hilar and mediastinal lymphadenopathy 
o Parenchymal masses or nodules
o Irregular thickening of the bronchial wall and bronchovascular bundles
o Fibrosis with traction bronchiectasis

Laboratory tests
 Acute sarcoidosis
o ↑ Inflammatory markers
o Findings typical for sarcoidosis are absent (e.g., ↑ ACE, ↑ IgG, ↑ calcium)
 Chronic sarcoidosis
o ↑ Calcium due to elevated levels of 1,25-(OH) -vitamin D  (see “Pathophysiology”
2 3

for mechanism)
o ↑ ACE blood levels: may be used to monitor disease activity and therapy 
o ↑ Inflammatory markers, possible lymphopenia
o Soluble interleukin-2 receptor (S-IL-2R), neopterin: parameters that also correlate
with disease activity [15]

o ↑ Alkaline phosphatase   [16]

o ↓ CD4  T cells: T helper cells are consumed during granuloma formation

+

→ low CD4  levels in serum and high in bronchoalveolar lavage.

+

o ↑ IgG (approx. 50% of patients)

o Urine analysis: hypercalciuria

Bronchoscopy  [8][17]

 Biopsy: the gold standard for diagnosis 

o Origin of specimen: lung tissue and lymph nodes
o Findings
Noncaseating granulomas with giant cells 

 Asteroid bodies, Schaumann bodies
o Specimens should be used for histology and culture with special stains for fungus
and mycobacteria
 Bronchoalveolar lavage (BAL): increased CD4/CD8 ratio 

Pulmonary function tests

 Restrictive or obstructive pattern (see “Restrictive lung disease” and “Obstructive lung
disease”)
Differential diagnoses

The differential diagnoses listed here are not exhaustive.

Treatment
  Isolated pulmonary sarcoidosis: Inmost cases, no treatment is required. The disease is often
asymptomatic, non-progressive, and has a high rate of spontaneous remission.
 Symptomatic or extrapulmonary sarcoidosis  [13]

o First line: glucocorticoids
o Second line: alternative immunosuppressive
therapy (e.g., methotrexate or azathioprine), possibly in combination
with glucocorticoids
o Antimalarial drugs (e.g., chloroquine, hydroxychloroquine) 
o Last resort in severe pulmonary disease: lung transplantation
o NSAIDs are always indicated for symptom relief.

Complications
 Patients with sarcoidosis have an increased risk of malignancy (especially lung cancer and
malignant lymphomas)
 Pulmonary complications 
o Bronchiectasis
o Lung fibrosis: Irreversible fibrotic remodeling together with compression of
large pulmonary arteries due to bilateral hilar lymphadenopathy may
increase pulmonary vascular resistance, resulting in pulmonary hypertension (PH).
 Chronic renal failure  (see “Clinical features” above)
We list the most important complications. The selection is not exhaustive.
Prognosis
 Increased calcium is associated with a poorer prognosis .
 Acute sarcoidosis: spontaneous remission in 60–70% of cases  [21]

 10–30% of cases may progress to chronic sarcoidosis.  [22]

 Chronic sarcoidosis (% remission rate) 

[13]

o Type IV: Life expectancy is limited because of severely impaired lung function.

o Type III: approx. 20%
o Type II: approx. 50%
o Type I: approx. 70%
The spontaneous remission rates in acute sarcoidosis are extremely high. In chronic sarcoidosis, the
remission rates vary depending on the type.