What is sarcoidosis and who gets it?
Sarcoidosis is a multisystem granulomatous disorder of unknown aetiology that primarily affects the lungs and lymphoid organs, though other organs may become involved over time. Most patients remain asymptomatic for a long period; others present with nonspecific symptoms or organ failure. Histopathology remains the gold standard for diagnosis.
- Age: all ages, most commonly 20 to 39 years.
- Race: a higher incidence in Black individuals, with an annual incidence of 17 to 35 per 100,000.
- Extrathoracic patterns: erythema nodosum in Europeans, chronic uveitis in Black individuals in the United States and lupus pernio in Puerto Ricans.
- Mortality: about 1% to 5%; cardiac involvement is the commonest cause of death, followed by respiratory failure.
What is the pathogenesis and the characteristic histology?
The cause is unknown, but the disease usually arises in genetically susceptible individuals after exposure to specific environmental agents. Risk loci include BTNL2, HLA-B, HLA-DPB1 and ANXA11, and the HLA-DRB1 alleles (03, 11, 12, 14, 15) raise risk. Environmental agents implicated include aluminium, zirconium, talc, pine pollen, clay and insecticides; among infectious agents, mycobacteria are the most strongly associated, followed by Leptospira, Mycoplasma, Chlamydia pneumoniae and Borrelia burgdorferi.
Pathogenesis is poorly understood. An exaggerated T helper 1 (Th1) response is thought to drive the disease, often with an inverted CD4/CD8 ratio, and tumour necrosis factor is elevated. This is a cell-mediated (type IV) response; compare hypersensitivity reactions.
Histology. A lymph node biopsy shows discrete or confluent non-caseating granulomas made of epithelioid cells and multinucleated giant cells, surrounded by only sparse lymphocytes, with minimal or no central necrosis. Cytoplasmic inclusions may be seen: asteroid bodies, Schaumann bodies and Hamazaki-Wesenberg bodies, as well as calcium oxalate crystals.
- Trigger: a genetically susceptible person (HLA-DRB1, BTNL2) meets an antigen, possibly mycobacterial or environmental.
- Th1 response: CD4 T cells accumulate in the lung and nodes, giving an inverted CD4/CD8 ratio, with raised TNF.
- Granuloma: epithelioid cells and giant cells aggregate, with a sparse lymphocyte rim and no caseation.
- Outcome: spontaneous remission in most; persistent inflammation can lead to fibrosis (stage IV), pulmonary hypertension and end-stage lung disease.
What are the clinical features of sarcoidosis?
Symptoms vary. The typical pulmonary presentation is a persistent dry cough, fatigue and shortness of breath. Other manifestations include painful red skin lumps, uveitis with blurred vision, hoarseness, palpable lymph nodes (axilla and neck), swollen joints, hearing loss, seizures and psychiatric disorders.
| System | Features to remember |
|---|---|
| Lung | Main site; persistent dry cough, dyspnoea; reduced DLCO, restrictive pattern in advanced disease (about 10% have an obstructive pattern) |
| Skin | Papular nodules on the upper face and back of the neck and at old scars and tattoos; lupus pernio (violaceous central facial plaques); erythema nodosum (painful shin nodules) |
| Eye | About 50% of patients; uveitis is the commonest feature |
| Heart | Cardiomyopathy, conduction block, sudden cardiac death; implantable cardioverter-defibrillator recommended in cardiac sarcoidosis; MRI or PET to diagnose |
| CNS | Diabetes insipidus followed by hyperprolactinaemia; seizures, anxiety, depression |
| Liver and kidney | Raised alkaline phosphatase suggests diffuse granulomatous hepatic involvement; hepatomegaly, nephrolithiasis; hypercalcaemia is screened for |
For the neurological link see diabetes insipidus and SIADH.
How is sarcoidosis investigated: ACE, imaging and staging?
Diagnosis needs laboratory, radiological and histological confirmation. Baseline tests include a full blood count, liver and renal function, glucose, electrolytes and serum calcium. ESR and CRP are nonspecific. Serum angiotensin-converting enzyme (ACE), adenosine deaminase, serum amyloid A and soluble interleukin-2 receptor can be considered. The Kveim test, which elicits a granulomatous reaction, has limited significance today.
| Stage | Chest film |
|---|---|
| I | Bilateral hilar adenopathy (BHL) |
| II | Bilateral hilar adenopathy plus reticular opacities |
| III | Reticular opacities with shrinking hilar nodes (mainly infiltrates) |
| IV | Reticular opacities with fibrosis |
- Normal chest film but symptoms? Consider high-resolution CT.
- Other imaging: CT chest, FDG-PET, gallium-67; MRI or PET for cardiac or CNS disease.
- Pulmonary function: reduced DLCO; restrictive pattern in advanced disease. A DLCO below 60% of predicted with oxygen saturation below 90% on a walk test needs evaluation for pulmonary hypertension.
- Tissue: transbronchial biopsy has a high yield; mediastinoscopy for lymph node biopsy if it is negative. After a positive biopsy, pulmonary function tests, ECG, echocardiography, urinalysis and tuberculin testing are considered to define systemic disease.
How is sarcoidosis treated and what is the prognosis?
Pulmonary sarcoidosis is often asymptomatic and non-progressive, and most patients undergo spontaneous remission; these patients need no treatment, only monitoring of symptoms, chest radiograph and pulmonary function tests every 3 to 6 months.
| Situation | Management |
|---|---|
| Asymptomatic, stable | Observe; review at 3 to 6 months |
| Worsening disease, stage II to III | Oral glucocorticoids 0.3 to 0.6 mg/kg for 4 to 6 weeks; may continue a further 4 to 6 weeks if no improvement |
| Maintenance | Taper to 0.25 to 0.5 mg/kg/day (usually 10 to 20 mg) over at least 6 to 8 months |
| Steroid intolerance | Steroid-sparing: methotrexate, azathioprine, infliximab, leflunomide, antimalarials |
| End-stage lung disease | Lung transplant (needs lifelong immunosuppression) |
- Monitor symptoms, chest radiograph and pulmonary function tests every 3 to 6 months in untreated patients.
- Taper steroids slowly: StatPearls advises maintenance steroids are not needed, and tapering is over at least 6 to 8 months.
- Prevent complications: smoking cessation, avoidance of environmental or occupational lung irritants, infection prevention and vaccination review.
Prognosis. Asymptomatic patients often stay stable for years; symptomatic lung or extrapulmonary disease has a more guarded outlook, and relapse is common. Complications include pulmonary hypertension and end-stage lung disease. Overall mortality in untreated patients is about 5%. Patients should be counselled to avoid unnecessary vitamin D or calcium supplements because of the risk of hypercalcaemia. Revise corticosteroids for the adverse effects of prolonged use.
Why does sarcoidosis cause hypercalcaemia?
Hypercalcaemia in sarcoidosis is PTH-independent. A 2026 case report with a review of the mechanism states that the culprit is increased activity of 1α-hydroxylase (in granuloma macrophages), giving extrarenal production of 1,25-dihydroxyvitamin D. Serum PTH is therefore suppressed, while ACE and 1,25-dihydroxyvitamin D are elevated. This pattern separates it from primary hyperparathyroidism (PTH not suppressed) and from familial hypocalciuric hypercalcaemia (low urinary calcium).
- Complications: kidney stones and renal impairment (acute kidney injury is reported in case reports; StatPearls lists nephrolithiasis among the features).
- Management: hydration, bisphosphonate for severe hypercalcaemia, and corticosteroids, which suppress granulomatous inflammation and extrarenal vitamin D activation. The case report cites prednisone 20 mg/day initially (European Respiratory Society 2021 guidance).
- Counselling: patients with sarcoidosis should avoid excessive sunlight and vitamin D supplements.
Which named syndromes of sarcoidosis are tested?
| Syndrome | Components | Remember |
|---|---|---|
| Löfgren syndrome | Hilar lymphadenopathy + erythema nodosum + arthritis | Acute, self-limited; HLA-DRB1*03 |
| Heerfordt syndrome (uveoparotid fever) | Parotid enlargement + uveitis + low-grade fever + facial nerve palsy | An uncommon extrapulmonary expression, in fewer than 1% of biopsy-confirmed cases |
| Lupus pernio | Violaceous papules, plaques or nodules on central facial skin | Cutaneous variant; seen in Puerto Ricans |
| Cardiac sarcoidosis | Conduction block, cardiomyopathy, sudden death | ICD recommended; diagnosed by MRI or PET |
What conditions mimic sarcoidosis?
The StatPearls differential for sarcoidosis includes tuberculosis, cat scratch disease (Bartonella henselae), lung cancer, lymphoma, pneumoconiosis and fungal infection. The first discriminator is the biopsy: caseating necrosis or demonstrable organisms point to infection rather than sarcoidosis.
| Feature | Sarcoidosis | Tuberculosis |
|---|---|---|
| Granuloma | Non-caseating, sparse surrounding lymphocytes | Caseating necrosis |
| Organisms | None (mycobacteria and fungi absent on biopsy) | Mycobacteria demonstrable |
| Treatment | Observation or glucocorticoids | Anti-tubercular therapy |
What are the common exam traps in sarcoidosis?
- Non-caseating granuloma, not caseating: the stem often adds asteroid or Schaumann bodies.
- Stage I = bilateral hilar adenopathy alone; stage IV = fibrosis.
- Löfgren = hilar adenopathy + erythema nodosum + arthritis, self-limited.
- Cardiac involvement is the commonest cause of death; ICD for cardiac sarcoidosis.
- Diabetes insipidus is the commonest CNS endocrine feature, then hyperprolactinaemia.
- Uveitis is the commonest eye feature; the inverted CD4/CD8 pattern reflects a Th1 response.
- Treatment is steroids only for symptomatic stage II to III disease; asymptomatic patients are observed.
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