Medicine chapters
Sarcoidosis
Sarcoidosis is a multisystem disease of non-caseating granulomas, usually with bilateral hilar lymphadenopathy; this chapter covers its lung stages, extrapulmonary features, investigations and when to treat.
- Sarcoidosis is a multisystem granulomatous disease of unknown cause with non-caseating granulomas; young adults present with bilateral hilar lymphadenopathy, dry cough, skin and eye disease, or an incidental chest X-ray.
- Key extrapulmonary features: erythema nodosum and lupus pernio (skin), anterior uveitis, hypercalcaemia (macrophage 1α-hydroxylase), heart block and arrhythmias, bilateral facial palsy, parotid swelling; Löfgren syndrome (BHL, erythema nodosum, arthralgia, fever) usually remits.
- Diagnose by tissue biopsy (non-caseating granulomas) with supportive raised serum ACE, BAL lymphocytosis with high CD4:CD8 and HRCT; treat with prednisolone only for symptoms, falling lung function, or eye, heart, nerve, kidney disease or hypercalcaemia.
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Overview
Sarcoidosis is a multisystem disorder of unknown cause in which non-caseating epithelioid granulomas form in many organs. The lungs and hilar lymph nodes are involved in about 90% of patients.
It affects young adults (peak 20s–40s), slightly more women, and is commoner and more severe in people of African-Caribbean origin.
The TOS focuses on recognising extrapulmonary manifestations, choosing investigations and deciding on treatment.
Pathology and immunology
- Granulomas of epithelioid macrophages and multinucleated giant cells surrounded by CD4 T lymphocytes, without caseation.
- Granulomas may contain Schaumann bodies and asteroid bodies (not specific).
- Activated T cells are drawn into the lung, so blood shows lymphopenia and the skin shows anergy (negative Mantoux).
- Granuloma macrophages contain 1α-hydroxylase, converting vitamin D to active calcitriol independent of PTH → hypercalcaemia and hypercalciuria.
A negative tuberculin test is typical of sarcoidosis. A strongly positive Mantoux should make you rethink the diagnosis (TB).
Pulmonary sarcoidosis
Cough, breathlessness, vague chest discomfort; often no symptoms and a normal chest examination despite an abnormal X-ray.
Radiological stages
| Stage | Chest X-ray | Approximate spontaneous remission |
|---|---|---|
| 0 | Normal (extrapulmonary disease only) | n/a |
| 1 | Bilateral hilar lymphadenopathy (BHL) alone | 55–90% |
| 2 | BHL plus pulmonary infiltrates | 40–70% |
| 3 | Infiltrates without BHL | 10–20% |
| 4 | Pulmonary fibrosis (upper zone), volume loss | Irreversible |
Patients can present at any stage and do not necessarily progress in order.
Differential diagnosis of bilateral hilar lymphadenopathy
- Sarcoidosis (symmetrical, often with paratracheal nodes).
- Tuberculosis (usually asymmetrical).
- Lymphoma (rarely only hilar).
- Carcinoma with nodal spread (usually one-sided).
- Berylliosis (identical granulomas; ask about work).
Symmetrical BHL in a well young adult with erythema nodosum = sarcoid until proven otherwise.
Extrapulmonary manifestations
| System | Features |
|---|---|
| Skin (about a quarter) | Erythema nodosum (tender red shins; acute disease, good outlook); lupus pernio (violaceous plaques on nose, cheeks, ears; chronic disease, often with lung fibrosis); papules, plaques, infiltration of old scars and tattoos |
| Eyes | Anterior uveitis (painful red eye, blurred vision), posterior uveitis, keratoconjunctivitis sicca, lacrimal gland swelling. Uveitis may be silent, so all patients need eye assessment |
| Calcium and kidney | Hypercalcaemia, hypercalciuria, renal stones, nephrocalcinosis, granulomatous interstitial nephritis, renal failure |
| Heart | Heart block (any degree), ventricular arrhythmias, cardiomyopathy and heart failure, sudden death; may be the first sign |
| Nervous system (neurosarcoidosis) | Cranial nerve palsies, especially facial (VII), often bilateral; aseptic meningitis; hypothalamic–pituitary disease (diabetes insipidus); seizures; spinal cord lesions; peripheral neuropathy, mononeuritis multiplex |
| Joints and bones | Arthralgia and arthritis (ankles in Löfgren); bone cysts in the phalanges |
| Liver and spleen | Granulomas common, mild raised ALP, hepatosplenomegaly; rarely portal hypertension |
| Lymph nodes and glands | Peripheral lymphadenopathy; parotid enlargement |
| Constitutional | Fever, weight loss, fatigue (often troublesome) |
Named syndromes
- Löfgren syndrome: bilateral hilar lymphadenopathy + erythema nodosum + arthralgia (ankles) + fever. Acute onset, excellent prognosis; usually resolves without steroids (NSAIDs for symptoms).
- Heerfordt syndrome (uveoparotid fever): uveitis + parotid enlargement + facial nerve palsy + fever.
Sarcoidosis is the commonest cause of erythema nodosum in many series (others: streptococcal infection, TB, drugs, inflammatory bowel disease, pregnancy, combined pill).
Cardiac and neurological sarcoidosis are the most dangerous, even though skin and eye disease are commoner. Every patient needs an ECG at diagnosis.
Investigations
| Test | What it shows |
|---|---|
| Chest X-ray | Staging; BHL, infiltrates, fibrosis |
| HRCT chest | Perilymphatic nodules along bronchovascular bundles and fissures ("beading"), nodes, fibrosis |
| Tissue biopsy (diagnostic) | Non-caseating granulomas; from the most accessible site: skin lesion, peripheral node, EBUS-guided needle aspiration of mediastinal nodes, transbronchial lung biopsy |
| Bronchoalveolar lavage | Lymphocytosis with a raised CD4:CD8 ratio (low ratio favours hypersensitivity pneumonitis); stains and cultures to exclude TB and fungi |
| Serum ACE | Raised in most untreated cases; made by granulomas; not specific (also TB, lymphoma, silicosis, asbestosis); used with caution for monitoring |
| Serum calcium, 24-hour urine calcium | Hypercalcaemia or hypercalciuria; PTH suppressed, 1,25-dihydroxyvitamin D high |
| FBC, ESR | Lymphopenia, mild anaemia, raised ESR; raised immunoglobulins |
| LFTs, renal function | Raised ALP; impaired kidney function |
| Lung function | Restrictive pattern with low gas transfer in parenchymal disease; may be obstructive with airway involvement; normal with BHL alone |
| ECG, Holter, echo, cardiac MRI or FDG-PET | Conduction defects, arrhythmias, scarring |
| Eye examination (slit lamp) | Uveitis |
| Tuberculin test or IGRA | Usually negative; helps exclude TB |
BAL CD4:CD8 ratio is high in sarcoidosis but low in hypersensitivity pneumonitis; both show a lymphocytosis.
The diagnosis rests on a compatible clinical and radiological picture + non-caseating granulomas on biopsy + exclusion of other granulomatous causes (TB, fungi, berylliosis, lymphoma). In typical Löfgren syndrome a biopsy may be unnecessary.
Management
Who needs no treatment
- Asymptomatic stage 1 BHL.
- Löfgren syndrome (NSAIDs for joint pain and erythema nodosum).
- Mild stage 2–3 disease with stable lung function: observe for about 6 months, as many improve spontaneously.
Indications for systemic treatment
- Hypercalcaemia (or hypercalciuria with stones or nephrocalcinosis).
- Cardiac involvement.
- Neurological involvement.
- Eye disease not controlled by topical steroids (posterior uveitis, optic nerve).
- Renal involvement.
- Progressive pulmonary disease: troublesome symptoms, falling lung function or worsening imaging.
- Disfiguring skin disease (lupus pernio).
Drugs
- First line: oral prednisolone (about 0.5 mg/kg/day, or 20–40 mg daily) for 4–6 weeks, then slowly reduced, with a low maintenance dose usually kept up for 12 months or more; relapse is common when it is stopped.
- Steroid-sparing agents: methotrexate (most used), azathioprine, mycophenolate, leflunomide; hydroxychloroquine for skin disease and hypercalcaemia.
- Anti-TNF drugs (infliximab) for refractory disease (screen for latent TB first).
- Topical steroids for anterior uveitis.
- Hypercalcaemia: hydration, prednisolone (switches off granuloma calcitriol production), avoid vitamin D supplements and excess sunlight; hydroxychloroquine or ketoconazole as alternatives.
- Cardiac: steroids, pacemaker or implantable defibrillator for heart block or ventricular arrhythmias.
- End-stage fibrosis: oxygen, treat pulmonary hypertension, lung transplantation.
Steroids improve the X-ray but do not always improve lung function, so pulmonary sarcoid is not treated just because the chest film is abnormal.
Prognosis
- Most patients (especially Löfgren syndrome and stage 1) remit within 2 years.
- Worse outcome: lupus pernio, chronic uveitis, stage 3–4 disease, cardiac or neurological involvement, chronic hypercalcaemia with nephrocalcinosis, older onset and African-Caribbean ethnicity.
- A small minority die, mainly from respiratory failure or cardiac sarcoid.
Expect: young adult with bilateral hilar lymphadenopathy and erythema nodosum (Löfgren syndrome, good prognosis), non-caseating granulomas on biopsy as the confirmatory test, hypercalcaemia from macrophage 1α-hydroxylase with suppressed PTH, raised but non-specific serum ACE, BAL lymphocytosis with high CD4:CD8, negative Mantoux, lupus pernio, anterior uveitis, bilateral facial palsy and Heerfordt syndrome, heart block and sudden death in cardiac sarcoid, chest X-ray staging, restrictive spirometry with low gas transfer, and indications for prednisolone (hypercalcaemia, eye, heart, CNS, kidney, progressive lung disease).
Quick revision
- Non-caseating granulomas; BHL in young adults.
- Löfgren: BHL + erythema nodosum + arthralgia + fever → remits.
- Heerfordt: uveitis + parotid + facial palsy + fever.
- Hypercalcaemia: macrophage 1α-hydroxylase → calcitriol; PTH low.
- Serum ACE raised but non-specific; BAL CD4:CD8 high.
- Mantoux negative; restrictive PFTs, low TLCO.
- Always do ECG and eye check.
- Prednisolone for hypercalcaemia, eye, heart, CNS, kidney or progressive lung disease; methotrexate as steroid-sparing.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Why does sarcoidosis cause high calcium?
Macrophages in the granulomas contain 1α-hydroxylase and make active vitamin D (calcitriol) without PTH control, so gut calcium absorption rises; PTH is suppressed.
Is a raised serum ACE diagnostic of sarcoidosis?
No. It is raised in most untreated cases but also in TB, lymphoma, silicosis and asbestosis, so diagnosis needs a biopsy showing non-caseating granulomas.
Does every patient with sarcoidosis need steroids?
No. Asymptomatic hilar lymphadenopathy and Löfgren syndrome usually settle on their own; steroids are for hypercalcaemia, eye, heart, nervous system or kidney disease, and progressive lung involvement.
What is the best biopsy site?
The most accessible involved tissue: a skin lesion or peripheral node if present, otherwise EBUS-guided sampling of mediastinal nodes or transbronchial lung biopsy.