Sarcoidosis Flashcards
Summarise sarcoidosis
Sarcoidosis is a diagnosis of exclusion of granulomatous lung diseases, including tuberculosis and histoplasmosis.
Typical history and biopsy from affected organs are essential for the diagnosis.
Treated with topical corticosteroids for mild local cutaneous disease. Systemic corticosteroids are the mainstay of treatment for severe disease.
Carries a mortality of 1% to 6%.
Poorer prognosis if black ancestry, chronic pulmonary involvement, lupus pernio, or chronic hypercalcaemia.
Spontaneous remissions occur in 55% to 90% of patients with stage I, 40% to 70% of patients with stage II, and about 20% of patients with stage III disease, but no remissions are expected in stage IV.
What is lupus pernio
Lupus pernio is a chronic raised indurated (hardened) lesion of the skin, often purplish in color. It is seen on the nose, ears, cheeks, lips, and forehead. It is pathognomonic of sarcoidosis.
Define sarcoidosis
Sarcoidosis is a chronic granulomatous disorder of unknown aetiology, commonly affecting the lungs, skin, and eyes. It is characterised by accumulation of lymphocytes and macrophages and the formation of non-caseating granulomas in the lungs and other organs. Although lungs and lymph nodes are involved in more than 90% of patients, virtually any organ can be involved. It has a bimodal age distribution with 2 peaks in the third and fifth decades. The clinical course is often heterogeneous and unpredictable.
Describe the epidemiology of sarcoidosis
Incidence is about 6 cases per 100,000 person-years.[1] The lifetime risk of sarcoidosis for black people in the US is slightly higher than for white people.[1] Sarcoidosis also has a higher incidence in people of Scandinavian origin.[1] Extrathoracic manifestations are more common in certain populations, such as chronic uveitis in black people in the US, lupus pernio in Puerto Ricans, and erythema nodosum in Europeans.[1] Cardiac and ocular sarcoidosis appear to be more common in Japan. A significantly elevated risk of sarcoidosis has been observed among first- and second-degree relatives of patients with sarcoidosis.[2] Women are more likely to have eye and neurological involvement and have erythema nodosum, whereas men are more likely to be hypercalcaemic. Black people are more likely to have skin manifestations (other than erythema nodosum) and have eye, liver, bone marrow, and extrathoracic lymph node involvement
Describe the aetiology of sarcoidosis
Aetiology is unknown. However, several aetiological factors have been suggested, including genetic, immunological, and infectious causes (e.g., viruses, Borrelia burgdorferi, Propionibacterium acnes, Mycobacterium tuberculosis, and Mycoplasma)
What is the characteristic finding in the pathophysiology of sarcoidosis
The characteristic finding is the presence of non-caseating granulomas with multinucleated giant cells in the centre. CD4 lymphocytes are spread out through the granuloma, and CD8 cells cluster around the periphery. The CD4 lymphocyte and associated cytokines, such as interferon gamma, interleukin (IL)-2, and IL-12, promote and maintain the granulomas.
Describe the role of alveolar macrophages in the pathophysiology of sarcoidosis
Alveolar macrophages behave as versatile secretory cells that release a variety of cytokines, including TNF-alpha, IL-12, IL-15, and growth factors. The immunological pattern of cells in the sarcoid infiltrate suggests that sarcoid granulomas are formed in response to a persistent and probably poorly degradable antigenic stimulus that induces a local T-cell-mediated immune response with an oligoclonal pattern. As a consequence of their chronic stimulation, macrophages release mediators of inflammation locally, leading to accumulation of T-helper type 1 cells at sites of ongoing inflammation and contributing to the development of the granuloma structure.
Outline a classification system for sarcoidosis
Commonly used classification according to organ/system involvement
Systemic sarcoidosis: multisystem involvement, sometimes with chronic fatigue
Pulmonary sarcoidosis: lungs involved in >90% of patients; further classified into stages I, II, III, and IV
Cutaneous sarcoidosis: plaques; lupus pernio
Ocular sarcoidosis: anterior uveitis is most common
Cardiac sarcoidosis: 5% of patients; various types of heart block; cardiomyopathy later in course; if pulmonary arterial hypertension occurs can be debilitating
Neurosarcoidosis: <10% of patients; headaches; seizures.
Describe one case history for a patient with sarcoidosis
A 29-year-old woman presents with shortness of breath, cough, and painful red skin lesions on the anterior surface of the lower part of both legs. CXR reveals bilateral hilar lymphadenopathy with pulmonary infiltrates.
Describe a second case history for a patient with sarcoidosis
A 35-year-old woman presents with skin lesions around her nose, which are indurated plaques with discoloration. She also reports a red, moderately painful right eye with blurred vision and photophobia.
Describe some other presentations of sarcoidosis
Multisystem involvement is characteristic, but pulmonary involvement usually dominates. Skin, eyes, and peripheral lymph nodes are involved in 15% to 30% of patients. Clinically significant involvement of spleen, liver, heart, CNS, bone, or kidney occurs in a few patients. Incidental diagnosis on routine CXR also occurs..
Summarise an approach to the diagnosis of sarcoidosis
Sarcoidosis is a diagnosis of exclusion of granulomatous lung diseases, including tuberculosis and histoplasmosis. Typical history and biopsy from affected organs are essential for the diagnosis. Diagnostic goals are as follows:[1]
Histological confirmation
Assessment of the extent and severity of organ involvement
Assessment of likelihood of progression
Determination of whether therapy will benefit the patient.
Outline an approach to the history in patients with sarcoidosis
Diagnosis is more common among females and non-smokers and in those with a family history of sarcoidosis. It is also more common in black people in the US and in people of Scandinavian origin.
Pulmonary symptoms such as cough and dyspnoea predominate. Costochondritis may also occur, resulting in chest wall pain.
Constitutional symptoms are common and include chronic fatigue, weight loss, and low-grade fever. Other symptoms include photophobia and skin lesions. Arthralgia, affecting the knees, ankles, elbows, and wrists, occurs in about one third of people with sarcoidosis.
It is important to consider berylliosis, especially in people with a history of occupational exposure to beryllium in the nuclear and aerospace industries.
Summarise an approach to the physical examination in patients with sarcoidosis
Chest signs include wheezing/rhonchi due to airway involvement, mimicking asthma.
Lymph nodes are enlarged and non-tender. Cervical, submandibular nodes are often involved. Rarely, lymphadenopathy is generalised.
Cardiac manifestations occur in 5% of cases and may present with arrhythmias or heart block. Pulmonary hypertension and CHF occur later in the course of the condition.
Hepatomegaly occurs in 20% of people. The liver is usually non-tender.
Describe some other signs of sarcoidosis
Erythema nodosum and lupus pernio are typical skin manifestations of sarcoidosis. Erythema nodosum presents as tender erythematous nodules on the lower extremities and is a predictor of a good prognosis. Lupus pernio presents as indurated plaques with discoloration of the nose, cheeks, lips, and ears. It is more common in black women and is a predictor of a poor prognosis.
Ocular sarcoidosis may present as anterior uveitis or conjunctival nodules. Anterior uveitis usually presents with red, painful eyes and blurred vision.[5]
Neurosarcoidosis occurs in <10% of cases and may present with facial palsy and signs of pituitary lesions (e.g., diabetes insipidus). Headaches and seizures also occur.
Joint examination does not usually reveal synovial thickening.
Summarise the initial tests in sarcoidosis
Initial tests to perform in people with suspected sarcoidosis include FBC, urea and creatinine, liver enzymes, serum calcium, CXR, ECG, PFTs (including spirometry and gas transfer analysis), and tuberculin testing.
The CXR typically shows hilar and/or paratracheal adenopathy with predominantly upper lobe bilateral infiltrates.
FBC may reveal modest leukopenia or lymphopenia and anaemia. Serum calcium may be elevated. Hypercalcaemia occurs due to the dysregulated production of calcitriol by activated macrophages and granulomas. Urea and creatinine may be elevated in the uncommon event of renal involvement.
The ECG may show conduction abnormalities if there is any cardiac involvement.
PFTs measure any lung impairment at diagnosis and are used to monitor any decline in lung function over time. Obstructive and restrictive defects in lung function may be found.
Tuberculin testing shows anergy in sarcoidosis.
What further investigations should be done in patients with pulmonary involvement
Further investigations for people with pulmonary involvement include chest CT, flexible bronchoscopy with bronchoalveolar lavage (BAL), and transbronchial biopsy. Other subsequent investigations include serum ACE measurement, 24-hour urine calcium measurement, skin biopsy, gallium-67 scan, and endobronchial ultrasound-transbronchial needle aspiration.
Summarise the Chest CT
Chest CT scan is not necessary in the routine evaluation or management of sarcoidosis. The usual indications are atypical presentation or to evaluate complications such as bronchiectasis, aspergilloma, pulmonary fibrosis, or a superimposed infection or malignancy.[6] Scans with contrast and high-resolution images show hilar and/or paratracheal adenopathy with predominantly upper lobe bilateral infiltrates.
Summarise the flexible bronchoscopy
Most patients with pulmonary symptoms, with no histological diagnosis of sarcoidosis from extrathoracic sites, require flexible bronchoscopy with BAL and transthoracic biopsy. BAL may reveal lymphocytosis with a CD4-to-CD8 ratio >3.5. Biopsy shows non-caseating granulomas, with negative stains for acid-fast bacillus and fungi.
Summarise the biopsy of skin lesions
Biopsy of skin lesions in people with lesions that are suspected to be manifestations of cutaneous sarcoidosis reveals classic non-caseating granulomas.
Summarise the 24 hour urine calcium
Twenty-four-hour urine calcium may be ordered in all patients to rule out hypercalciuria, which, when present, can cause nephrocalcinosis with progressive renal insufficiency.
Summarise the Gallium-67 scan
A gallium-67 scan may be used when the diagnosis is in doubt. Serial images sometimes require 48 hours to complete. The clinical value of this test remains controversial. Gallium scans can show typical uptake patterns. These include the panda sign (lacrimal and parotid gland uptake) or the lambda sign (parahilar, infrahilar, and right paratracheal or azygos node uptake), but the test lacks specificity.
Summarise serum ACE levels
Although serum ACE levels may be elevated in some patients with sarcoidosis, they cannot be used for diagnosis. ACE levels may not reflect disease activity. Utility is unreliable and controversial.
Summarise endobronchial ultrasound transbronchial needle aspiration
Endobronchial ultrasound-transbronchial needle aspiration is standard of care and routine practice for the diagnosis of mediastinal lymphadenopathy, with high sensitivity (88%) and specificity (100%)
Summarise the emerging tests available for the diagnosis of sarcoidosis
MRI is showing some use in identifying areas of sarcoidosis involvement, including the heart and the brain.[10] (18)F-fluorodeoxyglucose PET scanning has been shown to have a characteristic pattern of uptake in sarcoidosis and may aid in the diagnosis of cardiac sarcoidosis.[11] This test is much less invasive than endomyocardial biopsy, with minimal to no complications from the procedure.
Describe the key diagnostic factors in the history of sarcoidosis
cough
Non-productive.
dyspnoea
Usually gradual in onset.
May worsen with disease progression.
chronic fatigue
Fatigue is an under-recognised symptom in sarcoidosis[14] and is difficult to treat.
If fatigue is out of proportion to cardiopulmonary involvement, pulmonary arterial hypertension or CHF should be sought.
arthralgia
Pain in knees, ankles, and wrists.
No synovial thickening on examination.
wheezing
Bronchospasm, due to airway hyper-reactivity.
rhonchi
Bronchospasm, due to airway hyperactivity.
lymphadenopathy
Nodes are enlarged and non-tender.
Cervical, submandibular nodes are often involved.
photophobia
Usually indicates uveitis.
red painful eye
Symptom of uveitis.
May be associated with superficial punctuate keratitis.
blurred vision
Symptom of uveitis.
May be associated with superficial punctuate keratitis
Describe some other key but uncommon diagnostic factors in the history and exam in patients with sarcoidosis
erythema nodosum
Tender erythematous nodules on the lower extremities.
Predictor of good prognosis.
lupus pernio
Indurated plaques with discoloration of the nose, cheeks, lips, and ears.
More common in black women.
Predictor of poor prognosis.[1]
conjunctival nodules
With ocular involvement.
facial palsy
May be a presenting symptom/sign.
When occurs with uveoparotid fever (uveitis/parotitis/facial palsy), prognosis is relatively good.
Describe another common diagnostic factor
absent history of exposure to beryllium
If there is a history of exposure to beryllium, possibly through occupational exposure in the aerospace or nuclear industries, it is important to consider the diagnosis of berylliosis, as this can mimic the signs and symptoms of sarcoidosis.
Describe some other more uncommon diagnostic factors
chest wall pain
Worsens with respirations.
Tenderness at the costochondral junctions, indicating costochondritis.
haemoptysis
An uncommon presentation in early sarcoidosis. When it is the initial manifestation of sarcoidosis, endobronchial involvement is usually present. Haemoptysis is rarely massive or life-threatening, except when associated with mycetomas in radiographic stage IV.[13]
weight loss
Unexplained modest weight loss.
Can be mistaken for weight loss due to tuberculosis or lymphoma when associated with an abnormal CXR.
low-grade fever
Can be mistaken for fever due to tuberculosis or lymphoma when associated with an abnormal chest radiograph.
arrhythmias
Atrial or ventricular.
heart block
May rarely be the initial presentation.
hepatomegaly
Non-tender.
headache
May be a sign of neurosarcoidosis.
seizures
May be a sign of neurosarcoidosis.
symptoms and signs of pituitary lesion Rarely occurs (e.g., diabetes insipidus). Symptoms of a pituitary lesion include headache, loss of vision, double vision, nausea, and vomiting; signs include poor peripheral vision, signs of hypopituitarism such as hypogonadism, hypoadrenalism, hypothyroidism, and growth hormone deficiency
Describe some strong risk factors for sarcoidosis
age 20 to 40 years
Initial presentation most common in this age range.[1]
FHx sarcoidosis
Significantly elevated risk among first- and second-degree relatives of patients with sarcoidosis.
Scandinavian origin
Higher incidence in people of Scandinavian origin
Describe some weaker risk factors for sarcoidosis
female gender
Slight female preponderance, with variability among different ethnic groups.[1]
non-smokers
Appears to occur more commonly in non-smokers than in smokers.[4]
black ancestry (US): uveitis
The lifetime risk of sarcoidosis for black people is slightly higher than for white people in the US. Chronic uveitis more common in black people in the US.
Puerto Rican origin: lupus pernio
Lupus pernio is more common in people from Puerto Rico.
European origin: erythema nodosum
Erythema nodosum is more common in Europeans
Describe the purpose of the CXR as a first line investigation
Stage 0: normal
Stage I: bilateral hilar lymphadenopathy
Stage II: bilateral hilar lymphadenopathy plus pulmonary infiltrates
Stage III: pulmonary infiltrates without hilar lymphadenopathy
Stage IV: extensive fibrosis with distortion.
Result:
hilar and/or paratracheal adenopathy with upper lobe predominant, bilateral infiltrates; pleural effusions (rare) and egg shell calcifications (very rare) may be seen
Describe the purpose of the FBC as a first line investigation
Usually secondary to splenic and/or bone marrow involvement.
Result:
anaemia in 4%-20%; leukopenia in 40%
Describe the purpose of serum urea as a first line investigation
In cases of renal involvement.
Result:
May be elevated
Describe the purpose of serum creatinine as a first line investigation
In cases of renal involvement.
Result:
may be elevated
Describe the purpose of liver enzymes asa. first line investigation
Asymptomatic aminotransferase (AST and ALT) elevation possible.
Result:
Elevation
Describe the purpose of calcium as a first line investigation
Due to dysregulated production of calcitriol by activated macrophages and granulomas.
Result:
hypercalcaemia
Describe the purpose of PFTs in sarcoidosis as a first line investigation
To monitor disease.
Persistent decline in forced vital capacity indicates disease progression
Result:
restrictive or obstructive or mixed pattern
Describe the purpose of the ECG as a first line investigation
To exclude or confirm cardiac involvement.
About half of patients with cardiac sarcoidosis have abnormalities of rhythm, conduction, or repolarisation
Result:
conduction defects
Describe the purpose of a purified protein derivative of tuberculin (PPD) as a first line investigation
Partial to complete anergy in sarcoidosis, secondary to depressed cellular immunity
Result:
negative
Describe the purpose of the CT chest as a investigation to consider
Ground-glass appearance may indicate a potentially reversible condition.
Cystic architectural distortion suggests irreversible disease
Result:
hilar and/or paratracheal adenopathy with upper lobe predominance, bilateral infiltrates in a bronchovascular distribution; calcified hilar or mediastinal lymph nodes in patients with longstanding disease
Describe flexible bronchoscopy with transbornchial lung biopsy as an investigation to consider
Essential for diagnosis in most cases.
Transbronchial needle aspiration from large mediastinal lymph nodes if present
Result;
non-caseating granulomas
Describe the purpose of bronchoalveolar lavage as an investigation to consider
Specificity of 94%. Sensitivity of 53%
Result:
BAL lymphocytosis, with CD4-to-CD8 ratio >3.5
Describe the purpose of a skin biopsy asan investigation to consider
Skin biopsy of lesion suspicious for sarcoidosis may histologically confirm diagnosis.
Result:
non-caseating granulomas
Describe the 24-hour urine calcium as an investigation to consider
Hypercalciuria due to abnormal calcium and vitamin D regulation from macrophages inside granulomas
Result:
hypercalciuria
Describe serum ACE as an investigation to consider
Elevated in about half of patients.
May not reflect disease activity.
Utility is unreliable and controversial
Result:
elevated
Describe the Gallium-67 scan as an investigation to consider
Typical patterns include panda sign: lacrimal and parotid gland uptake; lambda sign: parahilar, infrahilar, and right paratracheal or azygos node uptake.[10]
Lacks specificity. Serial images sometimes require 48 hours to complete.
The clinical value of this test remains controversial.
Result:
may show typical uptake patterns
Describe endobrachial ultrasound-transbronchial needle aspiration as an investigation to consider
Endobronchial ultrasound-transbronchial needle aspiration is standard of care and routine practice for the diagnosis of mediastinal lymphadenopathy, with high sensitivity (88%) and specificity (100%)
Result:
non-caseating granulomas
Describe the MRI as an emerging investigation
May be useful in identifying areas of sarcoidosis involvement, including the heart and the brain
Result:
heart findings include nodular lesions and/or focal myocardial thickening; brain findings are varied and non-specific, and include meningeal enhancement with or without periventricular white matter lesions
Describe the PET scan as an emerging investigation
PET scanning has been shown to have a characteristic pattern of uptake in sarcoidosis and may aid in the diagnosis of cardiac sarcoidosis.[11] This is much less invasive than endomyocardial biopsy, with minimal to no complications from the procedure
Result:
heterogeneous myocardial FDG uptake
Describe TB as a differential
History of exposure or high-risk patients.
Differential diagnosis is especially challenging when patients present with upper lobe infiltrates, fever, and weight loss
Result:
Positive PPD.
Smear or culture positive for TB.
Caseating granulomas on lung biopsy.
Describe histoplasmosis as a differential
History of living in an endemic area (e.g., the Mississippi River valley).
Fungus isolation on silver stain from lung biopsy.
Positive urinary Histoplasma antigen.
The most common finding on CXR is pulmonary nodules; can also present as infiltrates, lymphadenopathy, fibrosis, and thickened pleura.[
Describe non-small cell lung cancer as a differential
More likely to have a history of smoking.
More pronounced haemoptysis and weight loss.
Lung mass on CXR.
Malignant cells on lung biopsy.
Describe lymphoma as a differential
Extrathoracic involvement is more common (cervical and supraclavicular lymphadenopathy).
Biopsy of mediastinal lymph nodes shows features of lymphoma.
Describe Berylliosis as a differential
History of occupational exposure to beryllium in nuclear and aerospace industries.
Non-caseating granuloma on lung biopsy that is difficult to distinguish from sarcoidosis.
Abnormal beryllium lymphocyte proliferation assay on serum or bronchoalveolar lavage fluid has a high positive predictive value in diagnosing chronic berylliosis.
Describe hypersensitivity pneumonitis as a differential
History of exposure to one of a multitude of agents (e.g., birds’ feathers and droppings, compost, peat moss, metalworking fluids).
Best described in farmers exposed to mouldy hay.
Positive precipitins to known antigens.
CT chest shows poorly defined nodules in the acute phase and fibrosis with bronchiectasis in the chronic form.
Poorly formed granulomas and intra-alveolar foci of organising pneumonia on lung biopsy.
CD8 cell predominance on bronchoalveolar lavage.
