nemoci-sympt/PLICNI/sarkoidoza/biomarkery
Úvod
- No single biomarker is adequately sensitive and specific for detecting and monitoring disease activity. [4]
- The serological markers used are
- C-reactive protein,
- Serum angiotensinconverting enzyme,
- Soluble interleukin (IL)-2 receptor
- Neopterin [7]
- Negative serological test results do not exclude the presence of inflammatory activity [7]
Aldolase
- May also be used to evaluate for myopathy [17]
Apoptosis in peripheral blood mononuclear cells
- From patients with sarcoidosis in stimulated and nonstimulated conditions
- Stimulation with MTB heat shock proteins induced CD4+ T-cell apoptosis in the peripheral blood of patients with sarcoidosis
- It was hypothesized that apoptosis was increased in T-lymphocytes from peripheral blood in comparison with BAL fluid lymphocytes [3]
Cardiac MRI and PET
- Patients with parenchymal pulmonary sarcoidosis
- Should receive
- Baseline electrocardiography
- Transthoracic echocardiography with ambulatory electrocardiography monitoring
- If any conduction or rhythm disturbance is detected [4]
Cardiac MRI, 18F-FDG PET, or technetium-99m plus sestamibiethallium-201 scan or gallium-67 scan
- Should be performed depending on local availability [4]
- Delayed contrastenhanced cardiac MRI
- May detect sarcoid-related cardiac damage
- Could be useful in patients on anti-inflammatory treatments that reduce FDG uptake [4]
- Nuclear medicine scans, particularly with special 18F-FDG PET protocols
- May indicate increased uptake indicating cardiac inflammation
- Associated with decreased myocardial function [4]
- Oncology-related 18F-FDG PET protocols are less useful
- Glucose is avidly taken up by the normal cardiac muscle [4]
Endomyocardial biopsy
- Usually not performed as the disease has a patchy distribution [4]
Creatinine kinase
- May also be used to evaluate for myopathy [17]
Electrophysiological studies
- Helpful to investigate patients with syncope or dysrhythmias
- But cannot exclude the development of granulomatous infiltration and myocardial fibrosis
- Unexplained bundle branch, heart block or frequent ventricular ectopics
- Indicate that other investigations are required to exclude ischaemic heart disease or cardiomyopathy
- Evaluation for cardiac sarcoidosis [4]
ESR
- May be elevated [17]
Endobronchial biopsy
- May also demonstrate noncaseating granulomas even if radiology results are normal
Transbronchial biopsy
- Diagnostic yield of 70-85%
- Higher rate of obtaining granulomas, at the risk of bleeding and pneumothorax
Angiotensinconverting enzyme (ACE)
- Indicator of the total granuloma burden
- But has modest sensitivity and specificity
- Elevated in other granulomatous conditions
- Limited utility in diagnosis and monitoring
- Influenced by
- ACE polymorphisms
- Use of ACE inhibitors [4]
- The most used
- Produced by epitheloid cells and alveolar macrophages
- Serum levels of ACE are thought to reflect the extent of granulomatous inflammation
- Sensitivity is cca 55% [6]
- When the diagnosis sarcoidosis is confirmed
- The specificity is 99% [6]
- Useful for treatment monitoring [6]
Abnormalities of calcium metabolism
- Due to dysregulated production of 1,25-(OH)[sub.2]-[D.sub.3] (calcitriol)
- By activated macrophages
- Trapped in pulmonary alveoli and granulomatous inflammation
- Serum calcium monitoring and 24-hour urinary calcium measurement
- Important in all patients with sarcoidosis [3]
High levels of antimycobacterial heat shock protein 70 (hsp70) antibodies
- In the sera of patients with sarcoidosis
- Antigen increases expression of costimulatory molecules
- Mycobacterial hsp70 positivity
- Could lead to a reduction in immune tolerance [3]
- May induce autoimmune inflammatory responses [3]
- Detection of mycobacterial hsp16, hsp65, and hsp70
- In lymph nodes, sera, and circulating immune complexes in the blood of patients with sarcoidosis [3]
Peripheral blood CD4+ T-cells x in BAL CD4+ T-cells
- BAL více express TH1-related receptors such as
- CXCR3
- CCR5,
- IL-12R,
- IL-18R in sarcoidosis [3]
- BAL reduced TH2 chemokine receptors
- CXCR4
- CCR4 [3]
Bronchoalveolar lavage (BAL) fluid analysis
- Elevated CD4+/CD8+ cell ratio above 3.5:1
- In the absence of known causes [3]
- Wide spectrum of this ratio among patients with pulmonary sarcoidosis
- Possibility of developing CD8+ alveolitis among patients with sarcoidosis
- With human immunodeficiency virus-1 (HIV-1) infections render this ratio less useful as an absolute diagnostic criterion [3]
- Can demonstrate [4]
- Lymphocytosis [4]
- Elevated ratios of CD4?:CD8? cells [4]
- Typically over 3.5:1
- In the absence of other causes
- BAL T lymphocyte subset analysis can identify
- Sarcoid alveolitis [4]
- Greater basal activation of BAL CD4? T cells compared with peripheral blood lymphocytes
- Indicative of compartmentalisation of the immune response [4]
- Bronchoalveolar lavage in sarcoidosis patients reveals an increased number of T-lymphocytes
- Expressed to an increased CD4+/CD8+ ratio
- Number of lymphocytes and the CD4+/CD8+ ratio do not have a predictive value.
Flow cytometric studies
- Under unstimulated conditions, BAL CD4+ and CD8+ T-cells were significantly activated
- Compared with peripheral blood lymphocytes
- Other cellular surface activation markers, also expressed on BAL lymphocytes of patients with active sarcoidosis, such as
- CD26,
- CD54,
- HLA-DR [3]
CD4+ HLA-DR+ T-cells
- Release IL-2 spontaneously
- Suggested measurement of the activation state of the IL-2-mediated immune system
- Based on frequencies of CD4+ HLA-DR+ T-cells
- Expected to decrease in inactive sarcoidosis
- May help to define different phases of the disease [3]
Beta2-microglobulin
- Marker of lymphocyte activation
- Elevated in the serum of ~25% of patients
- Elevated at the time of diagnosis
- Suppressed with corticosteroid therapy
- Increased with relapse [3]
- Acute sarcoidosis and erythema nodosum with elevated beta2-microglobulin with normal ACE activity
- Further study did not identify an association between beta2-microglobulin and ACE
- Lymphocyte and macrophage activation are not always present together
- Beta2-microglobulin is thus limited
- Reflects only lymphocyte activation
- Compared with sIL-2R, which indicates both macrophage and lymphocyte activation [3]
- Serum beta2-microglobulin has a low specificity and sensitivity
- Undermined its utility [3]
Biopsy
- Non-caseating granulomas on tissue biopsy and exclusion of other causes of granulomatous inflammation
- Required for diagnosis [4]
- Biopsy is unnecessary in Löfgren syndrome and difficult in neurosarcoidosis [4]
TH2 chemokine CCL17
- Increased in patients with sarcoidosis compared with controls [3]
- CCL17 levels were not significantly different in BAL of patients with active sarcoidosis compared with controls [3]
CD4+CD25bright FOXP3+ Treg (regulatory T) cells
- Elevated numbers
- Antiproliferative
- In the BAL fluid and peripheral blood of patients with active sarcoidosis [3]
CXCR3 ligands
CXCL9
- IFN-gamma-induced chemokine
- Produced by monocytic cells
- Signaling occurs through CXCR3
- An inflammatory receptor present on CD4+ and CD8+ cells
- Promotes T-cell recruitment to inflamed tissues
- In sarcoidosis
- Elevated CXCL9 in BAL fluid
- Transcripts and proteins of CXCL9 being upregulated in lung tissue
- Associated with disease progression [3]
CXCL10- or IFN-gamma-induced protein-10 (IP-10)
- Chemokine secreted in response to IFN-gamma
- Found to be associated with active sarcoidosis
- IP-10 levels were inversely correlated with pulmonary function and disease prognosis
- Predictive characteristics were superior to those of ACE
- IP-10 may be a diagnostic marker
- Could differentiate active from inactive sarcoidosis, but this needs confirmation [3]
CXCL11
- Another chemokine mediated through CXCR3
- IFN-inducible T-cell alpha-chemoattractant
- Gene expression and protein levels of CXCL11 were found to be elevated in the serum and BAL fluid of patients with sarcoidosis
- At radiological stage II [3]
- Potential use as a disease marker [3]
Cerebrospinal fluid analysis
- In neurosarcoidosis may indicate
- Non-specific lymphocytosis
- Elevated protein level [4]
- While CD4?:CD8? T cell ratios and lysozyme, b2-microglobulin and ACE levels may suggest the diagnosis [4]
Chitotriosidase
- Enzyme responsible for breaking down chitin
- Component of fungal cell wall
- Exoskeleton of certain animals and arthropods
- Produced by alveolar macrophages in BAL fluid of patients with sarcoidosis
- Its role in sarcoid pathogenesis remains unknown
- BAL and serum levels of chitotriosidase in patients with sarcoidosis
- Significantly higher than those in controls [3]
- Chitotriosidase levels generally
- Rise with disease progression
- Decrease with treatment
- Correlation between BAL chitotriosidase levels and
- Sarcoidosis radiological stages,
- Serum ACE levels,
- Pulmonary fibrosis [3]
- May be a useful biomarker of disease severity and prognostic factor for chronic fibrotic disease [3]
C-reactive protein (CRP)
- Simple tests for assessing the degree of systemic inflammation
- Very high levels of ESR and CRP have been measured in some patients with sarcoidosis who have active disease
- High CRP is associated with [3]
- Severe fatigue in sarcoidosis [3]
- CRP is generally lower compared with patients with tuberculosis [3]
High-resolution computed tomography of the chest
- Higher sensitivity than chest radiography in diagnosis and evaluation of airways, airspace, and interstitial disease in sarcoidosis.
- Useful findings on high-resolution computed tomography
- Reversed halo sign
- Sarcoid galaxy sign
- Headcheese sign [3]
- May indicate diffuse interstitial lung disease suggestive of sarcoidosis
- Less usefulness for prognosis [3]
Initial CT scan of the chest
- Can assess the lung parenchyma and lymph nodes (which may calcify)
- Useful information about the liver and spleen
- Can demonstrate classic parenchymal findings of
- Nodules clustered along the
- Bronchovascular bundles
- Interlobular septa
- Subpleural regions [4]
- Considered by some to be diagnostic of sarcoidosis.
- Nodules vary from a few in a subpleural distribution to profuse micronodules in a primarily upper lobe distribution;
- Larger nodules may coalesce
- Small nodules may surround larger [4]
- Ground glass opacification may represent profuse small nodules beyond the resolution of the CT scan
- In many patients with less marked disease, resolution may occur on CT
- However, in a minority, reticular opacities develop, often with an upper lobe distribution and sometimes honeycombing
- If the disease progresses to fibrosis
- Patchy reticular changes
- Dense opacification become more evident in an upper zone perihilar distribution
- Extending to the apices [4]
- Eventually, the distortion may result in traction bronchiectasis
- Cavity formation
- And the risk of aspergillomata [4]
- Bronchial abnormalities are relatively common
- Nodular wall thickening
- Sometimes endobronchial lesions [4]
- Small airway obstruction by active disease or fibrosis
- Can lead to gas trapping seen on expiratory views [4]
- Parenchymal disease evident on CT scanning
- Correlates with pulmonary function tests more than chest x-ray [4]
- Cardiac enlargement can be seen on chest imaging
- Suggesting cardiac sarcoidosis or pulmonary hypertension
- Right ventricular hypertrophy
- Enlargement of the pulmonary outflow tract [4]
Integrated functional and morphologic staging system for sarcoidosis
- Might allow a more confident assessment of treatment response [4]
Diagnoza
- Clinical and radiological findings alone are often inadequate to confirm the diagnosis.
- Usually a diagnosis of exclusion
- Confirmed by histological evidence of noncaseating granulomas in the absence of known granulomagenic agents
- Diagnosis of sarcoidosis is based on the criteria as proposed by the
- American Thoracic Society,
- European Respiratory Society
- World Association of Sarcoidosis
- Other Granulomatous Disorders [6]
- Histological confirmation of non-caseating granulomas
- Clinical signs of activity
- Radiological pictures are compatible with sarcoidosis [6]
Differential diagnoses
- Tuberculosis,
- Lymphoma
- Other causes of lung fibrosis [4]
Endobronchial ultrasound (EBUS) guided transbronchial fine needle aspiration
- High diagnostic yield up 90%
- Biopsy of hilar and mediastinal lymph nodes
- Largely replaced surgical biopsy [4]
Endothelin-1
- Associated with the
- Degree of lymphocytic alveolitis
- Number of macrophages in BAL fluid of patients with sarcoidosis
- Vasoactive, bronchoconstrictive peptide
- Identified in pulmonary fibroproliferative processes [3]
Exhaled breath analysis
Exhaled nitric oxide levels
- Greater in patients with sarcoidosis compared with healthy
- Significantly decreased following corticosteroid treatment
- May reflect disease activity
- Associated with amplified TH1 immune responses
- Resulting from induced nitric oxide synthase upregulation by TNF-alpha and IFN-gamma
- Elevated nitrite/nitrate in the serum of patients with sarcoidosis compared with healthy controls
- Lower levels of serum nitric oxide
- Induce production of bacterial hsp16
- A marker of the dormant stage of bacteria
- In mycobacteria
- Propionibacteria [3]
- Exhaled nitric oxide was not a clinically useful test for monitoring disease progression [3]
Exhaled carbon monoxide
- Significantly elevated in patients with sarcoidosis compared with healthy
- Reflecting increased oxidative stress [3]
Exhaled breath condensate (EBC) collection
- Noninvasive, simple technique for sampling airway lining fluids
- Investigating exhaled biomarkers in respiratory disease
- Total protein concentrations are greater in BAL than EBC
- 139 biomarkers have been found in the EBC of patients with sarcoidosis [3]
- Inflammatory markers correlated in BAL and EBC samples; such as
- Insulin-like growth factor-1
- TNF-alpha
- STNF-RII
- Plasminogen activator inhibitor-1
- M-CSF (macrophage colony stimulating factor)
- RANTES [3]
- TGF-beta1, vascular endothelial growth factor, and IL-8
- Have also been found in the EBC of patients with sarcoidosis [3]
- Markers of granulomatous inflammation increased in the EBC of patients with sarcoidosis compared with healthy control subjects
- TGF-beta1
- Neopterin
- May serve as airway biomarkers of disease activity [3]
exhaled eicosanoids
- Elevated levels in the BAL fluid and EBC of patients with sarcoidosis
- Including
- Cysteinyl leukotrienes [3]
- 8-isoprostane
- Elevated in active sarcoidosis, which may indicate disease severity or activity
- Leukotriene B4 [3]
- Correlation between the levels of leukotriene B4 and 8-isoprostane in BAL fluid and EBC of patients with sarcoidosis [3]
Hydrogen peroxide and end products of lipid peroxidation
- Increased in EBC and BAL of patients with sarcoidosis [3]
Gel electrophoresis proteomics
- To analyze BAL from patients genetically predisposed to chronic sarcoidosis (with the HLA-DRB1*15 genotype)
- Aberrant protein patterns in patients compared with healthy controls and those with chronic beryllium disease
- Patients with sarcoidosis had increased compared with controls
- Hsp70,
- Peroxiredoxin 5,
- Annexin A2,
- Complement C3
- Transthyretin [3]
Granuloma derived factors
- ACE
- TNF-alpha
- Neopterin
- TGF-beta
- IL-6
- Osteopontin
Takže přichází pacient s dříve diagnostikovanou sarkoidózou. Měl i postižení ledvin. Vše mu prý zmizelo, sarkoidózu již prý asi nemá. Léčbu nyní nepotřebuje, jen tu a tam chodí na kontroly. Nicméně má trvale vyšší CRP kolem 20, postupně ztrácí v jednom uchu sluch, ve druhém má tinitus a objevují se náznaky toho, že by mohl mít dráždivý močový měchýř, dle popisu ho spíše bolí kyčle formou startovacích obtíží, ale bylo to dříve označeno za neuropatii. Dále má vyšší jaterní testy. Vápník v krvi a moči je v normě. Na hypertenzi bere kombinaci léků. Na kašel či dušnost si nestěžuje. Nejnápadnějším krevním nálezem je ono chornicky trvale zvýšené CRP, jehož příčinu nikdo neodhalil. Nicméně mohlo by to znamenat, že je tam i ono vyšší IL-6 a že toto, ev. i další projevy jsou součástí pokračující sarkoidózy.
Bylo by tedy velmi zajímavé mít možnost nějakého dobrého biomarkeru.
Histologie
- Identifying sarcoid granulomas in other tissues
- Exclusion of other possible diagnoses
- An important step in the diagnosis of sarcoidosis
- Noncaseating granulomas with a compact core of epithelioid and giant cells
- Fusion of giant cells to form multinucleated giant cells
- Zone of lymphocytes in the periphery of granulomas
- Histological evidence of granulomas is alone nondiagnostic
- Other granulomatous disease needs to be excluded with
- Other clinical, radiological, and laboratory findings [3]
- Biopsy samples should be investigated for
- Alternative causes of granulomatous inflammation, including
- Mycobacteria,
- Fungi,
- Parasites,
- Foreign particles such as beryllium [3]
- Classic sarcoid granulomas are non-necrotizing
- Tightly packed central area composed of macrophages,
- Epithelioid cells, multinucleated giant cells,
- And T lymphocytes that are predominantly CD4-positive.
- This central area is surrounded by a mixture of
- CD8- and CD4-positive T lymphocytes,
- B lymphocytes,
- Monocytes, mast cells,
- And fibroblasts, which in turn are surrounded by lamellar rings of hyaline collagen
- Granulomas that may be present include
- www.uptodate.com/contents/pathology-and-pathogenesis-of-sarcoidosis?search=treatment-of-pulmonary-sarcoidosis-with-alternatives-to-glucocortic&topicRef=5586&source=see_link
- Occurs in about 10% of the patients with sarcoidosis
- Aggravated by consuming a vitamin D-rich diet
- Disordered calcium homeostasis in patients with sarcoidosis was similar to the one seen with vitamin D intoxication [1]
- Hypercalcemia occurs in 5%–10% of patients
- Caused by increased serum 1,25-dihydroxyvitamin D3 (also known as calcitriol)
- By increasing intestinal absorption
- Osteoclastic bone resorption [3]
- Prevalence of 5 - 11% [6]
- Activated macrophages in sarcoid granulomas are capable to upregulate extrarenal 1-alpha-hydroxylase
- Converts 25-hydroxy vitamin D (25-(OH)D) to its active form
- Can result in hypercalcemia [6]
- Expression of parathyroid hormone-related protein (PTH-rP) in sarcoid macrophages
- May exert an autocrine action of 1alpha-hydroxylase activity
- Increased levels of serum IFN-gamma
- Stimulates the production of 1,25(OH)2D by alveolar macrophages [6]
- Hypercalcaemia is found in 5–11% [16]
- Hypercalcaemia may occur at any time during the disease
- Accompanied by
- Excessive thirst,
- Nausea,
- Confusion
- Fatigue are rare [16]
- Such patients with severe hypercalcaemia must first of all
- Discontinue any ongoing calcium or vitamin D supplementation
- Receive rehydration therapy
- Corticosteroids
- Bisphosphonates administered intravenously in a single dose could be added [16]
- If the hypercalcaemia is due to sarcoidosis
- A rapid reduction (within a few days) is expected in the serum calcium [16]
- After a time lag
- The urinary excretion rate should decrease [16]
- Sarcoidosis-induced hypercalcaemia may be resistant to this approach
- Loop diuretic may need to be administered
- Calcitonin is an option [16]
- Lack of response can indicate increased PTH release
- Hyperparathyroidism should be suspected and investigated
- Coexisting malignancies and other granulomatous diseases should be excluded [16]
- More common than severe hypercalcaemia
- Can be corrected by corticosteroids alone in moderate doses (15–25 mg daily)
- Or by starting treatment with, or adding, the antifungal drug ketoconazole [16]
- Another option is to inhibit the activity of 25(OH)D3-1?-hydroxylase, the enzyme that catalyses the hydroxylation of calcidiol to calcitriol
- By administering hydroxychloroquine
- This decreases the 25-hydroxylation and thereby lowers serum calcium levels [16]
- Corticosteroids in combination with immunosuppressive drugs such as methotrexate, infliximab
- General effect on calcium levels by controlling the overall granulomatous process [16]
- The daily intake of fluid should be more than 2 L [16]
- Some authors have recommended that exposure to sunlight should be minimized to avoid formation of active vitamin D3 metabolites
- Others have argued that this will only have a marginal effect on calcium metabolism [16]
- Reasonable to recommend limited intake of calcium-rich food
- This will not protect against the formation of renal stones [16]
- Is about three times more frequent než hyperkalcemie
- Undetected can cause
- Nephrocalcinosis,
- Renal stones,
- Renal failure [1]
- Greater than 40% of patients with sarcoidosis develop [3]
- Common in patients with sarcoidosis
- The most common manifestation is hypercalciuria - in cca 30% of patients
- Hypercalciuria in combination with nephrolithiasis
- May be treated with bisphosphonates and corticosteroids
- Positive experiences of administering thiazide diuretics in patients with hypercalciuria
- Thiazides have also been reported to induce severe hypercalcaemia
- Close monitoring is recommended [16]
- Renal stones, often identified by ultrasound
- Reported to occur in 10% of patients
- Can be eliminated by shockwave lithotripsy [16]
- Avoidance of corticosteroid-induced osteoporosis in patients with sarcoidosis
- Especially in those with disturbed calcium metabolism
- Reasonable to perform bone density measurement before long-term corticosteroid treatment is started
- To repeat this at regular intervals [16]
- If there is reduced bone density and in postmenopausal women
- Bisphosphonates should be considered in combination with recommendations for physical activity
- In some cases, hormone-replacement therapy [16]
- Repeat serum calcium test and measurement of 24-h calcium excretion
- Recommended after starting treatment [16]
- Some physicians advocate cholecalciferol for primary prevention if hypercalcaemia has been excluded [16]
- Effects of vitamin D supplementation on surrogate markers of skeletal health in patients with sarcoidosis and mild vitamin 25(OH)-D insufficiency were reported.
- There were no beneficial effects observed but a slight risk of hypercalcaemia.
- At present, there seems to be little evidence for vitamin D supplementation in this group of patients [16]
- Can, in our opinion, be observational
- Often requires no treatment
- Bisphosphonates or corticosteroids should be considered if there is a history of stone formation [16]
- In populations that have a significantly high incidence of tuberculosis infection
- Utilize antigens specific for Mycobacterium tuberculosis (MTB) complex
- Higher sensitivity and specificity for detecting MTB complex infections than conventional tuberculin skin tests [3]
- Measures peripheral blood T-cell IFN-gamma production
- Using enzyme-linked immunosorbent assay (ELISA)
- Mononuclear cells and peripheral blood mononuclear cells (PBMCs)
- Following ex vivo stimulation with whole PPD, ESAT-6, and culture filtrate protein-10
- Patients with sarcoidosis
- BAL and PBMC IFN-gamma release was similar with controls
- Less compared with patients with tuberculosis [3]
- Higher PBMC and BAL TH1 responses to
- Recombinant MTB catalase–peroxidase (mKatG)
- MKatG peptides in patients with sarcoidosis compared with healthy controls
- no difference with PPD+ control subjects [3]
- Greater peripheral blood TH1 responses in patients with sarcoidosis
- Following PBMC stimulation with mycobacterial heat shock proteins
- MTB-related peptides from ESAT-6,16,25 mycolyl–transferase antigen 85A
- Superoxide dismutase A [3]
- Increased in patients with sarcoidosis compared with controls [3]
- IP-10 levels were higher in BAL fluid samples of patients with active sarcoidosis compared with controls [3]
- SIL-2R in serum have been shown to be associated with active disease
- IL-2 receptors are found on the surface of T- and B-lymphocytes, monocytes and macrophages
- Soluble form is associated with cellular immune reactions [6]
- May be increased in sarcoidosis [6]
- Presence of elevated numbers of CD4+ IFN-gamma+ T-cells
- Increased CD4+/CD8+ T-cell ratios
- In patients with active pulmonary disease [3]
- T-cell subsets in induced sputum and BAL fluid were also strongly correlated in patients with sarcoidosis [3]
- 10%–20% of patients have elevated serum aminotransferase and alkaline phosphatase levels on liver function tests
- Hepatic involvement is clinically silent in the majority of patients
- Used as the diagnostic test for sarcoidosis
- By intradermal injection of Kveim reagent
- A validated suspension of allogeneic human sarcoid tissue
- Typically spleen or lymph nodes, homogenized in phosphate-buffered saline [3]
- This would develop into a papule at the injection site
- Which was biopsied around 6 weeks later [3]
- Histopathological presence of noncaseating epithelioid granulomas indicated sarcoidosis
- The test was very useful in distinguishing sarcoidosis from other granulomatous diseases
- no commercially available preparation of the reagent exists
- Each new Kveim–Siltzbach preparation requires validation in vivo
- Risks of transmitting infections
- Attempts at developing in vitro Kveim reactions and isolating the antigenic agent in the Kveim reagent have been unsuccessful [3]
- May be useful in supporting a diagnosis in suspected neurosarcoidosis
- Particularly with meningeal disease
- Specific ophthalmological signs described by Herbort et al
- To ancillary clinical investigations
- Common as activated T-cells accumulate at disease sites
- Effect of the increased serum anti-inflammatory cytokine interleukin (IL)-10
- Increased circulating numbers of regulatory T-cells
- May contribute to the peripheral anergy seen in patients with sarcoidosis
- Enzyme
- Produced by macrophages and epithelioid giant cells in sarcoid granulomas
- Elevated in the serum of patients with active sarcoidosis
- Serum lysozyme was also positively correlated with serum ACE
- Clinical usage of lysozyme remains limited
- Relatively insensitive
- Nonspecific [3]
- Repress gene translation
- Association between aberrant miRNA expression and the fibrotic progression in sarcoidosis
- MiRNA-29 (miR-29) family
- Regulate the infectivity of HIV-1 virus [3]
- Downregulation and inhibition of miR-29a facilitate IFN-gamma expression in T-cells
- Lower miR-29a and higher IFN-gamma levels in EBC of patients with sarcoidosis compared with EBC of healthy controls.
- no significant differences in miR-29a and IFN-gamma expression levels in the PBMCs of both groups
- MiR-29a is lowered in the presence of inflammation
- May have a role in modulating the TH1 profile within PBMCs
- May also serve as an EBC marker of sarcoidosis (unpublished data) [3]
- Can detect sarcoid of the brain, spinal cord, meninges, skull vault and pituitary lesions [4]
- Identified in 55% of sample
- Were also a target of the humoral immune response in a large number of sarcoidosis subjects
- This undegradable mycobacterial protein is a target of the adaptive immune response
- Causing granulomatous inflammation in at least a subset of sarcoidosis tissues [3]
- Greater PBMC and BAL TH1 responses to MTB-related KatG peptides in sarcoidosis patients
- Compared with healthy subjects [3]
- Identified as an important marker of the dormant stage of mycobacteria
- PBMCs from patients with sarcoidosis and tuberculosis
- Were similarly activated by in vitro exposure to recombinant mycobacterial heat shock proteins
- Compared with PBMCs from healthy control subjects.125 [3]
- Following stimulation with pooled peptides from MTB-related ESAT-6 and KatG
- Induction of greater numbers of IFN-gamma-producing T-cells
- Increased IL-2, IL-6, and TNF-alpha, in subjects with sarcoidosis compared with PPD negative healthy controls [3]
- Released by activated macrophages
- Metabolite of guanosine triphosphate
- In response to IFN-gamma [3]
- Higher levels in serum and urine of patients with sarcoidosis
- Lower levels with disease resolution
- Combined elevation of neopterin and sIL-2R
- Associated with increased likelihood of progressive disease that requires long-term corticosteroid treatment [3]
- Serum of some patients with sarcoidosis has demonstrated higher levels of collagenase
- Combination of raised BAL levels of collagenase and fibronectin
- Associated with more severe fibrotic disease [3]
- Elevated elastase is found in chronic stage III radiological disease [3]
- Progressive disease
- Induced by TNF-alpha and IL-1beta
- Downregulation of inhibitors of apoptosis [3]
- Used to identify features of sarcoidosis and sites of disease
- Suitable for a confirmatory biopsy,
- To determine the involvement of particular organs
- Sarcoidosis classically appears on gallium-67 scanning as panda and lambda signs
- Salivary glands
- Conjunctivae
- Nasal passages create the impression of the facial characteristics of a panda
- Mediastinal and hilar lymph nodes represent the Greek letter lambda
- Largely replaced gallium-67 scanning
- Effective in identifying disease activity in sarcoidosis
- 18F-FDG has greater availability as it is used extensively in oncology
- Involves a lower radiation dose,
- Provides better resolution
- Able to co-register scans with CT imaging [4]
- 18F-FDG PET is not reimbursed for sarcoidosis by national medical programs [4]
- Identifying occult sites for diagnostic biopsy in challenging cases where diagnosis is uncertain [3]
- Useful in the diagnosis of cardiac sarcoidosis
- Most patients have minimal or no symptoms
- But can present with sudden and life-threatening arrhythmias
- no diagnostic gold standard exists [3]
- Making the patient fast for a prolonged period prior to 18F-FDG PET
- Useful in evaluating active cardiac sarcoid lesions
- Inhibiting physiological myocardial 18F-FDG uptake [3]
- Modification in technique appeared to improve the specificity of the PET scan in diagnosing cardiac sarcoidosis [3]
- Hypermetabolism detection
- Very sensitive technique to assess inflammatory activity in sarcoidosis by detecting and quantifying the degree of inflammatory and granulomatous reactions that occur in the lungs and elsewhere in the body [7]
- Negative serological test results do not exclude the presence of inflammatory activity [7]
- 80% of extrathoracic lesions were found [7]
- Abnormality occur in about 20% of patients with mild disease
- Increasing to 40-70% with more advanced disease [4]
- May occur [4]
- Occurring with decreased forced vital capacity and diffusing capacity
- These may improve [4]
- Is common, but pre and post-bronchodilator spirometry may not show a significant change, unlike in asthma [4]
- May be used as a marker that predicts clinical deterioration in patients with sarcoidosis
- Increased red cell diffusion width correlating with worsening radiographic stages of the disease [3]
- Provide cost-effective initial investigations
- Bilateral hilar lymphadenopathy
- Often found incidentally [4]
- Other mediastinal lymphadenopathy and upper zone intrapulmonary abnormalities may be identified.
- Abdominal adenopathy
- Splenic abnormalities (such as nodular spleen or enlargement)
- Can be seen on ultrasound [4]
- no consensus on whether interval chest x-ray or low dose high resolution computed tomography (CT) scanning is more appropriate [4]
- I
- Bilateral hilar lymphadenopathy
- Sometimes accompanied by paratracheal lymphadenopathy
- II
- Bilateral hilar lymphadenopathy with parenchymal infiltrates
- III
- Parenchymal infiltrates without hilar lymphadenopathy
- IV
- Pulmonary fibrosis [3]
- Often with honeycombing, hilar retraction, bullae, and cysts [3]
- Despite this nomenclature, patients do not progress through these stages in any sequential order [3]
- Just classification of radiographic appearances [3]
- Than other clinical presentations ESR is more likely to be elevated in
- Sarcoidosis-associated arthritis
- Erythema nodosum [3]
- Can also be considered as a nonspecific inflammatory marker of sarcoidosis
- Regulates granulomatous inflammation
- Through Toll-like receptor-2
- Also functions as an acute phase reactant
- Released together with CRP under systemic stimulation by IL-1 and IL-6 [3]
- The soluble form of the IL-2 receptor (sIL-2R) is a T-cell IL-2 receptor
- Used in monitoring graft rejection [3]
- Can be elevated in certain infections and autoimmune diseases [3]
- Increased in the serum and BAL of patients with sarcoidosis [3]
- Decreasing during remission and with therapy initiation [3]
- Significantly higher in patients with active sarcoidosis [3]
- SIL-2R may be a useful biomarker of disease activity [3]
- SIL-2R compared with serum amyloid A, CRP, and angiotensin-converting enzyme (ACE) [3]
- Only sIL-2R predicted severity of sarcoidosis [3]
- Identified 69 protein species significantly altered in patients with sarcoidosis compared with healthy controls
- Associated with the
- Clathrin-mediated endocytosis pathway
- Fcgamma-mediated phagocytosis pathway [3]
- Possibly providing insights into the role of macrophage phagocytosis in sarcoid immunopathogenesis
- A recent investigation has also interestingly identified
- Aberrant expression of receptors for the
- Fc fragment of immunoglobulin G (FcgammaR)
- Complement receptors (CRs) on peripheral blood monocytes from patients with sarcoidosis [3]
- Increased expression of the receptors
- FcgammaRI (CD64),
- FcgammaRII (CD32),
- FcgammaRIII (CD16)
- Decreased expression of CR1 (CD35) and CR4 (CD11c) on peripheral blood CD14+ monocytes
- In patients with sarcoidosis compared with controls
- This may be responsible for altered phagocytic activity in sarcoidosis
- Leading to high or persistent antigen load and increased circulating immune complexes in sarcoidosis [3]
- New technique
- Identified different disease-related proteins and protein patterns in serum
- BAL fluid of patients with sarcoidosis
- proteins that are related to clinical course
- Protocadherin-2 precursor
- Alpha1-antitrypsin
- Albumin [3]
- Identifying potential protein biomarkers in sarcoidosis
- Differ from those with other interstitial lung diseases [3]
- Implicated in autoimmune and granulomatous disease
- Investigated in sarcoid immunopathogenesis
- Increase in the number of BAL and peripheral blood IL-17A+ and IL-17A+ IFN-gamma+ memory T-cells identified in sarcoidosis
- Skin biopsies have also demonstrated increased TH1 and TH17 gene expression
- Together with increased IL-23 and IL-23R expression in patients with sarcoidosis [3]
- Multifunctional cell signaling molecule
- Attenuation of inflammation
- Implicated in various fibrotic conditions
- Induces fibroblast recruitment and transformation to the myofibroblast phenotype
- Role in fibrosis
- Association between increased TGF-beta levels and spontaneous clinical remission
- TGF-beta2 and TGF-beta3 genes were altered in sarcoidosis-associated pulmonary fibrosis
- Intrinsic alterations in TGF-beta may predispose to sarcoidosis-associated pulmonary fibrosis [3]
- Depressed delayed type hypersensitivity reactions
- Cutaneous anergy to the tuberculin skin test
- Diagnostic criterion for sarcoidosis
- Less reliable in diagnosis of sarcoidosis compared with interferon (IFN)-gamma release assays [3]
- Identified 85 proteins in BAL fluid
- 38 newly identified and possibly relevant proteins in BAL from patients with sarcoidosis [3]
- Proteins found were
- Locally secreted
- Plasma-derived proteins
- Proteolytic or cell damage products with proinflammatory, anti-inflammatory, and antiprotease activity [3]
- Hypercalcemia is a feature of sarcoidosis
- Hypercalcemia can be aggravated by consuming a vitamin D-rich diet
- vitamin D may be related to the calcium abnormality in the disease
- In 345 patients with sarcoidosis in North Carolina
- Mean serum calcium level during the winter months was 9.89 mg
- Rose to 10.26 mg/dL during the summer months [1]
- In 12,027 control subjects
- Levels in winter and summer remained unchanged [1]
- In two hypercalcemic patients further rise in serum calcium level occurred after whole-body ultraviolet light irradiation [1]
- In normal physiological states, the kidney hydroxylates vitamin D3 to its biologically active form
- Sarcoid macrophages also possess a 25-hydroxyvitamin D3-1?-hydroxylase enzyme
- Hydroxylates vitamin D3 to its active form
- Produced excessively in sarcoid granulomas [3]
- Sarcoid alveolar macrophages have been identified to be the source of excess calcitriol
- Elevated 25-hydroxyvitamin D3-1alpha-hydroxylase messenger ribonucleic acid (RNA) expression [3]
- vitamin D has important immunomodulating effects
- Inhibition of
- Antigen presentation by cells of the innate immune system
- Cytokine release
- Proliferation of TH1 cells
- Polymorphisms of the vitamin D receptor gene associated with
- Increased risk of granulomatous disease, including sarcoidosis
- Bone mineral density
- Hyperparathyroidism
- Hyperparathyroidism and parathyroid adenomas
- Sometimes the causative mechanism for hypercalcemia in patients with sarcoidosis
- Previtamin D3 can also be synthesized from 7-dehydrocholesterol in the skin under the influence of ultraviolet light.
- After spontaneous isomerization at body temperature, the previtamin D3 is converted to cholecalciferol (vitamin D3)
- Metabolically active form of vitamin D3, calcitriol (i.e. 1,25-(OH)2-D3)
- Two-step hydroxylation process that takes place first in the liver and then in the kidneys
- Second hydroxylation can also occur extrarenally in sarcoidosis
- In alveolar macrophages [16]
- Calcitriol
- Increases G-I absorption of calcium and phosphate
- Stimulates osteoclast activity in bones
- May play a role in immunoregulation by downregulating the activation of lymphocytes [16]
- Elevated
- May be low !!!
- Leading to the erroneous diagnosis of vitamin D deficiency !!!
- Of pulmonary sarcoidosis, tuberculosis, and other similar pulmonary diseases, before and after treatment, and in purified leukocyte populations
- Tuberculosis and sarcoidosis had similar blood transcriptional profiles
- Dominated by IFN-inducible transcripts
- Other pulmonary diseases, such as pneumonia and lung cancer
- Distinct signatures dominated by inflammatory genes [3]
- Genetic factors and transcriptional signatures of sarcoidosis could be compared with other diseases
- For rapid diagnosis and to determine appropriate patient treatment [3]
