SARCOIDOSIS
AKPABIO JESSICA
1003
INTRODUCTION
Sarcoidosis is granulomatous
disease(noncaseating in all tissues)
90% of cases involve hilar lymph nodes
women are more affected than men peak ages 2535, 45-65. american blacks are affected 10 times
more often than american whites
PATHOGENESIS
sarcoidosis is likely a disease of disordered immune response to
genetically predisposed individuals to certain environmental agents
evidence includes
association with specific HLA genotypes eg HLA-A1 and HLA-B8
accumulation of oligoclonal activated CD4+ Tcells
increased Th1 cytokine production(IL2 and interferone gamma)
causing Tcell expansion and macrophage activation
increased macrophage tumor necrosis factor(TNF) production
leading to granuloma formation
cutaneous anergy to common antigens eg tuberculin and candida
polyclonal hypergammaglobulinemia
MORPHOLOGY
Granulomas are the characteristically noncaseating with
tightly clustered epitheloid histiocytes and frequent
multinucleate giant cells. schaumann
bodies(laminated,calcified proteinaceous concretions) and
asteroid bodies(stellate inclusions within giant cells)
commonly occur but are not pathognomonic
lungs exhibit diffuse,scattered granulomas,forming a
reticulonodular pattern on x-ray films.pulmonary lesions tend
to heal and only residual hyalinized scars may be seen
lymph nodes are always involved commonly in the hilar and
mediastinal regions tonsils are involved in 25-33% of cases
spleen and liver are microscopically affected in 75% of
patients (although gross splenomegaly and hepatomegaly
occur in less than 20% of cases
bone marrow involvement is seen in 20% of cases
radiologically visible lesions have a pharyngeal predilection
skin involvement occurs in 33% to 50% of patients as
discrete subcutaneous nodules or erythematous scaling
plaques or macules; mucous membrane lesions also occur
eyes are affected in 20% to 50% of cases, including
iritis,indocyclitis or choroid retinitis often with lacrimal gland
inflammatory and reduced lacrimation,concurrent salivary
gland involvement constitutes the Mikulicz syndrome
PATHOPHYSIOLOGY
T cells play a central role in the development of sarcoidosis, as they likely
propagate an excessive cellular immune reaction. For example, there is an
accumulation of CD4 cells accompanied by the release of interleukin
(IL)–2 at sites of disease activity. This may manifest clinically by an
inverted CD4/CD8 ratio. Pulmonary sarcoidosis is frequently characterized
by a CD4+/CD8+ ratio of at least 3.5 in bronchoalveolar lavage fluid (BALF),
although up to 40% of the cases present a normal or even decreased ratio,
thus limiting its diagnostic value.Increased production of TH1 cytokines,
such as interferon, is also a feature.
Moreover, both tumor necrosis factor (TNF) and TNF receptors are
increased in this disease. The importance of TNF in propagating
inflammation in sarcoidosis has been demonstrated by the efficacy of antiTNF agents, such as pentoxifylline and infliximab,in treating this disease.
In addition to T cells, B cells also play a role. There is evidence of B cell
hyperreactivity with immunoglobulin production.
Soluble HLA class I antigens levels in serum and
BALF are higher in patients with sarcoidosis.
These levels tend to be significantly higher in
active than in inactive stages and correlate with
angiotensin-converting enzyme (ACE) levels.
Active sarcoidosis has also been associated with
plasmatic hypergammaglobulinemia. B-cell
accumulation has been shown in pulmonary
lesions, and a beneficial effect with anti-CD20
monoclonal antibody therapy has been reported in
select patients.
Glycoprotein KL-6 and surfactant protein D (SP-D) derived
from alveolar type II cells and bronchiolar epithelial cells are
significantly increased in pulmonary sarcoidosis and correlate with
the percentage of lymphocytes in BALF, reflecting an
inflammatory response in sarcoidosis. However, there is no
significant correlation between KL-6 or SP-D levels and chest
radiography findings, ACE levels, or CD4/CD8 ratio in BALF. KL-6
has been shown to be predictive of increased pulmonary
parenchymal infiltration.
A study by Facco et al suggests that Th17 cells may play a role in
the pathogenesis and progression of sarcoidosis; these cells were
noted to be present in the blood, BALF samples, and lung tissue
from patients with sarcoidosis, particularly in those with the active
form of the disease.
SYMPTOMS
Symptoms vary according to what organ is infected they include
generalized symptoms; fatigue fever swollen lymph node,weight loss
lung symptoms; persistent dry cough, shortness of
breath,wheezing,chest pain
skin symptoms; blurred vision,eye pain, severe redness, sensitivity to
light
others include; swollen and painful joints nasal stiffness hoarse voice
pain in hands and feet or other bony areas( due to formation of cyst in
bones)
SIGNS
kidney stone formation
enlarged liver
arrhythmias
pericarditis
heart failure
hearing loss
meningitis
seizures
dementia
depression
Pulmonary findings on physical examination are as follows:
• Usually normal
• Crackles may be audible
• Exertional oxygen desaturation may be present
Dermatologic manifestations may include the following:
• Erythema nodosum
• A lower-extremity panniculitis with painful, erythematous
nodules (often with Löfgren syndrome)
• Lupus pernio (the most specific associated cutaneous lesion)
• Violaceous rash on the cheeks or nose (common)
• Maculopapular plaques (uncommon)
Ocular involvement, which may lead to blindness if untreated,
may manifest as follows:
• Anterior or posterior granulomatous uveitis (most frequent)
• Conjunctival lesions and scleral plaques
Other possible manifestations are as follows:
• Osseous involvement
• Heart failure from cardiomyopathy (rare)
• Heart block and sudden death
• Lymphocytic meningitis (rare)
• Cranial nerve palsies and hypothalamic/pituitary
dysfunction (rare)
Löfgren syndrome (fever, bilateral hilar
lymphadenopathy, and polyarthralgias): Common
in Scandinavian patients, but uncommon in
African-American and Japanese patients
ETIOLOGY
Doctors don't know the exact cause of sarcoidosis. Some
people appear to have a genetic predisposition to
developing the disease, which may be triggered by
exposure to specific bacteria, viruses, dust or chemicals.
Researchers are still trying to pinpoint the genes and
trigger substances associated with sarcoidosis.
Normally, your immune system helps protect your body
from foreign substances and invading microorganisms,
such as bacteria and viruses. But in sarcoidosis, some
immune cells collect in a pattern of inflammation called
granulomas. As granulomas build up in an organ, the
function of that organ can be affected.
RISK FACTORS
While anyone can develop sarcoidosis, factors that may
increase your risk include:
• Age and sex. Sarcoidosis often occurs between the
ages of 20 and 40. Women are slightly more likely to
develop the disease.
• Race. African-Americans have a higher incidence of
sarcoidosis than do white Americans. Also, sarcoidosis
may be more severe and may be more likely to recur
and cause lung problems in African-Americans.
• Family history. If someone in your family has had
sarcoidosis, you are more likely to develop the disease
yourself.
DIAGNOSIS
• X-ray, to check for evidence of lung damage or enlarged lymph
nodes in your chest,pulmonary infiltrates
• CT scan, if complications are suspected.
• PET or MRI, if sarcoidosis seems to be affecting your heart or
central nervous system
• Blood tests, to assess your overall health and how well your
kidneys and liver are functioning.
• Lung function tests, to measure lung volume and how much
oxygen your lungs deliver to your blood.
• Eye exam, to check for vision problems that may be caused by
sarcoidosis.
Staging of sarcoidosis is as follows:
• Stage 0: Normal chest radiographic findings
• Stage I: Bilateral hilar lymphadenopathy
• Stage II: Bilateral hilar lymphadenopathy and infiltrates
• Stage III: Infiltrates alone
• Stage IV: Fibrosis
Biopsies
Your doctor may order a small sample of tissue
(biopsy) be taken from a part of your body believed to
be affected by sarcoidosis to look for the granulomas
commonly seen in the condition. Biopsies can most
easily be taken from your skin or the outer membrane
of your eye. Tissue is sent to a laboratory for analysis.
Lung biopsies or lymph node biopsies can be obtained
through a procedure (bronchoscopy) in which a thin,
flexible tube containing a camera is inserted down
your throat.
COMPLICATIONS
• Lungs. Untreated pulmonary sarcoidosis can lead to irreversible damage to
the tissue between the air sacs in your lungs, making it difficult to breathe.
• Eyes. Inflammation can affect almost any part of your eye and can eventually
cause blindness. Rarely, sarcoidosis also can cause cataracts and glaucoma.
• Kidneys. Sarcoidosis can affect how your body handles calcium, which can
lead to kidney failure.
• Heart. Granulomas within your heart can interfere with the electrical signals
that drive your heartbeat, causing abnormal heart rhythms and, in rare
instances, death.
• Nervous system. A small number of people with sarcoidosis develop
problems related to the central nervous system when granulomas form in the
brain and spinal cord. Inflammation in the facial nerves can cause facial
paralysis.
TREATMENT
Steroid treatment
Corticosteroids are the mainstay of therapy.
Generally, prednisone given daily and then tapered over a 6-month course is adequate
for pulmonary disease. Earlier recommendations suggested an initial dose of 1 mg/kg/d of
prednisone; however, more recent expert opinions endorse a lower dose (eg, 40 mg/d),
which is tapered to every-other-day long-term therapy over several weeks. In one study,
treatment of acute exacerbations of pulmonary sarcoidosis with steroid doses as low as
20 mg of prednisone for a median of 21 days improved spirometry back to baseline and
improved clinical symptoms.[54] Most patients who require long-term steroids can be
treated using 10-15 mg of prednisone every other day.
Some data suggest that corticosteroid use may be associated with increased
relapse rates. However, data suggest early treatment of stage II sarcoidosis with oral
prednisolone for 3 months followed by inhaled budesonide for 15 months improves 5-year
pulmonary function and reduces the need for future steroid treatment.[55]
High-dose inhaled corticosteroids may be an option, but conclusive data are lacking.
Inhaled corticosteroids, in particular, can be used in patients with endobronchial
disease.
Although corticosteroids are used for symptom relief and remain
the mainstay of therapy, their efficacy in this disease is unclear.
Since many patients' conditions improve spontaneously, showing
a true benefit to therapy requires a careful control arm.
The best study addressing corticosteroids was the recently
completed multicenter trial from Britain sponsored by the British
Thoracic Society. In this nonrandomized study, 55 patients were
selectively observed or treated with corticosteroids. Additionally,
patients who were thought to have an immediate indication for
steroids were treated. The trial required a 6-month run-in period to
exclude patients who improved spontaneously. At the end of the
trial, the groups treated with long-term steroids fared better on
some measures than did the patients who were observed and
treated with short bursts of steroids
Nonsteroid treatment
Noncorticosteroid agents are being increasingly tried. Common indications
for the initiation of such agents include steroid-resistant disease, intolerable
adverse effects, or patient desire not to take corticosteroids.
Methotrexate (MTX) has been a successful alternative to prednisone and is
a steroid-sparing agent.
Chloroquine and hydroxychloroquine are antimalarial drugs with
immunomodulating properties, which have been used for cutaneous lesions,
hypercalcemia, neurological sarcoidosis, and bone lesions. Chloroquine has
also been shown to be efficacious for the treatment and maintenance of
chronic pulmonary sarcoidosis.
Cyclophosphamide has been rarely used with modest success as a
steroid-sparing treatment in patients with refractory sarcoidosis.
Azathioprine is another second-line therapy, which is best used as a
steroid-sparing agent rather than as a single-drug treatment for sarcoidosis.
Chlorambucil is an alkylating agent that may be beneficial in patients with
progressive disease unresponsive to corticosteroids.[8]
Tumor necrosis factor-alpha (TNF-alpha)
inhibitors. These medications are most commonly
used to treat the inflammation associated with
rheumatoid arthritis. They can also be helpful in
treating sarcoidosis that doesn't respond to other
treatments. e.g. infliximab, pentoxifylline
CASE STUDY
29-year-old black woman was referred from a community hospital for evaluation of bilateral
infiltrates on chest radiograph and worsening shortness of breath. She had had a few weeks of
nonproductive cough, exertional dyspnea, fever, night sweats, and weight loss. She had had no
clinical response to intravenous cefoperazone and oral trimethoprim/sulfamethoxazole. He had
smoked one pack of cigarettes a week for 10 years. She had a history of multiple sexual contacts.
She denied any history of tuberculous exposure, recent travel, or occupational exposure.
Physical examination revealed a temperature of 100.6°F, respiratory rate 32/min, pulse rate
120/min, and blood pressure 120/80 mm Hg. She appeared ill and in obvious respiratory distress.
Head, eye, ear, nose, and throat examination was unremarkable. The neck was supple with no
lymphadenopathy. There were no rashes or skin lesions. Heart sounds were normal, with no
murmurs or gallops. Bilateral crackles were present on chest auscultation. Examination of the
abdomen, extremities, and neurologic function was unremarkable.
Arterial blood gas measurements on room air were PaO2 47 mm Hg, PaCO2 33 mm Hg, and pH
7.41. Complete blood count revealed a hemoglobin value of 16.4 g/dL, white blood cell count
5,800/mm3(68.3% neutrophils, 16% lymphocytes, 12.2% monocytes, 2.1% eosinophils, 1.4%
basophils), and platelet count 312,000/mm3. Serum urea nitrogen, creatinine, electrolytes,
prothrombin time, and partial thromboplastin time were normal. Serum lactate dehydrogenase was
314 IU/L (normal, 100 to 205 IU/L), alkaline phosphatase was 241 IU/L (normal, 36 to 125 IU/L),
aspartate aminotransferase was 48 IU/L (normal, 2 to 50 IU/L), and serum albumin was 3.1 g/dL. A
chest radiograph revealed extensive bilateral parenchymal infiltrates, with bilateral pneumothorax
and pneumomediastinum (Fig 1). High-resolution computed tomography (CT) of the chest revealed
diffuse bilateral infiltrates with a ground glass appearance, bullous disease, areas of cavitation, and
bilateral pneumothorax (Fig 2). Conventional CT of the chest revealed mild to moderate bilateral
pleural effusion. No mediastinal or hilar lymphadenopathy was seen.
Chest radiograph shows extensive bilateral parenchymal infiltrates with
pneumothorax (white arrows) and pneumomediastinum (black arrows).
High-resolution computed tomography of chest shows diffuse bilateral infiltrates with
ground glass appearance, bullous disease, areas of cavitation, and bilateral
pneumothorax.
A face mask with inspired oxygen of 40% was provided. Admitting house staff
initiated intravenous trimethoprim/sulfamethoxazole and oral prednisone 60 mg a
day for possible Pneumocystis cariniipneumonia. A chest tube was inserted in the right
pleural cavity. Pleural fluid analysis revealed a pH of 7.84, white blood cell count
7,449/mm3 (13% neutrophils, 86% lymphocytes, and 1% eosinophils), red blood cell
count 141,000/mm3, total protein 6.5 g/dL (serum total protein, 8.5 g/dL), lactate
dehydrogenase 504 IU/L (serum lactate dehydrogenase, 314 IU/L), and glucose 61
mg/dL (serum glucose, 79 mg/dL). Sputum, blood, and pleural fluid cultures were
negative for microorganisms. Simple spirometry revealed severe restrictive lung
impairment, with forced expiratory volume in 1 second (FEV1) of 1.34 L (42%
predicted), forced vital capacity (FVC) of 1.51 L (41% predicted), and FEV1/FVC
ratio of 89 (104% predicted).
Open lung biopsy resulted in the diagnosis of sarcoidosis, and
trimethoprim/sulfamethoxazole was discontinued. The patient showed dramatic
clinical improvement after 4 weeks of oral prednisone 40 mg/day, with an
improvement in restrictive lung impairment (FEV1 2.15 L [68% predicted], FVC 2.71
L [74% predicted], and FEV1/FVC 79% [93% predicted]). Follow-up chest radiograph
revealed complete reexpansion of the lungs and near-resolution of the parenchymal
disease, with no recurrence of pneumothorax to date. Recovery was complete,
without sequelae on chest radiograph
REFERENCES
ROBBINS PATHOLOGY BY KUMAR, ABBAS
INTERNAL MEDICINE BY DAVIDSON
www.mayoclinic.org
www.webmd.com
www.emedicine.medscape.com