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What is Sarcoidosis
 

What is Sarcoidosis?

Definition

"Sarcoidosis is an inflammatory disease characterized by the presence of noncaseating granulomas. The disease is often multisystem and requires the presence of involvement in two or more organs for a specific diagnosis. The finding of granulomas is not specific for sarcoidosis, and other conditions known to cause granulomas must be ruled out. These conditions include mycobacterial and fungal infections, malignancy, and environmental agents such as beryllium. While sarcoidosis can affect virtually every organ of the body, the lung is most commonly affected. Other organs commonly affected are the liver, skin, and eye. The clinical outcome of sarcoidosis varies, with remission occurring in over one-half of the patients within a few years of diagnosis; however, the remaining patients may develop a chronic disease that lasts for decades.

Etiology

Despite multiple investigations, the cause of sarcoidosis remains unknown. Currently, the most likely etiology is an infectious or noninfectious environmental agent that triggers an inflammatory response in a genetically susceptible host.

Incidence and Prevalence

Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years; a second peak is observed for women over 50. Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5/100,000 in men and 19/100,000 in women. The disease is most prevalent in Northern European countries, and the highest annual incidence of 60/100,000 is found in Sweden and Iceland. In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9/100,000, respectively. Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and Philippines.

Pathophysiology

The granuloma is the pathologic hallmark of sarcoidosis.

 

Clinical Manifestations

Lung
Lung involvement occurs in > 90 % of sarcoidosis patients. The most commonly used method for detecting lung disease is still the chest roentgenogram.
Although the CT scan has changed the diagnosis approach to interstitial lung disease, the CT scan is not usually considered a monitoring tool for patients with sarcoidosis.
The standard scoring system described by Scadding in 1961 for chest roentgenograms remains the preferred method of characterizing the chest involvement.
Stage 1 is hilar adenopathy alone, often with right paratracheal involvement .
Stage 2 is a combination of adenopathy plus infiltrates.
Stage 3 reveals infiltrates alone.
Stage 4 consists of fibrosis.
Usually the infiltrates are predominantly an upper lobe process. Cough is a very common symptom. Airway involvement causing varying degrees of obstruction underlies the cough in most sarcoidosis patients. Pulmonary arterial hypertension is reported in at least 5% of sarcoidosis patients. Either direct vascular involvement or the consequence of fibrotic changes in the lung can lead to pulmonary arterial hypertension. .

 

Skin
Skin involvement is eventually identified in over a third of patients with sarcoidosis. The classic cutaneous lesions include erythema nodosum, maculopapular lesions, hyper- and hypopigmentation, keloid formation, and subcutaneous nodules. A specific complex of involvement of the bridge of the nose, the area beneath the eyes, and the cheeks is referred to as lupus pernio and it diagnostic for a chronic form of sarcoidosis.
In contrast erythema nodosum is a transient rash that can be seen in association with hilar adenopathy and uveitis (Lofgren's syndrome). The maculopapular lesions from sarcoidosis are the most common chronic form of the disease.

Eye
The most common manifestation is an anterior uveitis, over a quarter of patients will have inflammation at the posterior of the eye, including retinitis and pars planitis. Sicca is seen in over half of the chronic sarcoidosis patients. Dry eyes appear to be a reflection of prior lacrimal gland disease.

Liver
Using biopsies to detect granulomatous disease, liver involvement can be identified in over half of sarcoidosis patients. However using liver function studies, only 20-30% of patients will have evidence of liver involvement. The most common abnormality of liver function is an elevation of alkaline phosphatase level, consistent with an obstructive pattern. In addition, elevated transaminase level can occur. An elevated bilirubin level is a marker for more advanced liver disease. Overall, only 5% of sarcoidosis patients have sufficient symptoms from their liver disease to require specific therapy. Although symptom can be due to hepatomegaly, more frequently symptoms result from extensive intrahepatic cholestasis leading to portal hypertension. In this case, ascites and esophageal varices can occur.

Bone Marrow and Spleen
The most common hematologic problem is lymphopenia which is reflection of sequestration of lymphocytes into the area of inflammation. Anemia occurs in 20% of patients and leucopenia is less common. Bone marrow examination will reveal granulomas in about a third of patients. Splenomegaly can be detected in 5-10% of patients, but splenic biopsy reveals granulomas in 60% of patients.

Calcium Metabolism
Hypercalcemia and/or hypercalciuria occur in about 10% of sarcoidosis patients. Serum calcium should be determined as part of initial evaluation of all sarcoidosis patients.

Renal Disease
Direct kidney involvement occurs in <5% of sarcoidosis patients. It is associated with granulomas in the kidney itself and can lead to nephritis. However, hypercalcemia is the most likely cause of sarcoidosis-associated renal disease. In 1-2% of sarcoidosis patients, acute renal failure has been encountered as a result of hypercalcemia.

Nervous System
Neurologic disease is reported in 5-10% of sarcoidosis patients. Any part of central or peripheral nervous system can be affected. The cerebral spinal fluid (CSF) findings include lymphocytic meningitis with a mild increase in protein. The CSF glucose is usually normal but can be low. Certain areas of nervous system are more commonly affected in neurosarcoidosis. These include cranial nerve involvement, basilar meningitis, myelopathy, and anterior hypothalamic disease with associated diabetes insipidus. Seizures and cognitive changes also occur. Of the cranial nerves, seventh nerve paralysis can be transient and can be mistaken for Bell's palsy. Optic neuritis is another cranial nerve manifestation of sarcoidosis. This manifestation is more chronic and usually requires long-term systemic therapy.

Cardiac
The presence of cardiac involvement is influence by race. Cardiac disease usually presents as either congestive heart failure or cardiac arrhythmia. Both manifestations result from infiltration of the heart muscle by granulomas. Diffuse granulomatous involvement of the heart muscle can lead to ejection fraction below 10%. If the AV node is infiltrated, heart block can occur. Ventricular arrhythmias and sudden death due to ventricular tachycardia are common cause of death.

Musculoskeletal System
Direct granulomatous bone and muscle involvement as documented by x-ray, MRI, gallium scan, or biopsy can be seen in about 10% of sarcoidosis patients. However, a larger percentage of sarcoidosis patients complain of myalgias and arthralgias. Fatigue associated with sarcoidosis may be overwhelming for many patients.

Complications
Sarcoidosis is usually a self-limited, non-life-threatening disease. However, organ threatening disease can occur. These complications can include blindness, paraplegia, or renal failure. Death from sarcoidosis occurs in about 5% of patients seen in sarcoidosis referral clinics. The usual causes of death related to sarcoiosis are from lung, cardiac, neurologic, or liver involvement. In respiratory failure, an elevation of the right arterial pressure is a poor prognostic finding. Lung complications can also include infections such as mycetoma, which can subsequently lead to massive bleeding. In addition, the use of immunosuppressive agents can increase the incidence of serious infections.

Laboratory findings

The chest roentgenogram remains the most commonly used tool to assess lung involvement in sarcoidosis. The CT scan has been used increasingly in evaluating interstitial lung disease.
Gallium 67 scanning has been used over the years to detect inflammatory activity in various part of the body. A negative scan can be easily misinterpreted as the scan will quickly revert to normal during glucocorticoid therapy. More recently, the positive emission tomography (PET) scan has provided information similar to the gallium scan. It is important to recognize that a positive PET scan may be due to the granuloma from sarcoidosis and not to disseminate malignancy.
Serum levels of angiotensin-converting enzyme (ACE) can be helpful in the diagnosis of sarcoidosis. However the test has somewhat low sensitivity and specificity. Elevated level of ACE is reported in 60% of patient with acute disease and only 20% of patient with chronic disease. The ACE level of lymphoma is usually lower than normal, which may provide a useful distinction from sarcoidosis.

Diagnosis

The chest roentgenogram remains the most commonly used tool to assess lung involvement in sarcoidosis. The CT scan has been used increasingly in evaluating interstitial lung disease.
Gallium 67 scanning has been used over the years to detect inflammatory activity in various part of the body. A negative scan can be easily misinterpreted as the scan will quickly revert to normal during glucocorticoid therapy. More recently, the positive emission tomography (PET) scan has provided information similar to the gallium scan. It is important to recognize that a positive PET scan may be due to the granuloma from sarcoidosis and not to disseminate malignancy.
Serum levels of angiotensin-converting enzyme (ACE) can be helpful in the diagnosis of sarcoidosis. However the test has somewhat low sensitivity and specificity. Elevated level of ACE is reported in 60% of patient with acute disease and only 20% of patient with chronic disease. The ACE level of lymphoma is usually lower than normal, which may provide a useful distinction from sarcoidosis.

In the second scenario, sign and symptoms suggesting sarcoidosis such as the presence of bilateral adenopathy may be present in otherwise asymptomatic patient or a patient with uveitis or a rash consistent with sarcoidosis. At this point a diagnostic procedure should be performed. For the patient with a compatible skin lesion, a skin biopsy should be considered. Other biopsies to consider could include liver, extrathoracic lymph node, or muscle. In some cases, a biopsy of the affected organ may not be easy to perform (such as a brain or spinal cord lesion). In other cases such as an endomyocardial biopsy, the likelihood of a positive is low. Because of the high rate of pulmonary involvement in these cases, the lung may be easier to approach by bronchoscopy. If the biopsy reveals granulomas, an alternative diagnosis such as infection and malignancy must be excluded. Since granulomas can be seen on the edge of lymphoma, the presence of a few granulomas from a needle aspiration may not be sufficient to clarify the diagnosis. Mediastinoscopy remains the procedure of choice to confirm the presence or absence of lymphoma. For patients with negative pathology, positive supportive test may increase the likelihood of the diagnosis of sarcoidosis. These tests include an elevated ACE level, which can also be elevated in other granulomatous disease but not in malignancy. A positive gallium scan can support the diagnosis if increased activity is noted in the parotids and lacrimal gland (Panda sign) or in the right paratracheal and left hilar area (lambda sign). An increase in the percentage of lymphocytes supports the diagnosis of sarcoidosis in the BAL fluid. A CD4/CD8 ratio of > 3.5 is strongly supportive of sarcoidosis but is less sensitive than an increase in lymphocytes alone in the BAL fluid. An increase in BAL lymphocytes is supportive of the diagnosis, other conditions must be considered. This supportive test when combine with commonly associated clinical features of the disease, which are not diagnostic of sarcoidosis, can enhance the diagnostic probability.

 

 

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