There is tremendous heterogeneity in the clinical manifestations of sarcoidosis. Pulmonary involvement is documented in >90% of patients. Nonpulmonary manifestations are present in many patients with or without pulmonary involvement (Table 54–1).
An initial diagnostic evaluation should consist of tests to evaluate the presence and extent of pulmonary involvement and screening for common extrathoracic involvement (Table 54–2). Specialized testing is indicated when symptoms or signs suggest extrapulmonary involvement.
Acute Sarcoidosis (Löfgren Syndrome)
This syndrome of acute sarcoidosis is characterized by erythema nodosum, bilateral hilar adenopathy, and often polyarthritis and uveitis (Figure 54–1). Löfgren syndrome is common among Scandinavians and Irish women but occurs in less than 5% of black patients with sarcoidosis. Acute sarcoidosis without erythema nodosum may also occur, often with disabling arthritis.
Pulmonary sarcoidosis. Posteroanterior chest radiographs illustrating pulmonary sarcoidosis categorized as stage 0 (normal chest film), stage I (bilateral hilar adenopathy alone), stage II (adenopathy plus interstitial infiltrates), stage III (interstitial infiltrates alone), and stage IV (fibrocystic). Thoracic disease (lung and lymph node involvement) represent the most common manifestations of sarcoidosis affecting over 70% of all patients. Bronchscopy remains the most common method of confirming a diagnosis of sarcoidosis.
The most common symptoms are progressive shortness of breath, nonproductive cough, and chest discomfort (Table 54–1). Chronic sputum production and hemoptysis are more frequent in advanced fibrocystic disease (chest radiograph stage IV, Figure 54–1). Typically, there are few physical findings of pulmonary sarcoidosis, with lung crackles heard in less than 10% of patients. Clubbing is rare. Airway obstruction is usually fixed (unresponsive to bronchodilators) and observed in a minority of patients. Bronchial hyperreactivity with occasional frank wheezing is found in 5–30% of patients.
Pulmonary hypertension or cor pulmonale is seen in >80% patients with advanced fibrocystic sarcoidosis with pulmonary fibrosis. Rarely, a granulomatous pulmonary vasculitis results in pulmonary hypertension with little evidence of interstitial lung disease. Dyspnea out of proportion to pulmonary function test results should prompt a search for pulmonary hypertension. Other causes of pulmonary hypertension, such as sleep disordered breathing or chronic thromboembolic disease, must be excluded. Severe pulmonary hypertension in patients with advanced lung disease is associated with higher rates of mortality while awaiting lung transplantation.
Uveitis is the most common eye lesion in sarcoidosis and may be the initial presenting manifestation. The uveitis is more commonly anterior, may be unilateral or bilateral, and is frequently associated with bilateral hilar adenopathy. Chronic uveitis occurs in as many as 20% of patients with chronic sarcoidosis and is more common in the black population. Granulomatous conjunctivitis appears as a granular or cobblestone-like appearance of the conjunctivae. Conjunctival nodules are also a common finding. Optic neuritis or retinitis may manifest dramatically with blindness. Severe chorioretinitis occurs uncommonly.
Chronic Cutaneous Sarcoidosis
Sarcoidosis commonly involves the skin (20–30%) and may be severe, especially in black patients. Cutaneous nodules, plaques and subcutaneous nodules, typically located around the hairline, eyelids, ears, nose, mouth, and extensor surfaces of the arms and legs, are common. Lupus pernio is a particularly disfiguring form of cutaneous sarcoidosis of the face with violaceous plaques and nodules covering the nose (Figure 54–2), nasal alae, malar areas, and around the eyes.
Lupus pernio. This form of cutaneous eruption in sarcoidosis is typified by violaceous plaques and nodules that involve the nose, nasal alae, malar areas, nasolabial folds, around the eyes, scalp, and along the hairline. (© Bernard Cohen, MD, Dermatlas; http://www.dermatlas.org.)
Peripheral lymph node enlargement occurs in 20–30% of patients as an early manifestation of sarcoidosis but then typically undergoes spontaneous remission. Persistent, bulky lymphadenopathy occurs less than 10% of the time. Splenomegaly, occasionally massive, occurs in less than 5% of cases and is often associated with hepatomegaly and hypercalcemia. Polyclonal hypergammaglobulinemia is present in 25% or more of patients. Anemia and peripheral lymphopenia are relatively common while leucopenia and thrombocytopenia are rare. A clinical association exists between sarcoidosis and common variable immunodeficiency (CVID); CVID should be suspected in patients with sarcoidosis who develop increased frequency of infections or hypogammaglobulinemia.
Systemic constitutional symptoms such as fever, malaise, and weight loss are seen in over 20% of patients and may be disabling. Arthralgias are common in active multisystem sarcoidosis, although joint radiographs are usually normal. Acute, often incapacitating polyarthritis involving the ankles, feet, knees, and wrists is commonly seen in patients with Löfgren syndrome; usually the polyarthritis regresses within weeks to several months with or without therapy. Persistent joint disease is found in less than 5% of patients with chronic sarcoidosis. Pain, swelling, and tenderness of the phalanges (sausage digit) of the hands and feet are most common.
Although random muscle biopsies in autopsy series often demonstrate muscle granulomas in patients with sarcoidosis, symptomatic myopathy with weakness and tenderness is uncommon. Rarely, sarcoidosis can present as a polymyositis with profound weakness and elevated serum creatine kinase and aldolase levels.
Radiographic skeletal findings are most typically noted as incidental findings and observed in <10% of all patients. These typically present as cystic and lytic lesions of varying sizes and may have associated sclerotic margins (Figure 54–3). Most commonly involved areas include bones of the skull, vertebrae, hands, and feet. The use of other imaging modalities (CT, MRI with gadolinium, technetium bone scan) has not been proven to be useful for judging the activity of such lesions or differentiating them from infection or malignancy.
Bone involvement in sarcoidosis. Multiple focal “punched-out” lesions (arrows) on a plain radiograph of the hand (Used, with permission, from William Herring, MD; http://www.learningradiology.com), CT of the pelvis (arrow), and MRI of the spine that are compatible with skeletal manifestations of sarcoidosis.
Fibromyalgia may be associated with sarcoidosis and causes considerable morbidity in such patients. This cause of pain does not respond to immunosuppressive therapy.
Although a liver biopsy demonstrates granulomatous inflammation in over 50% of patients, clinically significant liver involvement is documented in only 10–20% of patients and is rarely the sole manifestation of this disease. Active hepatic inflammation may be associated with fever, tender hepatomegaly, and pruritus. Characteristically, the serum alkaline phosphatase and γ-glutamyltransferase are elevated disproportionately higher than the transaminases or bilirubin. This is often part of a constellation of hepatic, spleen, and bone marrow involvement with or without hypercalcemia, sometimes referred to as “abdominal sarcoidosis.” Elevated serum liver function tests frequently revert to normal spontaneously or after treatment with glucocorticoids. Progressive cirrhosis may occur if severe, persistent granulomatous hepatitis is not treated.
Symptomatic gastrointestinal involvement in sarcoidosis is rare, and other causes, such as Crohn disease or ulcerative colitis, must be excluded.
This manifestation occurs in 5–10% of patients with sarcoidosis. The most common manifestation is cranial neuropathy with bilateral or unilateral seventh nerve (Bell) palsy or less commonly, glossopharyngeal, auditory, oculomotor, or trigeminal palsies. The palsies may resolve spontaneously or with glucocorticoid therapy but may recur years later. Optic neuritis can result in blurred vision, field defects, and blindness. Other manifestations include mass lesions, aseptic meningitis, obstructive hydrocephalus, and hypothalamic-pituitary dysfunction. Seizures, headache, change in mental status, confusion, and diabetes insipidus can be initial manifestations of sarcoidosis. Spinal cord involvement is rare, but paraparesis, hemiparesis, and back and leg pains may occur. Peripheral neuropathies account for about 15% of cases of neurosarcoidosis, often presenting as mononeuritis multiplex or a primary sensory neuropathy. Recently, small fiber neuropathy has been associated with a pain syndrome in sarcoidosis; a few case reports suggest TNF inhibitors may be helpful in treating this debilitating condition.
Sarcoidosis of the Upper Respiratory Tract (SURT)
This manifestation occurs in 5–10% of patients, usually in those with long-standing disease. Severe nasal congestion and chronic sinusitis usually are unresponsive to decongestants and topical (intranasal) glucocorticoids. Chronic disease or surgical intervention may result in destruction of the nasal septum and a “saddle-nose” deformity. Laryngeal sarcoidosis may present with severe hoarseness, stridor, and acute respiratory failure secondary to upper airway obstruction. Often, SURT is associated with chronic skin lesions, particularly lupus pernio (see Figure 54–2).
Although myocardial sarcoidosis is diagnosed in less than 10% of patients in the United States and Europe, autopsy series suggest that the histologic presence of sarcoidosis in the heart may be as high as 25%. In Japan, cardiac sarcoidosis occurs in nearly 50% of sarcoidosis patients. Arrhythmia, heart block, dilated cardiomyopathy, or sudden death can be the presenting clinical manifestations. Endomyocardial biopsies fail to demonstrate granulomatous inflammation in 80% of cases due to sampling inefficiencies in the setting of patchy inflammatory involvement and the lack of involvement of the right ventricle. A diagnosis of cardiac sarcoidosis can be inferred from a combination of biopsy-proven systemic sarcoidosis and a compatible myocardial imaging study, such as thallium or sestamibi scan, cardiac MRI with gadolinium enhancement, or cardiac positron emission tomography (PET) scan (Figure 54–4).
Cardiac sarcoidosis. Cardiac MRI demonstrates gadolinium enhancement in the submyocardial region (arrows) in a patient with cardiac sarcoidosis and nonsustained ventricular tachycardia.
Salivary, Parotid, and Lacrimal Gland Sarcoidosis
Parotid or lacrimal gland enlargement or sicca syndrome can occasionally be the dominant clinical manifestations of sarcoidosis. Heerfordt syndrome, or uveoparotid fever, is an uncommon acute presentation of sarcoidosis manifesting as fever, parotid and lacrimal gland enlargement, uveitis, bilateral hilar adenopathy, and often cranial neuropathies.
Endocrine Abnormalities in Sarcoidosis
In patients with neurosarcoidosis, disturbances to the hypothalamic-pituitary axis may result in diabetes insipidus and other manifestations of hypopituitarism. There is a higher association of autoimmune thyroid disease and sarcoidosis compared to control populations. Pancreatic sarcoidosis manifesting as a mass is a rare manifestation and must be distinguished from cancer.
Renal Involvement in Sarcoidosis
Sarcoidosis may be associated with hypercalcemia, and more commonly, hypercalciuria. The abnormalities are caused by the increased conversion of inactive 25-OH vitamin D3 to the active 1,25(OH)2 vitamin D3 by epithelioid macrophages within tissue granulomas. Primary care physicians must be aware that a low serum 25-OH vitamin D level (the standard serum vitamin D test) usually does not represent vitamin D deficiency in sarcoidosis patients, but rather is a result from this increased conversion to active 1,25(OH)2 vitamin D. Vitamin D supplementation in this instance may precipitate hypercalcemic crisis in untreated sarcoidosis patients. Vitamin D supplementation should only be based on serum levels of active 1,25(OH)2 vitamin D (which requires special ordering) in patients with sarcoidosis. Nephrocalcinosis may cause renal failure in sarcoidosis. Direct granulomatous involvement of the kidneys causing chronic interstitial nephritis or membranous glomerulonephritis is rare.
As many as 30–60% of patients with sarcoidosis report symptoms of depression. One study found this to be associated with female sex, lower socioeconomic status, poor access to health care and increased disease severity, but not race.
Recommended initial studies for all patients with presumed or biopsy-proven sarcoidosis include the following:
- A comprehensive metabolic panel is useful to assess abnormalities of renal function, calcium level, and liver function.
- The complete blood cell count is usually either normal or demonstrates peripheral lymphopenia. Pancytopenia may be caused by hypersplenism or bone marrow infiltration with granulomas.
Chest radiographs are abnormal in 90% or more of patients with sarcoidosis and can be categorized by stage or type by international convention (Figure 54–1). Stage 0 indicates a normal chest radiograph (ie, seen in extrapulmonary sarcoidosis). Stage I shows bilateral hilar adenopathy. Stage II shows bilateral hilar adenopathy plus interstitial infiltrates. Stage III demonstrates interstitial infiltrates only. Stage IV demonstrates fibrocystic lung disease.
Uncommon findings associated with pulmonary sarcoidosis include large, well-defined nodular infiltrates, miliary disease, a pattern of patchy air space consolidation with air bronchograms, termed “alveolar sarcoidosis,” or the presence of mycetomas. Differential diagnoses include mycobacterial or fungal infection, malignancy, or granulomatosis with polyangiitis (formerly Wegener granulomatosis). Pleural effusions and pneumothoraces are unusual in sarcoidosis.
Chest CT typically demonstrates reticulonodular infiltrates that follow bronchovascular distribution. Occasionally, ground-glass infiltrates, well-defined nodules, mass-like infiltrates, alveolar consolidation, or honeycombing are seen. Pleural effusions are rarely secondary to sarcoidosis inflammation.
Nuclear medicine studies, such as 67-gallium scanning and positron emission tomography using 18-fluorodeoxyglucose (FDG-PET), have been used to detect active inflammatory sites in sarcoidosis, potentially aiding in choosing sites for biopsy. FDG-PET uses less radiation exposure while offering better resolution and has largely replaced gallium scanning. Classic findings using gallium or PET scanning are uptake in the bilateral hilar and right paratracheal lymph node region (“lambda” sign) of the lungs, and uptake in the parotids or lacrimal and salivary glands (“panda” sign). The combination of signs (lambda-panda) is suggestive of sarcoidosis.
Joint radiographs may demonstrate “punched out” lesions with cystic changes and marked loss of trabeculae but without evidence of erosive chrondritis. Cystic lesions of the long bones, pelvis, sternum, skull, and vertebrae rarely occur (Figure 54–4).
MRI with gadolinium contrast enhancement has an important role in the evaluation of neurosarcoidosis, particularly in cases of suspected brain, cranial nerve, or spinal cord involvement.
Pulmonary Function Testing
Pulmonary function tests may show restrictive, obstructive, or combined impairment with a parallel reduction in diffusing capacity for carbon monoxide (DLCO). Resting gas exchange is usually preserved until extensive fibrocystic changes are evident, although oxygen desaturation with exercise occurs in less advanced disease.
A well-recognized feature of sarcoidosis is the impaired cutaneous response to common antigens that elicit delayed-type hypersensitivity reactions, seen in 30–70% of patients. Since anergy to purified protein derivative (PPD) testing is common in sarcoidosis, active tuberculosis must be strongly considered in any patient in whom a positive tuberculin skin test develops.
An electrocardiogram is routinely performed to screen for conduction abnormalities, which may signal the presence of early cardiac sarcoidosis. When cardiac sarcoidosis is suspected on the basis of symptoms or electrocardiographic abnormalities, Holter monitoring, and cardiac imaging is indicated. Two-dimensional echocardiography is useful as a screening tool but is insensitive to mild cardiac abnormalities. Radionuclide imaging with gated 201-thallium scanning, cardiac MRI, or cardiac PET are more sensitive studies to detect myocardial abnormalities related to sarcoidosis (Figure 54–4). Electrophysiologic testing may be indicated to exclude arrhythmias undetected by routine studies.
In patients with suspected neurosarcoidosis, MRI with gadolinium enhancement of the brain or spine is indicated. The characteristic inflammatory lesions by contrast MRI have a propensity for periventricular and leptomeningeal areas. These findings are nonspecific and can be produced by infectious (tuberculosis, fungal disease) or malignant (lymphoma, carcinomatosis) disease. A normal scan does not exclude neurosarcoidosis, particularly for cranial neuropathies, peripheral neuropathies, or in the presence of glucocorticoid therapy.
In neurosarcoidosis, the cerebrospinal fluid may demonstrate lymphocytic pleocytosis or elevated protein levels, providing supportive evidence of central nervous system or spinal cord inflammation. A diagnosis of neurosarcoidosis is usually confirmed by biopsy of a non–central nervous system site, generally by bronchoscopic or lymph node biopsy. Rarely, brain or spinal cord biopsy is needed to exclude infectious or malignant disease. In suspected cases of peripheral neuropathy or myopathy, electromyography or nerve conduction studies are often indicated.
Identifying the extent of specific organ involvement requires a careful review of localizing symptoms in the setting of biopsy-confirmed granulomatous inflammation. Biopsy of the easiest, most accessible abnormal tissue site is used for confirmation of the diagnosis and to exclude infection, malignancy, or other diseases that have similar clinical manifestations. Biopsy by fiberoptic bronchoscopy is frequently used to diagnose pulmonary sarcoidosis because of its relative safety and high yield. Endobronchial or transbronchial needle aspiration biopsies may increase the yield further. Bronchoalveolar lavage fluid in sarcoidosis is typically characterized by increased proportions and numbers of activated CD4+ alveolar lymphocytes reflective of enhanced cell-mediated immune processes at sites of granuloma formation. These findings are not specific for sarcoidosis and do not predict clinical outcome.
Mediastinoscopy or surgical lung biopsy (open-lung, thoracoscopic) should be considered in cases where lymphoma or other intrathoracic malignancy cannot be reasonably excluded. Biopsy of a skin nodule, superficial lymph node, nasal mucosa, conjunctiva, or salivary gland (lip biopsy) sometimes can establish a diagnosis. Biopsy of the liver or bone marrow is nonspecific and should be used to support a diagnosis of sarcoidosis only after malignancy, infectious granulomatous diseases, or other organ-specific diagnoses are excluded. In rare cases, biopsy of critical organs may be necessary to exclude malignancy, such as when sarcoidosis presents as a mass lesion in the brain. Biopsy confirmation of sarcoidosis is usually not necessary in Löfgren syndrome except in regions where histoplasmosis is endemic, and fungal infection must be excluded before initiating glucocorticoid therapy.