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Overview of extrapulmonary manifestations of sarcoidosis

Overview of extrapulmonary manifestations of sarcoidosis
Literature review current through: Jan 2024.
This topic last updated: Jan 11, 2024.

INTRODUCTION — Sarcoidosis is a multisystem granulomatous disorder that affects individuals worldwide. The disease was historically thought to present mainly in young or middle-aged adults, but more recent data suggest that it may also occur in the sixth and seventh decades of life, especially in females. Accumulation of nonnecrotizing granulomas and subsequent fibrosis in the lungs and other organs accounts for the clinical manifestations, which may be symptomatic or discovered incidentally when testing is ordered for other purposes. Clinical manifestations vary widely, depending on organ involvement. Some of the most common presentations include:

Bilateral hilar adenopathy

Pulmonary reticular and/or nodular opacities

Skin, joint, or eye lesions

This topic provides an overview of extrapulmonary manifestations of sarcoidosis. The initial diagnosis of sarcoidosis and organ-specific clinical manifestations and diagnosis of sarcoidosis involving the heart, neurologic system, gastrointestinal tract, skin, bone, and joints are discussed in more detail separately.

(See "Clinical manifestations and diagnosis of sarcoidosis".)

(See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

(See "Neurologic sarcoidosis".)

(See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

(See "Cutaneous manifestations of sarcoidosis".)

(See "Sarcoidosis of bone".)

(See "Sarcoid arthropathy".)

The pathogenesis of sarcoidosis and treatment of pulmonary sarcoidosis are also presented elsewhere.

(See "Pathology and pathogenesis of sarcoidosis".)

(See "Treatment of pulmonary sarcoidosis: Initial approach".)

(See "Treatment of pulmonary sarcoidosis refractory to initial therapy".)

EPIDEMIOLOGY — At initial presentation, up to 50 percent of patients have extrathoracic manifestations of sarcoidosis based on history and physical examination (table 1) [1-10]. More sensitive testing, such as 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) scan will reveal an even higher proportion of patients with clinically silent extrapulmonary disease. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes'.)

The most common sites of overt extrapulmonary disease include the skin, eyes, reticuloendothelial system, dysregulation of vitamin D metabolism, exocrine glands, heart, and central nervous system. Approximately 8 percent of patients with sarcoidosis present with disease at extrapulmonary sites without lung involvement; nearly half of these patients have cutaneous disease [6].

Extrapulmonary manifestations may vary on the basis of sex, age at presentation, and ethnicity (figure 1) [1,11]. As an example, in one study, women were more likely to have skin or ocular involvement, while men more frequently developed cardiac involvement [11].

Approximately 5 to 10 percent of patients with sarcoidosis present with Löfgren syndrome, which is defined by acute-onset fever, hilar adenopathy, and variable proportions of erythema nodosum (EN) or bilateral ankle inflammation. Löfgren syndrome is more common in the third and fourth decades of life and is seen more frequently in females than in males [10]. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes' and "Erythema nodosum" and "Sarcoid arthropathy", section on 'Acute arthritis and Lofgren syndrome'.)

Multiple groups have attempted to cluster patients with sarcoidosis based on organ manifestations [12,13]. Other than re-establishing the elements of Löfgren syndrome, however, these analyses have not generated consistent patient groupings.

EXTRAPULMONARY DISEASE IN INITIAL DIAGNOSIS — A few clinical presentations are so highly specific for sarcoidosis that a biopsy is unlikely to be informative [14]. These presentations include Löfgren syndrome (erythema nodosum [EN], hilar adenopathy, migratory polyarthralgia, and fever) and Heerfordt's syndrome (uveoparotid fever). Occasionally, there may also be sufficient manifestations in multiple organ systems to allow a presumptive clinical diagnosis. Otherwise, the diagnosis of sarcoidosis requires a step-wise approach to identify organs that may be affected and the exclusion of other multisystem granulomatous diseases [8]. A biopsy is generally recommended but can be deferred on an individual basis when the clinical presentation is strongly supportive of sarcoidosis and alternate causes are unlikely. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Initial evaluation' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Invasive diagnostic testing'.)

Baseline testing for occult extrapulmonary disease is recommended as part of the initial work-up of sarcoidosis. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Testing for occult extrapulmonary disease'.)

CLINICAL MANIFESTATIONS BY ORGAN SYSTEM

Cutaneous — Cutaneous involvement is seen in approximately 25 percent of patients with sarcoidosis, and it is often an early finding (table 1). (See 'Epidemiology' above.)

The cutaneous manifestations of sarcoidosis and their management are described in greater detail separately. (See "Cutaneous manifestations of sarcoidosis" and "Cutaneous sarcoidosis: Management".)

The following patterns are among the most common cutaneous manifestations:

Papular sarcoidosis is a common manifestation that usually involves the alae nares, lips, eyelids, forehead, rear of neck at the hairline, and/or previous trauma sites (eg, scars and tattoos) (picture 1A-B and picture 2 and picture 3).

Nodular sarcoidosis most frequently involves the face, trunk, and extensor surface of the arms and legs (picture 4).

Plaque-like lesions can occur in chronic sarcoidosis, frequently on the shoulders, arms, back, and buttocks (picture 5).

Lupus pernio is characterized by violaceous or erythematous indurated papules, plaques, or nodules that are primarily distributed on the nose, cheeks, chin, and ears (picture 6A-B).

Erythema nodosum (EN) is a panniculitis, characterized by painful nodules that are most common on the anterior surface of the lower extremities (picture 7 and picture 8), which is frequently associated with sarcoidosis. (See "Erythema nodosum".)

Subcutaneous sarcoidosis, which is different from EN, is characterized by asymptomatic or mildly tender nodules, usually on the upper extremities.

For patients without a confirmed diagnosis of sarcoidosis, a skin biopsy is typically performed to evaluate lesions suggestive of sarcoidosis. As an exception, EN is not biopsied, as it is characterized by panniculitis regardless of underlying disease. (See "Cutaneous manifestations of sarcoidosis".)

Ocular — Ocular involvement occurs in up to 25 percent of patients with sarcoidosis and is the presenting symptom in 5 percent [15]. Ocular manifestations are reported at higher rates in women and in African American and Japanese patient populations [16]. Sarcoidosis can involve the orbit, anterior and posterior segments of the eye, conjunctiva, lacrimal glands, and extraocular muscles [17,18]. For patients with sarcoidosis who do not have ocular symptoms, consensus guidelines from the American Thoracic Society (ATS) suggest a baseline eye examination to screen for ocular sarcoidosis [14]. The retinal manifestations of sarcoidosis and the diagnosis and treatment of uveitis in general are discussed in greater detail separately. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases' and "Uveitis: Treatment" and "Retinal vasculitis associated with systemic disorders and infections", section on 'Systemic immune-mediated causes'.)

In a series of 81 consecutive patients with sarcoidosis seen in an ophthalmology clinic, 40 percent had uveitis, 30 percent had keratoconjunctivitis sicca, and 15 percent had adnexal (eyelid or conjunctival) granulomas [17]. Symptoms included dry eye, blurry vision, photophobia, redness, and pain.

The combination of anterior uveitis, parotid gland enlargement, facial nerve palsy (due to compression by enlarged parotid gland), and fever (uveoparotid fever) is referred to as Heerfordt's syndrome, an uncommon but pathognomonic presentation of sarcoidosis [19,20]. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Pathognomonic presentations'.)

A diagnosis of ocular sarcoidosis can be difficult and requires input from an ophthalmologist. Patients with a new diagnosis of sarcoidosis should undergo visual acuity, tonometry, slit lamp, and funduscopic testing to assess for ocular involvement [21]. Fluorescein angiography may help in the detection of retinal blood vessel abnormalities, such as retinal vasculitis and retinal periphlebitis. Enlarged lacrimal glands can also be palpated just above and lateral to the orbit (picture 3) or visualized by everting the upper eyelid (picture 9). The conjunctivae harbor granulomas [22], and biopsy of the conjunctiva, even in asymptomatic patients, can be helpful to establish the diagnosis.

Diagnosis of intraocular sarcoidosis — Intraocular manifestations of sarcoidosis are classified as anterior, intermediate, and/or posterior uveitis [17,23]. As ocular involvement may be asymptomatic, all patients with sarcoidosis should undergo ophthalmologic examination. (See "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Etiology'.)

Anterior uveitis typically causes pain and redness primarily at the limbus (junction between cornea and sclera); posterior or intermediate uveitis are more likely to be painless but more often associated with floaters. Visual loss may occur with anterior, intermediate, or posterior involvement.

A consensus conference has identified seven signs suggestive of intraocular sarcoidosis [24,25]:

Mutton-fat keratic precipitates (KPs)/small granulomatous KPs and/or iris nodules (Koeppe/Busacca) (picture 10) are a manifestation of lymphocytes in the anterior chamber of the eye (anterior uveitis). The floating lymphocytes form gray-white clumps that have the appearance of mutton fat under slit lamp examination.

Trabecular meshwork nodules and/or tent-shaped peripheral anterior synechiae are seen in anterior uveitis. Patients complain of periocular pain and photophobia, but vision is often normal. The synechiae, or attachment, of the iris to the anterior surface of the lens or posterior surface of the cornea can cause an irregular pupil (picture 11).

Vitreous opacities displaying snowballs/strings of pearls are a manifestation of intermediate uveitis, also known as pars planitis.

Multiple chorioretinal peripheral lesions (active and/or atrophic).

Nodular and/or segmental periphlebitis (with or without candlewax drippings) (picture 12 and picture 13) and/or retinal macroaneurysm in an inflamed eye are manifestations of retinal vasculitis (posterior uveitis) due to sarcoidosis. These lesions may be associated with retinal hemorrhage.

Optic disc nodule(s)/granuloma(s) and/or solitary choroidal nodule.

Bilaterality.

For patients without known sarcoidosis who present with suspected sarcoidosis uveitis, other causes of granulomatous uveitis (eg, tuberculosis, angiitis) should be excluded [25]. Based on consensus guidelines from the International Workshop on Ocular Sarcoidosis (IWOS), the certainty of a diagnosis of ocular sarcoidosis is based upon the combination of intraocular findings and systemic evidence of sarcoidosis [25].

Uveitis compatible with sarcoidosis and an extraocular biopsy supporting sarcoidosis is felt to be diagnostic of ocular sarcoidosis.

A patient with two intraocular signs compatible with sarcoidosis and bilateral hilar adenopathy on chest imaging, but without a confirmatory biopsy, is presumed to have ocular sarcoidosis.

When a patient has a combination of three signs of uveitis compatible with sarcoidosis (eg, mutton fat precipitates, anterior synechiae, vitreous "string of pearls") and two other investigations in other organ systems supporting sarcoidosis (eg, chest imaging and negative tuberculin skin test) the diagnosis of sarcoidosis is felt to be probable.

The IWOS statement also included elevated serum angiotensin-converting enzyme, elevated serum lysozyme, elevated CD4/CD8 ratio (>3.5) in bronchoalveolar lavage fluid, and lymphopenia as evidence of sarcoidosis [25], but the accuracy of these biomarkers is not broadly accepted [26].

Extraocular orbital sarcoidosis — Sarcoidosis may affect extraocular orbital tissues, including the lacrimal glands, conjunctiva, extraocular muscles, and optic sheath; it may also present as a soft tissue orbital mass [27]. Xerostomia and keratoconjunctivitis sicca may also be seen, similar to the clinical manifestations of Sjögren's disease and IgG4-related systemic disease. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease", section on 'Dry eye'.)

In a case series of 20 patients with orbital sarcoidosis, the most common symptoms were a palpable mass and orbital swelling [27]. The most common findings on orbital computed tomography (CT) were lacrimal gland involvement and orbital masses. Conjunctival granulomas are seen in approximately 5 percent of patients and are often amenable to biopsy. However, conjunctival biopsy has a low yield unless there is a visible abnormality [27].

Vision outcomes — A retrospective study examined the long-term outcomes (≥3 years) in 83 patients with sarcoidosis uveitis [28]. At presentation, 31 patients had systemic sarcoidosis, while 52 did not; 4 developed extraocular disease in follow-up. Complete visual recovery occurred in 60 percent and best corrected visual acuity (BCVA) to >20/50 was achieved in 89 percent. Two patients experienced unilateral visual loss with BCVA ≤20/200, but no patient had bilateral severe visual loss. Chronic macular edema and persistent ocular inflammation were predictors of poor visual outcome.

Secondary glaucoma, cataract formation, and impaired vision are potential late complications of sarcoidosis that may be due to either the underlying disease or chronic glucocorticoid therapy.

Neurologic — Approximately 5 to 10 percent of patients with sarcoidosis have neurologic involvement, which can occasionally be the presenting symptom. Manifestations of central nervous system disease (eg, focal neurologic disorders, seizures, hypopituitarism, headache, granulomatous meningitis) usually occur early, while peripheral nerve involvement is characteristically seen in the later stages. (See "Neurologic sarcoidosis".)

Fatigue is a common, nonspecific symptom in patients with sarcoidosis, occurring in up to 80 percent of patients [29]. The level of fatigue appears to be associated with the presence of extrapulmonary sarcoidosis (ie, those with extrapulmonary disease have higher levels of fatigue than those with only pulmonary sarcoidosis) [30]. A separate study found higher resting energy expenditure and increased C-reactive protein levels in the subset of patients with sarcoidosis who have fatigue [31]. Thus, fatigue likely reflects inflammation and metabolic derangements rather than neurologic involvement.

The clinical manifestations, diagnosis, and management of neurologic sarcoidosis are discussed further separately. (See "Neurologic sarcoidosis".)

Endocrine and reproductive — The most common endocrine manifestations of sarcoidosis include hypothalamic/pituitary involvement (due to basilar granulomatous meningitis) and infiltration of the thyroid.

Sarcoidosis involvement of the anterior pituitary can result in deficiency of adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and insulin-like growth factor 1, along with elevated prolactin [32,33]. Presentations include diabetes insipidus, hypothalamic hypopituitarism, amenorrhea-galactorrhea, hypogonadotropic hypogonadism, and secondary hypothyroidism. In addition to endocrinologic evaluation, imaging with magnetic resonance imaging (MRI) to look for meningeal enhancement may be helpful diagnostically. (See "Evaluation of patients with polyuria" and "Clinical manifestations of hypopituitarism", section on 'Hormone deficiencies' and "Causes of hypopituitarism", section on 'Infiltrative lesions' and "Diagnostic testing for hypopituitarism" and "Neurologic sarcoidosis", section on 'Diagnostic approach'.)

Sarcoidosis can cause diffuse goiter or, rarely, a solitary thyroid nodule [34,35]. Almost all patients are euthyroid, although cases of clinical hypothyroidism caused by diffuse replacement of thyroid tissue have been reported [36,37]. (See "Infiltrative thyroid disease".)

In the absence of significant cardiopulmonary compromise or endocrine disruption, systemic sarcoidosis does not affect fertility. Ongoing disease likewise does not increase the incidence of fetal or obstetrical complications [38].

Sarcoidosis rarely involves the female genital tract. Case reports have described sarcoidosis of the endometrium, ovary, and uterine fibroids detected during the evaluation and treatment of menometrorrhagia or pelvic masses [39-41].

Sarcoidosis can involve the testes, where it must be differentiated from testicular cancer and tuberculosis [42]. Recurrent epididymitis due to sarcoidosis rarely can occur [36,43].

Parotid and salivary glands — Painless swelling of the salivary and parotid glands occurs in approximately 5 percent of patients with sarcoidosis (table 1) [19,44,45]. Severe parotid swelling can lead to facial nerve palsy due to direct compression of the cranial nerve. The combination of anterior uveitis, parotid gland enlargement, facial nerve palsy, and fever is referred to as uveoparotid fever or Heerfordt's syndrome, an uncommon but pathognomonic presentation of sarcoidosis. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Pathognomonic presentations'.)

Lymphatic system — Involvement of the lymphatic system is common in sarcoidosis and can manifest as:

Lymphadenopathy – Peripheral lymphadenopathy is present in up to 40 percent of patients. Hilar and/or paratracheal mediastinal adenopathy are seen on imaging studies in up to 90 percent [46]; isolated anterior and posterior mediastinal adenopathy are uncommon in sarcoidosis [47]. Approximately 30 percent of patients with sarcoidosis have intra-abdominal lymphadenopathy (two nodes >1 cm diameter on short axis) on abdominal CT scans [48].

Splenic enlargement – Approximately 6 percent of patients have splenomegaly on physical examination [49]. Radiographic cohorts vary in the recorded incidence of splenomegaly from 33 to nearly 80 percent [48,50-52]. In one cohort of 49 patients with complete splenic imaging, the greatest splenic dimension was ≥14 cm in 16 (33 percent) and ≥18 cm in 3 (6 percent) [51].

Splenic nodules – Splenic granulomas are found at autopsy in 50 percent of patients with sarcoidosis [52] but are often too small to visualize on imaging. Hypodense splenic nodules are seen on CT in approximately 15 percent [51]. In the absence of malignancy or known systemic infection, splenic nodules in a patient with systemic sarcoidosis almost always indicate splenic involvement.

Extrathoracic lymphadenopathy rarely results in additional symptoms. However, hypersplenism due to sarcoidosis can contribute to anemia, leukopenia, and thrombocytopenia [53,54]. Systemic anti-inflammatory therapy generally improves the cytopenias, although splenic nodules and splenomegaly may persist. Splenic enlargement may also cause left upper quadrant discomfort or early satiety.

Bone marrow — In a large United States-based cohort, bone marrow involvement of sarcoidosis was approximately 4 percent (table 1) [1]; however, incidence has varied greatly depending on the population studied [5,55]. In one study of 50 patients evaluated with bone marrow biopsy irrespective of symptoms, 5 patients (10 percent) demonstrated granulomas on bone marrow biopsy; these cases represented 27 percent of those with anemia [56]. Anemia in sarcoidosis may also be caused by iron deficiency or anemia of chronic disease without bone marrow involvement. Leukopenia and thrombocytopenia may be seen with bone marrow infiltration, splenic involvement, or compartmentalization of white blood cells in other organ sites. (See 'Lymphatic system' above.)

In addition to the presence of cytopenias, bone marrow involvement may be suspected based on diffuse increased uptake of axial and peripheral bone marrow on 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) imaging [57].

Cytopenias are uncommonly the deciding factor driving treatment decisions; however, methotrexate may be a less preferred steroid-sparing agent in such patients due to its known marrow toxicity.

Upper respiratory tract — Sarcoidosis of the upper respiratory tract (SURT) may involve the larynx, pharynx, nares, and/or sinuses; it should be suspected in all patients with systemic sarcoidosis and upper respiratory tract symptoms [58-68]. In general, SURT is challenging to treat and its presence portends a chronic, bothersome course for most patients.

The most frequent head and neck manifestation of sarcoidosis is cervical lymphadenopathy [69]. (See 'Lymphatic system' above.)

Laryngeal sarcoidosis – Laryngeal involvement typically affects the supraglottis, less commonly the subglottis, and true vocal fold involvement is rare [70]. Presenting symptoms include dysphagia, dyspnea, cough, and hoarseness [71,72]. The diagnosis is made by direct visualization and biopsy. Treatment may include systemic or lesional immunosuppressive agents, or laser excision with mitomycin (also known as mitomycin-C) application [71].

Nasal and sinus sarcoidosis – While sinonasal sarcoidosis occurs in approximately 1 percent of patients with sarcoidosis overall, involvement of the paranasal sinuses is common among patients with intranasal sarcoidosis [59,73]. (See "Chronic rhinosinusitis: Clinical manifestations, pathophysiology, and diagnosis", section on 'Consider evaluation for systemic diseases'.)

In a case series of 36 patients with rhinosinusitis due to sarcoidosis, the most common symptoms and signs were nasal obstruction (86 percent), nasal crusting (47 percent), and anosmia (44 percent) [65]. Epistaxis and nasal polyposis were present in approximately 25 percent. The coexistence of facial lupus pernio and rhinosinusitis due to sarcoidosis has been variably reported [64,65,74].

On endoscopic examination, mucosal hypertrophy is common and two main patterns are seen [65]. Among patients without crusting and epistaxis, small discrete nodules (sometimes called granulations) may be visible on the inferior turbinates and/or septum. In contrast, patients who complain of crusting and epistaxis typically have the appearance of atrophic rhinitis with focal areas of hemorrhage and diffuse crusting of dried blood. These features can also be observed together [64].

Biopsy of the nasal mucosa is typically obtained when sarcoidosis is suspected based on the presence of mucosal nodules, when the diagnosis of sarcoidosis is unclear and the nasal mucosa is an accessible location for a biopsy, or when endoscopic sinus surgery is performed. Depending on the patient's history, examination for fungus, acid-fast mycobacteria, spirochetes, or vasculitis may be helpful. Due to the small number of patients in case series, the exact yield of nasal mucosal biopsy is not known, but at least one series found noncaseating granulomata in all of the patients who underwent biopsy. The differential diagnosis includes granulomatosis with polyangiitis, leprosy, and syphilis.

Sinonasal sarcoidosis is typically treated like other causes of chronic rhinosinusitis. Regular nasal irrigation with saline solutions and instillation of intranasal glucocorticoids are the cornerstone of therapy. (See "Chronic rhinosinusitis without nasal polyposis: Management and prognosis".)

Systemic glucocorticoids and other immunosuppressive agents may occasionally be needed for severe disease, after exclusion of infection. Surgery should be avoided except in severe cases, due to the tendency for SURT to recur or even worsen after surgery.

For patients with atrophic rhinitis due to longstanding nasal sarcoidosis, the main treatment is nasal lavage with warmed isotonic saline at least twice daily (table 2). Intranasal lubricants and/or glucocorticoids may also be helpful. (See "Atrophic rhinosinusitis", section on 'Management'.)

Cardiovascular — Cardiac sarcoidosis can be a benign, incidentally discovered condition or a life-threatening disorder causing sudden death [75]. The frequency of myocardial involvement is unclear; small registries suggest a prevalence of 5 percent in patients with systemic sarcoidosis, while autopsy studies suggest subclinical cardiac involvement in 25 to 70 percent. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

The range of sarcoidosis involvement of the heart includes heart block (due to involvement of the conducting system), other arrhythmias, heart failure, valvular dysfunction, simulated infarction, and pericardial disease. Patients may be asymptomatic or may report palpitations, syncope, or dizziness. Clinically significant cardiac sarcoidosis is rare in subjects without symptoms and with a normal electrocardiogram (ECG). Patients with suspected cardiac involvement based on cardiac symptoms or ECG should be referred to a cardiologist and receive cardiac imaging, typically cardiac MRI. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)

Treatment of clinically significant cardiac sarcoidosis may involve immunosuppressive therapy, cardiac pacemaker or implantable cardioverter-defibrillator placement, and/or standard therapies for heart failure. (See "Management and prognosis of cardiac sarcoidosis".)

Pulmonary hypertension is a life-threatening complication of sarcoidosis that manifests clinically with progressive exertional dyspnea and hypoxemia. Although typically a result of advanced lung fibrosis and hypoxemia, pulmonary hypertension may also arise from granulomatous inflammation in the pulmonary vascular tree or complications of cardiac sarcoidosis. The evaluation and management of pulmonary hypertension due to sarcoidosis are discussed separately. (See "Sarcoidosis-associated pulmonary hypertension: Diagnostic evaluation in adults" and "Sarcoidosis-associated pulmonary hypertension: Treatment and prognosis in adults".)

Gastrointestinal and hepatic — Clinically recognizable gastrointestinal disease occurs in 0.1 to 0.9 percent of patients with sarcoidosis, although the incidence of subclinical involvement may be much higher. The stomach is the most involved portion of the gastrointestinal tract, but sarcoidosis of the esophagus, appendix, colon, and rectum has also been described. Sarcoidosis can also involve pancreas and, rarely, the small bowel or peritoneum. Clinical manifestations, diagnosis, and management of these conditions is discussed further separately. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

Liver involvement occurs in most patients with sarcoidosis but is frequently asymptomatic, with only 5 to 15 percent of patients developing abdominal pain, pruritus, or clinically significant hepatomegaly. For patients with sarcoidosis who have neither hepatic symptoms nor established hepatic sarcoidosis, consensus guidelines from the ATS suggest baseline serum alkaline phosphatase testing to screen for hepatic sarcoidosis [14]. Liver biopsy may sometimes be needed for patients with moderate or severe liver test abnormalities (eg, more than three times the upper limit of normal) to verify the diagnosis and determine severity of hepatic disease. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)

Renal and electrolyte — Disorders related to calcium metabolism are the most common renal and electrolyte abnormalities observed among patients with sarcoidosis. Manifestations of abnormal calcium metabolism include increased intestinal calcium absorption, hypercalciuria (which occurs in up to 20 percent of cases), hypercalcemia (which occurs in 5 to 10 percent), nephrocalcinosis, and nephrolithiasis. If untreated, renal calcium deposition can lead to chronic renal failure and end-stage kidney disease. (See "Hypercalcemia in granulomatous diseases" and "Kidney disease in sarcoidosis", section on 'Nephrocalcinosis'.)

Sarcoid interstitial nephritis is more commonly found on the initial presentation of sarcoidosis, rather than among patients with longstanding disease. The diagnosis is suggested by the combination of an elevated creatinine and bland urinary sediment in a patient with known or likely sarcoidosis. (See "Kidney disease in sarcoidosis", section on 'Tubulointerstitial nephritis'.)

Other renal complications of sarcoidosis include membranous nephropathy, a proliferative or crescentic glomerulonephritis, focal segmental glomerulosclerosis, polyuria (due to nephrogenic and/or central diabetes insipidus), hypertension, and a variety of tubular defects. (See "Kidney disease in sarcoidosis".)

Musculoskeletal — Musculoskeletal system involvement may occur in up to 10 percent of patients with sarcoidosis, usually as asymptomatic osseous involvement; other musculoskeletal manifestations occur in 1 to 2 percent of cases. Musculoskeletal sarcoidosis is discussed in detail separately. (See "Sarcoid arthropathy" and "Sarcoid myopathy".)

Common manifestations include:

Acute polyarthritis (especially symmetric involvement of the ankle joints), usually in association with EN and occasionally with acute uveitis. The swelling usually occurs in the soft tissue around joints, causing a periarthritis rather than a true arthritis [76]. Acute sarcoid arthritis may be present in isolation or in association with other features of Löfgren syndrome. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes' and "Erythema nodosum" and "Sarcoid arthropathy", section on 'Acute arthritis and Lofgren syndrome'.)

Chronic arthritis with periosteal bone resorption. Radiographically, this may appear as cysts, which can mimic rheumatoid disease (image 1). This form of arthritis is usually associated with a chronic protracted course. No correlation exists between the osseous lesions and the plasma calcium concentration.

Diffuse granulomatous myositis. An uncommon complication of sarcoidosis, it indicates progressive disease and is associated with a poor prognosis.

ONGOING MONITORING — Appreciation of the spectrum of extrapulmonary sarcoidosis is essential in the ongoing management of patients with known sarcoidosis. Routine monitoring of sarcoidosis includes evaluation for the types of extrapulmonary involvement that can lead to organ or life-threatening disease. This monitoring begins with questions on new symptoms (eg, visual changes, palpitations, presyncope/syncope), followed by appropriate additional evaluation and management. For asymptomatic patients, our authors suggest variable monitoring schedules based on disease activity (table 3). (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Ongoing monitoring'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Sarcoidosis".)

SUMMARY AND RECOMMENDATIONS

Spectrum of extrapulmonary disease – Sarcoidosis can involve all organ systems (table 1). The most common sites of extrapulmonary disease include the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system. Extrapulmonary manifestations vary on the basis of sex, age at presentation, and ethnicity (figure 1). (See 'Epidemiology' above.)

Extrapulmonary disease in initial diagnosis – In addition to clinical evaluation, baseline testing for occult extrapulmonary disease is recommended as part of the initial work-up of sarcoidosis. Löfgren syndrome (erythema nodosum [EN], hilar adenopathy, migratory polyarthralgia, and fever) and Heerfordt's syndrome (uveoparotid fever) are characteristic syndromes that allow for a clinical diagnosis of sarcoidosis. Occasionally, cumulative probable manifestations in multiple organ systems may also allow for a presumptive diagnosis. (See "Clinical manifestations and diagnosis of sarcoidosis", section on 'Common extrapulmonary findings and pathognomonic syndromes' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Testing for occult extrapulmonary disease' and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Invasive diagnostic testing'.)

Extrapulmonary manifestations, by organ system

Cutaneous – Approximately 25 percent of patients with sarcoidosis demonstrate skin findings. (See 'Cutaneous' above and "Cutaneous manifestations of sarcoidosis".)

Ocular – Sarcoidosis can cause anterior, intermediate, and posterior uveitis, as well as retinal periphlebitis. Extraocular involvement can affect the lacrimal glands, conjunctiva, and ocular muscles. All patients with suspected sarcoidosis should undergo baseline ophthalmologic examination and should be monitored for changes in vision, eye pain, and photophobia. (See 'Ocular' above and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Ongoing monitoring'.)

Nervous system – Neurologic involvement occurs in approximately 5 percent of patients with sarcoidosis and can be the presenting feature. Common syndromes include cranial mononeuropathy, neuroendocrine dysfunction, a focal or multifocal encephalopathy, myelopathy, hydrocephalus, aseptic meningitis, and peripheral neuropathy. (See 'Neurologic' above and "Neurologic sarcoidosis".)

Endocrine and reproductive – Endocrine manifestations of sarcoidosis include hypothalamic involvement and infiltration of the thyroid. Sarcoidosis can occasionally be found in reproductive organs. (See 'Endocrine and reproductive' above.)

Parotid and salivary glands – Painless swelling of the salivary and parotid glands occurs in approximately 5 percent of patients. (See 'Parotid and salivary glands' above.)

Lymphatic system – Lymphadenopathy is very common in sarcoidosis, with hilar, peripheral, and intra-abdominal lymphadenopathy seen in approximately 90, 40, and 30 percent of patients, respectively. Splenic involvement may result in splenomegaly or hypoattenuating splenic lesions; splenic sarcoidosis is usually subclinical but may contribute to leukopenia and thrombocytopenia. (See 'Lymphatic system' above.)

Upper respiratory tract – Sarcoidosis can involve the larynx, pharynx, nares, and/or sinuses and should be suspected in those with upper respiratory tract symptoms. (See 'Upper respiratory tract' above.)

Cardiovascular – The range of sarcoid involvement of the heart includes heart block and arrhythmias (due to involvement of the conducting system), heart failure, valvular dysfunction, and pericardial disease. The initial evaluation of all patients with sarcoidosis should include an electrocardiogram (ECG). (See 'Cardiovascular' above and "Clinical manifestations and diagnosis of cardiac sarcoidosis" and "Management and prognosis of cardiac sarcoidosis".)

Gastrointestinal and hepatic – Hepatic involvement is common but rarely symptomatic; surveillance for right upper quadrant pain, pruritus, and elevated alkaline phosphatase is appropriate. Clinically recognizable gastrointestinal disease occurs in less than 1 percent of patients with sarcoidosis. (See 'Gastrointestinal and hepatic' above and "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)

Renal and electrolyte – Abnormalities related to calcium metabolism are common in sarcoidosis, so surveillance of serum calcium is recommended to prevent nephrocalcinosis and nephrolithiasis. Other relatively common renal complications of sarcoidosis include interstitial nephritis and membranous nephropathy. (See 'Renal and electrolyte' above and "Kidney disease in sarcoidosis".)

Musculoskeletal – Acute periarthritis due to sarcoidosis typically causes symmetric involvement of the ankle joints but may involve other joints. Chronic erosive arthritis and granulomatous myositis may also occur later in the disease course. (See 'Musculoskeletal' above and "Sarcoid arthropathy" and "Sarcoid myopathy".)

Routine monitoring – Appreciation of the spectrum of extrapulmonary sarcoidosis is essential in the ongoing management of patients with known sarcoidosis. Routine monitoring includes clinical and laboratory evaluation for the types of extrapulmonary involvement that can lead to organ or life-threatening disease (table 3). (See 'Ongoing Monitoring' above and "Clinical manifestations and diagnosis of sarcoidosis", section on 'Ongoing monitoring'.)

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Topic 91259 Version 28.0

References

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