INTRODUCTION — Sarcoidosis is a multisystem granulomatous disorder of unknown etiology that affects individuals worldwide and is characterized pathologically by the presence of noncaseating granulomas in involved organs. It typically affects young adults and initially presents with one or more of the following abnormalities:
●Bilateral hilar adenopathy
●Pulmonary reticular opacities
●Skin, joint, and/or eye lesions
Sarcoidosis can involve all organ systems to a varying extent and degree [1-3]. An overview of the clinical manifestations and diagnosis of extrapulmonary sarcoidosis will be reviewed here. Issues relating to pulmonary sarcoidosis, or the epidemiology, pathogenesis, and treatment of sarcoidosis are discussed separately. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis" and "Pathology and pathogenesis of sarcoidosis" and "Treatment of pulmonary sarcoidosis: Initial approach to treatment" and "Treatment of pulmonary sarcoidosis refractory to initial therapy".)
EPIDEMIOLOGY — Up to 30 percent of patients present with extrapulmonary sarcoid (table 1) [1,4-10]. The most common sites of extrapulmonary disease include the skin, eyes, reticuloendothelial system, musculoskeletal system, exocrine glands, heart, kidney, and central nervous system. Approximately 8 percent of patients with sarcoidosis present with disease at extrapulmonary sites without lung involvement [8]. In these patients, the skin was the most common site and accounted for nearly half of the patients.
Extrapulmonary manifestations vary on the basis of sex, age at presentation, and ethnicity (figure 1) [1,11]. As an example, women are more likely to have skin or ocular involvement, while men more frequently have cardiac involvement [11].
A French retrospective multicenter center study (EpiSarc) of 562 men and 675 women identified five distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement [12]. These five phenotypes differ according to sex, geographical origin, and socioprofessional category:
●Pulmonary involvement with fibrosis and heart involvement (associated with being non-European/non-White)
●Hepatosplenic, peripheral lymph node and bone involvement (associated with being non-European/non-White)
●Erythema nodosum, joint involvement and hilar lymph nodes (associated with being European/White and female)
●Eye, neurological, digestive and kidney involvement nodes (associated with being European/White)
●Lupus pernio and a high percentage of severe involvement
An earlier European multicenter study of White patients with sarcoidosis (The Genotype–Phenotype Relationship in Sarcoidosis study) identified five subgroups that were different from those of the EpiSarc study: (1) abdominal organ involvement, (2) ocular-cardiac-cutaneous-central nervous system (CNS) disease involvement, (3) musculoskeletal-cutaneous involvement, (4) pulmonary and intrathoracic lymph node involvement, and (5) extrapulmonary involvement [13].
DIAGNOSTIC APPROACH — Only a few clinical presentations are felt to be sufficiently diagnostic for sarcoidosis that a biopsy is not necessary [14]. These presentations include Löfgren syndrome (erythema nodosum, hilar adenopathy, migratory polyarthralgia, and fever), Heerfordt's syndrome (uveoparotid fever), and asymptomatic bilateral hilar adenopathy [3]. Other than these exceptions, the diagnosis of sarcoidosis requires step-wise approach to identify organs that may be affected and are amenable to biopsy, histopathology demonstrating noncaseating granulomas, exclusion of other causes of granulomatous histopathology with special stains for mycobacteria and fungi, documentation of involvement of at least one additional organ system, and exclusion of other multisystem granulomatous diseases [10].
When biopsy is not possible, occasionally a gallium scan will be obtained looking for the "lambda" and "panda" signs. Gallium uptake in paratracheal and hilar lymph nodes creates the shape of the Greek letter "lambda." Involvement of the lacrimal, parotid, and submandibular glands in combination with the normal uptake by the nasopharyngeal mucosa creates the "panda" sign. The panda sign is not specific for sarcoid as bilateral accumulation of gallium in the lacrimal and salivary glands can also be seen in lymphoma, Sjögren’s syndrome, and AIDS. However, the combination of the panda and lambda signs (paratracheal and hilar uptake of gallium) is felt to be specific for sarcoid [15]; the sensitivity of the combination is approximately 50 percent [16]. (See 'Löfgren syndrome' below and 'Intraocular sarcoidosis' below and 'Lymph nodes, liver, and spleen' below and 'Exocrine glands' below.)
Monitoring — Appreciation of the spectrum of extrapulmonary sarcoidosis is also essential in the ongoing management of patients with known sarcoidosis. The American Thoracic Society (ATS) has published consensus guidelines for the detection and diagnosis of extrapulmonary sarcoidosis [3]. The committee made a strong recommendation for baseline serum calcium testing and suggestions for baseline screening to include complete blood cell count, serum creatinine, serum alkaline phosphatase, ocular examination, and electrocardiogram.
Routine monitoring of sarcoidosis includes evaluation for the types of extrapulmonary involvement that can lead to organ or life-threatening disease, although the validity of such monitoring has not been formally assessed (table 2). The ATS guideline suggests annual measurement of serum calcium, creatinine, and alkaline phosphatase, but advises that the need for ocular and cardiac examinations be based on symptoms in patients whose baseline testing was normal [3]. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Monitoring'.)
CUTANEOUS — Cutaneous involvement is seen in approximately 25 percent of patients with sarcoidosis, and is often an early finding. Several types of skin lesions can occur [17], and 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 specific manifestation of sarcoidosis. It 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).
●Lesions of nodular sarcoidosis are frequently distributed on the face, trunk, and extensor surface of the arms and legs (picture 4). Nodular involvement of the nose can have a rhinophymatous appearance.
●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). Lupus pernio is associated with an increased risk for nasal involvement with sarcoidosis. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)
●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). EN is a component of Löfgren syndrome, which is associated with a good prognosis and spontaneous remission in patients of European descent. A number of diseases should be considered in the differential diagnosis (table 3). Biopsy is nonspecific (panniculitis rather than granulomatous inflammation) and typically not helpful. (See 'Löfgren syndrome' below and "Erythema nodosum".)
●Subcutaneous sarcoidosis, which is different from EN, is characterized by asymptomatic or mildly tender nodules, usually on the upper extremities. They are often associated with hilar adenopathy. (See "Cutaneous manifestations of sarcoidosis", section on 'Subcutaneous sarcoidosis'.)
For patients without a confirmed diagnosis of sarcoidosis, a skin biopsy is typically performed to evaluate lesions suggestive of sarcoidosis other than EN. In addition to routine histopathologic analysis, biopsy specimens should be examined under polarized light for the presence of refractile material that could indicate granuloma formation secondary to a foreign body reaction, although polarizable material can also be seen in sarcoid granulomas. In addition, tissue staining for acid fast bacilli and fungi, microbial cultures of fresh tissue, and tuberculin skin testing should be performed if clinical or histopathologic features suggest the possibility of mycobacterial or fungal infection. (See "Cutaneous manifestations of sarcoidosis", section on 'Examination and biopsy'.)
OCULAR — Ocular involvement occurs in up to 25 percent of patients with sarcoidosis and is the presenting symptom in 5 percent [18]. Ocular manifestations are reported at higher rates in women and in African American and Japanese patient populations [19]. Sarcoidosis can involve the orbit, anterior and posterior segments of the eye, conjunctiva, lacrimal glands, and extraocular muscles [20,21]. 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 [3]. 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 [20]. Symptoms included dry eye, blurry vision, photophobia, redness, and pain.
A diagnosis of ocular sarcoid 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 [22]. 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 visualized by everting the upper eyelid (picture 9) or palpated just above and lateral to the orbit (picture 3).
Intraocular sarcoidosis — Intraocular manifestations of sarcoidosis are classified as anterior, intermediate, and/or posterior uveitis [20,23]. 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 (TM) nodules and/or tent-shaped peripheral anterior synechiae (PAS) 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 peri-phlebitis (± 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 sarcoid 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 sarcoid and an extraocular biopsy supporting sarcoidosis is felt to be diagnostic of ocular sarcoid.
●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 sarcoid.
●When a patient has a combination of three signs of uveitis compatible with sarcoid (eg, mutton fat precipitates, anterior synechiae, vitreous "string of pearls") and two other investigations supporting sarcoid (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 (ACE), 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 also affects extraocular orbital tissues, including the lacrimal glands, conjunctiva, extraocular muscles, and optic sheath, and may present as a soft tissue orbital mass [27]. In a case series of 20 patients with orbital sarcoid, the most common symptoms were a palpable mass and orbital swelling [27]. The most common findings on orbital computed tomography 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].
Outcomes — Secondary glaucoma, cataract formation, and impaired vision are potential late complications due to the underlying disease or chronic glucocorticoid therapy. A retrospective study examined the long-term outcomes (≥3 years) in 83 patients with sarcoid 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.
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 presentation of sarcoidosis [29,30].
UPPER RESPIRATORY TRACT DISEASE — Upper respiratory tract sarcoidosis may involve the larynx, pharynx, nares, and/or sinuses; it should be suspected in all patients with systemic sarcoidosis and upper respiratory tract symptoms [31-41]. The most frequent head and neck manifestation of sarcoidosis is cervical lymphadenopathy [42].
●Laryngeal sarcoid – Laryngeal involvement typically affects the supraglottis, less commonly the subglottis, and true vocal fold involvement is rare [43]. Presenting symptoms include dysphagia, dyspnea, cough, and hoarseness [44,45]. The diagnosis is made by direct visualization and biopsy. Treatment may include systemic or lesional glucocorticoids, or laser excision with mitomycin (also known as mitomycin-C) application [44].
●Nasal and sinus sarcoid – 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 [32,46]. (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) [38]. Epistaxis and nasal polyposis were present in about 25 percent. The coexistence of facial lupus pernio and rhinosinusitis due to sarcoidosis has been variably reported [37,38,47].
On endoscopic examination, mucosal hypertrophy is common and two main patterns are seen [38]. 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 [37].
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.
Treatment of sinonasal sarcoidosis is similar to other causes of chronic rhinosinusitis. Regular nasal irrigation with saline solutions and instillation of intranasal glucocorticoids form the cornerstone of therapy. Systemic glucocorticoids and other immunosuppressive agents may be needed for severe disease, after exclusion of infection. (See "Chronic rhinosinusitis: Management", section on 'Overview of medical therapies'.)
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 4). 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 [48]. The frequency of myocardial involvement is unclear; small registries suggest 5 percent of 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 sarcoid involvement of the heart includes heart block and arrhythmias (due to involvement of the conducting system), heart failure, valvular dysfunction, simulated infarction, and pericardial disease [49]. Patients may be asymptomatic or may report palpitations, syncope, dizziness, or chest pain. Cardiac sarcoidosis can cause sudden death due to ventricular tachyarrhythmias or bradyarrhythmias, and sudden death may be the first presentation of cardiac sarcoidosis [50]. An abnormal electrocardiogram (ECG) and cardiac related symptoms at disease onset are important predictors of a later diagnosis of clinically significant cardiac sarcoidosis. In contrast, cardiac sarcoidosis is very rare in subjects without symptoms and with a normal ECG [51]. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
The initial evaluation of all patients with sarcoidosis should include an electrocardiogram. For patients with suspected cardiac involvement, consensus guidelines from the ATS suggest cardiac magnetic resonance imaging (CMR), rather than cardiac positron emission tomography (cPET) or transthoracic echocardiography (TTE), to obtain both diagnostic and prognostic information [3]. For patients being managed in a setting in which CMR is not available, or when CMR results are inconclusive, a dedicated cPET, rather than a transthoracic echocardiography (TTE), should be obtained for both diagnostic and prognostic information [3,52]. Additional studies, such as 24 hour Holter monitoring and echocardiography, are performed based on symptoms, signs, and results of the electrocardiogram [53]. Among sarcoid patients with mildly impaired left ventricular ejection fraction, programmed ventricular stimulation during electrophysiologic study may be used in sudden death risk stratification. A negative electrophysiologic study appears predictive of the absence of ventricular arrhythmias [54]. Speckle tracking echocardiography may be useful as a new diagnostic tool for an assessment of cardiovascular disease in sarcoid patients [55]. (See "Clinical manifestations and diagnosis of cardiac sarcoidosis", section on 'Diagnosis'.)
Pulmonary hypertension (PH) and cor pulmonale can result from severe scarring of the pulmonary parenchyma and vascular obliteration (Group 5 PH) (table 5). In this setting, death from sarcoidosis usually results from right ventricular failure. The 2020 ATS consensus guidelines suggest initial testing with TTE when PH is suspected, ie, exertional chest pain and/or syncope, exam findings of a prominent P2 or S4, reduced six-minute walk distance, desaturation with exercise, reduced diffusing capacity (DLCO), increased pulmonary artery diameter relative to ascending aorta diameter (eg, by computed tomography [CT] scan), elevated brain natriuretic factor, and/or fibrotic lung disease [3]. Right heart catheterization may be required to definitively confirm or exclude PH [56]. (See "Clinical features and diagnosis of pulmonary hypertension of unclear etiology in adults" and "Treatment and prognosis of pulmonary arterial hypertension in adults (group 1)".)
LYMPH NODES, LIVER, AND SPLEEN — Involvement of the lymph nodes, liver, and spleen 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 [57]; anterior and posterior mediastinal adenopathy are uncommon in sarcoidosis [58]. Approximately 30 percent of patients with sarcoidosis have intraabdominal lymphadenopathy (two nodes >1 cm diameter on short axis) on abdominal CT scans [59].
●Liver – Patients with hepatic sarcoid are usually asymptomatic, but many have liver function test abnormalities or hepatomegaly, and a few may develop advanced liver disease. 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 [3].
On physical examination, approximately 20 percent have hepatomegaly. On abdominal CT scan, 30 percent of 59 patients had a liver span >20 cm [59]. In most studies, the liver is homogeneous in appearance, but hypoattenuating nodules may rarely be seen [59]. Noncaseating granulomas may be seen on liver biopsy with or without hepatomegaly in 50 to 65 percent of patients with sarcoidosis. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)
●Splenic enlargement – Approximately 6 percent of patients have splenomegaly on physical examination [60]. In a review of abdominal CT scans in 20 patients with known sarcoid, splenomegaly was present in 16 [61], while other studies have reported splenomegaly on imaging in about one-third of patients [59]. Of the 49 patients in whom the entire spleen was seen on CT scan, the greatest splenic dimension was ≥14 cm in 16 (33 percent) and ≥18 cm in 3 (6 percent) [62].
Hypodense splenic nodules are seen on CT in about 15 percent [62]. Splenic granulomas are found at autopsy in 50 percent of patients with sarcoidosis [63]. Hypersplenism due to sarcoidosis can lead to anemia, leukopenia, and thrombocytopenia [64,65].
We assess for liver involvement by obtaining liver function tests at the time of the initial diagnosis and then annually, or more often if needed due to symptoms, prior abnormalities, or medications (table 2). The finding of granulomas on biopsy of a lymph node or liver requires evidence of involvement of another organ in order to make a diagnosis of sarcoidosis. In particular, granulomas in the liver are associated with many other disorders, including infections (table 6), primary biliary cholangitis, drugs and toxins (eg, allopurinol, sulfa drugs, beryllium) (table 7), and malignancy (eg, lymphoma, renal cell carcinoma). (See "Evaluation of the adult patient with hepatic granuloma", section on 'Causes'.)
MUSCULOSKELETAL — Musculoskeletal system involvement may occur in up to 10 percent of patients with sarcoidosis. Musculoskeletal sarcoidosis is discussed separately. (See "Sarcoid arthropathy" and "Sarcoid myopathy".)
Manifestations include:
●Acute polyarthritis (especially symmetric involvement of the ankle joints), usually in association with erythema nodosum and occasionally with acute uveitis. The swelling usually occurs in the soft tissue around joints, causing a periarthritis rather than a true arthritis [66]. Acute sarcoid arthritis may be present in isolation or in association with other features of Löfgren syndrome. (See 'Löfgren syndrome' below.)
●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.
NEUROLOGIC — Approximately 5 percent of patients with sarcoidosis have neurologic involvement, which can occasionally be the presenting symptom. Manifestations of central nervous system (CNS) disease (eg, encephalopathy/vasculopathy, granulomatous meningitis) usually occur early, while peripheral nerve and skeletal muscle involvement are characteristically seen in the later stages. The clinical manifestations, diagnosis, and management of neurologic sarcoidosis are discussed separately. (See "Neurologic sarcoidosis".)
EXOCRINE GLANDS — Painless swelling of the salivary and parotid glands occurs in approximately 5 percent of patients with sarcoidosis [29,67,68]. Xerostomia and keratoconjunctivitis sicca may also be seen, similar to the clinical manifestations of Sjögren's syndrome and IgG4-related systemic disease. Sarcoidosis can also occur concomitantly with Sjögren's syndrome. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease", section on 'Dry eye' and "Interstitial lung disease associated with Sjögren syndrome: Clinical manifestations, evaluation, and diagnosis", section on 'Sjögren syndrome and sarcoidosis'.)
Pancreatic involvement with sarcoidosis is uncommon. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Pancreatic'.)
ENDOCRINE AND REPRODUCTIVE — Endocrine manifestations of sarcoidosis include hypothalamic involvement (due to basilar granulomatous meningitis noted above) and infiltration of the thyroid.
Sarcoid involvement of the anterior pituitary can result in deficiency of adrenocorticotropic hormone, thyroid stimulating hormone, follicle-stimulating hormone, luteinizing hormone, and insulinlike growth factor 1, and also elevated prolactin [69,70]. Presentations include diabetes insipidus, hypothalamic hypopituitarism, amenorrhea-galactorrhea, hypogonadotropic hypogonadism, and secondary hypothyroidism. In addition to endocrinologic evaluation, imaging with MRI looking 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 [71,72]. Almost all patients are euthyroid, although cases of clinical hypothyroidism caused by diffuse replacement of thyroid tissue have been reported [73,74]. (See "Infiltrative thyroid disease".)
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 [75-77]. Systemic sarcoidosis, in the absence of significant cardiopulmonary compromise, does not affect fertility and does not increase the incidence of fetal or obstetrical complications [78]. It will often improve during pregnancy, possibly due to increases of maternal free cortisol.
Sarcoidosis can involve the testes, and must be differentiated from testicular cancer and tuberculosis [79]. Recurrent epididymitis due to sarcoidosis rarely can occur [73,80].
RENAL AND ELECTROLYTE — For patients with sarcoidosis who have neither renal symptoms nor established renal sarcoidosis, consensus guidelines from the ATS suggest baseline serum creatinine testing to screen for renal sarcoidosis [3]. For patients with sarcoidosis who do not have symptoms or signs of hypercalcemia, consensus guidelines from the American Thoracic Society recommend baseline serum calcium testing to screen for abnormal calcium metabolism [3].
Disorders related to calcium metabolism are the most common renal and electrolyte abnormalities observed among patients with sarcoidosis. The defect in calcium metabolism is due to extrarenal production of calcitriol by activated macrophages. Manifestations of abnormal calcium metabolism include increased intestinal calcium absorption, hypercalciuria (which occurs in up to 50 percent of cases), hypercalcemia (which occurs in 10 to 20 percent), nephrocalcinosis, and nephrolithiasis. If untreated, renal calcium deposition can lead to chronic renal failure and end-stage kidney disease. Sarcoidosis-associated hypercalcemia has been shown to be associated with a more severe disease phenotype, particularly among patients carrying the HLA-DRB1*04 allele [81]. (See "Kidney disease in sarcoidosis", section on 'Nephrolithiasis and nephrocalcinosis' and "Hypercalcemia in granulomatous diseases".)
Sarcoid interstitial nephritis is more commonly found on the initial presentation of sarcoidosis, rather than among patients with longstanding disease [82,83]. The diagnosis is suggested by the combination of an elevated creatinine and bland urinary sediment in a patient with known or likely sarcoidosis. Renal biopsy reveals normal glomeruli, mononuclear cell infiltration, and noncaseating granulomas. (See "Kidney disease in sarcoidosis", section on 'Interstitial nephritis'.)
Although granulomatous infiltration of the kidney is not uncommon, it is rarely the sole cause of renal dysfunction. 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".)
GASTROINTESTINAL — Clinically recognizable gastrointestinal (GI) 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 commonly involved portion of the GI tract, but sarcoidosis of the esophagus, appendix, colon, and rectum has also been described [84,85]. Sarcoidosis can also involve the liver and pancreas. Small bowel sarcoidosis has been reported, but is very rare [85]. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)
LÖFGREN SYNDROME — Löfgren syndrome, which is observed in <5 to 10 percent of patients with sarcoidosis, is the combination of erythema nodosum (EN), hilar adenopathy, migratory polyarthralgia, and fever seen primarily in women. Men with acute sarcoidosis may present with signs of bilateral ankle arthritis typical of Löfgren syndrome, but without EN [86]. The presence of all features of the Löfgren syndrome has a 95 percent diagnostic specificity for sarcoidosis, allowing a clinical diagnosis to be made without biopsy [67]. Löfgren syndrome and erythema nodosum are discussed in greater detail separately. (See "Erythema nodosum" and "Sarcoid arthropathy", section on 'Acute arthritis and Lofgren syndrome'.)
In populations of European descent, Löfgren syndrome is associated with a good prognosis and spontaneous remission [67,87]. Treatment with nonsteroidal anti-inflammatory agents (NSAIDs) is usually adequate to control symptoms, but occasional patients will need additional therapy. (See "Sarcoid arthropathy", section on 'Treatment'.)
FATIGUE — Fatigue is a common symptom in patients with sarcoidosis, occurring in up to 80 percent of patients [88]. 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 sarcoid [89]. A separate study found higher resting energy expenditure and increased C-reactive protein (CRP) levels in the subset of patients with sarcoidosis who have fatigue [90]. Thus, fatigue may reflect a metabolic derangement.
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.)
●Cutaneous manifestations – Cutaneous involvement is seen in approximately 25 percent of patients with sarcoidosis, and is often an early finding. (See 'Cutaneous' above and "Cutaneous manifestations of sarcoidosis".)
●Ocular involvement – 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 ophthalmologic examination. (See 'Ocular' above.)
●Upper respiratory tract – Sarcoidosis can involve the larynx, pharynx, nares, and/or sinuses and should be suspected in all patients with systemic sarcoidosis and upper respiratory tract symptoms. (See 'Upper respiratory tract disease' above.)
●Cardiac sarcoidosis – Cardiac sarcoidosis can be a benign, incidentally discovered condition or a life-threatening disorder causing sudden death. 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. (See 'Cardiovascular' above and "Clinical manifestations and diagnosis of cardiac sarcoidosis".)
●Musculoskeletal – Acute polyarthritis due to sarcoidosis typically causes symmetric involvement of the ankle joints, but may involve other joints. A characteristic feature is that the swelling usually occurs in the soft tissue around joints, causing a periarthritis rather than a true arthritis. (See 'Musculoskeletal' above and "Sarcoid arthropathy".)
●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, peripheral neuropathy. (See 'Neurologic' above.)
●Löfgren syndrome – Löfgren syndrome (LS) is the combination of erythema nodosum (EN), hilar adenopathy, migratory polyarthralgia, and fever. The presence of all features of LS has 95 percent specificity for sarcoidosis. However, erythema nodosum without the other features has a broad differential (table 3). (See 'Löfgren syndrome' above and "Erythema nodosum".)
●Exocrine glands – Painless swelling of the salivary and parotid glands occurs in approximately 5 percent of patients with sarcoidosis. (See 'Exocrine glands' above.)
●Endocrine and reproductive – Endocrine manifestations of sarcoidosis include hypothalamic involvement (due to basilar granulomatous meningitis noted above) and infiltration of the thyroid. Sarcoidosis can occasionally be found in the uterus, ovaries, and testes. (See 'Endocrine and reproductive' above.)
●Renal and electrolyte – Abnormalities related to calcium metabolism are the most common renal and electrolyte abnormalities observed among patients with sarcoidosis. A baseline serum calcium should be obtained to screen for abnormal calcium metabolism, which can result in 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".)
●Gastrointestinal – Clinically recognizable gastrointestinal (GI) disease occurs in less than 1 percent of patients with sarcoidosis. Areas of involvement include the esophagus, appendix, colon, rectum, liver, pancreas, and rarely the small intestine. (See 'Gastrointestinal' above and "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis".)
●Routine monitoring – Appreciation of the spectrum of extrapulmonary sarcoidosis is also 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, although the validity of such monitoring has not been formally assessed (table 2). (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis", section on 'Monitoring'.)
