Sarcoidosis

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Sarcoidosis
Classification and external resources
APSarcoid.PNG
Chest xray showing the typical nodularity of sarcoidosis in the base of the lungs.
ICD-10D86
ICD-9135
OMIM181000
DiseasesDB11797
MedlinePlus000076
eMedicinemed/2063
MeSHD012507
 
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Sarcoidosis
Classification and external resources
APSarcoid.PNG
Chest xray showing the typical nodularity of sarcoidosis in the base of the lungs.
ICD-10D86
ICD-9135
OMIM181000
DiseasesDB11797
MedlinePlus000076
eMedicinemed/2063
MeSHD012507

Sarcoidosis (from sarc meaning "flesh", -oid, "like", and -osis, "diseased or abnormal condition"), also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a syndrome involving abnormal collections of chronic inflammatory cells (granulomas) that can form as nodules in multiple organs.[1] The granulomas are most often located in the lungs or the lymph nodes, but any organ can be affected. Onset is usually gradual. Sarcoidosis may be asymptomatic or chronic. It commonly improves or clears up spontaneously. More than two-thirds of people with lung sarcoidosis have no symptoms after 9 years. About 50% have relapses. About 10% develop serious disability. Lung scarring or infection may lead to respiratory failure and death.[1] In chronic cases, symptoms may fluctuate over many years.[2] Sarcoidosis seems to be caused by an immune reaction to an infection that continues after the cause of the infection is gone.[3]

Signs and symptoms[edit]

Signs and symptoms of sarcoidosis.[4]
Multiple reddish-brownish papules and plaques on the left mandibular region of an adult face
Systemic sarcoidosis

Sarcoidosis is a systemic inflammatory disease that can affect any organ, although it is often asymptomatic. Common symptoms, which tend to be vague, include fatigue (unrelieved by sleep), lack of energy, weight loss, aches and pains, arthritis, dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry, hacking cough, or skin lesions. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum, granuloma annulare, or lupus pernio. Sarcoidosis and cancer may mimic one another, making the distinction difficult.[5]

The combination of erythema nodosum, bilateral hilar lymphadenopathy, and arthralgia is called Löfgren syndrome; it has a relatively good prognosis.

Renal, liver (including portal hypertension), heart,[6] or brain involvement may cause further symptoms and altered functioning.

Lungs[edit]

Pulmonary localization is by far the most common in individuals with sarcoidosis. About 90% of patients have an abnormal chest X-ray at some time during the course of their disease. Overall, about 50% develop permanent pulmonary abnormalities, and 5 to 15% have progressive fibrosis of the lung parenchyma. Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the alveoli, small bronchi, and small blood vessels. In acute and subacute cases, physical examination usually reveals dry rales.[7]

Sarcoidosis of the lungs can be divided into four stages. Stage 0 - No intrathoracic involvement. Stage I - Bilateral hilar adenopathy. Stage II - Pulmonary parenchyma involved. Stage III - Pulmonary infiltrates with fibrosis

Liver[edit]

Although liver biopsy reveals liver involvement in 60 to 90% of tested cases, liver dysfunction is usually not clinically significant. About 20–30% of patients have hepatomegaly and/or biochemical evidence of liver involvement. Usually, these changes reflect a cholestatic pattern and include raised levels of alkaline phosphatase, while bilirubin and aminotransferases are only mildly elevated. Jaundice is rare.[7]

Skin[edit]

Sarcoidosis involves the skin in about 25% of patients. The most common lesions are erythema nodosum, plaques, maculopapular eruptions, subcutaneous nodules, and lupus pernio. Treatment is not required, since the lesions usually resolve spontaneously in two to four weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems.[7]

Heart[edit]

Although cardiac involvement is present in 20% to 30% of patients with sarcoidosis, only about 5% of patients with systemic sarcoidosis are symptomatic.[8] The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia.[9] Myocardial sarcoidosis can be a rare cause of sudden cardiac death.[10][11] Recently, retired hockey player Gaetano Orlando received a "total artificial heart" to replace ventricles damaged by sarcoidosis.[citation needed]

Eye[edit]

Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever, and is associated with Heerfordt-Waldenstrom syndrome. (D86.8) Development of scleral nodule associated with sarcoidosis have been observed.[12]

Blood[edit]

Abnormal clinical blood tests are frequent, but not diagnostic. Anemia occurs in 4-20% of patients with sarcoidosis. Leukopenia (due to a reduced number of circulating lymphocytes [13] or lymphopenia) occurs in as many as 40% of patients, but is rarely severe. In the absence of splenomegaly, leukopenia may reflect bone marrow involvement, but the most common mechanism is a redistribution of blood T cells to sites of disease.[14] Other nonspecific findings include monocytosis, occurring in the majority of sarcoidosis cases,[15] increased hepatic enzymes or alkaline phosphatase. Hypercalciuria and hypercalcemia are seen in <10% of patients.[16]

Lymph nodes[edit]

Lymphadenopathy is very common in sarcoidosis. Intrathoracic nodes are enlarged in 75 to 90% of all patients; usually this involves the hilar nodes, but the paratracheal nodes are commonly involved. Peripheral lymphadenopathy is very common, particularly involving the cervical (the most common head and neck manifestation of the disease),[17] axillary, epitrochlear, and inguinal nodes. Palpation causes no pain.[7]

Nervous system[edit]

All components of the nervous system can be involved. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis. Neurologic findings are observed in about 5% of patients. Cranial nerves are predominantly affected, and peripheral facial nerve palsy, often bilateral, is the most common neurological manifestation of sarcoidosis.[18] It occurs suddenly and is usually transient. Other common manifestations of neurosarcoid include optic nerve dysfunction, papilledema, palate dysfunction, hearing abnormalities, hypothalamic and pituitary abnormalities, chronic meningitis, and peripheral neuropathy.[7] Intramedullary sarcoidosis is rare and occurs in less than 1% of cases. Usually, granulomatous involvement of the basal meninges subsequently affects the cranial nerves. Myelopathy may be the initial clinical presentation of intramedullary neurosarcoidosis.[19]

Another common finding in Sarcoidosis with neurological involvement is autonomic or sensory small fiber neuropathy.[20][21] Autonomic involvement can mimic the Postural Orthostatic Tachycardia Syndrome

Exocrine glands[edit]

Parotid enlargement is a classic feature of sarcoidosis, but clinically apparent parotid involvement occurs in less than 10% of patients. Bilateral involvement is the rule. The gland is usually not tender, but firm and smooth. Xerostomia can occur; other exocrine glands are affected only rarely.[7]

Scalp[edit]

Sarcoidosis of the scalp presents with diffuse or patchy hair loss.[22]:762

Causes[edit]

The exact cause of sarcoidosis is not known. The current working hypothesis is, in genetically susceptible individuals, sarcoidosis is caused through alteration to the immune response after exposure to an environmental, occupational, or infectious agent.[23]

Genetics[edit]

Investigations of genetic susceptibility yielded many candidate genes, but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is BTNL2; several HLA-DR risk alleles are also being investigated.[24] In persistent sarcoidosis, the HLA haplotype HLA-B7-DR15 are either cooperating in disease or another gene between these two loci is associated. In nonpersistent disease, there is a strong genetic association with HLA DR3-DQ2.[25] Siblings have only a modestly increased risk (hazard ratio 5-6) of developing the disease, indicating genetic susceptibility plays only a small role. The alternate hypothesis that family members share similar exposures to environmental pathogens is quite plausible to explain the apparent hereditary factor.

Infectious agents[edit]

Several infectious agents appear to be significantly associated with sarcoidosis, but none of the known associations is specific enough to suggest a direct causative role. Propionibacterium acnes can be found in bronchoalveolar lavage of approximately 70% of patients and is associated with disease activity; however, it can be also found in 23% of controls.[26][27] A recent meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, but the meta-analysis also detected a possible publication bias, so the results need further confirmation.[28][29]

The disease has also been reported by transmission via organ transplants.[30]

Vitamin D dysregulation[edit]

Sarcoidosis frequently causes an increase in vitamin D production outside the kidney.[31] Macrophages / histiocytes inside the granulomas convert vitamin D from its inactive form 25-hydroxyvitamin D to its active form, resulting in elevated levels of the hormone 1,25-dihydroxyvitamin D and symptoms of hypervitaminosis D that may include fatigue, lack of strength or energy, irritability, metallic taste, temporary memory loss or cognitive problems. Physiological compensatory responses (e.g., suppression of the parathyroid hormone levels) may mean the patient does not develop frank hypercalcemia. This condition may be aggravated by high levels of estradiol and prolactin, such as in pregnancy, leading to hypercalciuria and/or compensatory hypoparathyroidism.[32] High levels of vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.

Hyperprolactinemia[edit]

Prolactin is frequently increased in sarcoidosis; between 3% and 32% of cases have hyperprolactinemia;[33] this frequently leads to amenorrhea, galactorrhea, or nonpuerperal mastitis in women. Prolactin also has a broad spectrum of effects on the immune system, and increased prolactin levels are associated with disease activity or may exacerbate symptoms in many autoimmune diseases; treatment with prolactin-lowering medication has been shown effective in some cases.[34] However, it is unknown if this relation holds in sarcoidosis, and the gender predilection in sarcoidosis is less pronounced than in some other autoimmune diseases, where such relation has been established. In pregnancy, the effects of prolactin and estrogen counteract each other to some degree, with a slight trend to improve pulmonary manifestations of sarcoidosis, while lupus, uveitis and arthralgia might slightly worsen.[32] Lupus, uveitis and arthralgia are known to be, in some cases, associated with increased prolactin levels, and respond to bromocriptin treatment, but so far, this has not been investigated specifically for sarcoidosis. The reasons for increased prolactin levels in sarcoidosis are uncertain. Prolactin has been shown to be produced by T-lymphocytes in some autoimmune disorders in amounts high enough to affect the feedback by the hypothalamic dopaminergic system.[35]

The extrapituitary prolactin is believed to play a role as a cytokine-like proinflammatory factor. Prolactin antibodies are believed to play a role in hyperprolactinemia in other autoimmune disorders, and high-prevalence endocrine autoimmunity has been observed in patients with sarcoidosis.[36] It may also be a consequence of renal disease or treatment with steroids. Neurosarcoidosis may occasionally cause hypopituitarism, but has not been reported to cause hyperprolactinemia.

Thyroid disease[edit]

In women, a substantial association of thyroid disease and sarcoidosis has been reported. The association is less marked, but still significant, for male patients. Female patients have a significantly elevated risk for hypothyroidism, hyperthyroidism and thyroid autoimmunity, and autoimmunity appears to be very important in the pathogenesis of thyroid disease in this population. Thyroid granulomatosis, on the other hand, is uncommon.[37]

Autoimmune[edit]

Association of autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known, but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence.[37][38]

Sarcoidosis has been associated with celiac disease, a condition in which a chronic reaction to certain protein chains, commonly referred to as glutens, found in some cereal grains, occurs. This reaction causes destruction of the villi in the small intestine, with resulting malabsorption of nutrients.

Sarcoidosis has been associated with type IV hypersensitivity.[39] Tests of delayed cutaneous hypersensitivity have been used to measure progression.[40]

Other[edit]

While disputed, some cases have been associated with inhalation of the dust from the collapse of the World Trade Center after the September 11, 2001 attacks.[41] See Health effects arising from the September 11, 2001 attacks for more information. Chicago comedian Bernie Mac suffered from sarcoidosis and died of pneumonia as a result of his compromised immune system.[42] Reggie White, a former standout National Football League player, also suffered from sarcoidosis, and the disease played a major role in his death.[43]

Pathophysiology[edit]

Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-alpha, IFN-gamma, and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation, resulting in accelerated inflammation, but immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypoactivity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. The regulatory T-lymphocytes in the periphery of sarcoid granulomas appear to suppress IL-2 secretion, which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.[44] Schaumann bodies seen in sarcoidosis are calcium and protein inclusions inside of Langhans giant cells as part of a granuloma. While TNF-alpha is widely believed to play an important role in the formation of granulomas, sarcoidosis can be triggered by treatment with the TNF-alpha antagonist etanercept.[45][46]

Diagnosis[edit]

Diagnosis of sarcoidosis is often a matter of exclusion. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve chest X-ray, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound and endoscopic ultrasound with FNA of mediastinal lymph nodes(EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi. Angiotensin-converting enzyme blood levels are used in diagnosis and monitoring of sarcoidosis.[47]

Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, Wegener's granulomatosis, varicella infection, and atypical infections, such as Mycobacterium avium complex, cytomegalovirus, and cryptococci.[48] Sarcoidosis is confused most commonly with neoplastic diseases, such as lymphoma, or with disorders characterized also by a mononuclear cell granulomatous inflammatory process, such as the mycobacterial and fungal disorders.[7]

Because of the wide range of possible manifestations, the investigations to confirm diagnosis may involve many organs and methods, depending on initial presentation.

Very often, sarcoidosis presents as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch); hence, chest X-ray and other methods are used to assess the severity or rule out pulmonary disease.

The disease typically limits the amount of air drawn into the lungs, but produces higher than normal expiratory flow ratios. Obstructive lung changes, causing a decrease in the amount of air that can be exhaled, may occur when enlarged lymph nodes in the chest compress airways or when internal inflammation or nodules impede airflow.

CT scan of the chest showing lymphadenopathy (arrows) in the mediastinum due to sarcoidosis

Chest X-ray changes are divided into four stages:[49]

Although patients with stage 1 X-rays tend to have the acute or subacute, reversible form of the disease, those with stages 2 and 3 often have the chronic, progressive disease; these patterns do not represent consecutive "stages" of sarcoidosis. Thus, except for epidemiologic purposes, this X-ray categorization is mostly of historic interest.[7]

Investigations to assess involvement of other organs frequently involve electrocardiogram, ocular examination by an ophthalmologist, liver function tests, renal function tests, serum calcium, and 24-hour urine calcium.

In sarcoidosis presenting in the Caucasian population, hilar adenopathy and erythema nodosum are the most common initial symptoms. In this population, a biopsy of the gastrocnemius muscle is a useful tool in correctly diagnosing the patient. The presence of a noncaseating epithelioid granuloma in a gastrocnemius specimen is definitive evidence of sarcoidosis, as other tuberculoid and fungal diseases extremely rarely present histologically in this muscle.[50]

In female patients, sarcoidosis is significantly associated with hypothyroidism, hyperthyroidism and other thyroid diseases, hence close surveillance of thyroid function is recommended.[37]

Common neurosarcoid locations noted on MR: (1) enveloping the infundibulum and extending into the parasellar region; (2) contiguous disease wrapping the inferior frontal lobes; and (3) synchronous lesions of the superior vermis and 4th ventricle choroid plexus. MR demonstrates significant thickening and mild enhancement of the optic chiasm and T2 hyperintensity in both optic tracts and hypothalamus. T1WI with contrast MR imaging may show diffuse dural and leptomeningeal thickening with enhancement.

Classification[edit]

Sarcoidosis may be divided into the following types:[22]:708–11

Treatment[edit]

Between 30 and 70% of patients do not require therapy.[51] For patients presenting with lung symptoms, unless the respiratory impairment is devastating, active pulmonary sarcoidosis is observed usually without therapy for two to three months; if the inflammation does not subside spontaneously, therapy is instituted.[7] Corticosteroids, most commonly prednisolone, have been the standard treatment for many years. In some patients, this treatment can slow or reverse the course of the disease, but other patients do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously.[52] Additionally, corticosteroids have many recognized dose- and duration-related side effects, and their use is generally limited to severe, progressive, or organ-threatening disease. The influence of corticosteroids or other immunosuppressants on the natural history is unclear.

Severe symptoms are generally treated with steroids, and steroid-sparing agents such as azathioprine and methotrexate are often used. Rarely, cyclophosphamide has also been used. As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some early indications of success using immunosuppressants, interleukin-2 inhibitors, or antitumor necrosis factor-alpha treatment (such as infliximab). Unfortunately, none of these has provided reliable treatment, and there can be significant side effects such as an increased risk of reactivating latent tuberculosis. Antitumor necrosis factor-alpha treatment with etanercept in rheumatoid arthritis has been observed to cause sarcoidosis.[45]

Because sarcoidosis can affect multiple organ systems, follow-up on a patient with sarcoidosis should always include an electrocardiogram, ocular examination by an ophthalmologist, liver function tests, serum calcium, and 24-hour urine calcium.[37]

Prognosis[edit]

Gross pathology image showing sarcoidosis with honeycombing: Prominent honeycombing is present in the lower lobes accompanied by fibrosis and some honeycombing in the upper lungs. Honeycombing consists of cystically dilated airways separated by scar tissue resembling the honeycomb of bees. It is a nonspecific end stage of many types of interstitial lung disease.

The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. About half of the cases resolve without treatment or can be cured within 12–36 months, and most within five years. Some cases persist several decades.[51] When the heart is involved, the prognosis is poor.[53] Patients with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, malignant lymphomas,[54] and cancer in other organs known to be affected in sarcoidosis.[55] In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma.[56] This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process.[57] Sarcoidosis can also follow cancer [58] or occur concurrently with cancer.[59][60] There have been reports of hairy cell leukemia,[61] acute myeloid leukemia,[62] and acute myeloblastic leukemia [63] associated with sarcoidosis.

Epidemiology[edit]

Sarcoidosis most commonly affects young adults of both sexes, although studies have reported more cases in females. Incidence is highest for individuals younger than 40 and peaks in the age-group from 20 to 29 years; a second peak is observed for women over 50.[51][53]

Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5 per 100,000 in men and 19 per 100,000 in women. The disease is most prevalent in Northern European countries and the highest annual incidence of 60 per 100,000 is found in Sweden and Iceland. In the United Kingdom the prevalence is 16 in 100,000.[64] In the United States, sarcoidosis is more common in people of African descent than Caucasians, with annual incidence reported as 35.5 and 10.9 per 100,000, respectively.[65] Sarcoidosis is less commonly reported in South America, Spain, India, Canada, and the Philippines. There may be a higher susceptibility to sarcoidosis in those with coeliac disease. An association between the two disorders has been suggested.[66]

The differing incidence across the world may be at least partially attributable to the lack of screening programs in certain regions of the world, and the overshadowing presence of other granulomatous diseases, such as tuberculosis, that may interfere with the diagnosis of sarcoidosis where they are prevalent.[53] There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease.[67]

Manifestation appears to be slightly different according to race and sex. Erythema nodosum is far more common in men than in women and in Caucasians than in other races. In Japanese patients, ophthalmologic and cardiac involvement are more common than in other races.[51]

Sarcoidosis is one of the few pulmonary diseases with a higher prevalence in nonsmokers.[68]

Pregnancy[edit]

Sarcoidosis generally does not prevent successful pregnancy and delivery; the endogenous estrogen in pregnancy may even have a slightly beneficial immunomodulatory effect. In most cases, the course of the disease is unaffected by pregnancy, with improvement in a few cases and worsening of symptoms in very few cases.[32]

Autoimmune disorders, including sarcoidosis, are listed as a significant risk factor for developing pre-eclampsia, a hypertensive complication of the second and/or third trimesters of pregnancy.

See also[edit]

References[edit]

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