SARCOIDOSIS 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 twothirds 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 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 Lfgren 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 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] Liver Although liver biopsy reveals liver involvement in 60 to 90% of tested cases, liver dysfunction is usually not clinically significant. About 2030% 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 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 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 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 HeerfordtWaldenstrom syndrome. (D86.8) Development of scleral nodule associated with sarcoidosis have been observed.[12] Blood 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 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

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

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% patients and is associated with disease activity; however, it can be also found in 23% of controls.[26][27] A recent metaanalysis 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 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 25hydroxyvitamin D to its active form, resulting in elevated levels of the hormone 1,25dihydroxyvitamin 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 immunesystem dysfunctions which tie into the sarcoid condition. Hyperprolactinemia 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 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 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. An association with type IV hypersensitivity has been described.[39] Tests of delayed cutaneous hypersensitivity have been used to measure progression.[40] Other 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 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 (Thelper 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