Sarcoidosis = A disease in which abnormal collections of chronic inflammatory cells (granulomas) form as nodules in multiple organs.

The cause is unknown. Granulomas (of the non-caseating type) often appear in the lungs or lymph nodes, but any organ can be affected. Lung scarring or infection may lead to respiratory failure and death. - Normally the onset is gradual. - More than 2/3 of people with lung - May be asymptomatic or chronic. sarcoidosis have no symptoms after 9 - Commonly improves or clears up years. spontaneously. - About 50% have relapses. - About 10% develop serious disability. Chronic patients may deal with waxing and waning symptoms over many years.
Neurosarcoidosis 5% Vague: Fatigue despite sleep Lack of energy Weight Loss Aches & Pains Arthritis Parotid Enlargement Dry Eyes Swelling of knees Blurry vision SOB Dry Hacking cough Skin Lesions

Lungs: 90% have abnormal CXR at some point 50% develop permanent abnormalities 5-15% have progressive parenchymal fibrosis Primarily interstitial lung disease o Alveoli o Small bronchi o Small blood vessels Acute/subacute Dry crackles Liver: NOT clinically significant 20-30% hepatomegaly or biochem derangements o Cholestatic picture ALP
Bilirubin Aminotransf

Heart 20-30%, but only 5% symptomatic Conduction abnormalities (asympt)

Jaundice is rare

Skin: 25% Erythema nodosum - PAINFUL Plaques Maculopapular eruptions S/C nodules Lupus Pernio Usually resolve in 2-4 weeks Lymph Nodes Lymphadenopathy - common o Often hilar nodes o (paratracheal) o Peripheral common o Cervical, Axillary o Epitrochlear o Inguinal

Also: Rashes Noduli

Blood Anaemia 4-20% Leukopenia 40% rarely severe) Monocytosis Increased hepatic enzymes (ALP) Hypercalciuria Hypercalcaemia

Causes: Exact Cause unknown The current working hypothesis is that in genetically susceptible individuals sarcoidosis is caused through alteration in immune response after exposure to an environmental, occupational, or infectious agent

Genetics BTNL2 & Several HLA-DR risk alleles. In persistent sarcoidosis: HLA-B7-DR15 In non-persistent disease: HLA DR3-DQ2. Siblings have only a modestly increased risk of developing sarcoidosis thus 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 None of the known associations is specific enough to suggest a direct causative role. Propionibacterium acnes found in bronchoalveolar lavage of 70% patients but can be also found in 23% of controls. Mycobacteria is present in 26.4% of cases, possible publication bias Organ transplant association Vitamin D dysregulation as a cause Sarcoidosis frequently causes an increase in vitamin D production outside the kidney. Macrophages inside the granulomas convert vitamin D to its active form, resulting in elevated levels of the hormone 1,25-dihydroxyvitamin D and symptoms of hypervitaminosis D: - fatigue, - lack of strength or energy, - irritability, - metallic taste, - temporary memory loss - cognitive problems. Physiological compensatory suppression of PTH levels may mean the patient does not develop frank hypercalcemia. Hypervitaminosis D may be aggravated by high levels of estradiol and prolactin such as in pregnancy, leading to hypercalciuria and/or compensatory hypoparathyroidism. High levels of Vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.

Hyperprolactinemia Prolactin frequently increased in sarcoidosis This frequently leads to amenorrhea, galactorrhea or nonpuerperal mastitis in women. Prolactin also has a broad spectrum of effects on the immune system - Increased prolactin associated with disease activity/may exacerbate symptoms in many autoimmune diseases - Treatment with prolactin lowering medication has been shown effective in some cases. 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. The reasons for increased prolactin levels in sarcoidosis are uncertain. It has been observed that prolactin is produced by T-lymphocytes in some autoimmune disorders in amounts high enough to affect the feedback by the hypothalamic dopaminergic system. 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. It may also be a consequence of renal disease or treatment with steroids. Neurosarcoidosis may occasionally cause hypopituiarism but has not been reported to cause hyperprolactinemia. Thyroid disease In women, an 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 it appears that autoimmunity is very important in the pathogenesis of thyroid disease in this population. Thyroid granulomatosis on the other hand is uncommon Autoimmune Association of autoimmune disorders has been frequently observed. The exact mechanism is not known but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence. Sarcoidosis has been associated with celiac disease. An association with type IV hypersensitivity has been described. Tests of delayed cutaneous hypersensitivity have been used to measure progression.

Pathophysiology Accumulation of monocytes, macrophages and activated T-lymphocytes, Increased in inflammatory mediators, TNF-alpha, IFN-gamma, and IL-12, o Characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Results in Granulomatous inflammation Sarcoidosis has paradoxical effects on inflammatory processes: - Increased macrophage and CD4 helper T-cell activation resulting in accelerated inflammation, - However, immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypo- activity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. It appears that regulatory T-lymphocytes in the periphery of granulomas suppress IL-2 secretion which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses. While it is widely believed that TNF-alpha plays an important role in the formation of granulomas, it was observed that sarcoidosis can be triggered by treatment with the TNF-alpha antagonist etanercept.