Types
Sarcoidosis may be divided into the following types:[6]:708-11
-
- Annular sarcoidosis
- Erythrodermic sarcoidosis
- Ichthyosiform sarcoidosis
- Hypopigmented sarcoidosis
- Löfgren syndrome
- Lupus pernio
- Morpheaform sarcoidosis
- Mucosal sarcoidosis
- Neurosarcoidosis
- Papular sarcoid
- Scar sarcoid
- Subcutaneous sarcoidosis
- Systemic sarcoidosis
- Ulcerative sarcoidosis
Signs and symptoms
Sarcoidosis is a systemic disease that can affect any organ. Common symptoms are vague, such as fatigue unchanged by sleep, lack of energy, weight loss, aches and pains, arthralgia, dry eyes, 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 or lupus pernio. It is often asymptomatic.
The combination of erythema nodosum, bilateral hilar lymphadenopathy and arthralgia is called Löfgren syndrome. This syndrome has a relatively good prognosis.
Renal, liver (including portal hypertension), heart[8] or brain involvement may cause further symptoms and altered functioning. Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis.
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)
Sarcoidosis of the scalp presents with diffuse or patchy hair loss.[6]:762
Investigations
Hypercalcemia (high calcium levels) and its symptoms may be the result of excessive conversion of vitamin D to its active form by epithelioid macrophages.
Sarcoidosis most often manifests as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch). The disease typically limits the amount of air drawn into the lungs, but produces higher than normal expiratory flow ratios. The vital capacity (full breath in, to full breath out) is decreased, and most of this air can be blown out in the first second. This means the FEV1/FVC ratio is increased from the normal of about 80%, to 90%. 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.
Chest X-ray changes are divided into four stages
- Stage 1 bihilar lymphadenopathy
- Stage 2 bihilar lymphadenopathy and reticulonodular infiltrates
- Stage 3 bilateral pulmonary infiltrates
- Stage 4 fibrocystic sarcoidosis typically with upward hilar retraction, cystic & bullous changes
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. In female patients sarcoidosis is significantly associated with hypothyroidism, hyperthyroidism and other thyroid diseases, hence close surveillance of thyroid function is recommended [9]
Causes and pathophysiology
The exact cause of sarcoidosis is not known. 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.[10]
Anergy
Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by 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 sarcoid granulomas suppress IL-2 secretion which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.[11]
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.[12][13]
Genetic associations
Investigations of genetic susceptibility yielded many candidate genes but only few were confirmed by further investigations and no reliable genetic markers are known. Currently most interesting candidate gene is BTNL2, several HLA-DR risk alleles are also investigated.[14] In persistent sarcoidosis the HLA haplotype HLA-B7-DR15 are either cooperating in disease or another gene between these two loci is associated. In non-persistent disease there is a strong genetic association with HLA DR3-DQ2.[15] Siblings have only a modestly increased risk (hazard ratio 5-6) to develop the disease, indicating that 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.
[edit] 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.[16][17] A recent meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, however the meta-analysis also detected a possible publication bias, so the results need further confirmation.[18][19]
There have also been reports of transmission of sarcoidosis via organ transplants.[20]
Vitamin D dysregulation
Sarcoidosis frequently causes a dysregulation of vitamin D production with an increase in extrarenal (outside the kidney) production.[21] Specifically, 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 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.[22] High levels of Vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.
The connection between Vitamin D dysregulation, its effects on immune function, and how the combined effect might mediate sarcoidosis, is currently being explored by Dr. Trevor Marshall. The theory which Dr. Marshall is currently researching via a protocol (the Marshall Protocol) under FDA oversight, asserts that L-form or cell wall deficient bacteria infect the body, and evade the immune system by inducing or enhancing this Vitamin D disregulation, which in turn suppresses the body's immune response to said bacterial infection. Dr. Marshall's research is highly controversial, and the Marshall Protocol's suggestion that people should avoid all sources of vitamin D contradicts a vast body of medical knowledge concerning the benefits of vitamin D. No research about the efficacy of the Marshall Protocol has been published in a medical journal. Marshall is not a medical doctor; his doctorate is in electrical engineering.[23]
Hyperprolactinemia
Prolactin is frequently increased in sarcoidosis, between 3–32% cases have hyperprolactinemia [24], 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 and treatment with prolactin lowering medication has been shown effective in some cases. [25] 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[22]. 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 hitherto 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 [26] . 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 [27] . 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.
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