Sarcoidosis
Overview
 
Sarcoidosis also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells (granulomas) form as nodules in multiple organs. The cause of sarcoidosis is unknown. Granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

s most often appear in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s or the lymph nodes, but virtually any organ can be affected. Normally the onset
Natural history of disease
The natural history of disease refers to a description of the uninterrupted progression of a disease in an individual from the moment of exposure to causal agents until recovery or death. Knowledge of the natural history of disease ranks alongside causal understanding in importance for disease...

 is gradual. Sarcoidosis may be asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

 or chronic
Chronic
Chronic may refer to:* Chronic , a disease that is long-lasting and reoccurring.* Chronic toxicity, a substance with toxic effects after continuous or repeated exposure* The Chronic, a 1992 album by Dr. Dre...

.
Encyclopedia
Sarcoidosis also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells (granulomas) form as nodules in multiple organs. The cause of sarcoidosis is unknown. Granuloma
Granuloma
Granuloma is a medical term for a tiny collection of immune cells known as macrophages. Granulomas form when the immune system attempts to wall off substances that it perceives as foreign but is unable to eliminate. Such substances include infectious organisms such as bacteria and fungi as well as...

s most often appear in the lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...

s or the lymph nodes, but virtually any organ can be affected. Normally the onset
Natural history of disease
The natural history of disease refers to a description of the uninterrupted progression of a disease in an individual from the moment of exposure to causal agents until recovery or death. Knowledge of the natural history of disease ranks alongside causal understanding in importance for disease...

 is gradual. Sarcoidosis may be asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

 or chronic
Chronic
Chronic may refer to:* Chronic , a disease that is long-lasting and reoccurring.* Chronic toxicity, a substance with toxic effects after continuous or repeated exposure* The Chronic, a 1992 album by Dr. Dre...

. It commonly improves or clears up spontaneously. More than 2/3 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. Chronic patients may deal with waxing and waning symptoms over many years.

Signs and symptoms

Sarcoidosis is a systemic disease that can affect any organ. Common symptoms are vague, such as fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

 unchanged by sleep, lack of energy, weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...

, aches and pains, arthritis
Arthritis
Arthritis is a form of joint disorder that involves inflammation of one or more joints....

, dry eyes
Xerophthalmia
Xerophthalmia is a medical condition in which the eye fails to produce tears. It may be caused by a deficiency in vitamin A and is sometimes used to describe that lack, although there may be other causes....

, swelling of the knees, blurry vision, shortness of breath
Dyspnea
Dyspnea , shortness of breath , or air hunger, is the subjective symptom of breathlessness.It is a normal symptom of heavy exertion but becomes pathological if it occurs in unexpected situations...

, a dry hacking cough or skin lesions. Sarcoidosis and cancer may mimic one another, making the distinction difficult. The cutaneous symptoms vary, and range from rash
Rash
A rash is a change of the skin which affects its color, appearance or texture. A rash may be localized in one part of the body, or affect all the skin. Rashes may cause the skin to change color, itch, become warm, bumpy, chapped, dry, cracked or blistered, swell and may be painful. The causes, and...

es and noduli (small bumps) to erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...

 or lupus pernio
Lupus pernio
Lupus pernio is a chronic raised indurated lesion of the skin, often purplish in color. It resembles frostbite as it is seen on ears, cheeks, lips, nose, hands, fingers and forehead. It is pathognomonic of sarcoidosis. Microscopically, it resembles lupus vulgaris...

. It is often asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...

.

The combination of erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...

, bilateral hilar
Hilum of lung
Above and behind the cardiac impression is a triangular depression named the hilum, where the structures which form the root of the lung enter and leave the viscus. These include the pulmonary artery, superiormost on the left lung, the superior and inferior pulmonary veins, lymphatic vessels and...

 lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....

 and arthralgia
Arthralgia
Arthralgia literally means joint pain; it is a symptom of injury, infection, illnesses or an allergic reaction to medication....

 is called Löfgren syndrome
Löfgren syndrome
Löfgren syndrome is a type of acute sarcoidosis that is frequent in Scandinavian, Irish, African and Puerto Rican women.It was characterized in 1953.Some have considered the condition to be imprecisely defined.-Presentation:...

. This syndrome has a relatively good prognosis.

Renal, liver (including portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...

), heart or brain involvement may cause further symptoms and altered functioning.

Lungs

Of individuals with sarcoidosis, 90 percent have an abnormal chest x-ray at some time during their course. Overall, approximately 50 percent develop permanent pulmonary abnormalities and 5 to 15 percent have progressive fibrosis of the lung parenchyma
Parenchyma
Parenchyma is a term used to describe a bulk of a substance. It is used in different ways in animals and in plants.The term is New Latin, f. Greek παρέγχυμα - parenkhuma, "visceral flesh", f. παρεγχεῖν - parenkhein, "to pour in" f. para-, "beside" + en-, "in" + khein, "to pour"...

. Sarcoidosis of the lung is primarily an interstitial lung disease in which the inflammatory process involves the aveoli, small bronchi, and small blood vessels. In acute and subacute cases, the physical examination usually reveals dry rales.

Liver

Although liver biopsy reveals liver involvement in 60 to 90 percent of cases, liver dysfunction is usually not important clinically. Approximately 20-30% have hepatomegaly and/or biochemical evidence of liver involvement. Usually these changes reflect a cholestatic pattern and include an elevated alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...

 level; the bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...

 and aminotransferases are only mildly elevated. Jaundice is rare.

Skin

Sarcoidosis involves the skin in about 25 percent of patients. The most common lesions are erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...

, plaques, maculopapular eruptions, subcutaneous nodules, and lupus pernio
Lupus pernio
Lupus pernio is a chronic raised indurated lesion of the skin, often purplish in color. It resembles frostbite as it is seen on ears, cheeks, lips, nose, hands, fingers and forehead. It is pathognomonic of sarcoidosis. Microscopically, it resembles lupus vulgaris...

. Treatment is not required, since the lesions usually resolve spontaneously in 2 to 4 weeks. Although it may be disfiguring, cutaneous sarcoidosis rarely causes major problems.

Heart

Although cardiac involvement is present in 20% to 30% of patients with sarcoidosis, only about 5% of patients with systemic sarcoidosis are symptomatic.

The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia. Myocardial sarcoidosis can be a rare cause of sudden cardiac death.

Eye

Manifestations in the eye include uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....

, uveoparotitis
Uveoparotitis
Uveoparotitis is a symptom of Sarcoidosis. It describes a chronic inflammation of the parotid gland and uvea. There is also a phenomenon called Waldenström's uveoparotitis. In this case, the symptom is related to Heerfordt's syndrome....

, and retinal inflammation, which may result in loss of visual acuity or blindness.
The combination of anterior uveitis
Uveitis
Uveitis specifically refers to inflammation of the middle layer of the eye, termed the "uvea" but in common usage may refer to any inflammatory process involving the interior of the eye....

, parotitis
Parotitis
Parotitis is an inflammation of one or both parotid glands, the major salivary glands located on either side of the face, in humans. The parotid gland is the salivary gland most commonly affected by inflammation.-Infectious parotitis:...

, VII cranial nerve paralysis and fever is called uveoparotid fever, and is associated with Heerfordt-Waldenstrom syndrome.

Blood

Abnormal clinical blood tests are frequent but not diagnostic. Anemia
Anemia
Anemia is a decrease in number of red blood cells or less than the normal quantity of hemoglobin in the blood. However, it can include decreased oxygen-binding ability of each hemoglobin molecule due to deformity or lack in numerical development as in some other types of hemoglobin...

 occurs in 4-20% of patients with sarcoidosis. Leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

 (due to a reduced number of circulating lymphocytes or lymphopenia) occurs in as many as 40% of patients but is rarely severe. In the absence of splenomegaly
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...

, leukopenia
Leukopenia
Leukopenia is a decrease in the number of white blood cells found in the blood, which places individuals at increased risk of infection....

 may reflect bone marrow involvement, however, the most common mechanism is a redistribution of blood T cells to sites of disease. Other non-specific findings include monocytosis
Monocytosis
Monocytosis is an increase in the number of monocytes circulating in the blood. Monocytes are white blood cells that give rise to macrophages and dendritic cells in the immune system....

, occurring in the majority of sarcoidosis cases , increased hepatic enzymes or alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...

. Hypercalciuria and hypercalcemia are seen in <10% of patients.

Lymph nodes

Lymphadenopathy
Lymphadenopathy
Lymphadenopathy is a term meaning "disease of the lymph nodes." It is, however, almost synonymously used with "swollen/enlarged lymph nodes". It could be due to infection, auto-immune disease, or malignancy....

 is very common in sarcoidosis. Intrathoracic nodes are enlarged in 75 to 90 percent 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
Cervical
In anatomy, cervical is an adjective that has two meanings:# of or pertaining to any neck.# of or pertaining to the female cervix: i.e., the neck of the uterus.*Commonly used medical phrases involving the neck are**cervical collar...

 (the most common head and neck manifestation of the disease ), axillary, epitrochlear, and inguinal nodes. Palpation causes no pain.

Nervous system

All components of the nervous system can be involved in sarcoidosis. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis
Neurosarcoidosis
Neurosarcoidosis refers to sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, involving the central nervous system . It can have many manifestations, but abnormalities of the cranial nerves are the most common...

. Neurologic findings are observed in about 5 percent of patients. Seventh nerve involvement with unilateral facial paralysis is most common. 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
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....

 . Intramedullary sarcoidosis is rare and occurs in less than 1% of cases. There is usually granulomatous involvement of the basal meninges that subsequently affects the cranial nerves. Myelopathy may be the initial clinical presentation of intramedullary neurosarcoidosis
Neurosarcoidosis
Neurosarcoidosis refers to sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, involving the central nervous system . It can have many manifestations, but abnormalities of the cranial nerves are the most common...

.

Exocrine glands

Parotid enlargement is a classic feature of sarcoidosis, but clinically apparent parotid involvement occurs in less than 10 percent of patients. Bilateral involvement is the rule. The gland is usually nontender, firm, and smooth. Xerostomia
Xerostomia
Xerostomia is the medical term for the subjective complaint of dry mouth due to a lack of saliva. Xerostomia is sometimes colloquially called pasties, cottonmouth, drooth, or doughmouth. Several diseases, treatments, and medications can cause xerostomia. It can also be exacerbated by smoking or...

 can occur; other exocrine glands are affected only rarely.

Scalp

Sarcoidosis of the scalp presents with diffuse or patchy hair loss.

Causes

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.

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
BTNL2
Butyrophilin-like protein 2 is a protein that in humans is encoded by the BTNL2 gene.-Further reading:...

; several HLA-DR risk alleles are also being investigated. In persistent sarcoidosis the HLA haplotype HLA-B7
HLA-B7
HLA-B7 is an HLA-B serotype. The serotype identifies the more common HLA-B*07 gene products. B7, previously HL-A7, was one of the first 'HL-A' antigens recognized, largely because of the frequency of B*0702 in Northern and Western Europe and the United States...

-DR15
HLA-DR15
HLA-DR15 is a HLA-DR serotype that recognizes the DRB1*1501 to *1505 and *1507 gene products. DR15 is found at high levels from Ireland to Central Asia. frequencies...

 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
HLA DR3-DQ2
HLA DR3-DQ2 is double serotype that specifically recognizes cells from individuals who carry a multigene HLA DR, DQ haplotype.Certain HLA DR and DQ genes have known involvementin autoimmune diseases. DR3-DQ2, a multigene...

.
Siblings have only a modestly increased risk (hazard ratio 5-6) of developing 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.

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
Propionibacterium acnes
Propionibacterium acnes is a relatively slow growing, typically aerotolerant anaerobic gram positive bacterium that is linked to the skin condition acne; it can also cause chronic blepharitis and endophthalmitis, the latter particularly following intraocular surgery...

 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.
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.

There have also been reports of transmission of sarcoidosis via organ transplant
Organ transplant
Organ transplantation is the moving of an organ from one body to another or from a donor site on the patient's own body, for the purpose of replacing the recipient's damaged or absent organ. The emerging field of regenerative medicine is allowing scientists and engineers to create organs to be...

s.

Vitamin D dysregulation

Sarcoidosis frequently causes an increase in vitamin D
Vitamin D
Vitamin D is a group of fat-soluble secosteroids. In humans, vitamin D is unique both because it functions as a prohormone and because the body can synthesize it when sun exposure is adequate ....

 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
Hypervitaminosis D
Hypervitaminosis D is a state of vitamin D toxicity.The recommended daily allowance is 400 IU per day. Overdose has been observed at 1925 µg/d...

 that may include fatigue
Fatigue (physical)
Fatigue is a state of awareness describing a range of afflictions, usually associated with physical and/or mental weakness, though varying from a general state of lethargy to a specific work-induced burning sensation within one's muscles...

, lack of strength or energy, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....

, metallic taste, temporary memory loss
Memory loss
Memory loss can be partial or total and it is normal when it comes with aging. Sudden memory loss is usually a result of brain trauma and it may be permanent or temporary. When it is caused by medical conditions such as Alzheimers, the memory loss is gradual and tends to be permanent.Brain trauma...

 or cognitive problems. Physiological compensatory responses (e.g., suppression of the parathyroid hormone
Parathyroid hormone
Parathyroid hormone , parathormone or parathyrin, is secreted by the chief cells of the parathyroid glands as a polypeptide containing 84 amino acids...

 levels) may mean the patient does not develop frank hypercalcemia. This condition may be aggravated by high levels of estradiol
Estradiol
Estradiol is a sex hormone. Estradiol is abbreviated E2 as it has 2 hydroxyl groups in its molecular structure. Estrone has 1 and estriol has 3 . Estradiol is about 10 times as potent as estrone and about 80 times as potent as estriol in its estrogenic effect...

 and prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...

 such as in pregnancy, leading to hypercalciuria
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....

 and/or compensatory hypoparathyroidism
Hypoparathyroidism
Hypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...

. High levels of Vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.

Hyperprolactinemia

Prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...

 is frequently increased in sarcoidosis, between 3–32% cases have hyperprolactinemia, this frequently leads to amenorrhea, galactorrhea
Galactorrhea
Galactorrhea or galactorrhoea is the spontaneous flow of milk from the breast, unassociated with childbirth or nursing.Contemporary Maternal-Newborn Nursing Care defines galactorrhea as "nipple discharge." -Causes:...

 or nonpuerperal mastitis
Nonpuerperal mastitis
The term nonpuerperal mastitis describes inflammatory lesions of the breast occurring unrelated to pregnancy and breastfeeding.It is sometimes equated with duct ectasia, but other forms can be described.-Duct ectasia:...

 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.
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. 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. 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
Cytokine
Cytokines are small cell-signaling protein molecules that are secreted by the glial cells of the nervous system and by numerous cells of the immune system and are a category of signaling molecules used extensively in intercellular communication...

 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, a substantial association of thyroid
Thyroid
The thyroid gland or simply, the thyroid , in vertebrate anatomy, is one of the largest endocrine glands. The thyroid gland is found in the neck, below the thyroid cartilage...

 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 of this relation 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. Celiac disease is a condition in which there is a chronic reaction to certain protein chains, commonly referred to as glutens, found in some cereal grains. This reaction causes destruction of the villi in the small intestine, with resulting malabsorption of nutrients.

An association with type IV hypersensitivity
Type IV hypersensitivity
Type IV hypersensitivity is often called delayed type hypersensitivity as the reaction takes two to three days to develop. Unlike the other types, it is not antibody mediated but rather is a type of cell-mediated response....

 has been described. Tests of delayed cutaneous hypersensitivity have been used to measure progression.

Other

While disputed, some cases have been associated with inhalation of the dust
Dust
Dust consists of particles in the atmosphere that arise from various sources such as soil dust lifted up by wind , volcanic eruptions, and pollution...

 from the collapse of the World Trade Center
World Trade Center
The original World Trade Center was a complex with seven buildings featuring landmark twin towers in Lower Manhattan, New York City, United States. The complex opened on April 4, 1973, and was destroyed in 2001 during the September 11 attacks. The site is currently being rebuilt with five new...

 after the September 11, 2001 attacks
September 11, 2001 attacks
The September 11 attacks The September 11 attacks The September 11 attacks (also referred to as September 11, September 11th or 9/119/11 is pronounced "nine eleven". The slash is not part of the pronunciation...

. See Health effects arising from the September 11, 2001 attacks
Health effects arising from the September 11, 2001 attacks
There has been growing concern over the health effects arising from the September 11 attacks in the Financial District of Lower Manhattan. Within seconds of the collapse of the World Trade Center, building materials, electronic equipment, and furniture were pulverized and spread over the area.In...

 for more information.

Chicago comedian, Bernie Mac
Bernie Mac
Bernard Jeffrey McCullough , better known by his stage name, Bernie Mac, was an American actor and comedian. Born and raised on the South Side of Chicago, Mac gained popularity as a stand-up comedian. He joined comedians Steve Harvey, Cedric the Entertainer, and D. L...

, suffered from sarcoidosis and died of pneumonia as a result of his compromised immune system. Reggie White
Reggie White
Reginald Howard "Reggie" White was a professional American football player. He played 15 seasons as a defensive end in the National Football League for the Philadelphia Eagles, Green Bay Packers and Carolina Panthers, becoming one of the most decorated players in NFL history...

, a former standout National Football League player, also suffered from sarcoidosis, and the disease played a major role in his death.

Pathophysiology

Granulomatous inflammation is characterized primarily by accumulation of monocyte
Monocyte
Monocytes are a type of white blood cell and are part of the innate immune system of vertebrates including all mammals , birds, reptiles, and fish. Monocytes play multiple roles in immune function...

s, macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...

s and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-alpha, IFN-gamma, and IL-12
IL-12
IL-12 or IL 12 can refer to:Medicine* Interleukin 12Airplanes* Ilyushin Il-12Politics* Illinois' 12th congressional districtRoads* Illinois Route 12...

, characteristic of a Th1
T helper cell
T helper cells are a sub-group of lymphocytes, a type of white blood cell, that play an important role in the immune system, particularly in the adaptive immune system. These cells have no cytotoxic or phagocytic activity; they cannot kill infected host cells or pathogens. Rather, they help other...

-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, 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
Anergy
Anergy is a term in immunobiology that describes a lack of reaction by the body's defense mechanisms to foreign substances, and consists of a direct induction of peripheral lymphocyte tolerance. An individual in a state of anergy often indicates that the immune system is unable to mount a normal...

. 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.

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
Etanercept
Etanercept is a drug that treats autoimmune diseases by interfering with the tumor necrosis factor by acting as a TNF inhibitor. Pfizer describes in a SEC filing that the drug is used to treat rheumatoid, juvenile rheumatoid and psoriatic arthritis, plaque psoriasis and ankylosing spondylitis...

.

Diagnosis

Diagnosis of sarcoidosis is often a matter of exclusion. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve chest X-ray
Chest X-ray
In medicine, a chest radiograph, commonly called a chest X-ray , is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures...

, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound and endoscopic ultrasound
Endoscopic ultrasound
Endoscopic ultrasound or echo-endoscopy is a medical procedure in endoscopy is combined with ultrasound to obtain images of the internal organs in the chest and abdomen. It can be used to visualize the wall of these organs, or to look at adjacent structures...

 with FNA of mediastinal lymph nodes(EBUS FNA). Tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...

 from biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...

 of lymph nodes is subjected to both flow cytometry
Flow cytometry
Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and/or chemical...

 to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain
Gomori methenamine silver stain
In pathology, the Grocott's methenamine silver stain, abbreviated GMS, is a popular staining method in histology.It is used widely as a screen for fungal organisms...

) to rule out microorganisms and fungi. Angiotensin-converting enzyme
Angiotensin-converting enzyme
Angiotensin I-converting enzyme , an exopeptidase, is a circulating enzyme that participates in the body's renin-angiotensin system , which mediates extracellular volume , and arterial vasoconstriction...

 blood levels are used in diagnosis and monitoring of sarcoidosis.

Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodule
Rheumatoid nodule
A rheumatoid nodule is a local swelling or tissue lump, usually rather firm to touch, like an unripe fruit, which occurs almost exclusively in association with rheumatoid arthritis. Very rarely rheumatoid nodules occur as 'rheumatoid nodulosis' in the absence of arthritis...

s, Wegener's granulomatosis
Wegener's granulomatosis
Wegener's granulomatosis , more recently granulomatosis with polyangiitis , is an incurable form of vasculitis that affects the nose, lungs, kidneys and other organs. Due to its end-organ damage, it is life-threatening and requires long-term immunosuppression...

, varicella infection, and atypical infections such as mycobacterium avium complex, cytomegalovirus, and cryptococcus.
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.

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. The vital capacity
Vital capacity
Vital capacity is the maximum amount of air a person can expel from the lungs after a maximum inspiration. It is equal to the inspiratory reserve volume plus the tidal volume plus the expiratory reserve volume....

 (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
Spirometry
Spirometry is the most common of the pulmonary function tests , measuring lung function, specifically the measurement of the amount and/or speed of air that can be inhaled and exhaled...

 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

Although patients with type I x-rays tend to have the acute or subacute, reversible form of the disease while those with types II and III 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.

Investigations to assess involvement of other organs frequently involve electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

, ocular examination by an ophthalmologist, liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...

, renal 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

Classification

Sarcoidosis may be divided into the following types:
  • Annular sarcoidosis
    Annular sarcoidosis
    Annular sarcoidosis is a cutaneous condition characterized by papular skin lesions arranged in annular patterns, usually with a red-brown hue....

  • Erythrodermic sarcoidosis
    Erythrodermic sarcoidosis
    Erythrodermic sarcoidosis is a cutaneous condition and very rare form of sarcoidosis....

  • Ichthyosiform sarcoidosis
    Ichthyosiform sarcoidosis
    Ichthyosiform sarcoidosis is a cutaneous condition resembling ichthyosis vulgaris or acquired ichthyosis, with fine scaling usually on the distal extremities, by caused by sarcoidosis....

  • Hypopigmented sarcoidosis
    Hypopigmented sarcoidosis
    Hypopigmented sarcoidosis is a cutaneous condition characterized by areas of hypopigmented skin. It is usually diagnosed in darkly pigmented races and may be the earliest sign of sarcoidosis....

  • Löfgren syndrome
    Löfgren syndrome
    Löfgren syndrome is a type of acute sarcoidosis that is frequent in Scandinavian, Irish, African and Puerto Rican women.It was characterized in 1953.Some have considered the condition to be imprecisely defined.-Presentation:...

  • Lupus pernio
    Lupus pernio
    Lupus pernio is a chronic raised indurated lesion of the skin, often purplish in color. It resembles frostbite as it is seen on ears, cheeks, lips, nose, hands, fingers and forehead. It is pathognomonic of sarcoidosis. Microscopically, it resembles lupus vulgaris...

  • Morpheaform sarcoidosis
    Morpheaform sarcoidosis
    Morpheaform sarcoidosis is a very rare cutaneous condition characterized by specific cutaneous skin lesions of sarcoidosis accompanied by substantial fibrosis, simulating morphea....

  • Mucosal sarcoidosis
    Mucosal sarcoidosis
    Mucosal sarcoidosis is a cutaneous condition characterized by pinhead-sized papules that may be grouped and fused together to form a flat plaque....

  • Neurosarcoidosis
    Neurosarcoidosis
    Neurosarcoidosis refers to sarcoidosis, a condition of unknown cause featuring granulomas in various tissues, involving the central nervous system . It can have many manifestations, but abnormalities of the cranial nerves are the most common...

  • Papular sarcoid
    Papular sarcoid
    Papular sarcoid is a cutaneous condition characterized by papules, which are the most common morphology of cutaneous sarcoidosis....

  • Scar sarcoid
    Scar sarcoid
    Scar sarcoid is a cutaneous condition characterized by infiltration and elevation of tattoos and old flat scars due to sarcoidosis....

  • Subcutaneous sarcoidosis
    Subcutaneous sarcoidosis
    Subcutaneous sarcoidosis is a cutaneous condition characterized by numerous 0.5- to 0.3-cm deep-seated nodules on the trunk and extremities....

  • Systemic sarcoidosis
  • Ulcerative sarcoidosis
    Ulcerative sarcoidosis
    Ulcerative sarcoidosis is a cutaneous condition affecting roughly 5% of people with sarcoidosis....


Treatment

Between 30 and 70% of patients do not require therapy. For patients presenting with lung symptoms, unless the respiratory impairment is devastating, active pulmonary sarcoidosis is observed usually without therapy for 2 to 3 months; if the inflammation does not subside spontaneously, therapy is instituted. Corticosteroid
Corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex. Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation, carbohydrate metabolism, protein catabolism, blood electrolyte...

s, most commonly prednisolone
Prednisolone
Prednisolone is the active metabolite of prednisone, which is also used as a drug.-Uses:Prednisolone is a corticosteroid drug with predominant glucocorticoid and low mineralocorticoid activity, making it useful for the treatment of a wide range of inflammatory and auto-immune conditions such as...

, 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. 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 immunosuppressant
Immunosuppressant
An immunosuppressant is any substance that performs immunosuppression of the immune system. They may be either exogenous, as immunosuppressive drugs, or endogenous, as ,e. g., testosterone...

s on the natural history is unclear.

Severe symptoms are generally treated with steroids, and steroid-sparing agents such as azathioprine
Azathioprine
Azathioprine is a purine analogue immunosuppressive drug. It is used to prevent organ rejection following organ transplantation and to treat a vast array of autoimmune diseases, including rheumatoid arthritis, pemphigus, inflammatory bowel disease , multiple sclerosis, autoimmune hepatitis, atopic...

 and methotrexate
Methotrexate
Methotrexate , abbreviated MTX and formerly known as amethopterin, is an antimetabolite and antifolate drug. It is used in treatment of cancer, autoimmune diseases, ectopic pregnancy, and for the induction of medical abortions. It acts by inhibiting the metabolism of folic acid. Methotrexate...

 are often used. Rarely, cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....

 has also been used. As the granulomas are caused by collections of immune system cells, particularly T cell
T cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...

s, there has been some early indications of success using immunosuppressants, interleukin-2 inhibitors or anti-tumor necrosis factor-alpha treatment (such as infliximab
Infliximab
Infliximab is a monoclonal antibody against tumour necrosis factor alpha . It is used to treat autoimmune diseases. Remicade is marketed by Janssen Biotech, Inc...

). Unfortunately, none of these has provided reliable treatment, and there can be significant side effects such as an increased risk of reactivating latent tuberculosis
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

. Anti-tumor necrosis factor-alpha treatment with etanercept in rheumatoid arthritis has been observed to cause sarcoidosis.

Because sarcoidosis can affect multiple organ systems, follow-up on a patient with sarcoidosis should always include an electrocardiogram
Electrocardiogram
Electrocardiography is a transthoracic interpretation of the electrical activity of the heart over a period of time, as detected by electrodes attached to the outer surface of the skin and recorded by a device external to the body...

, ocular examination by an ophthalmologist, liver function tests
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...

, 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.

Prognosis

The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis
Pulmonary fibrosis
Pulmonary fibrosis is the formation or development of excess fibrous connective tissue in the lungs. It is also described as "scarring of the lung".-Symptoms:Symptoms of pulmonary fibrosis are mainly:...

 and death. Approximately half of the cases resolve without treatment or can be cured within 12–36 months and most within 5 years. Some cases persist several decades. Where the heart is involved, the prognosis is poor. Patients with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...

, malignant lymphoma
Lymphoma
Lymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...

s, and cancer in other organs known to be affected in sarcoidosis. In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma
Non-Hodgkin lymphoma
The non-Hodgkin lymphomas are a diverse group of blood cancers that include any kind of lymphoma except Hodgkin's lymphomas. Types of NHL vary significantly in their severity, from indolent to very aggressive....

. This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. Sarcoidosis can also follow cancer or occur concurrently with cancer. There have been reports of hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia is an uncommon hematological malignancy characterized by an accumulation of abnormal B lymphocytes. It is usually classified as a sub-type of chronic lymphoid leukemia...

, acute myeloid leukemia
Acute myeloid leukemia
Acute myeloid leukemia , also known as acute myelogenous leukemia, is a cancer of the myeloid line of blood cells, characterized by the rapid growth of abnormal white blood cells that accumulate in the bone marrow and interfere with the production of normal blood cells. AML is the most common acute...

, and acute myeloblastic leukemia
Acute myeloblastic leukemia
Acute myeloblastic leukemia is a form of myeloid leukemia affecting myeloblasts.More specifically, it can refer to:* Minimally differentiated acute myeloblastic leukemia - * Acute myeloblastic leukemia without maturation -...

  associated with sarcoidosis.

Epidemiology

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.

Sarcoidosis occurs throughout the world in all races with an average incidence of 16.5/100,000 in men and 19/100,000 in women. The disease is most prevalent in Northern European countries, and the highest annual incidence of 60/100,000 is found in Sweden and Iceland. In the United States, sarcoidosis is more common in people of African descent than Caucasians
Caucasian race
The term Caucasian race has been used to denote the general physical type of some or all of the populations of Europe, North Africa, the Horn of Africa, Western Asia , Central Asia and South Asia...

, with annual incidence reported as 35.5 and 10.9/100,000, respectively. 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
Coeliac disease
Coeliac disease , is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy onward...

. An association between the two disorders has been suggested.

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
Tuberculosis
Tuberculosis, MTB, or TB is a common, and in many cases lethal, infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Tuberculosis usually attacks the lungs but can also affect other parts of the body...

, that may interfere with the diagnosis of sarcoidosis where they are prevalent.
There may also be differences in the severity of the disease between people of different ethnicities. Several studies suggest that the presentation in people of African origin may be more severe and disseminated than for Caucasians, who are more likely to have asymptomatic disease.

Manifestation appears to be slightly different according to race and sex. Erythema nodosum
Erythema nodosum
Erythema nodosum is an inflammation of the fat cells under the skin characterized by tender red nodules or lumps that are usually seen on both shins...

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.

Sarcoidosis is one of the few pulmonary diseases with a higher prevalence in non-smokers.

In pregnancy

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 sarcoidosis is unaffected by pregnancy; there is improvement in a few cases and worsening of symptoms in very few cases.

External links

The source of this article is wikipedia, the free encyclopedia.  The text of this article is licensed under the GFDL.
 
x
OK