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Photograph of a Lung with Sarcoidosis

Image: “Sarcoidosis – Honeycombing: Prominent honeycombing is present in the lower lobes accompanied by fibrosis and some honeycombing in the upper lungs. ” by Yale Rosen. Licence: CC BY-SA 2.0


Definition of Sarcoidosis

Sarcoidosis—A multisystem disease

CT Scan of Sarcoidosis

Image: Computed tomographic (CT) scan of stage II sarcoidosis (indicated by arrows). By Hellerhoff. License: CC BY-SA 3.0.

Sarcoidosis is a multisystem disease whose genesis is not yet completely known and that is characterized by noncaseating granulomas in the affected organs. The main manifestations of this disease occur in the lungs and the hilar lymph nodes. It is important to differentiate between acute sarcoidosis (which includes Löfgren’s syndrome, a special form of the disease) and chronic sarcoidosis. It is also important to understand that acute and chronic sarcoidosis progress differently, usually independently of one another. The chronic form of this disease does not follow the acute form of the disease, as is typical with many other illnesses.

Epidemiology of Sarcoidosis

Sarcoidosis as an interstitial lung disease

Sarcoidosis is among the most frequent interstitial lung diseases, with an annual incidence of 10 in 100,000 population in Western Europe. While considering this number, one has to assume that the number of individuals who have the disease but are not diagnosed is high. Sarcoidosis usually peaks between the ages of 20 and 40 and affects women slightly more frequently than men, especially the acute form of the disease.

Note: In typical case studies involving Löfgren’s syndrome, it is usually a young woman who is affected by the disease.

Etiology of Sarcoidosis

Causes of sarcoidosis

Crystallographic structure of HLA-DQA1 complexed with HLA-DQB1 and HCRT (magenta)

Image: Crystallographic structure of HLA-DQA1 (cyan) complexed with HLA-DQB1 (green) and xxxxx (HCRT) (magenta) based on PDB 1uvq. By Boghog. License: Public domain.

The cause of sarcoidosis is not yet known. Various theories, however, describe a multifactor genesis in which both genetic predisposition and certain environmental factors seem to be relevant. In many cases, family members of an affected patient also have the disease. Furthermore, studies have shown that a mutation of the gene BTNL2, as well as the HLA-DQB1 variant of the gene HLA, are associated with an increased risk for the disease.

The increased occurrence of the disease among hospital nursing staff members, the role of bacterial nucleic acids, and evidence of inhalation of talc or aluminum gathered from the patient’s medical history all point to the influence of many environmental factors.

Pathology and Pathophysiology of Sarcoidosis

Sarcoidosis on a cellular level

Histology of Sarcoidosis

Image: Sarcoidosis. By Leslie Ko. License: CC BY 2.0.

Immunologic hyperactivity occurs and is caused by a disturbance of T cell function and increased B cell activity. Macrophages accumulate locally and release mediators, which, in turn, cause those macrophages to change into epithelial cells. Some of these epithelial cells merge to become giant Langerhans cells. Lymphocyte accumulation occurs, i.e. they are surrounded by lymphocytes, and the result is referred to as a granuloma. The granulomas occurring within the scope of sarcoidosis do not show signs of necrosis in the center, which is why they are referred to as noncaseating granulomas. Although this information may not be very relevant during the examination, one may come across this in clinical practice, when a patient may want to know about this in more detail. Within the aforementioned giant cells, shell-shaped calcified inclusions can be found here and there, the so-called Schaumann bodies. These were named after J. N. Schaumann, who was the first to recognize that sarcoidosis is a systemic disease that can attack several organs and not only the skin, which had been the theory until that time.

Note: Histologically, in cases of sarcoidosis, noncaseating granulomas are present, whereas in cases of tuberculosis, the granulomas are caseating.

Symptoms of Sarcoidosis

General symptoms of sarcoidosis

While it would be best to further differentiate between acute and chronic sarcoidosis, there are some general symptoms displayed in many patients with sarcoidosis, including the following:

  • Fatigue and exhaustion
  • Fever
  • Weight loss
  • Night sweats

Acute sarcoidosis

In acute sarcoidosis (10% of cases), the fever is frequently high. Usually, the skin, lymph nodes, and joints (in cases of polyarthritis) are affected. An acute attack on the lungs manifests itself as dyspnea and cough and even thoracic pain. A special form of the disease is Löfgren’s syndrome. The following triad of symptoms of Löfgren’s syndrome is a popular topic for exams:

  • Polyarthritis (usually affects the ankle joints)
  • Bilateral hilar lymphadenopathy
  • Erythema nodosum (especially affects the extensor sides of the lower legs)

Chronic sarcoidosis and study table

Chronic sarcoidosis usually progresses slowly with few symptoms, which is why it is usually diagnosed by accident or so late in the progression that there is already structural damage to organs.

The following is an overview of the key locations where the disease manifests itself, as well as the symptoms associated with it.

Location of the manifestation and frequency Symptoms Image
Lungs: very frequently, ~ 95% In many cases, there are no symptoms at the beginning of the infection. It frequently happens that there is an astonishing discrepancy between the patient being in good clinical condition and the objective findings. (In many cases, the disease is found by accident when chest X-rays are obtained.) Dry cough and exertional dyspnea may occur as the disease progresses. Pulmonary hypertension and even pulmonary heart disease (cor pulmonale) are the most feared complications; these are caused by pulmonary fibrosis.

Sarcoidosis CT scan

Image: CT scan of sarcoidosis. By Hellerhoff. License: CC BY-SA 3.0.

Lymphoid organs: ~ 90% Lymph node enlargement, especially in the intrathoracic area (bilateral hilar), occurs in sarcoidosis, as well as peripheral lymph node enlargement. However, the enlargements may occur in the cervical or axillary region, and this should definitely be considered during the clinical examination.

Sarcoidosis_lymph_node_biopsy

Image: Histopathologic image of sarcoidosis. By KGH. License: CC BY-SA 3.0.

Liver: ~ 80% Elevated liver enzymes and, in some cases, hepatomegaly may be found. Clinically, there are usually no symptoms.
Joints: ~ 40% Joint pain and swollen joints occur frequently. In rare cases, the corresponding muscles are affected as well.
Skin: ~ 30% The typical clinical picture in cases of skin infection is erythema nodosum (an inflammation of the subcutaneous fat tissue in the form of red nodules that turn blue, especially on the extensor sides of the lower legs and are very painful) as well as lupus pernio (fibroid skin sarcoidosis that frequently affects extensive areas of the nose and cheeks and is accompanied by significant scar formation).
Photo of Erythema nodosum

Image: Erythema nodosum. By Xxxxx. License: Xxxxx.

Lupus_pernio in the face

Image: Lupus pernio. By M. Sand, D. Sand, C. Thrandorf, V. Paech, P. Altmeyer, and F. G. Bechara. License: CC BY 2.0.

Eyes: The frequency fluctuates between 25% and 80%, depending on the location In most cases in which sarcoidosis attacks the eyes, iridocyclitis or uveitis can be found. Calcium deposits in connective tissue or the cornea, tear duct enlargement, or retinal vasculitis may also occur.
Heart: ~ 25% Because the left ventricle, as well as the septum, is affected in many cases, cardiac arrhythmia, with an increased risk of sudden cardiac death, may occur during progression of the disease. Atrioventricular block formation, left ventricular insufficiency, and pericardial effusion have been reported.
Bones Sarcoidosis may attack the bones as well, causing, among other things, cystic changes in the phalanges of the fingers. This condition is referred to as Jüngling’s disease, which is very rare. Nevertheless, or possibly because of that very fact, this disease has been included in questions posed in medical exams.

X-Ray of Cysts in den Phalanges

Image: X-rays of cysts in the phalanges. By Xxxxx. License: xxxxx.

Nervous system In cases of infection of the nervous system, facial paralysis, diabetes insipidus, hypopituitarism, or granulomatous meningitis may occur. In 10% of cases, the peripheral nervous system is affected. In rare cases, psychiatric symptoms have been observed. The combination of facial paralysis, uveitis, and parotitis is called Heerfordt’s syndrome.
Other organs:
< 6%
The spleen, kidney, parotid gland, or gastrointestinal tract, for instance, are not as affected as other areas of the body.

CT Scan of Sarcoidosis in the Spleen

Image: CT showing sarcoidosis of the spleen. By Hellerhoff. License: CC BY-SA 3.0.

Diagnosis of Sarcoidosis

Diagnosing sarcoidosis in the lab

After clinical findings have been established, laboratory tests may reveal further indications that may support the suspected diagnosis of sarcoidosis.

In acute cases of the disease, the inflammatory parameters are usually significantly elevated (especially the erythrocyte sedimentation rate, or ESR).

In chronic cases of sarcoidosis, approximately half of the patients have elevated immunoglobulin G (IgG) levels. Furthermore, calcium levels in blood or urine may be elevated because the epithelial cells produce vitamin D. In some cases, leukocytopenia (leukopenia) or lymphocytopenia (lymphopenia) may occur. To monitor the activity parameters and to control progression of the disease, either an angiotensin-converting enzyme (ACE) or the soluble interleukin-2 (IL-2) receptor are frequently used. In cases of high disease activity, both of these are elevated; during remission or with successful therapy, the levels normalize.

Diagnosing sarcoidosis using radiology

The next step in testing for sarcoidosis should be obtaining chest X-rays. Depending on the results of these X-rays, one can classify chronic sarcoidosis into five different stages, according to Mitchell and Scadding:

Stages of sarcoidosis Radiographic correlate
Stage 0 Normal radiographic findings (positive findings on bronchoalveolar lavage or a rare case of pure extrapulmonary sarcoidosis)
Stage I Enlarged bilateral hilar lymph nodes only (these findings are usually present in acute cases of sarcoidosis as well)
Stage II Enlarged bilateral hilar lymph nodes with pulmonary involvement (increased reticulonodular, pulmonary infiltrates)
Stage III Pulmonary involvement without enlarged lymph nodes
Stage IV Advanced, irreversible pulmonary fibrosis
X-Ray of Bihilary lymphadenopathy

Image: X-ray appearance of bilateral hilar lymphadenopathy. By Xxxxx. License: Xxxxx.

In cases of unclear or not quite specific radiologic findings, but with the presence of typical clinical signs, it may be necessary to follow up with high-resolution CT (HRCT). This scan will show changes in pulmonary structure at a less advanced stage than chest X-rays. Interlobular septal thickening and fine nodular densification are signs of fibrotic changes in pulmonary tissue.

Transbronchial biopsy and histology in cases of sarcoidosis

Histologic examination of affected tissue is another important step in diagnosing sarcoidosis. The results of a biopsy can prove the presence of noncaseating granulomas or can histologically rule out other differential diagnoses. In cases of pulmonary tissue involvement, it would be appropriate to perform a bronchoscopy with transbronchial biopsy and bronchoalveolar lavage (BAL). The latter may reaffirm typical findings. In cases of active sarcoidosis, the CD4/CD8 ratio is > 5 (the higher the ratio, the more probable the diagnosis) and a shift of the T helper/T suppressor ratio in favor of the T helper cells can be seen; this leads to alveolitis, which is caused by the lymphocytes.

Hint: The CD4/CD8 ratio also plays a role in diagnosing other diseases. The CD4/CD8 ratio is also lower in cases of human immunodeficiency virus (HIV) infections, for instance.

Sarcoidosis and the pulmonary function test

Pulmonary function may reveal signs of restrictive ventilation disturbance, especially if pulmonary fibrosis has already begun. Reduced oxygen diffusion capacity is a very early and sensitive parameter for sarcoidosis activity.

Cardiologic diagnosis of sarcoidosis

As mentioned above, sarcoidosis may attack many organs. Therefore, it would be prudent to also follow up with cardiac diagnostic tests such as electrocardiography (ECG) and echocardiography and an ophthalmologic examination, and possibly even other specialist consultations, should such a suspicion exist.

Fragmented QRS in a 52-year-old patient with cardiac sarcoidosis

Image: Fragmented QRS in a 52-year-old patient with cardiac sarcoidosis. By Y. Take and H. Morita. License: CC BY 2.5.

Assessing chronic sarcoidosis activity

First and foremost, to assess disease activity, especially in cases of chronic sarcoidosis, observing the progression of the clinical signs as well as the laboratory findings (such as ACE, soluble IL-2 receptor, inflammatory parameters, and calcium levels) is appropriate. The parameters of the pulmonary function test (diffusion capacity, in particular) are suitable for monitoring the progression. Depending on symptoms, the corresponding organ-specific changes must be monitored regularly (i.e. chest X-rays in cases of pulmonary involvement and bilateral hilar lymphadenopathy or an ECG in cases of cardiac arrhythmia).

Differential Diagnosis of Sarcoidosis

Clinical pictures similar to sarcoidosis

Sarcoidosis can mimic many diseases. The differential diagnosis may include the following, among others:

  • Tuberculosis (However, the disease presents with caseating granulomas.)
  • Hodgkin’s disease (This is why a lymph node biopsy followed by a histologic examination is so important.)
  • Pneumoconiosis (This may be attributable to an occupational history of exposure—for instance, being employed in an industry that works with beryllium.)
  • Exogenous allergic alveolitis
  • In cases of acute sarcoidosis: arthritis of another genesis

Therapy for Sarcoidosis

Acute sarcoidosis, as well as chronic sarcoidosis stage I, has high rates of spontaneous resolution. Therefore, it is routine to wait and monitor the patient before starting long-term steroid therapy in order to avoid the adverse side effects of these drugs.

Indications for corticosteroid therapy in cases of sarcoidosis

  • When disease is at stage II, with simultaneous restricted pulmonary function
  • Presence of hypercalcemia and hyperuricemia (threat of chronic renal insufficiency)
  • Involvement of the eyes, liver, central nervous system (CNS), myocardium, or skin
  • Severe general symptoms, severe arthritis (i.e. Löfgren’s syndrome)

Should the patient’s disease not respond to therapy with glucocorticoids after 3 months, continuing with this therapy is not advisable. In this case, a combination of immunosuppressive drugs (i.e. azathioprine, methotrexate, anti–tumor necrosis factor (TNF)-alpha) can be tried.

Structural Formula of Azathioprine

Image: Structural formula of azathioprine. By: Xxxxx. License: Xxxxx.

In cases that include local symptoms such as uveitis or skin lesions, steroids can be administered locally as well.

If the patient reports severe pain (with arthritis, for instance), the additional supportive administration of nonsteroidal antirheumatic drugs (NSARs) is appropriate.

In cases of pronounced pulmonary fibrosis, lung transplantation is the last resort.

Progression and Prognosis of Sarcoidosis

Remission and spontaneous cure rates with sarcoidosis

Acute sarcoidosis has a remission rate of > 95% within 2 years. Stage I chronic sarcoidosis has a spontaneous cure rate of up to 70% within 1 to 3 years. The cure rate for stage II disease is only approximately 50%, and for stage III disease, the rate drops to 20%.

The risk factors for a more progressive and chronic progression are a patient age over 40 years at first diagnosis, hypercalcemia, lupus pernio, uveitis, neurosarcoidosis, cardiac involvement, and pulmonary sarcoidosis stage III.

The mortality rate for sarcoidosis is < 5%.

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