Diagnosing Sarcoidosis Print E-mail


Many sarcoidosis patients experience symptoms long before they’re correctly diagnosed because their symptoms can sound vague (e.g., blurry vision), appear to be due to aging (e.g., joint pain) or seem benign (e.g., rash). See Symptoms of Sarcoidosis.

Sarcoidosis is often misdiagnosed because symptoms are attributed to other diseases such as chronic fatigue syndrome, fibromyalgia or arthritis.

Diagnosis of exclusion

The only way to diagnose sarcoidosis is by excluding other diseases that might possible explain the symptoms. For example, cancer or infection must be ruled out because chest x-rays appear similar to lymphoma (enlarged chest lymph nodes) or tuberculosis.

Biopsy

Doctors usually insist on a definitive diagnosis before treatment because the drugs used have so many adverse effects. A definitive diagnosis requires a biopsy of non-necrotizing granulomas.

All biopsies are invasive and uncomfortable to some extent, even a simple skin biopsy. A lung biopsy is an invasive and risky procedure that can have long-term consequences to lungs status.

Presumptive diagnosis

If symptoms involve tissues that are not easily biopsied (e.g., heart, liver, eye, joints), a presumptive diagnosis may be declared based on medical history and clinical signs such as symptoms and labwork.

Dysregulated vitamin D metabolism

Sarcoidosis always results in dysregulated vitamin D metabolism and abnormally high levels of dihydoxyvitamin-1,25-D (hypervitaminosis-D), a powerful hormone because 1,25-D is secreted by the inflammatory macrophages that make up the granulomas.

A diagnosis of this systemic Th1 inflammation due to sarcoidosis can be made with a simple blood test for 1,25-D. See D-Metabolites Tests for details.

Inflammation Therapy

Neither a definitive diagnosis of sarcoidosis nor extensive (and often expensive) tests to quantify the location and extent of granulomatous tissue are necessary in order to prescribe Inflammation Therapy. D-metabolites results are definitive for systemic inflammation and (along with the clinical picture) is justification for treatment with safe and effective Inflammation Therapy. See Overview of InflammationTherapy.

Granuloma

Granulomas are tiny clumps of white blood cells - a sarcoid granuloma is less than 0.1mm (about 4 thousands of an inch) in diameter. They survive without a tissue-structure to support them because the inflammatory Th1 reaction has progressed to the point where the phagocytes can exist in clumps on their own. Lymphocytes are expelled to the periphery of granuloma and play little or no part in the Th1 immune system reaction.

Any disease where an extremely active bacterial infection is present can form granuloma. This includes tuberculosis, and a number of the other common infections. In the case of sarcoidosis, the granuloma are chronic and their bacterial pathogenesis is more important than the label that might be attached.

Non-caseating granulomas

There is some confusion about the use of the term "caseating." Caseation is what happens when necrosis changes what was once normal tissue so it looks "cheese-like" in appearance to the naked eye. (i.e., Swiss cheese.) Basically, caseation is what you get when there is necrosis.

A physician, Yale Rosen, M.D., who devoted his life to studying granuloma and granulomatous diseases explains, "The use of the terms "caseating" and "non-caseating" to describe the microscopic appearance of granulomas, although prevalent, is inappropriate since the term "caseous" applies only to the grossly visible cheese-like appearance that may be associated with necrotizing granulomas, necrotic neoplasms and other types of necrotic lesions. There is no typical microscopic appearance that corresponds to the gross appearance of caseation."

You might be interested in knowing that necrosis can occur in sarcoidosis, although it is small and involves few of the granuloma.

In summary, non-necrotizing (not dead/dying) is the best term to describe sarcoidosis granulomas viewed under the microscope and non-caseating (not cheese-like) is the best term to describe sarcoid tissue viewed with the naked eye.

See these photos of sarcoidosis gross pathology.

Cardiac involvement

Sarcoidosis cardiac inflammation is very difficult to diagnose. Th1 inflammation in the heart is subclinical long before the damage it causes is detected by tests. It’s only picked up by echocardiogram or MRI when it’s in advanced stages. A biopsy of the heart is dangerous, often imprecise and unnecessary. A diagnosis of sarcoidosis heart involvement is usually based on symptoms which can include most heart symptoms, including but not limited to... chest pain, tachycardia, bradycardia, mitral valve prolapse, atrial fibrillation and premature beats.

Staging system

Dr. Marc Judson had this to say about staging sarcoidosis:

"It is important to make several points about the staging system. First, it is only a chest X-ray staging system. It tells you nothing about involvement of sarcoidosis outside of the lungs. Second, it is in general, a poor staging system. Most sarcoidosis experts do not use it because it's so poor. It has a few major problems. The first is that it's inaccurate. When you do much better views of the lungs by chest CT scans, you find out that the actual stage is different than what appears on chest X-ray. The next problem with the staging system is that it does not predict the need for therapy, the level of disability, or the prognosis IN AN INDIVIDAL PATIENT with any good degree of accuracy. That is, if you had 100 patients with stage 1 disease and 100 with stage 2, the stage 1 would have better pulmonary function, less pulmonary symptoms, and a better prognosis. BUT many in the stage 2 group would have better pulmonary function, less pulmonary symptoms, and a better prognosis than in the stage 1 group...you can't tell what will happen to one specific patient. Probably the most useful part about the staging system is that patients with stage 4 generally have poor pulmonary function and have the worst prognosis. But I don't put too much weight on this staging system...it is antiquated and doesn't help me much at all." 14 August 2003

Tests that may be done to diagnose sarcoidosis

PET (Positive Emission Tomography) Scan

Imaging is unavoidably imprecise and only a rough approximation of the inflammatory process. In a PET (Positive Emission Tomography) scan, a radioactive marker is combined with a metabolite, usually glucose, and the degree of release of positron energy indicates the usage of glucose in that area which images metabolic activity and often reveals the systemic nature of sarcoidosis. In a PET scan, FDG may accumulate in non-neoplastic tissue such as new granulation tissue, areas of inflammation, and early post-op scarring.
But this diagnostic tool is not specific for differentiating sarcoidosis or tuberculosis from cancerous tumors.

Gallium Scan

A gallium scan should be avoided because it presents a risk to compromised kidneys and patients suspected of sarcoidosis are likely to have kidney inflammation.

Kveim test

The Kveim test involves injecting part of the spleen from dead sarcoidosis patients and is to be avoided at all costs because sarcoidosis has been proven to be communicated by transplanted lungs and other organs. Drs. Kveim and Silzbach developed the Kveim agent as a test for sarcoidosis. The Kveim test is produced by collecting lymph node of spleen samples from people already diagnosed with sarcoidosis. The sample is supposedly processed to eliminate infectivity and is injected into the patient's skin, Approximately 4 weeks later a skin biopsy is performed; specific histological changes are considered confirmatory for sarcoidosis. The Kveim test is poorly standardized, is not FDA-approved and is rarely used in the United States. There is still one hospital in New York City that uses it but, if we accept that sarcoidosis is transmissible, it would be irresponsible to use the Kveim test.

Bloodwork

Some patients with Th1 disease (sarcoidosis) have normal blood work for all tests (SED rate, CRP, etc.). SED rate and CRP and part of the body’s reaction to infection and aren’t generated when there is immune system dysfunction. The pathogens are so well secreted in the granuloma that the immune system doesn’t touch them. There are no antibodies formed, and, since the pathogens delay apoptosis, the SED rate is almost always very low. When the immune system is enabled by inflammation therapy and begins killing bacteria the SED rate may elevate.

ACE test (Serum Angiotensin Converting Enzyme or S.A.C.E.)

Serum A.C.E. is often used to help diagnose sarcoidosis, a condition in which ACE levels are sometimes increased. Elevated ACE levels may also be seen in several other disorders.

The ACE gene encodes two isozymes; the somatic isozyme is expressed in many tissues, especially vascular endothelium.

ACE is produced by epithelioid cells of sarcoid granulomata. As granulomas are formed (surrounding an invading agent) in what was previously healthy tissue, the inflamed tissue creates an ever decreasing size of blood delivery. This "choking" of the blood supply is what causes ACE to increase and signals the adrenal glands to increase the body's form of anti-inflammatories.

The design is perfect except in the case when the body cannot perform the reduction in inflammation as a result of the invader remaining. The inflammation remains, the ACE is high, blood delivery is low and eventually the granuloma tissue becomes non-functioning as the result of insufficient blood flow; fibrosis (scar) tissue is the result. Serum ACE not only reflects the changes in the body; it causes many of them.

Serum ACE is often used by doctors as an indication of active inflammation but it is an unreliable test. Genetic differences among individuals affect the normal range of ACE. Genetic factors determine what is "normal" and unless your doctor checks your ACE genotype, the indications of active disease will only be good for that 25% of people who have the DD genotype, the one with the highest 'normal' values of ACE.

ACE often returns to "normal" when the disease is quiescent. ACE only identifies the granuloma activity at the time of the test. One can have a sarcoid-like illness and low or "normal" ACE at the same time.

While serum ACE level is elevated in some sarcoidosis patients, not all sarcoidosis patients have elevated ACE levels. As a result, serum ACE is not a reliable diagnostic tool or measure of disease activity.

The serum ACE test is a non-specific test used in helping diagnose sarcoidosis. The major problem is that it is unreliable -- in the sense that some people who are very ill with sarcoidosis do not always produce a high number on the ACE test. So the ACE test is not clinically reliable, either as a diagnostic tool, or to monitor how well a patient is doing. There are also genetic differences among individuals that affect the normal range of ACE, which confounds the problem.

Conformational fingerprinting of the angiotensin I-converting enzyme (ACE). 1. Application in sarcoidosis

White blood cell count

Patients with Th1 inflammatory diseases commonly have low T-cells (e.g., lymphocytes, neutrophils, monocytes, NK cells) because intracellular bacteria cause the phagocytes to produce cytokines without the need for stimulation of any other immune system cells. There is no need for any T-cell recognition of pathogens so the body down-regulates the number of T-cells it manufactures which results in a low white count (lymphopenia).

In sarcoidosis this causes the lymphocytes to leave the area of highest inflammatory action (in the center of a granuloma) and migrate to the periphery. The down-regulation also reduces the number of lymphocytes being generated from stem cells. In less intense Th1 inflammation, that does not form granuloma, the down-regulation of the T-cells is observable primarily by the down-regulation of the lymphocytes.

Anemia

Granuloma sequester ferritin and iron, resulting in a low Hgb and Hct.

Triglycerides

Elevated triglycerides suggests liver inflammation.

BUN

BUN is often elevated because the bacterial endotoxins cause nitric oxide (NO) to be generated in the inflamed tissues.

Creatinine

Abnormal kidney function tests suggest subclinical kidney inflammation.

Alkaline phosphatase

This article says, "In the serum of many patients with sarcoidosis, alkaline phosphatase activity is increased due to sarcoid liver involvement."

Cutaneous anergy

In 1916, Boeck first described cutaneous anergy to tuberculin in patients with sarcoidosis. It was later on realized that this phenomenon was not limited to tuberculin alone, but that anergy to a variety of other skin tests-antigens such was also typical.

In 1994, Kataria and Holter proposed a mechanism for the cutaneous anergy seen in sarcoidosis. At sites of granulomatous inflammation, there is a predominance of helper T lymphocytes, which proliferate and secrete large amounts of lymphokines, including interleukin (IL)-2, monocyte chemotactic factor (MCF) and migration inhibition factor (MIF). These lymphokines induce and amplify the immune response by enhancing T-lymphocyte proliferation as well as recruiting and retaining monocytes from the circulation. The lymphokines and monokines produced at sites of granulomatous inflammation have their highest concentration locally. Nevertheless, the protein molecules diffuse into blood, establishing a concentration gradient between the granulomatous inflammatory site and the remote site of the delayed type hypersensitivity (DTH) skin test.

As a result, the traffic of T-helper lymphocytes and monocytes is preferentially directed towards site of granuloma formation. That leads to a preponderance of suppressor cells in the peripheral blood and competitively depletes the T-helper cells and monocytes available to sites of DTH.

See A study of pheripheral immunity in patients with sarcoidosis

Cancer and sarcoidosis

Sarcoidosis is a multi-systemic disease that can be confused with benign or malignant tumors.

Patients should make their doctors aware of any previous sarcoidosis diagnosis (even if only suspected) so sarcoidosis can be investigated as a possible cause of any lumps or tumors.

Patients should aware that some of the diagnostic tests used to identify cancers can be elevated in sarcoidosis, resulting in a "false positive."

Peritoneal sarcoidosis may "mimic" ovarian carcinoma in that it may present with peritoneal or abdominal findings and an elevated serum CA 125 level. Sarcoidosis Associated With an Elevated Serum CA 125 Level

Women facing a diagnosis of breast cancer will find the following references helpful:

Atlas of Granulomatus Diseases

Sarcoidosis of the breast: a rare case report and a review.

A case of granulomatous mastitis mimicking breast carcinoma.

Lobular Granulomatous Mastitis Mimicing Advance Breast Cancer

Idiopathic granulomatous mastitis lesion mimicking inflammatory breast cancer

Radiologic Evaluation of Uncommon Inflammatory and Reactive Breast Disorders

See Cancer and Diagnosing a biopsy properly in Lymph Nodes.

See also Coexistence of Sarcoidosis and Malignancy
"To date, the link between sarcoid and malignancy is unproved, and some authors continue to doubt whether any association truly exists. However, clinicians should be aware of the potential risk of malignancy in sarcoid patients. Until more definitive data are available, sarcoid patients who develop new lesions or adenopathy should be considered for histologic biopsy to rule out coexistent neoplasm. Furthermore, in patients with established malignancy and newly discovered radiographic findings, the possibility of sarcoidosis should be considered."

Pregnancy and sarcoidosis

1,25-D is manufactured by the placenta during pregnancy, In a healthy woman the production of 1,25-D in the kidneys will be down-regulated to compensate.
Plasma 1,25-dihydroxyvitamin D levels in pregnancy and lactation.

The kidneys of a woman with sarcoidosis have usually lost the ability to adequately down-regulate the 1,25-D levels because there is too much 1,25-D being manufactured in the inflamed tissues. This causes dysfunction of the normal hormonal vitamin-D feedback mechanism and results in even higher levels of this active D-metabolite.
Regulation of vitamin D metabolism in normal human pregnancy.

Studies show that pregnancy is usually carried to term and most women with sarcoidosis report they feel better during pregnancy. This is probably due to suppression of the immune system by high 1,25-D levels, lack of bacteria killing and, therefore, no Herxheimer symptoms.
Sarcoidosis and pregnancy

1,25-D diminishes post-partum and relapse is common with symptoms often worse than before pregnancy. Many woman are diagnosed during the post-partum period when their 1,25-D falls back to pre-pregnancy levels and they lose the palliation from the steroidal actions of this D-metabolite so symptoms increase.

Sarcoidosis and Scleroderma

See Diagnostic Tests.

Last updated January 31, 2013