Diagnosis and treatment of sarcoidosis

Clinicians see pulmonary sarcoidosis most often, but this difficult disease also causes dermatologic, ophthalmologic, cardiac, hepatic, renal, and neuromuscular signs and symptoms.

Sora Shim, PA-C

The author works at Bridgemill Family Practice, Canton, Ga. She has indicated no relationships to disclose relating to the content of this article.

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A 40-year-old black man comes to the clinic complaining of fatigue, weight loss, and nonexertional, nonproductive cough with occasional hemoptysis. During the interview, he reveals that he recently had positive findings on a chest radiograph. His sputum culture and blood tests are pending at the office of another practitioner. He has come to you seeking a second opinion. Could he have lung cancer? Could he have tuberculosis? Or could he have a much less common condition, such as sarcoidosis?

Sarcoidosis is a multisystemic disease of unknown etiology, characterized by the formation of noncaseating granulomas in various organs of the body, typically with bilateral hilar adenopathy and pulmonary infiltration. Although it affects men and women of all ages and races, sarcoidosis is most common in blacks and slightly more common in women than in men.¹ Incidence is highest between the ages of 20 and 40 years. Sarcoidosis occurs at a ratio of 1:3 in 100,000 whites versus 1:6 in 100,000 blacks.² Although it is uncommon, the disease should remain in the differential diagnosis for patients with certain presentations.

Pathophysiology

Although the cause of sarcoidosis is unknown, a number of indications suggest correlations with genetics, community outbreaks, and chemical exposure among firefighters, naval aircraft personnel, and health care workers.^2-4 Research supports the genetic theory; clusters of the disease have been noted in certain ethnic groups, and it is more likely to occur in first- and second-degree family members.³ Tumor necrosis factor (TNF) and its subtypes have also been considered in distinguishing the genotypic significance in relation to clinical symptoms.⁴ Other epidemiologic studies indicate that firefighters are more likely than emergency medical personnel to develop sarcoidosis, possibly because of their greater level of exposure to inhaled toxins.² Rural living, including the use of wood-burning stoves and fireplaces and obtaining drinking water from a nonpublic water supply, has also been linked to the development of sarcoidosis.⁵

The formation of a granuloma requires a sequence of events: 1) exposure to a triggering factor; 2), the body’s cellular response; and 3), an inflammatory response against the trigger. This granulomatous reaction, mediated by antigen-specific T cells, macrophages, mast cells, and fibroblasts, gradually damages local tissue, causing fibrosis and lung volume loss. The patients who suffer from chronic sarcoidosis demonstrate higher levels of cytokine interleukin (IL)-8, IL-12, and TNF. During the healing process, IL-10 helps suppress the inflammatory pathway.³  

Histology

The classic evidence of sarcoidosis is a histologic finding of noncaseating granulomas that are multiple, non-necrotic, hyalinized, and small, containing epithelioid histiocytes surrounded by lymphocytes, plasma cells, and fibroblasts. The epithelioid cells are transformed bone marrow monocytes and can secrete numerous enzymes, including angiotensin-converting enzyme, lysozyme, and calcitriol. Laminated calcifications, called Schaumann’s bodies, can often be seen within the granulomatous multinucleated giant cells. Golden, oval to rod-shaped inclusions called Hamazaki-Wesenberg bodies may be present within histiocytes or be seen extracellularly, often outside granulomas, and they autofluoresce when exposed to UV light.¹ These granulomas may resolve spontaneously, form mild scarring and fibrosis, or undergo total fibrosis resulting in destruction of local tissue.⁶ 

Types of sarcoidosis

Signs and symptoms of sarcoidosis differ according to whether the disease appears in the pulmonary, dermal, cardiac, ophthalmologic, otolaryngologic, musculoskeletal, neurologic, hepatic, GI, or renal system.

Pulmonary sarcoidosis constitutes about 90% of cases. Patients complain of nonspecific symptoms including weight loss, fatigue, anorexia, chills, night sweats, dyspnea, nonproductive cough, and vague, nonexertional chest pain. Hemoptysis can occur but is rare.^6-8 Pulmonary sarcoidosis can cause loss of lung volume and abnormal lung stiffness.⁶ If left untreated, sarcoidosis can progress to pleural effusion, pneumothorax, pleural cavitation, and lymph node calcification.^6,8 About 20% to 30% of patients with pulmonary sarcoidosis may be left with permanent lung damage.⁶ Cardiopulmonary failure occurring secondary to pulmonary fibrosis is the leading cause of death in patients who have pulmonary sarcoidosis.⁹

Cutaneous sarcoidosis, usually nonpruritic and painless, is the presentation in approximately 25% of patients. However, erythema nodosum manifests as painful, warm, and erythematous lesions that normally appear over the shins, arms, and buttocks, often accompanied by arthralgias and occasionally fever. Lupus pernio—purplish, indurated lesions over the nose, cheeks, and lips—are associated with bone cysts and pulmonary fibrosis. Alopecia, clubbing of the fingernails, and skin hypopigmentation and hyperpigmentation also occur.^7,8

Myocardial manifestations are seen in about 25% of patients with sarcoidosis. Chest pain, palpitations, and arrhythmias—including premature ventricular contractions, supraventricular arrhythmias, and heart block—can occur when the sinoatrial and atrioventricular nodes become obliterated as a result of the formation of sarcoid granulomas. In addition, mitral or tricuspid regurgitation can develop if the papillary muscles are affected by the formation of granulomas. Infiltrative myocardiopathy with congestive heart failure, pericarditis, and valvular and vasculitic dysfunction (including aneurysms) are rare but possible complications if the condition is left untreated. Bundle branch blocks and ventricular tachyarrhythmias can even cause sudden death when granulomatous changes obliterate the normal foci of automacity.^10,11   

Ophthalmologic sarcoidosis manifests as blurred vision, photophobia, diplopia, uveitis, conjunctivitis, and excessive lacrimation in about 25% of patients. If untreated, ophthalmologic sarcoidosis can lead to cataracts, glaucoma, keratoconjunctivitis sicca, dacryocystitis, and optic nerve involvement resulting in eventual blindness.^7,8 Dry mouth and bilateral, nontender, diffuse parotid gland swelling can occur in approximately 10% of patients as well.¹

Musculoskeletal sarcoidosis, seen as polyarthritis and generalized myopathy, may develop in about 25% of patients. Although bone involvement is rare, sarcoidosis that has been diagnosed with a bone scan demonstrates severe progression of the disease. The most common neurologic manifestations of sarcoidosis are headache, confusion, malaise, peripheral neuropathy, and unilateral facial nerve palsy. Although rarely seen, a space-occupying brain lesion can be the cause of hydrocephalus, seizures, and hypopituitarism.^7,8

Hepatic sarcoidosis can cause elevated levels of serum alkaline phosphatase, total bilirubin, and aminotransferase, as well as liver biopsy specimens that are granulomatous and nonnecrotizing. Hepatic dysfunction can include hepatomegaly, cholestasis, or end-stage liver disease with portal hypertension.^7,8 Also, space-occupying granulomas along the lining of the GI tract may cause bowel obstruction, protein-losing enteropathies, and malabsorption, though rarely.⁸

Renal involvement, usually from secondary hypercalcemia and hypercalciuria, manifests as nephrogenic diabetes insipidus, polyuria, glomerular nephritis, nephrolithiasis, and chronic renal failure. Granulomatous changes can cause renal obstruction in a small number of cases.⁸

Diagnosis

Because the symptoms of sarcoidosis can be vague and may at times go unnoticed, the diagnosis is often delayed. One study found that sarcoidosis was diagnosed on the first physician visit in only 15.3% of cases.¹² Slightly less than half of the cases required four or more visits to reach a diagnosis, and more than 20% required six or more visits. One patient had to make 23 visits before sarcoidosis was diagnosed.¹² Although sarcoidosis is an uncommon condition and a difficult disease to recognize, the approach to diagnosis may be facilitated through a combination of clinical, radiographic, and histologic findings in at least two organ systems (see the algorithm).³

Biopsy The first-line diagnostic test is the transbronchial lung biopsy, which yields approximately 80% accuracy. Biopsy specimens must be carefully scrutinized for any infectious pathogens, including mycobacteria or fungi, and malignant conditions such as lymphoma that could also cause granulomatous diseases.^3,8

Radiology When reviewing the chest film of a sarcoidosis patient, the clinician should consider the Scadding classification:

•   Stage 0: no abnormalities seen on the chest film

•   Stage I: bilateral hilar adenopathy without lung tissue involvement (this stage is linked with the highest rate of remission)

•   Stage II: hilar adenopathy with parenchymal infiltrates

•   Stage III: diffuse parenchymal infiltrates without hilar adenopathy (this stage has the least favorable prognosis)

•   Stage IV: pulmonary fibrosis with honeycombing and fibrocystic parenchymal changes, such as hilar retraction and bullous cysts.^8,12

The Scadding classification is used to differentiate the stages of lung involvement but does not define the severity of the disease.⁸

Gallium scintigraphy depicts the areas of sarcoidosis involvement as lambda and panda signs. When gallium uptake is increased around the tracheal areas and hilar nodes, the scintigram resembles the letter lambda; when uptake is increased in the facial area, such as around the lacrimal and parotid glands, the face of a panda bear may be visible.^8,11

The use of CT for routine screening purposes is controversial because of the high cost. Even though the chest film will pick up the classic bilateral hilar adenopathy, CT is far superior for assessing certain lobe predominances, peribronchial irregularities, and subpleural micronodules.³ MRI and positron emission tomography can also be utilized to diagnose sarcoidosis, although they have the disadvantage of high cost as well.

Other tests Pulmonary function testing (PFT) assesses the status of lung function, while spirometry is used to monitor disease progression. Many patients will show either an obstructive or a restrictive pattern on PFT, along with increased airway resistance and a low forced expiratory volume in 1 second. Other ways to visualize pulmonary dysfunction include abnormal vital capacity and carbon monoxide-diffusing capacity.⁸

Blood tests are necessary to look for anemia, thrombocytopenia, and leukopenia and to measure the serum calcium level. Liver function tests (LFTs) are also important.⁸ Serum angiotensin-converting enzyme levels are elevated in 50% to 80% of patients with sarcoidosis, but this finding is seen in other diseases as well.^1,11 Bronchoalveolar lavage fluid may also be analyzed for lymphocytosis, which is consistent with the diagnosis of sarcoidosis.³  

Differential diagnosis

The differential diagnosis of sarcoidosis is broad (see Table 1). The provider must rule out infections, especially those such as coccidioidomycosis, histoplasmosis, and toxoplasmosis that also possess the capability to form granulomas. Occupational or environmental lung diseases such as hypersensitivity pneumonitis, chronic beryllium disease, and other metal-induced lung diseases should be considered. Drug-induced granulomatous pneumonitides and autoimmune disorders such as Wegener’s granulomatosis, primary biliary cirrhosis, and Churg-Strauss syndrome can manifest similarly to sarcoidosis. The differential diagnosis also includes lymphoma, tuberculosis, brucellosis, metastatic carcinoma, extrinsic allergic alveolitis, fibrosing alveolitis, systemic lupus erythematosus, scleroderma, bullous emphysema, and bronchiectasis.⁸ With parotid gland involvement, diseases such as Sjögren’s syndrome, viral mumps, cat-scratch disease, actinomycosis, and neoplasm can mimic sarcoidosis.¹

Treatment and follow-up

If the patient is asymptomatic without any organ involvement, the only treatment is watchful observation. Once there are signs of airflow impairment and/or cough, high-dose inhaled corticosteroid therapy can be tried.

Pharmacotherapy If the patient has symptomatic pulmonary disease with other organ involvement, corticosteroid therapy has proven benefit. Chest films show that corticosteroids improve lung vital capacity and bilateral hilar adenopathy.^13,14 The usual starting dosage of prednisone is 40 mg daily for 6 weeks to 3 months, followed by gradual tapering to a maintenance dosage of 5 to 10 mg daily (or every other day) for 6 to 12 months.³ Corticosteroids can cause weight gain, mood swings, hypertension, and osteoporosis, and use should be monitored carefully.⁷ Methotrexate (10-20 mg per week orally) has been studied as an alternate therapy, but the clinician must also adjust for toxicities, including nausea and neutropenia.³

For the patient who has cutaneous sarcoidosis, hydroxychloroquine, 200 to 400 mg daily, or thalidomide, 50 to 200 mg daily, may be tried. Side effects of these drugs include nausea, ocular toxicity, constipation, and peripheral neuropathy. Thalidomide, which is teratogenic, is not effective for the pulmonary symptoms of sarcoidosis.³

Lung transplant The patient with sarcoidosis and end-stage pulmonary disease may be a candidate for lung transplantation, although the rejection rate is higher than in patients who do not have sarcoidosis. In one study, 23 of 43 patients with sarcoidosis and end-stage pulmonary disease died before receiving lung transplants. Of the 12 patients who underwent lung transplants, the mortality rate was 62% within 2 years and 50% between the second and third year after the surgery.¹⁵

Prevention and patient education

Sarcoidosis cannot be prevented since the etiology of the disease is unknown. It is not contagious and is rarely fatal;⁷ spontaneous resolution of the disease has even been known to occur.¹⁴ In one study, however, 4 of 490 patients with sarcoidosis (mean age, 74 years) died of respiratory failure secondary to pulmonary fibrosis.⁹ Patients with sarcoidosis should not smoke, which can worsen the prognosis.⁶

In patients with cardiac involvement, a 24-hour Holter monitor may be useful. As an adjunct to corticosteroid therapy, a pacemaker or an implantable cardioverter defibrillator can correct the varying arrhythmias seen in sarcoidosis. Echocardiography may also help to evaluate the status of mitral valve prolapse or ventricular aneurysms.¹⁰

It is not clear why some patients with sarcoidosis recover and some become sicker, nor do we know why sarcoidosis can recur after treatment with corticosteroids.¹³ By keeping sarcoidosis in the differential diagnosis when examining a patient with vague symptoms, however, the clinician may be able to avert a delayed diagnosis and prevent the disease from worsening. Online support groups are available for patients with sarcoidosis. More information is available online from the National Heart, Lung, and Blood Institute at www.nhlbi.nih.gov or the American Lung Association at www.lungusa.org.  

Conclusion

Signs and symptoms of sarcoidosis vary greatly, although most cases involve pulmonary symptoms—including dry, nonexertional cough—and skin lesions. A biopsy revealing granulomas is required for diagnosis, along with bilateral hilar adenopathy seen on chest radiograph and clinical symptoms. The mainstays of treatment consist of corticosteroids and preventing further complications of the disease.   •

REFERENCES

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