1. Extrapulmonary Sarcoidosis
Darrell Laudate
02/26/10 AM Report

2. Overview
Multisystem disorder of unknown etiology characterized by the accumulation of T lymphocytes, mononuclear phagocytes, and noncaseating granulomas in involved tissues

3. Epidemiology
Occurs most commonly in young and middle-aged adults with a peak incidence in the 3rd decade
Affects both sexes and all races but African Americans, Danes, and Swedes appear to have the highest prevalence
African Americans also typically have more widespread symptoms and greater severity

4. Several exposures including insecticides, agricultural employment, and microbial bioaerosols are associated
Cigarrette smoking is perhaps to be partially protective1.

5. Clinical Manifestations
Tend to be more widely distributed and severe in black Americans where as an incidental diagnosis is more common in Caucasians2

6. Most frequently involves the lung (90%)
commonly presents as cough, dyspnea, and chest pain.
Constitutional symptoms are also typically present such as fatigue, malaise, fever, arthralgias, and weight loss
However, up to 30% of patients will present with extrapulmonary disease

7. Ocular involvement Occurs in up to 20% of patients with sarcoidosis
Incidence > 70% in Japanese patients, incidence is also increased in African Americans
Can be the presenting symptom in as many as 5%
Lesions include:
anterior uveitis (iridocyclitis or iritis)
posterior uveitis (chorioretinitis)
retinal vasculitis
keratoconjunctivitis
conjunctival follicles

8. Anterior uveitis (with hypopyon)

9. Dermatologic Involvement
Seen in up to 20 percent of patients with sarcoidosis
Often an early finding
Several different skin lesions can occur:
A maculopapular eruption is the most common subacute lesion, usually involves the alae nares, lips, eyelids, forehead, rear of neck at the hairline, and/or previous trauma sites (eg, scars and tattoos).
Waxy, pink nodular lesions are frequently distributed on the face, trunk, and extensor surface of the arms and legs.
Lupus pernio: violaceous plaque-like lesions that occur in chronic sarcoidosis and typically involve the nose, cheeks, chin, and ears.
Erythema nodosum (8%)
Should not be biopsied as histopathology will demonstrate panniculitis and not granulomas
Atypical lesions may be ulcerative, psoriasiform, hypopigmented, follicular, angiolupoid, rosaeca-like, or morpheaform.

10. Erythema nodosum

11. Lupus pernio

13. Reticuloendothelial involvement
Common and can manifest as:
Peripheral lymphadenopathy (up to 40%)
Hepatomegaly (20%)
Noncaseating granulomas on liver biopsy with or without hepatomegaly (75%)
Splenic enlargement (25%)
80% of whom have granulomas.
Can lead to anemia, leukopenia, and thrombocytopenia.

14. Other Clinical manifestations
Cardiac involvement in 5%
> 25% in Japanese patients
usually presents as either congestive heart failure or cardiac arrhythmias
Neurosarcoidosis occurs in < 10%
Can affect both CNS and Peripheral Nervous System
Hematologic
Anemia occurs in up to 20% (often AoCD but sometimes due to hypersplenism, hemolytic anemia)
leukopenia in 40%, eosinophilia in 25%
Exocrine glands
Painless parotid gland swelling occurs in 4%
Xerostomia and keratoconjunctivitis sicca also may be seen (mimicing Sjogren’s)
Pancreatitis
Musculoskeletal manifestations occur in 10% of patients
acute polyarthritis, chronic arthritis with periosteal bone resorption, diffuse granulomatous myositis
Involvement of the GI and reproductive systems are possible but rare

15. Renal Involvement
Hypercalcuria and Hypercalcemia is most common renal manifestation of sarcoidosis
Hyperabsorption of dietary calcium occurs in up to 50 percent of cases of sarcoidosis
Occurs via increased production of calcitriol (1,25 dihydroxyvitamin D) by activated mononuclear cells (particularly macrophages
Excess calcium is excreted in the urine, leading to hypercalciuria and, in 2 to 20 percent of cases, to hypercalcemia
Nephrolithiasis, nephrocalcinosis, renal insufficiency, and polyuria are potential complications
Nephrocalcinosis, a condition observed in over 1/2 of patients with renal insufficiency
is the most common cause of chronic kidney disease in sarcoidosis

16. Renal involvement (continued)
Granulomatous interstitial nephritis is not uncommon4 but is rarely the sole cause of renal dysfunction.
UA is typical of other chronic tubulointerstitial diseases, being normal or showing only sterile pyuria or mild proteinuria
Renal Biopsy reveals normal glomeruli, interstitial infiltration mostly with mononuclear cells, noncaseating granulomas in the interstitium, tubular injury, and with more chronic disease, interstitial fibrosis
Other conditions that must be considered include drug- induced interstitial nephritis, tuberculosis, other mycobacterium infections, Wegener granulomatosis, brucellosis, histoplasmosis, and, rarely, Crohn's disease

17. Renal involvement (continued)
Glomerular involvement is rare but includes:
membranous nephropathy,
proliferative or crescentic glomerulonephritis
focal glomerulosclerosis
Polyuria (due to nephrogenic and/or central diabetes insipidus)
Obstructive uropathy
via Retroperitoneal lymph node involvement, retroperitoneal fibrosis, renal stones, and ureteral involvement
Hypertension
Sometimes via sarcoid angiitis of renal artery

18. Specific characteristic combinations of organ involvement occur:
Heerfordt’s syndrome
combination of anterior uveitis, parotid gland enlargement, facial palsy, and fever (uveoparotid fever)
Lofgren’s syndrome
Erythema nodosum, polyarthralgia, and bilateral hilar lymphadenopathy
strongly associated with the presence of HLA-DQB1*0201 and specific polymorphisms of C-C chemokine receptor 2 (CCR2
associated with a good prognosis and spontaneous remission

19. Diagnosis
Definite diagnosis requires compatible clinical picture, pathologic demonstration of noncaseating granulomas and exclusion of alternative explanations (in the case of suspected pulmonary sarcoid):
Infections, particularly tuberculosis and histoplasmosis.
Hypersensitivity pneumonitis
Eosinophilic granuloma
Collagen vascular disease
Pneumoconiosis
Chronic beryllium lung disease (ie, berylliosis)

20. Evaluation Evaluation of suspected Sarcoidosis should include:
PA and lateral CXR
Spirometery and DLCO
Any pattern of pulmonary physiologic impairment can be seen, including normal but typical findings reveal a restrictive pattern with a reduction in the diffusing capacity for carbon monoxide
Calcium, Cr, BUN, LFTs, CBC
Urinalysis
ECG
Routine ophthalmologic examination
Tuberculin Skin Test

21. Other labs
Serum ACE levels can be helpful in the diagnosis of sarcoidosis.
Reported to be elevated in 60-75% of patients with acute disease
only 20% of patients with chronic disease.
False positive results are unusual (<10 percent), but frequent enough to limit the usefulness of serum ACE as a diagnostic test
Other causes for mild elevation of ACE, including diabetes, leprosy, Gaucher's disease, hyperthyroidism, and disseminated granulomatous infections such as miliary tuberculosis.
Concurrent use of ACE Inhibitors will lead to a low ACE level
IgG can also be helpful as hypergammaglobulinemia is present 30-80%

22. Imaging CXR useful for diagnosis and prognosis High resolution CT
Can be particularly useful when disease is suspected but CXR is normal
Gallium scanning
Provides little for prognosis but can rarely be diagnostically useful

23. Siltzbach Radiographic Classification of Sarcoidosis
Stage
Radiographic Pattern
Frequency of presentation
Frequency of spontaneous and radiographic evidence
Normal
10% I
Hilar Lymphadenopathy
20%
50-90% II
Hilar adenopathy and abnormal lung parenchyma
50%
40-70%
III
abnormal lung parenchyma
10-20% IV
Parenchymal fibrotic change with architectural distortion
<5% 0%

24. Bronchoscopy BAL may be helpful for diagnosis
Likelihood of sarcoidosis increased when the lymphocyte count is 30-50% and granulocyte count is low5
CD4/CD8 ratio > 3.5 has sensitivity of 53% and specificity of 94%, PPV 76% and NPV of 85%
Also has a role in excluding infections as an alternative diagnosis
Endobronchial and transbronchial biopsies can be diagnostic in up to 90% of cases, even in whom the lung parenchyma is radiographically normal

25. Treatment Spontaneous remission occurs in up to 2/3 of patients
Treatment is indicated at time of diagnosis if:
There is cardiac, ocular, or neurologic disease
Hypercalcemia is present
Radiographic stage 2 disease with significant symptoms
Stage 3 disease

26. Treatment Glucocorticoids
Appropriate therapeutic approach is controversial but one recommended approach is prednisone 30-40mg PO daily for 2-3 months followed by a tapering schedule to 10-20mg PO every other day for 12 months
Can alleviate symptoms and improve spirometery and CXR appearance over 3-24 months6
which decrease inflammatory activity and therefore calcitriol synthesis

27. Treatment (continued)
For steroid resistant disease or those who are steroid- intolerant cytotoxic agents such as MTX or azathioprine can be used
TNF-alpha (infliximab) and Thalidomide have been used but experience with these agents is limited
Hydroxychloroquine can be useful for treatment of hypercalcemia, cutaneous disease and occasionally pulmonary sarcoid
Chloroquine and ketoconazole can also by used for management of hypercalcemia

28. References
Newman et al. A case control etiolic study of sarcoidosis: environmental and occupational risk factors. Am J Respir Crit Care Med ; 170:
Newman et al. Sarcoidosis. N Engl J Med 1997; 336:1224.
Harrison's Principles of Internal Medicine, 17th edition.
Casella et al. The kidney in sarcoidosis. J Am Soc Nephrol 1993; 3:1555.
Welker et al. Predictive value of BAL cell differentials in diagnosis of interstitial lung diseases. Eur Respir J ;24:1000-6
Paramothayan et al. Corticosteroids for pumonary sarcoidosis. Cochrane Database Syst Rev. 2005:CD