Extrapulmonary Sarcoidosis

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Extrapulmonary Sarcoidosis

• Darrell Laudate
• 02/26/10 AM Report

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Overview

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

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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

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

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Clinical Manifestations

• Tend to be more widely distributed and severe in
  black Americans where as an incidental diagnosis
  is more common in Caucasians2

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• 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

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Ocular involvement

• Occurs in up to 20 of patients with sarcoidosis
• Incidence gt 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

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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.

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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.

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Other Clinical manifestations

• Cardiac involvement in 5
• gt 25 in Japanese patients
• usually presents as either congestive heart
  failure or cardiac arrhythmias
• Neurosarcoidosis occurs in lt 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 Sjogrens)
• 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

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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

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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

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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

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• Specific characteristic combinations of organ
  involvement occur
• Heerfordts syndrome
• combination of anterior uveitis, parotid gland
  enlargement, facial palsy, and fever (uveoparotid
  fever)
• Lofgrens syndrome
• Erythema nodosum, polyarthralgia, and bilateral
  hilar lymphadenopathy
• strongly associated with the presence of
  HLA-DQB10201 and specific polymorphisms of C-C
  chemokine receptor 2 (CCR2
• associated with a good prognosis and spontaneous
  remission

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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)

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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

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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 (lt10 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

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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

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Siltzbach Radiographic Classification of
Sarcoidosis
Stage Radiographic Pattern Frequency of presentation Frequency of spontaneous and radiographic evidence
0 Normal 10
I Hilar Lymphadenopathy 20 50-90
II Hilar adenopathy and abnormal lung parenchyma 50 40-70
III abnormal lung parenchyma 20 10-20
IV Parenchymal fibrotic change with architectural distortion lt5 0
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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 gt 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

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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

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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

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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

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References

1. Newman et al. A case control etiolic study of
   sarcoidosis environmental and occupational risk
   factors. Am J Respir Crit Care Med. 2004
   1701324-30.
2. Newman et al. Sarcoidosis. N Engl J Med 1997
   3361224.
3. Harrison's Principles of Internal Medicine, 17th
   edition. http//www.accessmedicine.com/
4. Casella et al. The kidney in sarcoidosis. J Am
   Soc Nephrol 1993 31555.
5. Welker et al. Predictive value of BAL cell
   differentials in diagnosis of interstitial lung
   diseases. Eur Respir J. 2004241000-6
6. Paramothayan et al. Corticosteroids for pumonary
   sarcoidosis. Cochrane Database Syst Rev.
   2005CD001114.