Amyloid Sarcoid Flashcards
Amyloid finding under light microscope & stain
Congo red stain → apple green birefringence
** Mech of amyloid deposition**
– High [ ] normal protein (eg serum amyloid A in chronic inflamm, and B2microglobulin in dialysis related amyloid)
– Prolonged exposure to normal [ ] of weakly amyloidogenic protein (eg amyloid B protein)
– Acquired prot w/ amyloidogenic structure (monoclonal IgG light chains in AL amyloid eg MM, Waldenstrom, NHL)
– Inherited variant protein w/ amyloidogenic structure (eg TTR)
Common symptoms in HD related amyloid
-CTS
-Arthralgia - shoulder pad sign, noninflamm joint effusion
-Paravertebral erosions, Intervertebral disc destruction
-Cystic bone changes (Advanced glycation end products stimulate OC)
HD related amyloid Tx
Renal transplant
Signs and symptoms AL amyloid
Constitutional: Fatigue, wt loss, adenopathy
HEENT:
- Macroglossia,
- submandibular enlargement
Heart
-CHF: SOBOE/edema
GI:
- Hepatomegaly
- Abdo pain,
Renal:
- Nephrotic syndrome
- Edema
MSK:
- Seronegative arthropathy
Neuro:
- CTS,
- Painful sensory polyneuropathy
- Autonomic neuropathy → orthostasis, syncope, impotence, gut dysmotility
Derm:
- Purpura (upper chest, neck, face, eyelid on pinch, periorbital),
- Bleeding,
- Nail dystrophy
** Syndromes that suggest AL amyloid**
-Nephrotic syndrome
-CHF
-CTS, peripheral and autonomic neuropathy (orthostatic hypotension, gastric atony)
-Hepatic disease
Clues of hepatic amyloid
Hepatomegaly (>15cm) w/ out of proportion LFT (⅓ normal), ALP > 1.5x ULN
-Howell jolly bodies on smear (splenic infiltration → hyposplenism)
-Proteinuria (high assoc w renal involvement)
Amyloid Cardiomyopathy investigation findings
NTproBNP: high (if normal = NO cardiac amyloid) - poor prognostic marker
-ECG - reduced voltage (amyloid replaced myocardium)
-TTE: sparkling echogneicity and increased septal thickness >6mm
-cMRI shows delayed subendocardial gad enhancement
How amyloid mimic rheum diseases
Vascular involvement → claudication (~GCA)
-Arthropathy ~RA but NO inflamm and frequent periarticular hip/shoulders infiltration→ enlarged pelvic/shoulder pad sign
-Muscle → weakness/pain ~polymyositis
-Abeta prot amyloid in Alzherimer deposits in cerebral blood vessels → stroke/bleed ~CNS vasculitis
How does amyloid cause bleeding/bruising
- Bruising: Deposit in vessels → weakening → bruising
- Bleeding: Factor X can bind fibrils → deficiency
** Clinical features of AA amyloid **
- Renal involvement: proteinuria, nephrotic syndrome
- Organ involvement: liver, thyroid, spleen
- GI dysfcn: bleeding, SIBO, decreased motility
- Increased ALP
-Less common: Cardiac and autonomic nerve involvement
** Disease assoc’d w/ AA amyloid **
Infxn:
- TB, HIV, IE, IVDU, Leprosy
- Chronic Pyelo, OM
- Bronchiectasis,
Cancer:
- Lymphoma (HL, NHL) , Leukemia
- Melanoma,
- GI/GU/Lung Ca, RCC
- Castleman
Autoimmune:
- RA, JIA
- Seronegative Spondyloarthropathy (PEAR)
- IBD (UC, CD)
- Rare: SLE, Sjogren’s, IgG4, GCA, TAK, PMR, Behcet, PAN, gout
Autoinflammatory:
- FMF, TRAPS, HIDS, CAPS, DADA2
Amyloid that occur more in elderly
Age related (senile ) amyloid - transthyretin amyloid deposition (ATTR)in M>F >70yo;
-MC = heart (restrictive CM), CTS
-A-beta protein amyloid (Alzheimers)
Mech of localized AL amyloid & MC organs
Focal infiltrate of monoclonal B cells producing amyloidogenic light chains → tumor deposits
Skin, Airway (lungs, larynx), eyes, bladder
Treatment for familial amyloid polyneuropathy
Liver transplant (replace variant TTR production and replace w/ normal TTR)
-Diflunisal and Tafamidis meglumine → binds/stabilizes TTR tetramer preventing fibril formation and amyloid deposition
-Paitisiran (RNA targeted therapies) interfere w/ hepatic TTR production
** How to diagnose Amyloid**
Screening biopsy
- In order of sensitivity: Fat pad, bone marrow, rectal mucosa, gingiva/labial salivary gland, skin
If negative: biopsy clinically involved site (kidney, carpal ligament, sural nerve, skin, liver) = +bleeding risk (ie do not bx enlarged liver)
Under light microscopy
- Unstained = amorphous, homogeneous hyaline extracellular material
- Congo red stained = apple green birefringence
** Investigations to order when working up amyloid**
-
SPEP/UPEP, immunoelectrophoresis, free light chains to r/o plasma cell dyscrasia as cause
– DNA analysis if consistent with hereditary
– Imaging (MRI/US) of joints
– Radiolabeled SAP scintigraphy(monitor response and see extent of dz)
AL amyloid Tx
Tx proliferating plasma cells: chemo, stem cell transplant
AA amyloid Tx
-Treat underlying (eg biologic)
-Surgery if Crohn’s
-Colchicine (1.2-1.8mg/d) for FMF
Sarcoid diagnosis
-Consistent clinical/radiographic presentation: asymptomatic bilateral hilar adenopathy, Lofgren, Heerfordt without another cause
OR
-Noncaseating granuloma WITHOUT other cause (eg TB, fungal, berylliosis, drugs, tumor/lymphoma)
Pathology of sarcoid
Noncaseating granuloma
Pathophys sarcoid
-Unknown Ag activates macrophage and DC, which serves as APC to CD4+ Th1 lymphocytes → IFNgamma, IL2, TNFa → recruits B cells, plasma cells, Th1/17 that contribute to granuloma formation
-Clonal expansion of CD4+ T lymphocytes → inflamm, noncaseating granuloma +/- fibrosis
Sarcoid clinical presentation
Asymptotic with AbN CXR (hilar adenopathy, pulm infiltrates)
-Pulm involvement
-Skin rash
-Ophthalmologic involvement
** Resp manifestations Sarcoid**
-Sinusitis, crusting, nasal bleeding
-Saddle nose deformity
-Laryngeal inflamm, stridor
-CP, SOB, dry cough
-Asymptomatic hilar adenopathy
-ILD w/ alveolitis
-pHTN
-RARE effusions, hemoptysis, clubbing
CXR radiographic stages of sarcoid and prognosis
0 - normal
-1 - bilat hilar adenopathy (70-90% remission rate)
-2 - bilat hilar adenopathy w pulm infiltrate (30-60% remission rate)
-3 - pulm infiltrate w/ lung insuff (10-20% remission rate)
-4 - end stage pulm fibrosis (0% remission rate)
-*does not indicate chronicity or correl w/ PFT
** Derm sarcoid manifestations**
Acute: Erythema nodosum
Chronic:
- Subcutaneous nodules,
- Papules,
- Plaques,
- Lupus pernio
Ocular sarcoid manifestations
-Uveitis, scleritis, retinal vasculitis, conjunctivitis
-Dryness (lacrimal glands involved)
-Proptosis (orbital involvement)
** MSK sarcoid manifestations**
-Arthralgia/Arthritis - oligo/poly, MC = ankle
-Sacroiliitis
-Effusion: Periarthritis> Synovitis
-Dactylitis
Bone changes:
-Hand/feet phalanges, axial,
-SPARES MCP, wrists
-Osteolysis, cysts/punched out lesions, trabecular pattern
Muscle
- Asymptomatic
- Myopathy (chronic or nodular)
muscle involvement
-Myositis (<3%)
** Neuro sarcoid manifestations**
CNS:
-Encephalopathy, cog impairment, dementia
-Stroke, Seizure, Vasculitis
-Aseptic meningitis
-Mass lesion→ facial nerve palsy
PNS
-Peripheral/ small fiber neuropathy
-Mononeuritis multiplex
Cardiac sarcoid manifestations
-Arrhythmias
-Heart failure
Heme sarcoid manifestations
-Lymphadenopathy
-Splenomegaly causing sequestration
-Cytopenia: RBC, WBC, Plt
Other sarcoid manifestations
HSM
Diabetes insipidus
Vasculitis
** Ix for ANy suspected of Sarcoid**
- CBC, Cr, UA, LFT, CK,
-Ca, 1,25vitD, 25-vitD, 24h UCa
-ACE or serum lysozyme (neither specific)
-TBST, IGRA
-CXR, EKG, TTE
-Slit lamp, funduscopy
** Additional IxSarcoid **
Imaging:
Brain - MR
Chest - CT, PFT
Heart - MR or FDG/PET, Holter
GI -US for liver/spleen
Spine - MR
Joints - XR
-CSF analysis
-BM biopsy
Diseases w/ elevated ACE
Infxn:TB, HIV, fungal, Leprosy
Lung: asbestosis, silicosis, hypersensitivty pneumonitis, cancer
Endocrine: HyPERthyroid, DM
** Lofgren Syndrome triad, symptoms and Tx**
-Arthritis/periarthritis (self limited w/i weeks-months)
-Erythema nodosum
-Bilateral hilar adenopathy
-Fever, uveitis
-Tx: NSAIDs or low dose GC if severe
** Heerfordt sx and Tx**
(Uveoparotid fever)
-Fever
-Parotid enlargement
-Uveitis
-Facial nerve palsy
-Arthritis
-Tx: Moderate dose GC and chronic immunosuppressive therapy
Drugs causing medication induced sarcoid
Anticancer, HIV or Autoimmune
-Immune checkpoint inhibitor
-Antiretroviral therapy
-IFN
-TNFi
Sarcoid Tx
None for most
-Skin/MSK: HCQ
-GC 1mg/kg if organ involved, taper to 10mg by 6mo and stay on that for another 6mo
-Add DMARD (MTX, AZA, MMF, LFN) if can’t taper or upfront if cardiac or neuro (CYC and ritux also possible)
-AntiTNF if failure to respond to GC + DMARD
– Infliximab or Adalimumab > Etanercept
-Transplant
-**PJP ppx, vaccinations , CAUTION VitD/Ca bc increased hyperCa and hypercalciuria from high 1,25 dihydroxyvitD (increased 1a-hydroxylase in granulomas) → stones and renal dysfcn)
Poor prognostic factors sarcoid
-Black
-Onset after 40yo
-Sx lasting >6mo
-Severe presentation
-Advanced radiographic stage
->3 organs involved at diagnosis
-pHTN
-Extrathoracic involvement
** list hand x-ray features of sarcoidosis
- Osteolysis, Lytic lesions
- Cysts/punched out lesions seen at the phalanges
- Joint space erosion
** List 6-7 diseases that have arthritis and subcutaneous nodules**
- Sarcoidosis
- RA, Tophaceous gout, JIA
- Seroneg (ReA, IBD)
- SLE, Myositis, SSc
- Vasculitis
- Multicentric Castleman
- Rheumatic fever
** How do you differentiate active versus chronic ILD?**
Active:
- Rapid worsening of resp sx <1 month (SOB, cough, sputum, fever, hypoxemia)
-Newly developed, bilateral alveolar infiltrates (eg GGO +/- consolidation) on HRCT w/o other cause (MI, PE, CHF)
-Worsening PFT
-BAL shows increase in neutrophils
-Increased WBC, inflamm markers, LDH
** Different kinds of amyloidosis**
Systemic AL Amyloidosis (primary):
- Acquired monocloncal protein.
- Systemic or local (mimicking tumor)
Systemic AA Amyloidosis
- Chronic inflammation (serum amyloid A)
Senile transthyretin (ATTR) amyloid:
- Over 70yo, M<F, usually cardiac (constrictive CM)
A-beta amyloid:
- Beta-protein deposit in Alzheimers plaques, (strokes and hemorrhage)
AF:
- Familial 🡪 mutations.
Aβ2M
- Dialysis related
** List 5 differential diagnoses for the radiographic appearance of periostitis**
- Fracture (or healing after #)
- Inflammatory: PsA, ReA
- Infection: OM
- Paraneoplastic: HPOA
- Cancer: osteo/chondro/ewing-sarcoma, leukemia, mets
- Granulomatous: Langerhans
- Endocrine: Thyroid acropachy
- Drugs - fluorosis, hypervitaminosis A, prostaglandins
** Beighton score for hypermobility**
1.Knee hyperextension >10 degrees past 180 degrees (1/knee)
2. Elbow hyperextension >10 deg past 180 (1/elbow)
3. Passive thumb opposition to flexor aspect of forearm (1/thumb)
4. Passive extension of 5th finger beyond 90 deg with forearm flat on table (1/ finger)
5. Forward trunk flexion (knees fully extended) with palms flat on ground (1 pt)
**Criteria for joint hypermobility syndrome? **
Major criteria
1)Beighton 4/9 or greater (current or historical)
2)Arthralgia for >3 months in 4+ joints
Minor criteria
1) Beighton score <4/9
2) Back pain or arthralgia (≥3 months) in 1-3 joints, spondylosis, spondylolysis/spondylolisthesis.
3)Dislocation/subluxation in 1+ joint, or in 1 joint more than once
4) 3+ soft tissue lesions (epicondylitis, tenosynovitis, bursitis).
5) Marfanoid habitus.
6) Abnormal skin: striae, hyperextensibility, thin, papyraceous scarring.
7) Eye signs: drooping eyelids, myopia, or downslanted palpebral fissures.
8) Varicose veins or hernia or uterine/rectal prolapse.
Positive if 2 major, or 1 major + 2 minor, or 4 minor (1 & 2 of maj/min are mutually exclusive)
Amyloid Classification
Systemic/Generalized
- Primary = AL= heart, GI, liver, renal, skin, nerves
- 2ndary = AA = thyroid, liver, GI, spleen, kidney (LESS heart and autonomic)
- HD assoc’d = AB2Microglobulin = synovium, joints, tendons
- Hereditary = ATTR = heart, peripheral nerves, autonomic
- FMF = AA = liver, spleen, kidney (LESS heart and autonomic)
Localized
- Tumor forming = AL = lungs, larynx, skin, eye, bladder
- Senile Cardiac = ATTR = heart
- Senile Cerebral =Beta amyloid = Alzheimer plaques
