Amyloid Sarcoid Flashcards

1
Q

Amyloid finding under light microscope & stain

A

Congo red stain → apple green birefringence

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2
Q

** Mech of amyloid deposition**

A

– 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)

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3
Q

Common symptoms in HD related amyloid

A

-CTS
-Arthralgia - shoulder pad sign, noninflamm joint effusion
-Paravertebral erosions, Intervertebral disc destruction
-Cystic bone changes (Advanced glycation end products stimulate OC)

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4
Q

HD related amyloid Tx

A

Renal transplant

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5
Q

Signs and symptoms AL amyloid

A

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

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6
Q

** Syndromes that suggest AL amyloid**

A

-Nephrotic syndrome
-CHF
-CTS, peripheral and autonomic neuropathy (orthostatic hypotension, gastric atony)
-Hepatic disease

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7
Q

Clues of hepatic amyloid

A

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)

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8
Q

Amyloid Cardiomyopathy investigation findings

A

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

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9
Q

How amyloid mimic rheum diseases

A

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

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10
Q

How does amyloid cause bleeding/bruising

A
  • Bruising: Deposit in vessels → weakening → bruising
  • Bleeding: Factor X can bind fibrils → deficiency
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11
Q

** Clinical features of AA amyloid **

A
  • 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

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12
Q

** Disease assoc’d w/ AA amyloid **

A

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

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13
Q

Amyloid that occur more in elderly

A

Age related (senile ) amyloid - transthyretin amyloid deposition (ATTR)in M>F >70yo;
-MC = heart (restrictive CM), CTS

-A-beta protein amyloid (Alzheimers)

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14
Q

Mech of localized AL amyloid & MC organs

A

Focal infiltrate of monoclonal B cells producing amyloidogenic light chains → tumor deposits

Skin, Airway (lungs, larynx), eyes, bladder

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15
Q

Treatment for familial amyloid polyneuropathy

A

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

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16
Q

** How to diagnose Amyloid**

A

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

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17
Q

** Investigations to order when working up amyloid**

A
  • 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)
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18
Q

AL amyloid Tx

A

Tx proliferating plasma cells: chemo, stem cell transplant

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19
Q

AA amyloid Tx

A

-Treat underlying (eg biologic)
-Surgery if Crohn’s
-Colchicine (1.2-1.8mg/d) for FMF

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20
Q

Sarcoid diagnosis

A

-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)

21
Q

Pathology of sarcoid

A

Noncaseating granuloma

22
Q

Pathophys sarcoid

A

-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

23
Q

Sarcoid clinical presentation

A

Asymptotic with AbN CXR (hilar adenopathy, pulm infiltrates)
-Pulm involvement
-Skin rash
-Ophthalmologic involvement

24
Q

** Resp manifestations Sarcoid**

A

-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

25
Q

CXR radiographic stages of sarcoid and prognosis

A

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

26
Q

** Derm sarcoid manifestations**

A

Acute: Erythema nodosum

Chronic:
- Subcutaneous nodules,
- Papules,
- Plaques,
- Lupus pernio

27
Q

Ocular sarcoid manifestations

A

-Uveitis, scleritis, retinal vasculitis, conjunctivitis

-Dryness (lacrimal glands involved)

-Proptosis (orbital involvement)

28
Q

** MSK sarcoid manifestations**

A

-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%)

29
Q

** Neuro sarcoid manifestations**

A

CNS:
-Encephalopathy, cog impairment, dementia
-Stroke, Seizure, Vasculitis
-Aseptic meningitis
-Mass lesion→ facial nerve palsy

PNS
-Peripheral/ small fiber neuropathy
-Mononeuritis multiplex

30
Q

Cardiac sarcoid manifestations

A

-Arrhythmias
-Heart failure

31
Q

Heme sarcoid manifestations

A

-Lymphadenopathy
-Splenomegaly causing sequestration
-Cytopenia: RBC, WBC, Plt

32
Q

Other sarcoid manifestations

A

HSM
Diabetes insipidus
Vasculitis

33
Q

** Ix for ANy suspected of Sarcoid**

A
  • 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
34
Q

** Additional IxSarcoid **

A

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

35
Q

Diseases w/ elevated ACE

A

Infxn:TB, HIV, fungal, Leprosy

Lung: asbestosis, silicosis, hypersensitivty pneumonitis, cancer

Endocrine: HyPERthyroid, DM

36
Q

** Lofgren Syndrome triad, symptoms and Tx**

A

-Arthritis/periarthritis (self limited w/i weeks-months)
-Erythema nodosum
-Bilateral hilar adenopathy

-Fever, uveitis

-Tx: NSAIDs or low dose GC if severe

37
Q

** Heerfordt sx and Tx**

A

(Uveoparotid fever)
-Fever
-Parotid enlargement
-Uveitis
-Facial nerve palsy

-Arthritis

-Tx: Moderate dose GC and chronic immunosuppressive therapy

38
Q

Drugs causing medication induced sarcoid

A

Anticancer, HIV or Autoimmune

-Immune checkpoint inhibitor
-Antiretroviral therapy
-IFN
-TNFi

39
Q

Sarcoid Tx

A

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)

40
Q

Poor prognostic factors sarcoid

A

-Black
-Onset after 40yo
-Sx lasting >6mo

-Severe presentation
-Advanced radiographic stage
->3 organs involved at diagnosis
-pHTN
-Extrathoracic involvement

41
Q

** list hand x-ray features of sarcoidosis

A
  • Osteolysis, Lytic lesions
  • Cysts/punched out lesions seen at the phalanges
  • Joint space erosion
42
Q

** List 6-7 diseases that have arthritis and subcutaneous nodules**

A
  • Sarcoidosis
  • RA, Tophaceous gout, JIA
  • Seroneg (ReA, IBD)
  • SLE, Myositis, SSc
  • Vasculitis
  • Multicentric Castleman
  • Rheumatic fever
43
Q

** How do you differentiate active versus chronic ILD?**

A

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

44
Q

** Different kinds of amyloidosis**

A

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

45
Q

** List 5 differential diagnoses for the radiographic appearance of periostitis**

A
  • 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
46
Q

** Beighton score for hypermobility**

A

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)

47
Q

**Criteria for joint hypermobility syndrome? **

A

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)

48
Q

Amyloid Classification

A

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