Transcript ללא כותרת שקופית - Technion moodle

Hereditary periodic fevers syndromes
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Definition: recurrent attacks of inflammation with
genetic molecular basis for which no infectious or
auto-immune cause can be identified
Familial Mediterranean Fever (FMF) 88%
TNF-R-associated periodic syndrome (TRAPS) (55kd TNFRSF1A gene mutation: C70R, P46L)
Hyper IgD periodic fever syndrome (HIDS) (MVK
gene mutation--> mevalonate kinase deficiency)
Muckle-Wells syndrome (MWS)
Familial cold urticaria (FCU)
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Familial Mediterranean Fever (FMF)
Autosomal recessive inherited periodic disease
Sephardic, North African Jews, Armenians, Arabs,
Druze and Turks are affected
Major criteria: Fever attacks >38
Serositis (peritoneum, pleura, pericardium)
Monoarthritis (hip, knee, ankle)
6hr
Minor criteria: Incomplete attacks:
Exertional leg pain
incomplete
wk
12-72hr typical
Colchicine efficiency (1-2mg/day)
FMF. Supportive criteria:
1. Family history of FMF / parents consanguinity
2. Appropriate ethnic origin
3. Age <20 years at disease onset
4. Severe, requiring bed rest
5. Spontaneous remission
6. Acute phase reaction: ESR, SAP, fibrinogen
7. Appendectomy
8. Episodic proteinuria / hematuria
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FMF. The requirements for diagnosis:
•= or > 1 major criteria
•= or > 2 minor criteria
•1 minor plus 5 supportive criteria
1 minor plus 4 of the first 5 supportive criteria
Typical attacks:
recurrent: = or > 3 of the same type
febrile >38
short (12hr-3 days)
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Familial Mediterranean Fever
Genetic
FMF gene is mapped to short arm of chromosome
16p (The International FMF Consortium. Cell 1997.
The French FMF consortium. Nat Genet 1997)
FMF gene mutations (25) ---> transcription factor
deficit (pyrin) -----> cytoskeleton mobility---->
granulocyte activation ----> inflammation
Common FMF mutations:
M694V(3/52%), M680I(5/9%), V726A(2/3%),
M694I(0/0.4%), E148Q(1.2/4%)
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Familial Mediterranean Fever
Common MEFV (FMF gene) mutations among
Jewish ethnic groups in Israel:
M694V, 726A, M680I, E148Q
Carrier frequency of at least two mutations:
Ashkenazi 14%, Iraqi 29%, Moroccan Jews 21%
Ashkenazi carrier / non-carrier : no difference in
morbidity
V726A or E148Q: excess of febrile episodes
The frequency of MEFV mutation exceeds overt
FMF rate (phenotype III) by 40-240 fold.
Conclusions (MEFV mutations in Israel):
high carrier rate among Jews
most subjects are unaffected
Familial Mediterranean Fever
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Elevated pro-inflammatory cytokine expression in
circulating leukocytes:
TNF-alpha
IL-1beta
IL-6
IL-8
is found during attacks and in attack-free FMF
patients and supports subclinical inflammation
between attacks.
Familial Mediterranean Fever
Corticosteroid failure
Colchicine:
Daily administration
Life-long treatment
Dose:1-2mg/day
Reduces the frequency of attacks
Reduces the severity of attacks
Prevents amyloidosis
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Amyloidosis
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•Amyloid - extracellular fibrillar insoluble protein
deposition affecting organ structure and function.
•Amyloid has blue staining with iodine (Virchow
1854). Cellulose (amylum) has the same staining.
•Diagnose is established by demonstration of
amyloid in tissue:
Congo red staining in polarized light(apple-green
birefringence): + in 1/3 AL and 2/3 AA
Tissue biopsy is positive: abdominal fat 85% AL,
gingival, rectal 1/3-2/3, kidney,bone 30%,CTS 90%
Amyloidosis. Light-Chain Amyloid (AL)
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Primary (non-tumor type): derived from small
population of non-tumor plasma cells
Multiple myeloma (MM) (tumor-type): derived
from malignant clone of plasma cells
Pathology: monoclonal Ig light-chain deposits
Bence-Jones (light-chains) proteinuria is common
1/3 of light-chain amyloidosis show MM
15% of MM are complicated with Amyloidosis
Amyloidosis AL. Clinical features:
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•One organ shows predominant involvement
•Cardiovascular - in almost all cases, CHF 25%
•Proteinuria and azotemia - in most cases. AL
should be ruled out:>30 yrs+nephrotic syndrome
•Tongue enlargement (macroglossia) 20%
•Peripheral neuropathy 16%. CNS is not involved
•Carpal tunnel syndrome 20%
•GI tract: malabsorbtion, hepatomegaly, diarrhea
•Autonomic dysfunction: ortostatism, constipation..
Amyloidosis AL. Clinical features:
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• Rare splenomegaly. Functional hyposplenism
(Howell-Jolly bodies: blood cells remnants, CBC)
•Cutaneous echymoses (periorbital: “raccoon eye”)
•Nail dystrophy
•Alopecia
•Arthropathy: cold non-inflammatory effusion,
pad-like shoulders enlargement, DD hypothyroid
•Lung AL is usual. Decreased function is rare.
Amyloidosis AL. Laboratory abnormalities. 13
1. Serum protein electrophoresis: Ig monoclonal
spike 45%, hypogammaglobulinemia 25%
2. Immunoelectrophoresis/immunofixation:
monoclonal protein 90%, Bence-Jones proteinemia
(Light chain) 25%. Lambda light chains 65%.
kappa 35% (in contrast to MM).
3. Urine: Bence-Jones 75%. Low level<200mg/24hr
- occult malignancy:LY,CLL,MM, may be N serum
4. Monoclonality is not found in other amyloidosis
5. Renal failure 50%, Cr > 1.3 - shorter survival
Amyloidosis AL. Laboratory abnormalities. 14
6. Anemia 50%
7.Thrombocytosis 10%, functional hyposplenism
8. Leucocytosis
9. Increased ESR
10. Bone marrow: >5% plasma cells in 50% cases
7. Multiple myeloma laboratory abnormalities due
to infections, pancytopenia, hypercalcemia, hypoIg,
hypoalbuminemia
Amyloidosis AL. Treatment.
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Survival of AL without treatment -few months only
Multiple myeloma - VAD
Primary AL:
1. Cyclic oral therapy -mild efficacy.
Melphalan 0.2 mg/d + prednison 1mg/kg for 4 days
every 6 weeks
2. High dose of melphalan (200mg/m2+prednison
1mg/kg for 2 days) + autologic stem cells + GCSF
harvesting. Normal cardiac function is requested.
Efficacy 50 %. Heart, liver, kidney disease reverse.
Amyloidosis AL. Treatment.
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Primary AL:
3. Intermediate melphalan+autologic stem cells are
given at compromise cardio-renal function patients
with response 25%.
4. Organ transplantation + aggressive 2 schedule
5. IDOX (resorbtion of amyloid)
+dexamethasone+alkalating agent
6. Supportive: nutrition, pacemaker, dialysis,
transplantation
7. Contraindicated: digitalis, beta-, Ca-blockade
Amyloidosis AA Reactive Systemic (secondary) 17
Amyloid A Protein (acute phase reactant) deposits
Bence Jones proteinuria is absent. Signs resemble
AL. Better survival: 10 years, less due to infection.
Due To: Autoimmune dis.:RA, JRA, AS, IBD
Neoplasm: Hodgkin dis., adenocarcinoma
Chronic infections: osteomyelitis, TB
Heredofamilial: FMF
Neuropathic I-IV types
Diagnosis: tissue immuno-staining for AA protein
Amyloidosis AA. Treatment.
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Therapy for underlying disease: RA, TB, FMF
Colchicine 1.5-2mg/d, Chlorambucyle 2-8mg/d 2yrs
Other amyloidosis types ( no Bence Jones protein)
SSA senile cardiac amyloid: 24% >70yrs old, CHF
AF or ATTR familial: heart, renal, neuropathic
CAA cerebral, CNS plaques of Alzheimer disease
Beta 2-microglobulinemic amyloid due to dialysis
IAPP islet polypeptid amyloid of DM type II
FMF. ARTHRITIS.
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THREE FORMS OF ARTHRITIS IN FMF:
1. Asymmetrical non-destructive acute (75%).
Knees, ankle, wrist. One-two joints. Large effusion.
Resolution.
2. Chronic destructive including sacroiliitis (2-5%).
Hips, knees. One protracted.Repeated short attacks
Sacroiliitis 0.4%. HLA B27neg. Free lumbar spine.
3. Migratory, rheumatic fever-like.
Erysipelas-like erythema (7-40%). Unilateral.
Dorsum of ankle or foot. Fades away within 2-3ds
FMF.
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RARE MANIFESTATIONS
Mollaret’s meningitis
Fundoscopy: retinal colloid bodies
Splenomegaly, 30-50%. Nonamyloid.
Acute orchitis
Phenotype II: renal family amyloidosis+non history
of FMF + positive genetic for FMF