Transcript Document

‫بسم هللا الرحمن الرحيم‬
Familial Mediterranean Fever (FMF)
(New Look)
2011
Faculty of Medicine
Minia University
By: Yasser A. Abdelghani
FMF is more common in individuals of
Mediterranean background :
Turkish,
Israeli,
Arab descent,
Armenian
The FMF gene
( MEFV gene )
( Familial Mediterranean Fever )
MEFV is located on the short arm of
chromosome 16
MEFV encodes a 781 amino acid protein
Sites
At least 23 mutations have been identified
in this gene .
Inheritance of FMF

Autosomal recessive inheritance
(both parents must carry a recessive
gene)
FMF pathogenesis
The cause is MEFV gene mutations
lack
of pyrin, a neutrophil protein, expressed
mostly in the in serosal cells lining the
peritoneal and pleural spaces or
in synovial cells.
 It prevents neutrophils accumulation
when enough have reached an area (Hosp.
Pract. 33: 131, April 15, 1998.)
 Lacking pyrin, neutrophils mob body
cavities in a periodic manner.

CLINICAL MANIFESTATIONS
90 % before the age of 20 .
The initial attack occurs before the
age of 10 in 65 % ,
Prodrome
(pre-attack symptoms)
A prodrome is experienced by
about 50% of persons with FMF.
The
prodrome
manifests
unpleasant sensation at the site
of
the
forthcoming
spell,
emotional,
and
neuropsychological complaints
CLINICAL MANIFESTATIONS
The typical manifestations of the
disease are recurrent attacks of
severe pain and fever,
 lasting one to three days, and then
resolving spontaneously.


In between attacks, patients feel
entirely well.
Vigorous exercise is regarded
as an attack trigger by a few
patients
Attacks tend to abate during
the second half of
pregnancy
Skin rash on the ankles.
(looks like a strep infection)
The rash appears as a red, warm, swollen area about 4–6 in (10–15 cm) in
diameter.
CLINICAL MANIFESTATIONS
(Peritonitis )
• 91%
• Pain and tenderness may initially be
focal, and then progress to become more
generalized
(Peritonitis )
The pain may mimic appendicitis,
cholecystitis or renal colic and the patients
have frequently underwent surgery before
diagnosis of FMF
Recurrent attacks of
peritonitis may lead to
adhesions, with the
potential for causing small
bowel obstruction
CLINICAL MANIFESTATIONS
(Pleuritis )
• Painful FMF attacks may also be
localized to the chest.
• They may reflect either direct
inflammation of the pleura or referred pain
from subdiaphragmatic inflammation .
• Transient pleural effusion .
CLINICAL MANIFESTATIONS
(Synovitis)
• Arthritis is another common manifestation
of FMF .
• Its incidence correlates with the patient's
ethnicity.
• The arthritis is most often monoarticular or
oligoarticular
• Joint effusions are common during attacks of
synovitis.
CLINICAL MANIFESTATIONS
Other acute manifestations
Pericarditis (rare) has been described in
several patients with FMF ( 0.7 %)
Self-limited orchitis and recurrent aseptic
meningitis also can occur
Hepatic involvement:
Acute hepatitis and
recurrent hyperbilirubinemia
have been reported in the course of FMF
which are responsive to colchicine
Hepatic involvement:

Japanese patient with FMF, in whom acute
elevations of transaminase occurred. The
histological findings from the liver biopsy
specimens demonstrated a nonspecific hepatitis,
with liver cell necrosis and interlobular
inflammatory cell invasion, without the presence
of interface hepatitis or bile duct injury. This
case underscores the possibility that MEFV
mutations contribute to hepatic inflammation, as
seen in this case, by way of an alteration of the
pyrin function. ttt: Colchicine
CLINICAL MANIFESTATIONS

A few patients with FMF have reported
prolonged bouts of febrile myalgia that
may last as long as one month, and
sometimes involve the abdominal muscles

An enhanced incidence of some
vasculitides, such as polyarteritis nodosa
and Henoch-Schonlein purpura, has been
described
DIAGNOSIS
Labs: elevated WBC, ESR, CRP
 Imaging studies: pleural effusion and
synovial effusion
Non specific
 Genetic diagnosis possible

Genetic Diagnosis
• Is the only method to be certain of the
diagnosis.
MEFV molecular genetic
testing is used to confirm
the
diagnosis
However it is not yet possible to
detect all MEFV gene mutations that
might cause FMF.
Thus if DNA analysis is negative,
clinical methods must be relied upon.
Clinical Diagnosis
FMF should be suspected for any patient who:
1) Has had at least four Intermittent episodes of
fever abdominal pain or chest pain or both, lasting
from 1-3 days.
2) Without symptoms between attacks.
3) Does not have any other condition that
would explain the symptoms.
4) Has positive family history of FMF (usually -ve).
5) Responds to colchicine.
DIAGNOSIS
Other proposed tests for FMF :
• Metaraminol provocation test .
• Measurement of the serum concentration
of dopamine beta-hydroxylase (DBH):
increased.
Differential diagnosis
1 - Surgical emergencies – appendicitis,
intussusception, perforated peptic ulcer,
etc.
2 - Hereditary angioedema
3 - Acute intermittent porphyria
4 - Relapsing pancreatitis
5 - Systemic lupus erythematosus

6 - Hypertriglyceridemia
 7- PFAPA Syndrome (periodic fever,
aphthous stomatitis, pharyngitis, and
adenopathy syndrome).
The episodes of periodic fever in PFAPA are
frequently indistinguishable from those in
FMF; molecular testing of MEFV and close
follow-up may be needed to make the
correct diagnosis.
Treatment with steroids in the early stages of
an attack is effective. [Padeh 2005].

8 - Other rare hereditary periodic
fevers : tumor necrosis factor
receptor-1-associated periodic
syndrome (also called TRAPS), hyperIgD syndrome
‫ميدان التحرير ‪ ,,,,,‬جمعة النصر‬
Therapy
Therapy for FMF are two fold:
• Symptomatic relief from the acute
attacks: NSAIDs, Colchicine, Steroids
• Prevention of complications of the
disease: Colchicine
The regimen for acute attacks
in patients not taking daily
colchicine is
0.6 mg every hour for 4 doses, then 0.6
mg every 2 hours for 2 doses and then 0.6
mg every 12 hours for 4 doses
Prevention of complications of the
disease
Colchicine is effective in preventing,
delaying, or reversing renal disease
associated with amyloidosis.
• The dose is 0.6 mg PO, once daily, BID (TID,
rarely QID )
• In children the optimal effective dosage of
colchicine is about 0.02-0.03 mg/kg/24 hr
(maximum of 2 mg/24 hr)
• Patients who already have significant
proteinuria should receive a dose of 1.5 to 2.0
mg/day.
Daily Colchicine Therapy for life
Compliance with taking colchicine every
day may be hampered by its side effects,
which include diarrhea, nausea, abdominal
bloating, and gas.
Intermittent colchicine therapy
If attacks are rare and patients can
determine when they are beginning
(prodrome) , treatment with intermittent
colchicine therapy at the onset of attacks
may be sufficient therapy.
Unresponsiveness To Oral
Colchicine
IV Colchicine 1 mg IV once a week
,effective in reducing the number of
attacks
Colchicine use during
pregnancy and lactation:
Safe
Steroids in FMF
??
Patients who experience episodes
of prolonged myalgia with fever
and severe pain may need
treatment with prednisone
Dose: 1 mg/kg for as long as 6
weeks.
Colchicien-Resistant FMF
??
Colchicien-Resistant FMF
Several approaches can be tried :
1-Interferon alpha (single dose 3 to 10
million I.U. s.c )
The drug may suppress the acute inflammation of FMF only
if administered at the earliest phase.
2- alpha blocker prazosin (3 mg BID)
3- Adhering to a very low fat diet
Colchicine and fertility
There is a theoretical risk that colchicine use
could damage chromosomes in sperms and Ova,
therefore it might reduce fertility. However,
studies looking at reproduction in men and
women who have used colchicine have so far
not shown any increased risks.
 Recently, Untreated individuals with FMF,
especially those with multiple attacks and/or
amyloidosis, have a higher chance of infertility.

 Colchicine
treatment
increases fertility, BenChetrit & Levy 2003].
Prognosis
Patients who are compliant with daily
colchicine can probably expect to have a
normal lifespan if colchicine is started
before proteinuria develops.
The End