Familial Mediterranean Fever _ by Dr. Mohammad Al Suwi - Www.semajo.net - Www.medicsindex.com

8/14/2019 Familial Mediterranean Fever _ by Dr. Mohammad Al Suwi - Www.semajo.net - Www.medicsindex.com

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SynonymsSynonyms

Benign paroxysmal peritonitisBenign paroxysmal peritonitisHereditary Periodic Fever SyndromesHereditary Periodic Fever Syndromes

Mediterranean FeverMediterranean Fever

Periodic DiseasePeriodic DiseasePeriodic peritonitisPeriodic peritonitis

Recurrent polyserositisRecurrent polyserositis

Wolff Periodic DiseaseWolff Periodic DiseaseArmenian SyndromeArmenian Syndrome


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)%79()%79( )%13()%13( .)%4(.)%4( %50%50 ..

%97%97 amyloidamyloid ..

M694 64%M694 64%

M694V-V726AM694V-V726A (.(.E148Q )8%E148Q )8% 23%( (23%( ((( ))


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INTRODUCTIONINTRODUCTION

Familial Mediterranean feverFamilial Mediterranean fever(FMF) is a(FMF) is ahereditary inflammatory disorder that affectshereditary inflammatory disorder that affectsgroups of patients originating from around thegroups of patients originating from around the

Mediterranean Sea (hence its name). It isMediterranean Sea (hence its name). It is

prominently present in theprominently present in the ArmenianArmenian people (uppeople (up

to 1 in 7 affected), Sephardi Jews (and, to ato 1 in 7 affected), Sephardi Jews (and, to a

much lesser extent, Ashkenazi Jews), peoplemuch lesser extent, Ashkenazi Jews), people

from Turkey, and the Arab countries.from Turkey, and the Arab countries.


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HistoryHistory

A New York allergist,A New York allergist,Dr Sheppard SiegalDr Sheppard Siegal, first, firstdescribed the attacks of peritonitisdescribed the attacks of peritonitis in 1945; hein 1945; he

termed this "termed this "benign paroxysmal peritonitisben

ign paroxysmal peritonitis", as", as

the disease course was essentially benign.the disease course was essentially benign.Dr Hobart ReimannDr Hobart Reimann, working in the American, working in the AmericanUniversity in Beirut, described a more completeUniversity in Beirut, described a more complete

picture which he termed "picture which he termed "periodic disease

periodic disease..


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FrequencyFrequency

Ashkenazi Jewish people have a prevalence of 1Ashkenazi Jewish people have a prevalence of 1case per 73,000 population, with a genecase per 73,000 population, with a gene.frequency of 1:135.frequency of 1:135

Sephardic Jewish people have a prevalence of 1Sephardic Jewish people have a prevalence of 1

case per 250-1000 population, with a genecase per 250-1000 population, with a gene.frequency of 1:8-16.frequency of 1:8-16

Armenian persons have an estimated prevalenceArmenian persons have an estimated prevalenceof 1 case per 500 population and a geneof 1 case per 500 population and a gene

.frequency of 1:7.frequency of 1:7Turkish people 1 case per 1000 populationTurkish people 1 case per 1000 population

Arabic people 1 case per 2600 population and aArabic people 1 case per 2600 population and a.gene frequency of 1:50.gene frequency of 1:50


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TypesTypes

FMF type 1FMF type 1 is characterized by recurrent short episodes ofis characterized by recurrent short episodes of

inflammation and serositis including fever,inflammation and serositis including fever,

peritonitis, synovitis, pleuritis, and, rarely,peritonitis, synovitis, pleuritis, and, rarely,pericarditis and meningitis. The symptoms varypericarditis and meningitis. The symptoms vary

among affected individuals, sometimes evenamong affected individuals, sometimes even

among members of the same family.among members of the same family.

Amyloidosis, which can lead to renal failure, isAmyloidosis, which can lead to renal failure, is

the most severe complication of FMF type 1.the most severe complication of FMF type 1.


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TypesTypes

FMF type 2FMF type 2Is characterized by amyloidosis as the firstIs characterized by amyloidosis as the first

clinical manifestation of disease in an otherwiseclinical manifestation of disease in an otherwise

asymptomatic individualasymptomatic individualAmyloidosisAmyloidosis is a rare and potentially fatalis a rare and potentially fataldisease that occurs when substances calleddisease that occurs when substances called

amyloid proteins build up in your organs.amyloid proteins build up in your organs.

Amyloid is an abnormal protein usuallyAmyloid is an abnormal protein usually

produced by cells in your bone marrow that canproduced by cells in your bone marrow that can

be deposited in any tissue or organbe deposited in any tissue or organ


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Mortality/MorbidityMortality/MorbidityNephrotic syndrome: Before the institution of-Nephrotic syndrome: Before the institution of-

colchicine therapy, mortality from nephroticcolchicine therapy, mortality from nephrotic

.syndrome was almost universal by age 50.syndrome was almost universal by age 50

Appendectomies: Many undiagnosed FMF-Appendectomies: Many undiagnosed FMF-

.patients had appendectomies.patients had appendectomies

-Chronic arthritis: Approximately 5% of patients-Chronic arthritis: Approximately 5% of patients-

. may develop chronic arthritis. may develop chronic arthritis

Fertility and pregnancy: Approximately one third -Fertility and pregnancy: Approximately one third -

of female patients are infertile, and 20-30% ofof female patients are infertile, and 20-30% of

.pregnancies result in fetal loss.pregnancies result in fetal loss


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SexSex

In adults, FMF is more prevalent in men thanIn adults, FMF is more prevalent in men thanin women, with a male-to-female ratio of 1.5-in women, with a male-to-female ratio of 1.5-2:12:1..


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AgeAge

Of all persons with FMF, 50-60% areOf all persons with FMF, 50-60% areyounger than 10 years, 80-95% are youngeryounger than 10 years, 80-95% are youngerthan 20 years, and 5-10% are older than 20than 20 years, and 5-10% are older than 20

years. FMF is rare in persons older than 40years. FMF is rare in persons older than 40years.years.


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AttacksAttacks

There are seven types of attacks. 90% of allThere are seven types of attacks. 90% of allpatients have their first attacks before theypatients have their first attacks before theyare 20 years old. All develop over 2-4 hoursare 20 years old. All develop over 2-4 hours

and last anytime between 6 hours and 4and last anytime between 6 hours and 4.days.days


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Signs and SymptomsSigns and Symptoms

--Joint attacksJoint attacks , occurring in large joints, mainly, occurring in large joints, mainlyof the legs.of the legs. 75% of all FMF75% of all FMF

--Chest attacksChest attacks with pleuritis40% and pericarditiswith pleuritis40% and pericarditis

--Scrotal attacksScrotal attacks due to inflammation of thedue to inflammation of thetunica vaginalis. 5%tunica vaginalis. 5%

--Myalgia )rareMyalgia )rare((

---ErysipeloidErysipeloid a skin reaction on the legsa skin reaction on the legs ..rarerare---FeverFeverwithout any symptoms . 25%without any symptoms . 25%


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Skin reactionSkin reaction


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PathophysiologyPathophysiology

FMF is a recessive genetic disease likely causedFMF is a recessive genetic disease likely causedby missense and nonsense mutations in theby missense and nonsense mutations in the

MEFVMEFVgenegene that is located on the short arm ofthat is located on the short arm ofchromosomechromosome1616. This gene codes for the. This gene codes for theprotein known asprotein known aspyrinpyrin. or marenostrin. or marenostrin

The function of pyrin appears to be a suppressorThe function of pyrin appears to be a suppressor

of the activation of caspase 1, the enzyme thatof the activation of caspase 1, the enzyme that

stimulates production ofstimulates production of interleukin 1,interleukin 1,a cytokinea cytokine central to the process ofcentral to the process ofinflammationinflammation..


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MEFVMEFV

Human gene that provides instructions forHuman gene that provides instructions formaking a protein called pyrin (also known asmaking a protein called pyrin (also known asmarenostrin). Pyrin is produced in certainmarenostrin). Pyrin is produced in certainWBC`S blood cells (neutrophils, eosinophilsWBC`S blood cells (neutrophils, eosinophils

and monocytes) that play a role in inflammationand monocytes) that play a role in inflammationand in fighting infection. Inside these whiteand in fighting infection. Inside these whiteblood cells, pyrin is found with the cytoskeleton,blood cells, pyrin is found with the cytoskeleton,the structural framework that helps to define thethe structural framework that helps to define the

shape, size, and movement of a cell. Pyrin'sshape, size, and movement of a cell. Pyrin'sprotein structure also allows it to interact withprotein structure also allows it to interact withother molecules involved in fighting infectionother molecules involved in fighting infection.and in the inflammatory response.and in the inflammatory response


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GeneticsGenetics

Familial Mediterranean fever has an autosomalFamilial Mediterranean fever has an autosomal.recessive pattern of inheritance.recessive pattern of inheritance

TheTheMEFVMEFVgene is located on the short arm ofgene is located on the short arm of

chromosome 16. The disease inherits in anchromosome 16. The disease inherits in anautosomal recessive fashion. Therefore, twoautosomal recessive fashion. Therefore, two

asymptomatic carrier parents have a 25%asymptomatic carrier parents have a 25%

chance of a child with the disorder. FMFchance of a child with the disorder. FMF

patients who marry a carrier or another FMFpatients who marry a carrier or another FMF

patient have a 50% and 100% chance,patient have a 50% and 100% chance,

.respectively, in having a child with FMF.respectively, in having a child with FMF
http://en.wikipedia.org/wiki/Image:Autorecessive.jpg


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http://en.wikipedia.org/wiki/Image:Autorecessive.jpghttp://en.wikipedia.org/wiki/Image:Autorecessive.jpghttp://en.wikipedia.org/wiki/Image:Autorecessive.jpg


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Genetic analysisGenetic analysis

Since the cloning of the gene in 1997, geneticSince the cloning of the gene in 1997, geneticanalysis of the patients can be performedanalysis of the patients can be performedfor the presence of mutations that arefor the presence of mutations that arethought to be responsible for thethought to be responsible for the

development of FMF. The clinical diagnosisdevelopment of FMF. The clinical diagnosisof FMF is confirmed if the patient carriesof FMF is confirmed if the patient carries.two mutations; one from each parent.two mutations; one from each parent


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Blood Sample/Blood Sample/MEFVMEFV genegene


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IMPORTANT TESTSIMPORTANT TESTS

--ESR, )CRP(, whole blood count, fibrinogenESR, )CRP(, whole blood count, fibrinogen ,,are ordered during an attack to see the extentare ordered during an attack to see the extent. of inflammation. of inflammation

-

--Urine testUrine test: A sample of urine is also tested for: A sample of urine is also tested for. the presence of protein and red blood cells. the presence of protein and red blood cells---Rectal or renal biopsyRectal or renal biopsy : if the rectal biopsy: if the rectal biopsy

fails to show amyloid then a renal biopsy isfails to show amyloid then a renal biopsy isnecessary to confirm the diagnosisnecessary to confirm the diagnosis


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DiagnosisDiagnosis//TestingTesting

The diagnosis of FMF isThe diagnosis of FMF is clinicalclinical and isand issuspected in individuals with recurrentsuspected in individuals with recurrentepisodes of fever associated with abdominalepisodes of fever associated with abdominal

painpain ((peritonitisperitonitis)) andand//or pleuritic pain andor pleuritic pain and//oror

arthritisarthritis ((ankleankle//kneeknee)) usually lasting two to threeusually lasting two to three

daysdays.. A high erythrocyte sedimentation rate,A high erythrocyte sedimentation rate,

leukocytosis, and a high serum concentration ofleukocytosis, and a high serum concentration of

fibrinogen are characteristicfibrinogen are characteristic.. MEFVMEFVis the onlyis the onlygenegene currently known to be associated withcurrently known to be associated with

FMFFMF.. MEFVMEFVmolecular genetic testingmolecular genetic testing is usedis used

to confirm the diagnosisto confirm the diagnosis..


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Polymerase Chain ReactionPolymerase Chain Reaction

Is a technique widely used in molecular biology. ItIs a technique widely used in molecular biology. It

derives its name from one of its key components, aderives its name from one of its key components, a

DNA polymerase used to amplify (i.e., replicate) aDNA polymerase used to amplify (i.e., replicate) a

piece of DNA bypiece of DNA byin vitroin vitro enzymatic replication. As PCRenzymatic replication. As PCR

progresses, the DNA thus generated is itself used asprogresses, the DNA thus generated is itself used astemplate for replication. This sets in motion a chaintemplate for replication. This sets in motion a chain

reaction in which the DNA template is exponentiallyreaction in which the DNA template is exponentially

amplified. With PCR it is possible to amplify a single oramplified. With PCR it is possible to amplify a single or

few copies of a piece of DNA across several orders offew copies of a piece of DNA across several orders ofmagnitude, generating millions or more copies of themagnitude, generating millions or more copies of the

DNA piece. PCR can be performed without restrictionsDNA piece. PCR can be performed without restrictions

on the form of DNA, and it can be extensively modifiedon the form of DNA, and it can be extensively modified

.to perform a wide array of genetic manipulations.to perform a wide array of genetic manipulations

PCR C i


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PCR CopiesPCR Copies


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STEPSSTEPS


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DIFFERENTIAL DIANGOSISDIFFERENTIAL DIANGOSIS

- Hyperimmunoglobulinemia D syndrome- Hyperimmunoglobulinemia D syndrome ::

lymphadenopathy, skin eruption symmetricallymphadenopathy, skin eruption symmetrical

.oligoarthritis in HIDS.oligoarthritis in HIDS:Genetically Related (Allelic) Disorders:Genetically Related (Allelic) Disorders

-Behet's disease -Behet's disease ----Ulcerative colitisUlcerative colitis

---Rheumatoid arthritisRheumatoid arthritis


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ComplicationsComplications

Amyloidosis. -Amyloidosis. -the most commonthe most commoncomplication ,kidney , heart ,thyroid ,spleen.complication ,kidney , heart ,thyroid ,spleen.

- Nephrotic syndrome- Nephrotic syndrome

Infertility -Infertility -Chronic arthritis -Chronic arthritis -

-General discomfort -General discomfort ----vasculitis -related diseases :vasculitis -related diseases : HSPHSP

spondylarthropathy, prolonged arthritis ofspondylarthropathy, prolonged arthritis of

. certain joints and protracted myalgia. certain joints and protracted myalgia


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PreventionPrevention

Familial Mediterranean fever can't be prevented.Familial Mediterranean fever can't be prevented.

However, you can relieve your signs andHowever, you can relieve your signs and

symptoms and prevent complications bysymptoms and prevent complications by

adhering to the colchicine regimenadhering to the colchicine regimen


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TreatmentTreatment--Colchicine therapyColchicine therapy : Some people might need: Some people might need

to take just one dose a day, while others mightto take just one dose a day, while others might. require multiple doses. require multiple doses

---REMICADEREMICADE (Infliximab )is a chimeric IgG1(Infliximab )is a chimeric IgG1

monoclonal antibody. It is composed of humanmonoclonal antibody. It is composed of humanconstant and murine variable regions.constant and murine variable regions.

Infliximab binds specifically to human tumorInfliximab binds specifically to human tumor(necrosis factor alpha (TNF(necrosis factor alpha (TNF..

--Interferon-gammaInterferon-gammaanti-TNF treatment -anti-TNF treatment -thalidomide -thalidomide -


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Side effects of drug therapySide effects of drug therapy

colchicine is a safe drug with minor side effectscolchicine is a safe drug with minor side effectswhich usually respond to dose reduction. Thewhich usually respond to dose reduction. Themost frequent side effect is diarrhoea , nausea,most frequent side effect is diarrhoea , nausea,vomiting, and abdominal cramps , musclevomiting, and abdominal cramps , muscle

. weakness. weaknesswhite and red blood cells and platelets) may -white and red blood cells and platelets) may -.decrease.decrease

The decrease in the number of sperm is very-The decrease in the number of sperm is very-rarerare

Do not have to stop taking colchicine during -Do not have to stop taking colchicine during -.pregnancy or breast feeding.pregnancy or breast feeding


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Alternative medicineAlternative medicine

The following herbs have been evaluated withThe following herbs have been evaluated withsome positive responses, but more research issome positive responses, but more research is

needed before we know the ideal dosages,needed before we know the ideal dosages,

frequency of use and long term side effectsfrequency of use and long term side effects

..

Echinacea angustifolia & purpurea,Echinacea angustifolia & purpurea,Astragalus membranaceus, andAstragalus membranaceus, andEleutherococcus senticosus )SiberianEleutherococcus senticosus )Siberian

Ginseng herb(, Andrographis paniculata,Ginseng herb(, Andrographis paniculata,Schizandra chinensis, and GlycyrrhizaSchizandra chinensis, and Glycyrrhiza.)glabra )licorice.)glabra )licorice


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Self-careSelf-care

Take your medication on schedule -Take your medication on schedule -

Fine-tune your diet. -Fine-tune your diet. -Some people withSome people withFMF notice that their attacks are lessenedFMF notice that their attacks are lessened

by following a low-fat diet. One side effectby following a low-fat diet. One side effect

of colchicine therapy is lactoseof colchicine therapy is lactose

,intolerance,intolerance

PROGNOSISPROGNOSIS


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PROGNOSISPROGNOSIS

patients in whom amyloidosis has led topatients in whom amyloidosis has led to

nephrotic syndrome or uremia and who arenephrotic syndrome or uremia and who are

unable to receive a renal transplant or in whomunable to receive a renal transplant or in whom

renal transplantation has failed, the likelihood ofrenal transplantation has failed, the likelihood of

eventual death from renal failure remainseventual death from renal failure remains

The prognosis for normal longevity for patients inThe prognosis for normal longevity for patients in

the United States with FMF is excellent, andthe United States with FMF is excellent, and

since the recognition of colchicine's efficacy insince the recognition of colchicine's efficacy inthis diseasethis disease

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Familial Mediterranean Fever _ by Dr. Mohammad Al Suwi - Www.semajo.net - Www.medicsindex.com