In peo­ple with FMF the faulty genes re­sult in ex­ces­sive pro­duc­tion of a pro­tein called pyrin which ini­ti­ates an in­flam­ma­tory re­sponse

The Gulf Today - Time Out - - TRAVEL - Dr Asheesh Me­hta In­ter­nal Medicine Spe­cial­ist

Fa­mil­ial Mediter­ranean Fever (FMF) is a hered­i­tary dis­ease pre­sent­ing with re­cur­rent episodes of ab­dom­i­nal pain, fever and other symp­toms. FMF oc­curs mainly in peo­ple of Mediter­ranean ori­gin in­clud­ing those from the Mid­dle East, Turkey, Greece, Italy, Ar­me­nia and Azer­bai­jan. Cases have also been re­ported in indige­nous pop­u­la­tions in places atyp­i­cal for FMF like Ja­pan, In­dia, etc and aware­ness of this oth­er­wise rare dis­ease in other parts of the world too needs to be kept in mind. Fur­ther, peo­ple mi­grat­ing to or re­sid­ing in other coun­tries is now very com­mon and has re­sulted in glob­al­i­sa­tion of dis­eases also. This phe­nom­e­non has spe­cial rel­e­vance to a coun­try like UAE where peo­ple from more than 200 coun­tries re­side. FMF episodes usu­ally start in child­hood with most suf­fer­ers hav­ing had their first at­tacks be­fore the age of 20. Episodes may dis­ap­pear spon­ta­neously with age. Males are more prone to de­velop FMF episodes than fe­males.

The ba­sic func­tional and phys­i­cal unit of hered­ity in our cells is the gene. This is made up of DNA. Each gene pro­vides a par­tic­u­lar set of in­struc­tions to our cells. Genes are lo­cated on thread like struc­tures called chro­mo­somes which are them­selves lo­cated in the nu­clei of al­most all liv­ing cells. Hu­mans have 23 pairs of chro­mo­somes in their cells with one pair be­ing the sex chro­mo­somes and the other 22 pairs are called au­to­somes. Ge­netic ma­te­rial on our chro­mo­somes de­ter­mines our struc­ture and func­tions of our cells. Each type of gene is in­her­ited as a pair, one from each par­ent. In dom­i­nantly in­her­ited dis­eases hav­ing even one ab­nor­mal gene of a pair causes clin­i­cal dis­ease while in a re­ces­sive dis­or­der, dis­ease will be ev­i­dent only if both genes of the pair are faulty. FMF is an au­to­so­mal re­ces­sive dis­or­der. This means that both genes de­ter­min­ing the par­tic­u­lar ac­tiv­ity that are in­her­ited from mother and fa­ther are faulty and that these genes are car­ried on one of the au­to­somes pair rather than on the sex chro­mo­somes pair. Odds of in­her­it­ing an ab­nor­mal gene from both par­ents in­crease sub­stan­tially if the ab­nor­mal gene is com­mon in the com­mu­nity or if the cus­tom in a com­mu­nity is for mar­riage be­tween blood rel­a­tives such as cousins. An­other au­to­so­mal re­ces­sive dis­or­der that oc­curs with an in­creased fre­quency here is Tha­las­saemia.

In peo­ple with FMF the faulty genes re­sult in ex­ces­sive pro­duc­tion of a pro­tein called pyrin which ini­ti­ates an in­flam­ma­tory re­sponse. Sites com­monly in­volved are the peri­toneum, pleura, peri­cardium and joints. Peri­toneum is the mem­brane lin­ing the ab­dom­i­nal cav­ity and cov­er­ing most of the ab­dom­i­nal or­gans such as stom­ach, in­testines, etc. The pleura is the mem­brane lin­ing the chest cav­ity and cov­er­ing the lungs while the peri­cardium is the mem­brane cov­er­ing the heart. Fever is of­ten a prom­i­nent ac­com­pa­ni­ment of the in­flam­ma­tory re­sponse in FMF. Fever and ab­dom­i­nal pain be­cause of peri­toneal in­flam­ma­tion are the com­mon­est symp­toms with fever of­ten be­ing quite high. Symp­toms usu­ally ap­pear sud­denly and sub­side over a pe­riod of 2 to 4 days. Re­cur­rence of at­tacks oc­curs spo­rad­i­cally with some in­di­vid­u­als hav­ing quite fre­quent at­tacks. The sud­den on­set of ab­dom­i­nal pain along with fever may eas­ily be mis­taken for sur­gi­cal prob­lems like ap­pen­dici­tis and chole­cys­ti­tis which lat­ter refers to in­flam­ma­tion of the gall blad­der. It is not at all un­com­mon for peo­ple with FMF to have un­der­gone surgery for these di­ag­noses. The con­verse is also true. There is noth­ing to pre­vent a per­son with FMF de­vel­op­ing an­other prob­lem like ap­pen­dici­tis. Hence, each episode needs ad­e­quate clin­i­cal eval­u­a­tion to avoid over­look­ing a sur­gi­cal emer­gency or other med­i­cal prob­lem. Pleu­ral or peri­car­dial in­volve­ment presents with chest pain and fever while joint pain may be mis­taken for acute arthri­tis such as gout. Re­cur­rent arthri­tis may lead to chronic dam­age to joints which is more or less in­dis­tin­guish­able from chronic arthri­tis due to other causes. FMF is very easy to over­look but a his­tory of sim­i­lar episodes sub­sid­ing more or less spon­ta­neously in the past, es­pe­cially in an ap­pro­pri­ate eth­nic group may guide the doc­tor to the cor­rect di­ag­no­sis. A pos­i­tive fam­ily his­tory of FMF may also be avail­able. Spo­radic cases are no­to­ri­ously dif­fi­cult to di­ag­nose cor­rectly.

Di­ag­no­sis of FMF is es­sen­tially clin­i­cal. It may be sus­pected from the his­tory of re­peated episodes of pain and fever in a per­son with an ap­pro­pri­ate eth­nic back­ground. Ini­tial episodes can be very trou­ble­some till the pat­tern of symp­toms is recog­nised. It is quite com­mon for pa­tients to have symp­toms for many years be­fore the cor­rect di­ag­no­sis is made. Di­ag­no­sis is es­pe­cially easy to over­look in pop­u­la­tions where FMF is un­com­mon. Gen­eral screen­ing tests car­ried out in pa­tients pre­sent­ing with fever, ab­dom­i­nal pain, joint pain, etc re­veal only non­spe­cific ab­nor­mal­i­ties sug­gest­ing in­flam­ma­tory re­sponse. Imag­ing stud­ies like ul­tra­sound and CT scan may re­veal in­flam­ma­tory find­ings in­clud­ing col­lec­tion of fluid but are not able to pro­vide con­fir­ma­tion as to the cause be­ing FMF. Hence, dur­ing an acute episode, the doc­tor has to rely al­most ex­clu­sively on clin­i­cal judg­ment. Ge­netic test­ing is very use­ful and may re­veal ap­pro­pri­ate ge­netic mu­ta­tions. A num­ber of such mu­ta­tions could lead to the clin­i­cal fea­tures of FMF but in par­tic­u­lar eth­nic groups the cul­prit mu­ta­tions are usu­ally known and so these spe­cific mu­ta­tions can be tested for. The de­gree of ge­netic mu­ta­tion may not cor­re­spond well with sever­ity of clin­i­cal fea­tures with many peo­ple hav­ing mu­ta­tions but hardly any symp­toms. Ge­netic test­ing is con­sid­ered sup­port­ive rather than di­ag­nos­tic. A provoca­tive test in­volv­ing in­jec­tion of a drug called metaraminol which pre­cip­i­tates an acute at­tack, usu­ally milder than ones seen clin­i­cally, may also be use­ful in doubt­ful cases. A pos­i­tive test is sup­port­ive of a di­ag­no­sis of FMF but a neg­a­tive test does not rule it out.

Treat­ment is with a drug called colchicine. This needs to be con­tin­ued on main­te­nance ba­sis. Reg­u­lar use of colchicine is usu­ally ef­fec­tive in pre­vent­ing at­tacks of fever and in­flam­ma­tion. The prob­lem with colchicine is that it is an un­pleas­ant medicine with sig­nif­i­cant toxic ef­fects such as nau­sea, ab­dom­i­nal pain, vom­it­ing, di­ar­rhea, mus­cle pains, etc. The dose that needs to be taken to pre­vent acute episodes is of­ten moder­ately high and quite a few pa­tients with FMF re­gard colchicine with dis­fa­vor and are un­will­ing to take it reg­u­larly. This medicine used to be con­sid­ered the drug of choice for acute gout at­tacks also ear­lier but is now used very rarely only for re­ally bad at­tacks not re­spond­ing to other med­i­ca­tions. The rea­son for its dis­con­tin­u­a­tion in gout is be­cause of its toxic ef­fects which can on oc­ca­sion be dan­ger­ous. FMF pa­tients not well con­trolled even with max­i­mal doses of colchicine or those not able to tol­er­ate this prob­lem­atic drug may ben­e­fit from bi­o­log­i­cally ac­tive drugs which work on the im­mune sys­tem. These drugs also find use in au­toim­mune dis­eases like rheuma­toid arthri­tis. They are quite ef­fec­tive but suf­fer from the dis­ad­van­tages of be­ing quite ex­pen­sive and hav­ing their own, of­ten po­ten­tially se­ri­ous, side ef­fects.

A ma­jor long-term com­pli­ca­tion in some peo­ple with FMF is amy­loi­do­sis. This in­volves de­po­si­tion of waxy ma­te­rial called amy­loid in kid­neys, in­ter­fer­ing with their func­tion. Amy­loi­do­sis only oc­curs in peo­ple with par­tic­u­lar ge­netic types of FMF and un­like some other types of amy­loi­do­sis is more or less re­stricted to in­volve­ment of kid­neys. It is be­lieved that amy­loi­do­sis oc­curs in FMF as a con­se­quence of sus­tained in­flam­ma­tion within the body pro­vok­ing the im­mune sys­tem to gen­er­ate this un­de­sir­able pro­tein. Sim­i­lar amy­loi­do­sis may also oc­cur af­ter many years in other chronic in­flam­ma­tory con­di­tions like rheuma­toid arthri­tis or Crohn’s dis­ease too. An­other type of amy­loi­do­sis oc­curs with­out un­der­ly­ing dis­ease and is called pri­mary amy­loi­do­sis. Amy­loi­do­sis is a dif­fi­cult prob­lem which in case of FMF leads to kid­ney fail­ure. Since there is no spe­cific treat­ment for amy­loi­do­sis it­self the only rem­edy is main­te­nance dial­y­sis or kid­ney trans­plant. Reg­u­lar treat­ment of FMF with main­te­nance colchicine is quite ef­fec­tive in pre­vent­ing pro­gres­sion to amy­loi­do­sis. Thus colchicine is rec­om­mended in FMF pa­tients not only to pre­vent acute at­tacks but also to pre­vent amy­loi­do­sis. It needs to be started early be­fore kid­neys sus­tain dam­age. It is rec­om­mended not to stop tak­ing colchicine even dur­ing preg­nancy. Pres­ence of pro­tein in urine serves as a sim­ple and read­ily avail­able screen­ing and mon­i­tor­ing test for amy­loi­do­sis. De­tec­tion of pro­tein is an in­di­ca­tion to in­crease dose of colchicine in an at­tempt to halt pro­gres­sion of amy­loi­do­sis. In pa­tients un­able to tol­er­ate colchicine or those not re­spond­ing to it at max­i­mal doses, colchicine may be re­placed by bi­o­log­i­cally ac­tive drugs which are also used to pre­vent acute at­tacks to try and pre­vent amy­loi­do­sis.

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