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