Familial mediterranean fever is a genetic pathology characterized by a violation of the regulation of inflammatory processes, especially in the area of serous (peritoneum, pleura) and synovial membranes. The manifestations of this disease are different, abdominal pain (picture of acute peritonitis), disorders of the pleural cavity, attacks of fever, soreness and swelling of the joints are most often recorded. The diagnosis is made on the basis of the clinical picture, the study of the hereditary history and molecular genetic analyses, the determination of the patient’s nationality plays an auxiliary role. Treatment of periodic illness is only symptomatic and supportive, there is no specific therapy at the moment.
General information
Familial mediterranean fever is a hereditary disease caused by disorders in the regulation of inflammatory and immune response at the level of granulocytes. For the first time this pathology was described in 1948 by the American doctor Raymann, who, due to repeated severe attacks, gave it the name “periodic disease”. From the first years of study, the main feature of this pathology was revealed – it occurs only in natives of the Mediterranean region and Asia Minor, mainly in Armenians, Arabs, Greeks, Spaniards, Italians, Sephardic Jews and Turks. Representatives of other nationalities have only sporadic and statistically insignificant cases of periodic illness. Therefore, the factor of the nationality of the patient and his ancestors plays an important role in the diagnosis of this condition.
The frequency of periodic illness differs among different ethnic groups of the Mediterranean region, it is highest among Turks, Arabs and Armenians, somewhat lower among Sephardic Jews, and even less often this disease occurs among Greeks, Italians and Spaniards. According to some data, the carriage of a pathological gene in certain regions affects 20% of the population, and the incidence is 1:1000-2500. Familial mediterranean fever is inherited by an autosomal recessive mechanism and affects both boys and girls with the same frequency.
Causes
For a long time, the etiology and pathogenesis of the familial mediterranean fever remained unknown, only the achievements of modern genetics allowed us to learn more about this disease. The most common cause of this pathology is mutations of the MEFV gene located on the 16th chromosome. The gene encodes a protein called marenostrin (another name is pirin), which functions as one of the central regulators of the inflammatory response and the primary immune response. Marenostrin inhibits neutrophil degranulation and inhibits their adhesive properties, thereby weakening and inhibiting the overreaction of the immune system. In familial mediterranean fever, missense mutations of the MEFV gene lead to a change in the structure of marenostrin, thereby disrupting its functions. This reduces the threshold of neutrophil degranulation, which facilitates the development of acute inflammatory reactions and forms a clinical picture of periodic illness.
In addition, marenostrin defects lead to cascading pathological reactions in the immune system and the body as a whole. The activity of an inhibitor of one of the components of the complement system, C5a, is significantly reduced. The latter gradually accumulates in the serous membranes, and when high concentrations are reached, it provokes a violent inflammatory reaction. This circumstance explains certain properties of the familial mediterranean fever – the predominant lesion of serous membranes, as well as the seasonality of the disease (it takes several months to accumulate sufficient concentrations of C5a). In some cases, the familial mediterranean fever is also characterized by the early development of amyloidosis, but its pathogenesis remains unclear.
All of the above processes occur when a person has two alleles of the defective MEFV gene, that is, in homozygotes, since familial mediterranean fever is an autosomal recessive disease. There is a theory according to which heterozygotes have increased resistance to bacterial infections due to a decrease in inhibition of the adhesive properties of granulocytes. In part, this may explain such a high occurrence of the pathological form of the gene and its carrier among the ethnic groups of the Mediterranean region. In addition, there are indications that some forms of periodic illness are caused by a gene defect on the 19th chromosome, but it has not yet been possible to accurately identify them.
Symptoms
The clinical picture of familial mediterranean fever is very diverse, but the reasons for this are still reliably unknown – the relationship between individual types of mutations and forms of the disease is assumed. It was found out that, for example, amyloidosis, which affects 30-35% of patients on average, occurs much more often in Arabs and Turks than in Armenians. A constant symptom of familial mediterranean fever (observed in 99% of cases) is a pronounced fever, which is not stopped by traditional antipyretics and antibiotics. Depending on the clinical form of the disease, an increase in body temperature may be combined with other manifestations. To date, there are four main clinical forms of familial mediterranean fever: abdominal, thoracic, articular and pseudomalarial.
The abdominal form of pfamilial mediterranean fever is characterized by a typical picture of an “acute abdomen” with peritonitis, includes a sharp increase in body temperature to 40-41 degrees, shingling pains, rigidity of the abdominal wall muscles, nausea and vomiting. Such manifestations persist for several days, after which they gradually subside. During this time, more than half of patients with familial mediterranean fever are mistakenly diagnosed with purulent peritonitis (in fact, aseptic inflammation of the peritoneum develops with this pathology), appendicitis, perforated stomach ulcer, unnecessary surgical operations are performed. The thoracic form of familial mediterranean fever creates a picture of effusive pleurisy, which can have a one- or two-sided character. This leads to chest pain, difficulty breathing, shortness of breath and other typical manifestations of purulent or exudative pleurisy, which also often causes an erroneous diagnosis. Manifestations of the thoracic form of familial mediterranean fever gradually subside over 7-10 days.
The articular form of familial mediterranean fever is characterized by the development of edema and soreness of several (less often – one) joints, sharp redness of the skin on the affected area. Symptoms persist for 2-4 weeks, arthralgia can be observed for several months. At the same time, there are no permanent disorders in the joints (limited mobility, contractures) with periodic illness. The pseudomalarial form of the disease is characterized by attacks of severe fever lasting 3-7 days, after which the patient’s body temperature returns to normal. No manifestations on the part of other organs at the initial stages of the development of pathology are not determined.
According to medical statistics, isolated clinical forms (abdominal, thoracic and others) occur in about 20% of cases of periodic illness. A combination of several clinical types of pathology (thoracic and articular, fever on the background of abdominal symptoms) is much more common. In the absence of treatment for periodic illness, about a third of patients develop amyloidosis of the kidneys, which leads to chronic renal failure and uremia. In 20% of cases, dermatological symptoms may occur against the background of the above manifestations: papular rash, urticaria, erysipelas-like inflammation. Rarely, with periodic illness, aseptic meningitis and pericarditis develop, as well as testicular inflammation (orchitis).
Diagnostics
In some cases, the diagnosis of a familial mediterranean fever can be associated with significant difficulties due to the severity, and, at the same time, the non-specificity of its manifestations. This feature of the disease can cause diagnostic errors with far–reaching consequences – for example, with a picture of an “acute abdomen”, unnecessary operations are often performed on patients, with aseptic pleurisy and meningitis, high doses of antibiotics are prescribed. In the case of arthralgia and misdiagnosis (for example, rheumatoid arthritis), a patient with periodic illness may be prescribed potent immunosuppressive agents. Therefore, in the presence of such symptoms in patients who are natives of the Mediterranean region, it is necessary to take into account the possibility of this genetic disease.
In the process of diagnosis of familial mediterranean fever, data from the study of the hereditary history of patients and molecular genetic analyses are used. As a rule, the hereditary history in such patients is burdened (sporadic forms are extremely rare), such manifestations are detected in ancestors or relatives. A geneticist can finally confirm or deny the presence of a familial mediterranean fever through genetic research. There is a common method of searching for the most common mutations of the MEFV gene in this disease – M694V and V726A, which cause more than 75% of all cases of this pathology. However, rarer MEFV defects may go unnoticed – sequencing of the entire gene sequence is used to determine them.
Treatment
Treatment of periodic illness is mainly symptomatic. With severe pain in the abdomen, chest, joints, nonsteroidal anti-inflammatory drugs and other analgesics are used, in rare cases (with pain accompanying the abdominal form of the disease) narcotic painkillers may be prescribed. Hydrothorax is eliminated by puncture and the appointment of diuretics. To prevent seizures, reduce the severity of symptoms and generally improve the condition of patients, long-term colchicine is prescribed. With the development of renal insufficiency due to amyloidosis, regular hemodialysis is recommended for patients.
Prognosis and prevention
The prognosis of periodic illness largely depends on the presence or absence of amyloidosis. If it is not present, despite severe bouts of the disease, the prognosis is favorable, because in the inter-access period patients feel satisfactory, life expectancy is practically not reduced. In the case of amyloidosis against the background of periodic illness, the survival of patients is sharply reduced due to kidney damage. The risk of amyloidosis decreases with early diagnosis of Mediterranean familial fever and timely treatment with colchicine. Prevention of periodic illness is possible only within the framework of prenatal diagnosis, which is recommended in cases where both parents are suspected of carrying a defective form of the MEFV gene.
