Bennett: Cecil Textbook of Medicine,
Familial Mediterranean fever (FMF) is an inherited, recurrent inflammatory disease of unknown cause. The disease is characterized by acute self-limited attacks of fever and peritonitis, sometimes accompanied by pleuritis, arthritis, and erythematous skin lesions. Among affected individuals in the Middle East and Europe, FMF is frequently complicated by amyloidosis and progressive renal failure. Familial Mediterranean fever has been given a number of other names: familial paroxysmal polyserositis, benign paroxysmal peritonitis, periodic peritonitis, and periodic disease. The first of these is descriptively accurate and an appropriate alternative name for the disease; the other terms, however, are misleading. Familial Mediterranean fever is not a benign condition, given the potentially lethal complication of amyloidosis. Moreover, attacks of acute serositis in FMF affect sites other than the peritoneum, and they recur at irregular, unpredictable intervals that do not reflect true periodicity.
Although FMF has been recognized in many parts of the world, it is largely restricted to ethnic groups originating in the eastern Mediterranean area. It is an uncommon disease, even in Israel, where the largest number of cases are seen. Half the reported cases of FMF are in patients of Sephardic Jewish ancestry; approximately 20% of patients are Armenian, and another 20% are of Turkish or Arabic descent. Most of the remaining patients are of Italian, Greek, or Ashkenazi Jewish ancestry. However, the disease has also been recognized rarely in individuals with Anglo-Saxon or northern European origins. The disease is familial, and in well-studied affected kindreds it appears to be inherited as an autosomal recessive trait. Nonetheless, nearly 50% of patients do not give a positive family history for the disease. Among reported cases males predominate by a ratio of 3:2. Recently, genetic studies of affected kindreds have mapped the gene that causes FMF (termed the MEF gene) to the short arm of chromosome 16 (in the region of 16p13). Despite variations in the clinical phenotype of patients with FMF from different ethnic groups, the disease has been linked to the same gene region in all affected populations studied. The carrier state for FMF in populations in which the disease is most commonly seen may be as high as 1 out of 6.
Although many pathogenetic explanations have been suggested for the acute inflammatory episodes of FMF, the etiology of this disease remains unknown. Extensive studies have failed to establish an infectious or allergic basis for the disease, and no good evidence exists to support suggestions that FMF represents a hormonal or psychosomatic disturbance. Recently it has been proposed that FMF might be caused by a genetically determined defect in the normal regulation of acute inflammatory responses. Abnormalities of suppressor T lymphocytes, altered metabolism of lipoxygenase products of arachidonic acid, and absence of a normal inhibitor of the complement-derived anaphylatoxin C5a have been described in FMF. However, the possible etiologic significance of these observations remains to be clarified and confirmed. The recent identification of the chromosomal location of the gene associated with FMF should assist in the eventual elucidation of the biochemical defect that underlies this disease.
Pathologic findings in FMF are those of nonspecific, acute inflammation. Neutrophilic infiltration predominates in exudates recovered from peritoneal, pleural, or joint spaces at the time of acute attacks. Serosal thickening and secondary adhesions may occur, which in the abdomen can lead to mechanical bowel obstruction. Amyloidosis is the most serious histopathologic finding in FMF. In affected individuals, amyloid is deposited in the intima and media of arterioles and in the subendothelium of venules in all major organs. There is also parenchymal deposition of amyloid, particularly in the renal glomeruli, adrenals, spleen, and alveolar septa of the lung, while the liver and heart are characteristically spared.
In most patients the signs and symptoms of FMF begin during the first two decades of life, usually between the ages of 5 and 15 years. Rarely, however, the onset of the disease may occur in infancy or as late as the fifth or sixth decade. The duration and frequency of attacks vary considerably, even in the same patient. Acute attacks typically last 24 to 48 hours and recur once or twice a month. However, attacks may recur as frequently as several times a week or as infrequently as once a year, and symptoms may persist for as long as a week during individual episodes. Some patients experience spontaneous remission that persists for years, followed by recurrence of frequent attacks. Pregnancy is often associated with remission of attacks, which resume post partum. Some patients relate the occurrence of attacks to cold weather and find that they experience attacks more frequently during winter than summer. Recurrent attacks may also become less severe and/or less frequent as patients age or as they develop amyloidosis. Between attacks, patients typically feel entirely well.
Temperatures as high as 39° C to 40° C accompany almost all attacks. Fever may occur without concomitant evidence of serositis, but this is unusual. The rise in temperature is sometimes preceded by chills and typically peaks by 12 to 24 hours; diaphoresis frequently accompanies defervescence.
More than 95% of patients experience abdominal pain and signs of peritonitis during acute attacks. Pain often begins in one quadrant and then becomes diffuse, sometimes with distention, rigidity, rebound tenderness, and ileus with nausea and vomiting. Pain may radiate to the back or to the shoulders, and upright abdominal roentgenograms may show small air-fluid levels and edema of the bowel. Although these signs and symptoms are self-limited, they can be indistinguishable from those of an acute abdominal emergency, and patients may undergo one or more exploratory laparotomies before the true nature of their disease is recognized. Potential uncertainties about the clinical management of acute abdominal episodes have led to the recommendation that elective appendectomy be carried out during a symptom-free period so that acute appendicitis does not confuse a patient's subsequent care.
Pleuritic pain occurs during acute attacks in 75% of patients. Symptoms of pleuritis may sometimes precede abdominal pain, and a few patients experience pleuritic attacks without abdominal symptoms. Chest pain is usually one-sided and may be associated with diminished breath sounds, a friction rub, atelectasis, and transient pleural effusion.
Nonspecific, mild arthralgia is a common feature of febrile attacks, and acute, monoarticular, or oligoarticular arthritis may occur. Although arthritis is unusual among patients in the United States, it is a frequently observed manifestation of FMF among Israeli patients. Arthritis usually affects large joints, the knee in particular, and effusions are common. Although arthritis episodes are typically short lived, joint symptoms may also be protracted and follow a course distinct from that of the acute abdominal and/or pleuritic attacks. Roentgenographic findings are nonspecific.
As many as a third of patients experience transient, erysipelas-like skin lesions that appear typically on the lower leg, ankle, or dorsum of the foot. These lesions are well-circumscribed, painful, erythematous areas of swelling, 5 to 20 cm in diameter, that subside spontaneously within 24 to 48 hours.
Self-limited pericarditis with pericardial effusions, conjunctivitis, aseptic meningitis, and other forms of serositis have been reported as manifestations of this disease but are unusual. Migraine-like headaches and emotional lability have also been observed during acute attacks, but it is unclear whether these are primary or secondary manifestations.
The most serious complication of FMF is systemic amyloidosis of the AA type. The natural history of amyloidosis in this disease is one of relentless progression to renal failure and death, which may occur in adolescence or even earlier. While a substantial proportion of Turkish and Israeli patients develop amyloidosis, this complication has been very unusual among patients in the United States and in several well-studied Armenian and Arabic kindreds. The genetic and/or environmental factors that explain these differences in the incidence of amyloidosis remain unclear. In Israel, 90% of patients who develop amyloidosis (particularly common in Sephardic Jews) do so after experiencing typical attacks of FMF (phenotype I); however, amyloidosis may occur in asymptomatic siblings of FMF patients, or it may precede the onset of typical FMF attacks (phenotype II).
Laboratory findings in FMF are nonspecific. During acute attacks, prominent leukocytosis (up to 30,000 per cubic millimeter) is present, and the erythrocyte sedimentation rate and acute phase reactants are increased. These values return to normal between attacks. Elevated plasma dopamine beta-hydroxylase levels (which become normal during colchicine treatment) have been reported in patients with FMF, but confirmatory studies have yet to be done to determine whether this finding represents a specific diagnostic test for FMF. With amyloidosis, laboratory abnormalities reflect the associated nephrotic syndrome and renal failure.
The diagnosis of FMF is based primarily upon clinical presentation and history. In individuals of appropriate ethnic background with typical recurrent, self-limited attacks, diagnosis should not be difficult; in such individuals, delay in recognizing the disease is usually because the diagnosis is not considered. Chromosomal mapping studies that have determined the genomic location of the FMF gene have also identified microsatellite DNA markers that can be used for the preclinical diagnosis of the disease in most kindreds. Nonetheless, when a patient is first seen or when attacks are infrequent, a variety of other acute febrile conditions must be considered and excluded by appropriate diagnostic studies and follow-up--in particular, appendicitis, pancreatitis, cholecystitis, and intestinal obstruction. Familial hyperlipidemia and porphyrias associated with abdominal symptoms must also be considered.
The diagnosis is usually most elusive when patients have a limited or atypical symptom complex. Isolated pleural attacks may closely mimic acute infections or pulmonary emboli. Arthritis, when it is a prominent manifestation, can at first be clinically indistinguishable from various infectious and noninfectious arthritides, and skin lesions on the lower legs may resemble cellulitis or superficial thrombophlebitis. Rare patients have febrile episodes without serositis, and these may require orderly evaluation to determine their origin. Recently it has been reported that infusion of metaraminol diluted in normal saline provokes acute signs and symptoms of FMF with a high degree of specificity for the disease. However, the appropriate role of such a test in establishing the diagnosis remains unclear. At present, this procedure, which carries intrinsic risks from catecholamine effects and salt load, should be considered experimental and not for use in general practice.
Once FMF is diagnosed, a degree of diagnostic vigilance must be maintained, for patients are not immune to the more common acute illnesses that FMF mimics. Of note, these patients appear to be particularly prone to develop gallbladder disease.
Colchicine treatment is effective in FMF. Several controlled clinical trials, together with extensive, uncontrolled clinical experience since the mid 1970's, have shown that prophylactic colchicine, * 0.6 mg orally two or three times a day, prevents or substantially reduces the acute attacks of FMF in 75 to 90% of patients. Treatment failures are often associated with noncompliance and/or intolerance to the drug. Some patients can abort attacks with intermittent courses of colchicine, beginning at the onset of attacks (0.6 mg orally every hour for 4 hours, then every 2 hours for 4 hours, and then every 12 hours for 2 days). In general, patients who benefit from intermittent colchicine therapy are those who experience a recognizable prodrome before developing fever and clear-cut acute symptoms. Colchicine does not alter fully developed attacks. Patients who experience gastrointestinal intolerance to colchicine may benefit from reduced doses. Although definite chronic complications from colchicine have not become apparent with its long-term use in FMF, it is still recommended that a trial of intermittent colchicine therapy be attempted, particularly in young patients, before long-term colchicine prophylaxis is used. Azoospermia and chromosomal nondisjunctions have been associated with the use of this drug. This recommendation does not apply to individuals from ethnic groups and in geographic regions associated with a high risk of amyloidosis, for it is now evident that long-term colchicine therapy not only prevents the development of amyloidosis but may also arrest its progression in FMF.
Symptomatic and supportive treatment is indicated for patients who do not respond to colchicine. However, every effort should be made to avoid the use of narcotics. In the United States, addiction to narcotics has been a major long-term complication among FMF patients.
It has been estimated that patients with FMF and end-stage renal amyloidosis represent up to 6% of the candidates for renal transplantation in Israel. Many such patients have received successful renal grafts. Of note, it has been suggested recently that these patients may be particularly susceptible to gastrointestinal and other side effects of the immunosuppressive drug cyclosporine.
The prognosis for normal longevity for patients in the United States with FMF is excellent, and since the recognition of colchicine's efficacy in this disease, most patients can be maintained almost entirely symptom-free. Except in very rare cases, this disease does not affect the physical growth and development of children. Long-term colchicine therapy has also clearly improved the prognosis of patients in the Middle East who are prone to develop amyloidosis, even those whose symptomatic attacks continue. However, among patients in whom amyloidosis has led to nephrotic syndrome or uremia and who are unable to receive a renal transplant or in whom renal transplantation has failed, the likelihood of eventual death from renal failure remains great.
Barakat MH, Karnik AM, Majeed HWA, et al.: Familial Mediterranean fever (recurrent hereditary polyserositis) in Arabs--a study of 175 patients and review of the literature. Q J Med 60:837, 1986. Provides an extensive review of the clinical and pathologic manifestations of FMF and describes differences in the incidence of amyloidosis.
Pras E, Aksentijevich I, Gruberg L, et al.: Mapping of a gene causing familial Mediterranean fever to the short arm of chromosome 16. N Engl J Med 326:1509, 1992. The first report of the chromosomal location of the gene defect causing FMF.
Zemer D, Pras M, Sohar E, et al.: Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med 314:1001, 1986. A retrospective review of 1070 patients that provides convincing evidence that long-term colchicine therapy arrests the development of amyloidosis.