 Abstract | | |
Familial Mediterranean Fever (FMF) is a genetic disorder frequently diagnosed among the Arabs. It is also prevalent among Jews, Armenians and Turks. The clinical picture consists of febrile and painful attacks such as joint or chest pain that differ in quality across patients and even within the same patient. The gene responsible for FMF, MEFV, has been cloned and mutations were identified within its coding sequence. It encodes a protein that is expected to be a down regulator of inflammation. The major renal involvement in FMF is the occurrence of amyloidosis that primarily affects the kidneys causing proteinuria and ending in death from renal failure. It can be treated by dialysis and renal transplantation, but can be prevented by a daily regimen of colchicine. Other renal manifestations of FMF are discussed. Keywords: Familial Mediterranean Fever, Arabs, Abdominal Pain, Colchicine.
How to cite this article:
El-Shanti HI. Familial Mediterranean fever and Renal Disease. Saudi J Kidney Dis Transpl 2003;14:378-85 |
| Introduction | |  |
Familial Mediterranean fever More Details (FMF) was first described as a distinct disease entity, under the name of benign paroxysmal peritonitis, in 1945. [1] Although earlier on it had several names, the international medical community in the early sixties adopted the name suggested by the team led by Heller, [2] which reflects on three classical aspects of the disorder. Firstly, Familial, as it is autosomal recessive, [3] though about half of the patients do not have a family history. Secondly, Medi-terranean, as it is prevalent in the Mediterranean populations, namely, Jews (non-Ashkenazi), Armenians, Turks and Arabs. [4],[5],[6],[7],[8],[9],[10],[11] Thirdly, Fever, which is the most common component of the disorder; 12 however, some patients do not realize that they are febrile during the attacks.
| Clinical Picture | | |
The clinical picture consists of febrile and painful attacks that are usually of acute onset, variable frequency, mostly without a noticeable triggering factor but often occurring with menstruation, emotional stress or strenuous physical activity. [3] The pain is usually severe occurring in the abdomen, chest and joints due to inflammation of the peritoneum, pleura and synovial membrane. The attacks last from 12-72 hours and abort abruptly but the arthralgia may last longer. The attacks start, most commonly, during childhood or adolescence, with about 80% of patients presenting their symptoms before the age of 20 years and very few after theage of 40. [5],[6],[11],[13],[14] The intensity of symptoms and frequency vary from one attack to another and from one patient to another even within the same family. [15] All patients suffer from abdominal pain at one point, and it is reported in 50% of patients as the first symptom. [11] It can be diffuse or localized, ranging in intensity from mild bloating to peritonitis with rigidity and rebound tenderness. There can be constipation and the history may include a laparotomy for appendectomy. [15] Chest pain is present in about 50% of attacks, usually in the form of unilateral pleurisy with diminished breath sounds, friction rub and maybe effusion or collapse. [13] Joint pain is present in about 50-75% of attacks and it is in the form of arthritis or arthralgia. [16] The arthritis is usually monoarticular affecting the knee, hip or ankle joints. [5],[10],[16][17] Some patients develop protracted arthritis, synovitis, muscle atrophy, erosions and juxta-articular osteoporosis. [16],[18],[19],[20] The most characteristic skin lesion is the erysipelas-like erythema, occurring in 3-45% of attacks. [21],[22] It is unilateral or bilateral red, warm, swollen lesions about 10-15 cm in diameter, occurring below the knee or on the dorsum of the foot. [21],[22]
Uncommon manifestations include acute scrotal inflammation, [23],[24],[25] myalgia of variable intensity and duration, [26],[27],[28] meningeal irritation and increased CSF proteins and cells, [29],[30],[31] impaired female fertility, [32] pericarditis, [33] vasculitis, [34] purpuric lesions, [22] and nephropathy [35],[36],[37],[38]
The laboratory findings are non-specific and include leukocytosis with left shift, elevated erythrocyte sedimentation rate (ESR), high acute phase reactant titres like C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, haptoglobin, C3 and C4. [3] There may be transient albuminuria and microscopic hematuria. Between attacks, patients are mostly free of symptoms. However, there may be slight discomfort, slight fever, splenomegaly, anemia, increased fibrinogen and increased immunoglobulin levels. [3]
| Genetics | | |
The gene responsible for FMF, then named MEF, was mapped to the short arm of chromosome 16, with clear evidence for genetic homogeneity of the disorder. [39],[40],[41] The gene for FMF, now called MEFV, was cloned by two consortia independently and simultaneously. [42],[43]3 The gene is composed of 10 exons, the cDNA is 3505 nucleotides long and it encodes for a 781 amino-acid long protein called pyrin by the International consortium and marinostrin by the French consortium. [42],[43] Up till now, over 50 different mutations and polymorphisms have been identified, most of them clustered in the 10 th exon of MEFV. [44] However, the five mutations E148Q, M680I, M694V, M694I and V726A described around the time of the cloning of the gene, remain the most common across the major affected populations. [3]
| Renal Manifestations | | |
One of the significant impacts of FMF on the affected individuals is the occurrence of amyloidosis, which represents the major renal involvement in FMF. Although amyloidosis can affect other organs, it primarily manifests as a nephropathy that passes through consecutive stages of proteinuria, nephrotic syndrome, uremia, end-stage renal failure and death. [45],[46],[47] It is due to the deposition of AA protein, which is a cleavage product of the acute phase reactant SAA by the liver. [48] Chemically, it is the same type of reactive amyloidosis associated with chronic infections such as tuberculosis, bronchiectasis and rheumatoid arthritis. [49] Amyloid A usually deposits in kidneys, adrenal glands, intestine, spleen, liver, lung, thyroid, heart, stomach and testes. Intestinal malabsorption and adrenal insufficiency became recognizable signs of amyloidosis after the establishment of renal dialysis as a treatment for renal failure and thus the prolongation of the lives of those affected. Amyloidosis due to FMF does not result in a neuropathy or arthropathy. [15] Routine urinalysis in search of early albuminuria is imperative in the care of affected individuals, as it appears early in the course of renal involvement. [15] Once the proteinuria is confirmed the diagnosis of amyloidosis must be confirmed by renal biopsy, rectal biopsy, bone marrow biopsy, abdominal fat aspiration or gingival biopsy [50],[51],[52] The sensitivity of the renal biopsy is 88%, while that of the rectal and bone marrow biopsy is close to 75%. [50],[51] The abdominal fat tissue and the gingival biopsies are less sensitive and are not favoured in a diagnostic setting. [50],[52] The biopsy should be stained with congo red and viewed under polarized light where AA gives a characteristic apple green colour. [53]
From a clinical perspective, FMF patients are classified into three phenotypes; the classical form being phenotype I. Phenotype II denotes individuals who develop amyloidosis without previous painful attacks typical of FMF. [54],[55],[56] Individuals who have the disease genotype but are non-penetrant will have phenotype III. [57] The occurrence of amyloidosis is independent of the frequency, duration or intensity of the attack, [45] which is further supported by the presence of phenotype II.
Even before the introduction of colchicine, not every patient developed amyloidosis. Family history and consanguinity, as evidenced by homozygosity, are major determinants of amyloidosis in FMF. [9] Ethnicity contributes significantly to the risk of developing amyloidosis, which might be due to the presence of specific mutations in specific ethnic groups. [49] The frequency is higher in Jews of North African ancestry and in Turks, while it is less common in Arabs. [5],[17],[49],[58],[59] The possibility of an environmental influence in the predisposition to amyloidosis in FMF patients is shown by the higher incidence of amyloidosis in Armenians living in Armenia than in those living in the United States, even before the introduction of colchicine. [10]
Several investigators have noticed a correlation between the mutation M694V, especially in the homozygous state, and amyloidosis. [56],[60],[61],[62],[63],[64],[65],[66],[67] However, several others could not demonstrate that correlation. [68],[69],[70],[71] It was shown that serum amyloid A1 gene (SAA1) is a modifier for the FMF phenotype with seven fold increase in the risk for amyloidosis in patients with the SAA1 a/a genotype. [72] One study has suggested that there is an association between a common polymorphism in exon 2 (A138G) of the MEFV gene and the development of amyloidosis in FMF patients. [73] A recent study showed strong linkage disequilibrium between A138G and M694V and confirmed the strong association of amyloidosis and the SAA1 a/a genotype. [74] The correlation between the genotype and phenotype, specially regarding amyloidosis still remains an enigma. The treatment for amyloidosis is hemodialysis and renal transplantation. Colchicine plays an important role in the prevention of amyloidosis, as well as its reaccumulation in a grafted organ. [75]
In addition to amyloidosis, other renal lesions have been described in patients suffering from FMF. In a series of FMF patients, 13 out of 106 had amyloidosis but 23 had renal lesions other than amyloid. [76] The 23 patients had hematuria, albuminuria and a variety of glomerulonephritides. A number of kidney biopsies showed proliferative glomerulonephritis but the immunofluorescent studies were not available then. [76],[77] One report observed 10 episodes of Henoch-Shonlein purpura in eight FMF patients; two of the patients had kidney biopsy which showed focal mesangial proliferative glomerulonephritis with granular mesangial C3 deposits in one. [78] There is another report of three FMF patients with mesangial IgA deposits of granular pattern with proteinuria, microscopic hematuria and high serum IgA level during the painful episodes. [35] There is a report of two patients with biopsy proven rapidly progressive glomerulonephritis type 2 without amyloidosis; both presented with renal failure. [36] There is also a report of three patients with IgM nephropathy in the absence of amyloidosis. [37] A study from Jordan showed that about half of the renal involvement in FMF was non-amyloid. [38]
| Colchicine | | |
In the early 70s, two publications introduced colchicine as the primary therapy to reduce the frequency of FMF attacks. [79],[80] Its efficacy was established by few placebo controlled trials. [81],[82].,[83] A daily regimen of 1-2 mg of oral colchicine, introduced gradually, remains the recommended treatment ever since. [84] It has also been shown to be beneficial for the prevention of amyloidosis in patients before and after renal transplantation. [75],[85],[86],.[87]
While being a miracle therapeutic option for FMF, colchicine is not without its side effects. Many patients suffer from diarrhea and gastrointestinal upset but seem to tolerate it better when it is introduced gradually. [84] In addition, colchicine has been shown to induce lactose intolerance in FMF patients, which can be remedied by a lactose free diet and antiflatulents. [88] Uncommon side effects include myopathy and peripheral neuropathy but mostly in older patients with impaired renal function. [89] To avoid the teratogenic risk of colchicine, it is generally recommended to decrease the colchicine dose, during pregnancy and to perform amniocentesis early in the second trimester. [84] The concentration of colchicine in breast milk is very low, thus it seems safe for the child during lactation. [84] While oral colchicine has few risks, the intravenous administration of the drug carries major hazards and can lead to multiple organ failure and even death. [90]
| Conclusion | | |
The major renal involvement in FMF is the occurrence of amyloidosis. Amyloidosis primarily affects the kidneys causing proteinuria and ending in death from renal failure. It can be treated by dialysis and renal transplantation. Amyloidosis can be prevented in FMF patients with daily colchicine. Colchicine has the benefit of also decreasing the number and intensity of the painful attacks. It is imperative in the care of FMF patients to diagnose amyloidosis early enough to start the appropriate treatment and care.
| Acknowledgement | | |
The author is grateful for the support from Jordan University of Science and Technology, Irbid, Jordan (grant # 20020010).
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Correspondence Address:
Hatem I El-Shanti
University of Iowa Hospitals and Clinics, 2615 JCP, 200 Hawkins Drive, Iowa City, Iowa, 52242
USA
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