CASE REPORT

End-stage Renal Disease Associated with FamilialMediterranean Fever

Nozomi Tomiyama, Saori Oshiro, Yasushi Higashiuesato, Masanobu Yamazato, Atushi Sakima, Takeshi Tana,Masahiko TozAwa, Hiromi Muratani, Kunitoshi Iseki* and Shuichi Takishita

Abstract

A 39-year-old man had been suffering from periodic fe-ver since childhood. Hewas started on hemodialysis due tosecondary amyloidosis on December 2000. The patient wasbelieved to have Familial Mediterranean fever (FMF) be-cause of recurrent fever with peritonitis, arthritis and in-flammatory changes and secondary amyloidosis in his kid-neys, heart and colon. No other family member had recur-rent fever. IL-6, TNF, and dopamine (3-hydroxylase werenot increased in the febril phase. The patient was homozy-gous for the M694Imutation. Wereport the first Japanesecase of FMFassociated with amyloidosis and confirmed bya gene mutation.(Internal Medicine 41: 221-224, 2002)

Key words: periodic fever, amyloidosis, kidney, dialysis,MEFVgene, colchicine

Introduction

Familial Mediterranean fever (FMF) is an autosomal reces-sive disease, characterized by recurrent attacks of fever andperitonitis, pleuritis, arthritis, or erysipelas-like skin disease(1).

The disease is restricted to persons of Mediterranean de-scent especially sephardic Jews, Armenians, Turks, and Arabs.It is very rare in Japan. In 1997, the international and the FrenchFamilial Mediterranean fever consortia independently clonedthe gene responsible for FMF,found on the short arm of chro-mosome 16 (MEFV) (2, 3). The gene responsible for FMFspans10 exons, and encodes a 781 amino acid protein. To date, 26mutations have been found in MEFV(4). Most mutations aremissense mutations that result in the substitution of a singleamino acid (1). In Japan, only 15 cases have been reported (5,6). Wereport the first Japanese case of FMFassociated withamyloidosis and diagnosed by the existence of the FMFgene.

Case ReportA 39-year-old man had been suffering from periodic feverof unknown origin accompanied with arthritis, abdominal painand erythema nodosum-like skin lesions since he was 3 yearsold. He was diagnosed with rheumatic fever in infancy. Heentered a hospital for examination of renal failure (serumcreatinin level was 2. 1 mg/dl) and periodic fever with abdomi-nal pain in 1998. Spike fever of more than 38°C appeared andthe laboratory studies showedan accelerated erythrocyte sedi-mentation rate, leukocytosis with neutrophilia, and increasedlevels of C-reactive protein. He was diagnosed with secondaryamyloidosis by kidney and colon biopsy. Crohn's disease wasdiagnosed as a basal disease and treated by oral prednisoloneand mesalazine. Thereafter, he had frequent febrile attacks onceor twice a month lasting from 1 to 3 days accompanied byinflammatory findings, abdominal pain and arthritis. On Octo-ber 29, 2000, he was admitted to hospital because of fever andpain. At the time of admission to the department of internalmedicine of our hospital on October 31, he had a low gradefever and severe pain due to polyarthritis.The laboratory findings at that time are summarized in Table1. The thyroid was swollen and the TSH level was elevated butthyroid hormones were within normal range. Chest X-ray filmsshowed a small amount of fluid in the thoracic cavity and ab-dominal echocardiography and computed tomography showedslight accumulation of ascites, mild splenomegaly and atrophyof the bilateral kidneys (about 8 cm in size). X-ray films ofextremities did not show joint deformity or other findings ofrheumatoid arthritis. Cardiac ultrasonic examination showedmarked cardiac hypertrophy with sparkling signs and slightpericardial effusion. Cultures for bacteria in the urine and bloodand cultures for tuberculosis in the sputum and bone marrowwere negative. Bonemarrowexamination and muscle biopsydid not show apparent abnormalities. An increased dose of pred-nisolone (20 mg/day) and antibiotics (Sulperazone) were noteffective but fever and polyarthritis gradually disappeared intwo weeks and the accelerated erythrocyte sedimentation rate,leukocytosis, and increased levels of C-reactive protein were

From the Third Department of Internal Medicine and *Dialysis Unit, University of The Ryukyus, OkinawaReceived for publication July 18, 2001 ; Accepted for publication October 25, 2001Reprint requests should be addressed to Dr. Nozomi Tomiyama, the Third Department of Internal Medicine, University of The Ryukyus, 207 Uehara, Nishihara,

Okinawa903-0215

Internal Medicine Vol. 41, No. 3 (March 2002)221

Tomiyamaet al

Table 1. Laboratory Findings on Admission[S e ro lo g ic a l te st]

[P er i ph er a l bl oo d ] C R P 2 . 0 6 m g / d l U A 1 2 . 7 m g / d lW B C 2 8 , 7 0 0 / u l R A t e s t ( + ) N a 1 4 0 m E q / l

S e g + S ta b 9 3 .0 % R A I g G ( - ) K 4 . 2 m E q / /

L y 3 .0 % L E t e s t ( - ) C 1 1 0 2 m E q / lM o 2 .0 % A N A ( - ) C a 8 . 4 m g / d l

R B C 4 2 2 x 1 O 7 1 i l A n t i - D N A A b ( - ) T - b i 1 0 . 4 m g / d lH b l l . 5 g / d l A n t i - J o - 1 A b ( - ) A S T 1 7 I U / /

H c t 3 4 . 8 % A n t i - R N P A b ( - ) A L T 9 I U / /

P L T 3 9 . 9 x l O 4 / u l I g A 2 9 3 m g / d l L D H 2 2 5 IU /Z

E S R 4 6 m m / h I g G 1 , 1 2 0 m g / d l A L P 2 5 7 I U / /

I g M 2 0 8 m g / d l y - G T P 6 0 I U / Z

[U rin a ly sis ] I g D 2 m g / d l A M Y 4 8 IU //

P r o t e i n ( 2 + ) C 3 5 9 m g / d l C P K 1 8 9 I U / /

S u g a r (- ) C 4 3 4 m g / d l F e r r i t i n 1 0 5 n g / m l

B lo o d (2 + ) C H 5 0 3 4 I U / m l

B e n c e - J o n e s p r o t e i n ( - ) [E n d o c rin o lo g y ]

[ B i oc he mi st ry ] T S H 3 . 7 u l U / m l

[S to o l] T P 6 . 5 g / d l 1 . 40 p g /m l

O c c u l t b l o o d ( - ) A l b 3 . 7 g / d l F T 4 1 . 4 0 n g / d l

G l u 6 2 m g / d l T h y r o g l o b u l i n A b ( - )B U N 5 8 m g / d l A n t i T P O A b ( - )

C r 4 . 7 m g / d l

1 m g

0 . 5 m g c o l c h i c i n e p r e d o n i s o l o n e m 2 0 m g 0 . 1 2 5 m g 2 . 5

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P o ly arth ritis

F e v e r i n

G I b lee din g H em o d ialy sis (3/w ee k )

W B C i o 4 n n * * 一蝣- W B C C R P u n ¥ ) 4 3 - 4 0 0 - - - w ^ ( m g / d l ) . . . m ? v > S A A(u g /m l)

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50

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2 0 0 0 O c t . 3 1 N o v . 1 6 D e c . 2 2 2 0 0 1 J a n . l l F e b . 1 6 M a r . 1 3 A p r . 2 0

Figure 1. Clinical course.

2 2 2 Internal Medicine Vol. 41, No. 3 (March 2002)

ESRDDue to Familial Mediterranean Fever

normalized. Thereafter, he had severe bleeding of the upperdigestive tract, and the biopsies of the duodenumand colonshowed AAamyloid deposition. Crohn's disease was deniedby the finding of colon fiber. After treatment by IVH and aproton pomp inhibitor, the bleeding was improved.The patient did not satisfy the diagnostic criteria of rheuma-toid arthritis or other collagen diseases. Wesuspected FMF,because there was no evidence of any other disease and due tothe clinical manifestations such as recurrent fever with perito-nitis, arthritis and inflammatory changes, and the complica-tion of secondary amyloidosis. However, no other family mem-ber had recurrent fever. The patient was given a 0.5 mg ofcolchi-cine. After admission, renal insufficiency progressed gradu-ally and he had congestive heart failure. He was transferred toour department on December22, and he was placed on main-tenance hemodialysis on the same day (Fig. 1). The patienthad repeated febrile attacks once or twice a month lasting 6

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Figure 2. MEFVgene analysis.

hours to 1 day accompanied by inflammatory findings, abdomi-nal pain and arthritis. Colchicine was increased to 1 mg perday, but wehadto stop dueto the appearanceof bonemarrowsuppression (Fig. 1). IL-1 , TNF and dopamine P-hydroxylasewerenot increased in the febril phase. To makea definitivediagnosisof FMF,weperformedgeneanalysis after obtainingthe written informedconsent from the patient. Accordingtothe phenol chloroformmethod,genomicDNAwasextractedfromperipheral leukocytes. Wescreened the exon 10 in MEFVgenebecausethis region has morefrequent mutationsinFMF(1). Polymerase chain reaction (PCR) was performedincluding the lesion using the primer : forward primer (5'GAGC-CTGCAAGACATCCATA3')and reverse primer (5'TGACC-ACCCACTGGACAGAT3').The PCRproducts were analyzedon aABI 310 DNAsequencer in both directions.The patient was homozygousfor the M694Imutation whichis a knownMEFVmutation (G->Atransversion of nucleotidethat results in substitution of isoleucine for methionine)(Fig. 2).

Discussion

Familial Mediterranean fever (FMF) is an autosomal reces-sive disease, characterized by recurrent attacks of fever andperitonitis, pleuritis, arthritis, or erysipelas-like skin disease.Thesymptomsare not apparentbetweenattacks. Thediseaseaffects certain ethnic groups, mainly Sephardic Jews, Arme-nians, Turks, and Arabs. Atypical attack consists of fever andserositis, lasting from one to four days. Betweenattacks, pa-tients are free of symptoms.Until recently, a diagnosis of FMFwas based on clinical manifestations, ethnicity, family history,and response to colchicine. In 1997, two independentconsor-tia identified and isolated the gene responsible for FMF(MEFV)on the short arm of chromosome16 (2, 3). Cloning of MEFVnowallows a newand reliable diagnostic test for FMF.Thegene responsible for FMFspans 10 exons, and encodes a 781amino acid protein. The international FMFConsortium hasnamedthe protein encoded by MEFVPyrin, while the FrenchFMFConsortium namedit Marenostrin, the Greek nameforthe Mediterranean Sea. To date, 26 mutations have been foundin MEFV(4). Mostmutations are missense mutations that re-sult in the substitution of a single aminoacid.In Japan, FMFis a very rare disease. There are only 15 re-ported cases (2 cases with family history) since Hayashi et alreported the first case in 1976 (5, 6). One of the most signifi-cant complicationsof FMFis amyloidosis, usually affectingthe kidneys, resulting in end-stage renal disease (ESRD). Amy-loidosis mayalso affect the adrenal glands, gastrointestinal tract,spleen and liver. It less commonly,affects the lung, thyroid,

heart, stomach, and testes (7, 8). The patient presented withsecondary amyloidosis of kidneys, gastrointestinal tract, heartand perhaps thyroid. The amyloid protein is of the AAtype,typical of secondaryamyloidosis. Its prevalencediffers amongvariousethnic groupsandusuallydependson whetheror notthe patient is treated with colchicine, which significantly de-creases its incidence. Most patients whodevelop amyloidosisdo so by the age of 40 years. Several studies comparingpheno-

Internal Medicine Vol. 41, No. 3 (March 2002) 2 2 3

Tomiyamaet al

type manifestations and genotype analysis have disclosed thatpatients with FMFhomozygousfor the M694Vmutation havea more severe disease manifestation by early onset, more fre-quent attacks, joint disease, and require higher doses of colchi-cines (9-ll). Moreover, such patients are prone to developamyloidosis (ll, 12). The prevalence of amyloidosis amongthe FMFpopulation has been thought to be independent of thefrequency, duration, and intensity of flares (8). Shohat et al(10) and Livneh et al (12) showed that M694Vmutation sig-nificantly is correlated with the presence of amyloidosis com-pared with other mutations. Ben-Chetrit and Backenroth (13)showed that 23 patients with ESRDinduced by amyloidosiswere homozygous for the M694Vand M691I mutations andconcluded that amyloidosis is highly associated with the 694substitution in the MEFVgene causing FMF. The present pa-tient was homozygous for the M694I mutation and it may havea relation to amyloidosis. No case with amylidosis has beenreported in Japan.It is knownthat neutrophils accumulate in areas of inflam-mation during FMFattacks, but the molecular mechanism bywhich this happens has remained obscure. The secretion ofmediators of inflammation such as interleukin- 1 and the tumornecrosis factor (TNF) has been reported to increase during acuteattacks, whereas, interferon activity is decreased (14, 15). Se-rosal fluids, especially from the peritoneal cavity or from thesynovia, were reported to have reduced activity of the C5a in-hibitor (16), and, since C5a is a highly potent chemoattractantof granulocytes, it has been suggested that a lack of its inhibi-tor might account for the acute attacks of inflammation. Oth-ers have claimed that the disorder in FMFis related to cat-echolamine metabolism ( 17). Long-term colchicine treatmenthas been used for FMF(18). Colchicine inhibits the increasedchemotactic activity occuring during FMFattacks and is con-centrated mainly in neutrophiis ( 1 9). Colchicine is of paramountimportance in preventing FMFamyloidosis and it may alsoarrest the progression of amyloidosis in those who already haveit (20). Wetried to treat the patient with colchicine but had todecrease the dose due to bone marrowsuppression.

Conclusion

Wereported the 16th case of FMFin Japan, and diagnosedthe existence of the FMFgene. Our genotype analysis disclosedthat the patient was homozygousfor the M694Imutation whichis thought to be associated with complications of amyloidosis.The patient was placed on maintenance hemodialysis due torenal amyloidosis.

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