Familial Mediterranean fever (FMF) is an autosomal recessive chronic inflammatory disease with relapsing fever and polyserositis attacks. The gene causing FMF (MEFV) is located on the short arm of chromosome 16. The diagnosis of FMF is based on clinical grounds. Diagnostic difficulties occur especially in patients with atypical features, in younger age groups, and in patients with overlapping or associated disease such as vasculitis and inflammatory bowel disease (IBD). Genetic testing should be reserved for such patients. Recently, it has been reported that IBD is more frequent and severe in patients with FMF (1). The possible modifying effect of MEFV in the disease process in patients with IBD and the effects of MEFV variants on the IBD susceptibility were discussed by several groups (2–4). Previously we reported 3 infants with infantile ulcerative colitis and FMF (5). Their symptoms were controlled by adding colchicine to the immunosuppressive therapy. After this observation we kept FMF in mind as a comorbid disease in infants with chronic ulcerative colonic disease. Here, we would like to share and discuss the distinct observation about patients who were admitted to our clinic with ulcerative colonic disease. Clinical, laboratory, and follow-up characteristics of these patients suggest that colitis may be the only presenting finding for FMF (Table 1).
A 3-month-old girl presented with intermittent bloody mucoid diarrhea since 2 weeks after her birth. Her family history revealed nonconsanguineous parents and an uncle who had FMF disease. At physical examination, her body weight was 6 kg (90th percentile) and height 63 cm (75th percentile); systemic examination and perianal inspection were normal. Laboratory tests were as follows: hemoglobin (Hb), 9.4 g/dL (normal 10.5–14.0); white blood cell (WBC), 9.4 × 1000/mm3 (normal 6.0–14.0); and platelets (PLT), 307,000/μL (normal 150,000–350,000); acute-phase reactants, and liver and renal function tests were in the normal range. Stool samples were rich for leukocytes and erythrocytes in microscopy. Possible infectious agents such as Escherichia coli, Salmonella, Shigella, Yersinia, Clostridium difficile, and Campylobacter jejuni were ruled out. Elimination of cow's milk from diet helped partially, and the patient had intermittent episodes of abdominal pain and bloody mucoid stools during follow-up. The family did not comply with follow-up periods. She was readmitted to our clinic with chest pain at 2 years of age. Echocardiography showed pericardial effusion. Serum creatinine phosphokinase and CK-MB were found to be higher than normal levels: creatinine phosphokinase was 210 (normal 25–175) and CK-MB was 95 IU/L (normal 24–170). Especially viral agents were investigated for the etiology of pericarditis, but specific etiology could not be determined. A DNA analysis for FMF was planned. After 1 month, the patient was admitted to our department with intense bloody diarrhea, malaise, and fever. At the time of admission body weight was 13 kg (50th percentile) and height was 85.5 cm (50th percentile). Systemic examination was normal except for a faint appearance. Stool microscopy showed abundant leukocytes and erythrocytes. Bacterial, viral, and parasitic agents for diarrhea were ruled out. Serum electrolytes and renal and liver function tests were in the normal range. Other laboratory results were as follows: Hb, 10.4 g/dL (normal 10.5–14.0); mean corpuscular volume, 68 fL (normal 72–88); WBC, 18 × 1000/mm3 (normal 6.0–14.0); PLT, 550,000/μL (normal 150,000–350,000); albumin, 3.0 g/dL (normal 3.5–5.5); total protein, 6.1 g/dL (normal 6.3–8.6); erythrocyte sedimentation rate, 38 mm/h (normal 3–13); and C-reactive protein, 68 mg/L (normal 0–5). Congenital and secondary immune deficiencies were ruled out by normal immunoglobulin levels, normal nitroblue tetrazolium test, and normal T-cell populations. Upper gastrointestinal endoscopy was normal. Duodenal, antral, and esophageal histopathology was reported as normal. During colonoscopy, hyperemia, fragility, and patchy ulcerations covered with white exudate were observed in colonic mucosa (Fig. 1A). Histopathology was reported as a chronic active inflammatory process accompanied by polymorph leukocytes and eosinophils without granuloma formation (Fig. 1B). Microscopic colitis and collagenous colitis were ruled out. M694I/E148Q FMF mutation was detected by DNA analysis. Colchicine treatment was started. Within 1 week, all of the symptoms and laboratory abnormalities returned to normal. During the follow-up period, the patient received a diagnosis of Henoch-Schonlein purpura at age 3. Endoscopic examination at that acute stage showed widespread ulcerations in bowels. Steroids were administered for 4 weeks. The symptoms resolved with steroid therapy. In the last 2 years she was receiving colchicine treatment without symptoms.
A 4-year-old boy was admitted to our clinic with intermittent bloody mucoid diarrhea since early infancy. His medical history revealed unexplained fever episodes for the last year. Second-degree consanguinity was present between his parents. At physical examination, his body weight was 12.5 kg (3rd–10th percentile) and his height was 92 cm (<3rd percentile). Systemic evaluation was normal except for a weak and faint appearance. Stool microscopy revealed leukocytes and erythrocytes. Infectious states were ruled out by stool cultures. Laboratory results were as follows: WBC, 18 × 1000/mm3 (normal 6.0–14.0); Hb, 11.2 g/dL (normal 11.5–14.5); PLT, 550,000/μL (normal 150,000–350,000); ESR, 45 mm/h (normal 3–13); CRP, 54 mg/L (normal 0–5); fibrinogen, 380 (normal 180–350); albumin, 3.1 g/dL (normal 3.5–5.5); and total protein, 6.0 g/dL (normal 6.3–8.6). Renal functions and liver enzymes were normal. Upper gastrointestinal endoscopy visualization was normal, and celiac disease and eosinophilic enteritis were ruled out by histopathologic examination. Edema, hyperemia, and patchy ulcerations covered with white exudate in colonic mucosa were observed during colonoscopic examination (Fig. 2A). Histopathology was reported as cryptitis and crypt abscess accompanied by leukocyte and mixed-type inflammation without granuloma (Fig. 2B). The patient was diagnosed as having IBD, and steroids were started. At the time of reducing the steroids, azathioprine and mesalazine were added to therapy. DNA analyses for FMF were planned for the recurrent fever attacks. The result was reported as M694 V/0. Colchicine was administered to the patient. Azathioprine was stopped after 1 year. The patient remained in remission for 4 years with colchicine and mesalazine therapy. Colchicine was ceased to avoid azospermia in the preadolescent period and only mesalazine was given. After 2 months he was readmitted with severe colitis. Erysipelas-like erythema was observed at lower extremities. Stool samples were abundant for erythrocytes and leukocytes. Acute-phase reactants including ESR, CRP, and fibrinogen were higher than normal levels. Other laboratory tests were as follows: Hb, 12.6 g/dL (normal 11.5–14.5); WBC, 15.9 × 1000/mm3 (normal 6.0–14.0); PLT, 488,000/μL (normal 150,000–350,000); and albumin, 3.2 g/dL (normal 3.5–5.5). Liver and renal function tests were normal. The colitis state was considered to be FMF related and colchicine therapy was restarted. The symptoms and laboratory abnormalities returned to normal within 1 week under colchicine therapy. Mesalazine was gradually reduced and stopped. No relapse was seen in the last year.
A 3-year-old boy presented with fever and bloody mucoid diarrhea periods lasting for 3 to 4 days for the last 6 months. His medical and family history was normal. At physical examination, body weight was 16.5 kg (90th–97th percentile) and height was 93 cm (50th–75th percentile). Systemic examination was normal except for anxious and faint appearance. Stool microscopy revealed erythrocytes and leukocytes. Infectious states were ruled out by microscopic examination and stool cultures. Laboratory results were as follows: WBC, 23 × 1000/mm3 (normal 6.0–14.0); PLT, 634,000/μL (normal 150,000–350,000); ESR, 39 mm/hr (normal 3–13); CRP, 333 mg/L (normal 0–5); fibrinogen, 350 mg/dL (normal 180–350); total protein, 6.4 g/dL (normal 6.3–8.6); and albumin, 4 g/dL (normal 3.5–5.5); liver and renal function tests were in the normal range. Colonoscopy showed hyperemic edematous mucosa with nodularity, suggesting follicular lymphoid hyperplasia. Histopathology revealed cryptitis and mixed-type inflammation without granuloma. The symptoms and laboratory tests including WBC count, thrombocyte count, sedimentation rate, CRP, and fibrinogen level completely returned to normal without specific therapy within 4 days. The patient's state was considered as an attack of FMF, and mutation analyses were taken into consideration. FMF mutation was reported as M694 V/V726A. Colchicine treatment was started and the patient has no complaints for the last 2-year follow-up.
FMF is an autosomal recessive autoinflammatory disease characterized by recurrent attacks of fever and serosal inflammation. FMF is known to be common in Turks, Arabs, Armenians, and Jews. The carrier frequency in high-risk population is one of the highest rates for an autosomal recessive disease (1/5–1/10). More than 40 mutations have been reported to date. Genetic studies for the disease failed to exhibit distinct genotype and phenotype correlation. M694V homozygote mutations are known to show early-onset, frequent joint and dermal manifestations, high rate for amyloidosis, and high colchicine dosage requirement for disease control (1).
A typical FMF attack generally starts with instantaneous and rapidly increasing fever. Fever continues for 12 to 72 hours and subsides spontaneously. Attack type and frequency are variable. Attack intervals may be once in 3 days to once in every 3 to 4 months. Physical examinations and laboratory tests are normal between attacks. Fever may be the only finding in some FMF cases, but it is not a rule. Abdominal pain is the second most frequent finding in FMF (95%) (1). That is the reason why most of these patients are referred to gastroenterologists. Therefore, it is important to increase awareness in these specialists about FMF.
Colitis is described as inflammation of the colon and may arise in many conditions. Infectious states, allergic states, IBDs such as Crohn disease and ulcerative colitis, Behçet disease, immune deficiencies, microscopic colitis, and collagenous colitis may be the various causes of colitis. The colonoscopic appearance does not vary too much in these diseases, and it is tough to diagnose the etiology with colonic mucosal appearance (2,3).
Today, comorbidity of FMF and IBD continues to be one of the popular concerns of both pediatric and adult gastroenterologists. Giaglis et al (4) reported that MEFV mutation may be a modifier gene for colitis ulcerosa in a clinical study carried out in 2006. Thereafter, we started to screen all patients with IBD for FMF. In 2008, we found MEFV mutation in 3 patients presenting with pancolitis aging from 3 to 6 months (5). Bowel inflammations in these cases were controlled following solely colchicine treatment, supporting the previous study. Similarly, Nuray et al found MEFV mutation mostly in patients with Crohn disease but also with ulcerative colitis (2). Yildirim et al (6) reported a study in 4 groups of patients with ulcerative colitis consisting of distal colitis and pancolitis and with previous colectomy. They found that MEFV mutation in these patients was significantly more compared with patients with rheumatoid arthritis taken as a control group. In the present study, patients who underwent colectomy showed the highest rate of FMF mutations, which predicted the severity of the colitis state (6). MEFV mutation frequency was reported as 58.3% in this group, which is higher than the carrier frequency of the Turkish population (25%) (7). Villani et al (8) reported increased MEFV expression in experimental animal model studies in 2010; however, they did not find MEFV gene variants as the susceptibility supplier gene for IBD. FMF-related MEFV gene does not have a direct or an indirect effect on NOD2 and PLNR3 genes responsible for IBD; however, both diseases use similar cytokine pathways for inflammation (8). Thus, FMF and IBD should be considered as 2 different diseases. Many diseases and syndromes are described in the literature as accompanying FMF, such as Budd-Chiari syndrome, ascites, Behçet disease, polyarteritis nodosa, Henoch-Schonlein purpura, and protracted febrile myalgia (1). Under these circumstances, IBD may be considered as a disease associated with FMF. IBD is also more frequent and severe in patients with MEFV gene mutations.
All 3 patients in the present report presented with clinical colitis. Infectious diseases, allergic diseases, immune deficiencies, microscopic colitis, and collagenous colitis were ruled out. Case 2 was thought to be an IBD at presentation; however, during follow-up, the MEFV mutation was detected. All 3 cases responded to colchicine treatment without any other anti-inflammatory or immunosuppressive drugs. In these patients recurrence or relapse was not observed under colchicine therapy during the follow-up periods. This observation also supported the diagnosis of FMF.
Patients with FMF may have gastrointestinal involvement at the time of diagnosis, and this situation may manifest itself as constipation or diarrhea. FMF amyloidosis may affect many systems, including the kidneys, adrenals, intestine, spleen, liver, stomach, thyroid gland, heart, and lungs (9). Renal amyloidosis is the most notable type of FMF-associated amyloidosis. Amyloidal deposition in the gastrointestinal system appears early in FMF; however, it may be asymptomatic and may be recognized after a long period of follow-up. Two published cases demonstrated selective damage to the gastrointestinal tract, with kidneys remaining practically intact (10,11). Amyloidal deposition throughout the entire wall of the small intestine in FMF may cause constipation, intractable diarrhea, and severe malabsorption. Reduced motility caused by amyloidal deposition permits bacterial overgrowth, bile acid deconjugation, and, consequently, worsening diarrhea and steatorrhea. Cases are reported resulting in ischemic colitis and perforation of the large intestine, secondary to amyloidal deposition in the colon. Chronic ischemic colitis may lead to a fibrotic mass that may present as colonic obstruction (1,12).
Reviewing the literature, isolated gastrointestinal involvement of FMF presented with colitis has not been reported. In our cases symptoms started at younger than 2 years of age. Gastrointestinal involvement of FMF has been explained by bacterial overgrowth related to dysmotility and malabsorption caused by amyloidal deposition; however, our 3 cases are negative for amyloidal deposits. This fact indicates that colitis may not be explained by amyloidal deposition. The relation between clinical colitis and the M694V mutation needs further investigation because we report this mutation in only 3 cases.
In conclusion, many diseases can accompany FMF. Although sole gastrointestinal manifestation is not considered a diagnostic criterion for FMF, these 3 cases provide some food for thought about novel presentations of the disease. Isolated gastrointestinal involvement of FMF should be suspected in high-risk ethnic groups, especially during the infantile period.
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