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A 48-year-old Jewish woman presented to the emergency room complaining of sharp epigastric abdominal pain of acute onset. The pain was non-radiating and severe in intensity and had started 6 hours prior to presentation. It was associated with nausea and vomiting. The vomitus consisted of food particles. She denied complaints of diarrhoea, constipation, melaena, haematemesis or weight loss. The physical examination revealed a blood pressure of 110/64 mmHg, pulse rate 60 beats/min, temperature 38.2°C, and a respiratory rate of 16 breaths/min. She weighed 48 kg. She was anicteric and had no cervical lymphadenopathy. The abdomen was soft and diffusely tender. Rigidity, rebound tenderness, hepatosplenomegaly or masses were absent. Rectal examination showed guaiac-negative brown stool. The remainder of the examination was unremarkable. The patient was not taking any medications and denied use of alcohol, tobacco or intravenous drugs. Her diet consisted mainly of low fat vegetarian food products. Her family history was unremarkable.
A review of patient's medical records showed documentation of similar episodes on at least six occasions over the previous 18 months. During the attacks, the pain lasted 48 to 72 hours and was associated with a low-grade fever (37–38.5°C). Medical history was significant for long-standing back pain and degenerative joint disease involving the knees (for at least 15 years). There was a history of self-limited episode of viral meningitis 1 year prior to presentation. She had undergone tubal ligation 10 years prior to the onset of abdominal pain, followed by a laparotomy 6 years later for evaluation of pelvic pain. Adhesions were discovered during the laparotomy. The investigative work-up failed to reveal a definite diagnosis. On numerous occasions, laboratory data including complete blood count, erythrocyte sedimentation rate, and routine blood chemistry were within normal limits, except for minimal elevation of white blood cell count on two occasions. Antinuclear antibody assay was negative. Abdominal ultrasound and a HIDA scan did not reveal any abnormalities. Abdominal X-ray, upper gastrointestinal barium study, and a colonoscopy were normal. Computed tomography of the abdomen and pelvis was unremarkable.
The patient was admitted to the hospital for observation, as diagnostic studies were unrevealing. She became asymptomatic within 24 hours and was discharged home.
- What is the diagnosis ?
- Describe the pathogenesis of this clinical condition ?
- How was the diagnosis made ?
- Describe the most recent development in the diagnosis of this condition ?
- What is the treatment ?
The patient has familial Mediterranean fever (FMF).
Several theories have been proposed to explain the recurrent inflammation of the serosa in FMF.1 The most favored hypothesis suggest a deficiency of C5a and IL-8 inhibitors (chemotactic factor inactivating enzymes). The result is an ineffective breakdown of C5a and IL-8, which are released in response to subclinical injuries. This facilitates neutrophilic infiltration. The neutrophils release a variety of chemicals, including a C5a-generating enzyme, thus completing a vicious circle.1 2
FMF was a diagnosis of exclusion until recently, sometimes requiring exploratory laparotomy to rule out appendicitis.1 The diagnosis of FMF, especially during the initial attacks, requires a high index of suspicion and is based on positive family history. In some cases, therapeutic trial with colchicine may be attempted.1 However, when additional attacks precipitate and subside, diagnosis may be established according to the presence of clinical features (box), even in the absence of family history.1
The gene responsible for FMF, designatedMEFV, is located close to the α-globin gene on chromosome 16, and was recently identified after years of cloning.3 4 The gene is approximately 10 kb and encodes a 781-amino-acid protein called ‘pyrin’ or ‘marenostrin’. This protein is a transcription factor and regulates the expression of target genes, some of which may be involved in the suppression of inflammation.3 4 A polymerase chain reaction (PCR) can now be employed to establish the diagnosis of FMF in suspected patients.
Colchicine is known to suppress neutrophil chemotaxis.5 In prospective randomised double-blind studies, the chronic administration of colchicine at doses of 1–2 mg and rarely, 3 mg/day significantly reduced the frequency of the inflammatory attacks.5 Colchicine may result in diarrhoea and flatulence in some patients. The dosage of colchicine administered (1–2 mg/day) is inadequate to inhibit microtubule function. However, this dose may be sufficient to retard the migration of the neutrophils by an unknown mechanism.5
FMF is an inherited condition prevalent among Arabs, Turks, Armenians, and Sephardic Jews.1 It is transmitted as an autosomal recessive trait. Up to 50% of patients do not give a positive family history. By age 20, as many as 90% of patients have had their first attack.1 FMF is characterised by sporadic, self-limited febrile attacks with acute localised inflammation, usually involving the peritoneum, pleura, and joint spaces (box). Less commonly, the pericardial space and the tunica vaginalis of the testis may be involved. Peritonitis due to FMF may present as an acute abdomen, and exploratory laparotomy shows an inflamed peritoneum with a neutrophilic exudate.1 Recurrent abdominal pain is reported by more than 95% of patients, pain is accompanied by signs of peritonitis in most patients and often a diagnosis of appendicitis or acute abdomen is made. Chest pain, usually of a sharp stabbing type suggestive of pleuritic pain, is also reported by 75% of patients. Mono- or oligo-arthritis and sometimes migrating polyarthritis is reported by 70% of patients. Up to 25% of patients show skin lesions similar to those of erysipelas on the lower extremities. The localised erysipelas-like rash may be painful, and resolves in a few days. Meningitis may be noted in up to 1% of patients. In the preceding hours, some patients may experience a prodrome including chills. Fever is usually 38 to 40°C. In general, an attack may last from 12 to 72 hours. However, attacks involving the joints tend to last somewhat longer. The interval between attacks ranges from days to months.
Approximately 25% of patients with FMF develop renal amyloidosis.1 The accumulation of amyloid fibrillar protein AA (presumably due to recurrent inflammation) causes nephropathy, leading to proteinurea and nephrotic syndrome. The amyloidosis usually progresses to renal failure in 3–7 years, and almost all deaths attributable to FMF result from this complication. Otherwise, patients with FMF have a normal life expectancy. However, the quality of life may be impaired by the frequent and incapacitating episodes of inflammation. Prophylactic colchicine therapy appears to prevent amyloidosis.1
Clinical features of FMF
abdominal pain (most common symptom)*
joint pain (migratory polyarthritis or mono/oligo-arthritis)*
transient erysipelas-like rash (usually below the knee)
orchitis (rare episodes in childhood)
*features noted in our patient.
The laboratory findings are nonspecific and include an elevated peripheral white blood cell count, an accelerated erythrocyte sedimentation rate, and elevated acute-phase reactants, including C-reactive protein, fibrinogen, haptoglobin, C3, C4, and serum amyloid A.1 Urinalysis may show albuminurea and microhaematuria. Abdominal X-rays may be characterised by bowel oedema with air–fluid levels in the small intestine.1
The successful cloning of the gene has important consequences, as a PCR can now be employed to establish the diagnosis of FMF in suspected patients.3 Prophylactic colchicine therapy may be offered to patients with FMF, as the attacks under colchicine therapy are milder, of shorter duration, and may prevent renal failure.1
Familial Mediterranean fever.