Shirley Sze, Hull York Medical School, UK
A 32-year-old from Turkey (Kurdistan province) presented with a 4-year history of recurrent, severe, vague abdominal pain requiring numerous hospitalizations. The pain was non-radiating, dull and constricting in nature with acute onset. There were no associated symptoms apart from constipation. His C-reactive protein and white cell count were always raised during these acute episodes. The pain resolved spontaneously without any specific treatment. He was completely well in between these acute episodes. Investigations including diagnostic laparoscopy, endoscopy and colonoscopy, CT scans and porphyria and infection screens were performed and were found to be negative / normal. Subsequent analysis of the MEFV gene detected two pathogenic variants (Met680IGC and Glu148Gln) on exon 2 and 10 and a diagnosis of familial Mediterranean fever was made. He had no further acute episodes after colchicine treatment was initiated.
A 32 year old man from Turkey (Kurdistan province) presented with a 4 year history of intermittent central abdominal pains for which he had had at least 20 hospital admissions. The pain developed suddenly with no obvious triggering factor and resolved spontaneously in 2 to 3 days. It was severe, dull and constricting in nature and did not radiate. He had no nausea vomiting or diarrhea during the episodes but was frequently constipated.
His initial presentation was 4 years ago (08/10/2008) when he developed sudden-onset right iliac fossa pain with raised white cell count (WCC) and C-reactive protein (CRP) (Figure 1, Table 1). He was admitted under the surgeons and treated for acute appendicitis. However, diagnostic laparoscopy showed a normal appendix which was kept intact.
In July 2009, he was admitted with a two-day history of severe central abdominal pain which radiated to the right. Abdominal ultrasound showed multiple small stones in the gallbladder and he was diagnosed with cholecystolithiasis , although his blood tests showed slightly raised alkaline phosphatase (ALP) of 134 mmol/L and alanine aminotransferase (ALT) of 72 mmol/L, normal bilirubin of 12 mmol/L and normal full blood count (FBC). A CT scan of his abdomen and pelvis was normal. His symptoms and the laboratory abnormalities resolved within 24 hours after antibiotic treatment without any surgical intervention.
Three months later, he developed vague abdominal pain again and was admitted. He had mild epigastric and left iliac fossa tenderness. Per Rectal examination and bedside rigid sigmoidoscopy were normal. Blood results were shown in Figure 1. Amylase was normal. No abnormalities were found on abdominal X-ray. Again his symptoms resolved within 24 hours after treatment with buscopan and tramadol. He was referred to a gastroenterologist for flexible sigmoidoscopy which turned out to be normal. In July 2010, he presented with a similar episode of non-specific lower abdominal pain. A CT scan of his abdomen and pelvis showed no significant pathology. Again his symptoms resolved spontaneously after 12 hours but this time he was given broad-spectrum antibiotics as well as intravenous fluids and analgesia.
In May 2011, he was readmitted with acute abdominal pain and diarrhoea. There was no blood or mucus per rectum. The pain subsided with simple analgesia within a few hours. This time blood tests were all normal apart from a markedly raised CRP (Figure 1). In view of the recurrent nature of his episodes with raised inflammatory markers on most occasions he was referred to the Infectious Diseases team for assessment in case there was an underlying deep or unusual infection present. Serological testing was performed for Strongyloides, Yersinia, Whipples, hepatitis B and C and Brucella. A full colonoscopy with ileocaecal washings taken for Mycobacterial culture; Porphyrin screening; antinuclear antibody (ANA) and anti neutrophil cytoplasmic antibody (ANCA) were also requested and were all negative. Subsequently he was referred to the Immunology department for investigation of possible intermittent bowel angioedema. In the meantime, he had three further acute episodes, each consisting of sudden onset of severe abdominal pain with raised inflammatory markers that resolved within 24 to 48 hours regardless of what treatment he was given.
At the Immunology Clinic, he appeared well but suddenly started to suffer abdominal pain during consultation. Abdominal examination revealed tenderness in the hypogastric and umbilical regions. His blood pressure was 123/85 mmHg, pulse rate 84 /minute, respiratory rate 16/minute and ear temperature was 36.7ºC. The pain worsened upon movement and deep inspiration. History review revealed no significant past medical history. He was completely well in between acute episodes. He denied allergy to medications. There was no significant family history and none of his family has ever complained of similar symptoms. He smokes 20 cigarettes a day, rarely consumes alcohol and does not take illicit drugs. He is single and works as a chef in a takeaway shop.
Further blood tests were requested and the results are shown in Figure 1. Given his history and his ethnic origin, autoinflammatory disease was suspected (Table 2). He was initially commenced on prednisolone 30 mg for 7 day. This failed to lead to the expected improvement and he was therefore started on colchicine 500 micrograms 12 hourly. His symptoms completely resolved and he has not had further acute episodes. Genetic testing detected MEFV mutations at exon 2 and 10 (Met680IGC and Glu148Gln) and this together with the characteristic clinical symptoms and efficacy of colchicine led to the diagnosis of FMF.
Abdominal pain can be a diagnostic challenge due to the wide variety of potential causes. Abdominal pain without positive imaging findings can be due to diabetic ketoacidosis, acute intermittent porphyria, lead poisoning, bowel angioedema, conversion disorders, etc. Detailed history taking and physical examination are needed to determine the correct diagnosis.
Familial Mediterranean fever (FMF) is the most common inherited, autoinflammatory syndrome caused by mutations in the Mediterranean fever gene (MEFV) on chromosome 16p13.3. The prevalence of FMF is highest amongst Japanese, Mediterranean and Middle Eastern populations. It is characterized by recurrent, self-limiting attacks of fever with aseptic serositis and synovitis . Interestingly, our patient’s presented with heterogeneous abdominal pain, involving both iliac fossae, the epigastrium, the periumbilical region and both flanks.
Early-onset FMF is more common and typically has a more aggressive form. The majority of patients develop FMF before the age of 20 . However, cases with later onset have been reported with 66 years being the latest age of onset in Japan [3,4]. Sohar et al. studied the age at onset of 755 FMF patients and found that 65.5 % of patients presented between 0-10 years, 24% between 11-20 years and 8.2% between 21-30 years. Our patient presented at the age of 28 years. He experienced on average, 3 acute episodes every year, most with a significantly raised CRP.
FMF is diagnosed clinically based on the Tel Hashomer criteria1. Fever is a common feature and is associated with more than 90% of FMF cases , but is not a compulsory criterion for diagnosis , as seen in our case (our patient did not have fever in any of the acute episodes). Genetic testing and positive family history are also not mandatory. Our patient fulfilled all 3 major criteria (Table 2), which is >95% sensitive and specific for diagnosis of FMF . As the criteria are derived solely from clinical signs alone, diagnosis in patients with mild or atypical symptoms can be difficult. Our patient experienced significant diagnostic delay which led to a protracted course of illness and unnecessary expensive and invasive investigations and treatment.
The role of MEFV mutations is unknown. The MEFV gene encodes for pyrin, which is a protein that regulates IL-1β production and NF-κB activation. In FMF, cytokine overproduction from defective pyrin activity leads to inflammatory attacks . Up to date, no associations have been found between MEFV mutations and disease of severity , although MEFV mutations were seen in higher frequency in patients with Behcet’s disease , rheumatoid arthritis  and juvenile idiopathic arthritis . Interestingly, the type of MEFV mutations also varies according to geographical locations. Japanese patients typically have E148Q mutation on exon 2 and M6941 on exon 10 while M694V is the most common mutation in Mediterranean populations . The two pathogenic variants (Met680IGC and Glu148Gln) detected in our patient were also one of the most common mutations in Mediterranean populations.
Non-specific abdominal pain with raised inflammatory markers does not always point to an infectious aetiology.
Detailed history taking and review of routine investigations such as FBC and inflammatory markers are important initial steps in making the diagnosis of autoinflamatory diseases.
FMF must be suspected in patients of Mediterranean, Middle-Eastern or Japanese origin with recurrent acute abdomen, especially when associated with raised inflammatory markers despite a negative family history.