Can Peritoneal Biopsy Diagnose Atypical Cases of Familial Mediterranean Fever?: A Case Report

ABSTRACT

Background

Familial Mediterranean Fever (FMF) is a prevalent inherited monogenic autoinflammatory disease that predominantly affects populations from the Mediterranean basin. It is typically characterized by the recurrence of fever episodes and abdominal pain accompanied by recurrent short‐lived inflammatory attacks that usually resolve spontaneously within 1–3 days. It is uncommon to see ascites with large amounts of peritoneal fluid as a manifestation of FMF.

Case Presentation

A 36‐year‐old Arab female presented with generalized abdominal pain and bloating. No family history of FMF. Analysis of peritoneal fluid identified low‐grade ascites. A CT scan was performed, which did not reveal any suspicious lesions. Laparoscopic surgery was undertaken to rule out the differential diagnoses and obtain a peritoneal biopsy, even though the periton had a normal visual appearance. Histopathological examination of the biopsy specimens was compatible with a diagnosis of FMF, after other differential diagnoses were ruled out. The patient showed significant improvement within a month of taking colchicine. The ascites resolved progressively and completely, affirming the FMF diagnosis.

Conclusion

The occurrence of chronic ascites in a patient requires the consideration of FMF among the differential diagnoses. A diagnosis of FMF can also be suspected through a peritoneal biopsy, which may be sufficient for diagnosis without the need for genetic testing. Additionally, the patient's response to colchicine therapy can be considered for confirmation, as demonstrated in our case. Future research should focus on considering the inclusion of peritoneal biopsy among the diagnostic criteria for FMF particularly in cases with non‐specific presentations.

Abbreviations

C3, C4

complement 3, complement 4

CRP

C reactive protein

ELE

erysipelas‐like erythema

ESR

erythrocyte sedimentation rate

FMF

familial Mediterranean fever

MEFV

Mediterranean fever

SAA

serum amyloid A

1. Background

Familial Mediterranean Fever (FMF) is the oldest and most prevalent inherited monogenic autoinflammatory disease [1, 2]. FMF predominantly affects populations from the Mediterranean basin, such as the Turkish, Armenian, Jewish, and Arab communities [1]. There has been limited research conducted on FMF presenting in adulthood [1]. FMF is typically characterized by the recurrence of fever episodes (seen in 96% of cases) and abdominal pain (94% of cases) accompanied by recurrent short‐lived inflammatory attacks that usually resolve spontaneously within 1–3 days, and other manifestations of FMF include serositis, arthritis, and ELE [1, 3]. In certain cases of FMF, small quantities of peritoneal fluid have been observed during laparoscopic examinations, which may develop into ascites [4, 5]. Ascites with large amounts of peritoneal fluid is an uncommon manifestation of FMF [4, 5]. Diagnosis of FMF is based on clinical symptoms, supported by ethnic origin and family history [2]. In this report, we describe a 36‐year‐old female with no family history of FMF presenting with chronic low‐gradient ascites, abdominal pain, and without any other symptoms. This led to a suspected diagnosis of FMF via peritoneal biopsy, which was confirmed by the complete resolution of ascites following colchicine therapy.

2. Case Presentation

A 36‐year‐old Arab female presented with generalized abdominal pain and abdominal bloating. She consulted the gynecologist with her complaints and was subsequently referred to a gastroenterologist. Her medical history was unremarkable without any family history of FMF, with no prior surgeries or known diseases. Upon examination, her vital signs were within normal ranges, but she had a chronic ascites. Laboratory evaluation revealed leukocytosis with neutrophilia, a CRP level of 27.3 mg/L, and a CA 125 level of 13.1 U/mL. Peritoneal fluid analysis identified low‐grade ascites (Table 1), raising concerns for potential malignancy or tuberculosis. A CT scan was performed, which did not reveal any suspicious lesions. Due to the presence of low‐grade ascites, laparoscopic surgery was undertaken to rule out the differential diagnoses and obtain a peritoneal biopsy. Although there is a normal visual appearance of the periton, aiming to exclude tuberculosis. Histopathological examination of the biopsy specimens was compatible with a diagnosis of FMF after other differential diagnoses were ruled out (Figure 1). The patient was initiated on colchicine therapy at 1 mg/day, and showed significant improvement within a month. The ascites resolved progressively and completely, affirming the FMF diagnosis despite the absence of a familial history. The patient was subsequently monitored with several ultrasound examinations over 6 months, which showed no evidence of recurrent ascites and inflammation markers have returned to normal levels.

TABLE 1.

Ascitic fluid examination results.

Test	Result	Reference range
Color	Yellow	Clear
Clarity	Turbid	Clear
Red blood cells	1570	< 5000 cells/mm3
White blood cells	68	< 1000 cells/mm3
Neutrophilis	25	< 250 cells/μL
Lymphocytes	75	Approximately 50%
Glucose	105	< 60 mg/dL
Protein	5.07	1.0–2.9 g/dL
Albumin	3.27	0.5–1.7 g/dL

FIGURE 1.

Microscopic examination of the peritoneal biopsy specimen shows focal collection of neutrophils and fibrin strands with no malignancy. When taking into account the clinical presentation of the patient, the histopathological analysis was compatible with familial Mediterranean fever.

3. Discussion

Ascites, defined as the pathological accumulation of fluid within the peritoneal cavity, are often linked to an underlying gradient of 1.1 g/dL or greater, which accurately predicts portal hypertension in 97% of cases [6]. Conversely, a gradient less than 1.1 g/dL suggests conditions such as peritoneal carcinomatosis, peritoneal tuberculosis, pancreatitis, serositis, and nephrotic syndrome [6]. This patient, presenting with chronic low‐gradient ascites, was assessed for differential diagnosis of low‐gradient ascites such as peritoneal tuberculosis. Pyrin, the protein encoded by the MEFV gene located on the short arm of chromosome 16, interacts with components of the inflammasome that are activated in response to microbial agents [1, 2]. Mutations in pyrin result in heightened inflammation marked by the excessive secretion of IL‐1β in FMF [1, 2]. The clinical manifestations of FMF can vary, likely due to genetic diversity and environmental influences, including stress, exposure to cold, and the menstrual cycle in pubertal and post‐pubertal females [1]. Notably, while 90% of FMF cases manifest during childhood. It may still occur in older patients, typically in their early 30s, the symptoms tend to be milder with either fewer or no disease complications [1]. The episodes are sporadic and brief, typically lasting less than 3 days, and they resolve without any intervention. Patients are generally asymptomatic between these episodes [2]. The Tel Hashomer criteria, which stands as the most frequently referenced diagnostic criteria, encompasses a spectrum of symptoms, including fever, peritonitis, pleuritis, arthritis, ELE, amyloidosis, alongside a pertinent family history [3]. Attacks of FMF are marked by leukocytosis and an increase in acute phase reactants such as ESR, CRP, fibrinogen, haptoglobin, complement components C3 and C4, and SAA [2]. These inflammatory markers help physicians differentiate FMF attacks from other conditions like viral infections, fibromyalgia, functional abdominal pain, and irritable bowel syndrome [2]. While most acute‐phase reactants usually return to normal levels between attacks, they can remain elevated in some instances, particularly in patients with severe or poorly controlled disease [2, 3]. When assessing the differential diagnosis of our patient's low‐gradient ascites through laparoscopy, a peritoneal biopsy was conducted to rule out peritoneal tuberculosis; unexpectedly, the biopsy revealed microscopic characteristics compatible with FMF after other differential diagnoses were excluded. Genetic testing could allow physicians to entirely overcome the diagnostic challenges related to FMF, thereby preventing its complications [7]. However, it has emerged over time that the interpretation of diagnoses can be highly complex since some FMF patients may exhibit none or only one of the recognized MEFV mutations [7]. MEFV molecular genetic testing has a high diagnostic sensitivity of approximately 90%, but it has a relatively low specificity of around 15%. If both clinical assessment and genetic testing do not provide a clear diagnosis, a trial of colchicine treatment is administered after ruling out other potential differential diagnoses [3]. Since the 1970s, colchicine has been established as the primary treatment for FMF, colchicine's lifelong therapy aims to reduce inter‐attack inflammation and prevent the progression of amyloidosis [8]. Another therapy for FMF is Interleukin‐1 inhibitors, which represent a new approach to treating FMF, along with Anti‐IL‐6 agents [1]. Amyloidosis represents the most critical complication and leading cause of death in FMF [2]. In our case, the patient did not present with amyloidosis; instead, the diagnosis of FMF was suspected based on peritoneal biopsy and was even more likely following a positive response to colchicine therapy. However, genetic testing was not conducted due to financial constraints.

4. Conclusion

The occurrence of chronic ascites in a patient requires the consideration of FMF among the differential diagnoses. When assessing low‐gradient ascites, one should examine the abdomen to search for potential tumors or tuberculosis; performing a peritoneal biopsy is important, as it may indicate the presence of FMF or tuberculosis. A diagnosis of FMF can also be suspected through a peritoneal biopsy, which may be sufficient for diagnosis without the need for genetic testing. Additionally, the patient's response to colchicine therapy can be considered for confirmation, as demonstrated in our case. Future research should focus on considering the inclusion of peritoneal biopsy among the diagnostic criteria for FMF particularly in cases with non‐specific presentations.

Ethics Statement

The authors have nothing to report.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor‐in‐Chief of this journal.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

The authors have nothing to report.