Liver disease complicating Familial Mediterranean Fever: a study on 66 patients out of 533 adult from the JIR cohort

First author: M. DELPLANQUE et al,

Journal: Liver International

Link to the article: https://doi.org/10.1111/liv.16232

Abstract:

Background: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease, associated with MEFV mutations. FMF patients can experience liver involvement, potentially leading to cirrhosis.

Objectives: This study aimed to evaluate liver involvement in FMF patients at a French tertiary center for adult FMF.

Methods: We conducted an observational study with FMF patients displaying 2 pathogenic MEFV mutations at the Adult National Reference Centre for Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA) in Paris and included in the JIR cohort. MEFV heterozygous patients and those with other liver disease causes were excluded.

Results: Among 533 FMF patients 12.4% had chronic liver abnormalities, with 30% who developed cirrhosis 54 years [36-57] in median after disease onset. Forty-seven percent were colchicine resistant, and 41% received interleukin-1 inhibitors. Cirrhotic patients experienced delayed hepatopathy diagnosis, prolonged FMF diagnosis delay, and late-onset treatment initiation compared to those with only liver function test abnormalities. Colchicine resistance and interleukin-1 inhibitor use were more common in cirrhotic patients. Body mass index and AA amyloidosis rates did not differ significantly between groups. Twenty-one patients undergone liver biopsies including 14 cirrhotic patients revealing steatohepatitis in 12 cases and probable steatohepatitis in 4. Other lesions, like iron overload and sinusoidal dilatation, were sporadically observed.

Conclusion: FMF patients are at risk of chronic liver disease. Regular liver function monitoring is crucial, particularly in case of persistent inflammation, due to the risk of progression to cirrhosis and its associated morbidity and mortality.

Lay Summary

More than, 10% of FMF patients develop chronic liver abnomalities over time and 4% cirrhosis. High-risk includes those with 2 MEFV mutations and colchicine resistance and chronic liver disease often begins after age 55 in FMF patients. In FMF patient with impaired liver function optimizing treatment targeting chronic inflammation is a key point in their care.

Liver biopsy of FMF patient

a. Liver biopsy with cirrhosis (sirius red staining)

b. Same liver biopsy with steatohepatitis associating steatosis, hepatocellular ballooning and inflammation (H&E staining)

Biopsie du foie d'un patient atteint de FMF

Complications of cirrhosis in FMF patients

(A) Esophageal varices visualized by upper gastrointestinal endoscopy

(B) Hepatomegaly and ascite of a cirrhotic FMF patient detected in an abdominal CT scan

(C) Hepatomegaly and ascite of a cirrhotic FMF patient detected in an abdominal CT scan

Complications de la cirrhose chez les patients atteints de FMF

Table 1. Demographic and clinical characteristics of the enrolled cohort.

Data are presented as median [Q1-Q3]. N= number of patients

††CRP C protein reactive, BMI Body Mass Index, FMF Familial Mediterranean fever, W women, M men

Table 4. Complication and Child Pugh Score of FMF patients with cirrhosis (n=20)

Transjugular intrahepatic portosystemic shunts (TIPS)

(% among cirrhotic patients)

Liver Disease Complicating Familial Mediterranean Fever.

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Adult Familial Mediterranean Fever (FMF): is a single MEFV mutation sufficient to cause severe disease?

Article title: Clinical characteristics and outcomes of adult FMF patients: comparison between those with one versus two

pathogenic MEFV exon 10 mutations

First author: Anaël Dumont

Journal: Joint Bone Spine

Link to the article: doi.org/10.1016/j.jbspin.2025.105850

Author of the abstract: Rim BOURGUIBA

Introduction

Familial Mediterranean Fever (FMF) is an autoinflammatory disease caused by mutations in MEFV. While two pathogenic mutations typically lead to a classic and more severe phenotype, the clinical expression in patients with only one pathogenic mutation remains debated. This study compared adult FMF patients according to whether they carried one or two pathogenic MEFV mutations.

Methods

A French single‑center retrospective cohort included 581 adult FMF patients: 178 with a single pathogenic mutation and 403 with two pathogenic mutations. Diagnosis used Eurofever/PRINTO criteria, and all patients underwent MEFV sequencing. A focused analysis compared M694V/E148Q versus M694V/WT.

Results

Compared with biallelic patients, heterozygous patients were older at diagnosis and disease onset, had more personal and family history of recurrent aphthous stomatitis, and a higher BMI. No AA amyloidosis was observed in heterozygotes, and they required lower colchicine doses. These differences remained significant after adjustment for age at onset. No clinical difference was found between M694V/E148Q and M694V/WT.

Conclusion

Adult FMF patients with a single pathogenic MEFV mutation show distinct clinical features and outcomes compared with those carrying two mutations. Findings highlight FMF phenotypic heterogeneity and support tailoring management to the patient’s genetic profile.

FMF adulte : une seule mutation MEFV suffit‑elle à rendre la maladie sévère.

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Diagnosis traps for patients with acquired NLRP3 mutation (CAPS)

First author: M. DELPLANQUE et al,

Journal: European Journal of Internal Medicine

Reference: https://doi.org/10.1016/j.ejim.2024.01.028

Summary:

The article highlights the diagnostic challenges of cryopyrin-associated periodic syndromes CAPS, caused by NLRP3 gene mutations. These autoinflammatory diseases include three main forms: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome.

The study presents two cases of patients with acquired somatic NLRP3 mutations, illustrating the difficulty of diagnosis due to atypical phenotypes:

• Patient 1 (P1): A 46-year-old woman with neuroinflammatory symptoms (persistent headaches, aseptic meningitis, hearing loss), initially misdiagnosed. A somatic M406I mutation was identified after 10 years of diagnostic wandering, explaining her atypical presentation. Treatment with anti-IL-1 drastically improved her condition.

• Patient 2 (P2): A male patient with severe CINCA syndrome since infancy, presenting with urticaria, arthritis, and growth delay. His genetic diagnosis was challenging, and the M406V mutation was only detected at the age of 15 using deep sequencing techniques.

The authors emphasize that somatic mutations in the NACHT domain of NLRP3 lead to constitutive activation of the inflammasome, resulting in excessive IL-1β production and severe chronic inflammation. The study underscores the importance of advanced genetic sequencing to detect these mutations, particularly in atypical cases.

Conclusion

Identifying somatic mutations in NLRP3 is crucial to avoid misdiagnosis and ensure effective treatment. Diagnostic delays can be prolonged in the absence of classic clinical signs (such as urticaria), and next-generation sequencing is essential for detecting low-percentage mosaicism.

Nouvelles mutations CAPS.

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