Non‐amyloid liver involvement in familial Mediterranean fever: A systematic literature review

Abstract

Introduction: Familial Mediterranean fever (FMF), the most frequent autoinflammatory disease, is caused by mutations in the MEFV gene. It is characterized by recurrent febrile attacks of polyserositis. Liver abnormalities may develop during its course, but they remain poorly defined.Objective: To describe liver involvement in FMF patients. Methods:A systematic search was conducted through PubMed/Medline and Embase from 1946 to January 2020. All articles describing children and adults with FMF and liver involvement were included. Patients with amyloidosis were excluded. The selected full-text articles were independently reviewed by three investigators.Results: Forty-three articles were identified, of which 20 articles with a total of 99 patients were included: 74 adults, 23 children and two patients of unknown age. Ten patients had cryptogenic cirrhosis, 48 had nonalcoholic fatty liver disease (NAFLD), four had Budd-Chiari syndrome (BCS), 12 had isolated hyperbilirubinaemia and 25 had elevated liver enzymes. Conclusion:Despite a low prevalence of metabolic risk factors, FMF may be associated with NAFLD and cryptogenic cirrhosis as a consequence of chronic or recurrent inflammation. FMF patients should be regularly screened for liver injury. The latter may be prevented and treated by daily colchicine intake. The evidence was insufficient to establish an association with BCS, hyperbilirubinaemia or autoimmune hepatitis. K E Y W O R D Scolchicine, cytolysis, familial Mediterranean fever, inflammation, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis

Improvement of liver involvement in familial Mediterranean fever after introduction of canakinumab: a case report

“… 1 , 5 – 7 , 10 , 27 , 28 For a long time, the liver was not considered typically involved in FMF, and AA amyloidosis was considered the only possible culprit in the case of hepatic involvement. 12 However, an increase of liver enzymes does not occur in the case of amyloidosis, 13 as the most frequent signs of liver AA amyloidosis are an increased level of alkaline phosphatase and hepatomegaly. 29 …”

“… 30 , 31 Experiments in mice have shown that an abundant release of IL-1 causes inflammation, pyroptosis, and collagen deposition in the liver with subsequent increase of liver enzymes. 13 , 32 Two conflicting studies have enhanced our knowledge about the connection between FMF and liver involvement, and more between FMF and nonalcoholic fatty liver disease (NAFLD). The survey conducted by Rimar et al enrolled 27 patients with FMF but without a frank metabolic syndrome and found that 75% of patients had NAFLD.…”

“…12 To date, FMF has been linked to a spectrum of liver manifestations ranging from a mild-to-moderate increase of liver enzymes to cryptogenic cirrhosis. 13 Colchicine is the mainstay of FMF treatment since 1972, 14 , 15 and its efficacy has been largely proved. 16 Despite the maximum tolerated colchicine dose, 5–10% of FMF patients experience more than one attack monthly 17 , 18 and are defined as colchicine non-responders.…”

“…23 In fact, colchicine intoxication with daily doses higher than 5 mg might determine liver toxicity. 13,38 Of note, the usual doses used to prevent FMF attacks do not seem to bring about a significant increase in liver enzymes in most cases. 40 A potentially life-threatening complication of some autoinflammatory disorders like FMF may be macrophage activation syndrome, characterized by increased hemophagocytic activity in both bone marrow and liver, combined with fever and different signs of liver damage.…”

“…1,[5][6][7]10,27,28 For a long time, the liver was not considered typically involved in FMF, and AA amyloidosis was considered the only possible culprit in the case of hepatic involvement. 12 However, an increase of liver enzymes does not occur in the case of amyloidosis, 13 as the most frequent signs of liver AA amyloidosis are an increased level of alkaline phosphatase and hepatomegaly. 29 To date, liver involvement in FMF has been widely recognized and reported: both types of MEFV mutation and overproduction of IL-1 are probably involved in the damage progression.…”