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Mol Genet Metab. 2018 Apr;123(4):433-440. doi: 10.1016/j.ymgme.2018.01.009. Epub 2018 Feb 7.

Long-term liver disease in methylmalonic and propionic acidemias.

Author information

1
Biochemistry Laboratory, APHP, Robert Debré University Hospital, Paris, France; Paris Sud University, Chatenay Malabry, France.
2
Reference Center for Inborn Errors of Metabolism, APHP, Robert Debré University Hospital, Paris, France; Center for Molecular Diseases, CHUV, Lausanne, Switzerland.
3
Pediatric Unit, CHRU, Tours, France.
4
Hepatology and IEM Unit, Children Hospital, Toulouse, France.
5
Reference Center for Inborn Errors of Metabolism, APHP, Robert Debré University Hospital, Paris, France.
6
Biochemistry Laboratory, APHP, CHU Bicêtre, Le Kremlin Bicêtre, France.
7
Department of Pathology, APHP, CHU Bicêtre, Le Kremlin Bicêtre, France.
8
Neuropathology, Stanford University Medical Center, Palo Alto, CA, USA.
9
Reference Center for Inborn Errors of Metabolism, APHP, Robert Debré University Hospital, Paris, France; UMR1141, PROTECT, INSERM, Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
10
Biochemistry Laboratory, APHP, Robert Debré University Hospital, Paris, France; Paris Sud University, Chatenay Malabry, France. Electronic address: jean-francois.benoist@aphp.fr.

Abstract

BACKGROUND AND OBJECTIVES:

Patients affected with methylmalonic acidemia (MMA) and propionic acidemia (PA) exhibit diverse long-term complications and poor outcome. Liver disease is not a reported complication. The aim of this study was to characterize and extensively evaluate long-term liver involvement in MMA and PA patients.

PATIENTS AND METHODS:

We first describe four patients who had severe liver involvement during the course of their disease. Histology showed fibrosis and/or cirrhosis in 3 patients. Such liver involvement led us to retrospectively collect liver (clinical, laboratory and ultrasound) data of MMA (N = 12) or PA patients (N = 16) from 2003 to 2016.

RESULTS:

Alpha-fetoprotein (αFP) levels were increased in 8/16 and 3/12 PA and MMA patients, respectively, and tended to increase with age. Moderate and recurrent increase of GGT was observed in 4/16 PA patients and 4/12 MMA patients. Abnormal liver ultrasound with either hepatomegaly and/or hyperechoic liver was observed in 7/9 PA patients and 3/9 MMA patients.

CONCLUSIONS:

These data demonstrate that approximately half of the patients affected by MMA or PA had signs of liver abnormalities. The increase of αFP with age suggests progressive toxicity, which might be due to the metabolites accumulated in PA and MMA. These metabolites (e.g., methylmalonic acid and propionic acid derivatives) have previously been reported to have mitochondrial toxicity; this toxicity is confirmed by the results of histological and biochemical mitochondrial analyses of the liver in two of our MMA patients. In contrast to the moderate clinical, laboratory or ultrasound expression, severe pathological expression was found for three of the 4 patients who underwent liver biopsy, ranging from fibrosis to cirrhosis. These results emphasize the need for detailed liver function evaluation in organic aciduria patients, including liver biopsy when liver disease is suspected.

TAKE HOME MESSAGE:

MMA and PA patients exhibit long-term liver abnormalities.

KEYWORDS:

Alpha-fetoprotein; Hepatomegaly; Liver disease; Liver fibrosis; MMA; OXPHOS deficiency; Organic acidemias; PA

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