Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.
OBJECTIVE
Non-alcoholic steatohepatitis leading to fibrosis occurs in patients with abetalipoproteinemia (ABL) and homozygous or compound heterozygous familial hypobetalipoproteinemia (Ho-FHBL). We wanted to establish if liver alterations were more frequent in one of both diseases and were influenced by comorbidities.


METHODS
We report genetic, clinical, histological and biological characteristics of new cases of ABL (n =7) and Ho-FHBL (n = 7), and compare them with all published ABL (51) and Ho-FHBL (22) probands.


RESULTS
ABL patients, diagnosed during infancy, presented mainly with diarrhea, neurological and ophthalmological impairments and remained lean, whereas Ho-FHBL were diagnosed later, with milder symptoms often becoming overweight in adulthood. Despite subtle differences in lipid phenotype, liver steatosis was observed in both groups with a high prevalence of severe fibrosis (5/27 for Ho-FHBL vs. 4/58 for ABL (n.s.)). Serum triglycerides concentration was higher in Ho-FHBL whereas total and HDL-cholesterol were similar in both groups. In Ho-FHBL liver alterations were found to be independent from the apoB truncation size and apoB concentrations.


CONCLUSIONS
Our findings provide evidence for major liver abnormalities in both diseases. While ABL and Ho-FHBL patients have subtle differences in lipid phenotype, carriers of APOB mutations are more frequently obese. These results raise the question of a complex causal link between apoB metabolism and obesity. They suggest that the genetic defect in VLDL assembly is critical for the occurrence of liver steatosis leading to fibrosis and shows that obesity and insulin resistance might contribute by increasing lipogenesis.
UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France; INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France. Electronic address: mathilde.di-filippo@chu-lyon.fr.
Mathilde
M
Di Filippo
INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France; Fédération d'Endocrinologie, Maladies métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.
Philippe
P
Moulin
Service de Biostatistique, Hospices Civils de Lyon, Lyon, France; Centre National de la Recherche Scientifique UMR5558, Univ Lyon-1, Villeurbanne, France.
Pascal
P
Roy
INSERM UMR698, Paris 7-Université Paris Diderot, CHU X. Bichat Secteur C Bernard, Paris, France.
Marie Elisabeth
ME
Samson-Bouma
Service de pathologie, Hospices Civils de Lyon et Université Claude Bernard, CHU de Lyon, France.
Sophie
S
Collardeau-Frachon
UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France.
Sabrina
S
Chebel-Dumont
Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France.
Noël
N
Peretti
Fédération des Spécialités Digestives, Hôpital Edouard Herriot, Hospices Civils, Lyon, France.
Jérôme
J
Dumortier
Service d'Hépato-Gastro-Entérologie, Hôpital de la Croix Rousse, Hospices Civils, Lyon, France.
Fabien
F
Zoulim
Service d'Hépato-Gastro-Entérologie, Centre Hospitalier Pierre Oudot, Bourgoin Jallieu, France.
Thierry
T
Fontanges
Rare Metabolic Disease Unit, Department of Pediatrics, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.
Rossella
R
Parini
Rare Metabolic Disease Unit, Department of Pediatrics, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.
Miriam
M
Rigoldi
Rare Metabolic Disease Unit, Department of Pediatrics, Fondazione MBBM, San Gerardo Hospital, Monza, Italy.
Francesca
F
Furlan
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.
Grazia
G
Mancini
Unité pédagogique de Biochimie, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France; UPMC University Paris 6, UMR_S1166 Inserm ICAN, Paris, France; Service de Biochimie métabolique, Groupe hospitalier Pitié-Salpêtrière-Charles Foix, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Dominique
D
Bonnefont-Rousselot
Service d'Endocrinologie, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
Eric
E
Bruckert
Service de Gastroentérologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
Jacques
J
Schmitz
Service d'anatomie pathologique, Hôpital Edouard Herriot, Hospices Civils, Lyon, France.
Jean Yves
JY
Scoazec
INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France; Fédération d'Endocrinologie, Maladies métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.
Sybil
S
Charrière
Fédération d'Endocrinologie, Maladies métaboliques, Diabète et Nutrition, Hôpital Louis Pradel, Hospices Civils de Lyon, Bron, France.
Sylvie
S
Villar-Fimbel
Department of Pediatric Gastroenterology Hepatology and Nutrition, Jeanne de Flandre university hospital, Lille, France.
Frederic
F
Gottrand
Nutrition et Gastroentérologie Pédiatriques, Hôpital Trousseau, AP-HP, Paris, France; Institut de Cardiométabolisme et Nutrition (ICAN), INSERM UMRS U872 (Eq7) Nutriomique, Université Pierre et Marie Curie-Paris 6, Paris, France.
Béatrice
B
Dubern
Service de Neuropédiatrie, Hôpital Trousseau, Paris, France.
Diane
D
Doummar
Service de Gastroentérologie et d'Assistance Nutritive, Hôpital Beaujon, Clichy, France.
Francesca
F
Joly
Anatomie et Cytologie Pathologiques, Brive, France.
Marie Elisabeth
ME
Liard-Meillon
Service de Gastroentérologie Hépatologie et Nutrition Pédiatrique, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Bron, France; INSERM U 1111, Faculté de médecine Lyon Est, Université Lyon 1, Lyon, France.
Alain
A
Lachaux
UF Dyslipidémies Cardiobiologie, Département de Biochimie et de Biologie Moléculaire du GHE, Laboratoire de Biologie Médicale Multi Sites, Hospices Civils de Lyon, Lyon, France; INSERM U1060, INSA de Lyon, INRA U1235, Univ Lyon-1, Université de Lyon, Villeurbanne, Oullins, France.
Agnès
A
Sassolas
D000012:Abetalipoproteinemia / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D000293:Adolescent; D000328:Adult; D053299:Apolipoprotein B-100 / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D008076:Cholesterol, HDL / Q000097:blood; D015331:Cohort Studies; D015897:Comorbidity; D005260:Female; D005602:France / Q000453:epidemiology; D006801:Humans; D006995:Hypobetalipoproteinemias / Q000097:blood / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology; D009765:Obesity / Q000453:epidemiology / Q000235:genetics; D015995:Prevalence; D014280:Triglycerides / Q000097:blood
C569471:APOB protein, human; D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D008076:Cholesterol, HDL; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein
APOB; Abetalipoproteinemia; Homozygous or compound heterozygous familial hypobetalipoproteinemia; Hypocholesterolemia; Insulin resistance; Liver fibrosis; Liver steatosis; MTTP; NASH; Obesity