A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5)

doi:10.1016/S0168-8278(00)80270-6

Journal of Hepatology

Volume 33, Issue 3, September 2000, Pages 361-370

https://doi.org/10.1016/S0168-8278(00)80270-6 Get rights and content

Abstract

Background/Aims: Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder characterized by reduced plasma levels of low-density lipoproteins. It can be caused by mutations in the gene encoding apolipoprotein B-100 (apo B), leading to the formation of truncated apo Bs which have a reduced capacity to export lipids from the hepatocytes as lipoprotein constituents. Case reports suggest the occurrence of liver disease in FHBL, but there are no studies of liver involvement in FHBL with defined apo B gene mutations. The presence of fatty liver disease was investigated in a large FHBL kindred.

Methods: Plasma lipoprotein and apolipoprotein analysis, liver function tests, and apo B gene sequence were performed in 16 members of a FHBL kindred. The presence of fatty liver was assessed by ultrasound and computed tomography scanning.

Results: The proband, a non-obese heavy drinker male with hypobetalipoproteinemia, had steatohepatitis with fibrosis. He was heterozygous for a novel non-sense mutation of apo B gene producing a truncated apo B of 2745 amino acids (designated apo B-54.5, having half the size of normal apo B-100). Seven other members of his kindred carried apo B-54.5. Although all of them were hypolipidemic, their lipid levels showed a large inter-individual variability not accounted for by polymorphisms of genes involved in apo B metabolism. Four carriers (two heavy drinkers and two teetotallers), irrespective of their plasma lipid levels, had ultrasono-graphic evidence of fatty liver. In the other four carriers no evidence of fatty liver was found.

Conclusions: In this kindred apo B-54.5 predisposes to fatty liver, which however may require some additional factors to become clinically relevant.

Section snippets

Medical history of the proband and his family members

The proband (subject II-5 in Fig. 1). was a 45-year-old male with a long-standing history of high alcohol intake (>100 g/die). His past medical history had been characterized by two self-limited episodes of atrial fibrillation and unconfirmed angina pectoris. At the age of 42 he had been treated with amiodarone for a short period of time at the time of the observation he was under treatment with β-adrenergic blocking agents. He was referred to the hospital for hepatomegaly, altered liver

Clinical features of the proband

As shown in Table 1, plasma total cholesterol, LDL-cholesterol, and apo B of the proband were found to be greatly reduced as compared to the values found in age- and sex-matched subjects of the general population (TC=224.4±46.2 mg/dl; LDL-C=151.9±38.5 mg/ dl; apo B=125±29.8 mg/dl for healthy 40–50-year-old males). In addition, the proband had a slight elevation of SGPT (42 mU/ml; normal values: <40 mU/ml) and γ-GT (54 mU/ml; normal values <50 mU/ml), while the other liver function tests were

Plasma lipoproteins and apolipoproteins of the proband

The density profile of the proband's plasma lipoproteins (Fig. 2) was characterized by: i) a slight reduction of VLDL and IDL (fractions 1–4, d <1.030 g/ml); ii) a marked reduction of the LDL peak (fractions 5–9, d=1.035–1.060 g/ml); iii) the presence of a broad HDL peak (fractions 10–18, d=1.065–1.200 g/ml) as compared to the density profile of an unrelated normolipidemic subject of the same age and sex. The analysis of apo B in all lipoprotein density fractions (Fig. 3) revealed that in the

Analysis of apo B gene in the proband and his kindred

The size of the truncated form of apo B suggested that the putative mutation leading to a premature stop codon might be located in fragment 3 (1190 bp) of exon 26 of the apo B gene (from nt 6936 to 8125) (33). The sequence of this fragment revealed that the proband was heterozygous for a C→A transversion at position 7633, which converts serine 2475 codon (TCA) into a stop codon (TAA) (Fig. 5). The predicted translation product of this mutant allele is a truncated protein of 2474 amino acids,

Clinical features of apo B-54.5 carriers

None of the apo B-54.5 carriers had a history of obesity, diabetes or clinically relevant cardiovascular disease; echo-doppler, examination of the carotid arteries was negative in all of them. In all cases the most common causes of liver disease were ruled out; markers of ongoing HBV and HCV infection were negative and the oral glucose tolerance test, serum copper, α1-antitrypsin, and ceruloplasmin levels were in the normal range. None of the carriers had undergone cholecystectomy, nor had they

Plasma lipids and lipoproteins in carriers of apo B-54.5

Table 1 shows that in carriers of apo B-54.5 the mean plasma level of TC was 75% the value found in non-carrier family members (Table 2) (p<.02); the mean plasma levels of LDL-C and apo B were much lower (58% and 45%, respectively) than those found in noncarrier family members (p<.01). Despite a wide interindividual variability, the LDL-C and apo B values observed in all apo B-54.5 carriers were consistent with the FHBL phenotype defined as LDL-C <75 mg/dl and apo B<40 mg/dl. The lipoprotein

Plasma lipid variability in apo B-54.5 carriers

Table 1 shows that there was a large inter-individual variability in the levels of LDL-C and apo B among the apo B-54.5 carriers. In order to investigate the cause of this variability we analyzed some genetic polymorphisms, which have been associated with variations of the plasma level of LDL-C and/or apo B in the general population 37., 38., 40., 41.. We genotyped all family members for the following genetic polymorphisms: a) the insertion/deletion in the signal peptide of apo B (40); b) the

Discussion

To the best of our knowledge, the present study is the first report of the clinical correlates in a large kindred (16 subjects spanning 3 generations) with FHBL due to a novel nonsense mutation of apo B gene. The mutant allele, which was found in eight members of this family, encodes a truncated apo B of 2574 amino acids, corresponding to apo B-54.5 Four out of the eight carriers were found to have fatty liver disease.

On the grounds of our previous observations in two FHBL subjects with a

Acknowledgements

The authors thank Dr. G. Della Casa for referring the proband and Mrs Simona Tosatti for nursing assistance. The financial support of Telethon-Italy (Grant no. E.862) is gratefully acknowledged.

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Citation Excerpt :
If the clinical diagnosis suggests ABL, the first candidate gene is the MTP gene; the sequence of APOB gene is recommended if no mutations in MTP gene are found [14]. We have performed the molecular diagnosis in 69 patients with primary HBL referred to clinical settings (gastroenterology/hepatology and lipid clinic) for the presence of low LDL-C and apoB, associated with fatty liver disease or, less frequently, oral fat intolerance, intestinal lipid malabsorption and gallstones [11–14]. In our series a clear co-dominant transmission allowing the diagnosis of “definite” FHBL was found in 48% of patients; in 45% of patients the clinical diagnosis was of “possible” FHBL, since the lipid profile of family members was not available; in 7% of patients the transmission was clearly recessive, thus suggesting the diagnosis of ABL.
Primary hypobetalipoproteinemia (HBL) includes a group of genetic disorders: abetalipoproteinemia (ABL) and chylomicron retention disease (CRD), with a recessive transmission, and familial hypobetalipoproteinemia (FHBL) with a co-dominant transmission. ABL and CRD are rare disorders due to mutations in the MTP and SARA2 genes, respectively. Heterozygous FHBL is much more frequent. FHBL subjects often have fatty liver and, less frequently, intestinal fat malabsorption. FHBL may be linked or not to the APOB gene. Most mutations in APOB gene cause the formation of truncated forms of apoB which may or may be not secreted into the plasma. Truncated apoBs with a size below that of apoB-30 are not detectable in plasma; they are more frequent in patients with the most severe phenotype. Only a single amino acid substitution (R463W) has been reported as the cause of FHBL. Approximately 50% of FHBL subjects are carriers of pathogenic mutations in APOB gene; therefore, a large proportion of FHBL subjects have no apoB gene mutations or are carriers of rare amino acid substitutions in apoB with unknown effect. In some kindred FHBL is linked to a locus on chromosome 3 (3p21) but the candidate gene is unknown. Recently a FHBL plasma lipid phenotype was observed in carriers of mutations of the PCSK9 gene causing loss of function of the encoded protein, a proprotein convertase which regulates LDL-receptor number in the liver. Inactivation of this enzyme is associated with an increased LDL uptake and hypobetalipoproteinemia. HBL carriers of PCSK9 mutations do not develop fatty liver disease.

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^*: The first two authors contributed equally to this work.

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A study of fatty liver disease and plasma lipoproteins in a kindred with familial hypobetalipoproteinemia due to a novel truncated form of apolipoprotein B (APO B-54.5)

Abstract

Section snippets

Medical history of the proband and his family members

Clinical features of the proband

Plasma lipoproteins and apolipoproteins of the proband

Analysis of apo B gene in the proband and his kindred

Clinical features of apo B-54.5 carriers

Plasma lipids and lipoproteins in carriers of apo B-54.5

Plasma lipid variability in apo B-54.5 carriers

Discussion

Acknowledgements

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