Hepatic and Cardiovascular Consequences of Familial Hypobetalipoproteinemia

Abstract

Objective-Individuals with familial hypobetalipoproteinemia (FHBL) have been reported to be prone to fatty liver disease (FLD). Conversely, the profound reduction of low-density lipoprotein (LDL) cholesterol in this disorder might decrease cardiovascular risk. In the present study, we assessed hepatic steatosis as well as noninvasive surrogate markers for cardiovascular disease (CVD) in subjects with FHBL and in matched controls. Methods and Results-Hepatic steatosis was assessed by abdominal ultrasonography. Carotid intima-media thickness (IMT) and distal common carotid arterial wall stiffness as surrogate markers for CVD risk were measured using high-resolution B-mode ultrasonography. Whereas transaminase levels were only modestly elevated, both prevalence (54% versus 29%; Pϭ0.01) and severity of steatosis were significantly higher in FHBL individuals compared with controls. Despite similar IMT measurements, arterial stiffness was significantly lower in FHBL (Pϭ0.04) compared with controls. Additionally, the increase in arterial stiffness as seen in the presence of traditional risk factors was attenuated, suggesting that very low levels of apoB-containing lipoproteins can negate the adverse effects of other risk factors on the vasculature. Conclusions-FHBL is characterized by an increased prevalence and severity of fatty liver disease. The observed decreased level of arterial wall stiffness, most pronounced in the presence of nonlipid risk factors, is indicative of cardiovascular protection in these subjects. Key Words: apolipoprotein B Ⅲ arterial stiffness Ⅲ cardiovascular risk Ⅲ familial hypobetalipoproteinemia Ⅲ fatty liver disease F amilial hypobetalipoproteinemia (FHBL) is a hereditary disorder of lipoprotein metabolism characterized by very low levels of apolipoprotein (apo) B-100. Plasma levels below the fifth percentile are distinctive for this condition that inherits as an autosomal dominant trait. The prevalence in the general population is estimated to vary from 0.1% to 1.9%. 1,2 Genetic causes of hypobetalipoproteinemia include FHBL, abetalipoproteinemia, and chylomicron remnant disease (OMIM numbers 601519, 246700, and 200100, respectively). A small percentage of FHBL can be explained by mutations in the gene-encoding apolipoprotein B-100 (APOB). These include nonsense, frame-shift, and splicing mutations. Recently, it was reported that a missense mutation in the APOB gene can also lead to FHBL. 3 APOB gene mutations lead to truncated forms of apolipoprotein B (apoB) and are characterized by slower hepatic secretion, as well as more rapid plasma clearance compared with wild-type apoB-100 particles. 4,5 Because apoB is the main constituent of such lipoproteins, including very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL), FHBL subjects are characterized by exceptionally low levels of these proatherogenic particles from birth onwards.Whereas subjects with heterozygous FHBL are generally asymptomatic, 2 potential implications have been attribute...

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