Current and emerging issues in familial hypobetalipoproteinemia-related steatotic liver diseases

Familial Hypobetalipoproteinemia (FHBL), caused by variants in the apolipoprotein B (APOB) gene, is a rare autosomal co-dominant monogenic disorder characterized by lifelong low plasma levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C), and APOB. While FHBL is considered cardioprotective due to lifelong low LDL-C, recent evidence highlights its strong association with liver disease, positioning it as a unique monogenic model for steatotic liver disease independent of cardiometabolic risk factors. The pathogenesis of hepatic injury involves lipid overload, endoplasmic reticulum (ER) stress, oxidative damage, and autophagic dysfunction. Current challenges include underdiagnosis, sparse epidemiological data, and unclear disease progression mechanisms. Enhancing genetic testing, mechanistic research, and longitudinal studies is critical for improving the diagnosis, risk stratification, and therapeutic management of FHBL-associated liver disease.

Introduction
Familial Hypobetalipoproteinemia Type 1 (OMIM 615558) is a rare disorder caused by variants in the APOB gene on chromosome 2p24.1. Heterozygous carriers are often asymptomatic, whereas homozygous or compound heterozygous individuals present with severe manifestations such as malabsorption, vitamin deficiencies, and hepatic steatosis. In recent years, FHBL has garnered increasing attention for its association with liver disease, serving as a unique monogenic model to study steatotic liver disease pathogenesis independent of metabolic risk factors. This review aims to synthesize current knowledge on the molecular genetics of APOB, the clinical spectrum and progression of liver disease in FHBL, the underlying pathological mechanisms, and clinical management strategies, thereby establishing FHBL not only as a disorder of lipid metabolism but also as a valuable window into the pathogenesis of steatotic liver disease.

Molecular Pathogenesis of APOB
The APOB gene encodes two tissue-specific isoforms: APOB-100 in the liver and APOB-48 in the intestine, essential for the assembly and secretion of very-low-density lipoprotein (VLDL) and chylomicrons, respectively. To date, over 140 genetic variants in APOB have been identified in FHBL, including missense, frameshift, nonsense, and splice-site mutations. Most pathogenic variants result in truncated APOB proteins, and the extent of truncation is a key determinant of functional output. Beyond classic truncations, defects can also arise from splice-site variants and mobile element insertions. These molecular defects form the basis for impaired APOB function in lipid binding and transport.

Pathophysiology of the Liver in FHBL
Due to dysfunctional mutant APOB proteins, hepatic export of triglycerides via VLDL is impaired, leading to intrahepatic triglyceride accumulation. The development of liver disease involves multiple pathological factors, including disrupted lipid metabolism, ER stress, oxidative stress, and autophagic dysfunction. Notably, hepatic steatosis in FHBL often occurs in the absence of systemic insulin resistance and does not substantially increase diabetes risk, suggesting that lipid deposition and liver injury are primarily driven by lipoprotein metabolism abnormalities rather than insulin resistance. While the hepatic consequences of FHBL are partially understood, the precise mechanisms driving steatohepatitis and fibrosis remain elusive.

Abnormal Lipid Metabolism
Animal models demonstrate suppressed hepatic lipogenesis while fatty acid β-oxidation remains preserved, indicating a compensatory adaptation to hepatic lipid overload that is insufficient to prevent steatosis. Dietary fat content modulates hepatic steatosis through distinct pathways, highlighting the complex interplay between genetics and nutrition. Liver organoid models based on APOB knockout further confirm glucose-driven de novo lipogenesis as a primary cause of spontaneous steatosis.

Endoplasmic Reticulum Stress and Oxidative Stress
Lipotoxicity directly triggers ER stress and oxidative stress, supported by clinical biopsies and in vitro cell models. Oxidative stress, particularly lipid peroxidation, is a central regulator of hepatic APOB-100 stability and VLDL secretion. A vicious cycle exists between ER stress and oxidative stress, inducing apoptotic and inflammatory responses that ultimately lead to cellular homeostasis collapse.

Autophagy Dysfunction
Autophagy, specifically lipophagy (selective degradation of lipid droplets), is crucial for intracellular lipid turnover. Under appropriate stress, activation of the unfolded protein response promotes autophagy. However, excessive ER stress impairs autophagosome-lysosome fusion, inhibiting lipophagy and leading to further lipid droplet accumulation, thereby exacerbating ER stress and reactive oxygen species generation. Targeting the autophagy pathway may represent a potential therapeutic strategy.

Hepatic Manifestations and Clinical Heterogeneity in FHBL
FHBL exhibits substantial clinical heterogeneity, with liver disease being a core but variably expressed component. The degree and trajectory of liver involvement are influenced by APOB mutation type, residual protein function, and various genetic or environmental modifiers. Consequently, hepatic outcomes in FHBL range from isolated steatosis to steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC).

Hepatic Steatosis and Steatohepatitis
Retrospective studies indicate a young mean age of onset, with hepatic steatosis strongly correlating with fat-soluble vitamin deficiencies (particularly vitamins A and D). Notably, hepatic steatosis can occur even in heterozygous adolescents with normal serum transaminase levels. Patients may remain stable for prolonged periods, with only a subset progressing to steatohepatitis or fibrosis.

Liver Cirrhosis and HCC
The exact frequency of fibrosis and cirrhosis in FHBL remains uncertain. However, recent large cohort studies indicate that individuals with primary low LDL-C levels (including FHBL) have a significantly higher risk of cirrhosis and/or primary liver cancer, independent of other risk factors such as obesity, diabetes, alcohol use, and viral hepatitis. This risk is further increased in those with LDL-C levels below the 1st percentile, suggesting a potential direct role of low LDL-C in liver disease pathogenesis.

Contributing Factors to Disease Progression
The primary determinants of clinical heterogeneity are zygosity and APOB variant sites. Homozygous patients often present with multisystem complications from infancy, while heterozygous individuals are usually asymptomatic or have mild hepatic steatosis. Generally, shorter truncations lead to more severe phenotypes. However, genotype alone does not fully explain disease variability. Additional "hits" such as alcohol use, viral hepatitis, excessive caloric intake, and metabolic syndrome can accelerate disease progression. Furthermore, polygenic interactions (e.g., coexistence with MASLD risk genes like PNPLA3 and TM6SF2) can lead to more severe clinical phenotypes and promote liver disease progression. Overall, the variability in hepatic outcomes likely reflects the interplay of multiple factors.

Diagnosis and Differential Diagnosis
Diagnosis of FHBL requires a comprehensive clinical, biochemical, and genetic approach. Homozygous individuals typically present in infancy with chronic diarrhea, growth retardation, or characteristic endoscopic findings, while heterozygous individuals are often incidentally detected due to asymptomatic low serum LDL-C or APOB levels, with mildly elevated transaminases or imaging evidence of hepatic steatosis. Initial evaluation includes serum lipid profiling (showing significant reductions in total cholesterol, LDL-C, or APOB) and measurement of fat-soluble vitamin levels. Genetic testing for pathogenic APOB variants remains the gold standard. For patients with hepatic involvement, further assessment should incorporate non-invasive tools and, when indicated, histopathology. FHBL must be differentiated from other inherited and secondary causes of hypolipidemia.

Treatment
The management of FHBL aims to correct metabolic abnormalities, prevent and manage complications, and optimize long-term outcomes. The cornerstone of treatment is adherence to a low-fat diet combined with vitamin supplementation. Clinical management should be individualized based on genotype and phenotype severity. For all patients with liver injury, long-term follow-up is essential. Dietary interventions, regular exercise, and weight management are fundamental strategies. Vitamin E has been proposed as a potential therapeutic option, with evidence supporting its benefits in improving hepatic steatosis, inflammation, and fibrosis in MASLD populations. In cases of liver decompensation and HCC, liver transplantation may be considered.

Future Perspectives
Despite progress, critical gaps remain. Epidemiological data are skewed toward Western populations, necessitating global studies to clarify regional prevalence and genetic diversity. The mechanisms underlying FHBL-related hepatic steatosis, particularly fibrosis, are incompletely understood and warrant further investigation. The interplay between FHBL and modifier genes underscores the need for comprehensive genetic profiling to predict disease progression. A significant challenge is the lack of reliable prognostic biomarkers to identify patients at risk of advanced liver disease. Multi-omics approaches, including lipidomics, transcriptomics, and microbiome profiling, may uncover novel biomarkers and therapeutic targets in the future. From a translational perspective, elucidating the relationship between APOB variant types, truncation length, and functional kinetics can aid in predicting residual protein function, the likelihood of hepatic involvement, and the necessity for long-term surveillance. Recognizing the roles of ER stress, oxidative injury, and autophagy dysfunction not only advances mechanistic understanding but also points to potential therapeutic avenues. Epidemiological evidence reinforces the importance of genetic testing and early recognition for tailored monitoring and intervention. Clinical data suggest that oral vitamin E may be a valuable therapeutic choice for FHBL patients with liver injury, pending confirmation in prospective FHBL-specific trials.

Conclusions
Early diagnosis via lipid profiling and genetic testing is pivotal. Management focuses on dietary fat restriction, fat-soluble vitamin supplementation, and vigilant monitoring of liver injury. Emerging therapies targeting metabolic pathways (e.g., vitamin E) show promise but require validation in FHBL-specific cohorts. Gene therapy represents a future-oriented strategy with the potential to correct APOB defects and prevent progressive liver injury. The ultimate goal is to bridge molecular insights with tailored therapeutic strategies, providing a more comprehensive framework for the diagnosis and management of FHBL.

 

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The study was recently published in the Journal of Clinical and Translational Hepatology.

The Journal of Clinical and Translational Hepatology (JCTH) is owned by the Second Affiliated Hospital of Chongqing Medical University and published by XIA & HE Publishing Inc. JCTH publishes high quality, peer reviewed studies in the translational and clinical human health sciences of liver diseases. JCTH has established high standards for publication of original research, which are characterized by a study’s novelty, quality, and ethical conduct in the scientific process as well as in the communication of the research findings. Each issue includes articles by leading authorities on topics in hepatology that are germane to the most current challenges in the field. Special features include reports on the latest advances in drug development and technology that are relevant to liver diseases. Regular features of JCTH also include editorials, correspondences and invited commentaries on rapidly progressing areas in hepatology. All articles published by JCTH, both solicited and unsolicited, must pass our rigorous peer review process.

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