Hypolipidemia Due to Familial Hypobetalipoproteinemia in Adolescents

Introduction

Hypolipidemia, characterized by low plasma lipoproteins, can result from primary (genetic/familial) or secondary causes. Secondary causes include anemia, chronic illness, hepatitis C infection, malignancy, and hyperthyroidism. Familial hypobetalipoproteinemias (FHBL) are monogenic disorders further classified into secretion defects (FHBL-SD) and enhanced catabolism (FHBL-EC) of lipoproteins. This article discusses three adolescent cases of hypobetalipoproteinemia, two with confirmed heterozygous familial hypobetalipoproteinemia (h-FHBL) and one with suspected h-FHBL.

Case Report

Three asymptomatic adolescents presented with low lipid levels detected during screening laboratory studies. Patient 1, a 13-year-old male, and Patient 2, a 15-year-old female, were siblings. Patient 3 was a 12-year-old female. All had total cholesterol ranging from 61 to 87 mg/dL, low-density lipoprotein cholesterol (LDL-C) 10 to 28 mg/dL, and triglycerides 19 to 36 mg/dL. Aspartate transaminase (AST) and alanine transaminase (ALT) levels were normal in Patients 1 and 3 but elevated in Patient 2. Liver ultrasounds of Patients 2 and 3 showed hepatic steatosis. Molecular testing identified a pathogenic variant of the apolipoprotein B (APOB) gene in Patients 1 and 2, confirming the diagnosis of h-FHBL.

Clinical Findings

All three patients had fasting lipid panels obtained as part of laboratory studies for the evaluation of overweight/obesity. Patients 1 and 2 were siblings with a mother who reported similarly low lipid concentrations. Patient 3’s family history of lipid disorders was unavailable. All patients had normal growth and development, no history of anemia, abnormal thyroid function, chronic illnesses, or malignancy, and were not on chronic medication. Examination revealed acanthosis nigricans in Patients 2 and 3, elevated blood pressure in Patient 1, and hypertension in Patient 3. None had hepatomegaly. AST and ALT were elevated in Patient 2. Patient 3 was diagnosed with type 2 diabetes based on a hemoglobin A1c of 7% with negative pancreatic autoantibodies.

Discussion

Individuals with h-FHBL are often asymptomatic with mild liver dysfunction. The prevalence of h-FHBL is estimated to be 1:1000 to 1:3000. These patients can have elevations in liver transaminases and low total cholesterol and LDL-C levels that are often detected incidentally. In some patients, liver dysfunction can progress from hepatic steatosis to steatohepatitis and cirrhosis in the presence of other risk factors for liver disease, such as alcohol use, obesity, or liver injury.

Genetic Basis

Loss-of-function mutation in the APOB gene can result in FHBL-SD2. Frameshift or nonsense mutation or splicing variant of the APOB gene results in the synthesis of truncated forms of APO B protein. The mode of inheritance of FHBL-SD2 is often described as autosomal semidominant or codominant. The severity of h-FHBL is inversely proportional to the length of the variant APO B protein formed. Patients 1 and 2 carried a mutation of the APOB gene causing premature termination of the protein, resulting in a truncated protein. Genetic diagnosis was not available for Patient 3, though her clinical picture is suggestive of h-FHBL.

Laboratory Findings

Laboratory findings of individuals with h-FHBL include plasma total cholesterol, LDL-C, and APO B levels below the fifth percentile for age and sex, and triglycerides <45 mg/dL. Decreased secretion of APO B results in reduced hepatic VLDL export, which can lead to hepatic steatosis in individuals with h-FHBL. Other laboratory parameters that help to distinguish h-FHBL from other forms include acanthocytes and creatinine kinase. Molecular genetic testing showing a heterozygous pathogenic variant in the APOB gene confirms the diagnosis as h-FHBL.

Conclusion

Health care providers should be aware that persistent hypolipidemia may indicate h-FHBL, which can be a risk factor for liver dysfunction. Youth with h-FHBL should be counseled about lifestyle modifications and screened for the development of metabolic dysfunction-associated steatotic liver disease (MASLD).

References

1. Elmehdawi R. Hypolipidemia: a word of caution. Libyan J Med. 2008;3(2):84-90.
2. Bredefeld C, Hussain MM, Averna M, et al. Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol. 2022;16(6):797-812.
3. Cariou B, Challet-Bouju G, Bernard C, et al. Prevalence of hypobetalipoproteinemia and related psychiatric characteristics in a psychiatric population: results from the retrospective HYPOPSY Study. Lipids Health Dis. 2018;17(1):249.
4. Burnett JR, Hooper AJ, Hegele RA. APOB-related familial hypobetalipoproteinemia. In: Adam MP, Mirzaa GM, Pagon RA, et al., eds. GeneReviews® [Internet]. University of Washington, Seattle; 2021:1993-2023.
5. Martin SS, Giugliano RP, Murphy SA, et al. Comparison of low-density lipoprotein cholesterol assessment by Martin/Hopkins estimation, Friedewald estimation, and preparative ultracentrifugation: insights from the FOURIER trial. JAMA Cardiol. 2018;3(8):749-753.
6. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930.
7. Vitamin E, Serum or Plasma. Accessed February 1, 2024. https://ltd.aruplab.com/Tests/Pub/0080521
8. Vitamin A (Retinol), Serum or Plasma. Accessed February 1, 2024. https://ltd.aruplab.com/Tests/Pub/0080525
9. Molk N, Bitenc M, Urlep D, et al. Non-alcoholic fatty liver disease in a pediatric patient with heterozygous familial hypobetalipoproteinemia due to a novel APOB variant: a case report and systematic literature review. Front Med (Lausanne). 2023;10:1106441.
10. Lee J, Hegele RA. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management. J Inherit Metab Dis. 2014;37(3):333-339.
11. Mouzaki M, Shah A, Arce-Clachar AC, Hardy J, Bramlage K, Xanthakos SA. Extremely low levels of low-density lipoprotein potentially suggestive of familial hypobetalipoproteinemia: a separate phenotype of NAFLD? J Clin Lipidol. 2019;13(3):425-431.
12. Musialik J, Boguszewska-Chachulska A, Pojda-Wilczek D, et al. A rare mutation in the APOB gene associated with neurological manifestations in familial hypobetalipoproteinemia. Int J Mol Sci. 2020;21(4):1439.

Authors: Sabitha Sasidharan Pillai, MD; Meghan E. Fredette, MD; Jose Bernardo Quintos, MD; Lisa Swartz Topor, MD, MMSc