Gene variants and clinical characteristics of children with sitosterolemia.

OBJECTIVE: To enhance the detection, management and monitoring of Chinese children afflicted with sitosterolemia by examining the physical characteristics and genetic makeup of pediatric patients. METHODS: In this group, 26 children were diagnosed with sitosterolemia, 24 of whom underwent genetic analysis. Patient family medical history, physical symptoms, tests for liver function, lipid levels, standard blood tests, phytosterol levels, cardiac/carotid artery ultrasounds, fundus examinations, and treatment were collected. RESULTS: The majority (19, 73.1%) of the 26 patients exhibited xanthomas as the most prevalent manifestation. The second most common symptoms were joint pain (7, 26.9%) and stunted growth (4, 15.4%). Among the 24 (92.3%) patients whose genetics were analyzed, 16 (66.7%) harbored ABCG5 variants (type 2 sitosterolemia), and nearly one-third (8, 33.3%) harbored ABCG8 variants (type 1 sitosterolemia). Additionally, the most common pathogenic ABCG5 variant was c.1166G > A (p.Arg389His), which was found in 10 patients (66.7%). Further analysis did not indicate any significant differences in pathological traits among those carrying ABCG5 and ABCG8 variations (P > 0.05). Interestingly, there was a greater abundance of nonsense variations in ABCG5 than in ABCG8 (P = 0.09), and a greater frequency of splicing variations in ABCG8 than ABCG5 (P = 0.01). Following a change in diet or a combination of ezetimibe, the levels of cholesterol and low-density lipoprotein were markedly decreased compared to the levels reported before treatment. CONCLUSION: Sitosterolemia should be considered for individuals presenting with xanthomas and increased cholesterol levels. Phytosterol testing and genetic analysis are important for early detection. Managing one's diet and taking ezetimibe can well control blood lipids.

Patient With Sitosterolemia With Slow Healing Sternal Wound From Coronary Artery Bypass Surgery.

BACKGROUND: Sitosterolemia, also known as phytosterolemia, is a rare recessive genetic disorder characterized by accumulation of sitosterol from vegetable oils, nuts, and other plant-based foods in the body. In those with sitosterolemia, there is an increase of fatty deposits in the arteries (atherosclerosis), which may occur in early childhood, impeding blood flow and increasing the risk of a heart attack, stroke, or sudden death at a very early age. Visual signs of sitosterolemia may include small yellowish xanthomas beginning in early childhood. Xanthomas are accumulated lipids that develop in the heels, elbows, and buttocks. CASE: A clinical case study of a patient with sitosterolemia with slow healing surgical wound from coronary artery bypass surgery is described. Treatment of sitosterolemia is aimed at lowering plasma plant sterol levels with dietary restriction intake of both animal- and plant-based sterols. However, plant-based products (collagen, chitosan, etc) are also used for wound dressings, so alternative wound dressings were selected to decrease the possibility of systemic absorption. CONCLUSION: This case study describes a young adult male with sitosterolemia who presented with a slow healing surgical incision following coronary artery bypass surgery. Sitosterolemia is often characterized by atherosclerosis of the coronary arteries that occurs in children and early adulthood, especially affecting men. Treatment is aimed at lowering plasma sterol levels with the restriction of animal and plant sterols. There is considerable interest today in natural versus synthetic wound care products. Dressings containing chitosan, cellulose, collagen, etc, to be avoided to decrease the chance of systemic absorption.

[Child with sitosterolemia initially presenting with hemolytic anemia and thrombocytopenia: a case repore and literrature review].

This article focuses on a case study of sitosterolemia in a child who initially presented with hemolytic anemia and thrombocytopenia. Sitosterolemia is a rare autosomal recessive lipid metabolism disorder, difficult to diagnose due to its non-typical clinical manifestations. The 8-year-old patient was initially misdiagnosed with pyruvate kinase deficiency. Comprehensive biochemical and molecular biology analyses, including gene sequencing, eventually led to the correct diagnosis of sitosterolemia. This case highlights the complexity and diagnostic challenges of sitosterolemia, emphasizing the need for increased awareness and accurate diagnosis in patients presenting with similar symptoms.

A Clinical Case of Probable Sitosterolemia.

Sitosterolemia is a rare genetic lipid disorder characterized by elevated plant sterols in the serum. A 24-year-old Japanese woman was referred to our hospital due to a high serum low-density lipoprotein cholesterol (LDL-C) level of 332 mg/dL. At first, she was suspected to suffer from familial hypercholesterolemia, and thus received lipid-lowering agents. Although her LDL-C level remained high (220 mg/dL) with diet therapy plus 10 mg/day rosuvastatin, it was drastically decreased to 46 mg/dL with the addition of 10 mg/day ezetimibe. Finally, her LDL-C level was well-controlled at about 70 mg/dL with 10 mg/day ezetimibe alone. Furthermore, while her serum sitosterol level was elevated at 10.5 µg/mL during the first visit to our hospital, it decreased to 3.6 µg/mL with the 10 mg/day ezetimibe treatment alone. These observations suggest that she might probably suffer from sitosterolemia. Therefore, targeted gene sequencing analysis was performed using custom panels focusing on the exome regions of 21 lipid-associated genes, including ABCG5, ABCG8, and familial hypercholesterolemia-causing genes (LDL receptor, LDLRAP1, PCSK9, and apolipoprotein B). We finally identified a heterozygous ABCG8 variant (NM_022437.2:c.1285A>G or NP_071882.1:p.Met429Val) in our patient. The same gene mutation was detected in her mother. We report here a rare case exhibiting probable sitosterolemia caused by a heterozygous Met429Val variant in the ABCG8 gene and additional unknown variants.

Genetic analysis and functional study of a novel ABCG5 mutation in sitosterolemia with hematologic disease.

Sitosterolemia is a rare autosomal recessive hereditary disease caused by loss-of-function genetic mutations in either ATP-binding cassette subfamily G member 5 or member 8 (ABCG5 or ABCG8). Here, we investigate novel variants in ABCG5 and ABCG8 that are associated with the sitosterolemia phenotype. We describe a 32-year-old woman with hypercholesterolemia, tendon and hip xanthomas, autoimmune hemolytic anemia and macrothrombocytopenia from early life, which make us highly suspicious of the possibility of sitosterolemia. A novel homozygous variant in ABCG5 (c.1769C>A, p.S590X) was identified by genomic sequencing. We also examined the lipid profile, especially plant sterols levels, using gas chromatography-mass spectrometry. Functional studies, including western blotting and immunofluorescence staining, showed that the nonsense mutation ABCG5 1769C>A hinders the formation of ABCG5 and ABCG8 heterodimers and the function of transporting sterols. Our study expands the knowledge of variants in sitosterolemia and provides diagnosis and treatment recommendations.

Blood phytosterols in relation to cardiovascular diseases and mediating effects of blood lipids and hematological traits: a Mendelian randomization analysis.

BACKGROUND: Short-term clinical trials have shown the cholesterol-lowering potentials of phytosterols, but their impacts on cardiovascular disease (CVD) remain controversial. This study used the Mendelian randomization (MR) to investigate the relationships between genetic predisposition to blood sitosterol concentration and 11 CVD endpoints, along with the potential mediating effects of blood lipids and hematological traits. METHODS: Random-effect inverse-variance weighted method was used as the main analysis of MR. Genetic instruments of sitosterol (seven SNPs, F = 253, and R2 = 15.4 %) were derived from an Icelandic cohort. Summary-level data of the 11 CVDs were obtained from UK Biobank, FinnGen, and publicly available genome-wide association study results. RESULTS: Genetically predicted one unit increment in log-transformed blood total sitosterol was significantly associated with a higher risk of coronary atherosclerosis (OR: 1.52; 95 % CI: 1.41, 1.65; n = 667,551), myocardial infarction (OR: 1.40; 95 % CI: 1.25, 1.56; n = 596,436), all coronary heart disease (OR: 1.33; 95 % CI: 1.22, 1.46; n = 766,053), intracerebral hemorrhage (OR: 1.68; 95 % CI: 1.24, 2.27; n = 659,181), heart failure (OR: 1.16; 95 % CI: 1.08, 1.25; n = 1,195,531), and aortic aneurysm (OR: 1.74; 95 % CI: 1.42, 2.13; n = 665,714). Suggestive associations were observed for an increased risk of ischemic stroke (OR: 1.06; 95 % CI: 1.01, 1.12; n = 2,021,995) and peripheral artery disease (OR: 1.20; 95 % CI: 1.05, 1.37; n = 660,791). Notably, blood non-high-density lipoprotein cholesterol (nonHDL-C) and apolipoprotein B mediated about 38-47 %, 46-60 %, and 43-58 % of the associations between sitosterol and coronary atherosclerosis, myocardial infarction, and coronary heart disease, respectively. However, the associations between sitosterol and CVDs were less likely to depend on hematological traits. CONCLUSION: The study suggests that genetic predisposition to higher blood total sitosterol is linked to a greater risk of major CVDs. Moreover, blood nonHDL-C and apolipoprotein B might mediate a significant proportion of the associations between sitosterol and coronary diseases.

Proinflammatory mediators in lipid emulsions and parenteral nutrition-associated liver disease: Review of leading factors.

Lipid injectable emulsions have been in clinical use for over 60 years. The first product launched was Intralipid, which consisted of an emulsion of soybean oil in water for intravenous administration. It was a key source of essential fatty acids and an alternative source of energy for patients with gastrointestinal dysfunction requiring long-term parenteral nutrition. With clinical experience, a condition known as parenteral nutrition-associated liver disease (PNALD), or intestinal failure-associated liver disease (IFALD), was observed, with a focus on carbohydrate and fat energy. Modifying the daily doses and infusion rates had some salutary effects, but PNALD persisted. Subsequently, on closer inspection of the fatty acids profile and phytosterol concentrations, degradation products arising from chemical and physical stability issues of the available lipid injectable emulsions were implicated. Recently, the US Food and Drug Administration convened an online workshop entitled "The Role of Phytosterols in PNALD/IFALD," with an emphasis on (1) the multifactorial pathophysiology of PNALD/IFALD, (2) risk associated with phytosterols, and (3) regulatory history. The scope of this review includes the multifactorial pathophysiology of PNALD/IFALD as it relates to the pharmaceutical aspects of the various lipid injectable emulsions on the market, with respect to potential proinflammatory components, as well as physical and chemical stability issues that may also affect products' safe intravenous administration to patients.

Update on Sitosterolemia and Atherosclerosis.

PURPOSE OF REVIEW: The purpose of this review was to summarize important and updated information on sitosterolemia. Sitosterolemia is an inherited lipid disorder consisting of high levels of plasma plant sterols. This sterol storage condition is caused by biallelic loss-of-function genetic variants in either ABCG5 or ABCG8, leading to increased intestinal absorption and decreased hepatic excretion of plant sterols. Clinically, patients with sitosterolemia usually exhibit xanthomatosis, high levels of plasma cholesterol, and premature atherosclerotic disease, but presentation can be highly heterogeneous. Therefore, recognition of this condition requires a high level of suspicion, with confirmation upon genetic diagnosis or through measurement of plasma phytosterols. Treatment of sitosterolemia with both a plant sterol-restricted diet and the intestinal cholesterol absorption inhibitor ezetimibe can reduce efficiently the levels of plasma plant sterols, consisting in the first-line therapy for this disease. RECENT FINDINGS: Since hypercholesterolemia is often present in individuals with sitosterolemia, it is important to search for genetic variants in ABCG5 and ABCG8 in patients with clinical criteria for familial hypercholesterolemia (FH), but no variants in FH implicated genes. Indeed, recent studies have suggested that genetic variants in ABCG5/ABCG8 can mimic FH, and even when in heterozygosis, they may potentially exacerbate the phenotype of patients with severe dyslipidemia. Sitosterolemia is a genetic lipid disorder characterized by increased circulating levels of plant sterols and clinically manifested by xanthomatosis, hematologic disorders, and early atherosclerosis. Awareness about this condition, a rare, but commonly underdiagnosed and yet treatable cause of premature atherosclerotic disease, is imperative.

Single-Cell Transcriptomics Reveals the Difference of Aortic Atherosclerosis Response to Phytosterols and Oxidation Products of Sterols.

SCOPE: Phytosterols (PS) and sterol oxidation products are key dietary factors influencing atherosclerosis besides cholesterol, although the mechanisms remain elusive. Recently, single-cell RNA sequencing (scRNA-seq) has revealed the heterogeneity of multiple cell types associated with complex pathogenesis in atherosclerosis development. METHODS AND RESULTS: Here, scRNA-seq is performed to investigate the alterations in the aortic cells from ApoE-/- mice induced by diet-derived PS or two sterol oxidation products, phytosterols oxidation products (POPs), and cholesterol oxidation products (COPs). The study identifies four fibroblast subpopulations with different functions, and immunofluorescence demonstrates their spatial heterogeneity, providing evidence that suggests the transformation of smooth muscle cells (SMCs) and fibroblasts in atherosclerosis. The composition and gene expression profiles of aortic cells change broadly in response to PS/COPs/POPs exposure. Notably, PS exhibits an atheroprotective effect where different gene expressions are mainly found in B cells. Exposure to COPs accelerates atherosclerosis and results in marked alternations in myofibroblast subpopulations and T cells, while POPs only alter fibroblast subpopulations and B cells. CONCLUSION: The data elucidate the effects of dietary PS/COPs/POPs on aortic cells during atherosclerosis development, especially on the newly identified fibroblast subpopulations.

Xenosterolemia in clinical practice: what is in a name?

PURPOSE OF REVIEW: The aim of this study was to assess the potential value of the measurement of plasma xenosterols (or phytosterols) concentrations in clinical practice. RECENT FINDINGS: Recent genetic studies suggest that individuals with elevated plasma phytosterol concentrations due to monogenic and polygenic variants are at an increased risk of coronary artery disease. This supports early observations that elevated plasma phytosterol concentrations are per se atherogenic. SUMMARY: Measurement of plasma phytosterols can identify individuals with xenosterolemia (or phytosterolemia). This may be clinically useful in four ways: Establishing a diagnosis and informing management of patients with homozygous phytosterolemia; Providing a comprehensive differential diagnosis for familial hypercholesterolemia; Providing an index of cholesterol absorption that may inform personalized pharmacotherapy; and Informing more precise assessment of risk of cardiovascular disease.

Clinical characteristics of sitosterolemic children with xanthomas as the first manifestation.

BACKGROUND: Sitosterolemia (STSL) is an extremely rare genetic disease. Xanthomas as the first symptom are frequently misinterpreted as familial hypercholesterolemia (FH) in children. Inappropriate treatment may deteriorate the condition of STSL. OBJECTIVES: To present the clinical and laboratory characteristics of xanthomatous children diagnosed with sitosterolemia in comparison with childhood FH with xanthomas. METHODS: We summarized and compared the clinical characteristics of STSL and FH patients with xanthomas as the first manifestations and investigated the different indicators between the STSL and FH groups, as well as their diagnostic values for STSL. RESULTS: Two tertiary pediatric endocrinology departments contributed ten STSL cases. Five of the STSL patients (50%) experienced mild anemia, whereas two (20%) had vascular complications. The xanthomas of the STSL group displayed morphologies comparable to those of the FH group. There were ten cases of homozygous FH (HoFH) with xanthomas as the predominant symptom of the control group who had no anemia. The serum cholesterol (Chol) levels of the STSL and FH groups were 12.57 (9.55 ~ 14.62) mmol/L and 17.45 (16.04 ~ 21.47) mmol/L, respectively (p value 0.002). The serum low-density lipoprotein cholesterol (LDL-c) levels of the STSL and FH groups were 9.26 ± 2.71 mmol/L and 14.58 ± 4.08 mmol/L, respectively (p value 0.003). Meanwhile, the mean platelet volume (MPV) levels of the STSL and FH groups were 11.00 (9.79 ~ 12.53) fl. and 8.95 (8.88 ~ 12.28) fl., respectively (p value 0.009). The anemia proportions of the STSL and FH groups were 50% and 0%, respectively (p value 0.033). The AUC values of Chol, LDL-c, MPV, hemoglobin (Hb) for the diagnosis of STSL were 0.910, 0.886, 0.869, 0.879, respectively. Chol ≤ 15.41 mmol/L, LDL-c ≤ 13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L were the best thresholds for diagnosing STSL with childhood xanthomas. CONCLUSION: The xanthoma morphology of STSL patients resembles that of FH patients. Xanthomas as the initial symptom of a child with Chol ≤ 15.41 mmol/L, LDL-c≤13.22 mmol/L, MPV ≥ 9.05 fl., or Hb≤120 g/L, he was most likely to have STSL.

Sitosterolemia.

Sitosterolemia is an inherited metabolic disorder characterized by increased levels of plant sterols, such as sitosterol. This disease is caused by loss-of-function genetic mutations in the ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively), both of which play important roles in the selective excretion of plant sterols from the liver and intestine, leading to a failure to excrete plant sterols. Sitosterolemia, which is currently considered a rare genetic disorder, has been described as a phenocopy of homozygous familial hypercholesterolemia (FH). Typical phenotypes of sitosterolemia, including elevated low-density lipoprotein (LDL) cholesterol, tendon xanthomas, and premature coronary artery disease, overlap those of homozygous FH; however, there are substantial differences between these two diseases in terms of treatments and prognoses. Moreover, it is of note that sitosterolemia appears to be quite underdiagnosed, although accurate diagnosis and appropriate interventions will likely to lead to better prognoses compared with homozygous FH. Unlike cases of homozygous FH, dietary counseling is quite effective in reducing the LDL cholesterol as well as sitosterol of patients with sitosterolemia. In this chapter, we summarize the current understandings of this disease and provide useful tips for the diagnosis as well as better treatment of patients with sitosterolemia.

Foamy Cell Histiocytosis Is a Diagnostic Pitfall: A Case Report of Xanthomatosis Secondary to Sitosterolemia Mimicking Progressive Nodular Histiocytosis.

ABSTRACT: We report a noteworthy case of a 10-year-old girl who presented with papular and nodular lesions on the skin that were clinically and histologically mistaken for progressive nodular histiocytosis. During the clinical management of the patient, the high lipid levels raised the suspicion of lipid metabolism disease and helped us to make the correct diagnosis of sitosterolemia. In sitosterolemia, proper management such as restriction of plant sterol intake and administration of cholesterol absorption inhibitor can improve prognosis.

A Case of Peripheral Precocious Puberty May Be Caused by a Diet Containing Phytosterols in a 20-Month-Old Boy.

INTRODUCTION: Precocious puberty in boys generally remains an etiology. In addition to the causes of endogenous hormone changes, endocrine-disrupting chemicals of exogenous substances may interfere with children's pubertal development. CASE PRESENTATION: A 20-month-old boy presented with peripheral precocious puberty may be due to a phytosterol-containing diet. The patient came to see a doctor because of acne, hairiness, increased penis size, and coarse voice. Genital examination revealed a Tanner stage of 2 for pubic hair and a stretched penile length of 5 cm, which disagreed with the prepubertal testicular volume (2 mL bilaterally). At the same time, he was found to have pigmentation on both nipples and areola. The concentrations of estradiol and testosterone increased significantly. Since the age of 6 months, the patient had taken food added with a large amount of chicken essence seasoning (a flavoring in Chinese cooking), with an average of 15 g of this seasoning a day. A kind of phytosterol (C29H48O) was detected in chicken essence seasoning by high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS). After avoidance of the chicken essence seasoning, the patient's sex hormone levels decreased, all clinical symptoms returned to normal, and no further development of secondary sexual characteristics was detected. CONCLUSION: This phytosterol-containing diet may be responsible for the sexual development of this patient. However, the mechanism of how phytosterols affect the process of development in children needs to be further explored.

Plant sterol hyperabsorption caused by uncontrolled diabetes in a patient with a heterozygous ABCG5 variant.

Plant sterol intake is widely recommended for patients with cardiovascular risk factors based on the inhibitory effect on intestinal cholesterol absorption. Although plant sterols, once absorbed, can promote atherosclerosis, their intake is believed to be safe because of poor absorption, except in rare hyperabsorbers with homozygous ABCG5/8 mutations. We report a case of new-onset type 1 diabetes accompanied by hypercholesterolemia. At the initial presentation with diabetic ketoacidosis, the patient showed marked hypercholesterolemia. Whole-exome sequencing revealed a heterozygous pathogenic variant in ABCG5 (p.R419H). The initial serum plant sterol levels were markedly high (sitosterol 32.5 µg/mL, campesterol 66.0 µg/mL), close to the range observed in patients with homozygous ABCG5/8 mutations, which were largely reduced by insulin treatment without ezetimibe. The addition of ezetimibe normalized plant sterol levels. These findings provide the first evidence that uncontrolled diabetes plays a causal role in the pathogenesis of phytosterolemia.

Screening of ABCG5 and ABCG8 Genes for Sitosterolemia in a Familial Hypercholesterolemia Cascade Screening Program.

BACKGROUND: Sitosterolemia is a rare autosomal recessive disorder caused by homozygous or compound heterozygous variants in ABCG5/ABCG8. The disease is characterized by increased plasma plant sterols. Small case series suggest that patients with sitosterolemia have wide phenotypic heterogeneity with great variability on either plasma cholesterol levels or development of atherosclerotic cardiovascular disease. The present study aims to characterize the prevalence and clinical features of sitosterolemia participating in a familial hypercholesterolemia genetic cascade screening program. METHODS: From 443 familial hypercholesterolemia index cases, 260 were negative for familial hypercholesterolemia genes and were sequenced for the ABCG5/8 genes. Clinical and laboratory characteristics of affected individuals were determined. RESULTS: Eight (3.1%) index cases were found to be homozygous or compound heterozygous variant for ABCG5/ABCG8 genes, confirming the genetic diagnosis of sitosterolemia. Screening their relatives led to the identification of 6 additional confirmed sitosterolemia cases (3 homozygous and 3 compound heterozygous variant) and 18 carriers (heterozygous). The mean age of identified sitosterolemia cases (n=14) was 37.2±19.8 years, 50% were females, and 78.6% (all adults) presented either clinical or subclinical atherosclerotic cardiovascular disease. As expected, affected individuals presented elevated plasma plant sterol levels (mean ß-Sitosterol and campesterol, respectively, 160.3±107.1 and 32.0±19.6 µg/mL) and the highest plasma LDL (low-density lipoprotein)-cholesterol was 269.0±120.0 mg/dL (range: 122-521 mg/dL). LDL-cholesterol mean reduction with therapy among cases was 65%. Eighty-three percent (83%) of identified sitosterolemia patients presented hematologic abnormalities. CONCLUSIONS: Testing genes associated with sitosterolemia in the molecular routine workflow of a familial hypercholesterolemia cascade screening program allowed the precise diagnosis of sitosterolemia in a substantial number of patients with varying LDL-C levels and high incidence of early atherosclerotic cardiovascular disease and hematologic abnormalities.

Clinical and genetic features of sitosterolemia in Japan.

BACKGROUND AND AIM: Clinical manifestations and genetic backgrounds of Japanese patients with sitosterolemia have been unclear. MATERIALS AND METHODS: We searched PubMed for studies using the keywords "sitosterolemia" or "phytosterolemia" and "Japan". Moreover, we added information from the members of the Committee on Primary Dyslipidemia under the Research Program on Rare and Intractable Disease of the Ministry of Health, Labour and Welfare (MHLW) of Japan. RESULTS: We identified 36 patients with sitosterolemia caused by biallelic pathogenic mutations in the ATP-binding cassette subfamily G member 5 (ABCG5) or ATP-binding cassette subfamily G member 8 (ABCG8) from 31 families in Japan. The diagnosed age ranged from 0 to 64 years (median 13 years). The median sitosterol and LDL cholesterol levels were 100 µg/ml (IQR: 50-183), and 193 mg/dl (IQR: 108-295), respectively. All the patients exhibited cutaneous and/or tendon xanthomas, up to 9 (25%) patients exhibited premature coronary artery disease, 5 (16%) patients exhibited arthritis, and 8 (22%) patients exhibited blood abnormalities. Ezetimibe was administered to all the patients, including infantile cases, while statins, colestimide, evolocumab, probucol, and LDL apheresis were also used. CONCLUSION: We are providing a demographic overview of the clinical and genetic backgrounds of Japanese patients with sitosterolemia.

Common variant p.D19H of the hepatobiliary sterol transporter ABCG8 increases the risk of gallstones in children.

INTRODUCTION: Gallstones are increasingly common in children. Genetic analyses of adult cohorts demonstrated that the sterol transporter ABCG8 p.D19H and Gilbert UGT1A1*28 variants enhance the odds of developing gallstones. The genetic background of common lithiasis in children remains unknown. METHODS: Overall, 214 children with gallstone disease (1 month-17 years, 107 boys) were inclueded. The control cohorts comprised 214 children (age 6-17 years, 115 boys) and 172 adults (age 40-92 years, 70 men) without gallstones. The ABCG8 p.D19H and UGT1A1*28 polymorphisms as well as ABCB4 (c.504C>T rs1202283, c.711A>T rs2109505) and NPC1L1 variants (p.V1296V rs217434, c.-18C>A rs41279633) were genotyped using TaqMan assays. Serum concentrations of plant sterols and cholesterol precursors were measured by gas chromatography/mass spectrometry. RESULTS: The ABCG8 risk allele was associated with an increased risk of stones (OR = 1.82, p = .03). Children carrying the p.19H allele presented with lower serum concentrations of surrogate markers of intestinal cholesterol absorption and decreased ratios of phytosterols to the cholesterol precursor desmosterol. Carriers of the common NPC1L1 rs217434 allele had an increased gallstone risk compared with stone-free adults (OR 1.90, p < .01). This variant also affected the ratio of phytosterols to cholesterol precursors (p = .03). Other tested variants were not associated with gallstone risk. CONCLUSIONS: The p.D19H ABCG8 and, to a lesser extent, NPC1L1 rs217434 variants increase the risk of early-onset gallstone formation. These results point to the presence of a common lithogenic pathway in children and adults.