Ten non FH ADH probands fulfilled
Ten non-FH ADH probands fulfilled the diagnostic criteria of hyperabsorbers. Table 2 shows the main lipid characteristics of these subjects and of 10 non-hyperabsorber probands used for comparison. There were differences between groups in body mass index, waist circumference and triglycerides. Other clinical variables, including dietary characteristics, did not differ between hyperabsorber and non-hyperabsorber probands. Mean values of cholestanol, sitosterol, campesterol and stigmasterol showed statistically significant (P = 0.003 for cholestanol and P < 0.001 for phytosterols) between both groups.
Table 3 shows the clinical and biochemical characteristics of the family members in both, hyperabsorber and non-hyperabsorber families. In families with a hyperabsorber proband, there were significant differences between affected and non-affected subjects for total cholesterol, LDL cholesterol, non-HDL cholesterol and apolipoprotein B, without differences in BMI. Intestinal cholesterol avibactam markers were higher in affected subjects, with significant differences for cholestanol. In non-hyperabsorber families, there were similar lipid differences than in hyperabsorber families and affected subjects had higher BMI than non-affected subjects. The concentration of cholesterol absorption markers was not significantly different in the non-hyperabsorber families, except for cholestanol. No difference was found in desmosterol between affected and non-affected subjects in hyperabsorber families and significant difference was found between affected and non-affected subjects in non-hyperabsorber families (P = 0.004), probably associated with a significantly higher BMI. Desmosterol, was significantly lower in affected subjects from hyperabsorber families than in affected subjects from non-hyperabsorber families (2.76 (2.26–2.94) vs. 2.96 (2.67–3.32), P = 0.035). An opposite pattern although without reaching statistical significance was found for intestinal cholesterol absorption markers (6.87 (5.43–8.75) vs. 5.90 (4.90–6.77), P = 0.083).
Spearman's rank correlations between LDL cholesterol levels and cholesterol absorption markers are reported in Table 4. Sitosterol and stigmasterol in hyperabsorber families had a positive correlation with LDL cholesterol. However, no correlation was found for cholesterol absorption markers in non-hyperabsorber families. When subjects were divided in hyperabsorbers and non-hyperabsorbers, there was a significant association between LDL cholesterol and cholestanol and sitosterol only in hyperabsorber subjects (Supplementary Figure). The diagnosis of hyperabsorber in the families was associated with a higher risk to be affected by high LDL cholesterol with OR 3.47 (confidence interval 1.60–7.51) and B 1.24 (P = 0.002). This risk was substantially increased when only family members from families with an hyperabsorber proband were considered ((OR = 6.80 (confidence interval 1.656–27.9), B = 1.917, P = 0.008)).
In hyperabsorber families the percentage of affected hyperabsorber subjects was higher (76.5%) than in families with non-hyperabsorber probands (Fig. 1). Among non-affected subjects, the number of hyperabsorber and non-hyperabsorber subjects was identical. In non-hyperabsorber families, the percentage of non-affected non-hyperabsorber subjects was higher (73.2%) than in hyperabsorber families. The 60.5% of subjects in hyperabsorber families were hyperabsorbers and 76% of them were affected. The 38.3% of the subjects in non-hyperabsorber families were hyperabsorbers and 63% of them were affected (Fig. 1).
Discussion This is the first study, to our knowledge, to analyze the cholesterol intestinal absorption in families with non-FH ADH. Our results show that 78% of the family members with high LDL cholesterol with a hyperabsorber proband show an increase in serum non-cholesterol sterols of intestinal origin, with a positive correlation between these sterols and LDL cholesterol levels. Because phytosterols and cholestanol are a well established tool to study cholesterol intestinal absorption, our results highly support that inter-individual variation in the efficiency of cholesterol absorption plays an important role in the pathophysiology of non-FH ADH. Previous reports had established that serum cholesterol and phytosterols are increased in this population , , consequently, these data all together suggest that genetic variation in cholesterol absorption is involved in non-FH ADH families.