Lessons from chylomicron retention disease: a potential new approach for the treatment of hypercholesterolemia?

During the last decades, the identification of different rare diseases inducing fat intestinal malabsorption, namely the genetic hypocholesterolemias, has led to the characterization of the physiological steps involved in the intestinal absorption of lipids. Chylomicrons are essential for intestinal absorption of lipids since they are the main carriers of dietary lipids. These triglyceride-rich lipoproteins are secreted exclusively from the enterocyte. The SAR1B gene was identified as responsible for chylomicron retention disease (CMRD), previously called Anderson’s disease (OMIM #246700) [1]. Historically, the first clinical description was in 1961 of a 7-month-old child with a persistent neonatal diarrhea [2]. Finally, in 2003, genotyping demonstrated that Anderson’s disease and CMRD were in fact the same disease [1].

The identification of the gene SAR1B in the pathophysiology of this disease improved our understanding of the physiological secretion of chylomicron. The SAR1B gene is abundant in the intestine, the liver, and muscles. This gene encodes the SAR1b protein, which is involved in chylomicron transport from the endoplasmic reticulum (ER) to the Golgi apparatus [3]. SAR1b is also involved in the hepatic secretion of very low-density lipoprotein (VLDL).

Genetic experiments highlight the pivotal role of SAR1B in lipid metabolism. First, SAR1B surexpression in rodents increased the risk of metabolic syndrome, as revealed by incremental weight gain, fat deposition, dyslipidemia, hepatic steatosis, insulin insensitivity, and intestinal fat absorption [4]. In contrast, deletion of the 2 SAR1 isoforms (A and B) suppressed the secretion of chylomicron in vitro by Caco2 cells [5].

However, this genetic approach also demonstrates the limits of experimental models. The SAR1 protein has 2 isoforms, namely SAR1B the most abundant in the human intestine (3-higher) which is depleted in CMRD, and SAR1A. There is incongruity between patients with CMRD who have only a mutation of SAR1B and the cellular or animal models who need a double deletion of the 2 SAR1 isoforms to induce the severe phenotype of the disease [5,6]. Indeed, the deletion of SAR1B alone did not nullify the secretion of chylomicron in Caco2 cells [5]. Interestingly, in duodenal biopsies of patients with CMRD, the compensatory increase of SAR1A (1.5 times) seems insufficient to compensate for the staggering decrease in SAR1B expression [7]. Therefore, it seems reasonable to suppose that surexpression of SAR1A in patients could not compensate the SAR1B suppression.

The genotype-phenotype correlation is not obvious in CMRD [8], since less deleterious mutations such as missense mutations are not necessarily associated with less severe phenotypes [9]. Interestingly, the mutation of SAR1B may be involved in different tissue-specific failures: hepatocyte secretion of nascent VLDL in a SAR1B-dependent mechanism may be involved in the hepatic steatosis described in CMRD. Furthermore, the skeletal muscle and the myocardium have been shown to express the SAR1B gene; therefore, increased creatinine kinase and cardiomyopathy described in some patients may be also related to this mutation [10].

Diagnosing this extremely rare disease (probably fewer than 1 in 1,000,000 people worldwide have this autosomal recessive disease) will be the first challenge for the physician. Until now, around 60 cases have been described; but only 40 with their genotype, including about 20 different mutations. Furthermore, the nonspecificity of the initial symptoms (diarrhea and steatorrhea, abdominal distension, vomiting and a rapid failure to thrive) explain the delayed diagnosis. Only one-third of children described in the literature were diagnosed with CMRD during their first year of life [10]. Therefore, a newborn with a chronic diarrhea without any confirmed classical diagnosis should have a lipid profile performed. A severe decrease in total and low-density lipoprotein (LDL) cholesterol (50% normal value) but a moderate decrease in high-density lipoprotein (HDL) and normal triglycerides (TG). This is very different in patients with other intestinal primary hypocholesterolemias associated with intestinal malabsorption, namely abetalipoproteinemia (ABL) and homozygous familial hypobetalipoproteinemia type I (FHBL-1), who have almost undetectable LDL, a normal HDL, and very low TG levels.

Others biological abnormalities may point to the diagnosis of CMRD: Liposoluble vitamins are decreased with a severe and permanent vitamin E deficiency even with supplementation. In contrast, vitamins D and K are normalized easily with oral supplementation. Acanthocytosis on blood film is rare in CMRD, in contrast to ABL and FHBL-1. A transaminitis is frequent and early but not specific, with an elevated transaminases (1.5–3 times normal), associated with normal gamma-glutamyltransferase (GGT), bilirubin and alkaline phosphatase values. An increase of creatinine kinase (1.5–4 times normal) is frequent in CMRD but not in other genetic hypocholesterolemias.

Diagnosis is frequently clarified by anatomopathology with intestinal biopsies that show normal villi but enterocytes that appear grossly distended by lipid droplets; with chylomicron-like aggregates that are membrane bound in electron microscopy. The upper endoscopy may be performed in the fasting state, but we recommend practicing it after a 3-day enriched fat diet to enhance the accuracy of this exam. However, this enriched fat diet needs to be monitored at the hospital because the possible increase of diarrhea could induce dehydration in the newborn. During the exam, a nonspecific but suggestive white duodenal mucosa will be shown.

Finally, genotyping characterizes the mutation of the SAR1B gene on chromosome 5.

Long-term evolution of digestive symptoms was suspected to be variable, and an adaptive phenomenon was thought to occur, since the intensity of symptoms decreased over time, independent of the level of fat in the diet in some previously reported patients [10]. However, the majority of patients will have steatorrhea after a TG-rich meal. Even though the patients’ gastrointestinal symptoms improve on a low-fat diet, diarrhea begins again when fat is reintroduced, even in adult patients. Furthermore, there is no improvement in steatorrhea after an average of 5 years of follow up [10]. This malabsorption explains the failure to thrive, which persists if a low-fat diet is not followed, leading to growth retardation from −1 to −4 standard deviations (SDs) in infancy. Very few data about size in adulthood are available.

During the chronic evolution, complications may arise with delayed or inappropriate treatment. These complications are explained either by the accumulation of lipids due to problems of secretion (intestinal malabsorption and hepatic steatosis); or by deficiency of liposoluble vitamins (neurological and ophthalmic impairment, decreased bone mineralization or clotting disorders). In our experience, patients with CMRD treated during childhood with high doses of vitamins A and E do not develop neurological complications (ataxia, sensory neuropathy, and tremor) [10].

Treatment is based on two main objectives: First, to exclude long-chain fatty acids to decrease the steatosis of enterocytes and hepatocytes, and then to improve intestinal absorption; second, to provide a high amount of liposoluble vitamins to decrease the consequences of vitamin deficiency (for more details about treatment see [11]). Whether it is best to use parenteral versus oral administration has been discussed in the literature. In our experience, the oral route is usually sufficient in CMRD [11]. A liposoluble form of vitamin E at a dosage of 50 mg/kg/d is sufficient in CMRD; this is in contrast to patients with ABL and homozygous FHBL, who require a double dose (100 mg/kg/d). Treatment with a hydrosoluble form of vitamin E (tocopheryl polyethylene glycol succinate) showed a marked and statistically significant increase in the absorption of tocopherol in malabsorbing patients with cystic fibrosis or cholestatic disease compared with a classic oil-based formulation [12,13]; it would be pertinent to evaluate the effectiveness of this formulation of vitamin E in patients with CMRD, even if the pathophysiology is different from that in cholestatic patients. Even if the intravenous route is not necessary for vitamin supplementation in CMRD, it should be required if compliance cannot be obtained orally, since the neurological prognosis depends on the vitamin status.

The follow up and adaptation of vitamin E doses is crucial for the long-term outcome of CMRD. Since the plasma concentration does not reflect the vitamin status of tissues, we suggest that concentrations in erythrocyte membranes and adipose tissue are more accurate for adjusting the dosages of liposoluble vitamins. Since erythrocyte membrane and adipose tissue have very different kinetics for storage and release of lipophilic molecules, they could provide different information. For example, adjusting treatment could be based on erythrocyte assessment, but vitamin reserve and long-term compliance could be based on analysis of adipose tissue. Further clinical studies are necessary to answer this practical and important question. However, these determinations are not universally available, but reference values are available in children [14].

In conclusion, this very rare disease inducing a severe hypocholesterolemia could be a model to develop new therapeutic approaches for hypercholesterolemias, which are common diseases and important in terms of public health. Previously, the understanding of pathophysiology of other genetic hypocholesterolemias, namely ABL and FHBL, led to the development of inhibitors of microsomal transfer protein (MTP) and of apoB, respectively, with powerful effects [15]. Inhibitors of SAR1b-dependent transport could be new tools to treat hypercholesterolemia. The large diversity of molecules transported through this pathway, and the risk of hepatic or muscular consequences appear to be the main problems in developing such therapies. Therefore, molecules specific to the enterocytes should probably be developed to reduce the risk of side effects.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

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