The lower is better”: genetic pitfalls of a paradigmatic approach for dyslipidemia

Several clinical trials stressed the importance of an aggressive approach in LDL cholesterol (LDL-c) reducing for primary and secondary cardiovascular prevention. The concept of ”Lower is Better” is based on the evidence of how cholesterol reduction induces a proportional decrease in the probability of incurring in the clinical complications of atherosclerotic disease. If, on the one hand, it is necessary to use all the pharmacological tools currently available for the massive abatement of atherogenic cholesterol, on the other hand we must not always remain worry-free in front of very low values of cholesterol, because they could be a sign of complex and life-threatening clinical events, as well as vascular events caused by hypercholesterolemia. Very low (<30 mg/dL) LDL-c can be found in patients with genetic conditions characterized by hypocholesterolaemia: for example, loss-of-function mutations in Proprotein Convertase Subtilisin/Kexin 9 gene (PCSK9), familial hypobetalipoproteinemia, abetalipoproteinemia, chylomicron retention disease and Smith-Lemli-Opitz syndrome are genetic conditions characterized by congenital, lifelong, very low LDL-c values. Among these, abetalipoproteinemia (ABL) is a rare autosomal recessive genetic disease caused by mutation of the triglyceride microsomial transfer protein (MTP), involved in ApoB lipoproteins assembling. This disease is characterized by the absence of lipoproteins containing ApoB, undetectable LDL and lack of fat-soluble vitamins (A, D, E, K). Affected individuals may have severe neurological manifestations (retinal degeneration, spinocerebellar ataxia, peripheral neuropathy), steatorrhea, hepatic steatosis, haemorrhagic diathesis, osteoporosis, myositis, and acanthocytic anemia. The clinical manifestations related to ABL are induced by vitamin deficiency and cholesterol reduction and the currently approved therapy involves vitamin supplementation, in particular A and E, to stop ocular and neurological degeneration. Among the possible complications of ABL, there is hepatic steatosis, due to the accumulation of triglycerides in the liver. In these patients, steatosis can evolve into cirrhosis, that sometimes could require liver transplantation. A late or missed diagnosis can lead to a fatal outcome even by the third decade of life. Our Rare Disease Centre takes care of patients with lipid metabolism disorders, even during the transition from childhood to adulthood. In April 2023, a 23-years-old patient, diagnosed with ABL in a Paediatric Centre during the first year of life, came to our attention. Since the first months of life, due to persistent diarrhea and growth delay, the patient performed several laboratory and instrumental tests to exclude most common pathologies, such as celiac disease. Given the negativity of the laboratory tests and jejunal biopsy, further investigations were done. Acanthocytic anemia, elevation of transaminases and appearance of widespread skin haemorrhagic manifestations were found. Lipid profile showed: TOTc 61 mg/dl, LDLc not dosable, HDLc 57 mg/dl, triglycerides 56 mg/dl, ApoB 23.4 mg/dl, ApoA1 69 mg/dl. According to the tests performed and the familiarity for ABL, a diagnostic hypothesis about abetalipoproteinemia was done and the young patient was treated with fat-soluble vitamin supplementation (E, A and K) and a specific hypo-lipidic diet, with considerable clinical benefit. Subsequently, diagnosis has been confirmed in 2019 with genetic analysis, showing mutations of theMTP gene and the apoB gene. The patient performed periodic eye check for initial rods dystrophy, regressed with early vitamin supplementation. In our Centre, the patient underwent to a clinical, laboratory and instrumental reevaluation that led to dosage adjustment of the therapy with vitamin E (deficient in recent laboratory tests); because of the persistent elevated transaminase values, he also underwent to an abdominal ultrasound, showing mild-to-moderate hepatic steatosis that should be periodically checked, in the light of the young age and the possibility of evolution into liver cirrhosis. This clinical case is an example of how low LDL cholesterol does not necessarily associate with a favourable clinical prognosis. The so rightly exalted concept of ”Lower is Better” should not lead us to underestimate the meaning of hypocholesterolemia. In fact, even if it plays a cardioprotective role, on the other hand it can become part of some clinical conditions characterized by a particularly important impairment of quality-of-life and life expectancy. In this context, the importance of knowledge of Rare Diseases is emphasised, especially when the ”time” factor plays a crucial role: recognizing rare pathologies can often make the difference between life and death.