According to this paper, those who have below 5th percentile LDL and apoB in which the gene affected is APOB, there are side effects. However, those who have a below 5th percentile LDL and apoB through the PCSK9 gene being affected, there is no adverse effects.
From cited paper:
Genetic conditions include a heterogeneous group of disorders characterized by reduced plasma levels of total cholesterol, LDL-C, or apolipoprotein B (apoB) less than the 5th percentile.4 The most severe multisystem phenotypes due to ultrarare homozygous mutations (defined as mutations on both alleles or biallelic pathogenic mutations) including abetalipoproteinemia (ABL), homozygous familial hypobetalipoproteinemia (FHBL), and chylomicron retention disease, are characterized by the absence, or near absence, of LDL-C. Clinical findings include steatorrhea, failure to thrive, and fat-soluble vitamin deficiencies, sometimes with retinopathy, coagulopathy, and progressive neurologic abnormalities. Most patients with these severe disorders present in infancy or early childhood with one or more findings, whereas the low-to-undetectable LDL-C is generally identified during the evaluation. In contrast, individuals with homozygous mutations in proprotein convertase subtilisin/kexin type 9 (PCSK9) encoding PCSK9, or ANGPTL3 encoding angiopoietin-like protein 3, have low but detectable LDL-C, without systemic involvement.
Certain genetic conditions which lower LDL and apoB have serious side effects, while others do not
which obtained LDL-C values as low as 30 mg/dL and 50 mg/dL, respectively, demonstrated a reduction in the number of CVD-related events without development of fatty liver disease.10, 33, 34 These interventions are considered to reduce LDL-C through enhanced LDL receptor activity. In contrast, other newer LDL-C–lowering therapies including, mipomersen, an oligonucleotide inhibitor of apoB synthesis, and, lomitapide, a small molecule inhibitor of MTP, lower LDL-C by compromising production and secretion of apoB-containing lipoproteins. Both agents are associated with accumulation of intrahepatic fat.35 These findings suggest that low LDL-C may be a marker of, rather than a causal factor for, fatty liver, the latter more likely the result of compromised assembly and secretion of apoB-containing lipoproteins.
What’s causing fatty liver? More likely that it is the mechanism of LDL / apoB lowering and not the low LDL or apoB on its own, because of different side effects depending on the mechanism for lowering.
Lifelong genetically determined low but not absent levels of LDL-C are associated with significantly reduced CVD risk and longer life expectancy,29, 30
Based on our current understanding, it has been suggested that those with confirmed heterozygous APOB-related FHBL should undergo monitoring for liver disease (Table 1). If present, fat-soluble vitamin deficiencies are generally mild and easily corrected.
Although the prevalence is low and the long-term consequences are generally not severe, individuals with heterozygous APOB-related FHBL appear to be at increased risk of fatty liver disease.
The paper cited first here:
This case report is reflective of a family with normal development without known adverse clinical complications despite very low levels of LDL-C. Given the finding of an APOB LoF as the cause for the low LDL-C, routine screening for liver disease and other associated compilations should be pursued long term. Importantly, this patient and affected family members had normal development with very low LDL-C levels, and will likely gain protection against atherosclerotic cardiovascular disease.
So what I’ve think I’ve learned that LDL lowering through loss of function of apoB can have side effects to the liver and fat soluble vitamin absorption. However through other genetic mechanisms there has not been. Pharmacological drugs that decrease LDL / apoB through LDL receptor activity has not caused problems for the liver, but those targeting apoB have, which makes it likely it is because of the mechanism of action.
It’s interesting also that too much fat accumulation of the pancreas relative to individual susceptability causes type 2 diabetes (according to this interview), and we know that there is a small diabetes risk of statins, I don’t know if there is any pattern here, my estimation is 10% chance.
There was this rare other type of apoB loss of function that did not cause problems in this case. I’ll have to read a bit about PCSK9 loss of function causing very low LDL levels more and see what side effects they have (a certain percent of these have very low LDL), but these suggest none. I think I’m more certain now that very low LDL levels aren’t harmful, but there are questions about the liver and vitamin absorption, but it seems unlikely this is caused by the low LDL and not the way the LDL was lowered?
