The Barcelona Macula Foundation, in conjunction with other members of the European EYE-RISK consortium, has examined the relationship between lipids and age-related macular degeneration (AMD) in Progress in Retinal and Eye Research, the journal with the greatest impact in ophthalmology. The study’s title is “A new perspective on lipid research in age-related macular degeneration.”
Lipids are non-water-soluble molecules but they are very soluble in organic solvents. There are many types, such as phospholipids, sphingolipids and sterols. In human beings and other living creatures, lipids are essential and are used as a reserve source of energy. They form part of cell membranes and are molecular signallers.
It has been suspected for some years that lipids play an important role in the development of AMD. In the 1960s, lipids were identified in the composition of drusen, the characteristic lesions of AMD (in fact, we now know that around half of the components of drusen are lipids). In the 1990s, the Pauleikhoff group saw that with age there was a growing deposit of lipids in the Bruch membrane, which reduces its transferability and facilitates the growing accumulation of deposits (drusen) between this structure and the retinal pigment epithelium (RPE) in a sort of vicious circle. These retained lipids come both from systemic circulation and the retina (probably from the external segment of photoreceptors and the RPE) and could cause a pathological response that manifests itself clinically as AMD. This theory, called the “retention response hypothesis”, also explains the relationship between arteriosclerosis and cardiovascular disease.
With age, more lipids are deposited in the Bruch membrane, which reduces its transferability and facilitates the growing accumulation of deposits
At the same time, there was discovery of an association between AMD and different genes related to the metabolism or the transportation of lipids, such as ABCA4, APOE, CETP, IPC or ELOVL4. All these findings would confirm the influence of lipids on the disease. However, the relationship is more complex than it appears.
Much clinical research into lipids in AMD has focused on cholesterol. It is well known that high levels of LDL-C (low-density lipoprotein Cholesterol, “bad cholesterol”) increases the risk of cardiovascular morbidity and mortality. Similarly, low-levels of HDL-C (high-density lipoprotein Cholesterol, “good” cholesterol) have been associated with an increase in the risk of cardiovascular disease. However, this relationship is different in AMD. The association between LDL-C and AMD is disputed, while high levels of good cholesterol, HDL-C, have been linked to an increase (not a reduction) in the risk of developing the disease.
How can we clarify this relationship? Research in animal models is important but difficult to apply in humans as their lipid profile is very different. One aspect to consider is to measure the amount of cholesterol more accurately as in most studies LDL-C is not determined directly but estimated using the Friedewald formula. It is also necessary to study whether systemic cholesterol levels, those that are usually measured through a blood test, can be linked to AMD or whether it is necessary to develop methods of measuring cholesterol directly in the external retina. Furthermore, it appears that the composition and functionality of these lipids is of more importance than their number, so this does not involve simply measuring them but determining what fraction of these molecules functions properly. Finally, 75% of cholesterol in the retina is of endogenous origin (compared to 100% of what is found in the brain) so that our analysis should take other factors into account. It is clear that further research is needed to clarify the relationship between AMD and lipids.
These issues explain the failure to develop AMD treatments on the basis of lipid regulation. For example, a study stated that approximately half of patients with large high-risk drusen in both eyes showed a disappearance of lesions after more than 12 months of treatment with high doses of one of the medicines that is most used to reduce LDL-C, statins. Unfortunately, it has been impossible to generalise these results consistently in meta-analyses that include thousands of patients. Statins may benefit patients with some specific characteristics but this has been impossible to confirm so far and their use in AMD patients is not recommended.
These aspects and others are contained in Progress in Retinal and Eye Research with the aim of discovering more about the role played by lipids in macular degeneration.
MARC BIARNÉS OD MPH PhD, A MEMBER OF THE BMF RESEARCH TEAM