More Harm Than Good

As average life expectancy continues to increase, the number of people with age-related macular degeneration (AMD) is predicted to more than double by 2050.¹ AMD is the leading cause of irreversible central vision loss and affects more than 2 million Americans.² As people age, they are also more susceptible to acid-related gastrointestinal disorders such as gastroesophageal reflux disease (GERD),³ which is typically treated with a proton pump inhibitor (PPI). However, use of PPIs in the elderly population has been shown to be problematic because they can increase the incidence of osteoporosis, infections, and electrolyte abnormalities. Some small studies have shown that use of PPIs in patients with advanced AMD can cause development of Charles Bonnet syndrome (CBS), a condition leading to visual hallucinations (see Charles Bonnet Syndrome Quick Facts).⁴ Other literature has shown that PPIs can interfere with the function of lysosomes,⁵ which are organelles responsible for waste product degradation in the retinal pigment epithelium (RPE).⁶ Disruption in functions of the RPE can contribute to the formation of yellow deposits called drusen that are associated with increased risk of developing AMD.⁷

The pathophysiology of PPIs in patients with AMD, however, is still unclear. This article attempts to raise awareness of the potential complications associated with PPI use in patients with AMD.

SPOTLIGHT ON LYSOSOMES

The retina contains photoreceptors, rods and cones, which are responsible for vision in low light and color vision, respectively.⁸ These photoreceptors are structured as stacked membranes, with the distal tips of their outer segments contacting the RPE. One of the functions of the RPE is to phagocytose the photoreceptor outer segments and break them down through lysosomes.^6,7 These organelles maintain an acidic environment, with a pH value around 4.5 to 5.^9,10

Lysosomal Inhibition

Aging is associated with a decline in lysosomal degradation.⁶ Additionally, the RPE is highly metabolically active; therefore, a high rate of autophagy is expected.⁶ As people age, not only will they have fewer lysosomes, but the existing lysosomes will have a higher work burden,⁷ which can lead to a buildup of excess biologic waste, such as lipofuscin and other undigested proteins. For this reason, the dysfunction in the lysosomal pathway is thought to be a risk factor for AMD.⁶

Sparrow et al found that lipofuscin and its component bis-retinoid N-retinylidene-N-retinylethanolamine (A2E) accumulated in the macula as residue from lysosomal degradation.¹⁰ A2E has been shown to cause cellular toxicity and is associated with blinding retinal diseases such as AMD. Sparrow and colleagues found that A2E had an affinity for acidic organelles (eg, lysosomes) and exhibited a detergent-like effect that disrupted the organelle’s membrane. De and Sakmar reported similar effects, in that A2E was detrimental to cells once above a critical concentration.¹¹ These studies determined that A2E affected liposomal function, but the mechanism was unclear.

In 2004, a study by Bergmann et al revealed that lysosomes had severely impaired function due to reduced lysosomal acidification subsequent to inhibition of the H+ ATPase pump by A2E.¹² The increase in intraliposomal pH leads to inhibition of lysosomal hydrolases and results in intracellular accumulation of undegraded material. The study was performed by loading cultured human RPE cells with various levels of A2E and measuring lysosomal phagocytic action on exogenous iodinated photoreceptor outer segments added to the culture medium.

PPIs and Lysosomal Function

PPIs may also interfere with the pH gradient needed for lysosomal function. Lysosomes use H+ ATPases to create a proton gradient, while proton pumps normally target H+/K+ ATPases in the parietal cells.¹³ However, research in oncology has found that H+/K+ ATPases aren’t completely specific for parietal cells only. A study by Liu et al found that PPIs also inhibit lysosomal enzyme function in other organs such as the spleen.⁵ This means that, through systemic absorption, PPIs may be able to reach RPE cells and contribute to the inhibition of lysosomal function there as well, although this requires further study.

The morbidity effects of long-term PPI use in other conditions is well known. For example, Yepuri et al found that esomeprazole impaired lysosomal function by increasing lysosomal pH.⁴ This led to accumulation of protein aggregates, which promoted vascular senescence in their experiment and may explain why PPI use increased cardiovascular morbidity and mortality.

A Connection to Alzheimer Disease?

The inhibition of lysosomal function by PPIs is also being studied as a risk factor that predisposes patients to Alzheimer disease. In fact, Fallahzadek et al hypothesize that the increase in pH has an effect on the degradation of fibrillar A beta.¹⁴

RISK OF CBS

Aside from the lysosomal inhibition by PPIs, there is another reason that PPIs should be avoided in patients with AMD. There have been studies that indicated an association with PPI use and CBS in patients who had AMD. Leandro et al found that, among patients with AMD, PPIs doubled the risk (15%) of CBS compared with patients who were not taking PPIs (7%) in a total population of 471 patients.¹⁵ The researchers believe that PPIs may block horizontal cell feedback to photoreceptors, which can lead to hallucinatory activity.

BETTER SAFE THAN SORRY

It is now known that inhibition of lysosomal pumps, whether through A2E or PPIs, leads to accumulation of intracellular waste.¹⁶ Because there is no treatment to prevent the buildup of A2E, we should not add to the burden by prescribing PPIs to patients with AMD to increase intraliposomal pH. In addition to the lysosomal pump inhibition, PPIs may also increase the risk of visual hallucinations in patients who already have AMD. For these reasons, it is important that over-the-counter PPIs not be used for more than 14 consecutive days. Further, this 14-day regimen should not be repeated more frequently than every 4 months. Other drug classes, such as H₂ receptor antagonists, should also be considered in this patient population. Despite this knowledge, additional research is needed, specifically regarding how PPIs affect lysosomes in the RPE, to improve our understanding and to help clinicians be better informed in our recommendations.