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Nutritional and Metabolic Imbalance in Keratoconus: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Giulio Ferrari.

Keratoconus (KC) is a progressive corneal degeneration characterized by structural changes consisting of progressive thinning and steepening of the cornea.

  • keratoconus
  • nutrients
  • metabolites

1. Introduction

Keratoconus (KC) is the most common ectatic degeneration of the cornea. It is characterized by corneal thinning and steepening, which result in irregular astigmatism and vision loss. Initial presentation typically occurs during infancy/adolescence and usually progresses for 10 to 20 years, after which the disease is generally stable [1].The prevalence varies widely across the globe, from 0.2/100,000 in Russia to 4790/100,000 in Saudi Arabia [2], with an estimated global prevalence of 1.38/1000 [3]. Pediatric/young adult populations usually display a higher prevalence and a more aggressive form of disease, as opposed to later-onset KC [4,5,6][4][5][6]. Moreover, it seems that the genetic background predisposes some ethnicities to KC [7].

2. Pathogenesis of Keratoconus

The structural alterations observed in KC corneas affect the epithelium, the epithelial basal membrane, the Bowman layer, and the stroma [25][8]. Morphological alterations of epithelial basal cells and degradation of extracellular matrix (ECM) occur [26][9], leading to thinning of the corneal stroma, keratocyte apoptosis, and nerve damage [27,28][10][11]. In fact, ECM remodeling is significantly influenced by these biochemical factors. For instance, metal ions such as copper and iron, and vitamins (e.g., vitamin C) are essential cofactors of enzymes involved in collagen synthesis and crosslinking [30][12].

2.1. Vitamins

Vitamins are essential nutrients indispensable to many corneal functions. In recent years, tThe specific role of vitamin D (Vit D) in the maintenance of corneal integrity has been studied in detail [34][13]. Vit D maintains the corneal epithelial barrier function [35,36][14][15] and is needed for survival of endothelial cells [37][16]. In addition, anti-inflammatory and antimicrobial properties have been described [38][17]. Lastly, Vit D participates in the redox homeostasis as it has an antioxidant role [39][18].

2.2. Minerals

Nutritional deficiency can also affect the concentration of metal ions, such as copper (Cu), iron (Fe), selenium (Se), and zinc (Zn). These are all cofactors of enzymes involved in collagen synthesis, crosslinking, or antioxidant activity. Therefore, an imbalance in these minerals can be an independent risk factor for KC development [58][19]. In line with this hypothesis, KC patients display lower serum levels of Cu, Se, and Zn [46,59,60,61][20][21][22][23]. Moreover, Cu deficiency can be exacerbated in KC by increased tear alkalinity. This would inhibit transfer of Cu ions to the center of the cornea [62][24], thus generating a localized deficit of Cu. In this vein, peripheral Cu deposition is a common clinical feature in KC patients (i.e., Fleischer ring) [62,63,64][24][25][26]. The mechanism(s) through which deficiency of metal ions may promote KC formation are manifold. Some relevant examples are the Cu-dependent lysyl oxidase (LOX), which promotes collagen crosslinking [65][27], antioxidant enzymes such as Cu,Zn-Superoxide dismutase (SOD1 and SOD3) [60,61,66,67][22][23][28][29] and Se-dependent glutathione peroxidase (GPx) [66][28], and Zn-dependent matrix metalloproteinases (MMPs), which regulate collagen degradation [60][22]. Dysregulated iron metabolism has also been hypothesized in KC corneas. In fact, Fe has been detected, together with Cu, in the corneal Fleischer ring [62,63][24][25]. Due to Fe peripheral deposition, it was hypothesized that central unavailability of Fe contributes to KC development, because it works as a cofactor of lysyl hydroxylase (LH), which is required for the collagen crosslinking process. While no significant differences were found in the serum levels of Fe [59][21], KC patients show lower levels of iron-binding proteins serotransferrin and lactoferrin in tears [47,68][30][31] and the corneal epithelium [69][32], suggesting that iron homeostasis is locally altered in KC cornea. Interestingly, certain polymorphisms of the transferrin gene have been identified as risk factors for KC [70][33]. Deranged iron metabolism could contribute to KC development not only by reducing the function of crosslinking enzymes, but also by producing reactive oxygen species (ROS) through the Fenton reaction [71][34]. This may result in oxidative stress, a well-established cause of KC development.

2.3. Hormones

2.3.1. Thyroid Hormones

The contribution of thyroid hormones is still under scrutiny. Some studies have reported a higher thyroid gland dysfunction prevalence among KC patients [72[35][36],73], but others failed to prove an association between them [74,75,76][37][38][39]. Nevertheless, increased levels of thyroxine hormone (T4) were found in tears [72,77][35][40] and aqueous humor [78][41]. Moreover, the expression of thyroxine receptor (T4R) was elevated in keratocytes of KC patients compared to controls [72][35], suggesting an active role of T4 in the pathophysiology of KC.

2.3.2. Sex Hormones

The imbalance of sexual hormone levels has been studied in KC patients. However, data are heterogeneous, and it is still unclear when (age and disease stage) those hormones impact on KC corneas or which molecular pathways are involved [79][42]. A longitudinal evaluation of middle-aged KC patients failed to show any difference in progression between males and females, or in females with or without hormone treatment [80][43]. Interestingly, KC typically develops in puberty with stabilization after 40 years of age [9,81][44][45]. This is consistent with the profile of significant hormonal changes, supporting a potential role in KC pathophysiology. Lastly, there are reports of KC development and progression during or immediately after pregnancy [82,83][46][47].

2.4. Metabolites

2.4.1. Redox Metabolism

The redox metabolism involves the broad range of biochemical reactions that maintain the balance between oxidant and antioxidant compounds [89][48]. When this balance shifts toward the pro-oxidant species, oxidative stress takes place, which may result in massive cell damage [90,91][49][50]. The eyes, particularly the cornea, are constantly exposed to environmental stressors, such as UV radiation, pollutants, and injuries. For this reason, enzymatic and nonenzymatic antioxidants are highly expressed in the human cornea [92][51]. In fact, alterations of the redox balance are involved in several corneal diseases, including KC [93][52]. The role of redox metabolism alterations in the pathogenesis of KC has been extensively studied [94][53]. It has been shown that KC corneas display increased production of reactive oxygen and nitrogen species (ROS and RNS, respectively) [95,96][54][55]. As a consequence, large amounts of cytotoxic byproducts from both lipid peroxidation (e.g., malondialdehyde) and nitric oxide pathways (e.g., nitrotyrosine, peroxynitrites) were observed [95,97][54][56]. In addition, mitochondrial DNA damage has been reported [98][57]. A possible explanation for the increased oxidative stress is a reduction in the total antioxidant capacity of the KC cornea. In line with this hypothesis, levels of non-enzymatic antioxidants (e.g., glutathione) [54,97,99][58][56][59] and antioxidant enzymes, including SOD and aldehyde dehydrogenase (ALDH) [94,98[53][57][60][61],100,101], are reduced in KC corneas. Another indicator of oxidative stress is the increase in lactate/pyruvate (L/P) ratio, which was found in both in vitro [102][62] and in vivo [99][59] studies.

2.4.2. Arachidonic Acid Pathway

Arachidonic acid (AA) is a polyunsaturated fatty acid that is implicated in several biological functions. Due to its four cis double bonds, AA helps in maintaining cell membrane fluidity and ability to interact with proteins [105][63]. Moreover, AA can be metabolized by phospholipase A2s (PLA2s), cyclooxygenases (COXs), and lipoxygenases into prostaglandins and leukotrienes, important proinflammatory mediators [106][64]. The AA pathway is involved in different pathophysiological processes in the eye [107][65]. 

2.4.3. Tricarboxylic Acid Cycle

The tricarboxylic acid cycle, also known as the citric acid cycle or Krebs cycle, is an amphibolic series of chemical reactions occurring in respiring organisms that eventually lead to the production of energy [113][66]. Defects in this cycle are associated with pathological conditions in different body sites, including the eye [114,115][67][68]. Metabolic imbalances involving the citric acid cycle have been reported in KC patients and are confirmed by detection of increased lactate production [53,87,102][69][70][62]. This has deep implications for the cell fate, since abundant lactate synthesis (anaerobic respiration) results in lower extracellular pH, increased oxidative stress, and apoptosis [116][71]. For these reasons, the lactate/malate ratio has been proposed as an indicator of oxidative stress, which may play a role in KC progression [96,102][55][62]. Interestingly, it has been shown that in vitro models of KC receiving collagen crosslinking respond with a shift toward aerobic respiration, with marked increase in ATP synthesis [53][69].

2.4.4. Glycolysis and Gluconeogenesis

Glycolysis and gluconeogenesis are two metabolic pathways involved in glucose catabolism and anabolism, respectively, which play a key role in cell survival [117,118][72][73]. Studies performed on in vitro models of KC demonstrated that glucose metabolism is upregulated [119,120,121][74][75][76]. In particular, anaerobic glycolysis appears to be the most affected, since concentrations of lactate are higher than pyruvate [102][62]. Interestingly, it was shown that sex hormones are able to alter glucose metabolism in human keratoconus cells (HKCs), a finding that is corroborated by the observation that KC typically develops in puberal age [122,123][77][78]. Metabolomic analysis of tears from KC patients showed a significant increase in metabolic intermediates involved in anaerobic glycolysis, confirming the in vitro results [99][59].

2.4.5. Urea Cycle Metabolism

The urea cycle, also known as the ornithine cycle, is a human metabolic pathway, which serves for ammonia detoxification [125][79]. Stimulation of HKCs with dehydroepiandrosterone (DHEA), a sex hormone upregulated in the serum of KC patients, directly upregulated urea cycling [111][80]. This stimulation led to an altered availability of precursors necessary for the biosynthesis of proline and hydroxyproline, two major components of collagen [123][78], thereby altering collagen metabolism. 

2.4.6. Fatty Acid Metabolism

Lipids and fatty acids are two of the major components of the human cornea. They are involved in different cellular pathways, modulating pro- and anti-inflammatory reactions, promoting corneal tissue proliferation and repair, and contributing to neovascularization [126][81]. The most representative fatty acids in the human cornea are oleic, stearic, and palmitic acids [127][82]. In a recent study, gas chromatography and mass spectrometry were used to define a metabolomic signature to discriminate between healthy and KC corneas [128][83]. A significantly reduced amount of both saturated fatty acids, such as stearic, palmitic, myristic, and pentadecanoic acid, and unsaturated fatty acids (e.g., linoleic and trans-13-octadecenoic acid) was reported. Lower levels of fatty acids in KC patients may be explained by the reduced amount of malonyl CoA observed in previous studies [99,129][59][84]. In fact, malonyl CoA is an essential precursor for fatty acid biosynthesis [130][85].

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