Vitamin A deficiencies and alcohol use
Although nutritional deficits in vitamin A are uncommon in the United States, liver disease can result in functional vitamin A deficiencies. Vitamin A is a fat-soluble vitamin derived from animal sources such as milk and eggs or from plant sources such as green leafy vegetables and yellow fruits. Ingested retinol is esterified to retinol palmitate, which then travels to the liver [
7]. Thus, the liver is closely linked to vitamin A, as this nutrient is stored in hepatic stellate cells.
Vitamin A deficiency results in the deficiency of two metabolites that serve a vital function in the eye: chromophore 11-cis-retinal and all-trans-retinoic acid [
1]. 11-cis-retinal, also known as vitamin A aldehyde, plays a key role in the phototransduction pathway, whereas all-trans-retinoic acid is key in tissue development and immune system function [
1]. Defects in this pathway can result in a reduction of efficient visual stimulus detection and the accumulation of toxic metabolites in the retina [
8]. Deficiencies in vitamin A can therefore result in several manifestations in the eye, including night blindness, retinal dystrophies, photoreceptor cell death, keratomalacia, and corneal ulceration [
1]. In addition to these signs, corneal xerosis is also a possible outcome due to vitamin A deficiency caused by liver pathologies [
9]. Corneal xerosis is the drying of the cornea and often occurs with acute vitamin A deficiencies [
9]. This is attributed to the poor function of glands in the conjunctiva, resulting in the loss of mucus [
10]. Another possible outcome is the development of a corneal ulcer or keratomalacia. The spectrum of ocular pathologies that arise from a deficiency of vitamin A is referred to as xerophthalmia [
11].
There are several liver pathologies that can result in vitamin A deficiency and can subsequently be associated with the previously mentioned ocular manifestations of the deficiency. In one such example, vitamin A deficiency can result from alcoholic liver cirrhosis. Chronic alcohol intake results in decreased oral retinoid intake while also increasing retinol breakdown by inducing enzyme activity [
12]. In patients with cirrhosis, decreased oral intake of vitamin A along with decreased intestinal absorption of vitamin A results in vitamin deficiency that can cause ocular symptoms [
13]. Bitot spots are one such manifestation, presenting as keratinous accumulations on the cornea usually preceded by ocular xerosis and ultimately leading to keratoconjunctivitis. If extensive, a vitamin A deficiency in cirrhotic patients can even lead to corneal necrosis [
13].
In 2005, a case report by Cruz et al. described a patient with a history of chronic alcoholism that presented with bilateral ocular pain, photophobia, and decreased visual acuity. He was treated for vitamin malabsorption and was given dietary supplements, after which his ocular pathologies significantly improved, and his visual acuity completely recovered [
14]. Thus, especially in cases where autoimmune causes of ocular pathologies have been ruled out, vitamin deficiencies should be considered. Other malabsorptive conditions that can result in a vitamin A deficiency include cystic fibrosis, Crohn’s disease, bariatric surgery, short bowel syndrome, celiac disease, and liver disease caused by toxic agents, viruses, and other causes [
14].
Moreover, alcohol use disorders can also lead to Wernicke’s encephalopathy which is an acute, neuropsychiatric syndrome characterized by nystagmus, ophthalmoplegia, mental status changes, and difficulties with balance [
15]. Wernicke’s encephalopathy is caused by thymine deficiencies which can develop from a combination of factors such as poor diet, decreased gastrointestinal activity, low levels of hepatic storage, and impaired utilization. Its ocular manifestations are nystagmus, an involuntary rhythmic side-to-side, up-and-down, or circular motion of the eyes, and ophthalmoplegia, the paralysis or weakness of the eye muscles [
16]. Less common ocular findings with Wernicke’s encephalopathy are optic disc edema, retinal hemorrhage, ptosis, and vision loss [
16].
Aside from ocular manifestations associated with alcohol use, vitamin A deficiencies can also occur in chronic cholestatic liver disease, progressive liver diseases that lead to hepatic fibrosis, and liver failure. This group of diseases includes primary biliary cholangitis, primary sclerosing cholangitis, and biliary atresia. The main source of vitamin A for mammals is dietary intake, after which retinoids are stored in the hepatic stellate cells within the liver [
17]. Cell injury during the progression of the disease results in the loss of intracellular storage of vitamin A, a mechanism associated with the PNPLA3 gene [
18]. The rs738409 single nucleotide polymorphism has been speculated to decrease the activity of this enzyme and has been linked with disease progression of non-alcoholic fatty liver disease [
18]. Manifestations of this vitamin deficiency could present in the eye, after which a hepatology consult should be considered to check the health of the patient’s liver.
There are a few other liver diseases that result from metabolic deficiencies with ocular features that do not fit into the described categories above and will be discussed in the following section. Wilson’s Disease is characterized by copper buildup in the liver, leading to hepatic failure and liver disease due to the defective metabolism of copper [
19]. It involves defective ATP7B protein production and can also be accompanied by cirrhosis and neurological symptoms [
20]. This disease can present with ocular signs including the Kayer-Fleisher ring and sunflower cataracts in the lens. The Kayer-Fleisher ring in the eye occurs due to the deposition of copper in Descemet’s membrane and is common in patients with this pathology [
21,
22]. With early detection of this disease, early treatment with chelating agents allows for an excellent prognosis.
Another metabolic issue is galactosemia is a rare carbohydrate metabolism disease caused by the lack of the galactose-1-phosphate uridylyltransferase enzyme. Galactosemia presents itself during the neonatal period upon exposure to galactose-containing milk resulting in symptoms such as difficulties feeding,
E. coli sepsis, hypotonia, renal tubular disease, and elevated liver enzymes [
23]. The main ocular symptom that develops in galactosemia is cataracts, which are extremely unusual in infants [
24]. A study in 2019 by Rubio-Gozalbo et. al observed cataracts in over 25% of subjects. Of these subjects, approximately half had their cataracts disappear after the removal of galactose from the diet and the other half had residual cataracts even with the change in diet [
25]. The presence of cataracts in infants, especially right after feeding, can be indicative of galactosemia as well as increased levels of liver enzymes.
Glycogen storage diseases (GSD), also known as glycogenoses, are congenital metabolic disorders of improper metabolism of glycogen because of enzyme deficiencies, defective transporters, and glycogen degradation. GSDs primarily affect the liver as the liver is the major storage site of glycogen [
26]. There are over 20 types of GSD and some present with ocular pathologies. For instance, McArdle disease (GSD type V) is a rare metabolic myopathy due to PYGM gene mutations and may have an association with pattern dystrophy of the retinal pigment epithelium. However, only 3 cases have been reported so further research is required to establish an definite association [
27,
28]. Additionally, Allegrini et al. reports a case of a woman with GSD type Ia who presents with ocular changes such as cataract and optic nerve head drusen. However, they indicate that a clear causative mechanism between the two pathologies was not found [
29].