Vitamin A Toxicity and Liver Dysfunction: Exploring Mechanisms, Symptoms, and Clinical Management

Vitamin A toxicity, also known as hypervitaminosis A, can occur when the body absorbs excessive amounts of vitamin A from foods, dietary supplements, over-the-counter medications having vitamin A. There are both acute and long-term signs of toxic poisoning. Vitamin A overdose can result in acute toxicity. On the other hand, because of the significant build-up of vitamin A into the body, prolonged exposure results in chronic toxicity. Plants (pro-vitamin A) along with animal (preformed vitamin A) are the two sources of vitamin A. Beta-carotene is the most well known kind. Preformed vitamin A that is made up of a substance called retinol, retinoic acid, and esters of retinyl (1, 2). They are essential in the body's eyesight, reproduction, and immune system maintenance, among other physiological processes (3). The primary source of preformed vitamin A is dairy products, including milk, yogurt, and butter. Animal sources include chicken, beef, organ meats, fish, and fish-derived oils (2, 4). The body converts the provitamin A carotenoids found in vibrantly colored fruits and vegetables, such as papayas, sweet potatoes, and carrots, into the active vitamin A form (5).

After the intestinal breakdown of retinyl esters, the liver can store the resulting retinol. Hepatic stellate cells store most of the body's vitamin A in lipid droplets. Thus, the body can have enough vitamin A for long periods, even when food is not consumed. Upon release from the liver, retinol undergoes various metabolic processes, including oxidation to retinal (retinaldehyde) by retinol dehydrogenases (RDHs). Retinal can further oxidize to form retinoic acid, a potent signalling molecule that regulates gene expression. However, this conversion is irreversible, meaning that retinol cannot be converted back into retinal or retinoic acid once it has been converted. Retinoic acid binds to nuclear receptors, affecting gene transcription in cellular growth, differentiation, and immune response (5–7).
When someone unexpectedly consumes more than the suggested daily value of vitamin A, they are said to have acute hypervitaminosis A. Many upsetting symptoms may follow, showing up in days or weeks. Abdominal pain, nausea, vomiting, and excruciating headaches are possible side effects. They may experience additional changes to their skin and hair, such as peeling skin and hair loss, in addition to blurred eyesight and unusually lightheaded or irritated sensations. In more serious cases, excessive vitamin A can cause elevated blood pressure, which can lead to confusion and coma. On the other hand, chronic hypervitaminosis A develops more slowly and is typically brought on by prolonged high vitamin A administration. Numerous symptoms may appear, including exhaustion, dry skin, cheilosis (cracked lips), joint and muscular discomfort, and a generalised feeling of mental sluggishness. Liver damage may be indicated by abnormalities found in blood tests, such as increased liver enzymes and jaundice. Over time, chronic poisoning can cause serious liver issues including inflammation and scars, which can result in conditions like portal hypertension and cirrhosis. All forms of hypervitaminosis A serve as a crucial reminder to be cautious while taking vitamin A, particularly through certain foods and nutritional supplements. It's imperative to keep an eye on your vitamin A consumption to avoid serious health problems that could lead to both acute and chronic toxicity (4, 8).

Sources of Vitamin A:

Eggs, dairy products (such as cheese, butter, and dairy products), fish oils, liver, and orange and yellow produce (such as sweet potatoes, pumpkin, and carrots) are some of the animal and plant sources of vitamin A. Vitamin A is necessary for many different body functions. Papayas, mangoes, and apricots are among the fruits that increase the amount of vitamin A in the diet. Furthermore, some foods like cereals and margarine are enriched with vitamin A, and those who require them can obtain dietary supplements. Getting vitamin A from food products is generally advised to guarantee a balanced intake (9, 10).

Table: 01 Vitamin A content in dietary supplements and without the prescription product (1, 2).

Table: 02 The recommended dietary Requirement for vitamin A according to the National Institutes of Health [NIH] (1, 2).

Vitamin A absorption occurs in the lumen of the small intestine. Micelles created with the help of bile acids are expelled from the gallbladder and picked up in the duodenum. Retinoid undergo further hydrolysis to yield retinol, and transport proteins help retinol absorb past the small intestine's brush barrier (2, 4). In the range of 70%-90% (preformed), vitamin A is absorbed through the stomach. Conversely, passive diffusion is how carotenoids are transferred. Retinol levels may take several months to return to normal following vitamin A poisoning due to the estimated 128-day half-life of vitamin A. In terms of storage, retinyl-esters are the most common. Enterocytes absorb the retinol and fatty acids produced when the digestive system breaks down the stored form of vitamin A. Retinol is made from beta-carotene and retinaldehyde, which are generated by the enzymatic conversion of carotenoids. Liver cells and cells lining of the intestines are responsible for processing. Retinol is converted into retinyl-esters by esterification with fatty acids. They enter the circulation after being integrated into chylomicrons in the liver. The circulatory system carries retinol to the hepatocytes and hepatic stellate cells. The most accurate measure of Vitamin A status is the hepatic retinyl-ester content. Only a small percentage of Vitamin A is deposited in the pancreas, intestines, kidneys, and lungs, which are the hepatic organs of the body; the majority (80%–90%) is stored in the liver (2, 4, 9, 11, and 12).  The most common place to store vitamin A is lipocytes, pericytes, fat-storing cells, or vitamin A-storing cells. Renin is converted to retinyl-esters in the liver's stellate cells and then stored in lipid droplets when taken in through the diet. Whenever there is a shortage of retinol in the body, these retinyl-esters are transferred back to hepatocytes for their utilization. Retinol-binding proteins are solely responsible for retinyl esters' bidirectional transport (2, 4, 9, and 13) (as illustrated in figure: 01).

Vitamin A Cells & Pathway:

Vitamin A is a growth factor for cells, an immunocompetent vitamin, and an imperative vitamin for vision, among other biological functions. Thus, the levels of vitamin A in the organism are regulated by a large combination of enzymes and a few specific cell types within the liver. Among the many metabolic activities carried out by the hepatocytes, the primary activity of liver cells is the uptake and processing of vitamin A. Liver cells, or hepatocytes, take up retinol from the bloodstream, primarily obtained from the diet. Transport protein, the retinol-binding protein (RBP), in the blood, carries retinol to the tissues that need vitamin A. When the chylomicron remnants have been cleared from the circulation, the liver absorbs the remaining retinol through specific transport proteins, including the retinol transporter STRA6 and the fatty acid translocase CD36. The retinol is received into the liver cells, where retinol dehydrogenases, RDHs, degrade it into retinaldehyde. Another step is catalyzed by aldehyde dehydrogenases, mainly ALDH1A1 and ALDH1A2, which can further oxidize retinaldehyde into retinoic acid, the active form of vitamin A. This is a critical reaction, as retinoic acid controls cell differentiation and gene expression. Another vital role of hepatocytes is to excrete retinoic acid into bile. This action maintains proper vitamin A levels in the system and prevents accumulation. Another liver cell type is the hepatic stellate cells (HSCs), which store an unstated amount of vitamin A. LRAT is an enzyme that converts retinol into retinyl ester at the time of absorption in the liver. Such enzymes catalyze the interaction of retinol with fatty acyl-CoA, which is a necessary step in the mechanism by which HSCs maintain vitamin A in lipid droplets. Because of renin ester hydrolases, retinyl esters can be converted back into retinol either for release into circulation or to be converted to active forms under excess need for vitamin A. Kupffer cells are not principally storage cells, they can take up retinol and further contribute to to the conversion to retinoic acid by expressing enzymes that oxidize retinaldehyde (14–16) (as illustrated in figure: 02).

Figure: 02 Metabolism of Vitamin A in the Liver (6,12,17)

LRAT- lecithin retinol acyltransferase; DGAT- diglyceride acyltransferase; ADH1A- alcohol dehydrogenase 1A; AKR1B10- aldo-keto reductase family 1 member B10; BCMO1- beta-carotene monooxygenase; ALDH1A- aldehyde dehydrogenase 1 family member A; RBP4- retinol-binding protein 4.

Mechanisms of Liver Injury Due to Vitamin A Toxicity:

Damage to the liver due to vitamin A poisoning is dose-structured and can occur after short or sustained exposure to dangerously high dietary levels. When large doses are consumed, they can induce acute poisoning and liver damage. On the other hand, regular exposure to large dosages of vitamin A which can exceed 25,000 IU daily for extended periods of time causes chronic toxicity. The liver's natural structure and characteristics are compromised by this process. Additionally, oxidative strain, which is brought on by the accumulation of retinoic acid and retinaldehyde due to elevated vitamin A levels, can harm hepatocytes and produce inflammation in the liver. When reactive oxygen species are produced it damages the liver and other cells. Liver fibrosis and cirrhosis can occur as a result of chronic vitamin A poisoning. The dynamics of the liver's structural framework can be altered by excess collagen and other extracellular matrix proteins, leading to portal hypertension and compromised hepatic characteristics(13,18–23).

Signs Of Liver Toxicity Due To Hypervitaminosis A:

There are abnormally high alkaline phosphatase and aminotransferase levels, which can reach four times the suggested normalcy. Elevated serum antioxidant levels can be revealed. Liver biopsies reveal stellate cells, which are expanded and filled with lipids. The degree of sinusoidal sclerosis varies among these cells. The clinical evaluation is further guided by hypervitaminosis A symptoms, including skin changes, bone pain, and vision. Therefore, a multimodal approach integrating serum indicators, liver functioning tests, and clinical signs is necessary to accurately diagnose hypervitaminosis A and evaluate its effect on liver health(4,9) (as illustrated in Figure: 03)

Figure: 03 Signs of Liver Toxicity

Hypervitaminosis A Biomarkers:

The leading indicator used is serum retinol level, which typically has values between 20 and 60 mcg/dL. Levels above 200 mcg/dL indicate severe hypervitaminosis A, whereas levels over 100 mcg/dL may be toxic. Liver damage indicative of vitamin A overdose may be proven with the aid of necessary liver checks such as aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Other signs may additionally emerge when liver function is disturbed, which include improved alkaline phosphatase and blood lipid levels. In addition, an entire blood count (CBC) can screen hematological abnormalities associated with diet A intoxication(24,25).

Enzymes Involved in Vitamin A Liver Toxicity:

1. Retinol Dehydrogenases (RDHs): A key player in the metabolism of vitamin A, retinal dehydrogenases (RDHs) transform retinol (dietary vitamin A alcohol) into retinaldehyde, which is subsequently broken down into retinoic acid, the active form that controls gene expression and cellular growth. A buildup of retinaldehyde results from the liver's inability to metabolize retinol in cases of hypervitaminosis A. This accumulation may lead to hepatotoxicity by causing oxidative stress and cellular damage in the liver (5–7,14,15,21).
2. Aldehyde Dehydrogenases (ALDHs): In hypervitaminosis condition retinaldehyde level is increased due to the inability of ALDHs to convert retinaldehyde to retinoic acid using enzymes ALDH1A1 and ALDH1A2. This inability may affect the regular activities of cells and damage liver due to retinaldehyde accumulation (26, 27).
3. Lecithin Retinol Acyltransferase (LRAT): LRAT enzyme is necessary for converting retinol to retinyl ester for storage of vitamin A in the liver but the inability of LRAT may  lead to the accumulation of retinol and its metabolites and damage liver cells by oxidative stress and hepatotoxicity(16,26).
4. Cytochrome P450 Enzymes (CYPs): Essential enzymes CYP26A1 and CYP26B1 guard Retinoic acid levels. These enzymes protect against oxidative toxicity but their activity may be compromised in hypervitaminosis condition leading to severe liver damage (16, 25).

Diagnosis:

Doppler method is used to diagnose the liver, which comes under the ultrasound category. Several assessment parameters are used for the diagnosis of hypervitaminosis, which include the medical history of the patient, blood samples, and physical examination. Blood samples are usually taken from several frame components, which include the liver, kidneys, breast milk, crimson blood cells, and adipose tissue while testing for nutrition degrees. One more technique that is commonplace is immunoassays, including the retinoids-unique enzyme-related immunosorbent check (ELISA). This technique has a quicker detection time, reduces bioanalysis expenses, and is easy. By looking at the affected person's medical history, we will decide what caused the nutrition extra (10). A clinical exam can help hit upon any physical signs or signs of liver toxicity. Stopping excessive-dose vitamin A dietary supplements is the way to move for this circumstance. The majority of sufferers get better within a few weeks (4).

Table: 03 Technique for determination of carotenoids and retinoid in a biological system [4], [11].