Vitamin A toxicity and hepatic pathology: A comprehensive review

Abstract

Vitamin A is essential for vision, immunity, and cellular function, but excessive intake, known as hypervitaminosis A, leads to liver toxicity. Toxicity can be acute (from high single doses) or chronic (from prolonged overconsumption), causing symptoms like nausea, bone pain, and liver damage. The normal values of vitamin A in adults, measured as serum retinol, can range from 0.3 mg/L to 1.2 mg/L. The liver, which stores vitamin A in hepatic stellate cells, becomes overwhelmed, leading to retinoid accumulation, oxidative stress, and inflammation. Pathologically, vitamin A toxicity progresses from hepatic steatosis (fatty liver) to fibrosis and cirrhosis. Histological changes include hepatocellular ballooning, stellate cell activation, and perisinusoidal fibrosis. Molecular mechanisms involve oxidative stress from reactive oxygen species, apoptosis, and dysregulated pathways (tumor growth factor-beta, nuclear factor-kappa B), which drive fibrogenesis. Chronic toxicity also disrupts lipid metabolism, worsening liver injury. Clinically, management includes limiting vitamin A intake and exploring antioxidants (e.g., N-acetylcysteine) or anti-fibrotic therapies. Research gaps include the need for better biomarkers, personalized risk assessment, and refined dietary guidelines. Future studies should focus on therapeutic interventions and experimental models to improve outcomes. In conclusion, while vitamin A is vital, its toxicity poses serious hepatic risks. Understanding its mechanisms and developing targeted treatments are crucial for preventing liver damage and ensuring safe consumption.

Key Words: Hypervitaminosis A; Hepatic fibrosis; Oxidative stress; Stellate cells; Retinoids; Cirrhosis

Core Tip: Vitamin A toxicity (hypervitaminosis A) causes serious liver damage, progressing from steatosis to fibrosis and cirrhosis. The liver’s storage capacity is overwhelmed, leading to retinoid accumulation, oxidative stress, and inflammation. Key mechanisms include reactive oxygen species generation, apoptosis, and dysregulated pathways (tumor growth factor-beta, nuclear factor-kappa B), which drive stellate cell activation and fibrosis. Clinically, chronic toxicity manifests as hepatomegaly, portal hypertension, and potential liver failure. Management involves limiting vitamin A intake and exploring antioxidants (e.g., N-acetylcysteine) or anti-fibrotic therapies. Future research should focus on biomarkers, personalized risk assessment, and safer dietary guidelines. Public awareness and therapeutic advancements are crucial to prevent liver disease.

INTRODUCTION

Vitamin A, a fat-soluble vitamin, is essential for vision, immune function, cellular differentiation, and reproduction[1]. It exists in forms such as retinol, retinoic acid, and carotenoids, each with unique biological roles[2]. While crucial for health, its narrow therapeutic index means that both deficiency and excess can cause significant problems[3].

Vitamin A toxicity, known as hypervitaminosis A, is classified into acute and chronic forms[4]. Acute toxicity arises from a single, excessively high dose, often due to accidental ingestion or over-supplementation, and manifests rapidly with symptoms such as nausea, dizziness, and intracranial hypertension[5]. Chronic toxicity develops from sustained high intake, exceeding recommended daily allowances, and presents with gradual symptoms like fatigue, bone pain, and liver dysfunction[6]. Both forms highlight the narrow therapeutic index of vitamin A[7].

The liver, the primary site of vitamin A metabolism and storage, is particularly susceptible to damage from retinoid overload[8]. The pathological anatomy of liver damage in vitamin A toxicity includes hepatic steatosis, fibrosis, and cirrhosis. The early stages are characterized by lipid accumulation in hepatocytes, progressing to scar tissue formation and structural distortion of the liver[9].

Understanding the molecular mechanisms of vitamin A-induced liver toxicity is essential for developing targeted interventions[10]. Excessive vitamin A metabolism causes oxidative stress and the generation of reactive oxygen species (ROS), causing lipid peroxidation, DNA damage, and protein modifications[11]. Mitochondrial dysfunction and inflammatory cytokines induce apoptosis and necrosis, further contributing to hepatocyte loss[12]. Dysregulation of signaling pathways like tumor growth factor-beta (TGF-β) and nuclear factor-kappa B (NF-κB) exacerbates fibrogenesis and inflammation[13].

Clinicians and researchers must prioritize studying vitamin A toxicity due to its public health implications[14]. At-risk populations, such as those consuming high-dose supplements or diets rich in animal liver, require tailored guidelines to prevent toxicity[15]. Advancing our understanding of these mechanisms will inform therapeutic strategies to mitigate liver damage[16]. This review focuses on the pathological anatomy of liver damage induced by vitamin A toxicity, emphasizing its clinical significance and future research directions[17].

LIVER PATHOLOGY DUE TO VITAMIN A TOXICITY

Common pathological effects

Vitamin A toxicity is associated with hepatic steatosis, fibrosis, and cirrhosis, arising from the liver's central role in vitamin A metabolism and storage. Excessive intake overwhelms the liver’s capacity to store retinol in stellate cells, leading to hepatocellular damage and systemic toxicity[18].

Hepatic steatosis is an early manifestation and results from disrupted lipid homeostasis and triglyceride accumulation due to excessive retinoid metabolism[19]. Over time, oxidative stress, inflammation, and stellate cell activation contribute to fibrosis, marked by extracellular matrix deposition and architectural distortion. Advanced cases progress to cirrhosis, characterized by bridging fibrosis and irreversible liver damage[20].

Chronic toxicity also leads to portal hypertension, hepatomegaly, and impaired liver function, manifesting as abdominal pain, jaundice, and ascites. Severe cases may result in liver failure and death[21].

Histological changes

Histopathological examination reveals vacuolar degeneration, hepatocellular ballooning, and Mallory-Denk bodies in early stages, indicating cellular stress[22]. A key feature is the activation of hepatic stellate cells, which expand, occupy the space of Disse, and develop cytoplasmic microvacuoles. These cells transform into myofibroblasts, driving collagen production and fibrosis[23]. Perisinusoidal fibrosis, particularly in the space of Disse, often progresses to bridging fibrosis and cirrhosis[24]. Additional findings include inflammatory infiltrates, bile duct proliferation, and cholestasis. Advanced cases show regenerative nodules and extensive fibrosis, disrupting normal lobular architecture (Figure 1)[25].

Figure 1 Histology. A: Hematoxylin-eosin (HE)-stained liver biopsy section, with appearance of occlusion of the sinusoids due to Ito cell hyperplasia; B: Masson’s trichrome-stained liver biopsy section with marked sinusoidal fibrosis; C: Periodic acid Schiff-stained liver biopsy section with HE, liver biopsy section with evident cytoplasmic vacuolization of Ito cells; D: Immunostaining of smooth muscle actin. Marked positivity was observed in activated Ito cells such as myofibroblasts. Magnification: 10 ×.

Mechanisms of hepatic injury

Excessive retinoid intake disrupts cellular metabolism, generating ROS and causing oxidative stress[26,27]. ROS damage organelles, impair hepatocyte function, and trigger apoptosis and necrosis[28]. Retinoic acid influences gene expression via nuclear receptors (i.e. retinoic acid receptors, and retinoid X receptors), altering cellular proliferation, apoptosis, and fibrogenesis[29].

Although retinoic acid tends to inhibit fibrogenesis in most studied contexts, in diseases such as liver fibrosis retinoic acid reduces the activation of stellate cells by regulating the expression of factors like TGF-β (a key mediator of fibrosis) and modulating the activity of matrix metalloproteinases. However, experimental models show that high doses of retinoic acid can indirectly promote profibrotic effects by inducing inflammation[30].

Toxic accumulation of retinyl esters in stellate cells activates them and impairs vitamin A storage, perpetuating fibrosis[31]. Retinoid-induced changes in lipid metabolism also contribute to steatosis and liver damage[32].

Molecular mechanisms

Oxidative stress: Oxidative stress is central to vitamin A-induced liver damage. Excessive retinol and retinoic acid generate ROS through mitochondrial dysfunction and peroxisomal oxidation, causing lipid peroxidation, protein oxidation, and DNA damage[33]. This can lead to increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), products of lipid peroxidation and indicators of oxidative damage to cell membranes. Additionally, thiol groups in proteins (e.g., cysteine) are sensitive to oxidation. Vitamin A toxicity reduces the levels of free thiol groups, reflecting oxidative damage. Hypervitaminosis A can induce DNA damage due to increased ROS, elevating levels of 8-hydroxydeoxyguanosine.

ROS also activate Kupffer cells, releasing pro-inflammatory cytokines like tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6, amplifying inflammation and fibrosis[34].

Apoptosis and necrosis: Vitamin A-induced hepatocyte death involves mitochondrial dysfunction, cytochrome c release, and caspase activation in apoptosis, while oxidative stress depletes adenosine triphosphate, leading to necrosis. These processes result in significant hepatocellular loss[35].

Alterations in signaling pathways: Retinoic acid dysregulates TGF-β and NF-κB pathways, promoting stellate cell activation and fibrosis. Excess retinoids also disrupt Wnt/β-catenin signaling, impairing hepatic regeneration[36].

Retinoid metabolism and storage: Chronic hypervitaminosis A saturates the liver’s storage capacity, causing retinoid leakage and systemic toxicity. Retinol ester accumulation in hepatocytes and stellate cells leads to lipotoxicity, steatosis, and organelle dysfunction. Impaired retinoid metabolism exacerbates oxidative stress and inflammation[19,34]. Inflammatory response and fibrogenesis: Hypervitaminosis A triggers inflammation by activating Kupffer cells and macrophages to release TNF-α and IL-1β, subsequently promoting stellate cell activation and fibrosis. Retinoic acid also influences matrix metalloproteinases and tissue inhibitors of metalloproteinases, disrupting extracellular matrix turnover[37].

CLINICAL IMPLICATIONS

Implications for clinical management

Targeted therapies, such as antioxidants (e.g., N-acetylcysteine) and TGF-β inhibitors, show promise in mitigating oxidative stress and fibrosis[38]. Limiting vitamin A intake is crucial for at-risk populations[2,14].

Future perspectives

Vitamin A toxicity poses a significant challenge in hepatology, with pathological effects ranging from steatosis to cirrhosis. The molecular mechanisms involve oxidative stress, apoptosis, necrosis, and dysregulated signaling pathways[39]. While progress has been made, translating these insights into clinical applications remains a priority[40].

Excessive vitamin A intake overwhelms the liver’s storage capacity, leading to oxidative stress, inflammation, and fibrosis[2,35]. Apoptosis and necrosis contribute to hepatocellular loss, while dysregulated signaling pathways exacerbate fibrogenesis[35,37].

Research gaps and opportunities

Biomarker development: Identifying reliable biomarkers for early detection is critical. Oxidative stress markers (e.g., MDA, 4-HNE,) and pro-inflammatory cytokines (e.g., IL-6, TNF-α) are potential candidates[11].

Therapeutic interventions: Antioxidants and TGF-β inhibitors show promise in mitigating liver damage[41]. Individualized risk assessment: Genetic polymorphisms in retinoid metabolism enzymes and hepatic storage capacity should be studied to tailor dietary recommendations[42].

Dietary guidelines: Establishing safe upper limits for vitamin A intake is essential, particularly for vulnerable populations[2].

Experimental models: Developing physiologically relevant models, such as organ-on-a-chip systems, will enhance translational research[43].

Future directions

Addressing vitamin A toxicity requires interdisciplinary collaborations, public awareness, and policy development. Clinical trials evaluating antioxidants and anti-fibrotic agents are necessary to advance therapeutic strategies[44].

CONCLUSION

Vitamin A toxicity remains a significant contributor to liver disease. Although toxicity is not as prevalent as deficiency, severe cases may require hospitalization and treatment, generating costs for healthcare systems. Additionally, congenital defects related to toxicity during pregnancy have a significant impact on both maternal and child health. In contexts of mass supplementation, the lack of data on the short-term kinetics of high doses and their effects on lactating women and children limits the ability to prevent toxicity. This underscores the need for further research on subclinical toxicity and its long-term impact. Advances in understanding its mechanisms provide a foundation for future research, but gaps in biomarker development, therapeutic strategies, and dietary guidelines must be addressed. Balancing the benefits and risks of vitamin A is essential for optimal liver health and public well-being.