Vitamin A - discovery, metabolism, receptor signaling and effects on bone mass and fracture susceptibility.

The first evidence of the existence of vitamin A was the observation 1881 that a substance present in small amounts in milk was necessary for normal development and life. It was not until more than 100 years later that it was understood that vitamin A acts as a hormone through nuclear receptors. Unlike classical hormones, vitamin A cannot be synthesized by the body but needs to be supplied by the food as retinyl esters in animal products and ß-carotene in vegetables and fruits. Globally, vitamin A deficiency is a huge health problem, but in the industrialized world excess of vitamin A has been suggested to be a risk factor for secondary osteoporosis and enhanced susceptibility to fractures. Preclinical studies unequivocally have shown that increased amounts of vitamin A cause decreased cortical bone mass and weaker bones due to enhanced periosteal bone resorption. Initial clinical studies demonstrated a negative association between intake of vitamin A, as well as serum levels of vitamin A, and bone mass and fracture susceptibility. In some studies, these observations have been confirmed, but in other studies no such associations have been observed. One meta-analysis found that both low and high serum levels of vitamin A were associated with increased relative risk of hip fractures. Another meta-analysis also found that low levels of serum vitamin A increased the risk for hip fracture but could not find any association with high serum levels of vitamin A and hip fracture. It is apparent that more clinical studies, including large numbers of incident fractures, are needed to determine which levels of vitamin A that are harmful or beneficial for bone mass and fracture. It is the aim of the present review to describe how vitamin A was discovered and how vitamin A is absorbed, metabolized and is acting as a ligand for nuclear receptors. The effects by vitamin A in preclinical studies are summarized and the clinical investigations studying the effect by vitamin A on bone mass and fracture susceptibility are discussed in detail.

Bilateral bartholin's gland abscesses in a 4-year-old girl with vitamin a deficiency: a case report.

BACKGROUND: A Bartholin's gland abscess is one of the most common infections in women of reproductive age. Although Bartholin's gland abscesses have been reported in prepubertal children, they are rarer in prepubertal children than in adults. Herein, we report a case of bilateral Bartholin's gland abscesses in a 4-year-old girl with vitamin A deficiency. CASE PRESENTATION: A 4-year-old girl diagnosed with autism spectrum disorder was admitted to the hospital for close examination and treatment because of persistent fever and malaise. The child was a marked fussy eater and was diagnosed with corneal ulceration and night blindness secondary to vitamin A deficiency. Both of the patient's labia were swollen, and a diagnosis of a bilateral Bartholin's gland abscess was made using computed tomography. Incisional drainage was performed under general anesthesia. The patient's postoperative course was uneventful, and she was discharged from the hospital on day 8 after the surgery. During hospitalization, attempts were made to correct the vitamin deficiency by adding nutritional supplements to the diet. Three months after the surgery, no recurrence of abscesses was noted. CONCLUSIONS: Decreased immunocompetence and mucosal barrier function due to vitamin A deficiency is thought to be the underlying cause of Bartholin's gland abscesses. Although prepubertal Bartholin's gland abscesses have been reported, they are rare. To the best of our knowledge, no reports of bilateral Bartholin's gland abscesses potentially caused by vitamin A deficiency have been reported. When prepubertal girls present with Bartholin's gland abscesses, the presence of immunodeficiency due to vitamin or trace element deficiency should also be considered.

Ocular manifestations of liver disease: an important diagnostic aid.

PURPOSE: This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and immune liver conditions. METHODS: Recent data were compiled from PubMed from 2000 to 2020 using keywords that were relevant to the assessed pathologies. Ocular presentations of several liver pathologies were researched and then summarized in a comprehensive form. RESULTS: Several ocular manifestations of liver disease were related to vitamin A deficiency, as liver disease is associated with impaired vitamin A homeostasis. Alcoholic liver cirrhosis can result in vitamin A deficiency, presenting with Bitot spots, xerosis, and corneal necrosis. Congenital liver diseases such as mucopolysaccharidoses and peroxisomal disorders are also linked with ocular signs. Viral causes of liver disease have associations with conditions like retinal vasculitis, keratoconjunctivitis sicca, retinopathies, Mooren's ulcer, and Sjogren's syndrome. Autoimmune hepatitis has been linked to peripheral ulcerative keratitis and uveitis. CONCLUSIONS: Building strong associations between ocular and liver pathology will allow for early detection of such conditions, leading to the early implementation of management strategies. While this review outlines several of the existing connections between hepatic and ophthalmic disease, further research is needed in the area in order to strengthen these associations.

Hepatic Vitamin A Concentrations and Association with Infectious Causes of Child Death.

OBJECTIVES: To assess postmortem vitamin A (VA) concentrations in children under 5 years of age and evaluate the association between VA deficiency (VAD) and infectious causes of death (CoD). STUDY DESIGN: In this cross-sectional study from the Child Health and Mortality Prevention Surveillance (CHAMPS) Network, liver biopsies collected within 72 hours of death were analyzed from 405 stillbirths and children under 5 years in Kenya and South Africa. Total liver VA (TLVA) concentrations were quantified using ultra-performance liquid chromatography, and cutoffs of ≤0.1 µmol/g, >0.1 to <0.7 µmol/g, ≥0.7 to <1.0 µmol/g, and ≥1.0 µmol/g were used to define VAD, adequate VA status, high VA, and hypervitaminosis A, respectively. CoD were determined by expert panel review. RESULTS: Among 366 liver samples with viable extraction, pooled prevalences of VAD, adequacy, high VA, and hypervitaminosis were 34.2%, 51.1%, 6.0%, and 8.7%, respectively. VAD was more common among neonates compared with stillbirths, infants, or children, and among those with low birthweight (LBW), underweight, or stunting (P < .05). When adjusting for site, age, and sex, there was no significant association of VAD with increased infectious CoD (OR 1.9, 95% confidence interval [CI] 0.9, 3.8, P = .073). In stratified analyses, VA deficient boys, but not girls, had an increased risk of infectious CoD (OR 3.4, 95% CI 1.3, 10.3, P = .013). CONCLUSIONS: Definitive postmortem assessment of VA status identified both VAD and VA excess among children under 5 years of age in Kenya and South Africa. VAD in boys was associated with increased risk of infectious mortality. Our findings may inform a transition from universal VA supplementation (VAS) to targeted strategies in certain countries.

Characteristics of Vitamin A Deficiency Retinopathy at a Tertiary Referral Center in the United States.

PURPOSE: To explore the risk factors and fundus imaging features of vitamin A deficiency retinopathy (VADR) in an academic tertiary referral center in Atlanta, GA, United States, and to propose guidance regarding diagnostic workup and management of affected patients. DESIGN: Single-center retrospective case series. SUBJECTS: Nine patients seen between 2015 and 2021 at the Emory Eye Center diagnosed with VADR. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: Baseline serum retinol level, Snellen visual acuity, multimodal fundus imaging findings, and electroretinography findings. RESULTS: Nine patients, 4 (44.4%) female, with a median (range) age of 68 (50-75) years were identified. The most common underlying etiologies for vitamin A deficiency included history of gastrointestinal surgery (55.6%), liver disease (44.4%), and nutritional depletion due to low-quality diet (44.4%). Only 1 (11.1%) patient had a history of bariatric surgery. Four (44.4%) patients were on some form of vitamin A supplementation before the diagnosis of VADR. Median (range) serum retinol level was 0.06 (< 0.06-0.19) mg/L. All patients had macular subretinal hyperreflective deposits resembling subretinal drusenoid deposits, although in some cases, these were scant and sparsely distributed. Six eyes of 3 patients with longstanding deficiency had defects in the external limiting membrane (ELM). Three of these eyes additionally had macular areas of complete retinal pigment epithelium and outer retinal atrophy (cRORA). Full-field electroretinography demonstrated severe rod dysfunction and mild to moderate cone system dysfunction. Many findings of VADR were reversible with vitamin A repletion. However, all eyes with ELM defects or cRORA had persistence or continued growth of these lesions. CONCLUSION: Vitamin A deficiency retinopathy is uncommon in the developed world. However, given that early intervention can lead to dramatic visual improvement and avoid potentially permanent retinal damage, retina specialists should be familiar with its clinical presentation. The presence of nyctalopia and subretinal hyperreflective deposits in a patient with a history of gastrointestinal surgery, liver disease, and/or poor diet can be suggestive of this diagnosis, even in the presence of ongoing vitamin A supplementation. Vitamin A supplementation can vary in route and dosage and can be tailored to the individual with serial testing of serum retinol. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any materials discussed in this article.

Integration of multiomics analysis to reveal the major pathways of vitamin A deficiency aggravates acute respiratory distress syndrome in neonatal rats.

Acute respiratory distress syndrome (ARDS) is a major disease that threatens the life and health of neonates. Vitamin A (VA) can participate in early fetal lung development and affect lung immune function. Researches revealed that the serum VA level in premature infants with ARDS was lower than that in premature infants without ARDS of the same gestational age, and premature infants with VA deficiency (VAD) were more likely to develop ARDS. Moreover, the VA levels can be used as a predictor of the development and severity of neonatal ARDS. However, the critical question here is; Does ARDS develop due to VAD in these systemic diseases? Or does ARDS develop because these diseases cause VAD? We hypothesize that VAD may aggravate neonatal ARDS by affecting immunity, metabolism, barriers and other pathways. In this article, we used multiomics analysis to find that VAD may aggravate ARDS mainly through the Fc epsilon RI signaling pathway, the HIF-1 signaling pathway, glutathione metabolism, and valine, leucine and isoleucine degradation signaling pathways, which may provide the molecular pathogenic mechanism behind the pathology of VAD-aggravated ARDS and can also provide potential molecular targets for subsequent research on ARDS.

Retinol Levels and Severity of Patients with COVID-19.

The new coronavirus infection represents a serious threat to global health and economies. In this sense, it is paramount to know the nutritional factors that may be related to the prognosis of the disease. Evidence shows that vitamin A may play an important preventive and therapeutic role in supporting respiratory infections as in COVID-19. The aim of our study was to evaluate the association of vitamin A (retinol) status with the prognosis of the disease. A case-control study from a cohort study was conducted in Brazil between May and October 2020. The study population was chosen by convenience, consisting of participants diagnosed with COVID-19. Recruitment was carried out using different approaches, including through dissemination on social media and in four hospitals in the city of Natal/RN, Brazil, recruiting participants from the COVID-19 ward and hospitalized participants who tested positive for the disease. The participants were allocated into two groups according to severity, with a group of mild (n = 88) or critical (n = 106) patients and compared to a control group (selected before the pandemic, n = 46). The extraction of retinol serum was performed and analyzed using the high-performance liquid chromatography method (HPLC). The retinol level was calculated in mmol/L, and levels below 0.7 µmol/L (20 µg/dL) were considered to be a vitamin A deficiency. Our findings suggest that the participants with mild and critical COVID-19 had lower retinol levels compared to the healthy controls (p = 0.03). In addition, milder cases of COVID-19 were associated with increased symptoms and prolonged symptoms after 90 days since the beginning of infection. However, the survival analysis showed no association with higher cases of death among participants with vitamin A deficiency (p = 0.509). More studies are needed to understand how nutritional status, including vitamin A levels, can influence prognosis and is a risk factor for the development of long COVID syndrome.

Vitamin A deficiency retinopathy related to medical interventions in a Swiss cohort: a case series.

AIMS OF THE STUDY: Vitamin A deficiency retinopathy is a potentially blinding disease. In developed countries, vitamin A deficiency due to malnutrition is rare. However, vitamin A deficiency can be caused by malabsorption resulting from bowel resection or medication. In this retrospective study, we present five cases of vitamin A deficiency retinopathy related to malabsorption secondary to medical interventions. METHODS: Electronic charts over a ten-year period (2012-2022) were screened for vitamin A deficiency retinopathy. Only patients with vitamin A deficiency confirmed by laboratory tests were included. Symptoms, medical history, visual acuity, optical coherence tomography, fundus autofluorescence, electrophysiological examination, and vitamin A levels were reviewed. RESULTS: Five eligible cases were identified. Median age was 44.7 years (range 22.2-88.9), median duration of ocular symptoms prior to diagnosis was 14 months, and median visual acuity was 1.0 (range 0.5-1.0, Snellen, decimal). Three patients had a history of bariatric surgery, one patient had a small bowel resection and was on octreotide treatment, and one patient suffered from cystic fibrosis and had a history of small bowel resection and severe hepatopathy. Optical coherence tomography showed various abnormalities, including a reduced interdigitation zone, subretinal drusenoid deposits, and a thinned outer nuclear layer. Electroretinogram findings ranged from abnormal oscillatory potentials to non-recordable rod responses. CONCLUSIONS: Vitamin A deficiency retinopathy can occur following medical interventions associated with malabsorption. In cases of night blindness, vitamin A levels should be measured.

Gestational Serum Retinol Deficiency Is Associated with Enamel Hypoplasia.

Enamel hypoplasia (EH) is a prevalent developmental defect of teeth that can result from various insults, including prenatal nutrient deficiencies. This study aimed to evaluate the association between prenatal serum retinol deficiency and EH in the deciduous teeth of offspring at 2-y of age. A cohort of 1,450 pregnant women was enrolled, and their prenatal nutritional status was assessed between 12 and 14 wk of gestation. Maternal serum retinol, serum 25-hydroxyvitamin D (25OHD), hemoglobin, body mass index, and birth outcomes, infant feeding practices, family socioeconomic status, and demographic information were recorded. Oral health examinations were conducted for the children semiannually, and EH was diagnosed using the Modified DDE index on all the surfaces of erupted teeth. A modified Poisson regression analysis was used to assess the cumulative risk of EH over a period of 2-y. A total of 920 (63.4%) mother-child pairs completed the study, and the cumulative EH prevalence among offspring after 2-y of follow-up was 16.5% (N = 152; 87/1,114 children in the first year and 132/920 in the second year, with 20/920 having EH only in the first year). After adjusting for potential confounders, maternal serum retinol deficiency significantly increased the risk of deciduous EH (risk ratio [RR], 2.0; 95% confidence interval [CI], 1.1-3.7). In addition, deficient serum 25OHD (RR, 6.5; 95% CI, 4.0-10.7), caesarean delivery (RR, 1.6; 95% CI, 1.0-2.4), Muslim (RR, 2.9; 95% CI, 2.0-4.1) and Christian (RR, 2.4; 95% CI, 1.6-3.5) versus Hindu religions, and very preterm birth (RR, 1.7; 95% CI, 1.1-2.9) increased the risk of EH. Children presenting with EH had 2 or more teeth affected, and the maxillary incisors were the most frequently affected, followed by the first primary molars and canines. In conclusion, maternal serum retinol deficiency during the 12 to 14 wk of gestation may increase the risk of deciduous EH, besides the well-established 25OHD deficiency.

Comparison of Published Estimates of the National Prevalence of Iron, Vitamin A, and Zinc Deficiency and Sources of Inconsistencies.

Micronutrient deficiencies result in a broad range of adverse health and functional consequences, but the true prevalence of specific deficiencies remains uncertain because limited information is available from nationally representative surveys using recommended biomarkers. The present review compares various reported national deficiency prevalence estimates for nutrients and years where the estimates overlap for individual countries that conducted nationally representative surveys and explores possible reasons for any discrepancies discovered. Nationally representative micronutrient status surveys that were conducted since 2000 among preschool-aged children or women of reproductive age and included assessment of iron, vitamin A, or zinc status based on recognized biomarkers were considered eligible for inclusion, along with any modeled deficiency prevalence estimates for these same countries and years. There was considerable variation across different published prevalence estimates, with larger inconsistencies when the prevalence estimate was based on proxies, such as hemoglobin for iron deficiency and dietary zinc availability for zinc deficiency. Numerous additional methodological issues affected the prevalence estimates, such as which biomarker and what cutoff was used to define deficiency, whether the biomarker was adjusted for inflammation, and what adjustment method was used. For some country-years, the various approaches resulted in fairly consistent prevalence estimates. For other country-years, however, the results differed markedly and changed the conclusions regarding the existence and severity of the micronutrient deficiency as a public health concern. In conclusion, to determine micronutrient status, we consider the assessment of one of the recommended biomarkers in a population representative survey as the best available information. If indicated, results should be adjusted for inflammation and generally acceptable cutoffs should be applied to facilitate comparisons, although individual countries may also apply nationally defined cutoffs to determine when and where to intervene. Global consensus is needed on best practices for presenting survey results and defining the prevalence of deficiency.

Factors and Molecular Mechanisms of Vitamin A and Childhood Obesity Relationship: A Review.

Childhood obesity has become a public health concern. As the importance of vitamin A (VA) in the body has become increasingly acknowledged, there is limited clinical trial evidence to substantiate the association between VA and childhood obesity. Vitamin A deficiency (VAD) increases the risk of childhood obesity, a finding consistently reported in pregnant women. VA could regulate the adipogenic process, inflammation, oxidative stress and metabolism-related gene expression in mature adipocytes. VAD disrupts the balance of obesity-related metabolism, thus affecting lipid metabolism and insulin regulation. Conversely, VA supplementation has a major impact on efficacy in obesity, and obese individuals typically have a lower VA status than normal-weight individuals. Several studies have attempted to identify the genetic and molecular mechanisms underlying the association between VA and obesity. In this review, we summarize and discuss recent new developments focusing on retinol, retinoic acid, and RBP4 and elucidate and provide an overview of the complex interrelationships between these critical components of VA and childhood obesity. However, the causal relationship between VA status and childhood obesity remains unclear. It is also unknown whether VA supplementation improves the overall obesogenic metabolic profile.

Potential blindness from nutritional xerophthalmia in autistic patients.

BACKGROUND: Vitamin A is vital to retinal rod function and epithelial cell differentiation. Although uncommon in the developed world, vitamin A deficiency (VAD) secondary to poor diets or gastrointestinal disease has been reported and can lead to xerophthalmia, which is characterized by night blindness and a spectrum of ocular surface changes. Patients with autism spectrum disorder have been shown to have restrictive diets secondary to sensory issues leading to rejection of foods except for those of certain color or texture. METHODS: We present a case series of 6 pediatric patients with autism who developed varying degrees of xerophthalmia due to VAD, which resulted from restrictive eating. RESULTS: All patients presented with a history of eye irritation that was not relieved by antibiotic or allergy eye drops. Further questioning revealed they had restrictive diets consisting of only or mostly white and tan foods, and serum vitamin A testing confirmed severe VAD. Most stages of xerophthalmia were completely reversed with vitamin A supplementation, but in 2 patients more advanced xerophthalmia resulted in irreversible blindness and ocular damage. CONCLUSIONS: Both pediatricians and pediatric eye care providers must be vigilant for VAD as an etiology of eye irritation, photophobia, or new-onset visual impairment in autistic children. A review of the child's diet must be implemented as a standard part of routine history taken in this vulnerable population. Early identification and vitamin A supplementation can prevent irreversible ocular compromise and vision loss.

Multimodal Imaging Study of Patients With Vitamin A Deficiency Retinopathy.

OBJECTIVES: To describe multimodal imaging findings of vitamin A deficiency retinopathy. METHODS: A retrospective study of patients with serum retinol < 0.3 mg/L. Fundus color photos, spectral domain-optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were reviewed and, when available, electrophysiological tests were analyzed. RESULTS: Forty-five eyes (63.9 ± 15.7 years) were included. Ultra-widefield fundus photography showed drusen-like deposits (53.3%) and macular retinal pigment epithelium (RPE) mottling (40%). The deposits were hypoautofluorescent, and a perifoveal hyperautofluorescent ring was present in 8.9%. By SD-OCT, the ellipsoid zone had an irregular appearance (100%) and conical deposits anterior to the RPE (33.3%). Electroretinogram (ERG) (66.7%) showed a decrease in b-wave in the scotopic registers, and microperimetry (4.4%) showed decreased foveal sensitivity. After vitamin A supplementation, SD-OCT and FAF showed resolution of all findings. Forty percent of eyes had restoration of the scotopic registers in ERG and improved macular sensitivity by microperimetry (4.4%). CONCLUSIONS: Vitamin A deficiency causes a mild cone dysfunction in addition to the more severe absent rod response. [Ophthalmic Surg Lasers Imaging Retina 2023;54:330-336.].

Vitamin A Deficiency, COVID-19, and Rhino-Orbital Mucormycosis (Black Fungus): An Analytical Perspective.

Mucormycosis is a rare but serious opportunistic fungal disease characterized by rhino-orbito-cerebral and pulmonary involvement. It is mainly seen in people with secondary immunosuppression, isolated vitamin A deficiency, measles, and AIDS patients. It showed a rise during the second wave of the COVID-19 epidemic in the spring of 2021 in India, especially in diabetic COVID-19 patients. Vitamin A deficiency is known to cause nutritional immunodeficiency and hence leading the way to increased opportunistic fungal, bacterial, and viral infections. In the eye, it causes keratitis, night blindness, xerophthalmia, conjunctivitis, Bitot spots, keratomalacia, and retinopathy. It also causes decreased tear secretion and deterioration of the anatomical/physiological defense barrier of the eye. The negative impact of vitamin A deficiency has been previously demonstrated in measles, AIDS, and COVID-19. We think that mucormycosis in COVID-19 might be rendered by vitamin A deficiency and that vitamin A supplementation may have preventive and therapeutic values against mucormycosis and other ocular symptoms associated with COVID-19. However, any vitamin A treatment regimen needs to be based on laboratory and clinical data and supervised by medical professionals.

The role of genes and environment in the etiology of congenital diaphragmatic hernias.

Structural birth defects are a common cause of abnormalities in newborns. While there are cases of structural birth defects arising due to monogenic defects or environmental exposures, many birth defects are likely caused by a complex interaction between genes and the environment. A structural birth defect with complex etiology is congenital diaphragmatic hernias (CDH), a common and often lethal disruption in diaphragm development. Mutations in more than 150 genes have been implicated in CDH pathogenesis. Although there is generally less evidence for a role for environmental factors in the etiology of CDH, deficiencies in maternal vitamin A and its derivative embryonic retinoic acid are strongly associated with CDH. However, the incomplete penetrance of CDH-implicated genes and environmental factors such as vitamin A deficiency suggest that interactions between genes and environment may be necessary to cause CDH. In this review, we examine the genetic and environmental factors implicated in diaphragm and CDH development. In addition, we evaluate the potential for gene-environment interactions in CDH etiology, focusing on the potential interactions between the CDH-implicated gene, Gata4, and maternal vitamin A deficiency.

Measuring the impact of malaria infection on indicators of iron and vitamin A status: a systematic literature review and meta-analysis.

Inflammation and infections such as malaria affect estimates of micronutrient status. Medline, Embase, Web of Science, Scopus and the Cochrane library were searched to identify studies reporting mean concentrations of ferritin, hepcidin, retinol or retinol binding protein in individuals with asymptomatic or clinical malaria and healthy controls. Study quality was assessed using the US National Institute of Health tool. Random effects meta-analyses were used to generate summary mean differences. In total, forty-four studies were included. Mean ferritin concentrations were elevated by: 28·2 µg/l (95 % CI 15·6, 40·9) in children with asymptomatic malaria; 28·5 µg/l (95 % CI 8·1, 48·8) in adults with asymptomatic malaria; and 366 µg/l (95 % CI 162, 570) in children with clinical malaria compared with individuals without malaria infection. Mean hepcidin concentrations were elevated by 1·52 nmol/l (95 % CI 0·92, 2·11) in children with asymptomatic malaria. Mean retinol concentrations were reduced by: 0·11 µmol/l (95 % CI -0·22, -0·01) in children with asymptomatic malaria; 0·43 µmol/l (95 % CI -0·71, -0·16) in children with clinical malaria and 0·73 µmol/l (95 % CI -1·11, -0·36) in adults with clinical malaria. Most of these results were stable in sensitivity analyses. In children with clinical malaria and pregnant women, difference in ferritin concentrations were greater in areas with higher transmission intensity. We conclude that biomarkers of iron and vitamin A status should be statistically adjusted for malaria and the severity of infection. Several studies analysing asymptomatic infections reported elevated ferritin concentrations without noticeable elevation of inflammation markers, indicating a need to adjust for malaria status in addition to inflammation adjustments.