Hypervitaminosis A Following the Ingestion of Fish Liver: Report on 3 Cases from the Poison Control Center in Marseille.

In European countries, vitamin A toxicity is most often the result of an excessive intake of vitamin supplements and rarely the consequence of the ingestion of a large carnivorous fish liver. We report 3 cases of vitamin A poisoning after fish liver ingestion in mainland and overseas France. The patients were a 12-y-old girl, a 36-y-old pregnant woman, and a 62-y-old man. They experienced headache, nausea, emesis, and desquamation. Laboratory examination showed a high serum retinol level in the girl. The woman's pregnancy progressed to a miscarriage. This case series shows that this kind of poisoning is not restricted to the polar regions. In patients presenting with flushing combined with signs of intracranial hypertension, accurate questioning of the patient's diet is crucial to avoid misdiagnosis and unnecessary examinations. Pregnant women or women of child-bearing age should be informed of the risk to pregnancy in the case of excessive fish liver ingestion.

Hypervitaminosis A is associated with immunological non-response in HIV-1-infected adults: a case-control study.

For people living with HIV, determinants of immunological non-response (INR) to combined antiretroviral therapy (cART) have not been fully elucidated. In a case-control study, we evaluated the influence of the nutritional and antioxidant status in HIV-1 adults whose cART was initiated between January 2001 and December 2013. Cases had persistent CD4 counts < 350/µL vs. > 350/µL for controls, after at least 2 years of cART with persistent viral loads (VL) < 50 copies/mL. Twelve cases and twenty-eight control subjects with the same CD4 count at cART initiation were compared for their nutritional and antioxidant status after age adjustment at dosage assessment. Patients were predominantly male (70%), Caucasian (82%) and at AIDS stage (62%). The median age was 53, and the median CD4 count was 245/mm3 for cases and 630/mm3 for controls after a median time of 7 years on cART. Despite higher energy intakes in cases, anthropometric data was comparable between groups who had similar vitamins B9/B12/C/D/E, zinc, citrulline and glutamine levels. Nine cases (75%) and 8 controls (29%) had hypervitaminosis A (> 2.70 µmol/L) (p = 0.030). Cases had lower erythrocyte resistance when exposed to a controlled free radical attack (p = 0.014). Most cases had hypervitaminosis A and altered antioxidant capacities that could affect immunological response. Wide-scale studies are required, but in the meantime, screening of their vitamin A status must be encouraged in these patients.

Hypercarotenemia / Hipercarotenemia

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South African preschool children habitually consuming sheep liver and exposed to vitamin A supplementation and fortification have hypervitaminotic A liver stores: a cohort study.

BACKGROUND: In some regions, multiple vitamin A (VA) interventions occur in the same target groups, which may lead to excessive stores. Retinol isotope dilution (RID) is a more sensitive technique than serum retinol to measure VA status. OBJECTIVE: We evaluated VA status before and after a high-dose supplement in preschool children living in a region in South Africa with habitual liver consumption and exposed to VA supplementation and fortification. METHODS: After baseline blood samples, subjects (46.7 ± 8.4 mo; n = 94) were administered 1.0 µmol [14,15]-13C2-retinyl acetate to estimate total liver retinol reserves by RID with a follow-up 14-d blood sample. Liver intake was assessed with a frequency questionnaire. In line with current practice, a routine 200,000 IU VA capsule was administered after the RID test. RID was repeated 1 mo later. Serum retinyl esters were evaluated using ultra-performance liquid chromatography. RESULTS: At baseline, 63.6% of these children had hypervitaminosis A defined as total liver retinol reserves ≥1.0 µmol/g liver, which increased to 71.6% after supplementation (1.13 ± 0.43 to 1.29 ± 0.46 µmol/g; P < 0.001). Total serum VA as retinyl esters was elevated in 4.8% and 6.1% of children before and after supplementation. The odds of having hypervitaminosis A at baseline were higher in children consuming liver ≥1/mo (ratio 3.70 [95% CI: 1.08, 12.6]) and in children receiving 2 (4.28 [1.03, 17.9]) or 3 (6.45 [0.64, 65.41]) supplements in the past 12 mo. Total body stores decreased after the supplement in children in the highest quartile at baseline compared with children with lower stores, who showed an increase (P = 0.007). CONCLUSIONS: In children, such as this cohort in South Africa, with adequate VA intake through diet, and overlapping VA fortification and supplementation, preschool VA capsule distribution should be re-evaluated. This trial was registered at https://clinicaltrials.gov/ct2/show/NCT02915731 as NCT02915731.

Serum retinyl esters are positively correlated with analyzed total liver vitamin A reserves collected from US adults at time of death.

Background: Minimal human data exist on liver vitamin A (VA) compared with serum biomarkers. Cutoffs of 5% and 10% total serum VA as retinyl esters (REs) suggest a VA intoxication diagnosis. Objectives: We compared total liver VA reserves (TLRs) with the percentage of total serum VA as REs to evaluate hypervitaminosis with the use of US adult autopsy samples. Secondary objectives evaluated serum retinol sensitivity, TLRs among lobes, and hepatic α-retinol concentrations, an α-carotene cleavage product. Design: Matched serum and liver samples were procured from cadavers (n = 27; mean ± SD age: 70.7 ± 14.9 y; range: 49-101 y). TLRs and α-REs were quantified by ultra-performance liquid chromatography. Pearson correlations showed liver and serum associations. Sensitivity and specificity were calculated for >5%, 7.5%, and 10% total serum VA as REs to predict TLRs and for serum retinol <0.7 and 1 µmol/L to predict deficiency. Results: Serum RE concentrations were correlated with TLRs (r = 0.497, P < 0.001). Nine subjects (33%) had hypervitaminosis A (≥1.0 µmol VA/g liver), 2 of whom had >7.5% total serum VA as REs; histologic indicators corroborated toxicity at 3 µmol/g liver. No subject had >10% total serum VA as REs. Serum retinol sensitivity to determine deficiency (TLRs <0.1 µmol VA/g) was 83% at 0.7 and 1 µmol/L. Hepatic α-retinol was positively correlated with age (P = 0.047), but removing an outlier nullified significance. Conclusions: This study evaluated serum REs as a biomarker of VA status against TLRs (gold standard), and abnormal histology suggested that 7.5% total serum VA as REs is diagnostic for toxicity at the individual level in adults. The long-term impact of VA supplements and fortificants on VA status is currently unknown. Considering the high prevalence of hypervitaminotic TLRs in this cohort, and given that many countries are adding preformed VA to processed products, population biomarkers diagnosing hypervitaminosis before toxicity are urgently needed. This trial was registered at clinicaltrials.govas NCT03305042.

Insights of hypercarotenaemia: A brief review.

Carotenoids are generally 40-carbon tetraterpenoids responsible for most of the yellow, orange and red colours throughout the natural world. Pro-vitamin A carotenoids serve as the precursors of vitamin A. In addition to that, carotenoids exhibit range of important protective mechanisms in human health. Hypercarotenaemia is characterized by carotenodermia resulting in yellowing of the skin specially palms and soles. Hypercarotenaemia develops in subjects consuming high levels of carotenoid rich foods or ß-carotene supplements (>30 mg day-1) over a period of months. Less or normal intake of carotenoids very rarely gives rise to metabolic carotenaemia due to genetic defects of the enzyme 15-15'-carotenoid dioxygenase. Moreover, it is known that those with hypothyroidism and diabetes mellitus tend to develop hypercarotenaemia with the normal intake of carotenoid rich foods. Further, hypercarotenaemia has been reported in anorexia nervosa. However, recently some studies have been shown that there is no major correlation between carotenoid intake and hypercarotenaemia indicating that a genetic factor is at play in development of hypercarotenaemia. Therefore, the subjects appear to need to be genetically pre-disposed to hypercarotenaemia.

Hypercarotenodermia in Zambia: which children turned orange during mango season?

Vitamin A (VA) deficiency is a public health problem in many countries. The World Health Organization recommends high-dose VA supplements to children aged 6-59 months based on unequivocal evidence that supplements decreased mortality risk. VA supplements were meant as a temporary intervention until more sustainable approaches could be implemented. Fortification of processed foods with preformed VA is a means to improve VA status. The most recent addition of retinyl palmitate to cooking oil in countries that may also fortify margarine and milk will undoubtedly have a positive impact on VA status. However, quantitative measures have not been used to assess the underlying VA status of the groups who have adopted widespread fortification. The addition of preformed VA to otherwise adequate diets in VA may cause excessive total body stores. Monitoring population status will require accurate VA assessment to ensure that hypervitaminosis does not prevail. This perspective describes a cohort of rural Zambian children who have adequate diets in VA, mostly as provitamin A carotenoids; who were given high-dose VA supplements till the age of 5 years; who have access to VA-fortified sugar; and whose mothers had access to VA-fortified sugar throughout pregnancy and lactation. Many of these children turned orange during mango season, and this phenomenon occurred at estimated liver reserve concentrations >1 µmol retinol equivalents/g liver. It will be necessary to continue to monitor VA status, including all sectors of the population that have access to successful interventions, to optimize health with the intent to lower retinol content of fortified foods or better target VA supplementation to areas of most need.

Comparisons among Equations Used for Retinol Isotope Dilution in the Assessment of Total Body Stores and Total Liver Reserves.

Vitamin A plays an essential role in animal biology and has negative effects associated with both hypo- and hypervitaminosis A. Many notable interventions are being done globally to eliminate vitamin A deficiency, including supplementation, fortification, and biofortification. At the same time, it is important to monitor vitamin A status in nations where preformed vitamin A intake is high because of consumption of animal source foods (e.g., liver, dairy, eggs), fortified foods (e.g., milk, cereals, oil, sugar, margarine), or vitamin supplements (e.g., one-a-day multivitamins) to ensure the population does not reach hypervitaminosis A. To accurately assess population status and evaluate interventions aimed at improving vitamin A status, accurate assessment methods are needed. The primary storage site of vitamin A is the liver; however, routinely obtaining liver samples from humans is impractical and unethical. Isotope dilution using deuterium- or (13)C-labeled retinol is currently the most sensitive indirect biomarker of vitamin A status across a wide range of liver reserves. The major drawback to its application is the increased technicality in sample analysis and data calculations when compared to less sensitive methodology, such as serum retinol concentrations and dose response tests. Two main equations have emerged for calculating vitamin A body pool size or liver concentrations from isotope dilution data: the "Olson equation" and the "mass balance equation." Different applications of these equations can lead to confusion and lack of consistency if the underlying principles and assumptions used are not clarified. The purpose of this focused review is to describe the evolution of the equations used in retinol stable-isotope work and the assumptions appropriate to different applications of the test. Ultimately, the 2 main equations are shown to be fundamentally the same and differ only in assumptions made for each specific research application.

Hypervitaminosis A causing hypercalcemia in cystic fibrosis. Case report and focused review.

Hypercalcemia is a rare complication of hypervitaminosis A. We report a pediatric patient with cystic fibrosis (CF) and pancreatic insufficiency who was found to have hypervitaminosis A causing hypercalcemia, complicated by nephrocalcinosis and renal impairment. The patient is a 4-year-old girl with pancreatic-insufficient CF, gastroesophageal reflux, oral aversion, and failure to thrive requiring gastrostomy tube placement. She was prescribed Source CF vitamins, but rarely received the full dose, due to emesis and intolerance. She had routine annual labs that revealed hypercalcemia with elevated blood urea nitrogen and creatinine, which were not present in her previous annual labs. Upon further questioning, her mother reported that she seemed more fatigued for a few weeks, had abdominal pain, and was urinating more frequently. Upon admission to the hospital, laboratory results revealed elevated HCO3, while serum levels of potassium, phosphorus, and albumin were within normal limits. Vitamin D (25-hydroxy) level was low, and vitamin A level was elevated. Extensive metabolic and hormonal workup for the etiology of the hypercalcemia revealed evidence of chronic renal insufficiency and elevated vitamin A levels. She had a renal ultrasound that revealed bilateral nephrocalciosis. Diagnosis of chronic hypervitaminosis A complicated by hypercalcemia was made and was managed by holding vitamin A supplements, aggressive diuresis, and prednisolone. This case emphasizes the importance of regular vitamin A monitoring in patients with CF. There is a wide variability for the lowest intake required to cause toxicity, and the lower limit to cause toxicity has not been determined.

Hypercalcemia, hypervitaminosis A and 3-epi-25-OH-D3 levels after consumption of an "over the counter" vitamin D remedy. a case report.

Intoxication from vitamin D supplements has been rarely reported but, nowadays, it occurs more frequently. 3-epi-25-OH-D(3) is highly prevalent in adults and it is considered of biological relevance. We report a case of vitamin D toxicity with hypercalcemia, acute renal failure and hypervitaminosis A after consuming an over-the-counter vitamin D supplement. Our data suggest that the contribution of 3-epi-25-OH-D(3) is not altered during vitamin D toxicity, although the serum levels of 25-OH-D(3) and 3-epi-25-OH-D(3) may display a different rate of clearance. The patient also displayed hypervitaminosis A unrelated to diet, possibly caused by renal failure related to the hypercalcemia induced by vitamin D toxicity. Because of the increasing use of over-the-counter vitamin D supplements and the potential iatrogenic hypercalcemia related to hypervitaminosis A, the present case highlights the importance of evaluating both the use of (non-) prescribed medication and vitamin A status during vitamin D toxicity.

Studies on hypercarotenemia due to excessive ingestion of carrot, pumpkin and papaw.

Hypercarotenemia is diagnosed by yellowing of skin. The present study was carried out to study the carotenoids, their metabolites and the vitamin A levels in hypercarotenemics on reporting, changes in serum carotenoids following cessation of feeding carotenoid-bearing foods, and to determine the carotenoids in stools of hypercarotenemics and non-hypercarotenemics. Hypercarotenemic subjects (n = 35) were tested on reporting for a 2-month to 3-month period. Feces from hypercarotenemics (n = 5) and non-hypercarotenemics (n = 8) were extracted and subjected to reverse phase-high-performance liquid chromatography. A questionnaire was administered to parents (n = 35) of these hypercarotenemic children. The serum α- and ß carotenoids varied from 119 g/dl to trace and from 149 g/dl to trace respectively, with the monohydroxy metabolites varying from 214 g/dl to nondetectable and polyhydroxy metabolites from 823 g/dl to 7.0 g/dl. Longitudinal studies indicated that serum carotenoid levels declined while vitamin A levels were maintained. α-Carotenes and ß-carotenes were not detected in the feces of hypercarotenemics but were present in non-hypercarotenemics.

Mathematical modeling of serum 13C-retinol in captive rhesus monkeys provides new insights on hypervitaminosis A.

Hypervitaminosis A is increasingly a public health concern, and thus noninvasive quantitative methods merit exploration. In this study, we applied the (13)C-retinol isotope dilution test to a nonhuman primate model with excessive liver stores. After baseline serum chemistries, rhesus macaques (Macaca mulatta; n = 16) were administered 3.5 mumol (13)C(2)-retinyl acetate. Blood was drawn at baseline, 5 h, and 2, 4, 7, 14, 21, and 28 d following the dose. Liver biopsies were collected 7 d before and 2 d after dosing (n = 4) and at 7, 14, and 28 d (n = 4/time) after dosing. Serum and liver were analyzed by HPLC and GC-combustion-isotope ratio MS for retinol and its enrichment, respectively. Model-based compartmental analysis was applied to serum data. Lactate dehydrogenase was elevated in 50% of the monkeys. Total body reserves (TBR) of vitamin A (VA) were calculated at 28 d. Predicted TBR (3.52 +/- 2.01 mmol VA) represented measured liver stores (4.56 +/- 1.38 mmol VA; P = 0.124). Predicted liver VA concentrations (13.3 +/- 9.7 micromol/g) were similar to measured liver VA concentrations (16.4 +/- 5.3 micromol/g). The kinetic models predict that 27-52% of extravascular VA is exchanging with serum in hypervitaminotic A monkeys. The test correctly diagnosed hypervitaminosis A in all monkeys, i.e. 100% sensitivity. Stable isotope techniques have important public health potential for the classification of VA status, including hypervitaminosis, because no other technique besides invasive liver biopsies, correctly identifies excessive liver VA stores.

Retinol to retinol-binding protein (RBP) is low in obese adults due to elevated apo-RBP.

Elevated serum retinol-binding protein (RBP) concentration has been associated with obesity and insulin resistance, but accompanying retinol values have not been reported. Assessment of retinol is required to discriminate between apo-RBP, which may act as an adipokine, and holo-RBP, which transports vitamin A. The relations between serum RBP, retinol, retinyl esters, BMI, and measures of insulin resistance were determined in obese adults. Fasting blood (> or =8 h) was collected from obese men and women (n = 76) and blood chemistries were obtained. Retinol and retinyl esters were quantified by HPLC and RBP by ELISA. RBP and retinol were determined in age and sex-matched, nonobese individuals (n = 41) for comparison. Serum apo-RBP was two-fold higher in obese (0.90 +/- 0.62 microM) than nonobese subjects (0.44 +/- 0.56 microM) (P < 0.001). The retinol to RBP ratio (retinol:RBP) was significantly lower in obese (0.73 +/- 0.13) than nonobese subjects (0.90 +/- 0.22) (P < 0.001) and RBP was strongly associated with retinol in both groups (r = 0.71 and 0.90, respectively, P < 0.0001). In obese subjects, RBP was associated with insulin (r = 0.26, P < 0.05), homeostatic model assessment of insulin resistance (r = 0.29, P < 0.05), and quantitative insulin sensitivity check index (r = -0.27, P < 0.05). RBP was associated with BMI only when obese and nonobese subjects were combined (r = 0.25, P < 0.01). Elevated serum RBP, derived in part from apo-RBP, was more strongly associated with retinol than with BMI or measures of insulin resistance in obese adults. Investigations into the role of RBP in obesity and insulin resistance should include retinol to facilitate the measurement of apo-RBP and retinol:RBP. When evaluating the therapeutic potential of lowering serum RBP, consideration of the consequences of vitamin A metabolism is paramount.

[Hypercalcemia revealing iatrogenic hypervitaminosis A in a child with autistic troubles]. / Hypercalcémie révélant une hypervitaminose A iatrogène chez un enfant atteint de troubles autistiques.

UNLABELLED: Hypervitaminosis A is an unusual cause of infant hypercalcemia. The way it occurs can be very surprising, as one can notice from the following case report. CASE REPORTS: A three-year-old boy, presenting important behavioral disorders, was hospitalized because of a deterioration of his general state of health associated with vomiting, cephalgias, fever and cutaneous abnormalities. A 168 mg/L hypercalcemia was found. The only etiology is a deviant consumption of vitamin A within the framework of an "autistic diet": 100000 UI/d during three months, and then 150000 UI/d the three following months. Intoxication was confirmed by the increased vitamin A plasmatic level, and vitamin A/RBP molar ratio and by the presence of plasmatic retinyl palmitate. An emergency treatment by rehydration, biphosphonates and furosemide led to effective calcemia normalization. CONCLUSION: In the case of nonobvious causes of hypercalcemia, a thorough cross-examination must look for vitamin A intoxication. Our observation illustrates the danger of certain diets suggested for autistic children.

Hypercalcemia caused by iatrogenic hypervitaminosis A.

Vitamin A toxicity produces protean clinical manifestations involving a wide variety of tissues and systems. Hypercalcemia can occasionally be associated with high vitamin A levels, but is rare. In this report we describe a patient who was receiving a commercially prepared enteral feeding formula for 2 years. He developed asymptomatic hypercalcemia and had serum vitamin A levels several fold above normal. Subsequently, a custom-made enteral feed was used which contained negligible amounts of vitamin A. Several months later, vitamin A levels diminished substantially and serum calcium levels returned to normal.