A suspected hypervitaminosis A.

BACKGROUND AND AIM: Vitamin A toxicity is uncommon, but when it occurs can be serious and even fatal. A case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions of this phenomenon are necessary. CASE REPORT: Here, we report a case vitamin A intoxication with high levels in liver tests, thrombocytopenia and appearance virosis. The patient showed several clinical signs abdominal pain, including mild anemia and thrombocytopenia. CONCLUSIONS: We believe that Laboratory testing is one of the most widely used diagnostic interventions supporting medical decisions, and further investigations regarding the etiology and prevalence of this phenomenon are necessary. (www.actabiomedica.it).

Did hypervitaminosis A have a role in Mawson's ill-fated Antarctic exploration?

Douglas Mawson is a national hero of Australia, having led the Australasian Antarctic expedition of 1911, and survived. His three-man sledging team was beset by a series of catastrophes. First, expert skier Belgrave Ninnis died after he fell into a deep crevasse taking with him half the dogs and a sledge of essential food and supplies. The remaining two explorers immediately turned back to base which was 315 miles away. With their rations diminished they resorted to eating their remaining six dogs over 23 days. Xavier Mertz became progressively ill with diarrhea, delirium, vocal outbursts in rages, and finally several seizures. He died after another seizure. Mawson, alone with negligible food and no dogs for transportation, through his own sheer grit made it back to base camp a month later and was saved. His journal records medical complications with skin desquamation, alopecia, and muscle pain. It has been proposed that these symptoms in both Mertz and Mawson were the manifestations of hypervitaminosis A. They likely consumed greater than a 1,200,000 IU of vitamin A each day from the dog liver they decided was essential to eat to survive. Mertz, a vegetarian, possibly consumed more of the liver than muscle meat, and consequently suffered the more severe encephalopathy and seizures associated with acute vitamin A poisoning.

Persistent hypercobalaminemia three months after successful gradual attenuation of extrahepatic shunts in dogs: a prospective cohort study.

BACKGROUND: Deficiencies in vitamin A and D and disorders in the vitamin B complex are often present in people with chronic liver diseases. So far, the serum concentrations of these vitamins have not yet been studied in dogs with congenital extrahepatic portosystemic shunts (EHPSS), who also have some degree of liver dysfunction. The objective was to assess serum vitamin concentrations in dogs with EHPSS from diagnosis to complete closure. A prospective cohort study was performed using ten client-owned dogs with EHPSS, closed after gradual surgical attenuation. Serum concentrations of vitamin A, 25-hydroxyvitamin D, folic acid, cobalamin and methylmalonic acid (MMA) were measured at diagnosis prior to institution of medical therapy, prior to surgery, and three months after gradual attenuation and complete closure of the EHPSS. RESULTS: At diagnosis, median serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid were 18.2 µg/dL (8.8 - 79.5 µg/dL), 51.8 ng/mL (19.4 - 109.0 ng/mL), and 8.1 µg/L (5.2 - 14.5 µg/L), respectively, which increased significantly postoperatively (88.3 µg/dL (51.6 - 182.2 µg/dL, P=0.005), 89.6 ng/mL (49.3 - >150.0 ng/mL, P =0.005), and 14.8 µg/L (11.5 - 17.7 µg/L, P <0.001), respectively). Median serum cobalamin concentrations were 735.5 ng/L (470 - 1388 ng/L) at diagnosis and did not significantly decrease postoperatively (P =0.122). Both at diagnosis and three months postoperatively 7/10 dogs had hypercobalaminemia. CONCLUSIONS: Serum concentrations of vitamin A, 25-hydroxyvitamin D and folic acid significantly increase after surgical attenuation. Nevertheless, persistent hypercobalaminemia is suggestive of ongoing liver dysfunction, despite successful surgery.

Chronic and acute hypervitaminosis A are associated with suboptimal anthropometric measurements in a cohort of South African preschool children.

BACKGROUND: Excessive vitamin A (VA) can cause bone resorption and impair growth. Government-mandated VA supplementation (VAS) and adequate intake through dietary fortification and liver consumption led to excessive VA in South African children. OBJECTIVES: We evaluated the relation between VAS and underlying hypervitaminosis A assessed by retinol isotope dilution (RID) with measures of growth and bone turnover in this cohort. METHODS: Primary outcomes in these children (n = 94, 36-60 mo) were anthropometric measurements [height-for-age (HAZ), weight-for-age (WAZ), and weight-for-height (WHZ) z scores], serum bone turnover markers [C-terminal telopeptide of type I collagen (CTX) and N-terminal propeptide of type I procollagen (P1NP)], and inflammation defined as C-reactive protein (CRP; ≥5 mg/L) and/or α1-acid glycoprotein (AGP; ≥1 g/L). VA status was previously measured by RID-estimated total body VA stores (TBSs) and total liver VA reserves (TLRs), and serum retinol and carotenoid concentrations, before and 4 wk after children were administered 200,000 IU VAS. Serum 25-hydroxyvitamin D3 was measured by ultra-performance LC. RESULTS: In this largely hypervitaminotic A cohort, HAZ, WAZ, and WHZ were negatively associated with increasing TLRs, where TLRs predicted 6-10% of the variation before VAS (P < 0.05), increasing to 14-19% 4 wk after VAS (P < 0.01). Bone resorption decreased after VAS (P < 0.0001), whereas formation was unaffected. Neither CTX nor P1NP were correlated with TLRs at either time. Serum carotenoids were low. One child at each time point was vitamin D deficient (<50 nmol/L). CRP and AGP were not associated with growth measurements. CONCLUSIONS: Excessive TLRs due to dietary VA intake and VAS are associated with lower anthropometric measures and bone resorption decreased after supplementation. VA supplementation programs should monitor VA status with biomarkers sensitive to TLRs to avoid causing negative consequences in children with hypervitaminosis A. This trial is registered at clinicaltrials.gov as NCT02915731.

Hypervitaminosis A in Pediatric Patients With Advanced Chronic Kidney Disease.

OBJECTIVE: Hypervitaminosis A is well-described but overlooked in chronic kidney disease (CKD) and has been associated with hypercalcemia, contributing to mineral bone disease. Our objective is to assess prevalence of hypervitaminosis A and its association with bone health in an advanced-CKD population. METHODS: We performed a retrospective review of 58 children with CKD 4-5 to examine the association between vitamin A levels and bone health and compared these values between a primarily formula-fed (FF) and nonprimarily formula-fed cohort (NFF). RESULTS: Fifty-six of 58 patients (97%) had hypervitaminosis A with a mean vitamin A level of 1,475 ± 597 mcg/dL. When compared with the upper limit of normal vitamin A level for age, the FF group's vitamin A level was 2.9x upper limit of normal and the NFF group's vitamin A level was 2.2x upper limit of normal (P = .02). The mean calcium level was 10.3 mg/dL in the FF group and 9.8 mg/dL in the NFF group (P = .057). Percent of patients lower than, within, or greater than goal parathyroid hormone range was statistically significant with 15 (62%) of the FF group lower than goal and 16 (72%) of the NFF cohort greater than goal (P = .006). CONCLUSIONS: We concluded vitamin A and calcium levels are higher in the FF versus the NFF population. FF patients are more likely to have parathyroid hormone levels lower than the goal range, placing them at risk for adynamic bone disease. We recommend monitoring vitamin A levels as part of routine nutritional assessments and dietary interventions to prevent hypervitaminosis A to improve bone health in late CKD.

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.

Hypercalcaemia due to Hypervitaminosis D in a Self-Supplementing Multiple Sclerosis Patient: A Case Report

There is an increasing literature with regard to vitamin D supplementation in Multiple Sclerosis (MS). We report the case of a 45 year-old male with MS who presented with symptomatic hypercalcaemia secondary to self-supplementation of vitamin D3 purchased online. Treatment was with IV hydration, glucocorticoids, calcitonin and bisphosphonates. This case highlights a lack of consensus guidance regarding safe vitamin D supplementation dosages and the importance of a thorough history with regard to non-prescribed supplements, particularly those easily available online.

Rubella Virus Infection, the Congenital Rubella Syndrome, and the Link to Autism.

Rubella is a systemic virus infection that is usually mild. It can, however, cause severe birth defects known as the congenital rubella syndrome (CRS) when infection occurs early in pregnancy. As many as 8%-13% of children with CRS developed autism during the rubella epidemic of the 1960s compared to the background rate of about 1 new case per 5000 children. Rubella infection and CRS are now rare in the U.S. and in Europe due to widespread vaccination. However, autism rates have risen dramatically in recent decades to about 3% of children today, with many cases appearing after a period of normal development ('regressive autism'). Evidence is reviewed here suggesting that the signs and symptoms of rubella may be due to alterations in the hepatic metabolism of vitamin A (retinoids), precipitated by the acute phase of the infection. The infection causes mild liver dysfunction and the spillage of stored vitamin A compounds into the circulation, resulting in an endogenous form of hypervitaminosis A. Given that vitamin A is a known teratogen, it is suggested that rubella infection occurring in the early weeks of pregnancy causes CRS through maternal liver dysfunction and exposure of the developing fetus to excessive vitamin A. On this view, the multiple manifestations of CRS and associated autism represent endogenous forms of hypervitaminosis A. It is further proposed that regressive autism results primarily from post-natal influences of a liver-damaging nature and exposure to excess vitamin A, inducing CRS-like features as a function of vitamin A toxicity, but without the associated dysmorphogenesis. A number of environmental factors are discussed that may plausibly be candidates for this role, and suggestions are offered for testing the model. The model also suggests a number of measures that may be effective both in reducing the risk of fetal CRS in women who acquire rubella in their first trimester and in reversing or minimizing regressive autism among children in whom the diagnosis is suspected or confirmed.

Restricting vitamin A intake increases bone formation in Zambian children with high liver stores of vitamin.

This analysis was performed in Zambian children who had a high prevalence of hypervitaminosis A, defined as > 1.0 µmol retinol/g liver. Bone parameters included markers of bone formation (P1NP), bone resorption (CTX), parathyroid hormone, calcium, vitamin A, and vitamin D. Low dietary vitamin A intake increased P1NP. PURPOSE: Vitamin A (VA) interacts with bone health, but mechanisms require clarification. In countries where multiple interventions exist to eradicate VA deficiency, some groups are consuming excessive VA. Bone metabolism and inflammatory parameters were measured in Zambian children who had high prevalence of hypervitaminosis A determined by 13C-retinol isotope dilution. METHODS: Children (n = 143), 5 to 7 years, were recruited into a placebo-controlled biofortified orange maize feeding study for 90 days. Bone turnover (P1NP and CTX) and inflammatory (C-reactive protein (CRP) and alpha-1-acid glycoprotein) biomarkers were measured in fasting blood samples before and/or after intervention with the following: (1) VA at the recommended dietary allowance (400 µg retinol activity equivalents/day (as retinyl palmitate)), (2) maize enhanced with the provitamin A carotenoid ß-carotene (2.86 mg/day), or (3) a placebo. Parathyroid hormone, calcium, and 25(OH)-vitamin D were measured at end line. RESULTS: Bone formation, as measured by P1NP, increased (P < 0.0001) in the placebo group who consumed low preformed VA during the intervention. Bone resorption, measured by CTX, was not affected. P1NP and CTX were negatively associated with inflammation, most strongly with CRP. Serum calcium did not differ among groups and was low (7.29 ± 0.87 µg/dL). Serum 25(OH) D did not differ among groups (54.5 ± 15 nmol/L), with 91% < 75 nmol/L and 38% < 50 nmol/L. CONCLUSIONS: Reduction of dietary preformed VA in Zambian children for 4 months improved bone formation. Chronic consumption of preformed VA caused hypervitaminosis A and may impair bone formation. In children, this could be associated with failure to accrue optimal peak bone mass. TRIAL REGISTRATION: The NIH Clinical Trial registry number is NCT01814891; https://clinicaltrials.gov/ct2/show/NCT01814891 .

Correction osteotomy for bilateral varus knee deformity caused by premature epiphyseal closure induced by hypervitaminosis A: a case report.

BACKGROUND: A vitamin A derivative, 13-cis-retinoic acid (isotretinoin), has been administered to treat several types of pediatric cancer and has improved survival rates in patients despite being known to induce premature epiphyseal closure. As the number of patients treated by 13-cis-retinoic acid increases, demands for salvage treatment after systemic retinoid therapy are emerging. However, few studies have described the surgical treatment of this disease. CASE PRESENTATION: We report a case with bilateral varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin for neuroblastoma. The patient was successfully treated with correction osteotomy using a Taylor spatial frame in the right knee joint and femoral closed wedge osteotomy using a locking plate in left knee joint. Histopathological examination of the growth plate showed polar irregularity of chondrocytes and decreased cartilage matrix without apoptosis. In contrast, arthroscopic findings showed an intact joint surface. No recurrence of varus deformity was evident on follow-up at 1 year. CONCLUSIONS: To the best of our knowledge, this represents the first report of correction osteotomy for varus knee deformity due to premature epiphyseal closure that occurred during treatment with isotretinoin.

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.

Long-term dietary intake of excessive vitamin A impairs spermatogenesis in mice.

Vitamin A and its derivatives contribute to many physiological processes, including vision, neural differentiation, and reproduction. Vitamin A deficiency causes early cessation of spermatogenesis, characterized by a marked depletion of germ cells. However, there has been no clear understanding about the role of chronic intake of vitamin A excess (VAE) in spermatogenesis. The objective of this study was to investigate whether chronic intake of VAE diet causes arrest of spermatogenesis. To examine the effects of VAE on spermatogenesis, we used ICR male mice fed with control (AIN-93G purified diet: 4 IU/g) diet or VAE (modified AIN-93G diet with VAE: 1,000 IU/g) diet for 7 weeks (from 3 to 10 weeks of age). At 10 weeks of age, the retinol concentration in the testes of VAE mice was significantly higher than that of control mice. Testicular cross sections from control mice contained a normal array of germ cells, while the seminiferous tubules from VAE mice exhibited varying degrees of testicular degeneration. Daily sperm production in VAE testes was dramatically decreased compared to that in control testes. Sperm viability, motility, and morphology were also impaired in VAE mice. Furthermore, we examined the effects of VAE on the expression of genes involved in retinoid signaling and spermatogenesis to determine the underlying molecular mechanisms. Therefore, we are the first to present results describing the long-term dietary intake of VAE impairs spermatogenesis using a mouse model.

Liver Cirrhosis From Chronic Hypervitaminosis A Resulting in Liver Transplantation: A Case Report.

Herein we report a case of liver dysfunction caused by consumption of vitamin A supplements leading to liver transplantation. The patient was a 48-year-old male with a medical history of congenital ichthyosiform erythroderma in treatment with vitamin A until 12 years of age, at which point he discontinued the supplements because he had developed ascites. Liver cirrhosis was diagnosed as secondary to hypervitaminosis A on the basis of histologic examination of liver biopsy and the absence of other potential causes of chronic liver disease. Despite interruption of administration of vitamin A, the patient continued to deteriorate over the years, with development of portal hypertension signs. His medical conditions were aggravated with the development of hepatic insufficiency manifested by refractory ascites, renal insufficiency, and severe encephalopathy and he underwent orthotopic liver transplantation, followed by disappearance of all signs of portal hypertension. This case highlights the need to take a careful history of consumption of vitamin A when evaluating a patient with liver failure.

Overlapping vitamin A interventions in the United States, Guatemala, Zambia, and South Africa: case studies.

Vitamin A (VA) deficiency is a serious public health problem, especially in preschool children who are at risk of increased mortality. In order to address this problem, the World Health Organization recommends periodic high-dose supplementation to children 6-59 months of age in areas of highest risk. Originally, supplementation was meant as a short-term solution until more sustainable interventions could be adopted. Currently, many countries are fortifying commercialized common staple and snack foods with retinyl palmitate. However, in some countries, overlapping programs may lead to excessive intakes. Our review uses case studies in the United States, Guatemala, Zambia, and South Africa to illustrate the potential for excessive intakes in some groups. For example, direct liver analysis from 27 U.S. adult cadavers revealed 33% prevalence of hypervitaminosis A (defined as ≥1 µmol/g liver). In 133 Zambian children, 59% were diagnosed with hypervitaminosis A using a retinol isotope dilution, and 16% had ≥5% total serum VA as retinyl esters, a measure of intoxication. In 40 South African children who frequently consumed liver, 72.5% had ≥5% total serum VA as retinyl esters. All four countries have mandatory fortified foods and a high percentage of supplement users or targeted supplementation to preschool children.

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.

Clinically relevant doses of vitamin A decrease cortical bone mass in mice

Excess vitamin A has been associated with decreased cortical bone thickness and increased fracture risk. While most studies in rodents have employed high dosages of vitamin A for short periods of time, we investigated the bone phenotype in mice after longer exposure to more clinically relevant doses. For 1, 4 and 10 weeks, mice were fed a control diet (4.5 µg retinyl acetate/g chow), a diet modeled from the human upper tolerable limit (UTL; 20 µg retinyl acetate/g chow) and a diet three times UTL (supplemented; 60 µg retinyl acetate/g chow). Time-dependent decreases in periosteal circumference and bone mineral content were noted with the supplemented dose. These reductions in cortical bone resulted in a significant time-dependent decrease of predicted strength and a non-significant trend toward reduced bone strength as analyzed by three-point bending. Trabecular bone in tibiae and vertebrae remained unaffected when vitamin A was increased in the diet. Dynamic histomorphometry demonstrated that bone formation was substantially decreased after 1 week of treatment at the periosteal site with the supplemental dose. Increasing amount of vitamin A decreased endocortical circumference, resulting in decreased marrow area, a response associated with enhanced endocortical bone formation. In the presence of bisphosphonate, vitamin A had no effect on cortical bone, suggesting that osteoclasts are important, even if effects on bone resorption were not detected by osteoclast counting, genes in cortical bone or analysis of serum TRAP5b and CTX. In conclusion, our results indicate that even clinically relevant doses of vitamin A have a negative impact on the amount of cortical bone.