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.

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.

Acute fish liver intoxication induced blisters formation and generalized skin peeling.

INTRODUCTION: Acute fish liver intoxication, including hypervitaminosis A and hypervitaminosis D, may result from the ingestion of certain fish livers. The typical symptoms of hypervitaminosis A include nausea, headache, blurred vision, and cutaneous manifestations, such as flushing, vesicles formation, and desquamation. Hypervitaminosis D may result in hypercalcemia. We report a case of acute fish liver intoxication with systemic and cutaneous manifestations. CASE: A 63-year-old male presented to the clinic with generalized desquamation and multiple clear-fluid filled flaccid vesicles after eating approximately two fist-sized portions (about 300-400 g) of cooked seerfish (Scomberomorus spp.) liver. Laboratory examination showed a high serum level of vitamin A and D, and hypercalcemia. CONCLUSIONS: Fish liver consumption from particular fish may result in acute hypervitaminosis A and D. In patients with skin detachment or blister formation, headache, drowsiness, and other symptoms and signs consistent with hypervitaminosis A and/or hypercalcemia, a history of fish intake should be sought, and a serum level of vitamin A and D should be measured.

Hypervitaminosis A-induced hepatic fibrosis in a cat.

RATIONALE: The excessive intake of vitamin A in the form of vitamin concentrate, supplement or vitamin-rich liver can result in hypervitaminosis A in man and animals. Although osteopathologies resulting from chronic vitamin A intoxication in cats are well characterized, no information is available concerning feline hypervitaminosis A-induced liver disease. CLINICAL SUMMARY: We report the first case of hepatic stellate cell lipidosis and hepatic fibrosis in a domestic cat that had been fed a diet based on raw beef liver. Radiographic examination revealed exostoses and ankylosis between vertebrae C1 and T7, compatible with deforming cervical spondylosis. Necropsy showed a slightly enlarged and light yellow to bronze liver. Microscopic and ultrastructural analyses of liver tissues revealed diffuse and severe liver fibrosis associated with hepatic stellate cell hyperplasia and hypertrophy. These cells showed immunopositive staining for α-smooth muscle actin and desmin markers. The necropsy findings of chronic liver disease coupled with osteopathology supported the diagnosis of hypervitaminosis A. PRACTICAL RELEVANCE: As in human hepatology, if there is dietary evidence to support increased intake of vitamin A, then hypervitaminosis A should be considered in the differential diagnosis of chronic liver disease in cats.

Increased dietary intake of vitamin A promotes aortic valve calcification in vivo.

OBJECTIVE: Calcific aortic valve disease (CAVD) is a major public health problem with no effective treatment available other than surgery. We previously showed that mature heart valves calcify in response to retinoic acid (RA) treatment through downregulation of the SRY transcription factor Sox9. In this study, we investigated the effects of excess vitamin A and its metabolite RA on heart valve structure and function in vivo and examined the molecular mechanisms of RA signaling during the calcification process in vitro. METHODS AND RESULTS: Using a combination of approaches, we defined calcific aortic valve disease pathogenesis in mice fed 200 IU/g and 20 IU/g of retinyl palmitate for 12 months at molecular, cellular, and functional levels. We show that mice fed excess vitamin A develop aortic valve stenosis and leaflet calcification associated with increased expression of osteogenic genes and decreased expression of cartilaginous markers. Using a pharmacological approach, we show that RA-mediated Sox9 repression and calcification is regulated by classical RA signaling and requires both RA and retinoid X receptors. CONCLUSIONS: Our studies demonstrate that excess vitamin A dietary intake promotes heart valve calcification in vivo. Therefore suggesting that hypervitaminosis A could serve as a new risk factor of calcific aortic valve disease in the human population.

Adverse effects of antioxidative vitamins.

High doses of synthetic antioxidative vitamins: A, E, C and ß-carotene are often used on long-term basis in numerous preventive and therapeutic medical applications. Instead of expected health effects, the use of those vitamins may however lead to cases of hypervitaminosis and even to intoxication. The article points out main principles of safety which are to be observed during supplementation with antioxidative vitamins. Toxic effects resulting from erroneous administration of high doses of those substances on organs and systems of the organism are also discussed. Attention is drawn to interactions of antioxidative vitamins with concomitantly used drugs, as well as intensification of adverse effects caused by various exogenous chemical factors. Moreover, the article presents the evaluation of supplementation with these vitamins, which was performed in large studies.

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.

[Morphological characteristic of erythrocytes in experimental hypervitaminosis A].

This investigation was aimed at the analysis of the shape and morpho-densitometric parameters of the erythrocytes in rats with experimental hypervitaminosis A. Male Wistar rats received 0.64 mg/g (1167 IU/g) of retinol palmitate (RP) in oil solution orally for 11 consecutive days. Rats fed oil alone and intact animals were used as control groups. At days 5 and 6 of the experiment, the first manifestations of hypervitaminosis A were observed (body mass loss, localized erythema and hemorrhages). In contrast to control groups, in rats with hypervitaminosis A, the area of erythrocyte cytoplasm decreased gradually in response to RP administration. Discocyte/spherocyte/stomatocyte ratio also changed dynamically: the proportion of discocytes progressively decreased, while the amount of spherocytes and stomatocytes increased. These results show that excess of the vitamin A alters the erythrocyte membrane structure. Integral optical density of erythrocyte cytoplasm in RP-treated rats as well as in oil-fed rats was lower than in intact animals. This may be an indirect evidence of the fall in erythrocyte hemoglobin content. The changes observed in erythrocytes of RP-treated rats may serve as an additional criterion for evaluation of hypervitaminosis A severity.

Neuromuscular adverse effects associated with systemic retinoid dermatotherapy: monitoring and treatment algorithm for clinicians.

Although neuromuscular adverse effects represent significant clinical manifestations of hypervitaminosis A syndrome, surprisingly little attention has been paid to the potential neuromuscular toxicity of vitamin A derivatives (retinoids). Since isotretinoin and acitretin are currently the two most commonly used oral retinoids in systemic dermatotherapy, this review focuses exclusively on their neuromuscular adverse effects and proposes a neuromuscular algorithm for appropriate monitoring of patients treated with these two compounds. The most frequent CNS adverse effect associated with oral isotretinoin is headache, either as an independent adverse effect or as part of benign intracranial hypertension, which is additionally characterized by nausea and visual changes. Isolated cases of stiff-person-like syndrome, epileptic seizures and generalized muscle stiffness syndrome, possibly or probably related to oral treatment with isotretinoin, have also been reported. In addition, oral isotretinoin has reportedly been associated with muscular adverse effects that most frequently manifest as myalgia and stiffness and, in rare cases, as true myopathy or rhabdomyolysis. Creatine phosphokinase, a specific marker of muscle destruction, has been found to be elevated, occasionally by up to 100 times the normal value (with or without muscular symptoms and signs), in a variable percentage of patients receiving isotretinoin treatment and particularly in those undergoing vigorous physical exercise. Oral acitretin has been found to cause peripheral nerve dysfunction, particularly of sensory fibres, which in rare cases leads to clinically evident sensory disturbances. Less clear is the causal relationship between acitretin and benign intracranial hypertension or myopathy, whereas an isolated case of cranial nerve IV (oculomotor) palsy and a further case of thrombotic stroke during treatment with oral acitretin have been reported. Systemic diseases with involvement of nervous and/or muscle tissue and neuromuscular disorders should be regarded as exclusion criteria for initiation of oral retinoid therapy. Additionally, intense physical exercise and concurrent treatment with neurotoxic or myotoxic drugs should be avoided during treatment with oral retinoids. In order to minimize the potential risk of neuromuscular adverse effects, a neuromuscular algorithm is suggested that may be useful for monitoring patients taking oral retinoids.

Acute renal failure and hypercalcemia in an athletic young man.

Hypercalcemia is a life-threatening disorder and is related primarily to neoplastic diseases and primary and secondary hyperparathyroidism. The association of hypercalcemia and renal failure is frequent in the medical literature, although pathogenetic mechanisms remain to be elucidated. In this article, we present a case of hypercalcemia and acute renal failure secondary to vitamin D and vitamin A intoxication, after an over-the-counter intramuscular use by a young man starting an athletic performance program. A discussion of clinical picture, diagnosis and treatment is made, and we highlight the risk of pathological conditions triggered by inadvertent use of supplementation products and formulas available in health and fitness commercial centers.

Hypervitaminosis A-induced liver fibrosis: stellate cell activation and daily dose consumption.

UNLABELLED: Hypervitaminosis A-related liver toxicity may be severe and may even lead to cirrhosis. In the normal liver, vitamin A is stored in hepatic stellate cells (HSC), which are prone to becoming activated and acquiring a myofibroblast-like phenotype, producing large amounts of extracellular matrix. AIMS: In order to assess the relationship between vitamin A intake, HSC activation and fibrosis, we studied nine liver biopsies from patients belonging to a well-characterized series of 41 patients with vitamin A hepatotoxicity. METHODS: Fibrosis was underlined by Sirius-red staining, whereas activated HSC were immunohistochemically identified using an antibody against alpha smooth muscle actin. The volume density (Vv) of sinusoidal and total fibrosis and of sinusoidal and total activated HSC was quantified by the point-counting method. RESULTS: Morphology ranged from HSC hypertrophy and hyperplasia as the sole features to severe architectural distortion. There was a significant positive correlation between Vv of perisinusoidal fibrosis and the daily consumption of vitamin A (P=0.004). CONCLUSION: The close correlation between the severity of perisinusoidal fibrosis and the daily dose of the retinol intake suggests the existence of a dose-effect relationship.

Subclinical hypervitaminosis A in rat: measurements of bone mineral density (BMD) do not reveal adverse skeletal changes.

We have previously shown that subclinical hypervitaminosis A in rats causes fragile bones. To begin to investigate possible mechanisms for Vitamin A action we extended our previous study. Forty-five mature female Sprague-Dawley rats were divided into three groups, each with 15 animals. They were fed a standard diet containing 12IU Vitamin A per g pellet (control, C), or a standard diet supplemented with 120 IU ("10xC") or 600 IU ("50xC") Vitamin A/g pellet for 12 weeks. At the end of the study, serum retinyl esters were elevated 4- and 20-fold. Although neither average food intake nor final body weights were significantly different between groups, a dose-dependent reduction in serum levels of Vitamin D and E, but not Vitamin K, was found. In the 50xC-group the length of the humerus was the same as in controls, but the diameter was reduced (-4.1%, p<0.05). Peripheral quantitative computed tomography (pQCT) at the diaphysis showed that bone mineral density (BMD) was unchanged and that periosteal circumference had decreased significantly (-3.7%, p<0.05). Ash weight of the humerus was not affected, but since bone volume decreased, volumetric BMD, as measured by the bone ash method, even increased (+2.5%, p<0.05). In conclusion, interference with other fat-soluble Vitamins is a possible indirect mechanism of Vitamin A action. Moreover, BMD measurements do not reveal early adverse skeletal changes induced by moderate excesses of Vitamin A in rats. Since the WHO criterium for osteoporosis is based on BMD, further studies are warranted to examine whether this is also true in humans.

In vivo studies of altered expression patterns of p53 and proliferative control genes in chronic vitamin A deficiency and hypervitaminosis.

Several clinical trials have revealed that individuals who were given beta-carotene and vitamin A did not have a reduced risk of cancer compared to those given placebo; rather, vitamin A could actually have caused an adverse effect in the lungs of smokers [Omenn, G.S., Goodman, G.E., Thornquist, M.D., Balmes, J., Cullen, M.R., Glass, A., Keogh, J.P., Meyskens, F.L., Valanis, B., Williams, J.H., Barnhart, S. & Hammar, S. N. Engl. J. Med (1996) 334, 1150-1155; Hennekens, C.H., Buring, J.E., Manson, J.E., Stampfer, M., Rosner, B., Cook, N.R., Belanger, C., LaMotte, F., Gaziano, J.M., Ridker, P.M., Willet, W. & Peto, R. (1996) N. Engl. J. Med. 334, 1145-1149]. Using differential display techniques, an initial survey using rats showed that liver RNA expression of c-H-Ras was decreased and p53 increased in rats with chronic vitamin A deficiency. These findings prompted us to evaluate the expression of c-Jun, p53 and p21WAF1/CIF1 (by RT-PCR) in liver and lung of rats. This study showed that c-Jun levels were lower and that p53 and p21WAF1/CIF1 levels were higher in chronic vitamin A deficiency. Vitamin A supplementation increased expression of c-Jun, while decreasing the expression of p53 and p21WAF1/CIF1. Western-blot analysis demonstrated that c-Jun and p53 showed a similar pattern to that found in the RT-PCR analyses. Binding of retinoic acid receptors (RAR) to the c-Jun promoter was decreased in chronic vitamin A deficiency when compared to control hepatocytes, but contrasting results were found with acute vitamin A supplementated cells. DNA fragmentation and cytochrome c release from mitochondria were analyzed and no changes were found. In lung, an increase in the expression of c-Jun produced a significant increase in cyclin D1 expression. These results may explain, at least in part, the conflicting results found in patients supplemented with vitamin A and illustrate that the changes are not restricted to lung. Furthermore, these results suggest that pharmacological vitamin A supplementation may increase the risk of adverse effects including the risk of oncogenesis.

Infant hypervitaminosis A causes severe anemia and thrombocytopenia: evidence of a retinol-dependent bone marrow cell growth inhibition.

Vitamin A is a pivotal biochemical factor required for normal proliferation and differentiation as well as for specialized functions, such as vision. The dietary intake of 1500 IU/day is recommended in the first year of life. Here, we report the case of an infant who had been given 62 000 IU/day for 80 days. The infant showed several clinical signs of retinol intoxication, including severe anemia and thrombocytopenia. Bone marrow showed a remarkably reduced number of erythroid and megakaryocytic cells. The interruption of vitamin A treatment was immediately followed by clinical and biochemical recovery. To clarify whether the effects of retinol are due to a direct action on bone marrow cell proliferation, we investigated the activity of retinol (both the drug and the pure molecule) on the growth of K-562, a multipotent hematopoietic cell line, and on bone marrow mesenchymal stem cells. We observed that vitamin A strongly inhibited the proliferation of the cells at concentrations similar to those reached in vivo. Subsequent biochemical analyses of the cell cycle suggested that the effect was mediated by the up-regulation of cyclin-dependent kinase inhibitors, p21(Cip1) and p27(Kip1). These are the first findings to demonstrate that infant hypervitaminosis A causes a severe anemia and thrombocytopenia and that this is probably due to the direct effect of the molecule on the growth of all bone marrow cellular components. Our data also suggest potential bone marrow functional alterations after excessive vitamin A intake because of emerging social habits.