Physeal Closure from Chronic Vitamin A Intoxication Deborah Wenkert 1, William H. McAlister 2, Michael P. Whyte 3. 1Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO, USA, 2Mallinckrodt Institute of Radiology, and, 3Division of Bone & Mineral Diseases; Washington University School of Medicine, St. Louis, MO, USA. Abstract: An excess of vitamin A or its analogues have a number of adverse effects on multiple organ systems including on the Symptoms of Vitamin A Toxicity (Myhre et al. 2003) skeleton. Premature growth plate fusion from vitamin A and D toxicity was first reported in animal hind limbs (“hyena Constitutional Symptoms Nervous System Gastrointestinal System Skin and Hair and Vision disease”). Subsequently, in 1962, 3 of 7 children with growth retardation from vitamin A toxicity had early lower limb Loss of appetite Vomiting Alopecia Bulging of fontanel Fever Constipation Desquamation physeal closure (JAMA; 182:980). Further reports concerned vitamin A derivatives used in severe pediatric dermatoses Cerebral irritability Sleep disturbance Cirrhosis Dryness or cancers. Increased CSF pressure Tiredness Abdominal pain Exanthema Photophobia Fatigue Diarrhea Hemorrhage Hydrocephalus A 6-yr-old boy with a history of hypervitaminosis A, associated with liver fibrosis, was referred for “epimetaphyseal Weight loss Nausea Pigmentation change Blurred vision Impaired Immunity Hepatomegaly Pruritus disease”. Birth weight was 10 lbs, and he walked at 10 mo. At that time, gastroenteritis was reportedly treated by a Depression Splenomegaly Lip fissure chiropractor with a dose of 3 million units (U) of vitamin A over 16 days, followed by 60,000 U/d except when intercurrent Musculoskeletal System Dizziness Osteopenia Headache illness prompted ~20 additional 3 million U, 16-day courses. By age 2 ½ yrs, fingernails reportedly “bubbled up and fell Vascular System Urogenital System Hyperostosis Ataxia off”, speech regressed, and gross motor skills were lost. Hospitalization elsewhere revealed a critically ill, anorexic child Edema, head Dysuria or altered urination Skeletal pain Papilledema Edema, face pattern with shiny, hairless, jaundiced skin, icterus, mouth sores, mucosal bleeding, pseudotumor cerebri, ataxia, and marked Joint pain Menstrual changes Edema, leg or ankle Muscular stiffness hepatosplenomegaly. Laboratory studies revealed a coagulopathy, hepatitis, anemia, and thrombocytopenia, but normal and pain serum Ca, P, and Mg levels. Alkaline phosphatase was elevated at 827 IU/l. Hypervitaminosis A was diagnosed. After Growth plate fusion* vitamins were stopped, he resumed walking and eating within 9 mo. Nevertheless, leg bowing, noted at age 3, Proliferative enthesopathies worsened. Radiographs at age 5 showed physeal closure within distal femurs and proximal and distal tibias. Periostitis Upon referral, he had dysphagia, dyspnea, anemia, bleeding tendency, morning stiffness, knee and ankle pain, but took * Not listed by Myhre Our patient had the symptoms in blue. only vitamin K. Height was 5%, weight 75%, sitting height 50%, arm span 75%, and head circumference >>95%. He had petechia, bruises, telangiectasias, hypertelorism, cupped optic discs, and splenomegaly (17 cm) without hepatomegaly, 2 10/12 years 6 years 30° knee contractures, enlarged warm ankles and knees, and bowed tibias. Radiographs revealed the physeal closure, Sample of currently now with relative overgrowth of fibulae, and 1/2 yr later, closure of the proximal fibular physes. Physes elsewhere SERUM VITAMIN LEVELS 2 9/12 YEARS 6 YEARS Ref Range available Vitamin A Discussion (cont) remained open. Vitamin A (Retinol) 49 20 20-43 mcg/dl 6 years 6 ½ years 5years supplement. Vitamin E : Alpha-Tocopherol 9.1 8.2 2.9-16.6 mg/l Thus, clinicians should be alert to vitamin supplement use in their patients, The bony manifestations of Long-term follow-up of physeal fusion from vitamin A toxicity (eg. 12 yrs: JBJS[Am] 1974;56:1283) suggests Beta Gamma Tocopherol 0.3 0.5-3.8 mg/l Vitamin C: (Ascorbic Acid) < 0.24 0.2-1.9 mg/dl hypervitaminosis A can range from pain, with or without fractures, to significant skeletal deformity. Osteopenia disproportionate, assymetric shortening of lower limbs. Narrowing of physes from isotretinoin can resolve (Am J Dis Child from vitamin A or retinoic acid derivatives can result from subperiosteal cortical bone loss as shown by CT which Vitamin D: 1,25(OH)2 11.74 15-80 pg/ml 6 years Discussion 1988;142:316-8). Experience with our patient suggests that reversal of physeal fusion is not possible if vitamin A toxicity 25(OH) 26 15-40 ng/ml can be blocked by biphosphonates acting on the osteoclasts. In a 1950 paper regarding vitamin A toxicity, Dr. has been severe and prolonged. Vitamin B12 > 2000 200-1000 pg/ml Caffey commented, “In no case did a manufacturer’s label state the harmful effects of overdosage (which) is a Vitamin K1 13.39 0.1-2.2 ng/ml We have described a 6 1/2-year-old boy with irreversible physeal fusion series of physeal fractures (21), distal femur physes had a disproportionately high incidence of posttraumatic bridge serious error of omission and should be corrected”. BIOCHEMISTRIES 2 9/12 YEARS 6 YEARS Ref Range from vitamin A toxicity. His radiographs at age 5 years were illustrated in formation, accounting for 33% of all premature physeal bridges but only 1.4% of physeal fractures. Also noted, was ESR Sedrate 47 8 0-20 mm/hr Introduction 2007 in a brief report. (2) the earliest physiologic (as well as pathologic) closure site of the distal femoral physis is the central region relating to PT 17.6 17.3 12.1-14.1 seconds retinol INR 1.38 2 the central physeal undulation. Thus, the pattern of involvement in physeal closure in vitamin A toxicity in our patient Skeletal manifestations of hypervitaminosis A in adults include periosteal elevation and thickening, bone pain, Experience with our patient’s abnormal appearance of the growth plates, as References PTT 52.7 37.7 26.5-38.5 seconds O parallels that of other causes of premature physeal closure. hyperostosis, osteoporosis, periarticular calcification, ligament and tendon calcification, DISH, and osteophyte H well as his subsequent physeal fusion, raise a number of issues concerning Biliburin: Total 3 1.5 0.2-1.0 mg/dl Vitamin A and growth plate biology: 1. Nesher G Zuckner J. Rheumatologic complications of vitamin A and retinoids. Semin ArthritisRheum. 1995;24:291-296. formation.(1) In children, whose skeletons are growing and undergoing modeling, additional complications can occur. Direct 1.5 - < 0.3 mg/dl 2. Saltzman MD, King EC. Central physeal arrests as a manifestation of hypervitaminosis A. J Pediatr Orthop 2007;27: 351-353. Calcium: Total 9.3 8.6 8.8-10.8 mg/dL 3. Toomey J Morissette R. Hypervitaminosis A. Am J Dis Child. 1947;473-480. 4) What is the histopathology of Vitamin A excess in the growth plate? 4. Pickup JD. Hypervitaminosis A. Archives of Disease in Childhood. 1956;31:229-232. Ionized 1.27 mMol/L 4.9 mg/dl Physeal fusion due to vitamin A toxicity is not as well known as the painful periostitis leading to undulating diaphyseal 1.08-1.34 mMol/L isotretinoin 1) Our patient received a number of vitamin supplements. Did 5. Woodard JC Donovan AG Eckhoff C. Vitamin (A and D)-induced premature physeal closure (Hyena Disease) in calves. J Comp Path. 1997;353-366. 4.5-5.3 mg/dL (age 6) Deficiency of vitamin A inhibits longitudinal bone growth (22). The long bones of vitamin A deficient animals are 6. Woodard JC Donovan GA Fisher LW. Pathogenesis of vitamin (A and D)-induced premature growth-plate closure in calves. Bone. 1997;21:171-182. cortical thickening , skin and liver disease and increased intracranial pressure. Accordingly, here we report a case of Magnesium 2.2 1.7 1.8-2.4 mg/dL vitamin A cause his premature physeal closure? 7. Yamamoto K Sadahito K Yoshikawa M Nobuyuki O Mikami O Yamada M Nakamura K Yasuyuki N. Hyena disease (premature physeal closure) in calves due to shorter and thicker than those of healthy animals, with the shortness being viewed as a failure of endochondral bone overdose of vitamins A, D3, E. Vet Hum Toxicol. 2003;45:85-87. severe vitamin A intoxication in a 6 1/2-year-old boy which led to irreversible lower extremity growth plate fusion. Phosphate 4.6 4.5 4.0-7.0 mg/dL O O The teratogenicity, hepatic toxicity, as well as the dermatologic, growth. Of note, there are receptors for retinoic acid located on osteoblasts and osteoclasts. (23) 8. Cho DY, Frey RA, Guffy MM, Leipold HW. Hypervitaminosis in the dog. Am J Vet Res. 1975;36:1597-1603. Alkaline Phosphatase 369 241 106-315 IU/L H 9. De Luca F Uveda JA Mericq V Mancilla EE Yannovski JA Barnes KM Zile MH Baron J. Retinoic acid is potent regulator of growth plate chondrogenesis. hematologic, and neurologic manifestations of vitamin A toxicity are well Endocrinology 2000;141:346-353. LDH 569 267 246-448 IU/L 5 years In vitamin A excess, animals have a dose-dependent acceleration of the processes of bone growth (epiphyseal documented(table). Bone manifestations of acute vitamin A toxicity include 10. Kodaka TT Takaki H soeta S Mori R Naiot Y. Local disappearance of epiphyseal growth plates in rats with hypervitaminosis A J Vet Med Sci. 1998;60:815-821. ALT (SGPT) 31 50 2-30 IU/L cartilage sequences, resorption of bone, and appositional bone formation) (22, 9). “In the rat, mitoses appear fewer 11. Hough S Avioli LV Muir H Gelderblom D Jenkins G Kurasi H Slatopolsky E Bergfeld MA Teitelbaum SL. The effects of hypervitaminosis A on the bone and Case Report etretinate periosteal elevation reminiscent of Caffey’s disease.