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Abstract
A 4-year-old boy presented with severe bone pains, refusal to walk, diffuse bony swelling of forelimbs, skin changes and abdominal pain, with symptoms evolving over 6 weeks. Blood screening tests were normal except for raised aspartate aminotransferase (AST). Radiographs revealed thickened periosteum, widening of the diaphyses of long bones and lifted periosteum in mid-shaft of ulnae and right femur. Skeletal scintigraphy showed a high uptake of radionuclide at clinically affected and unaffected sites, suggestive of multifocal osteoblastic skeletal lesions. After repeated enquiries, his parents admitted to giving him massive doses of preformed vitamin A for over 3 months as ‘health tablets’. Surprisingly, he did not have overt liver disease typically found with much smaller doses, although the dermal changes and musculoskeletal pathology were florid. He made a full clinical recovery within 2 months of cessation of vitamin A.
- Vitamin A toxicity
- bone pains
- oily skin
- raised periosteum
- skeletal scintigraphy
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Case report
A previously healthy 4-year-old boy presented with a history of illness for about 1½ months. An intermittent fever, cough and cold had subsided but poor appetite and occasional vomiting persisted, followed by severe recurrent abdominal pain and cracking of his lips. The child also presented with excruciating pain in both legs and winced on touch. There was no history of trauma. He refused to stand or walk and was empirically treated as having suspected viral myositis at the local district hospital with a partial improvement in symptoms. Another 2 weeks later, the skin over his hands and feet started peeling off and papular rash appeared over his back. At this stage his parent took him to our hospital 6 weeks after the onset of illness.
At admission, the child was irritable but afebrile with normal pulse, respiration and blood pressure. He had mild pallor but no jaundice. History of any drug administration was denied by the parents. Scalp hair was sparse, coarse and brittle that was reported to be soft and abundant prior to this illness. There was peeling and deep painful cracking of both lips. Skin was shiny over the shins and face as if smeared with oil. There was peeling of skin over palms and soles that appeared flushed. Papular non-itchy erythematous rash was seen over the lower back. Tibiae were thickened and painful with extreme tenderness to touch. On examination of abdomen, soft, 4 cm non-tender liver was palpable. Spleen was not palpable. Examination of respiratory, cardiovascular and central nervous systems did not reveal any abnormal findings.
Initial laboratory work up revealed mild normocytic, normochromic anaemia (haemoglobin 98 G/L) with normal blood cell counts including platelets. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were 32 mm in the 1st hour and 4.8 mg/dL, respectively. Serum calcium was 2.5 mmol/L with normal serum phosphorus. Serum urea and creatine concentrations were within normal limits. Liver function tests were normal except for slightly elevated aspartate aminotransferase (AST) (102 IU/L). Serum alkaline phosphatase was very high (1593 IU/L). Serum creatine kinase was normal. Echocardiogram did not show any coronary aneurysms. X-ray examination of the lower limbs at admission revealed normal bones and soft tissue. Ultrasonogram of the abdomen and Doppler examination of renal and lower limb vessels were normal. Bone marrow examination showed normal haematopoiesis. Venereal Disease Research Laboratory (VDRL) was negative.
On day 3 of admission, a diffuse tender bony swelling similar to that in the middle of the lower legs appeared in the right mid-thigh and forearm. Repeat radiographs revealed thickening of the periosteum along the widened diaphyses of all long bones with lifting of the periosteum in the mid-shaft of ulnar bones (figure 1) and right femur. Skeletal scintigraphy (figure 2) revealed abnormally high uptake of technetium radionuclide in lateral parts of the supraorbital region, multiple bilateral ribs and metatarsals (clinically unaffected sites) besides the clinically affected mid-shafts of multiple long bones, suggestive of multifocal osteoblastic skeletal lesions. Multiple clinically and radiographically normal areas were also revealed to be involved besides the affected sites. Absence of mandibular involvement differentiated it from Caffey's disease.
Radiograph of the left upper limb showing widened long bone diaphyses and lifted periosteum over the ulnar shaft.
Skeletal scintigram showing increased tracer uptake in clinically affected and unaffected areas.
Majority of clinical and laboratory features now appeared to be consistent with the possibility of vitamin A toxicity. After repeated enquiries, the parents reported giving him ‘health tonic tablets’. The child was given vitamin A tablets, 200 000 units each, three tablets (600 000 units) every day for more than 3 months. A diagnosis of chronic vitamin A toxicity was made. Serum vitamin A (retinol) concentration by high Performance liquid chromatogpaphy (HPLC) was elevated at 4.19 µmol/L (normal range 1.13–2.63 µmol/L).
Supplements were immediately stopped. Gradually, the symptoms subsided and he started walking over a period of 2 weeks with normalisation of serum AST concentration. Limb radiographs taken after 2 months showed resolution of bone lesions.
Discussion
Vitamin A is an essential micronutrient for humans. Acute toxicity of preformed vitamin A (retinol and its esterified form, retinyl ester) in children results from intake of doses >300 000 IU. Chronic toxicity is likely to occur at doses greater than 1500 IU/kg/day, though symptoms and severity vary among individuals.1 Ingestion of large doses of provitamin A (carotenoids) on the other hand does not cause such toxicity and is harmless. Signs and symptoms are non-specific and overlap with many other conditions.
Vitamin A is involved in all normal cellular proliferation and differentiation processes. Preformed vitamin A is absorbed to the extent of 70%–90% and primarily stored in the liver where excess storage can lead to fibrosis and cirrhosis leading to hepatosplenomegaly, portal hypertension, mild to moderate rise in liver transaminase levels and rarely, death.2 Spillover of vitamin A from liver and saturation of the binding capacity of retinol binding protein lead to high serum levels resulting in lyses of cell membranes. Receptors for retinoic acid are located on osteoblasts and osteoclasts,1 which accounts for the observed cortical hyperostosis, reports of osteoporosis and fractures.
In our patient, who had been administered an extremely high dose of 600 000 IU every day for more than 3 months, the major presentation of toxicity was of pathological periosteal reaction with normal underlying bone characteristic of vitamin A toxicity and skin changes (peeling skin, coarse thinning scalp hair). Although serum retinol is not a sensitive marker of retinol toxicity, a raised concentration was seen in our patient supporting the diagnosis. He also had hepatomegaly and mild elevation of serum AST concentration, but no other overt signs of liver disease.
Severe life-threatening complications have been reported at much lower doses than those received by our patient. Rise in intracranial pressure is the most well known serious complication of hypervitaminosis A, the causative mechanism of which is not known.2 Hypercalcaemia, a potentially life-threatening complication3 of hypervitaminosis A develops secondary to its direct effect of bone resorption and responds to steroids. It is also reported to be associated with severe anaemia and thrombocytopenia suggestive of a retinol-dependent bone marrow cell growth inhibition.4 All these complications have been reported at much lower doses than those received by our patient. Our patient had none of these complications despite ingesting massive amounts of preformed vitamin A. Tolerance to vitamin A seems to be highly variable, for example, even within one family5 where among three siblings who consumed similar amounts of vitamin A, one child died of hypervitaminsois A.
The toxic potential of vitamin A and other fat soluble vitamins may be underestimated by parents and professionals alike. Although our patient appears to have only a mild disturbance to his liver despite enormous doses of vitamin A, he experienced considerable morbidity related to his skin and hair and was unable to walk because of vitamin A mediated damage to his musculoskeletal system. We conclude that it is essential to take a comprehensive dietary history and vitamin/health supplements as well as drug history for all children, especially those with abnormal liver function and multisystemic symptoms.
Acknowledgments
The authors thank Dr Nandini Pandit, Department of Nuclear Medicine, JIPMER, for providing the skeletal scintigram.
Footnotes
Contributors RB and RG managed the patient, performed literature search and wrote the manuscript. DKCG managed the patient and participated in writing the manuscript.
Competing interests None declared.
Patient consent Parental/guardian consent obtained.
Provenance and peer review Not commissioned; externally peer reviewed.