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Refractory hypercalcemia owing to vitamin A toxicity in a 4-year-old boy
Someone posted this on the Ray Peat forum.
Refractory hypercalcemia owing to vitamin A toxicity in a 4-year-old boy
The patient’s main sources of vitamin A included 1–2 cups of kale, 2–3 cups of green vegetables, 2–3 cups of fruit and 4 oz of meat per day (nonliver), plus a multivitamin containing vitamin A as β-carotene (28 μg RAE). He had previously been taking cod liver oil supplements (276 μg/day RAE) for more than 1 year, but had stopped many months previously.
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Discussion
We present a case of a 4-year-old boy with hypercalcemia and classic cutaneous features of vitamin A toxicity, including dry skin, cheilitis and alopecia.1 He also had commonly reported symptoms of vitamin A toxicity (i.e., fatigue, anorexia, pruritis, headache and bone pain) and clinical features (i.e., nephrocalcinosis, pseudotumour cerebri and liver toxicity).1 He had a low level of parathyroid hormone, low 1,25(OH)2D, normal 25(OH)D, and normal parathyroid hormone-related peptide, which helped to narrow the differential diagnosis for hypercalcemia (Figure 3). Ultimately, his vitamin A level was 2.5 times greater than the normal range, which was likely caused by high vitamin A intake.
Vitamin A can be consumed either as preformed vitamin A, in the form of retinol found in animal sources (e.g., meat, liver, liver oils), some multivitamins and fortified foods (e.g., milk, butter, cereals), or as provitamin A (α- or β-carotene), found in fruits and vegetables (e.g., kale) and some multivitamins3 (Box 2). Vitamin A quantities are measured using RAE, with 1 RAE equal to 1 μg retinol, 12 μg β-carotene, or 24 μg α-carotene. Traditionally, IU were used to measure vitamin A, with 1 IU equal to 0.3 μg retinol. It is thought that toxicity cannot be reached with provitamin A foods, as the efficiency of intestinal absorption falls as intake increases and conversion of carotenoids to retinol is regulated.4 No pediatric cases of toxicity have been associated with provitamin A, whereas toxicity from preformed vitamin A has been reported with acute ingestions exceeding 200 000 IU/day over the course of days,5 and chronic ingestions of 1500 IU/kg/day over months to years.3,6
Our patient was ingesting 1850–3780 IU/kg/day of predominantly provitamin A for years. While children can develop toxicity at lower total doses of preformed vitamin A than those required to cause toxicity in adults, our case is somewhat unusual in that the patient was consuming large quantities of provitamin A from fruits and vegetables, notably kale.3,6,7 One explanation is that intake of large quantities of provitamin A and preformed vitamin A from cod liver supplements together may have caused toxicity, as the effect of high levels of preformed vitamin A on the metabolism of provitamin A may be synergistic.4
Dietary recall is fraught with difficulty, especially with children. Even in optimal circumstances, parents may be uncertain about the dose or duration of supplementation, or inadvertently overlook other supplements.
Vitamin A storage and metabolism is complex. The liver stores 80% of the body’s vitamin A and is susceptible to toxic doses;3,8 therefore, liver diseases such as viral hepatitis and cirrhosis may increase susceptibility to vitamin A toxicity and worsen liver damage. In 1 study of 41 mostly adult cases of vitamin A hepatotoxicity, some developed cirrhosis with doses as low as 25 000 IU/day.8 Therefore, it is possible that liver damage from vitamin A toxicity from preformed vitamin A could have affected our patient’s ability to appropriately regulate high intakes of provitamin A. Although viral and autoimmune workup for liver disease was negative, we did not do a liver biopsy, so we cannot definitively rule out liver disease from another cause.
Vitamin A is also stored in the kidneys and adrenal glands and excreted partly in urine. Our patient had mild pre-renal acute kidney injury secondary to hypercalcemia, which may have reduced vitamin A clearance and exacerbated toxicity. Other factors that modulate vitamin A potency include low-protein diets, chronic kidney disease and concurrent use of certain vitamins, such as vitamin D and E,7 none of which were pertinent in this case.7,9 Furthermore, heritable variability in vitamin A metabolism is known, which may explain why toxicity occurs at a wide range of intakes.7,10 Interestingly, our patient had a 6-year-old brother who was consuming a similar diet, yet did not develop symptoms of vitamin A toxicity.
Our case may be of relevance to families shifting to plant-based diets and using vitamin supplements on a regular basis. Short-term dietary studies have shown that as much as 75% of the general population is ingesting more than the recommended daily allowance of vitamin A, mostly in the preformed form.3 Only a fraction of consumers discuss with their physicians their use of dietary supplements such as vitamins.7 Our case describes an extreme presentation, but patients may present with milder symptoms of vitamin A toxicity, which may be overlooked or dismissed as vague and nonspecific.
Vitamin A toxicity is an important diagnosis to consider in patients with hypercalcemia. Although our patient had classic findings of vitamin A toxicity, his case had unique features that made the diagnosis challenging, including toxic ingestion with predominantly provitamin A rather than preformed vitamin A, refractory hypercalcemia and bicytopenia despite a normal bone marrow biopsy. Chronic vitamin A toxicity is particularly challenging, as toxicity may occur at what people perceive as a “safe doses” of vitamin A from dietary sources and supplementation.