Description

A teenage girl, who had been treated with phenytoin sodium for seizure disorder since she was 4 years old, presented with failure to gain height and progressive bowing of her legs for the preceding 3 years. She had received adequate sun exposure and milk intake. She had been treated with oral cholecalciferol (60 000 U/week) for 8 weeks about a year before her presentation to us. Clinical examination revealed gingival hypertrophy (figure 1A), short-limb dwarfism, genu valgum (figure 1B), dry coarse skin and delayed relaxation of the Achilles reflex. Laboratory investigations documented low 25-hydroxy vitamin D (25-OHD) (6 ng/ml) and central hypothyroidism (free thyroxin (T4) 0.72 ng/dl (reference 0.86–1.4 ng/dL); thyroid stimulating hormone (TSH) 0.37 µIU/mL (reference 0.4–4.27 µIU/mL)). Radiography showed fraying of metaphyses consistent with rickets (figure 1C). MRI of the brain revealed normal hypothalamo-pituitary region and cerebellar atrophy (figure 1D). Serum phenytoin level was elevated (39 mg/L (reference 10–20 mg/L)). Levetiracetam and levothyroxine were initiated, and phenytoin was gradually withdrawn. The patient was also treated with pulse oral cholecalciferol followed by daily cholecalciferol and calcium. Repeat imaging revealed healing lines at the involved metaphyses. Levothyroxine supplementation was subsequently withdrawn and the girl remained euthyroid.

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Figure 1

(A) Gingival hypertrophy. (B) Genu valgum. (C) X-ray of the knees suggestive of rickets. (D) T1-weighted non-contrast MRI showing normal hypothalamo-pituitary area and cerebellar atrophy (white arrow).

Phenytoin has a narrow therapeutic index and adversely affects multiple organ systems (table 1). Due to its long half-life, it may be administered in a less frequent daily dosage. It follows non-linear pharmacokinetics; hence, a small increment in dose above the required maintenance dose often results in side effects.

Phenytoin induces gingival hypertrophy, causes cerebellar atrophy, and alters vitamin D and thyroid hormone (TH) homeostasis (figure 2, illustrated by AA, one of the authors).1 The association between long-term anticonvulsant therapy and rickets/osteomalacia was first described back in the 1960s. Phenytoin interferes with vitamin D metabolism at multiple steps. It enhances hepatic catabolism and subsequent excretion of both 25-OHD and 1,25-dihydroxy vitamin D (1,25-OH₂D) by upregulating 24-hydroxylase expression. It also induces target organ resistance to active 1,25-OH₂D. Moreover, it inhibits calcitonin secretion and thereby reduces calcitonin-induced enhanced renal 1-ɑ hydroxylase activity. Furthermore, phenytoin decreases intestinal calcium and phosphate absorption and decreases osteocalcin; thus, it adversely affects bone health. Though clinically overt bone disease is relatively rare, radiological changes and biochemical alterations are detected in up to 50% and 70% of cases, respectively, with long-term anticonvulsant use—phenytoin, phenobarbitone and primidone in particular. The risk factors for anticonvulsant-induced bone disease are duration of treatment, combination therapy, decreased dietary vitamin D, limited exposure to sunlight, and reduced physical activity.2

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Figure 2

Effects of phenytoin on calcium and thyroid hormone homeostasis. CYP24A1, gene encoding 24-hydroxylase; CYP27B1, gene encoding 1ɑ-hydroxylase; PTH, parathyroid hormone; TBG, thyroxine binding globulin; TRH, thyrotropin-releasing hormone; TSH, thyroid-stimulating hormone. *Conflicting reports regarding induction of CYP24A1. #Experimental rat model. ##Rat model. ∮In vitro cultured rat anterior pituitary cells. The figure has been created by Avivar Awasthi, one of the co-authors.

Phenytoin shares structural similarities with T4. It displaces T4 from the binding proteins, increases TH catabolism by inducing hepatic microsomal enzymes, stimulates type 1 deiodinase, and inhibits nuclear binding of liothyronine (T3). In addition, it inhibits thyrotropin-releasing hormone-stimulated TSH release leading to a decrease in circulatory TSH. Total and free TH concentrations are often decreased, suggesting central hypothyroidism, as seen in this patient. Phenytoin is known to cause diffuse atrophy of the Purkinje cells of the cerebellum, and the atrophic change correlates with dose and duration of therapy.

Long-term phenytoin therapy often leads to a plethora of adverse effects. Physicians should be aware of such toxic features because replacing phenytoin with another antiepileptic agent often reverses many of these complications. Recommendations for monitoring of patients being treated with phenytoin are summarised in box 1.