Changes of thyroid hormonal status in patients receiving ketogenic diet due to intractable epilepsy

Engin Kose 1 , Orkide Guzel 2 , Korcan Demir 3 ,  and Nur Arslan 4 , 5
  • 1 Dokuz Eylul University, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey
  • 2 Behçet Uz Children Hospital, Division of Pediatric Neurology, Izmir, Turkey
  • 3 Dokuz Eylul University, Division of Pediatric Endocrinology, Izmir, Turkey
  • 4 Dokuz Eylul University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Metabolism and Nutrition, Izmir, Turkey
  • 5 Dokuz Eylul University, Izmir Biomedicine and Genome Center (iBG-izmir), Izmir, Turkey
Engin Kose, Orkide Guzel, Korcan Demir and Nur Arslan

Abstract

Background:

Ketogenic diet (KD), which is high in fat and low in carbohydrates, mimics the metabolic state of starvation and is used therapeutically for pharmacoresistant epilepsy. It is known that generation of triiodothyronine (T3) from thyroxine (T4) decreases during fasting periods. The aim of this study was to evaluate the thyroid function of children receiving KD for at least 1 year due to drug-resistant epilepsy.

Methods:

A total of 120 patients [63 males, 52.5%; mean age 7.3±4.3 years, median interquartile range (IQR): 7.0 (4–10 years)] treated with KD for at least 1 year were enrolled. Seizure control, side effects, and compliance with the diet were recorded, and free T3, free T4, and thyroid-stimulating hormone (TSH) levels were measured at baseline and at post-treatment months 1, 3, 6, and 12. The Mann-Whitney U-test, repeated measures analysis of variance (ANOVA) with post-hoc Bonferroni correction, and logistic regression analysis were used for data analysis.

Results:

Hypothyroidism was diagnosed and L-thyroxine medication was initiated for eight, seven and five patients (20 patients in total, 16.7%) at 1, 3, and 6 months of KD therapy, respectively. Logistic regression analysis showed that baseline TSH elevation [odds ratio (OR): 26.91, 95% confidence interval (CI) 6.48–111.76, p<0.001] and female gender (OR: 3.69, 95% CI 1.05–12.97, p=0.042) were independent risk factors for development of hypothyroidism during KD treatment in epileptic children.

Conclusions:

KD causes thyroid malfunction and L-thyroxine treatment may be required. This is the first report documenting the effect of KD treatment on thyroid function. Thyroid function should be monitored regularly in epileptic patients treated with KD.

  • 1.

    Simeone TA, Matthews SA, Samson KK, Simeone KA. Regulation of brain PPARgamma2 contributes to ketogenic diet anti-seizure efficacy. Exp Neurol 2017;287:54–64.

    • Crossref
    • PubMed
    • Export Citation
  • 2.

    Viggiano A, Stoddard M, Pisano S, Operto FF, Iovane V, et al. Ketogenic diet prevents neuronal firing increase within the substantia nigra during pentylenetetrazole-induced seizure in rats. Brain Res Bull 2016;125:168–72.

    • Crossref
    • PubMed
    • Export Citation
  • 3.

    Ni FF, Li CR, Liao JX, Wang GB, Lin SF, et al. The effects of ketogenic diet on the Th17/Treg cells imbalance in patients with intractable childhood epilepsy. Seizure 2016;38:17–22.

    • Crossref
    • PubMed
    • Export Citation
  • 4.

    Maciejak P, Szyndler J, Turzyńska D, Sobolewska A, Kołosowska K, et al. Is the interaction between fatty acids and tryptophan responsible for the efficacy of a ketogenic diet in epilepsy? The new hypothesis of action. Neuroscience 2016;313:130–48.

    • Crossref
    • PubMed
    • Export Citation
  • 5.

    Rho JM. How does the ketogenic diet induce anti-seizure effects? Neurosci Lett (in press). doi: .

    • Crossref
    • Export Citation
  • 6.

    Smith J, Rho JM, Teskey GC. Ketogenic diet restores aberrant cortical motor maps and excitation-to-inhibition imbalance in the BTBR mouse model of autism spectrum disorder. Behav Brain Res 2016;304:67–70.

    • Crossref
    • PubMed
    • Export Citation
  • 7.

    Barañano KW, Hartman AL. The ketogenic diet: uses in epilepsy and other neurologic illnesses. Curr Treat Options Neurol 2008;10:410–9.

    • Crossref
    • PubMed
    • Export Citation
  • 8.

    Mavropoulos JC, Yancy WS, Hepburn J, Westman EC. The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study. Nutr Metab (Lond) 2005;2:35.

    • Crossref
    • PubMed
    • Export Citation
  • 9.

    Castaldo G, Monaco L, Castaldo L, Galdo G, Cereda E. An observational study of sequential protein-sparing, very low-calorie ketogenic diet (Oloproteic diet) and hypocaloric Mediterranean-like diet for the treatment of obesity. Int J Food Sci Nutr 2016;67:696–706.

    • Crossref
    • PubMed
    • Export Citation
  • 10.

    Bertoli S, Neri IG, Trentani C, Ferraris C, De Amicis R, et al. Short-term effects of ketogenic diet on anthropometric parameters, body fat distribution, and inflammatory cytokine production in GLUT1 deficiency syndrome. Nutrition 2015;31:981–7.

    • Crossref
    • PubMed
    • Export Citation
  • 11.

    Zajac A, Poprzecki S, Maszczyk A, Czuba M, Michalczyk M, et al. The effects of a ketogenic diet on exercise metabolism and physical performance in off-road cyclists. Nutrients 2014;6:2493–508.

    • Crossref
    • PubMed
    • Export Citation
  • 12.

    Özdemir R, Güzel O, Küçük M, Karadeniz C, Katipoglu N, et al. The effect of the ketogenic diet on the vascular structure and functions in children with intractable epilepsy. Pediatr Neurol 2016;56:30–4.

    • Crossref
    • PubMed
    • Export Citation
  • 13.

    Güzel O, Yılmaz U, Uysal U, Arslan N. The effect of olive oil-based ketogenic diet on serum lipid levels in epileptic children. Neurol Sci 2016;37:465–70.

    • Crossref
    • PubMed
    • Export Citation
  • 14.

    De Pedro N, Delgado MJ, Gancedo B, Alonso-Bedate M. Changes in glucose, glycogen, thyroid activity and hypothalamic catecholamines in tench by starvation and refeeding. J Comp Physiol B 2003;173:475–81.

    • Crossref
    • PubMed
    • Export Citation
  • 15.

    Wasniewska M, Salerno M, Cassio A, Corrias A, Aversa T, et al. Prospective evaluation of the natural course of idiopathic subclinical hypothyroidism in childhood and adolescence. Eur J Endocrinol 2009;160:417–21.

    • Crossref
    • PubMed
    • Export Citation
  • 16.

    Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism in childhood – current knowledge and open issues. Nat Rev Endocrinol 2016;12:734–46.

    • Crossref
    • PubMed
    • Export Citation
  • 17.

    Svalheim S, Sveberg L, Mochol M, Taubøll E. Interactions between antiepileptic drugs and hormones. Seizure 2015;28:12–7.

    • Crossref
    • PubMed
    • Export Citation
  • 18.

    Kundra P, Burman KD. The effect of medications on thyroid function tests. Med Clin North Am 2012;96:283–95.

    • Crossref
    • PubMed
    • Export Citation
  • 19.

    Turan MI, Cayir A, Ozden O, Tan H. An examination of the mutual effects of valproic acid, carbamazepine, and phenobarbital on 25-hydroxyvitamin D levels and thyroid function tests. Neuropediatrics 2014;45:16–21.

    • PubMed
    • Export Citation
  • 20.

    Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, et al. Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: A meta-analysis. Seizure 2016;35:72–9.

    • Crossref
    • PubMed
    • Export Citation
  • 21.

    Scriba PC, Bauer M, Emmert D, Fateh-Moghadam A, Hofmann GG, et al. Effects of obesity, total fasting and re-alimentation on L-thyroxine (T4), 3,5,3′-L-triiodothyronine (T3), 3,3′,5′-L-triiodothyronine (rT3), thyroxine binding globulin (TBG), cortisol, thyrotrophin, cortisol binding globulin (CBG), transferrin, alpha 2-haptoglobin and complement C’3 in serum. Acta Endocrinol (Copenh) 1979;91:629–43.

    • PubMed
    • Export Citation
  • 22.

    Vagenakis AG, Portnay GI, O’Brian JT, Rudolph M, Arky RA, et al. Effect of starvation on the production and metabolism of thyroxine and triiodothyronine in euthyroid obese patients. J Clin Endocrinol Metab 1977;45:1305–9.

    • Crossref
    • PubMed
    • Export Citation
  • 23.

    Van der Geyten S, Van Rompaey E, Sanders JP, Visser TJ, Kühn ER, et al. Regulation of thyroid hormone metabolism during fasting and refeeding in chicken. Gen Comp Endocrinol 1999;116:272–80.

    • Crossref
    • PubMed
    • Export Citation
  • 24.

    Pittman CS, Shimizu T, Burger A, Chambers JB Jr. The nondeiodinative pathways of thyroxine metabolism: 3,5,3′,5-tetraiodothyroacetic acid turnover in normal and fasting human subjects. J Clin Endocrinol Metab 1980;50:712–6.

    • Crossref
    • PubMed
    • Export Citation
  • 25.

    Portnay GI, O’Brian JT, Bush J, Vagenakis AG, Azizi F, et al. The effect of starvation on the concentration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J Clin Endocrinol Metab 1974;39:191–4.

    • Crossref
    • PubMed
    • Export Citation
  • 26.

    Suda AK, Pittman CS, Shimizu T, Chambers JB Jr. The production and metabolism of 3,5,3′-triiodothyronine and 3,3′,5-triiodothyronine in normal and fasting subjects. J Clin Endocrinol Metab 1978;47:1311–9.

    • Crossref
    • PubMed
    • Export Citation
  • 27.

    Azizi F. Effect of dietary composition on fasting-induced changes in serum thyroid hormones and thyrotropin. Metabolism 1978;27:935–42.

    • Crossref
    • PubMed
    • Export Citation
  • 28.

    Stokholm KH. Decrease in serum free triiodothyronine, thyroxine-binding globulin and thyroxine-binding prealbumin whilst taking a very-low-calorie diet. Int J Obes 1980;4:133–8.

    • PubMed
    • Export Citation
  • 29.

    Carlson HE, Drenick EJ, Chopra IJ, Hershman JM. Alterations in basal and TRH-stimulated serum levels of thyrotropin, prolactin, and thyroid hormones in starved obese men. J Clin Endocrinol Metab 1977;45:707–13.

    • Crossref
    • PubMed
    • Export Citation
  • 30.

    Alvero R, Kimzey L, Sebring N, Reynolds J, Loughran M, et al. Effects of fasting on neuroendocrine function and follicle development in lean women. J Clin Endocrinol Metab 1998;83:76–80.

    • PubMed
    • Export Citation
  • 31.

    Ingenbleek Y, Malvaux P. Peripheral turnover of thyroxine and related parameters in infant protein-calorie malnutrition. Am J Clin Nutr 1980;33:609–16.

    • Crossref
    • PubMed
    • Export Citation
  • 32.

    Chopra IJ, Smith SR. Circulating thyroid hormones and thyrotropin in adult patients with protein calorie malnutrition. J Clin Endocrinol Metab 1975;40:221–7.

    • Crossref
    • PubMed
    • Export Citation
  • 33.

    Orbak Z, Akin Y, Varoglu E, Tan H. Serum thyroid hormone and thyroid gland weight measurements in protein energy malnutrition. J Pediatr Endocrinol Metab 1998;11:719–24.

    • PubMed
    • Export Citation
  • 34.

    Bergqvist AG, Chee CM, Lutchka L, Rychik J, Stallings VA. Selenium deficiency associated with cardiomyopathy: a complication of the ketogenic diet. Epilepsia 2003;44:618–20.

    • Crossref
    • PubMed
    • Export Citation
  • 35.

    Sirikonda NS, Patten WD, Phillips JR, Mullett CJ. Ketogenic diet: rapid onset of selenium deficiency-induced cardiac decompensation. Pediatr Cardiol 2012;33:834–8.

    • Crossref
    • PubMed
    • Export Citation
  • 36.

    Moriyama K, Watanabe M, Yamada Y, Shiihara T. Protein-losing enteropathy as a rare complication of the ketogenic diet. Pediatr Neurol 2015;52:526–8.

    • Crossref
    • PubMed
    • Export Citation
  • 37.

    Suo C, Liao J, Lu X, Fang K, Hu Y, et al. Efficacy and safety of the ketogenic diet in Chinese children. Seizure 2013;22:174–8.

    • Crossref
    • PubMed
    • Export Citation
  • 38.

    Rumińska M, Witkowska-Sędek E, Majcher A, Pyrżak B. Thyroid function in obese children and adolescents and its association with anthropometric and metabolic parameters. Adv Exp Med Biol 2016;912:33–41.

    • Crossref
    • PubMed
    • Export Citation
  • 39.

    Marwaha RK, Tandon N, Garg MK, Ganie MA, Narang A, et al. Impact of body mass index on thyroid functions in Indian children. Clin Endocrinol (Oxf) 2013;79:42–8.

Purchase article
Get instant unlimited access to the article.
$42.00
Log in
Already have access? Please log in.


or
Log in with your institution

Journal + Issues

The Journal of Pediatric Endocrinology and Metabolism (JPEM) is the only international journal dedicated exclusively to endocrinology in the neonatal, pediatric and adolescent age groups, and publishes the results of clinical investigations in pediatric endocrinology and basic research. JPEM publishes Review Articles, Original Research, Case Reports, Short Communications and Letters to the Editor.

Search