Table 2.

Main results on thyroid function of the ketogenic diet

Author	Type of Study	Clinical setting and number of participants	Age (Mean ± SD) Sex (male/female)	Composition of ketogenic diet	Duration	Result on thyroid function
Iacovides et al. [17•]	Randomized crossover-controlled study	Healthy and normal-weight (BMI: 24.0 ± 2.0 kg/m2) N = 11	Age: 30 ± 9 years Male = 1 Female = 10	Isocaloric dietary interventions: HCLF diet: 55% carbohydrate, 20% fat, 25% protein) KD: 15% carbohydrate, 60% fat, 25% protein	A minimum of three weeks on each diet, with a one-week washout (habitual diet) between the diets	Compared to baseline levels, the change in plasma T3 concentration was significantly different between the two diets (p = 0.003). Plasma T3 concentration was significantly lower following the KD diet (4.1 (3.8—4.4) pmol/L, p < 0.0001) but not different following the HCLF diet (4.8 (4.5—5.2) pmol/L, p = 0.171). There was a significant increase in T4 concentration from pre-diet levels following the KD diet (19.3 (17.8—20.9) pmol/L, p < 0.0001), but not following the HCLF diet (17.3 (15.7—18.8) pmol.L, p = 0.28). The magnitude of change in plasma T4 concentration was not different between the two diets (p = 0.4). There was no effect of diet on plasma TSH concentration (p = 0.27). There was a significantly greater T3:T4 ratio following the HCLF diet (0.41 (0.27—0.55), p < 0.0001) compared to pre-diet levels but not following the KD diet (0.25 (0.12—0.39), p = 0.80)
Tragni et al. [7]	Multi-center, prospective, uncontrolled trial in a real-life setting	Overweight or obesity (BMI: 30.9 ± 2.7 kg/m2) N = 44	Age 49.5 ± 7.2 years Only female	VLCKD multi-step dietary model Phase 1: 700 kcal (50 g/day of CHO); 4 weeks Phase 2: 820 kcal (50 g/day of CHO); 4 weeks Phase 2: 1100 kcal (50 g/day of CHO); 4 weeks Phase 2: 1250 kcal (50 g/day of CHO); 4 weeks	Total intervention duration of 24 weeks	TSH: Baseline: 2.40 ± 0.77 mUI/L, Post-VLCKD: 2.31 ± 0.86 mUI/L; Absolute Change (% Change): − 0.09 (− 3.8), p = 0.629 Thyroid function markers with no change
Yılmaz et al. [106•]	Retrospectively reviewed	Children with drug-resistant epilepsy N = 66	Aged 3—193 months (median, 52 months) Male = 35 Female = 31	KD was started at a 3:1 ratio with a non-fasting gradual initiation protocol and the ratio was then adjusted between 2:1 and 4:1 as needed to maintain ideal ketone levels for seizure control and minimize adverse effects	KD for at least 12 months	No significant changes in fT4 and TSH concentrations, nor in the number of patients with low fT4 and high TSH concentrations. However, four patients who received L-T4 replacement therapy had increase in serum fT4 levels: and an insignificant decrease in TSH concentrations It appears that ketogenic diet therapy does not impair thyroid functions in children with drug-resistant epilepsy. In addition, KD can be safely used even in children with pre-existing subclinical hypothyroidism along with L-thyroxine replacement
Khodabakhshi et al. [112]	Randomized controlled open-label clinical trial	Locally advanced or metastatic breast cancer and without a history of renal disease or diabetes N = 80	Age: 44.8 ± 8.4 year (KD group) 45.2 ± 15.0 years (control group) Only female	Eucaloric dietary interventions: KD: 6% CHO, 19% protein, 20% MCT oil, and 55% fat Control group: standard diet consisting of 55% CHO, 15% protein, and 30% fat	12 weeks	Thyroid markers with no change
Gomez-Arbelaez et al. [113]	Open, uncontrolled, nutritional intervention clinical trial	Patients with obesity N = 20	Age: 47.2 ± 10.2 year Male = 8 Female = 12	VLCKD multi-step dietary model: The first three steps 600–800 kcal/day, < 50 g daily from vegetables and lipids (only 10 g of olive oil per day. The amount of high-biological-value proteins ranged between 0.8 and 1.2 g per each kg of ideal body weight In steps 4 and 5: 800–1500 kcal/day Step 6: 1500 and 2000 kcal/day and the target was to maintain the weight lost and promote healthy life styles	Patients followed the different steps of the method until they reach the target weight or up to a maximum of 4 months of follow-up	TSH and fT4 did not significantly change, free T3 had a significant although expected decrease
Lee et al. [99]	Retrospective longitudinal cohort study	Children with medically intractable epilepsy N = 28 children	Age at start of KD 3.2 ± 2.4 (0.5–9.9) Boys = 17 Girls = 11	Ratio of KD 4:1/3:1/2:1/1:1	Mean duration of KD was 1.9 ± 1.5 years	There was no significant longitudinal change in the mean fT4 (0.99 ± 0.25 vs. 0.94 ± 0.71 ng/dL, p = 0.28) and TSH (2.94 ± 1.32 vs. 3.18 ± 1.21 μIU/mL, p = 0.44) levels from the start of the KD to last follow-up The patients with a younger age of seizure onset the earlier initiation of KD had a significant decrease in fT4 levels and increase in TSH levels during the KD Sex, duration of the seizure or KD therapy, seizure types, seizure frequency, seizure outcomes, brain lesion, ratio of KD, and being overweight did not affect the longitudinal change of fT4 and TSH levels during KD However, it is advisable to carefully monitor the serum levels of fT4/TSH in children on KDs, particularly in those who had an earlier onset of seizures, commenced KD treatment earlier, or have higher levels of lipid profiles
Kose et al. [95]	Single-center design clinical trial	Children receiving KD for at least one year due to drug-resistant epilepsy N = 120 patients	Age: 7.3 ± 4.3 years Males = 63 Female = 57	All children were started on a 3:1 or 4:1 KD ratio [fat/(protein plus carbohydrate)]. A Mediterranean-style KD was prepared with extra virgin olive oil as the principal fat source and common, locally available food as described before	The mean duration of KD was 14.5 ± 3.9 months [12 (12–18 months)]. Maximum duration of follow-up on KD was 24 months (9 patients)	Hypothyroidism was diagnosed and L-T4 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 Baseline TSH elevation [OR: 26.91, 95% 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 KD causes thyroid malfunction and L-thyroxine treatment may be required. TSH elevation and female gender were independent risk factors for developing hypothyroidism in epileptic children during KD treatment

SD standard deviation, BMI body mass index, HCLF High carbohydrates and low-fat diet, KD Ketogenic Diet, T4, thyroxine, T3 triiodothyronine, VLCKD Very low-calorie ketogenic diet, CHO carbohydrate, fT4 free T4, L-T4 levothyroxine, MCT Medium Chain Triglycerides, OR odds ratio, CI confidence interval