Re: 케톤생성 식사를 하다가 위 배출시간이 느려지는 경우 카르니틴 보충제 효과 2024 네이처

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케톤생성 식사

음식치료제 베타하이드로 뷰티레이트 생성식사

왜 배가 덜 고픈지를 알게되었다!!

위배출시간이 느려짐

카르니틴 보충제를 먹으면 개선된다!

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Impact of L-carnitine supplementation on gastric emptying and bowel function in pediatric ketogenic diet therapy: a clinical trial

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• Published: 15 November 2024

Impact of L-carnitine supplementation on gastric emptying and bowel function in pediatric ketogenic diet therapy: a clinical trial

• May Fouad Nassar, 
• Mennatallah Osama Shata, 
• Shrouk Mohamed Awadallah, 
• Mennatallah Ayman Youssef & 
• Haya Essam Ibrahim 

Scientific Reports volume 14, Article number: 28099 (2024) Cite this article

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Abstract

Ketogenic diet (KD) is an excess fat, enough protein, and minimal carbohydrate diet. The high fat content in KD lowers the oesophageal sphincter tone, slows gastric emptying, and decreases intestinal transit time. The primary aim of the current clinical trial was to study the effect of L-carnitine supplementation on gastric emptying in children with drug resistant epilepsy (DRE) on KD. Assessment of the protective effect of L-carnitine on bowel function and habits in those patients was a secondary aim. The current study recruited 30 patients aged 12 months to 18 years newly diagnosed with DRE assigned to start KD who were following up at the Pediatric Clinical Nutrition and Neurology Outpatient Clinics or were admitted due to DRE at the Pediatric Neurology Inpatient Department, Children’s Hospital, Ain Shams University (Egypt). Participants were assigned randomly into 2 arms; arm I: received KD with L-carnitine supplementation, arm II: received KD only. Patients were assessed at baseline and after 3 months of starting KD, the assessments of children included: 24-hour dietary recall, Chalfont Seizures Severity Scale, gastrointestinal symptoms score and Bristol stool chart, frequency of defecation per week, anthropometric measurements assessment, fasting serum lipid profile and measurement of the antral length by ultrasound. There was significant increase in antral length in the patients who received KD with L-carnitine supplementation compared to the non-supplemented group. The antral length showed a significant negative correlation with GI symptoms score in all cases and the L-carnitine supplemented group. It also showed a significant positive correlation with Bristol stool score in all patients and a significant positive correlation with stool frequency in the L-carnitine supplemented group only. L-carnitine supplementation to children with DRE on KD has a significant role in improving gastric motility and it increases the frequency of defecation. Further studies are recommended to explore additional benefits, meanwhile it is prudent to advise L-carnitine supplementation for such patients.

초록

케토제닉 다이어트(KD)는 

과도한 지방, 충분한 단백질, 최소한의 탄수화물을 섭취하는 식이요법입니다. 

KD의 높은 지방 함량은 

식도 괄약근의 긴장도를 낮추고 

위 배출 속도를 늦추며 장 통과 시간을 감소시킵니다. 

본 임상 연구의 주요 목적은 KD를 시행 중인 

약물 저항성 간질(DRE) 환아에서 

L-카르니틴 보충이 위 배출에 미치는 영향을 연구하는 것이었습니다. 

해당 환자에서 

L-카르니틴의 장 기능 및 배변 습관에 대한 보호 효과를 평가하는 것은 

부차적 목적이었입니다. 

본 연구는 이집트 아인 샴스 대학교 어린이 병원 소아 임상 영양 및 신경과 외래 클리닉에서 추적 관찰 중이거나

 DRE로 입원 중인 12개월에서 18세 사이의 DRE 신규 진단 환자 

30명을 대상으로 진행되었습니다. 

참가자는 무작위로 2개 그룹으로 배정되었습니다: 

그룹 I: KD와 L-카르니틴 보충제를 투여받은 그룹, 

그룹 II: KD만 투여받은 그룹. 

환자들은 KD 시작 시점과 3개월 후 평가를 받았으며, 

어린이 평가 항목에는 24시간 식이 회상, Chalfont 발작 중증도 척도, 

위장관 증상 점수, Bristol 변비 차트, 주당 배변 횟수, 인체 측정 평가, 공복 혈청 지질 프로파일, 

초음파를 통한 위장관 길이 측정 등이 포함되었습니다. 

L-카르니틴 보충제를 투여받은 KD 치료군에서 

위체부 길이가 

보충제 미투여군에 비해 유의미하게 증가했습니다. 

위체부 길이는 

모든 사례에서 위장 증상 점수와 유의미한 음의 상관관계를 보였으며, 

L-카르니틴 보충제 투여군에서도 동일한 경향을 나타냈습니다. 

또한 

모든 환자에서 브리스톨 변형 점수와 유의미한 양의 상관관계를 보였으며, 

L-카르니틴 보충제 투여군에서만 

배변 빈도와 유의미한 양의 상관관계를 나타냈습니다. 

KD를 받는 DRE 환아에게 L-카르니틴 보충은 

위 운동성 개선에 중요한 역할을 하며 배변 빈도를 증가시킵니다. 

추가적인 혜택을 탐구하기 위한 추가 연구가 권장되며,

현재로서는 이러한 환자에게 L-카르니틴 보충을 권장하는 것이 적절합니다.

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Introduction

Ketogenic diet (KD) is an excess fat, enough protein, and minimal carbohydrate diet which is administered under medical supervision to maintain chronic ketosis while providing adequate protein and calories for growth and development1. KD is an efficient treatment for pediatric drug-resistant epilepsy (DRE). The latter is defined as failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug (AED) schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom2. KD is more effective than several novel anticonvulsant medications and families of affected children accept it because of its tolerability as well as its efficiency3.

The high fat content in KD lowers the oesophageal sphincter tone, slows gastric emptying, and decreases intestinal transit time4,5.

Gastrointestinal disturbances, constipation, dyslipidemia, and micronutrient deficiencies are common side effects in the KD regimen which is often discontinued earlier than recommended because such symptoms are difficult to be controlled6.

Carnitine deficiency has been widely reported in patients with epilepsy being treated with valproic acid and there have been reports that carbamazepine and phenobarbital may also deplete carnitine levels especially if used in combination with valproic acid. It has been suggested that the KD may also induce carnitine deficiency due to the high fat content7.

In patients with severe intellectual and motor disabilities, Murata and collaborators reported that the level of free carnitine was significantly correlated with gastric emptying and the severity of constipation and this level was significantly lower in the patients who suffered from constipation. Moreover, the severity of constipation was significantly relieved after supplementation with carnitine8.

Gastric emptying is a complex physiologic process controlled by the physical and chemical composition, sympathetic and parasympathetic innervations of the stomach, and circulating neuro-endocrine transmitters. The type of food, volume, and caloric content significantly affect the rate of gastric emptying9.

Gastric emptying can be assessed by ultrasonography which is a non-invasive technique that can be repeatedly performed because of its safety with good correlation to radionuclide estimates of gastric emptying10.

소개

케토제닉 다이어트(KD)는

과도한 지방, 충분한 단백질, 최소한의 탄수화물을 섭취하는 식이로,

만성 케토시스를 유지하면서 성장과 발달에 필요한 충분한 단백질과 칼로리를 공급하기 위해

의료 감독 하에 시행됩니다1.

KD는

소아 약물 저항성 간질(DRE)의 효과적인 치료법입니다.

후자는 두 가지 이상 용인 가능한 항경련제(AED)를 단독 요법 또는 병용 요법으로 적절히 선택하고 투여한 후 지속 가능한 발작 자유를 달성하지 못한 경우로 정의됩니다2. KD는 여러 새로운 항경련제보다 효과적이며, 영향을 받은 어린이의 가족들은 내약성과 효과 때문에 이를 수용합니다3.

KD의 높은 지방 함량은

식도 괄약근의 긴장을 낮추고

위 배출을 늦추며 장 통과 시간을 감소시킵니다4,5.

위장 장애, 변비, 이상지질혈증, 미량 영양소 결핍은

KD 요법에서 흔한 부작용으로,

이러한 증상이 관리하기 어려워 권장보다 일찍 중단되는 경우가 많습니다6.

발프로산으로 치료받는 간질 환자에게

카르니틴 결핍이 널리 보고되었으며,

카르바마제핀과 페노바르비탈도 특히 발프로산과 병용 시 카르니틴 수치를 감소시킬 수 있다는 보고가 있습니다.

KD의 높은 지방 함량으로 인해 카르니틴 결핍을 유발할 수 있다는 제안도 있습니다7.

중증 지적 및 운동 장애를 가진 환자에서 Murata와 동료들은 자유 카르니틴 수치가 위 배출 속도와 변비 심각도와 유의미하게 관련되어 있으며, 변비를 겪은 환자에서 이 수치가 유의미하게 낮았다고 보고했습니다. 또한 카르니틴 보충 후 변비 심각도가 유의미하게 완화되었다고 보고되었습니다8.

위 배출은

위의 물리적 및 화학적 구성, 교감신경과 부교감신경의 신경 분포,

순환하는 신경내분비 전달물질에 의해 조절되는 복잡한 생리적 과정입니다.

음식의 종류, 양, 칼로리 함량은 위 배출 속도에 크게 영향을 미칩니다9.

위 배출은 초음파 검사로 평가될 수 있으며,

이는 안전성으로 인해 반복적으로 수행 가능하며

방사성 동위 원소 측정 결과와 좋은 상관관계를 보이는 비침습적 기술입니다10.

Aim of the work

Primary aim: Assessment of the effect of L-carnitine supplementation on gastric emptying in pediatric patients with DRE on KD through measuring antral length.

Secondary aim: Assessment of the protective effect of L-carnitine on bowel function and habits in patients with DRE on KD by assessing frequency of defecation, stool form and response to laxatives.

Patients and methods

Setting

This randomized controlled clinical trial study was conducted on 30 patients who presented to the Pediatric Clinical Nutrition and Neurology Units, Children`s Hospital, Faculty of Medicine, Ain Shams University (Cairo, Egypt), during the period from January 2023 to November 2023. These units run a multidisciplinary clinic for children with DRE which means failure of two or more well selected and proper dosed AED to achieve sustained seizure freedom2. This clinic supports the use of KD for children with DRE.

Ethical considerations

Written informed consent was obtained from all children’s guardians. The study was performed according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for studies involving humans.

This study was conducted after approval by the Research Ethical Committee of Faculty of Medicine, Ain Shams University with approval number (FMASU M S 630/2022) in 22/6/2022. The study was also registered as a clinical trial [ClinicalTrials.gov Identifier NCT06255873 (13/02/2024)]. The CONSORTreporting guidelines was used to present the clinical trial data11.

Patients

The current study recruited 30 patients aged 12 months to 18 years newly diagnosed with DRE assigned to start KD who were following up at Pediatric Clinical Nutrition and Neurology Outpatient Clinics or were admitted due to drug resistant seizures at Pediatric Neurology inpatient department.

Patients with intolerance or non-compliance to ketogenic diet therapy (KDT), patients who fit the criteria for epilepsy surgery or vagal nerve stimulation, patients with history of previous abdominal operations or gastrointestinal (GI) diseases affecting GI motility before starting KD, and patients with tube feeding or feeding gastrostomy or jejunostomy were excluded from the study.

Participants were assigned randomly by the field researchers using simple randomization with 15 patients in each group using a shuffled deck of cards (even–group arm I, odd–group arm II) into 2 arms; arm I patients received KD with L-carnitine supplementation and arm II patients received only KD.

All Patients started KDT under supervision of physicians. Ketogenic ratio was assigned {total fat intake (gram) divided by the sum of total protein intake (gram) and total carbohydrate intake (gram)}.

The type and initial ratio of KD therapy were selected according to age, type of feeding, needs and the preferences of the child and his/her family were considered. KD ratio ranged from 1.5:1 to 3:1 of lipids to carbohydrates plus proteins, in grams12.

L-carnitine supplementation in arm I patients was taken after feed in the form of tablets or dissolved tablets with a daily dose of 50 mg/kg/day, up to a maximum of 2 g/day, once per day8,13.

Side effects as nausea, diarrhea, and fishy body odor13 were monitored.

Every case from arm I was matched for gender, age (1 year range was allowed between the selected patients), and BMI Z score (1 SD range was allowed between them) with a patient from arm II to serve as controls.

Sample size: Thirty patients were enrolled. Using jepi-info program for sample size calculation and reviewing results from previous study8, sample size of 30 patients were sufficient to explore and achieve the study objectives. Patients assigned randomly into 2 groups 15 patients in each group.

Methods

All the data mentioned below was obtained from both groups at the initiation of KD and after 3 months of intervention and all enrolled patients completed the follow up assessment.

Detailed medical history was taken with special emphasis on age of onset and duration of the disease, frequency of epileptic attacks and number of hospital admissions due to severe attacks, as well as history of antiepileptic drugs (AEDs) (drug name, number of drugs, dosage, and duration of therapy). Dietary assessment using 24-hour recall was obtained and analyzed using software based on food composition tables of the National Nutrition Institute, 200614.

Complete physical and neurological examination were performed laying stress on anthropometric measurements [weight (kg), height or length (cm) and body mass index (kg/m2)] which were measured and plotted on the WHO Z score for children up to 5 years of age15, while CDC 2000 growth charts have been used for those above 5 years of age.

Gastro-intestinal symptoms score was assessed based on the score of Adam and collaborators16 as follows:

Parents were asked to indicate whether their children had experienced specific GI symptoms nausea, vomiting, bloating, abdominal cramps, early satiety, eructation or heartburn, loss of appetite, retrosternal discomfort and epigastric pain or abdominal pain over the past month. Children or their care givers were asked to rate the intensity of each individual symptom on a validated 5-point Likert scale (0 indicates no problem, 1 indicates mild problem, 2 indicates moderate problem, 3 indicates severe problem and 4 indicates very severe problem). The sum score ranged from (0–40). Score of (1–10) indicates mild problem, (11–20) indicates moderate problem, (21–30) indicates severe problem, (31–40) indicates very severe problem16.

Constipation was assessed by frequency of defecation, response to laxatives and feces forms which were classified according to Bristol stool scale, (type 1 = separate hard lumps) (type 2 = sausage shaped and lumpy) (type3 = sausage shaped with cracks on its surface) (type 4 = sausage or snake with smooth surface) (type 5 = soft blobs) (type 6 = fluffy pieces) (type 7 = entirely liquid)17.

Severity of seizures was assessed using the Chalfont seizure severity scale (CSSS)18.

Radiological assessment

Initial pelvi-abdominal ultrasound (PAUS) using a GE healthcare LOGIQ P9 ultrasound device was done 15 min after a meal of KD milk formula containing 25% of the recommended dietary allowance (RDA) of daily calories for each patient19. The same operator performed all the ultrasound studies.

All patients were studied in a supine position, measurements of the gastric antrum were always taken from the outer profile of the wall because the lumen of the antrum is usually very narrow, the cross section of the gastric antrum was measured, corresponding to the antral diameter, (forms an elliptical shape). The longitudinal area was measured representing antral length, as described by Bolondi and collaborators in 198520.

Laboratory assessment

Specimen Collection: Blood collection was performed with care to avoid stasis, hemolysis or contamination by tissue fluids, or exposure to glass. Specimens were kept at room temperature. Laboratory tests: Fasting Lipid profile was assessed after 10 h of fasting, and dyslipidemia was defined as the presence of any of the following four measurements: high total-cholesterol (≥ 200 mg/dL), high LDL-cholesterol (≥ 130 mg/dL), low HDL-cholesterol (≤ 35 mg/dL), or high triglycerides (≥ 130 mg/dL)21.

Statistical analysis

The collected data was coded, processed, and analyzed using the SPSS (Statistical Package for Social Sciences) version 27 for Windows® (IBM SPSS Inc, Chicago, IL, USA). Categorical variables were conveyed as frequency with percentage while continuous variables were described as mean and standard deviation (SD) or median with interquartile range (IQR). Quantitative data were tested for normality by Kolmogorov-Smirnov test. The categorical variables were contrasted utilizing Chi-square test or Fisher’s exact test. To compare continuous variables among groups, Student’s t test, Mann-Whitney U test and Friedman test were utilized. The statistical significance of the difference between two means assessed twice for the same research group was eval‎uated using a paired t-test or and Wilcoxon signed-rank test. P value ≤ 0.05 was considered significant.

Results

The current study comprised 30 patients with DRE who completed the 3 months clinical trial. There were no major side effects that led to withdrawal from the clinical trial prior to the last assessment. Enrolled patients were divided into two groups. Each group included 15 patients and only patients in group one (arm I) received L-carnitine supplementation in addition to KDT.

Regarding CSSS, there was a significant decrease in CSSS in all studied patients after intervention (the range decreased from an initial of 19–118 to 10–99 after intervention with a P-value of 0.025). Nevertheless, comparison between the two studied groups after 3 months follow up revealed no significant difference (P-value = 0.097).

As regards the anthropometric measurements, the current study showed significant increase in weight z-score and height z-score with non-significant change in BMI z-score after 3 months of KD initiation (with P-values of 0.002, 0.002 and 0.06 respectively).

Significant increase in antral length in the patients who received KD with L-carnitine supplementation after intervention is demonstrated in Table 1. On the other hand, there was no significant difference regarding antral length in the patients who only received KD upon follow up (P-value 0.925).

결과

본 연구는 DRE를 진단받은 30명의 환자가 3개월 임상 시험을 완료한 것을 대상으로 진행되었습니다. 마지막 평가 전까지 임상 시험에서 탈락으로 이어진 주요 부작용은 없었습니다. 등록된 환자는 두 그룹으로 나누어졌습니다.

각 그룹에는 15명의 환자가 포함되었으며,

그룹 1(군 I)에 속한 환자만 KDT와 함께

L-카르니틴 보충제를 추가로 투여받았습니다.

CSSS와 관련하여, 개입 후 모든 연구 대상 환자에서 CSSS가 유의미하게 감소했습니다(초기 19–118에서 개입 후 10–99로 감소했으며, P-값 0.025). 그러나 3개월 추적 관찰 후 두 그룹 간 비교에서는 유의미한 차이가 관찰되지 않았습니다(P-값 0.097).

인체 측정 결과,

본 연구에서는 KD 시작 후 3개월 후 체중 z-점수와 신장 z-점수에서 유의미한 증가가 관찰되었으나 B

MI z-점수에서는 유의미한 변화가 없었습니다(P-값 각각 0.002, 0.002, 0.06).

L-카르니틴 보충제를 함께 투여받은

KD 치료 환자의 위장관 길이(antral length)가

유의미하게 증가한 것은 표 1에 제시되어 있습니다.

반면, KD만 투여받은 환자의 위장관 길이는

추적 관찰 시 유의미한 차이가 없었습니다(P-값 0.925).

Table 1 Comparison between the patients received KD with L-carnitine supplementation at time of enrollment and after intervention regarding the antral length assessed by ultrasound.

Full size table

Additionally, Table 2 shows a significant negative correlation between the antral length by ultrasound and GI symptoms score in all cases and the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with clinical improvement of GI symptoms. Additionally, there was a significant positive correlation between the antral length by ultrasound and Bristol stool score in all cases and a distinct positive (almost significant) with the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with higher Bristol stool score hence a softer stool consistency. Also, there was a significant positive correlation between the antral length by ultrasound and frequency of defecation in KD with L-carnitine supplementation group only after intervention.

Table 2 Correlation between antral length by ultrasound and GI symptoms score, Bristol stool scale and frequency of defecation after intervention.

Full size table

Worth noting here is that no significant difference was detected between the two studied groups regarding initial laxative use. Additionally, the correlation studies showed no significant correlations between the KD ratio and frequency of defecation, Bristol stool scale, vomiting score, GI symptoms` score and antral length after intervention in all patients.

Regarding 24-hour dietary recall Table 3 revealed that there was a positive correlation between fibers content in 24 h dietary recall and antral length after intervention in KD with L-carnitine supplementation group indicating that an increase in fibers content in 24 h dietary recall was associated with higher antral length, but there was no correlation between antral length by ultrasound and KD ratio or the other micronutrients. On the other hand, there was a significant negative correlation between GI symptoms score and 24 h dietary contents of potassium and fibers with P-values of 0.027 and 0.016 (respectively), that indicates the higher potassium or fibers dietary contents, the lower the GI symptoms score.

Table 3 Correlation between antral length by ultrasound and 24 h dietetic recall including KD ratio and micronutrients after intervention.

Full size table

As shown in Table 4, there was highly significant increase in the of frequency of defecation in KD with L-carnitine supplementation group by 50% in comparison to KD only group that showed decrease in frequency of defecation per week by 33%. Although there was a decrease in the median (IQR) of GI symptoms score in the patients on KD with L-carnitine supplementation in comparison to KD only group indicating clinical improvement in GI symptoms, and an increase in the median (IQR) of the Bristol stool scale indicating that the stool was softer, these results didn’t reach statistical significance.

Table 4 Comparison between the two studied groups regarding the rate of change in GI symptoms score, Bristol stool scale and frequency of defecation after intervention.

Full size table

Considering serum lipid profile result, Table 5 shows there was highly significant increase in HDL levels after intervention in the L-carnitine supplemented group, while serum cholesterol, LDL and triglycerides results were comparable before and after intervention.

Table 5 Comparison between the patients received KD with L-carnitine supplementation regarding fasting lipid profile at time of enrolment and after intervention.

Full size table

Discussion

The aim of the current study was to assess the effect of implementing L-carnitine as an adjuvant therapy with KD on gastric emptying in children with DRE, and to assess its protective effect of L-carnitine on bowel function and habits. Previous data is scarce in this domain; thus, the current study can be considered a pioneer in studying the effect of L-carnitine on gastro-intestinal symptoms in pediatric patients on KDT.

The significant improvement in CSSS in our series of studied DRE patients on KDT comes in agreement with several previous research. Recently, El-Rashidy and co-researchers reported a significant decrease in the severity of the seizure after KDT22. Similar finding was reported by Nassar and collaborators who studied twenty-one patients on KDT, and their results showed more than 50% reduction in their seizures23.

The fact that L-carnitine supplementation didn`t add to the patients` seizure control was previously reported by Selter and collaborators who studied carnitine supplementation as one of dietary modifications to improve seizure control in patients on KDT and reported that this dietary modification wasn`t ideal for improving seizure control24. On the other hand, the research of Fukuda and co-researchers showed that there was a significant negative correlation between blood ammonia and free carnitine concentrations in epileptic children (P = 0.003) and this high serum level of ammonia was associated with increased severity of seizures in their series of patients25. The work of the latter authors has opened the field for further research regarding the role of L-carnitine supplementation in seizure control.

Regarding L-carnitine supplementation, the current results showed that there was a decrease in the median (IQR) of GI symptoms score in the patients on KD with L-carnitine supplementation in comparison to KD only group indicating clinical improvement in GI symptoms. There was also an increase in the median (IQR) of the Bristol stool scale indicating that the stools were softer. These results although distinct, didn’t reach statistical significance. Nevertheless, the current study showed a highly significant increase in frequency of defecation (50%) in KDT with L-carnitine supplementation group in comparison to 33% in KD only group.

In 2017, Murata and collaborators reported that serum carnitine level was negatively correlated with severity of constipation in 27 patients; age range, 2 to 45 years with severe motor and intellectual disabilities, and it was significantly lower in the constipation group compared to the non-constipation group8. This was attributed to the involvement of L-carnitine in mitochondrial transport of fatty acids thus its deficiency affects multiple organs including the smooth muscles in the gastrointestinal tract. Murata and coresearchers also added that infants on a diet deficient in carnitine, had gastrointestinal dysmotility manifested by postprandial vomiting, oral drooling and delayed gastric emptying and infrequent bowel movements8.

As regards antral length, the current results revealed a significant increase in antral length in the patients who received KD with L-carnitine supplementation after intervention in comparison to the time of enrolment, while there was no significant change noticed in the non-supplemented group. Additionally, there was a negative correlation between antral length and GI symptoms score in all studied patients and the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with clinical improvement of GI symptoms. This could be explained by the fact that longitudinal smooth muscles contractions cause increase in its length26 these contractions improve gastric emptying and provide proper food mixing.

A significant positive correlation between enteral length and Bristol stool score was demonstrated in all studied patients and a distinct positive one in the group who received KD with L-carnitine supplementation indicating that an increase in antral length was associated with higher Bristol stool score thus a softer stool consistency. Moreover, a positive correlation between the antral length and frequency of defecation per week was found in KD with L- carnitine supplementation group denoting that an increase in antral length was associated with more frequent defecations.

A significant positive correlation between fiber content in 24 h dietetic recall and antral length after intervention in KD with L-carnitine supplementation group indicating that an increase in fiber content in 24 h dietary recall was associated with higher antral length. Contrary to these results, Gill and collaborators, showed that dietary fibers increase gut luminal viscosity and consumption of viscous dietary fibers, alter transit time in the upper gut, including decreasing gastric emptying rate and modulating small intestinal transit27. Nevertheless, the current results can be supported by the previous literature data on fifty-six chronically constipated children (not on KDT) which showed that the children who received cocoa husk (fibers) supplements tended to increase the number of bowel movements more than the children of the placebo group28.

Inadequate fiber intake in children on KDT is poorly understood and could go beyond constipation and gastrointestinal discomfort29. Moreover, a study by Lopez and collaborators found that patients with constipation tended to have higher incidence of hypokalemia but these results didn’t reach statistical significance30. In this domain, the current study revealed a significant negative correlation between GI symptoms scores and 24 h dietary contents of potassium and fibers in all studied patients. These results signify that the higher potassium and fibers dietary contents, the lower the GI symptoms score which indicates clinical improvement. Although, only scarce data had been found to highlight the correlation between 24 h macronutrient or micronutrients dietary contents of patients on KDT and GI symptoms, the current results highlight the importance of dietary potassium and fibers for better gut function.

On studying the effect of L-carnitine on fasting lipid profile, our study showed that the patients who received KD with L-carnitine supplementation showed highly significant increase in HDL level after intervention. On the other hand, the comparison between both groups regarding Cholesterol, LDL and TG levels showed no significant difference at time of enrolment and after intervention. This protective effect of L-carnitine is of utmost importance since increase in total cholesterol and triglyceride concentrations upon KD therapy has been previously reported in children21. Moreover, the present study agrees with a study performed on 25 children with type 1 diabetes mellitus and revealed that L- carnitine supplementation caused a significant decrease in serum total cholesterol and LDL cholesterol and showed a significant increase in HDL serum levels31.

Finally, regarding the results of anthropometric measurements, the present study showed significant increase in weight z-score and height z-score with non-significant change in BMI z-score after 3 months of KD initiation. These results agree with El-Rashidy and collaborators who reported that there was significant increase in the weight, z-score for weight, height, and z score for height with non-significant change in BMI and BMI z-score after KD treatment22. Additionally, Nassar and co-researchers reported that there was non-significant increase in z-score for weight, z-score for height and BMI after 6 months of KD. Thus, we highlight the importance of maintaining proper physical growth assessment during KDT23.

In conclusion, although L-carnitine supplementation for pediatric DRE didn`t improve the seizure control during KDT, this supplementation improved stool consistency and increased the frequency of defecation. There was a positive correlation between antral length and improvement of the gastro-intestinal symptoms in those patients. Additionally, L-carnitine supplementation has a positive effect on fasting lipid profile since it led to a significant increase in HDL levels in pediatric patients on KDT. Further longer term, larger scale and preferably multi-center studies are recommended to explore additional benefits, meanwhile it is prudent to advise L-carnitine supplementation for such patients.

논의

본 연구의 목적은 DRE를 가진 어린이에서 KD와 병용 요법으로 L-카르니틴을 투여했을 때 위 배출에 미치는 영향을 평가하고, L-카르니틴의 장 기능 및 배변 습관에 대한 보호 효과를 평가하는 것이었습니다. 이 분야에서의 기존 데이터는 매우 제한적이며, 따라서 본 연구는 KDT를 받는 소아 환자에서 L-카르니틴의 위장관 증상에 미치는 영향을 연구한 선구적인 연구로 볼 수 있습니다.

본 연구에서 KDT를 시행 중인 DRE 환자의 CSSS(발작 심각도 척도)에서 유의미한 개선이 관찰된 것은 이전 연구 결과와 일치합니다. 최근 El-Rashidy와 공동 연구진은 KDT 후 발작의 심각도가 유의미하게 감소했다고 보고했습니다22. Nassar와 공동 연구진도 KDT를 시행 중인 21명의 환자를 대상으로 연구한 결과, 발작 빈도가 50% 이상 감소했다고 보고했습니다23.

L-카르니틴 보충이 환자의 발작 조절에 추가적인 효과를 보이지 않았다는 점은 Selter와 동료들이 KDT를 받는 환자의 발작 조절을 개선하기 위한 식이 조절 방법 중 하나로 카르니틴 보충을 연구한 결과에서도 보고되었습니다. 이 연구에서는 이 식이 조절 방법이 발작 조절 개선에 이상적이지 않다고 결론지었습니다24. 반면, Fukuda와 공동 연구자들은 간질 아동에서 혈중 암모니아 농도와 자유 카르니틴 농도 사이에 유의미한 음의 상관관계가 있음을 보여주었습니다 (P = 0.003), 그리고 이 높은 혈청 암모니아 수치는 그들의 환자 시리즈에서 발작의 심각도와 연관되었습니다25. 후자의 연구자들은 L-카르니틴 보충제의 발작 조절 역할에 대한 추가 연구의 분야를 열었습니다.

L-카르니틴 보충에 관하여, 현재 결과는 KD 단독 그룹에 비해 KD와 L-카르니틴 보충을 받은 환자에서 위장 증상 점수의 중간값(IQR)이 감소했으며, 이는 위장 증상의 임상적 개선을 나타냈습니다. 또한 브리스톨 변비 척도의 중간값(IQR)이 증가해 변이 더 부드러워졌음을 나타냈습니다. 이 결과는 명확했지만 통계적 유의미성에 도달하지는 않았습니다. 그럼에도 불구하고 현재 연구에서는 L-카르니틴 보충제를 투여받은 KD 그룹에서 배변 빈도가 50%로 증가한 반면, KD만 투여받은 그룹에서는 33%로 증가해 통계적으로 유의미한 차이를 보였습니다.

2017년 Murata와 동료들은 2세에서 45세 사이의 중증 운동 및 지적 장애를 가진 27명의 환자에서 혈청 카르니틴 수치가 변비 심각도와 음의 상관관계를 보였으며, 변비 그룹에서 비변비 그룹에 비해 유의미하게 낮았다고 보고했습니다8. 이는 L-카르니틴이 지방산의 미토콘드리아 운반에 관여하기 때문에 그 결핍이 소화관 평활근을 포함한 여러 장기에 영향을 미치기 때문으로 해석되었습니다. Murata와 공동 연구자들은 카르니틴 결핍 식이를 섭취한 영아에서 식후 구토, 구강 침 흘림, 위 배출 지연 및 배변 빈도 감소와 같은 소화관 운동 장애가 나타났다고 추가로 언급했습니다8.

위체부 길이에 관해서는, 현재 연구 결과 KD에 L-카르니틴 보충제를 투여받은 환자들은 개입 후 위체부 길이가 등록 시점과 비교해 유의미하게 증가했으며, 보충제를 투여받지 않은 그룹에서는 유의미한 변화가 관찰되지 않았습니다. 또한, 모든 연구 대상 환자 및 KD와 L-카르니틴 보충제를 투여받은 그룹에서 위장관 증상 점수와 위장관 길이 사이에 음의 상관관계가 관찰되었으며, 이는 위장관 길이 증가가 위장관 증상의 임상적 개선과 연관되어 있음을 시사합니다. 이는 장의 평활근 수축이 그 길이를 증가시키기 때문일 수 있습니다26. 이러한 수축은 위 배출을 개선하고 적절한 음식 혼합을 제공합니다.

모든 연구 대상 환자에서 위장관 길이와 브리스톨 변비 점수 사이에 유의미한 양의 상관관계가 관찰되었으며, KD와 L-카르니틴 보충제를 투여받은 그룹에서는 명확한 양의 상관관계가 나타났습니다. 이는 위장관 길이의 증가가 더 높은 브리스톨 변비 점수와 연관되어 변의 일관성이 더 부드러워졌음을 의미합니다. 또한 KD와 L-카르니틴 보충제를 투여받은 그룹에서 위장 길이と 주당 배변 횟수 사이에 양의 상관관계가 발견되었으며, 이는 위장 길이 증가가 더 빈번한 배변과 연관되어 있음을 나타냅니다.

KD와 L-카르니틴 보충제를 투여받은 그룹에서 24시간 식이 회상 조사에서의 식이 섬유 함량과 개위부 길이 사이에 유의미한 양의 상관관계가 관찰되었으며, 이는 24시간 식이 회상 조사에서의 식이 섬유 함량 증가가 개위부 길이 증가와 연관되어 있음을 나타냅니다. 이 결과와 달리, Gill과 동료들은 식이 섬유가 장 내강 점도를 증가시키고 점성 식이 섬유의 섭취가 상부 장의 통과 시간을 변화시키며, 위 배출 속도를 감소시키고 소장 통과 시간을 조절한다고 보고했습니다27. 그러나 현재 결과는 KDT를 받지 않은 만성 변비 아동 56명을 대상으로 한 이전 문헌 데이터와 일치합니다. 이 연구에서 코코아 껍질(식이 섬유) 보충제를 복용한 아동은 위약 그룹에 비해 배변 횟수가 더 증가하는 경향을 보였습니다28.

KDT를 섭취하는 어린이의 식이 섬유 섭취 부족은 잘 이해되지 않으며, 변비와 위장관 불편감을 넘어 더 심각한 문제를 초래할 수 있습니다29. 또한 Lopez와 동료들의 연구에서는 변비 환자가 저칼륨혈증 발생률이 높았지만, 이 결과는 통계적 유의성을 달성하지 못했습니다30. 본 연구에서는 모든 연구 대상 환자에서 위장 증상 점수와 24시간 식이 칼륨 및 식이 섬유 함량 사이에 유의미한 음의 상관관계가 관찰되었습니다. 이 결과는 칼륨과 식이 섬유 섭취량이 높을수록 위장 증상 점수가 낮아져 임상적 개선을 나타냅니다. 그러나 KDT를 받는 환자의 24시간 매크로영양소 또는 미세영양소 섭취량과 위장 증상 간의 상관관계를 강조하는 데이터는 제한적입니다. 그럼에도 불구하고 현재 결과는 장 기능 개선을 위해 식이 칼륨과 식이 섬유의 중요성을 강조합니다.

L-카르니틴이 공복 지질 프로파일에게 미치는 영향을 연구한 결과, KD와 L-카르니틴 보충제를 투여받은 환자들은 개입 후 HDL 수치가 유의미하게 증가했습니다. 반면, 두 그룹 간 콜레스테롤, LDL 및 TG 수치를 비교한 결과, 등록 시점과 개입 후 모두 유의미한 차이는 관찰되지 않았습니다. L-카르니틴의 이 보호 효과는 KD 치료 시 총 콜레스테롤 및 트리글리세라이드 농도가 증가한다는 이전 연구 결과21와 일치합니다. 또한 본 연구는 1형 당뇨병을 가진 25명의 어린이를 대상으로 한 연구와 일치하며, L-카르니틴 보충이 혈청 총 콜레스테롤 및 LDL 콜레스테롤 수치를 유의미하게 감소시키고 HDL 혈청 수치를 유의미하게 증가시켰다는 결과를 보여주었습니다31.

마지막으로, 인체 측정 결과에서 본 연구는 KD 시작 후 3개월 후 체중 z-점수와 신장 z-점수가 유의미하게 증가했으며, BMI z-점수는 유의미한 변화를 보이지 않았습니다. 이 결과는 El-Rashidy와 동료들이 KD 치료 후 체중, 체중 z-점수, 신장, 신장 z-점수가 유의미하게 증가했으며 BMI와 BMI z-점수는 유의미한 변화를 보이지 않았다고 보고한 내용과 일치합니다22. 또한 Nassar와 공동 연구자들은 KD 시작 후 6개월 후 체중 z-점수, 신장 z-점수 및 BMI가 유의미한 증가를 보이지 않았다고 보고했습니다. 따라서 우리는 KDT 동안 적절한 신체 성장 평가를 유지하는 것이 중요함을 강조합니다.23.

결론적으로,

소아 DRE 환자에게 L-카르니틴 보충제가 KDT 동안 발작 통제에 개선을 가져오지 않았지만,

이 보충제는 대변 일관성을 개선하고

배변 빈도를 증가시켰습니다.

위장관 증상의 개선과 위장관 길이 사이에

양의 상관관계가 관찰되었습니다.

또한

L-카르니틴 보충은 KDT를 받는 소아 환자에서 HDL 수치의 유의미한 증가를 초래하여

공복 지질 프로파일 개선에 긍정적인 영향을 미쳤습니다.

추가적인 장기적, 대규모 연구, 특히 다기관 연구가 추가적인 혜택을 탐구하기 위해 권장되며,

그 사이에는 이러한 환자에게 L-카르니틴 보충을 권장하는 것이 적절합니다.

Study limitations

Although the current findings are consistent and coherent, strongly indicating the external validity of the study, we do recommend future preferably large prospective clinical trials, to increase their internal validity.

The current study has its own limitations, no comparisons were made with patients on traditional AEDs or placebo and the short follow up duration are among these limitations.

Data availability

‘The datasets generated and /or analyzed during current study available from the corresponding author upon reasonable request.

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