Energy exchangers with LCT as a precision method for diet control in LCHADD

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (LCHADD) is a rare genetic disease. The LCHADD treatment is mainly based on special diet. In this diet, energy from long-chain triglycerides (LCT) cannot exceed 10%, however energy intake from the consumption of medium-chain triglycerides (MCTs) should increase. The daily intake of energy should be compatible with energy requirements and treatment should involve frequent meals including during the night to avoid periods of fasting. In fact, there are no recommendations for total content of LCT in all of the allowed food in the LCHADD diet. The aim of the study was to present a new method of diet composition in LCHADD with the use of blocks based on energy exchangers with calculated LCT content. In the study, the diet schema was shown for calculating the energy requirements and LCT content in the LCHADD diet. How to create the diet was also shown, based on a food pyramid developed for patients with LCHADD. The blocks will make it possible, in a quick and simple way, to create a balanced diet which provides adequate energy value, essential nutrients and LCT content. This method can be used by doctors and dietitians who specialize in treating rare metabolic diseases. It can also be used by patients and their families for accurate menu planning with limited LCT content.

LCHADD (long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency) is a rare genetic disease, inherited in an autosomal recessive pattern.The disease is caused by 3-hydroxyacyl-CoA dehydrogenase deficiency, an enzyme complex taking part in mitochondrial β-oxidation of fatty acids. 1 Deficiency of the enzyme contributes to accumulation of toxic metabolites which can lead to metabolic decompensation, associated with damage to the mechanisms of the body homeostasis.This results in the occurrence of life-threatening disorders in the functioning of one or more organs.Symptoms of metabolic decompensation are: myopathy, cardiomyopathy, hepatitis, peripheral neuropathy and retinitis pigmentosa, as well as hypoketotic hypoglycemia. 2,3Clinical symptoms result from a significant reduction in energy production in the long-chain triglycerides (LCT), the toxic effects of carnitine acyl derivatives and the incidence of hypoglycemia. 4hese symptoms occur or worsen due to dietary mistakes and in a time of increased catabolism during a course of fasting, an infectious disease, stress or vaccinations. 5t is estimated that in Poland about 400 newborns are born each year with metabolic defects. 6The expected incidence of LCHADD in Poland is around 1 in 120,000 newborns.It most frequently occurs in Pomeranian Voivodeship (1 in 16,900 births). 7Since 2014, testing aimed at detection of 21 inborn metabolic defects, including LCHADD, has been applied to all newborns in Poland. 8Presently, thanks to neonatal screening, it is possible to diagnose the disease in children before symptoms occur.In this case, application of the appropriate pharmacological and dietary treatment prevents or reduces the risk of the occurrence of clinical symptoms of the disease, its complications and sudden death.

The purpose of the study
The aim of the study is to present a new method for preparing the menu in LCHADD using blocks based on energy exchangers with calculated LCT content.Currently, there are no dietary computer programs or scientific studies determining the total amount of LCT in all products allowed in the LCHADD diet.Patients should not have the option of self-modifying their own diet because of the probability of making mistakes.Blocks will allow a faster and easier way to prepare a balanced menu in terms of energy value and essential nutrients, as well as the LCT content in the diet.

Nutrition in LCHAD deficiency
Patients with LCHADD require application of a recommended dietary caloric intake with limited LCT.

Energy requirements
In patients with LCHADD, it is important that the energy nutrient intake from the diet is correct and fasting is avoided by taking frequent meals, including at night, especially in the infancy period and during infection. 9,10On the other hand, a large energy nutrient supply is also unfavorable as it leads to development of overweight and obesity in patients. 9

Age
Rest periods between meals break per day break per night   5 The authors recommend that in states of exacerbation, rest periods between meals should be shorter.
Energy requirements should be set individually for each patient with LCHADD, taking into account age, weight, height and physical activity. 11][14] Table 2 shows the energy requirements for healthy infants in the first year of life while Table 3 shows the energy needs for healthy children between 1 and 10 years of age according to the WHO. 14Table 4 presents the energy requirements for healthy adults with moderate physical activity developed on the basis of Polish norms. 12lthough the daily energy requirements given in the standards and recommendations are determined for healthy people, these values can be used for preparing a diet for patients with LCHADD, including monitoring the energy supply from the diet and the patient's health and controlling body weight.

The structure of the diet
The optimal LCHADD diet is considered to be norm-caloric, norm-protein and high-carbohydrate with a limited content of LCT -up to 10% of the energy nutrient intake in daily food rations. 9,13Due to the reduced percentage of LCT in the diet, the intake of medium chain fatty acids (medium-chain triglycerides, MCT) should be increased up to 10-25%.The appropriate distribution of the meals throughout the day should also be taken into account (Table 1).
In the case of overweight and obesity in children with LCHADD, a higher intake of protein and a proportional reduction in the calorie intake from carbohydrates is recommended in order to maintain proper metabolic balance. 9,15Gillingham et al. observed a positive impact of higher protein intake in the diet on energy balance and metabolic control in patients with LCHADD. 15However, more studies are needed to confirm these observations.Table 5 shows the structure of the diet in LCHADD developed on the basis of the current scientific findings.

MCT oil
In the treatment of LCHADD, the use of MCT oil reduces the risk of catabolism caused by peri-  ods of fasting, and has a beneficial effect on improving the fatty acids profile and acylcarnitine concentration in the blood. 9The MCT oil should cover 10-20% of the daily caloric intake. 13The study of Gillingham et al. in children with LCHAD deficiency whose caloric intake of LCT was ≤ 10% of the total calories in daily food rations and the intake of MCT was ≥ 10% of the calories in daily food rations, indicated lower concentrations of the toxic acyl derivatives of carnitine. 16edium chain fatty acids play an important role during physical effort in patients with LCHADD and can provide an alternative source of energy for muscular work.Insufficient calorie intake both before and during doing physical exercise can lead to cardiomyopathy and rhabdomyolysis. 17,18Some authors suggest that supplementation of MCT with a dose of 0.5 g per kg of the non-fat body mass during increased physical activity can prevent the occurrence of metabolic disorders in children with LCHADD. 9A study by Gillingham et al. demonstrated that supply of MCT immediately before exercise improved exercise tolerance and reduced the risk of rhabdomyolysis in 6 out of 10 patients with disorders of fatty acid oxidation disorders (FAODs). 19 study by Behrendt et al. indicated that the intake of MCT before doing exercise increased medium chain fatty acid oxidation, caused a reduction in glucose oxidation and a reduction of the burden on the heart during exercise in 8 of 11 patients with LCHADD, compared to providing exclusively carbohydrates.17 However, the study's authors point out that, in practice, MCT intake (0.3-0.4 per kg) before physical effort contributes to their greater use, especially when the MCT are given with a beverage containing carbohydrates.This allows patients with FAODs to safely perform the training for up to one hour of moderate intensity (60-70% of maximum heart rate, HRmax).
An example of food for a special medical purpose (FSMP) which can be administered prior to the scheduled physical effort is MCT Procal. 1 portion (16 g) provides 105 kcal, 10 g of MCT and 0.14 g of LCT. 20Fantomalt is an example of a FSMP containing a mixture of carbohydrates in which the complex ones constitute 90%.Three measuring spoons of this preparation (3 × 5 g) provide 57 kcal.Fantomalt in its composition consists mainly of maltodextrin with less maltose and glucose.The preparation can be diluted with water or juice or added to a ready dish.The number of portions of these FSMP should be selected individually for each patient depending on their physical activity.

Linoleic acid (LA, C18:2, omega-6) and α-linolenic acid (ALA, C18:3, omega-3)
Adequate intake of fatty acids LA and ALA with the diet is particularly important and should be included in the total consumption of LCT with the diet.LA and ALA prevent diseases of the retina, peripheral neuropathy, growth deficit and dermatitis. 9,13According to the recommendations made by the European Food Safety Authority (EFSA) of 2013, the demand for fatty acids LA and ALA in healthy children up to 12 months of age, is 4 and 0.5% of the total energy intake, respectively. 21,22However, according to the recommendations of German, Austrian and Swiss Experts (DACH), intake of LA with the diet for children over 4 months of age up to 12 months of age should constitute 3.5% of the energy requirements.In the diet of children between 1 and 4 years of age and between 4 and 10 years of age the intake of LA should constitute 3% and 2.5% of the total energy requirements, respectively. 23Because of the risk of deficiency of essential fatty acids (EFA), their intake in the diet in LCHADD should be similar to the dietary intake of healthy children and adults.][26] The use of linseed oil, camelina oil or walnut oil, in comparison with rapeseed oil may reduce the accumulation of the various acyl-CoA intermediates, preventing peripheral neuropathy. 9Spiekerkoetter et al. recommend the use of walnut oil, soybean oil or wheat germ oil for an optimal ratio of omega-6 to omega-3. 5 However, in the studies of Charles et al. in patients with the β-oxidation of fatty acids disorder, it has been indicated that the combination of linseed oil and walnut oil is more favorable than rapeseed oil. 27It is associated with a higher proportion of essential fatty acids (EFAs) in linseed oil and walnut oil, compared to rapeseed oil.  5.Estimated energy structure of the diet in LCHADD developed on the basis of the current scientific findings 5,13,15,24,25 *Some authors suggest a higher intake of protein and a proportional reduction in the calorie intake from carbohydrates in patients who have problems with maintaining a healthy weight.
seeds in one energy exchanger (1 EE ≈ 50 kcal, discussed later in the paper).
In connection with the recommendations concerning adequate dietary intake of essential fatty acids in LCHADD, the market offers food for special medical purposes, which in their composition in addition to MCT also contain EFAs, e.g.Lipistart. 28

Supplementation with DHA acids
Opinions regarding the dietary intake of DHA in LCHADD are divided.Some authors recommend DHA acid as a dietary supplement, due to its negligible dietary intake with the intake in the diet with limited LCT.In the research studies of Gillingham et al. of children with LCHADD (n = 14), the only source of DHA in the diets were dietary supplements. 16upplementation with DHA ethyl esters, about 100 mg/day can be considered, due to the possibility of improving visual acuity. 9Spiekerkoetter et al. recommend dietary supplementation with DHA at a dose of 60 mg per day for children weighing less than 20 kg and 120 mg per day for children weighing more than 20 kg. 5

Cornstarch
The use of raw corn starch in the diet of patients with LCHADD reduces the risk of nocturnal fasting. 9Consumption of raw starch before bedtime prevents the morning hypoglycemia after an overnight break in nutrition. 9,24orn starch in the diet of children with LCHADD below 2 years of age is recommended in doses of 1-1.5 g per kg of body mass.At the age of 2 years of age, the dose is gradually increased (1.75-2.5 g per kg of body mass). 9,24,25,29piekerkoetter et al. believe that routine enriching of the diet with corn starch and glucose polymers is not recommended, yet may be a part of an oral prophylaxis and treatment in emergency cases related to the risk of clinical symptoms caused by too long a night break. 5The oral intake of raw corn starch is not recommended for infants less than 9 months of age, due to the insufficient action of pancreatic enzymes. 30

Carnitine supplementation
For patients with carnitine deficiency, supplementation of carnitine may be considered. 9Gillingham et al. found no sign of toxicity during application of carnitine at a dose of 50 mg per kg of body mass. 24However, there is no published data concerning the potential benefits of supplementation with long term carnitine in LCHADD.It is forbidden to use it during acute metabolic decompensation. 5,9

Intake of glucose intravenously
The occurrence of metabolic decompensation in a patient with LCHADD frequently requires hospitalization and ensuring the adequate intake of glucose as an energy source.When the oral intake of carbohydrates before hospitalization does not give the expected results, the patient receives an intravenous infusion of glucose in amounts of 8-10 mg/kg of body mass/min.The intake Grams of selected fatty acids and ratio of omega-6 to omega-3 in 1EE = in some oils   7. The contents of LA, ALA, LCT and the ratio of omega-6 to omega-3 in vegetable oils and linseeds in one energy exchanger (1 EE ≈ 50 kcal) 1 6.0 g of vegetable oil is about 1 teaspoon, and 9.0 g of flaxseed is less than 1 spoon, however in LCHADD, all food products should be weighed. of glucose stimulates insulin secretion and inhibits peripheral lipolysis.However, some patients with abnormal response to insulin should additionally be supplemented with insulin therapy without diminishing the adequate dietary intake of glucose. 9,31

Supplementation with vitamins and minerals
Intake of certain vitamins and minerals in the form of dietary supplements, especially fat-soluble vitamins, is recommended in the case of low dietary intake or documented deficiency. 5It is important that fat-soluble vitamins were served with meals containing fat, in this case MCT, to be absorbed better.

The method developed for dietary control in LCHADD
LCHADD treatment is based mainly on dietary therapy.Parents or guardians of a sick child should have knowledge concerning the allowed and forbidden products.The aim of dietary therapy in LCHADD is to adequately balance the diet as regards energy values and the diet structure, i.e. adequate intake of proteins, fats and carbohydrates and the content of LCT.The available Polish studies give the nutritional value of foods and specify the composition of fatty acids in food products.However, the calculation of the sum of LCT, which is important in preparing a menu in LCHADD, has to be done independently and it is rather time consuming. 32ue to the lack of a clear and easy method for preparing the diet in LCHADD, this paper presents a new method for preparing the menu in this rare metabolic disease.
The basis for dietary calculations in LCHADD is correctly calculating the energy requirements individually for each patient.Meals should be spread evenly throughout the day and with adequate caloric content, in order to prevent a starvation period.Parents and caregivers of children with LCHADD often make dietary mistakes.The most common error, resulting from the fear of the occurrence of fasting and symptoms connected with it, is to give an excessive amount of simple carbohydrates, which can lead to overweight or obesity in a patient.Treatment of obesity or overweight in patients with LCHADD is difficult and may be limited due to the possibility of the occurrence of disease symptoms resulting from catabolism.In the body of a patient with LCHADD, at the time of fasting there is no production of ketone compounds, which substitute a substrate for the brain in the case of a deficiency of glucose.Therefore controlling energy intake, the LCT content in daily food rations and an appropriate diet structure in LCHADD are important elements in preventing both catabolism and obesity.
The developed block method of preparing a menu in LCHADD applies energy exchangers (EE).One energy exchanger is the weight of the product expressed in g, which provides 50 kcal (210 kJ).LCT content was calculated with regard to the energy exchangers of various food products.The values of energy exchangers and LCT are based on data from the Polish "Tables of Composition and Nutritional Value of Food", published in 2005. 32nergy requirements calculated as the number of energy exchangers are shown in Table 8.The dose of LCT (g/day) sufficient for energy requirements was calculated, depending on the desired LCT energy input in the diet.
In the Polish study, the total LCT value is not calculated, yet the contents of each of 26 individual fatty acids for particular food products are given. 32On the basis of the tables, LCT calculations were made by summing up the fatty-acids containing 12 and more carbon atoms in the chain in different food products.Then the LCT content in 100 g of food was converted into the LCT content in a portion of products including 50 kcal.
Safe products which can be used in the diet in LCHADD were regarded to be all the products in which the LCD content does not exceed 2 g in 100 g.Other products have been conventionally classified as hazardous.Unsafe products are marked in red, and some of them are presented in the form of blocks as some of them may be used in limited and controlled amounts in the LCHADD diet, e.g.linseed oil, walnut oil, soybean oil and beef.
Selection of food products allowed in LCHAD deficiency is important due to the proper balance of the diet in terms of the caloric content, LCT input in daily food Table 10.The energy expenditure (-EE) of various physical activities calculated for a person weighing about 60 kg 33,34 Fig. 1.Food pyramid for patients with LCHADD for 1500 kcal (30 EE) 1 It can use more EE from low-fat dairy products or lean meat, fish and egg white whereas the amount of food for a special medical purpose (FSMP), like Humana with MCT or Lipistart, should be proportionally reduced. 2 It can use more EE from low-fat grain products whereas the amount of carbohydrate-containing foods should be proportionally reduced. 3Flaxseed oil or walnut oil should not be used during acute metabolic decompensation.
+ Humana with MCT or Lipistart 1 EE 1 rations and proper diet structure.Blocks created based on EE and LCT content are assigned to the appropriate groups of food products according to the nutrition pyramid in LCHADD (Fig. 1).Food products are situated on 5 walls rows of blocks and the LCT content in energy exchangers is given.Each block is positioned with a drawing on its upper surface, and adjusted to a given group of food products.23 food blocks and 2 sports blocks have been developed in the new method.
A description of the blocks is presented in Table 9.
In the sports blocks the concept of energy expenditure (-EE) has been introduced, which is defined as the amount of energy expended by the human body during a given activity at a certain time.One energy expenditure (-EE) is the amount of time the activity is done expressed in min and s, which corresponds to the energy expenditure of 50 kcal (210 kJ).In contrast to energy exchangers, the shortcut of energy expenditure has a minus sign, and all the squares of energy expenditure are marked in black.Each side of the square in the sports block shows the energy expenditure of 50 kcal (210 kJ).Energy expenditures were calculated for a person weighing about 60 kg.Table 10 shows the energy expenditure of various physical activities. 33,34dequate increase of caloric content of the diet in LCHADD in relation to the planned additional vigorous exercise is one of the basic elements of the diet to prevent metabolic decompensation.For this purpose, the relevant measures of specific nutritional purposes with MCT are used and should necessarily be administered before and during exercise.Sports blocks in the form of energy expenditure will allow a quick way to determine if the daily The structure of diet: 16% energy from proteins, 60% energy from carbohydrates, 24% energy from fats, 6.7% energy from LCT, including 3.8% energy from EFAs (ALA + LA); 100 mg of DHA.
energy requirement in a patient with LCHADD should be increased depending on their physical activity.
The scheme for preparing a menu using energy exchangers with LCT Below, the description shows the exact diet nutrition plan to propose a menu for a particular patient with LCHADD using energy exchangers with LCT.
Knowing the basic data of a patient with LCHADD, i.e. age, height, body weight and level of physical activity, the energy requirement should be determined using Tables 2-4.Example of patient data: a boy with LCHADD, 6 years of age, weighing 20.8 kg, height of 120 cm, moderate level of physical activity.The daily energy requirement calculated from Table 3 for a 6 year-old-boy was 1508 kcal (≈ 1500 kcal).
The energy requirements of the patient converted to the energy exchangers and LCT content (g/d) should be read in Table 8.The energy exchangers given value for 1500 kcal is 30 EE. Daily energy intake with LCT in the diet in LCHADD should not exceed 10% of the total energy intake and should be determined individually by the patient's doctor.The given value in Table 8 for 10% of energy with LCT equals 16.7 g.This means that the LCT content in the diet should not exceed a sum of 16.7 g in a boy with LCHADD whose energy requirement equals 1500 kcal.
The intervals between meals and their number should be consulted with a doctor and a nutritionist (Table 1).
In some cases, as a night meal, a patient can be given raw corn starch prepared e.g. with cold water.The amount of corn starch depends on the weight and age of the patient.For a 6-year-old patient, weighing 20.8 kg, the starch content of the night meal is 42 g (3 EE), assuming 2 g/kg of body mass/meal.
The next stage is preparing the menu using the blocks based on EE with the calculated LCT content.The number of portions from a given group of food products should be read in the food pyramid for LCHADD patients in Fig. 1.A one-day menu for the 6-year-old boy with LCHADD (30 EE) is described in the Table 11.

Summary
The presented method of composing a menu in LCHADD with 25 blocks with LCT allows the preparation of a menu for a sick child or an adult in a very fast and precise way.This method can prove to be effective in the hands of both the doctor and the nutritionist, dealing with the dietary therapy of inborn defects of metabolism, but above all it makes it easier for the patients themselves and their families to plan and precisely control the diet in LCHADD every day.

Table 1 .
5stimated rest periods between meals depending on the age of children with LCHADD5

Table 2 .
14e energy requirements for healthy infants in the first year of life14

Table 1
presents estimated rest periods between meals depending on the age of children with LCHADD, as developed by Spiekerkoetter et al.

Table 3 .
14e energy requirements for healthy children between 1 and 10 years of age14

Table 4 .
12e energy requirements for healthy adults with a moderate physical activity (PAL = 1.6)12 Table 6presents the recommended daily dose of the vegetable oils mentioned above, depending on the age of the patient.Table7shows the contents of LA, ALA and LCT in vegetable oils and lin-

Table 6 .
5he recommended daily amount of vegetable oils such as soybean oil, wheat germ oil and walnut oil, depending on the age of the patient5 Table

Table 8 .
The energy requirements of the patient converted to the amount of energy exchangers and LCT content (g/d)

Table 9 .
Description of blocks in the developed method in LCHADD