2023 Volume 30 Issue 10 Pages 1507-1515
A one-year-and-nine-month-old Japanese boy was admitted with hypertriglyceridemia (fasting triglycerides 2548 mg/dL). After close examination, he was diagnosed with lipoprotein lipase (LPL) deficiency (compound heterozygous) and was immediately started on a fat-restricted dietary therapy. He responded well to the regimen (1200 kcal/day, 20 g fat/day) and his triglycerides decreased to 628 mg/dL within 7 days of starting the dietary therapy. It was decided to manage his illness without using any drugs because he was still an infant and responded well to a fat-restricted diet. During his hospital stay, dietitians provided him with nutritional counseling using a food exchange list, which was designed to easily calculate the fat content by including foods that are commonly served. His family quickly learned the skills to prepare a fat-restricted diet. Moreover, since dietary restrictions may have impaired the child’s growth and development, the dietitians continued to intervene regularly after the child was discharged from the hospital. The dietitians confirmed that the patient was receiving nutritional intake appropriate for his growth and discussed the dietary concerns in his daily life and how to participate in school events that involved eating and drinking. Nutritional counseling was provided every 3–4 months from disease onset to age 23 years, except for a 14-month break at age 20 years. The patient grew up without developing acute pancreatitis, a serious complication of LPL deficiency. The long-term intervention of dieticians is necessary to achieve a balance between living on a strict diet for disease management and ensuring appropriate nutritional intakes for growth/development.
Lipoprotein lipase (LPL) deficiency is a genetic disorder with an autosomal recessive pattern of inheritance. It usually presents in childhood and is characterized by severe hypertriglyceridemia and chylomicronemia. LPL deficiency is a rare disease, with a prevalence of approximately one in a million in the general population1).
LPL deficiency usually presents with abdominal pain, hepatosplenomegaly, acute pancreatitis, and eruptive cutaneous xanthomata in childhood. The disease may present directly in adulthood, and recurrent pancreatitis is one of the most debilitating complications.
The mainstay of long-term management for people with chylomicronemia is the restriction of dietary fat to ≤ 15–20 g/day with plasma triglyceride (TG) monitoring2, 3). Although strict dietary control is currently the primary treatment for chylomicronemia, it is often inadequate and challenging to maintain in the long run3, 4).
In this case report, we continued to provide nutritional counseling to a patient diagnosed with an LPL deficiency at the age of 1 year and 9 months, who had been on a fat-restricted diet from infancy to adulthood.
We report a valuable case in which dietitians gave the child long-term dietary support. Throughout the course of treatment, the child showed good dietary adherence, did not experience any growth or developmental issues, and has not developed acute pancreatitis to date.
A one-year-and-nine-month-old Japanese boy was admitted for the investigation and treatment of fasting hypertriglyceridemia. His height and weight were 84.0 cm (＋0.3 SD) and 12.0 kg (＋0.87 SD, percentage of overweight [POW 6.5%]; POW 6.5% indicates that 106.5% of the age- and sex-specific standard weight for a particular height from the Japanese national data 2000 5)), respectively. Physical examination revealed no significant signs of pallor, hepatosplenomegaly, eruptive xanthoma, retinal lipofuscinosis, or abdominal pain.
He was born in 1997, at 40-week gestation, spontaneously delivered, weighing 2962 g, with no birth abnormalities. Infancy nutrition was provided through a combination of breast milk and infant formula. He lived with his father (age 35 years) who was a company employee, his mother (age 33 years), and his older brother (age 4 years) in a peri-urban area in Kobe. There was no consanguineous family history. The parents understood the condition of their child, as clearly explained by the medical staff. Table 1 shows the laboratory data, LPL and hepatic triglyceride lipase (HTGL) activities, and immunoreactive LPL mass of the patient. The patient had markedly high fasting TG (2548 mg/dL) and low high-density lipoprotein (HDL, 10 mg/dL) and low-density lipoprotein (LDL, 27mg/dL) cholesterol levels due to increased TG-rich lipoprotein fractions and was diagnosed with primary type 1 hyperlipoproteinemia based on the WHO phenotypic classification. The patient’s Apo C-II concentration was within the normal range, and its biological function was found to be normal since the patient’s sera activated pure human LPL in vitro. The patient’s LPL activity and protein were markedly low (＜2% of normal); however, the HTGL activity and protein were within normal limits. Thus, the patient was diagnosed with LPL deficiency (Table 1). The patient had a compound heterozygote for a novel missense mutation (G105R) in exon 3 and a missense mutation (D204E) in exon 5 of the LPL gene6). His mother was heterozygous for the G105R mutation and his father for the D204E mutation, but both had normal levels of serum TG and cholesterol levels (mother: serum TG 143 mg /dL, serum Chol 170 mg/dL; father: serum TG 140 mg /dL, serum Chol 183 mg/dL).
| Patient | Control (n = 4) | |
|---|---|---|
| Serum-TG (mg/dL) | 2548 | 101±10 |
| (CM+VLDL) -TG (mg/dL) | 2445 | 38±9 |
| Serum-Chol (mg/dL) | 276 | 168±14 |
| LDL-Chol (mg/dL) | 27 | 102±16 |
| HDL-Chol (mg/dL) | 10 | 46±7 |
| Serum-apo A-I (g/L) | 0.38 | 1.20±0.19 |
| Serum-apo A-II (g/L) | 0.08 | 0.23±0.03 |
| Serum-apo B (g/L) | 0.46 | 0.82±0.20 |
| Serum-apo C-II (g/L) | 0.04 | 0.03±0.01 |
| Serum-apo C-III (g/L) | 0.10 | 0.06±0.01 |
| Serum-apo E (g/L) | 0.03 | 0.04±0.01 |
| LPL-activity (μmol/h/L) | ND | 9.8±2.5 |
| LPL-mass (ng/mL) | 3.0 | 186±46 |
| HTGL-activity (μmol/h/L) | 23.7 | 22.5±9.0 |
| HTGL-mass (ng/mL) | 1628 | 1242±517 |
As a control group for the patient, four healthy male children (age 2.1±0.9; mean±SD) were recruited with their parent’s agreement5). Abbreviations: TG, triglyceride; CM, chylomicron; Chol, cholesterol; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HTGL, hepatic triglyceride lipase; ND, not detectable.
The biological significance of both missense mutations was assessed by an in vitro study of the expression of mutant G105R LPL cDNA and D204E LPL cDNA in COS-1 cells. Both mutant LPLs were catalytically inactive and were barely released by heparin from the expressing COS-1 cells6).
TreatmentDuring hospitalization, a low-fat diet of 1200 kcal energy and 20-g fat (including 5-g medium-chain triglyceride [MCT] oil) was provided, and serum TG, which was 1640 mg/dL on admission, decreased to 628 mg/dL on the 7th day of hospitalization.
Before discharge, nutritional dietary counseling on a fat-restricted diet with a fat-to-energy ratio of 15% was provided to the family by dietitians. Table 2 shows the list of foods prepared from age 2 to 3 years. Energy settings were started at 1200 kcal (age 2 years) and increased by 100 kcal for every succeeding year. Due to increased activity in sports at the age of 12 years, the energy setting was adjusted and based on the Japanese Dietary Reference Intakes (2005 edition) to consider the amount of activity.
| Food group | Foods | Daily servings | Fat |
|---|---|---|---|
| Grain | Rice | 260 g | 1.3 g |
| Bread | 60 g | 1.9 g | |
| Potatoes and starches | Potatoes or Sweet potato | 40 g | 0.1 g |
| Fats and oils | MCT oil | 5 ml | 4.7 g |
| Seafood | Use of food exchange lists of fat | Salmon 24 g (1U) | 10 g |
| Meat | (Table 3) | Chicken tender 80 g (2U) | (5U) |
| Eggs | 2 g Fat = 1 Unit | Egg 18 g (1U) | |
| Soy foods | 5U/day | Regular tofu 40 g (1U) | |
| Dairy products | Skim milk | 40 g | 0.4 g |
| Vegetables | Green and yellow vegetable | 60 g | 0.1 g |
| Other vegetables | 130 g | 0.1 g | |
| Fruits | Fruit | 180 g | 0.2 g |
| Confectionery | Rice Flour Crackers | 5 g | 0 g |
| Candy | 10 g | 0 g | |
| Nutrients | Energy 1200kcal | ||
| Protein 45 g (15%E) | |||
| Fat 20 g (15%E) | |||
| Carbo hydrate 210 g (70%E) |
＊%E: %energy
We devised a food exchange list to serve as a guide for meal planning. This food exchange list is a teaching method to help control daily fat intake by converting one unit of food weight per two grams of fat weight.
In the case of this patient, a daily fat intake of 20 g was allowed, of which approximately 5 g was from rice, bread, dairy products, and sweets; 5 g was from MCT oil for cooking fats; and the remaining 10 g was from meat, seafood, eggs, and soy foods. The foods listed in the food exchange table are the foods that the patient’s family consumed habitually. For the protein-rich foods (e.g., nuts and cheese) or processed foods that are consumed infrequently, we instructed them on how to convert fat weight by reading the Standard Tables of Food Composition in Japan and the Nutrition Facts label of processed foods. The use of food exchange tables has simplified the calculation of daily fat intake. A food exchange list allows added flexibility with food choices and works well for the way children like to eat (Table 3).
| Food Group | Food Lists | Food weight per 2 g of fat ( = 1 unit) |
|---|---|---|
| Seafood | Cod | 500 g |
| Bonito | 100 g | |
| Sea bream | 59 g | |
| Flatfish | 91 g | |
| Salmon | 24 g | |
| Shrimp | 400 g | |
| Crab | 222 g | |
| Squid | 200 g | |
| Octopus | 286 g | |
| Clams | 200 g | |
| Meat | Chicken tender | 400 g |
| Chicken breast without skin | 16 g | |
| Chicken thigh without skin | 27 g | |
| Beef thighs without fat | 27 g | |
| Beef shoulder without fat | 38 g | |
| Pork thighs without fat | 56 g | |
| Pork shoulder without fat | 38 g | |
| Pork ham, boneless | 50 g | |
| Pork ham, loin | 14 g | |
| Pork sausage | 8 g | |
| Eggs | Egg | 18 g |
| Soy foods | Freeze-dried tofu | 6 g |
| Regular tofu | 40 g | |
| Kinugoshi tofu | 61 g |
The parents had mastered the calculations of the fat contents of various foods and meals by the time the patient was discharged.
Follow-UpAfter discharge from the hospital, nutritional counseling, including education for cooking skills (oil-free cooking methods such as boiling and steaming dishes), by dietitians was provided along with outpatient consultations every 3–4 months. Additionally, nutritional counseling was given to the parents until the child reached elementary school age, and thereafter, more information was gradually addressed directly to the child. A fixed diet was never ordered, the counseling was individualized, and the child’s recent food record was used as a basis for suggestions for dietary changes. Concomitantly, we checked the growth curve to ensure that the child was receiving adequate nutrition for proper growth and development (Fig.1).
The 2000 National Growth Survey on Preschool Children & School Health Statistics Research Source: T Isojima, N Kato, Y Ito, S Kanzaki, M Murata, Clin Pediatr Endocrinol 25: 71-76, 2016
One of the characteristics of this case was that the family had implemented strict fat control, with the fat-to-energy percentage derived from fat remaining below 10%. Extremely inadequate intake of fat can lead to a lack of energy and fat-soluble vitamins, which can induce growth disturbances; thus, we provided nutritional counseling on proper intake while ensuring not to reduce it too much.
OutcomeThe implementation of the fat-restricted diet at home showed a promising outcome, and a nutritional intake assessment using the dietary record method conducted at the age of 5 years and 6 months showed 1355 kcal of energy, 65.9 g (19%E) of protein, 8.3 g (6%E) of fat, and 242 g (75%E) of carbohydrates. During the regular checkups, from the time he was discharged until he entered elementary school, his TG level did not exceed 1000 mg/dL (nonfasting: 2.5–3.0 h after eating). Although fat restriction was strictly followed, the energy intake was lower than the recommended amount (age 5 years; 1500 kcal/day). Because the early childhood diet intake was dependent on the parents who were concerned about the elevated TG level, they were cutting back on the amount of food they provided. However, since his growth was normal, the dietitian decided to allow him to continue with his current dietary intake and a careful follow-up plan.
When the child was in elementary school, he did not eat school lunches but brought homemade lunches made with a low-fat diet. Overall, he maintained remarkably good health. However, there were three occasions, between the ages of 6 and 13 years, when his TG level exceeded 1000 mg/dL. During this period (elementary school), he was a member of a baseball club, which expanded his social relationships and opportunities to eat snacks with friends. Despite understanding the fat restriction, he was eating snacks without his parents’ permission. Dietitians provided nutritional counseling while keeping his self-esteem in mind.
From age 13 to 18 years (junior high school to high school), his TG level did not exceed 1000 mg/dL. During this period, he was a member of a soccer team and exercised regularly. Consequently, his energy intake was relatively low in relation to his activity level, and his weight and height increased slowly. During nutritional consultations, the dietitians suggested ways to increase calories, and by the age of 16 years, he had reached a standard weight and stature.
His TG level was good between the ages of 18 and 20 years. However, after the age of 20 years, he began living alone and started drinking alcohol, which increased his TG level to more than 1000 mg/dL (Fig.2). It was found out later that he had also started smoking. Additionally, he did not consult a doctor for 14 months.
He was discharged from hospital at the age of one year and nine months and did not develop acute pancreatitis nor was readmitted to the hospital. During this time he had 88 nutritional counseling.
However, he had changed his diet after marriage (age 22 years). His wife attended every nutritional consultation and received guidance from dietitians regarding his dietary regimen. His wife also understood the need for fat restriction and helped him practice his dietary regimen. Since his marriage, his TG levels had not once exceeded 1000 mg/dL again, and from the onset of the disease to the present time, he has taken nutritional counseling 88 times and has not developed acute pancreatitis during that period.
Thirty percent of LPL deficiency cases are diagnosed before the age of 1 year and more than 50% before the age of 10 years7). Patients with LPL deficiency present with severe hyperchylomicronemia, and the most common symptoms are recurrent abdominal pain, growth disturbances, and acute pancreatitis. Current lipid-lowering medications (e.g., fibrates, n-3 polyunsaturated fatty acids, and niacin) generally have minimal TG-lowering effects on patients with LPL deficiency, as they lower plasma TGs mainly by enhancing the LPL pathway and reducing very low-density lipoprotein (VLDL) levels2). Moreover, a gene therapy for LPL deficiency approved by the European Medicines Agency in 2012 is costly and has been withdrawn from the market2). Therefore, the only universal long-term treatment for LPL deficiency is to restrict the total fat intake to less than 10%–15% of daily calories (15–20 g per day)2). In this case, as the patient was a young child aged 1 year and 9 months and because his TG level was significantly lowered only by the inpatient controlled diet, we decided not to use lipid-lowering drugs and to manage his illness with diet therapy (Table 4).
| Energy | Equal to healthy children of the same age |
|---|---|
| Energy settings were started at 1200 kcal (age 2) and increased by 100 kcal for each year of age, reaching 1500 kcal by age 5 and 2200 kcal by age 12. 12 years of age and later, due to increased activity from sports, the energy setting was based on the Japanese Dietary Reference Intakes to take into account the amount of activity. | |
| Fat restriction | ＜15% of total energy intake |
| Medium-chain triglycerides (MCTs) | Within 25% of the daily allowable fat. |
|
MCT oil was used to supplement calorie deficits caused by strict fat restriction; because MCT oil lacks essential fatty acids, it was limited to no more than 25% of the daily allowable fat intake. |
|
| EX: MCTs account for 5 g of the daily fat allowance of 20 g. | |
|
It was exchanged for regular oil as a cooking oil for dressings and other cooking uses in order to increase caloric density without elevating TG. |
|
| Carbohydrate restriction | Restriction of fructose and other simple and refined carbohydrates beverages, such as soft drinks or fruit juices. |
| Alcohol restriction | Alcohol intake should be restriction (age 20 ~) |
| Educational tool | Food exchange list for fat restriction |
| Standard Tables of Food Composition in Japan |
Nevertheless, although fat-restricted diets are effective, they are reported to be difficult for 90% of patients8). Strict fat-restricted diets have been reported to limit social life due to the need to plan meals, stress from having to carry precooked meals, inability to eat or share the food inducing burden on the family, and the difficulties brought to friends and relatives8, 9). Recent studies10) on the quality of life of patients with LPL deficiency highlight the inadequate and inconsistent dietary advice provided as well as unmet educational and information resources on LPL deficiency for patients and their families. Importantly, it was noted that patients generally received little useful dietary support from healthcare providers.
For patients with LPL deficiency to receive proper health care, dietary guidelines across the lifespan are critical. However, due to the rarity of this disease, there are no randomized controlled trials or meta-analyses on dietary therapy3). Current published guidelines for the dietary management of patients with primary chylomicronemia state that besides adherence to a strict diet, childhood and adolescent patients should be carefully monitored to ensure proper growth and development2).
The effect of nutritional counseling from childhood to adulthood is significant11), and long-term nutritional counseling has been reported to be effective in regulating blood TG levels and serum lipoproteins12, 13).
In this case, the patient was diagnosed at an early age and remained on fat-restricted nutritional counseling for more than 20 years, without growth retardation or pancreatitis. This could be attributed to several possible reasons. In this case, the boy was treated by dietitians at an early age and continued into adulthood. We believe that we were able to intervene before his eating habits were formed (in early childhood), which contributed to his good adherence to a strict diet.
Moreover, the dietitians were able to assist the family in learning cooking skills, allowing the parents to prepare a consistent and stable fat-restricted diet. One to two months after discharge, the parents had mastered making low-fat meals and could pack lunches for their child. Thereafter, the dietitians met with them every 3–4 months to discuss how to deal with various dietary issues that arose as the child grew. This enabled the family to prepare fat-restricted diets while ensuring food variety.
When the child reached primary school age, we also provided him with nutritional counseling on the need for a fat-restricted diet. At each consultation, the dietitians assessed the diet, growth curve, and skin findings characteristic of fat deficiency. The dietitians advised the child on how to adjust his nutritional intake to avoid growth disturbance caused by a strict fat-restricted diet and report the results back to the doctors. His understanding of and adherence to a fat-restricted diet were good, as he had been on it since early childhood.
Fat is a nutrient found in beef, pork, poultry, eggs, fish, soy foods, and milk and has a strong influence on the blood lipid profile. Maintaining a strict fat-restricted diet is difficult due to dietary dissatisfaction. Therefore, we used the fat food exchange list [Supplemental Table 1] as an effective tool when implementing strict dietary restrictions14, 15). We believe that the use of the fat food exchange list allowed for a wider choice of foods, which was advantageous for the continuation of the diet.
Food exchange list used for nutr itional counselling (English version)
The traditional Japanese food environment was also a factor in his ability to maintain a strict fat-restricted diet. In Japan, detailed tables of food composition are published and the fat content of several foods can be easily checked. Additionally, the traditional Japanese diet is one of the lower-fat diets worldwide16, 17). A variety of low-fat dishes such as Udon and Japanese stew “Nabe” are available at restaurants and as take-away foods, thereby reducing his and his family’s burden of nutritional intake, which has helped him in maintaining his diet.
Although there is concern about fat-soluble vitamin and essential fatty acid deficiencies due to the low-fat diet, such deficiencies were not observed. This could be because, even on a strict fat-restricted diet, he was able to consume diverse foods without being biased toward any particular food.
In conclusion, in this case report, a 20-year low-fat diet intake was achieved by a patient with LPL deficiency through continuous nutritional counseling. The fact that the patient progressed without complications such as growth retardation and pancreatitis can be attributed to the nutritional intervention by the dietitians from the early onset and over a long period, as well as the safe, long-term adherence to a low-fat diet. The long-term intervention of dieticians plays a vital role in achieving a balance between living on a strict diet for disease management and ensuring appropriate nutritional intakes for growth/development.
None.
Written informed consent was obtained from the patient for the publication of this case report.
The authors declare no conflicts of interest associated with this manuscript.
