Medium-chain Triglyceride Supplementation Research Articles

Medium-chain triglycerides supplement therapy with a low-carbohydrate formula can supply energy and enhance ammonia detoxification in the hepatocytes of patients with adult-onset type II citrullinemia.

Citrin, encoded by SLC25A13, constitutes the malate-aspartate shuttle, the main NADH-shuttle in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD) and adult-onset type II citrullinemia (CTLN2). Citrin deficiency is predicted to impair hepatic glycolysis and de novo lipogenesis, resulting in hepatic energy deficit. Secondary decrease in hepatic argininosuccinate synthetase (ASS1) expression has been considered a cause of hyperammonemia in CTLN2. We previously reported that medium-chain triglyceride (MCT) supplement therapy with a low-carbohydrate formula was effective in CTLN2 to prevent a relapse of hyperammonemic encephalopathy. We present the therapy for six CTLN2 patients. All the patients' general condition steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in a few days. Before the treatment, plasma glutamine levels did not increase over the normal range and rather decreased to lower than the normal range in some patients. The treatment promptly decreased the blood ammonia level, which was accompanied by a decrease in plasma citrulline levels and an increase in plasma glutamine levels. These findings indicated that hyperammonemia was not only caused by the impairment of ureagenesis at ASS1 step, but was also associated with an impairment of glutamine synthetase (GS) ammonia-detoxification system in the hepatocytes. There was no decrease in the GS expressing hepatocytes. MCT supplement with a low-carbohydrate formula can supply the energy and/or substrates for ASS1 and GS, and enhance ammonia detoxification in hepatocytes. Histological improvement in the hepatic steatosis and ASS1-expression was also observed in a patient after long-term treatment.

Preventive effects of medium‐chain triglycerides supplementation on the dysfunction of mitochondrial oxidative phosphorylation in skeletal muscle under cachectic condition

Cachexia is a complex metabolic syndrome associated with underlying chronic diseases and is characterized dysfunction of mitochondrial oxidative phosphorylation in skeletal muscle. The preventive effects of medium‐chain triglycerides (MCT) supplementation on the dysfunction of mitochondrial oxidative phosphorylation in skeletal muscle under cachectic condition have been investigated in the present study. ICR mice were randomly divided into 4 groups; control, lipopolysaccharide (LPS), LPS plus long‐chain triglycerides (LCT), LPS plus MCT supplementation. LCT and MCT oil (The Nisshin OilliO Group, Ltd, Tokyo, Japan) were administered to the LPS+LCT and LPS+MCT groups orally by a catheter for 1 week. Cachexia was induced in the LPS, LPS+LCT and LPS+MCT groups via LPS injection (7.5 mg/kg body weight, i.p.) after the supplementation. LPS resulted in a decrease in succinate dehydrogenase (SDH) activity, which is an indicator of mitochondrial function, and PGC‐1α, which is an indicator of mitochondrial biogenesis, in tibialis anterior muscles. LPS also induced a reduction of total ketone bodies concentration level in blood plasma. Meanwhile, MCT supplementation suppressed the decrease of SDH activity and total ketone bodies concentration. In addition, MCT supplementation increased the level of citrate synthase activity in the muscles. These results suggested that MCT supplementation could prevent dysfunction of mitochondrial oxidative phosphorylation in skeletal muscle under cachectic condition.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Proposal for an individualized dietary strategy in patients with very long-chain acyl-CoA dehydrogenase deficiency

Background Patients with very long chain acyl-CoA dehydrogenase deficiency (VLCADD), a long chain fatty acid oxidation disorder, are traditionally treated with a long chain triglyceride (LCT) restricted and medium chain triglyceride (MCT) supplemented diet. Introduction of VLCADD in newborn screening (NBS) programs has led to the identification of asymptomatic newborns with VLCADD, who may have a more attenuated phenotype and may not need dietary adjustments. Objective To define dietary strategies for individuals with VLCADD based on the predicted phenotype. Method We evaluated long-term dietary histories of a cohort of individuals diagnosed with VLCADD identified before the introduction of VLCADD in NBS and their beta-oxidation (LC-FAO) flux score (rate of oleate oxidation) in cultured skin fibroblasts in relation to the clinical outcome. Based on these results a dietary strategy is proposed. Results Sixteen individuals with VLCADD were included. One had an LC-FAO flux score >90%, was not on a restricted diet and is asymptomatic to date. Four patients had an LC-FAO flux score <10%, and significant VLCADD related symptoms despite the use of strict diets including LCT restriction, MCT supplementation and nocturnal gastric drip feeding. Patients with an LC-FAO flux score between 10 and 90% (n = 11) showed a more heterogeneous phenotype. Conclusions This study shows that a strict diet cannot prevent poor clinical outcome in severely affected patients and that the LC-FAO flux is a good predictor of clinical outcome in individuals with VLCADD identified before its introduction in NBS. Hereby, we propose an individualized dietary strategy based on the LC-FAO flux score.

The Effect of Medium Chain Triglycerides on Time to Nutritional Ketosis and Symptoms of Keto-Induction in Healthy Adults: A Randomised Controlled Clinical Trial.

Medium chain triglycerides (MCTs) are ketogenic and might reduce adverse effects of keto-induction and improve time to ketosis and the tolerability of very low carbohydrate diets. This study investigates whether MCT supplementation improves time to nutritional ketosis (NK), mood, and symptoms of keto-induction. We compared changes in beta-hydroxybutyrate (BOHB), blood glucose, symptoms of keto-induction, and mood disturbance, in 28 healthy adults prescribed a ketogenic diet, randomised to receive either 30 ml of MCT, or sunflower oil as a control, three times per day, for 20 days. The primary outcome measured was the achievement of NK (≥0.5 mmol·L−1 BOHB). Participants also completed a daily Profile of Mood States and keto-induction symptom questionnaire. MCT resulted in higher BOHB at all time points and faster time to NK, a result that failed to reach significance. Symptoms of keto-induction resulted from both diets, with a greater magnitude in the control group, except for abdominal pain, which occurred with greater frequency and severity in the MCT-supplemented diet. There was a possibly beneficial effect on symptoms by MCT, but the effect on mood was unclear. Based on these results, MCTs increase BOHB compared with LCT and reduce symptoms of keto-induction. It is unclear whether MCTs significantly improve mood or time to NK. The trial was registered by the Australia New Zealand Clinical Trial Registry ACTRN12616001099415.

GHRELIN ACTIVATION BY INGESTION OF MEDIUM-CHAIN TRIGLYCERIDES IN HEALTHY ADULTS: A PILOT TRIAL

Objective: To investigate the efficacy of dietary supplementation of medium-chain triglycerides (MCTs) and its effects on ghrelin activation in healthy adults. Methods: The present study examined two protocols with six healthy volunteers: 1) 12-hour profiles of the plasma levels of acylated and desacyl ghrelin without MCT ingestion, and 2) changes in serum ghrelin levels after oral ingestion of 45 g/day of MCTs for 1 week. Results: At baseline, serum acylated and desacyl ghrelin levels were 18.2±10.3 and 77.1±23.4 fmol/mL, respectively. The ratio of acylated/desacyl ghrelin was 19%. There were no significant differences in the 12-hour profiles of acylated and desacyl ghrelin. Significant increases were observed in all sampling times of serum acylated ghrelin after 1-week MCTs ingestion. The ratio of acylated/desacyl ghrelin increased to 37.7%. Conclusions: Oral ingestion of MCTs increased serum acylated ghrelin levels in healthy adults, suggesting that MCTs administration stimulates food intake.

Bilateral Chylothorax Secondary to Cirrhosis and Chylous Ascites

SESSION TITLE: Disorders of the Pleura SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Chylothorax is commonly caused by injury or obstruction of the thoracic duct within the thorax. Rarely, chylothorax can occur as a manifestation of decompensated liver disease with chylous ascites. CASE PRESENTATION: A 61 year old male with decompensated alcoholic liver disease was hospitalized for progressive dyspnea and abdominal distension. Physical examination and radiographic imaging identified large, bilateral pleural effusions and ascites. He did not respond to diuresis and therapeutic paracentesis, so bilateral thoracentesis was performed. Gross appearance of the bilateral pleural fluid was milky and amber in color, contrary to the expected appearance seen with transudative hepatic hydrothorax. Pleural fluid analysis was consistent with bilateral exudative chylothorax (triglycerides of 183 mg/dl and 197 mg/dl from the right and left, respectively). Pleural fluid to serum triglyceride ratio was 4.925 and cholesterol ratio was 0.333, definitively characterizing the pleural fluid as chyle. Although basic initial ascites fluid studies were consistent with portal hypertension as the mechanism, retrospective analysis was consistent with chylous ascites (triglycerides 148 mg/dl). Based on a MELD-Na of 26 and lack of responsiveness with aggressive medical management including diuretics, dietary modification, and abstinence from alcohol, the patient was referred for liver transplantation. DISCUSSION: The mechanism for chylothorax secondary to cirrhosis is due to portal hypertension causing rupture of small lymphatics and leakage of whole intestinal lymph into ascitic fluid, which then passes through diaphragmatic recesses. This mechanism is akin to the more commonly encountered hepatic hydrothorax which is typically transudative in nature. Management of chylothorax resulting from decompensated liver disease is similar to that of hepatic hydrothorax, although there are some additional considerations including use of octreotide to decrease lymphatic flow and post-prandial triglycerides, bowel rest with TPN, and use of orlistat. Medium-chain triglyceride supplementation, used in post-surgical chylous ascites, leads to increased hepatic encephalopathy and death in cirrhotic patients. CONCLUSIONS: For patients with cirrhosis, ascites, and pleural effusions, thoracentesis with thorough pleural fluid analysis can lead to accurate diagnosis of chylothorax, leading to appropriate identification and treatment. When suspected in patients with cirrhosis and ascites, pleural fluid studies should include triglycerides, cholesterol, and chylomicrons, in addition to serum cholesterol and triglycerides to allow for accurate recognition of chylothorax and the underlying etiology. Reference #1: Doerr, CH. “Etiology of Chylothorax in 203 Patients.” Mayo Clin Proc 80.7 (2005): 867-70. Print. Reference #2: Romero, S, and C Martin. “Chylothorax in Cirrhosis of the Liver: Analysis of Its Frequency and Clinical Characteristics.” Chest 114.1 (July 1998): 154-59. Print. DISCLOSURE: The following authors have nothing to disclose: Mark Nau, David Ferraro No Product/Research Disclosure Information

Lipemia retinalis in an infant treated for retinopathy of prematurity

Lipemia retinalis is an unusual ocular finding associated with hypertriglyceridemia. We report the case of an infant treated for retinopathy of prematurity who later developed lipemia retinalis, with triglyceride levels of 4736mg/dl. There was a paradoxical worsening of hypertriglyceridemia with the use of medium chain triglyceride supplement. On discontinuing the supplement, the triglycerides level drastically dropped, and retinal vasculature returned to a normal hue.

Tricaprylin Alone Increases Plasma Ketone Response More Than Coconut Oil or Other Medium-Chain Triglycerides: An Acute Crossover Study in Healthy Adults

BackgroundKetones are the brain’s main alternative fuel to glucose. Dietary medium-chain triglyceride (MCT) supplements increase plasma ketones, but their ketogenic efficacy relative to coconut oil (CO) is not clear. ObjectiveThe aim was to compare the acute ketogenic effects of the following test oils in healthy adults: coconut oil [CO; 3% tricaprylin (C8), 5% tricaprin (C10)], classical MCT oil (C8-C10; 55% C8, 35% C10), C8 (>95% C8), C10 (>95% C10), or CO mixed 50:50 with C8-C10 or C8. MethodsIn a crossover design, 9 participants with mean ± SD ages 34 ± 12 y received two 20-mL doses of the test oils prepared as an emulsion in 250 mL lactose-free skim milk. During the control (CTL) test, participants received only the milk vehicle. The first test dose was taken with breakfast and the second was taken at noon but without lunch. Blood was sampled every 30 min over 8 h for plasma acetoacetate and β-hydroxybutyrate (β-HB) analysis. ResultsC8 was the most ketogenic test oil with a day-long mean ± SEM of +295 ± 155 µmol/L above the CTL. C8 alone induced the highest plasma ketones expressed as the areas under the curve (AUCs) for 0–4 and 4–8 h (780 ± 426 µmol ⋅ h/L and 1876 ± 772 µmol ⋅ h/L, respectively); these values were 813% and 870% higher than CTL values (P < 0.01). CO plasma ketones peaked at +200 µmol/L, or 25% of the C8 ketone peak. The acetoacetate-to-β-HB ratio increased 56% more after CO than after C8 after both doses. ConclusionsIn healthy adults, C8 alone had the highest net ketogenic effect over 8 h, but induced only half the increase in the acetoacetate-to-β-HB ratio compared with CO. Optimizing the type of MCT may help in developing ketogenic supplements designed to counteract deteriorating brain glucose uptake associated with aging. This trial was registered at clinicaltrials.gov as NCT 02679222.

Very long-chain acyl-CoA dehydrogenase (VLCAD-) deficiency-studies on treatment effects and long-term outcomes in mouse models.

Very-long-chain-acyl-CoA-dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid (LCFA) oxidation, with an incidence of 1:50,000-1:100,000 in newborns. Catabolic situations contribute to the aggravation of symptoms and induce severe metabolic derangement. Treatment for VLCAD-deficiency includes avoidance of fasting and a long-chain fat-restricted and fat-modified diet in which LCFAs are fully or partially replaced by medium-chain triglycerides (MCT). The aim of this work was to investigate the outcome and the effects of long-term treatment in a mouse model of VLCAD-deficiency. The application of a single MCT bolus in a mouse model of VLCAD-deficiency (VLCAD-/- mice) immediately prior to exercise protected the muscles from the accumulation of acylcarnitines providing the required energy and it did not affect hepatic lipid metabolism. However, when MCT was applied over the course of a year as a regular part of the diet, female VLCAD-/- mice developed a severe clinical phenotype comparable to the human metabolic syndrome. Indeed, they were characterized by massive visceral fat infiltration, hepatosteatosis, disturbed fatty acid composition, hyperlipidemia, and systemic oxidative stress. In contrast, male VLCAD-/- mice seemed to be protected and displayed only signs of insulin resistance. Besides the sex-specific response to MCT supplementation with regard to the lipid metabolism, all VLCAD-/- mice developed progressive cardiac dysfunction over time which worsened when they were treated with regular MCT resulting in severe dilated cardiomyopathy. While long term use of MCT oil in mice has adverse effects, no such effects have been demonstrated in humans, likely reflecting the differences in long chain fatty acid oxidation between the two species.

Medium-Chain Triglycerides in Combination with Leucine and Vitamin D Benefit Cognition in Frail Elderly Adults: A Randomized Controlled Trial.

The combined supplementation of medium-chain triglycerides (MCTs), L-leucine-rich amino acids, and cholecalciferol (vitamin D3) increase muscle strength and function in frail elderly individuals. However, their effects on cognition are unknown. We enrolled 38 elderly nursing home residents (mean age±SD, 86.6±4.8 y) in a 3-mo randomized, controlled, parallel group trial. The participants were randomly allocated to 3 groups: the first group received a L-leucine (1.2 g)- and cholecalciferol (20 μg)-enriched supplement with 6 g of MCT (LD+MCT); the second group received the same supplement with 6 g of long-chain triglycerides (LD+LCT); and the third group did not receive any supplements (control). Cognition was assessed at baseline and after the 3-mo intervention. The difference in changes among the groups was assessed with ANCOVA, adjusting for age and the baseline value as covariates. After 3 mo, the Mini-Mental State Examination (MMSE) score in the LD+MCT group increased by 10.6% (from 16.6 to 18.4 points, p<0.05). After 3 mo, the Nishimura geriatric rating scale for mental status (NM scale) score in the LD+MCT group increased by 30.6% (from 24.6 to 32.2 points, p<0.001), whereas that in the LD+LCT and control groups decreased by 11.2% (from 31.2 to 27.7 points, p<0.05) and 26.1% (from 27.2 to 20.1 points, p<0.001), respectively. The combined supplementation of MCTs (6 g), L-leucine-rich amino acids, and cholecalciferol may improve cognitive function in frail elderly individuals.

Dietary stimulation of the endogenous somatotropic axis in weaner and grower-finisher pigs using medium chain triglycerides and cysteamine hydrochloride.

BackgroundThree experiments were conducted to examine the overall hypothesis that addition of medium chain triglycerides (MCT) and cysteamine hydrochloride (CSH) into the diets of young and growing pigs would stimulate the endogenous somatotropic axis to improve growth and performance.ResultsIn Experiment 1, weaner pigs were given either a 5 d dietary supplement of 5 % MCT (n = 8) or a control diet (n = 8). MCT increased the plasma concentration of growth hormone (GH; P < 0.05) and the GH secretagogue, ghrelin (P < 0.05). Additionally, the MCT treatment reduced scouring (P < 0.05), maintained villous height in the small intestine (P < 0.05) and stabilised daily weight gain (P < 0.05), compared to the controls. Experiment 2 compared the effects of 4 levels (0, 1, 3 and 6 % v/v) of MCT supplementation in grower-finisher male pigs, of approximately 35 kg live weight (n = 15 per treatment). Blood samples taken after 7 wk of treatment showed that the MCT supplementation increased circulating ghrelin (P < 0.001), GH (P < 0.01) and insulin (P < 0.05) concentrations in a dose-dependent manner. Daily weight gain, feed intake and feed conversion ratio were not affected by the MCT diets. In Experiment 3, 64 female pigs of approximately 60 kg live weight were allocated to one of three dietary treatments: control (n = 20); 6 % MCT (n = 21); and 70 mg/kg CSH (n = 21). After 3 wk of supplementation, the MCT treated pigs had a higher plasma concentration of ghrelin compared to the control and CSH pigs (P < 0.05). Plasma concentrations of GH and weight were not affected by any of the dietary treatments.ConclusionsEvidence is provided in Experiment 1 to support the use of dietary MCT supplements, perhaps acting via stimulation of somatotropic endocrine pathways, to minimise weaning-associated disorders such as slowing of growth and diarrhoea. In Experiments 2 and 3, although there was no effect on weight gain or feed conversion ratio in either experiment, MCT and CSH increased endocrine components of the somatotropic axis.

Management of an LCHADD Patient During Pregnancy and High Intensity Exercise.

In this report we describe a female Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase Deficiency (LCHADD) patient who suffered from severe exercise intolerance. At age 34, the patient became pregnant for the first time. After an uneventful first 32 weeks of pregnancy she developed sinus tachycardia (resting heart rate 120-134bpm) and lactate and creatinine kinase levels increased (3.3mmol/L and 264U/L, respectively). Increasing MCT supplementation (dose and frequency of administration) lowered heart rate and improved biochemical parameters. At 34 weeks the heart rate rose again and it was decided to deliver the child by caesarean section. Postpartum both mother and child did well.Prior to pregnancy, she performed exercise tests with different doses of medium chain triglycerides (MCTs) to establish a safe and effective exercise program (baseline test, second test with 10g MCTs and third test with 20g of MCTs). In the MCT supplemented tests the maximal power output was 23% (second test) and 26% (third test) higher, while cardiac output at maximal power output was the same in all three tests (~15.8L/min).In conclusion, this is the first report of pregnancy in an LCHADD patient, with favourable outcome for both mother and child. Moreover, in the same patient, MCT supplementation improved cardiac performance and metabolic parameters during high intensity exercise. Using impedance cardiography, we got a clear indication that this benefit was due to improved muscle energy generation at high intensity exercise, since at the same cardiac output a higher power output could be generated.

Medium Chain Triglyceride Oil: An Intended Placebo with Unexpected Adverse Effects

Background: Medium chain triglyceride (MCT) oil is a synthetic oil made from medium chain C8 and C10 fatty acids. It has been traditionally used as a neutral “placebo” in lipid clinical trials. Thus, we had selected MCT oil capsules as a placebo, intended for comparison with an omega-3 polyunsaturated fatty acid containing supplement, to measure fatty acid profiles and inflammation in healthy people. Methods: The trial was a double-blinded, randomized, placebo controlled trial with cross-over, 4 weeks each study arm. Using serum, the fatty acids were measured and analysed by FAME analysis. HDL and LDL cholesterol profiles and C-reactive protein as a measure of inflammation were also quantified. Blood samples were collected at each time point, and participants assessed for serum lipid profiles. Results: The outcomes of interest were taken from the differences between measures for each phase of the trial. There were no significant changes in HDL or LDL cholesterol in this time, and CRP also showed no significant changes. However, levels of the fatty acids eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) showed significant decreases after MCT supplementation. Conclusion: These results revealed an unexpectedly adverse effect of the MCT oil. Such comparisons raise questions about the use of MCT oil as a placebo, as it was not neutral in its effect on blood lipid biomarkers. The results have ramifications for claims made about the positive benefits of MCT oils.

A Case of Primary Intestinal Lymphangiectasia Presented With Small Bowel Bleeding and Improved by Antiplasmin Therapy: Presidential Poster

Primary intestinal lymphangiectasia (PIL) is a rare disorder of intestinal lymphatic channel malformation and is characterized by dilated lacteals and impaired lymphatic drainage leading to leakage of lymph into intestinal lumen resulting in lymphopenia, hypoalbuminemia and hypogammaglobulinemia. The diagnosis is based on histology and exclusion of secondary causes such as congestive heart failure, nephrotic syndrome, inflammatory bowel disease, rheumatologic disease, infectious disease, etc. A low fat, high protein, medium-chain triglyceride supplemented diet is mainstay of management. Octreotide and tranexamic acid is reported to decrease lymphatic permeability and can be used for laboratory and symptomatic improvement. We report a case of PIL which presented with small bowel bleeding and improved in clinical and laboratory abnormalities with antiplasmin therapy. A 32 year-old female visited emergency department for melena and peripheral edema. Laboratory finding revealed anemia, hypoalbuminemia and lymphopenia. Gastroduodenoscopy showed that whitish spots and finger like elongated mucosal lesion was scattered in the second portion of the duodenum. Colonoscopy revealed that tarry stool was shown and nodular lesion with whitish spots was scattered at terminal ileum, but colon mucosa was intact. Capsule endoscopy revealed that bleeding was shown at proximal jejunum and small bowel villi was elongated with whitish spots and chylous products gushed out. Small bowel biopsy showed dilated lymphatics in mucosa and submucosa. Secondary causes of lymphatic obstruction like heart failure, liver cirrhosis, retroperitoneal fibrosis, mesenteric venous thrombosis, neoplasm excluded. And also, mucosal diseases increased lymphatic permeability such as inflammatory bowel disease, rheumatic disease, allergic disease, gastrointestinal malignancy, infection, celiac disease, amyloidosis ruled out. Bleeding and edema continued despite of medium-chain triglycerides supplementation. As antiplasmin therapy was administered, melena and edema decreased and lymphopenia and hypoalbuminema improved. We reports a case of primary intestinal lymphangiectasia presented with small bowel bleeding, and improved clinical and laboratory findings by MCT diet and antiplasmin therapy.Table 1: Comparison of laboratory test before and after dischargeFigure 1Figure 2Figure 3

Treatment and Pathomechanism of Citrin Deficiency

Citrin, encoded by SLC25A13, is a component of the malate-aspartate shuttle, which is the main NADH-transporting system in the liver. Citrin deficiency causes neonatal intrahepatic cholestasis (NICCD), which usually resolves within the first year of life. However, a small number of adults with citrin deficiency develop adult-onset type II citrullinemia (CTLN2), which causes hyperammonemic encephalopathy leading to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. Hepatic glycolysis is coupled with hepatic lipogenesis via the NADH shuttles composed of the malate-aspartate shuttle and malate-citrate shuttle. Citrin deficiency is expected to impair glycolysis and lipogenesis in hepatocytes. We noticed that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. We extended this therapy for CTLN2 and found that an MCT supplementation therapy under a low-carbohydrate formula prevented the relapse of hyperammonemic encephalopathy, normalized the liver dysfunction (including the Fisher ratio), and gradually improved the level of plasma citrulline and fatty liver. An MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to improvement of the cytosolic NAD+/NADH ratio via the malate-citrate shuttle. MCT supplementation could be a promising therapy for citrin deficiency.

Sexual dimorphism of lipid metabolism in very long-chain acyl-CoA dehydrogenase deficient (VLCAD−/−) mice in response to medium-chain triglycerides (MCT)

Medium-chain triglycerides (MCT) are widely applied in the treatment of long-chain fatty acid oxidation disorders. Previously it was shown that long-term MCT supplementation strongly affects lipid metabolism in mice. We here investigate sex-specific effects in mice with very-long-chain-acyl-CoA dehydrogenase (VLCAD) deficiency in response to a long-term MCT modified diet. We quantified blood lipids, acylcarnitines, glucose, insulin and free fatty acids, as well as tissue triglycerides in the liver and skeletal muscle under a control and an MCT diet over 1year. In addition, visceral and hepatic fat content and muscular intramyocellular lipids (IMCL) were assessed by in vivo 1H magnetic resonance spectroscopy (MRS) techniques. The long-term application of an MCT diet induced a marked alteration of glucose homeostasis. However, only VLCAD−/− female mice developed a severe metabolic syndrome characterized by marked insulin resistance, dyslipidemia, severe hepatic and visceral steatosis, whereas VLCAD−/− males seemed to be protected and only presented with milder insulin resistance. Moreover, the highly saturated MCT diet is associated with a decreased hepatic stearoyl-CoA desaturase 1 (SCD1) activity in females aggravating the harmful effects of a saturated MCT diet. Long-term MCT supplementation deeply affects lipid metabolism in a sexual dimorphic manner resulting in a severe metabolic syndrome only in female mice. These findings are striking since the first signs of insulin resistance already occur in female VLCAD−/− mice during their reproductive period. How these metabolic adaptations are finally regulated needs to be determined. More important, the relevance of these findings for humans under these dietary modifications needs to be investigated.

Orphan drugs in development for long-chain fatty acid oxidation disorders: challenges and progress

Fatty acid oxidation disorders are inborn errors of metabolism resulting in failure of β-oxidation within or transport of fatty acids into the mitochondria. The long-chain fatty acid oxidation disorders are characterized by variable presentations ranging from newborn cardio- myopathy, to infantile hypoketotic hypoglycemia resulting from liver involvement, to skeletal myopathy often resulting in rhabdomyolysis in adolescents and adults. Treatments for these long-chain fatty acid oxidation disorders have typically focused upon avoidance of fasting with dietary fat restriction and medium-chain triglyceride supplementation. These treatments have resulted in only a partial response with improvements in hypoglycemia, reduction in frequency of rhabdomyolysis, and improvement in cardiomyopathy with early therapy, but significant risk remains. Recent advances in therapies for long-chain fatty acid oxidation disorders are reviewed in this article. These include sodium D,L-3-hydroxybutyrate, triheptanoin, gene therapy, and bezafibrates. Sodium D,L-3-hydroxybutyrate has shown clinical effect, with improvements in muscle tone, neurological abnormalities, and some cases of cardiomyopathy and leukodystrophy. Triheptanoin has been used as an alternative medium-chain triglyceride in a number of fatty acid oxidation disorders and has shown promising findings in the treatment of cardiomyopathy and hypoglycemia. However, it does not significantly reduce episodes of rhabdomyolysis. Gene therapy has been shown to improve acylcarnitine levels in very-long-chain acyl-coenzyme A dehydrogenase deficiency mouse models, with preservation of glucose levels. Bezafibrates have shown improvements in acylcarnitine concentrations in fibroblast studies, but clinical observa - tions have not demonstrated consistent effects. Together, these treatments have shown some improvements in individual case reports, but there is still a significant need for randomized controlled trials to investigate these therapies, given the ongoing need for improved treatments in these disorders.

Urinary Dicarboxylic Acid Excretion in Formula-Fed Infants

Purpose. The common practice of medium-chain triglyceride (MCT) feeding has been associated with high urinary dicarboxylic acid excretion levels in infants. The purpose of this study was to investigate the effect of MCT supplementation on urine metabolite excretion by infants on different formulas. Methods. Urine sample data from a Metabolic Screening Laboratory were provided, medical records were accessed to record infant formula, and ingredient lists of formulas were reviewed. The urinary acid profiles were compared based on the percentage of fat content coming from MCT. Results. A MANOVA was conducted and there was a statistically significant effect of acid profiles. Pairwise comparisons indicate a significant difference between high and low %MCT ( P = .0002), low and medium %MCT ( P = .0156), and high and low/medium %MCT ( P = .0030) for adipic acid. For both suberic acid and sebacic acid, there was a significant difference between high and low %MCT ( P = .0001), high and medium %MCT ( P = .0001, P = .0015), and high and low/medium %MCT ( P = .0001). This study suggests that relative amounts of dicarboxylic acids cannot be used alone as a diagnostic criteria. The exact amount of MCT in each formula needs to be considered.

Gastro-entéropathies exsudatives

Protein-losing enteropathy is a rare syndrome of gastrointestinal protein loss. The primary causes can be classified into lymphatic leakage due to increased interstitial pressure and increased leakage of protein-rich fluids due to erosive or non-erosive gastrointestinal disorders. The diagnosis of protein-losing enteropathy should be considered in patients with chronic diarrhea and peripheral oedema. The diagnosis of protein-losing enteropathy is most commonly based on the determination of fecal alpha-1 antitrypsin clearance. Most protein-losing enteropathy cases are the result of either lymphatic obstruction or a variety of gastrointestinal disorders and cardiac diseases, while primary intestinal lymphangiectasia (Waldmann's disease) is less common. Treatment of protein-losing enteropathy targets the underlying disease but also includes dietary modification, such as high-protein and low-fat diet along with medium-chain triglyceride supplementation.

Pilot feasibility and safety study examining the effect of medium chain triglyceride supplementation in subjects with mild cognitive impairment: A randomized controlled trial

BackgroundImpaired brain glucose metabolism appears to be a potential pathogenic feature of mild cognitive impairment (MCI). This study examined the potential for increasing circulating ketone bodies through medium chain triglyceride (MCT) supplementation, as a means to beneficially modulate brain homeostasis in subjects with MCI. MethodsSix participants with MCI were enrolled in a randomized placebo-controlled trial. Participants received 56g/day of either medium chain triglycerides (MCTs) or placebo for 24weeks. Serum β-hydroxybutyrate concentrations, apolipoprotein-E4 status, and cognitive assessments were carried out. Due to the small number of participants only the raw scores were examined. ResultsIntake of MCT oil increased serum ketone bodies and improved memory, while intake of placebo did not show improvement in any of the cognitive measures tested. ConclusionsConsumption of 56g/day of MCTs for 24weeks increases serum ketone concentrations and appears to be a candidate for larger randomized control trials in the future that quantify the modulation of cognitive function through supplementation with ketone precursors, in patients with MCI.