Medium-chain triglyceride supplementation under a low-carbohydrate formula is a promising therapy for adult-onset type II citrullinemia

Abstract

BackgroundCitrin, 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, small numbers of adults with citrin deficiency develop hyperammonemic encephalopathy, adult-onset type II citrullinemia (CTLN2), which leads to death due to cerebral edema. Liver transplantation is the only definitive therapy for patients with CTLN2. We previously reported that a lactose (galactose)-restricted and medium-chain triglyceride (MCT)-supplemented formula is notably effective for patients with NICCD. Citrin deficiency may impair the glycolysis in hepatocytes because of an increase in the cytosolic NADH/NAD+ ratio, leading to an energy shortage. MCT administration can provide energy to hepatocytes and was expected to have a good effect on CTLN2.MethodsAn MCT supplementation therapy under a low-carbohydrate formula was administered to five patients with CTLN2. Four of the patients had episodes of hyperammonemic encephalopathy, and one patient had postprandial hyperammonemia with no symptoms.ResultsOne of the patients displaying hyperammonemic encephalopathy completely recovered with all normal laboratory findings. Others notably improved in terms of clinical and or laboratory findings with no hyperammonemic symptoms; however, the patients displayed persistent mild citrullinemia and occasionally had postprandial mild hyperammonemia most likely due to an irreversible change in the liver.ConclusionsAn MCT supplement can provide energy to hepatocytes and promote hepatic lipogenesis, leading to a reduction in the cytosolic NADH/NAD+ ratio. MCT supplementation under a low-carbohydrate formula could be a promising therapy for CTLN2 and should also be used to prevent CTLN2 to avoid irreversible liver damage.

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

“…Before the treatment, plasma glutamine levels did not increase over the normal range in hyperammonemic patients, including our previously reported patients, and decreased to lower than the normal range in some patients (Table 1, Fig. 2) (Hayasaka et al 2014). The treatment decreased the blood ammonia level, which was accompanied by a mild decrease in plasma citrulline levels and an increase in plasma glutamine levels (Table 1, Suppl.…”

“…We treated six CTLN2 patients by MCT supplement with a low-carbohydrate diet as previously reported (Hayasaka et al 2014). The general condition of all patients steadily improved and five patients with hyperammonemic encephalopathy recovered from unconsciousness in 1 day or a few days (Table 1).…”

“…A 68-year-old man presented with hyperammonemic encephalopathy at age 62 years and was successfully treated with MCT supplement under a low-carbohydrate formula as previously reported (Hayasaka et al 2014). Before the treatment, fatty liver and steatosis were observed by abdominal ultrasonography and by liver biopsy, respectively (Suppl.…”

“…A lactose-restricted formula can avoid the accumulation of toxic galactose metabolites and the MCT supplement can supply energy and acetyl-CoA to the hepatocytes. In 2014, we extended the clinical trials of MCT supplement therapy with a low-carbohydrate formula to five CTLN2 patients and found its preventive effect on hyperammonemic encephalopathy (Hayasaka et al 2014). Citrin deficiency is predicted to impair glycolysis in hepatocytes due to the impairment of the NADH shuttle.…”

“…Each marker represents as follows. cross: carbamoylphosphate synthetase deficiency, plus: ornithine transcarbamylase deficiency, open pentagram: CTLN1, open circle: case 1, open triangle: case 2, open square: case 3, closed circle: case 4, closed triangle: case 5, closed square: case 6 = case 2 inHayasaka et al (2014), open diamond: case 1 inHayasaka et al (2014), open star: case 5, case 3 inHayasaka et al (2014), closed diamond: case 4 inHayasaka et al (2014), closed star: case 5 inHayasaka et al (2014)…”