Citrin Deficiency: Clinical and Nutritional Features

Abstract

SLC25A13 gene mutations are responsible for diseases related to citrin deficiency (CD), such as neonatal intrahepatic cholestasis caused by citrin deficiency and adult-onset type II citrullinemia (CTLN2). From childhood to adulthood, CD patients are apparently healthy due to metabolic compensation with peculiar dietary habits-disliking high-carbohydrate foods and liking fat and protein-rich foods. Carbohydrate overload and alcohol consumption may trigger the sudden onset of CTLN2, inducing hyperammonemia and consciousness disturbance. Well-compensated asymptomatic CD patients are sometimes diagnosed as having non-obese (lean) non-alcoholic fatty liver disease and steatohepatitis, which have the risk of developing into liver cirrhosis and hepatocellular carcinoma. CD-induced fatty liver demonstrates significant suppression of peroxisome proliferator-activated receptor α and its downstream enzymes/proteins involved in fatty acid transport and oxidation and triglyceride secretion as a very low-density lipoprotein. Nutritional therapy is an essential and important treatment of CD, and medium-chain triglycerides oil and sodium pyruvate are useful for preventing hyperammonemia. We need to avoid the use of glycerol for treating brain edema by hyperammonemia. This review summarizes the clinical and nutritional features of CD-associated fatty liver disease and promising nutritional interventions.

Keywords: PPARα; avoidance of glycerol administration; lean NAFLD; peculiar dietary habits.

Figure 1

Liver histology of CD patient. Hematoxylin and eosin staining (left, ×100) revealed microvesicular and macrovesicular steatosis and ballooned hepatocytes. Azan–Mallory staining (right, ×40) showed marked pericellular fibrosis with disorganization of hepatic lobules. This figure is reprinted/adapted with permission from Ref. [24]. 2007 by the AGA Institute.

Figure 2

Comparison of BMI and serum PSTI between fatty liver patients without (−) and with (+) SLC25A13 gene mutations. (−), conventional NAFLD/NASH; (+), CD-associated fatty liver disease. Each value is plotted, and median values are indicated in the lines. The cut-off values of BMI and serum PSTI were calculated as 20 kg/m² and 29 ng/mL, respectively. ***, p < 0.001. This figure is reprinted/adapted with permission from Ref. [26]. 2008 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd. All rights reserved.

Figure 3

A schematic diagram of metabolic change in CD patients. (a) Citrin (aspartate–glutamate carrier; AGC) works as part of the malate–aspartate shuttle and this shuttle is the main pathway to translocate NADH from the cytosol to the mitochondrial matrix. The NADH-NAD+ balance is kept in good condition in the cytosol and mitochondrial matrix. (b) Since citrin (AGC) does not work sufficiently in CD patients’ hepatocytes, the NADH supply depends on the TCA cycle. As a result, citrate is increased in the cytosol and used as a source of fatty acid synthesis. Cit, citrate; OAA, oxaloacetate; Mal, malate; αKG, α-ketoglutarate; Asp, aspartate; Glu, glutamate; NADH, nicotinamide adenine dinucleotide; CT, citrate transporter; OMC, oxoglutarate malate transporter; IM, intermembrane space. This figure is reprinted/adapted with permission from Ref. [26]. 2008 European Association for the Study of the Liver. Published by Elsevier Ireland Ltd.

Figure 4

FA/TG metabolism in the liver. The mRNA-encoding enzymes/proteins associated with FA oxidation, very low-density lipoprotein secretion, and FA transport were markedly downregulated in CD livers. Cit, citrate; CPT1A, carnitine palmitoyl–CoA transferase 1α; FABP1, FA-binding protein 1; FFA, free fatty acid; MCAD, medium-chain acyl-CoA dehydrogenase; MTTP, microsomal TG transfer protein; VLCAD, very-long-chain acyl-CoA dehydrogenase; VLDL, very-low-density lipoprotein.