Jos Jansen

5 111 Screening for abnormal glycosylation in a cohort of adult liver disease patients Introduction Congenital Disorders of glycosylation (CDG) are a group of inborn errors of metabolism characterized by abnormal glycosylation. Most CDG share a multisystem phenotype with dysmorphic features, failure to thrive and neurological symptoms.(1) Involvement of the liver is frequent in CDG but usually not the dominant feature. (2) In recent years, a novel subgroup of CDG patients has emerged that presents predominantly with a hepatic phenotype. (3-7) Pathological variants in this group are in genes that code for assembly factors of the vacuolar -ATPase (V-ATPase), the proton pump for intracellular acidification. The glycosylation pattern resembles a type 2 CDG with loss of sialic acid and galactose. The hepatic clinical spectrum ranges frommildly elevated serum transaminases and steatosis, resembling non-alcoholic fatty liver disease, to cirrhosis and end-stage liver disease warranting liver transplantation (LTx). Liver cirrhosis develops as a response to chronic liver injury. The central pathological event in cirrhosis is deposition of extracellular matrix increasing hepatic flow resistance with ensuing hepatocyte dysfunction.(8) Patients with cirrhosis have a high risk of decompensation of their liver disease. It can develop in end-stage liver disease (ESLD), necessitating (LTx) Abnormal glycosylation is a known phenomenon in chronic liver disease and can be used to discriminate between different fibrosis stages and cirrhosis and provides an interesting and non-invasive alternative for liver biopsy.(9). Abnormal glycan structures of liver-derived proteins such as transferrin (TF) and haptoglobin have been described in alcoholic liver disease, non-alcoholic steatohepatitis and primary sclerosing cholangitis.(10-12) These abnormalities include hyperfucosylation due to increased fucosyltransferase activity and hyposialylation as a result of lower sialyltransferase activity. Traditionally, new CDG patients are identified through isoelectric focusing of TF (tIEF).(13) TF possesses two biantennary glycans at amino acids Asn432 and Asn630, both negatively charged because of the terminal sialic acids.(14) tIEF uses loss of these sialic acids to separate the various isoforms. A disadvantage of tIEF is that it only provides information on desialylation and not for example on hypogalactosylation and fucosylation. The use of quadruple time-of-flight mass-spectrometry (QTOF-MS) may overcome this disadvantage by providing in-depth high-resolution information on the glycans attached to TF.(15)