Liver manifestations in a cohort of 39 patients with congenital disorders of glycosylation: pin-pointing the characteristics of liver injury and proposing recommendations for follow-up

Abstract

Background The congenital disorders of glycosylation (CDG) are a heterogeneous group of rare metabolic diseases with multi-system involvement. The liver phenotype of CDG varies not only according to the specific disorder, but also from patient to patient. In this study, we sought to identify common patterns of liver injury among patients with a broad spectrum of CDG, and to provide recommendations for follow-up in clinical practice. Methods Patients were enrolled in the Frontiers in Congenital Disorders of Glycosylation natural history study. We analyzed clinical history, molecular genetics, serum markers of liver injury, liver ultrasonography and transient elastography, liver histopathology (when available), and clinical scores of 39 patients with 16 different CDG types (PMM2-CDG, n = 19), with a median age of 7 years (range: 10 months to 65 years). For patients with disorders which are treatable by specific interventions, we have added a description of liver parameters on treatment. Results Our principal findings are (1) there is a clear pattern in the evolution of the hepatocellular injury markers alanine aminotransferase and aspartate aminotransferase according to age, especially in PMM2-CDG patients but also in other CDG-I, and that the cholangiocellular injury marker gamma-glutamyltransferase is not elevated in most patients, pointing to an exclusive hepatocellular origin of injury; (2) there is a dissociation between liver ultrasound and transient elastography regarding signs of liver fibrosis; (3) histopathological findings in liver tissue of PMM2-CDG patients include cytoplasmic glycogen deposits; and (4) most CDG types show more than one type of liver injury. Conclusions Based on these findings, we recommend that all CDG patients have regular systematic, comprehensive screening for liver disease, including physical examination (for hepatomegaly and signs of liver failure), laboratory tests (serum alanine aminotransferase and aspartate aminotransferase), liver ultrasound (for steatosis and liver tumors), and liver elastography (for fibrosis).

Liver Involvement in Congenital Disorders of Glycosylation and Deglycosylation

“…Elevated serum transaminases observed in the majority of our CDG patients were associated with the presence of coagulation disorders, including protein C, protein S, and antithrombin deficiency. Similar observations were reported by Starosta et al ( 13 ). However, only two patients developed thrombotic events.…”

“…In the recently published paper on liver manifestations in 39 CDG patients, Starosta et al found that 48.6% of those persons had elevated values of alanine aminotransferase and 70.3% of them had elevated values of aspartate aminotransferase ( 13 ). These parameters mostly increased during the first 5 years of life in most types of CDG (apart from ALG8-CDG, CCDC115-CDG, MPI-CDG, PGM1-CDG, and TMEM165-CDG patients), but they improved significantly afterwards.…”

“…In neurovisceral phenotypes, the liver disease was generally diagnosed based on elevated serum transaminases, independently from the neurological disease (7,9,10). However, both liver steatosis and fibrosis (and even cirrhosis) have been reported in the course of some of them (7,(11)(12)(13). There are also some subtypes, like MPI-CDG, TMEM199-CDG and CCDC115-CDG, with clinical and biochemical phenotype expressed mainly in the liver (no neurological involvement) (7,(14)(15)(16)(17)(18)(19).…”

Manifestations and Management of Hepatic Dysfunction in Congenital Disorders of Glycosylation

“…Liver disease is highly penetrant in CDG, and all patients require screening for hepatic injury via physical examination, laboratory investigations, and liver imaging 2 . The most frequent serum markers of liver injury are elevated TAs, which improve spontaneously with age in most type I CDG 2 .…”

“…Liver disease is highly penetrant in CDG, and all patients require screening for hepatic injury via physical examination, laboratory investigations, and liver imaging 2 . The most frequent serum markers of liver injury are elevated TAs, which improve spontaneously with age in most type I CDG 2 . Gamma‐glutamyl transferase (GGT) and alkaline phosphatase (AP) are elevated in some cases, and ceruloplasmin and copper levels are altered in some CDG, as presented in Table 1.…”