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. Author manuscript; available in PMC: 2022 Jul 5.
Published in final edited form as: J Pediatr Gastroenterol Nutr. 2021 Oct 1;73(4):444–454. doi: 10.1097/MPG.0000000000003209

Liver involvement in congenital disorders of glycosylation. A systematic review

Rossella Colantuono 1,◦, Elisa D’Acunto 1,◦, Daniela Melis 1, Pietro Vajro 1, Hudson H Freeze 2, Claudia Mandato 3,*,◦
PMCID: PMC9255677  NIHMSID: NIHMS1813104  PMID: 34173795

Abstract

An ever-increasing number of disturbances in glycosylation have been described to underlie certain unexplained liver diseases presenting either almost isolated or in a multi-organ context. We aimed to update previous literature screenings which had identified up to 23 forms of congenital disorders of glycosylation (CDG) with associated liver disease. We conducted a comprehensive literature search of PubMed and Google Scholar databases looking at articles published during the last 20 years (January 2000 - October 2020). Eligible studies were case reports/series reporting liver involvement in CDG patients. Our systematic review led us to point out 41 forms of CDG where liver is primarily affected (n = 7) or variably involved in a multisystem disease with mandatory neurological abnormalities (n=34). Herein we summarize individual clinical and laboratory presentation characteristics of these 41 CDGs, and outline their main presentation and diagnostic cornerstones with the aid of two synoptic tables. Dietary supplementation strategies have hitherto been investigated only in 7 of these CDG types with liver disease, with a wide range of results. In conclusion the systematic review recognized a liver involvement in a somewhat larger number of CDG variants corresponding to about 30% of the total of CDG so far reported, and it is likely that the number may increase further. This information could assist in an earlier correct diagnosis and a possibly proper management of these disorders.

Keywords: CDG, Congenital Disorders, Glycosylation, Liver, Liver Function Tests

INTRODUCTION

Congenital disorders of glycosylation (CDG) are heterogeneous genetic defects affecting the synthesis of glycoprotein and glycolipid glycans or their attachment to proteins and lipids. Glycosylation is an important process in most of human proteins, influencing their structure and function. The deficiency of glycoconjugates is the biochemical basis of multi-organ diseases which nearly always occurs in CDG, resulting in multisystem clinical manifestations. Over 130 different types of CDG are now known (1), and the number appears to keep rising (2). If considered individually, they represent rare disorders of metabolism, but as a group, they are not negligible disorders. The total number of diagnosed CDG cases in Europe might reasonably exceed 2500 (2), (3). The inheritance is mainly autosomal recessive (AR), moreover an increasing number of X-linked types have been reported. Only two are inherited by autosomal dominant way (GANAB-CDG, and PRKCSH-CDG) (4).

CDG nomenclature was previously divided in two main types based on analysis of transferrin (Tf) glycosylation: CDG I affecting N-glycan precursor synthesis and its addition to protein, and CDG II altering the processing of protein-linked N-glycans. In 2009 the CDG nomenclature was changed and today it includes the official defective gene symbol followed by –CDG. For instance, PMM2-CDG stands for CDG-Ia (due to mutations in the gene encoding Phosphomannomutase 2 (5).

Despite proteins related to glycosylation pathways have different subcellular locations (6) and a wide variety of alterations, some common clinical features are shared among patients (e.g. coagulation proteins abnormalities) pointing out the interconnection between the different glycosylation pathways (7).

The liver is the organ which is responsible for the production of most of the glycosylated serum proteins and its diseases may therefore also affect the glycosylation processes (8, 9). However, because alteration of glycosylation patterns can themselves primarily derange liver functions, the screening for CDG should always be considered in patients with unexplained liver disease (10), either in isolation or involving a multi-organ context. In 2017 Marques-da-Silva et al meritoriously screened the presence of liver involvement among 100 types of CDG known at that time and found 17 forms with associated liver disease (11). Since then, however, at least 30 new CDG forms have been identified, several of them with an accompanying liver disease. In order to help the hepatologist to an earlier suspicion and correct diagnosis, this article updates the systematic review of those authors, and points out 24 additional CDG types with hepatic involvement. The diagnosis will be guided by two synoptic tables [Tables 1A,1B] and one guideline flow (Figure 1).

Table 1.

Biochemical, histological and clinical findings in seven CDG in which liver is predominately affected (Group 1)

Patients in studies ↑TA ↓ albumin ↓ glycaemia ↑ LDL-C ↑ AP ↓ AT ↓ γ-globulins ↑ H-Cu ↓S-Cu ↓ Cr Liver Fibrosis Liver Steatosis Liver Cirrhosis Liver involvement Neurologic involvement Bone involvement Heart involvement G.I. involvement Kidney involvement Dysmorphism Vision involvement Hearing involvement Immune involvement.
GANAB-CDG (13),(14) 21 X X
* MPI-CDG (15),(16),(17),(18) 37 X X X X X X X X X X
* PGM1-CDG (19),(20) 20 X X X X X X X
PRKCSH-CDG (21),(22),(23) 8 X X
SEC23B-CDG (24),(25) 32 X X X
TMEM199-CDG (26),(27) 7 X X X X X X X X X +/
VMA21-CDG (28) 3 X X X X
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Abbreviations: AP: Alkaline Phosphatase; AT: Antithrombin; CDG: Congenital disorders of glycosylation; Cr: Ceruloplasmin; G.I.: Gastrointestinal; H-Cu: Hepatic copper; LDL-C: Low Density Level Cholesterol; S-Cu: Serum copper; TA: Transaminases

*

Dietary supplementation attempted.

Arrows: ↑ Increased ↓Decreased

Legend: Different colours indicate % of patients/disease presenting laboratory/ clinical findings. Inline graphic

Fig.1.

Fig.1

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Flow chart showing the selection process to identify studies meeting the inclusion for liver involvement.

METHODS

We retrieved published articles from PubMed, Scopus and Medline by the following free text words: “Congenital disorders of glycosylation” or “CDG” and “liver” or “transaminases” or “immune” and others. The timeframe for our search was from January 2000 and October 2020. Study selection inclusion criteria were: English language; all ages CDG patients; peer-review studies; all clinical settings; all study design and type of publication including case reports.

Papers were excluded for the following reasons: - irrelevant topics; - no full-text available (conference abstracts, proceedings); - absence of results comparable with data from previous periods; - opinion and perspective papers without quantitative outcomes.

Data extracted from each study comprised reference, country, study design/type, number of patients, summary of findings.

Data extraction was done in duplicate by two of the authors. For the original search, one author conducted the initial screening of the titles and abstracts of articles identified. For the updated search, the titles and abstracts of the articles identified were screened by the other author. Subsequently, the relevant studies were assessed on their eligibility for inclusion depending on full texts. When there was no agreement about whether a study should be included based on the full text, one additional contributor (PV) helped resolve the controversy. The flow-chart of our search is summarized in a PRISMA Supplementary Figure (Figure S1). The search queries applied and relative results were included as PRISMA Supplementary Table.

We allocated CDG with liver involvement into two groups: in group 1 the liver is primarily affected and its puzzling derangement is often the most determinant of clinical outcome (n = 7), in group 2 the liver can possibly get involved in a multisystem disease with a mandatory albeit variable neurological involvement (n=34). Sometimes hepatomegaly or an isolated increase of transaminases could be the only hepatic evidence as part of other likely prevalent multisystem clinical manifestations (12).

We summarized the whole constellation of accompanying non-hepatic features in 2 synoptic tables [Tables 1A, and 1B], aiming to help to make a diagnosis and/or to raise the suspicion of CDG in a patient with an alleged cryptogenic liver disease. In all sections, CDG types are listed in alphabetic order. A possible guideline flow based on clinical synopsis and Tf isoelectrofocusing (Tf-IEF) is presented as well (Figure 2). Abnormal Tf can also be detected by ESi-MS or HPLC.

Fig 2.

Fig 2.

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CDG diagnosis guideline

Abbreviations: AP= Alkaline Phosphatase; APO C III= Apolipoprotein C III; AT= Antithrombin; CDG= congenital disorders of N-glycosylation; Cr= Ceruloplasmin; HPLC= High-Performance Liquid Chromatography; IEF= Isoelectrofocusing; LDL= Low-Density Lipoprotein; NGS= Next Generation Sequencing; S-Cu= Serum Copper; TA= Transaminases.

* APO C III analysis confirms a combined N and O glycosylation defect.

RESULTS

GROUP 1: CONGENITAL DISORDERS OF GLYCOSYLATION PRIMARILY AFFECTING THE LIVER (TABLE 1)

  • GANAB-CDG (OMIM #600666) due to deficiency of the catalytic alpha subunit of Glucosidase Alpha Neutral AB affects twenty-one patients described worldwide, with polycystic kidney and polycystic liver disease (13), (14).

  • MPI-CDG (CDG-Ib, OMIM #602579). The disease is due to mutations of the gene encoding for MPI (mannose phosphate isomerase). Thirty-seven affected patients have been reported, all presenting hepatic dysfunction (15), (16), (17), (18). In the majority of cases the disease occurs during early infancy. Liver features hepatomegaly, ascites, liver failure (reported in two cases), liver fibrosis and rarely cholangitis. Ductal plate malformation and bile duct abnormalities are seen. Other clinical findings include gastrointestinal dysfunctions, thrombotic events, hyperinsulinaemic hypoglycemia, coagulation disturbances.

  • PGM1-CDG (CDG-It, OMIM #614921) previously identified as a muscular glycogenosis (type XIV), is characterized by a wide range of clinical manifestations and severity. It is due to mutations in the phosphoglucomutase 1 gene, with thirty patients reported in the literature. Although patients displayed a variety of clinical features, this disorder is included in the group with primary liver disease because all had signs of hepatopathy with abnormal liver enzymes and frequent steatosis and fibrosis/cirrhosis. (19), (20). Transferrin analysis shows both absence of entire glycans and hypogalactosylated glycans (mixed type I/II). Providing dietary supplements of galactose improves biochemical parameters and clinical symptoms.

  • PRKCSH-CDG (OMIM #174050) The defect in non-catalytic subunit of α-glucosidase II which is also called protein kinase c substrate, is a 80-KD, heavy chain, is responsible for Polycystic liver disease 1, which causes a phenotype with multiple liver cysts (21), (22), (23).

  • SEC23B-CDG (OMIM #224100) Defects on SEC23B gene cause congenital dyserythropoietic anemia type II. Considering liver involvement, patients present cholelithiasis and iron overload potentially with liver cirrhosis or cardiac failure. Neonatal jaundice is reported in one case (24), (25).

  • TMEM199-CDG (CDG-IIp,OMIM #616829). This CDG is caused by the malfunction of the TMEM199 gene product, a transmembrane protein involved in Golgi homeostasis. There are seven cases reported in literature (26), (27). Differently from the other CDG of this category, patients look healthy and display hypertransaminasemia without liver failure and liver steatosis. In addition, they may experience high cholesterol levels, and hypoceruloplasminemia. Only one patient had neurological involvement (intellectual disability and hypotonia), but its actual correlation with TMEM199 has not been confirmed yet (27).

  • VMA21-CDG. X-linked (Xq28) mutation of the V-ATPase assembly factor VMA21 has been very recently associated to a novel form of CDG. Three patients from three unrelated families presented chronic hypertransaminasemia, fatty liver and dyslipidemia (28).

GROUP 2: CONGENITAL DISORDERS OF GLYCOSYLATION AFFECTING THE LIVER TOGETHER WITH A MAIN NEUROLOGICAL/MUSCULAR INVOLVEMENT (TABLE 2)

Table 2.

Biochemical, histological and clinical findings in 34 types of CDG in which liver can be involved in a multisystem disease including neurological symptoms (Group 2)

CDG Patients in studies ↑TA ↓ albumin ↓ glycemia ↑ LDL-C ↑ AP ↓ AT ↓ γ-globulins ↑ H-Cu ↓S-Cu ↓ Cr Liver Fibrosis Liver Steatosis Liver Cirrhosis Liver involvement Neur. involvement Muscle involvement Bone involvement Heart involvement G.I. involvement Kidney involvement Dysmorphism Vision involvement Hearing involvement Immune involvement
ALG1-CDG (46),(47),(12) 59 X X X X X X X X X
ALG2-CDG (29),(30) 3 X X X X
ALG3-CDG (38),(39),(40) 26 X X X X X X X X X X X
ALG6-CDG (43) 89 X X X
* ALG8-CDG (41),(42),(48) 18 X X X X X X X X X X X X
ALG9-CDG (44),(45) 13 X X X X X X X
ALG11-CDG (31),(32),(33) 8 X X X X X X
ALG12-CDG (34),(35),(36),(37),(12) 8 X X X X X X X X X X
ATP6AP1-CDG (50),(51),(52),(53),(54),(12) 17 X X X X X X X X X X X X X X X X
CCDC115-CDG (54),(55) 11 X X X X X X X X X X X X X
COG1-CDG (66),(67) 3 X X X X X X
COG2-CDG (69) 1 X X X X
COG4-CDG (64),(12) 16 X X X X X X X X X X X X
COG5-CDG (62),(63) 8 X X X X X X X X
COG6-CDG (59),(60),(61),(68),(12) 18 X X X X X X X X X X X
COG7-CDG (65),(12) 8 X X X X X X X X X
COG8-CDG (71),(72) 3 X X X X X X
DDOST-CDG (73) 1 X X X X X X
DHDDS-CDG (74) 1 X X X X X X
DPAGT1-CDG (75),(76),(77),(12) 39 X X X X X X X X X X X
DMP1-CDG (78) 9 X X X X X X X X X
EXT2-CDG (79),(80) 4 X X X X X X X
GNE-CDG (81),(82) 5 X X X X
MOGS-CDG (83),(84),(85),(86),(12) 5 X X X X X X X X X X X
MPDU1-CDG (87),(88),(89),(90) 7 X X X X X X X X X
PIGA-CDG (91),(92) 76 X X X X X X X
* PMM2-CDG (93)(94)(95)(96)(97)(98)(99) 1000 X X X X X X X X X X X X X X X X X
RFT1-CDG (116),(117) 11 X X X X X X
* SLC35A2-CDG (100),(101),(102),(103),(12) 30 X X X X X X X X X X
* SLC39A8-CDG (104),(105),(106),(12) 12 X X X X X X X X X X
SRD5A3-CDG (107),(108),(109),(110) 10 X X X X X
STT3B-CDG (111) 1 X X X X
* TMEM165-CDG (112) 8 X X X X X X X X X X X
TRAPPC11-CDG (113),(114),(115) 13 X X X X X X X X X
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Abbreviations: AP: Alkaline Phosphatase; AT: Antithrombin; CDG: Congenital disorders of glycosylation; Cr: Ceruloplasmin; G.I.: Gastrointestinal; H-Cu: Hepatic copper; LDL-C: Low Density Level Cholesterol; S-Cu: Serum copper; TA: Transaminases; Neur. Involvment:

*

Dietary supplementation attempted.

Arrows: ↑ Increased ↓Decreased

Legend: Different colours indicate % of patients/disease presenting laboratory/ clinical findings. Inline graphic

The results with shaded areas have the purpose to help a clinician to recognize a possible diagnosis of CDG. They have not statistic value, due to the limited number of patients involved in the studies and the possibility that some parameters might not have been mentioned in the studies at all.

This category includes 34 types of CDG with a variegate pattern of liver dysfunctions along with neurological/muscular involvement.

All ALG-CDG patients show neurological involvement. ALG2-CDG (OMIM #607906) an emerging CDG, where some cases show a myasthenic myopathic syndrome with hepatomegaly and coagulation abnormalities (29), (30). Dysmorphisms occur often in ALG3-CDG (OMIM #601110), ALG6-CDG (OMIM #603147), ALG9-CDG (OMIM #608776), ALG11-CDG (OMIM #613661), ALG12-CDG (OMIM #607143) and in the large majority of cases in ALG8-CDG (OMIM #608104) (including brachydactyly and distinctive facial features) (31), (32), (33), (34), (35), (36), (37). ALG3-CDG, ALG6-CDG and ALG9-CDG present also skeletal abnormalities (38), (39), (40). Visual impairment, and less frequently, deafness can be found. ALG6-CDG can present feeding problems, deep vein thrombosis, pubertal abnormalities (hyperandrogenism); in ALG8-CDG gastrointestinal symptoms, hematopoietic issues and skin symptoms can occur (41), (42), (43). Other signs/symptoms include immunological involvement in ALG1-CDG and ALG12-CDG, which causes recurrent infections (12). Renal involvement can be found in ALG8-CDG and ALG9-CDG; in the latter, also failure to thrive and pericardial effusion could be present (44), (45), (46), (47), (48).

  • ATP6AP1-CDG (Immunodeficiency 47, OMIM # 300972) results in the deficiency of ATPase H+ transporting accessory protein 1. Key features of the seventeen patients reported (49), (50), (51), (52), include immunodeficiency and liver involvement (12), ranging from cholestasis and mild hypertransaminasemia to cirrhosis, and end-stage liver failure requiring liver transplantation (53). Other symptoms include also neurological involvement, hearing loss, muscle weakness, cutis laxa, plantar abscesses, pancreatic and renal dysfunction, alopecia.

  • CCDC115-CDG (CDG IIo, OMIM #616828). It is due to coiled-coil domain containing 115 (CCDC115) deficiency. In addition to the eight originally described (54), three new unrelated patients have recently been reported (55). All show hepatic manifestations, including, in order of frequency, hepato(spleno)megaly, jaundice, liver failure, cholestasis. Five patients had also neurological symptoms, and five presented facial dysmorphisms, as well. Of the three patients described recently, two presented severe liver fibrosis and cirrhosis associated with neurological symptoms, the other one instead showed isolated liver involvement.

  • COG-CDG (Conserved Oligomeric Golgi-CDG). The conserved oligomeric Golgi (COG) complex is a hetero-octomeric tethering complex with a role in vesicle tethering (56), (57), so its mutations cause perturbation of the in- and outward vesicular trafficking at the Golgi apparatus and result in defects in N-linked glycans processing causing a type II Tf IEF pattern (58). Liver involvement exhibits a wide variability of clinical presentation (59) ranging from a mild hypertransaminasemia (COG2, COG8 described below in section 2.2), to severe hepatomegaly (COG1, COG7), cholestasis (COG6) and liver cirrhosis (COG4, COG5, COG6) (60), (61), (62), (63), (64), (65). All COG-CDG lead to a wide variety of neurological (microcephaly, hypotonia) and developmental abnormalities. Dysmorphisms and skeletal abnormalities are common in COG1-CDG and COG7-CDG (66), (67), (68). Visual and hearing impairment can include nystagmus in COG4-CDG, blindness and deafness in COG5-CDG. Gastrointestinal involvement is present in COG4-CDG and COG6-CDG. Other symptoms include failure to thrive, cardiac and immunological abnormalities, unexplained fever, feeding difficulties in COG1-CDG, and unspecified coagulation problems in COG2-CDG (69), (70). In COG6-CDG there is hypohidrosis/hyperkeratosis. COG4-CDG and COG7-CDG can cause early death. COG2-CDG (OMIM #617395) liver dysfunction was occasionally associated to transient hypocupremia/ hypoceruloplasminemia, and severe neurological abnormalities. COG8-CDG (OMIM #611182) includes four patients with elevated transaminases and neurological abnormalities (71), (72).

  • DDOST-CDG (CDG-Ir, OMIM #602202) The only reported patient had mild to moderate liver dysfunction associated to coagulopathy and neuromotor delay (73).

  • DHDDS-CDG (CDG-Ibb, OMIM #613861) dehydrodolichyl diphosphate synthase; it is caused by the deficiency of polyprenyl chain elongation that leads to synthesis of dehydrodolichyl diphosphate. The clinical picture (blindness, deafness, renal failure and epilepsy) also includes hepatomegaly and a mild dilatation of the biliary duct. (74).

  • DPAGT1-CDG (CDG-Ij, OMIM #608093) is due to the defect of dolichyl-phosphate N-acetylglucosamine phosphotransferase. Fifty-two patients are reported that present either an encephalopathy in the context of a multisystem disorder or a congenital myasthenic syndrome. Laboratory findings show hypertransaminasemia and coagulation defects, hyperproteinemia and chronic anemia (12), (75), (76), (77).

  • DPM1-CDG (CDG1e, OMIM #608799) is due to defect of dolichol phosphate mannose synthase. Nine reported patients presented predominant neurological and eye involvement, dysmorphic features, food protein-induced enterocolitis syndrome, hepatomegaly, elevated transaminases and low antithrombin (78).

  • EXT2-CDG (Exostosin glycosyl transferase 2) (OMIM # 133701). The autosomal dominant form of multiple exostoses (EXT1/EXT2 CDG) is the most common of the benign bone tumors (79). Some patients (OMIM # 616682) with an AR transmission have no bone disease but show instead a seizures-scoliosis-macrocephaly syndrome including developmental disorder, seizures and, very rarely, renal and/or hepatic dysfunction (80).

  • GNE-CDG (OMIM #605828, OMIM #269921) is due to defect of UDP-N-acetylglucosamine 2-epimerase/n-acetylmannosamine kinase. It can cause both Nonaka myopathy and Sialuria showing increased serum creatine kinase (CK) and enlargement of the liver (81), (82).

  • MOGS-CDG (CDG-IIb, OMIM #606056) is due to mutations in the α-glucosidase I which removes the outermost glucose from the N-linked glycans found on newly synthesized glycoproteins. Four patients presented faciodigital dysmorphisms, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency (12), (83), (84), (85), (86).

  • MPDU1-CDG (CDG If, OMIM #609180) is reported in seven patients with mannose p-dolichol utilization 1 deficiency: one had hepatomegaly, hepatocellular dysfunction and coagulopathy (87), (88), (89); two presented massive dilation of the biliary duct system along with dystroglycanopathy characteristics including hypotonia, dilated cardiomyopathy, buphthalmos, and congenital glaucoma (90).

  • PIGA-CDG (OMIM #300868, OMIM #300818) is due to phosphatidylinositol glycan anchor biosynthesis deficiency. The seventy-six affected patients reported variable liver involvement (91), (92).

  • PMM2-CDG (CDG Ia or Jaeken syndrome, OMIM #212065). Patients present defect of phosphomannomutase 2, catalyzing the second step of mannose activation (Man-6-P to Man-1-P) that produces GDP-Man used for several major glycosylation pathways, including N-glycosylation. It’s the most frequent CDG. Previously, more than 700 patients were reported worldwide (93). As shown in Table 1A, the verified number is now nearly 1000. Patients usually present dysmorphisms and multiorgan involvement. Liver involvement may occur as two distinct phenotypes: severe neonatal/infantile liver failure and mild phenotype characterized by hepatomegaly and hypertransaminasemia, generally without progression towards severe liver dysfunction (94), (95), (96), (97), (98). Hypertransaminasemia tends to improve over time. Neurological symptoms, immunological involvement and failure to thrive are the most frequent symptoms, with hyperinsulinemic hypoglycemia reported in a few patients in the first year of life. Liver, endocrine and coagulation abnormalities as well as motor disabilities seem to improve over time. In a small cohort of patients, neurological involvement did not get worse over time (12), (99).

  • SLC35A2-CDG (CDG-IIm, OMIM #300896) is due to deficiency of UDP-galactose transporter. The latest major study featured 30 patients with neurodevelopmental deficiencies, hypertransaminasemia and mild hepatomegaly, coagulopathy, growth retardation (100), (101), (102), (103), (12).

  • SLC39A8-CDG (CDG-IIn, OMIM #616721) is caused by the deficiency of solute carrier family 39 (zinc and manganese transporter), member 8. It can cause both a type II CDG with patients having defective glycan processing based on Tf IEF and Leigh-like syndrome. One of the 12 reported patients presented impaired coagulation, hypertransaminasemia and liver disease (12), (104), (105), (106).

  • SRD5A3-CDG (CDG-Iq, OMIM #612379) is due to defect of steroid 5α-reductase type 3 needed to convert polyprenol to dolichol, the lipid carrier of the precursor glycan for N-glycosylation. Nine patients presented microcytic anemia, transient hypertransaminasemia and coagulation abnormalities. Variable eye and skin involvement are predominant (107), (108), (109), (110).

  • STT3B-CDG (CDG-Ix, OMIM #615597) A single patient is reported in literature. Beyond other features, he also had unspecified liver involvement (111).

  • TMEM165-CDG (CDG-IIk, OMIM #614727). The defect of transmembrane protein 165 is characterized by a mild to moderate hypertransaminasemia. Among the seven patients reported, two showed hepatosplenomegaly (112).

  • TRAPPC11 CDG (OMIM #610969) due to the lack of trafficking protein particle complex 11. One of the thirteen affected patients showed cholestasis and fatty liver (113), (114), (115).

  • RFT1-CDG (CDG-In, OMIM #612015) is caused by a defect of lipid-linked oligosaccharide (LLO) assembly. Some of the nine patients reported with hypotonia, development delay, and seizures also had hepatomegaly and coagulopathy (116), (117).

ROUTINE LABORATORY EVIDENCE

Routine laboratory evidence usually shows multiples abnormalities, depending either on the specific organs involved (e.g. elevated transaminases, creatine kinase, etc.) or on the hypoglycosylation of proteins used in clinical chemistry laboratory panels (e.g. low coagulation factors, including antithrombin III and low levels of ceruloplasmin). Wilson disease exclusion is often needed due to the finding also of increased hepatic/urinary copper content in some types of CDG (TMEM199-CDG, CCDC115-CDG, ATP6AP1-CDG, PMM2-CDG, COG2-CDG) (118), (119), (120).

DIAGNOSIS OF CONGENITAL DISORDERS of GLYCOSYLATION

The first step in the screening often is still serum transferrin analysis, but - as already stated (2),(3) - some 50 % of CDG cannot be detected by this test. However, IEF of serum transferrin is still the simplest and most widely available method for the diagnosis of N-glycosylation disorders associated with sialic acid deficiency. Some caution is however due to secondary disorders of glycosylation (e.g. in inborn errors of fructose metabolism and uncontrolled galactosemia) which may cause erroneous diagnosis (121). Furthermore, patients with other liver disease may display on their own abnormal glycosylation of glycoproteins, resulting in altered CDG screening tests (8), most often with increased asialo-Tf as well as monosialo-Tf isoforms and normal percentage of trisialoTf isoform (9). Next-generation sequencing, via whole-exome sequencing or targeted gene panels, in combination with clinical phenotyping is the most efficient diagnostic protocol for CDG gene identification and is essential for a definitive diagnosis. Glycan and glycopeptides structural analysis by mass spectrometry can be very useful to substantiate or confirm potential pathological genetic variants in enzymes and transporters involved in the Golgi processing of glycan (122). Though, an increasing number of new technologies continue to be proposed (123).

Based on the results of our review abridged in Tables 1 A and 1B we could readapt some existing diagrams (8), (124) and propose a simplified step-by-step approach to diagnose a CDG-related liver disease as schematized in Figure 2 and further commented in Supplementary materials, Table S1 (125).

HISTOLOGY

Most types of CDG show more than one kind of liver injury as histopathological changes. These include hepatic micro-macrovesicular steatosis, and fibrosis and cirrhosis often already in the early phase of the disease, and do not allow to identify/suspect the exact CDG type. However, abnormal lysosomal lamellar inclusions in the hepatocytes (so-called myelinosomes) were originally described in CDG-I but not in CDG II (126).

The literature regarding ultrastructural microscopic liver features of CDG is sparse and there are a limited number of studies focusing on this point of view. Recently, ultrastructural anomalies such as endoplasmic reticulum with enlarged tubules containing microfibrillar material inside, and various mitochondrial abnormalities have also been described (127). Typical Wilsonian like mitochondrial abnormalities however were not reported in CDG patients with hypoceruloplasminemia (26).

CDG testing should be envisaged also in the case of biliary system abnormalities resulting from ductal plate malformations and the spectrum of congenital hepatic fibrosis (128).

EFFECTS OF DIET-THERAPY IN CONGENITAL DISORDERS of GLYCOSYLATION WITH LIVER DISEASE

The CDG therapeutic strategy with sugar supplementation aims to provide exogenous monosaccharides to circumvent the disruption of glycosylation through recruitment of complementary mechanisms or upregulation of affected pathways. With the exception of MPI-CDG and PGM1-CDG most of therapeutic experiences however are based on individual CDG cases rather than on clinical trials (129), (130), so that a convincing proof of efficacy remains open. Moreover, while glycosylation changes were frequently described, effects on liver involvement were not always reported. In general, there is no targeted nutritional treatment for liver disease in most of CDG, apart from the general indications of liposoluble vitamins supplementations and medium chain triglycerides dietary integration in those cases with cholestasis. Details regarding therapeutic strategies and treatment regimens are reported in Supplementary Materials Table S2 (131–141).

PROGNOSIS OF LIVER DISEASE

In several CDG cases, transaminases tend to normalize with growth, even if sometimes their levels could rise when the patient gets ill (142). In CDG type I, also coagulation parameters and blood glucose levels may show a spontaneous improvement, often independent of medical treatments. Coagulation abnormalities require special attention in CDG. They typically affect both procoagulant and anticoagulant factors, whereas antithrombin deficiency, protein C and S deficiency, and factor XI deficiency were mainly observed (143). These deficits are related to the hypoglycosylation of glycoproteins and can lead to both thrombosis and haemorrhages. Moreover, altered platelet membrane glycoproteins can alter the coagulation cascade. Thrombosis has also been reported as the presenting sign of CDG (144). Coagulation abnormalities however do not truly reflect liver failure because protein defective glycosylation may represent by itself the cause of pathological laboratory results. In 39 CDG patients, Starosta et al found that almost half of them had elevated ALT and 70% of them had elevated values of AST. 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 (145). In some affected individuals (e.g. in TMEM1199) however transaminases remain elevated for years, and/or liver fibrosis and cirrhosis may develop (e.g. CCDC115). PMM2-CDG long-term course is not well documented: in a retrospective study, 41 of 96 patients showed elevated transaminases at diagnosis, and levels significantly decreased during follow-up. At last observation (mean age : 12 years old) hepatomegaly regression was noted in some, but 38 patients still showed liver disease including liver failure (one died) (99). Liver transplant has been reported to be a successful treatment as the last step for progressive liver fibrosis and cirrhosis (e.g. MPI-CDG, or CCDC1115-CDG).

DISCUSSION

Our systematic review updated previous screening studies and found that overall 41 types of the CDG so far known (about 30%) has some liver involvement: hepatopathy was prevalent in 7, and in the context of a multisystem disease with associated neurological/muscular involvement in 34.

It is difficult to understand why CDG types have a wide range of presenting liver symptoms that may span the spectrum from silent hypertransaminasemia up to cirrhosis, with either a static/improving outcome or a progressive liver disease eventually needing organ transplant. The understanding of the mechanisms underlying the complexity of the connections between pathological liver features and CDG has started to be clarified recently only for a few conditions. Some genes related to both glycoprotein processing control mechanisms along with polycystin expression/localization [i.e. SEC63 homolog (S. cerevisiae) (SEC63) and PRKCSH protein kinase C substrate 80K-H (80 kDa protein, Heavy chain) (PRKCSH)] have for example recently been related to hepatic cystogenesis (146), (147). PRKCSH defective glycosylation in the ER may lead to protein degradation possibly explaining the cystogenesis of some CDG (e.g. ALG 8-CDG). Deglycosylation of proteins synthesized in the ER but retro-translocated in the cytoplasm are deficient in N-glycanase 1 (EC 3.5.1.52) patients. This may determine liver impairment associated to hypertransaminasemia and micro-macro vesicular steatosis (148). Another possible effect of hypoglycosylation has been assumed for the finding of increased liver copper content and hypoceruloplasminemia in some CDG patients (TMEM199-/ CCDC115-CDG), similarly to Wilson disease. Vajro et al discussed that the mechanisms behind these disturbances are at the moment uncertain, but potentially involve at least partial loss of the copper transporting proteins (ATP7A, ATP7B), impairing the copper excretion into the serum and the subsequent hypoceruloplasminemia. ATP7A is glycosylated and deficient glycosylation could potentially directly affect its function. Notably, ATP7B is not glycosylated, but its residence in the Golgi might explain the postulated link between V-ATPase malfunction and loss of ATP7B mediated copper transportation. Also, several COG subunits (involved in Golgi homeostasis and glycosylation) are within the interactome of ATP7B, linking Golgi homeostasis, glycosylation and intracellular copper homeostasis (26).

CDG has rarely been reported as a cause of acute liver failure (ALF) (149) and in a retrospective analysis of metabolic diseases presenting as ALF, only 1/127 patients resulted affected by CDG (CCDC115-CDG) (150). However, more recently, another CDG has been reported to present as ALF (e.g. COG4-CDG), adding on to other rare types (e.g. the severe phenotype of ATP6AP1-CDG) (51), (52), (53) which therefore require to be considered in the ALF diagnostic work-up.

CONCLUSIONS

We have reported the case history of forty-one CDG with liver involvement published during the last 20 years and analysed their presentation characteristics. The diagnosis remains a challenge not only because of the vast phenotypic heterogeneity of the different subtypes, but also for the unavailability of simple screening methods for about half of them. Poor awareness of and information on CDG in the medical community is another cause. Although liver disease of most CDG patients may have a long and not infrequently remitting course, prompt recognition of some subtypes may be of importance for alerting about the possible progression to early liver failure eventually needing liver transplantation.

Supplementary Material

Supplementary Figure 1.
1

What Is Known.

  • Congenital disorders of glycosylation (CDG) may underlie a number of unexplained liver diseases, either in a multi-organ (prevalently neuro/muscular) context or almost isolated.

  • An earlier literature review had screened 23 forms of CDG with liver disease.

What Is New.

  • Amongst the phenotypic heterogeneity of the CDG our updated screening recognized 41 forms with liver involvement.

  • Presenting liver symptoms of CDG types span the spectrum from silent hypertransaminasemia up to cirrhosis, eventually needing liver transplant.

  • The index of suspicion of a CDG-related liver disease may be raised by pinpointing the whole constellation of other non-hepatic/non –neuromuscular features.

ACKNOWLEDGEMENTS

This work was supported by the Rocket Fund and the National Institutes of Health grants R01DK99551. H.H.F. is supported by the Rocket Fund and R01DK99551

Footnotes

CONFLICT OF INTEREST

All declare that they have no conflict of interest.

SUPPORTING INFORMATION

Additional supporting information may be found online in the Supporting Information section at the end of this article.

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