Manifestations and Management of Hepatic Dysfunction in Congenital Disorders of Glycosylation

Abbreviations

A1AT

alpha‐1‐antitrypsin

ACTH

adrenocorticotropic hormone

AFP

alpha‐fetoprotein

ALG

asparagine‐linked glycosylation homolog

ALS

acid‐labile subunit

AP

alkaline phosphatase

ApoCIII

apolipoprotein CIII

aPTT

activated partial thromboplastin time

ATIII

antithrombin III

ATP6AP1

ATPase, H+ transporting, lysosomal, accessory protein 1

CBC

complete blood count

CCDC115

coiled‐coin domain‐containing protein 115

CDG

congenital disorders of glycosylation

CDT

carbohydrate‐deficient transferrin

CHF

congenital hepatic fibrosis

CK

creatine kinase

COG

component of oligomeric Golgi complex

del

deletion

dup

duplication

ER

endoplasmic reticulum

Gal‐1‐P

galactose‐1‐phosphate

GDP

guanosine‐diphosphate

GGT

gamma‐glutamyl transferase

GI

gastrointestinal

GlcNAc

N‐acetylglucosamine

GSD

glycogen storage disease

HbA1C

hemoglobin A1c

IgA

immunoglobulin A

IGF1

insulin‐like growth factor 1

IGFBP‐3

insulin‐like growth factor binding protein 1

IgG

immunoglobulin G

IgM

immunoglobulin M

IV

intravenous

LDL

low‐density lipoprotein

MPI

mannosephosphate isomerase

PGM1

phosphoglucomutase 1

PLE

protein‐losing enteropathy

PMM2

phosphomannomutase 2

PT

prothrombin time

PTH

parathyroid hormone

SLC35A2

solute carrier family 35, member 2

SLC39A8

solute carrier family 39, member 8

SRD5A3

steroid 5 alpha reductase type 3

T4

thyroxine

TA

transaminase

TBG

thyroxine binding globulin

TMEM199

transmembrane protein 199

TSH

thyroid‐stimulating hormone

UDP

uridine‐diphosphate

US

ultrasound

WES

whole‐exome sequencing

WGS

whole‐genome sequencing

The congenital disorders of glycosylation (CDG) are rare genetic disorders that disrupt the posttranslational modification of glycoproteins and the synthesis of glycolipids. These disorders exhibit cellular and tissue dysfunction across nearly every organ system, including the liver, which is a major source of glycoprotein production and secretion. The initial presentation of CDG often involves liver or gastrointestinal (GI) dysfunction.¹ There are approximately 150 identified genetic causes of CDG, and an increasing number of treatment options are being discovered, including manipulation of monosaccharide biochemical pathways. The cellular process of glycosylation and key steps associated with liver dysfunction are illustrated in Fig. 1. The GI specialist should be able to recognize and diagnose these disorders so that treatment, when available, can quickly be initiated and other organ dysfunction identified and treated.

FIG 1.

Glycosylation pathway for CDG with liver involvement, in three stages: (1) Synthesis of nucleotide‐linked sugars (GDP‐mannose and others) from glucose‐1‐phosphate in the cytosol. In PGM1‐CDG, MPI‐CDG, and PMM2‐CDG, these first steps are interrupted. GDP‐mannose and other sugar units are attached to dolichol phosphate to form glycan chains on the outside of the ER. (2) The resulting oligosaccharide is flipped into the ER lumen, where further sugar units are added. (3) The glycan chain is transferred to a protein and transported to the Golgi, where different factors are responsible for accurate final processing (such as homeostasis factors, transporters for the influx of ions and metabolites, and trafficking proteins). Transferrin is one of the resulting N‐glycosylated proteins and normally has two glycan chains with four sialic acid residues (tetrasialo‐transferrin). In type I CDG, one whole glycan chain is missing (disialo‐transferrin). In type II CDG, individual sugar units are missing (possibly resulting in mono‐ and/or trisialo‐transferrin isoforms).

Liver Involvement

Liver and GI dysfunction in CDG is variable and may include elevated transaminases (TAs), hepatomegaly, coagulopathy, hypoalbuminemia, protein‐losing enteropathy (PLE), failure to thrive, steatosis, fibrosis, cirrhosis, and acute liver failure. A recent evaluation of 16 different CDG implicated hepatocytes as the primary cellular source of liver dysfunction.² CDG cluster into those that present with (1) predominant or isolated liver disease, (2) liver disease with other significant multisystem comorbidities, and (3) isolated TA elevations (Table 1).

TABLE 1.

Clinical and Laboratory Features, Diagnostic Characteristics, and Treatment of CDG With Liver Involvement

CDG	Liver Phenotype	Other Characteristic Phenotype	Laboratory Features	Diagnostic Testing Results	Treatment
CDG with predominant liver involvement
MPI‐CDG	Fibrosis	Intestinal symptoms: ‐Diarrhea ‐Failure to thrive ‐PLE ‐Vomiting	↑ TAs	Type 1 CDT pattern	Mannose resolves intestinal symptoms, endocrine symptoms, coagulation, and laboratory abnormalities (liver transplantation may still be required because of cirrhosis and is curative)
	Hepatomegaly		↓ Albumin	Deficient MPI enzyme activity in leukocytes
	Hepatopathy		↓ PT
	Portal hypertension		↓ ATIII
	Rare: ‐Cirrhosis ‐Cholestasis ‐Cholangitis ‐Hepatopulmonary syndrome		↓ Protein C
		Endocrine symptoms: ‐Hyperinsulinism ‐Growth restriction ‐Hypothyroidism	↓ Protein S
			↓ Factor XI
	Biopsy: periportal fibrosis, microvesicular steatosis, abnormal development of biliary tree, ductal plate malformation (CHF‐like appearance)	Coagulation symptoms: ‐Thrombotic events ‐GI bleeding ‐Coagulopathy
TMEM199‐CDG	Steatosis	Isolated liver phenotype	↑ TA	Type 2 CDT pattern	No specific treatment available
	Biopsy: mild hepatic copper accumulation	Onset often in adolescence	↑ AP	Abnormal ApoCIII glycosylation
			↓ ATIII
			↑ LDL‐cholesterol
			↓ Ceruloplasmin
CCDC115‐CDG	Hepatosplenomegaly	Developmental disability (seizures in some patients)	↑ Bone‐derived AP	Type 2 CDT pattern	No specific treatment available
	Cirrhosis		↑ TAs	Abnormal ApoCIII glycosylation	Liver transplantation has been successfully performed
	Cholestatic hepatitis		↑ Ceruloplasmin
	Biopsy: hepatic copper accumulation, steatosis, fibrosis, necrosis, cirrhosis, glycogen accumulation with fine hepatocellular vacuolization		↑ Cholesterol
ATP6AP1‐CDG	Neonatal jaundice	Immunodeficiency	↑ TA	Type 2 CDT pattern	No specific treatment available
	Cholestasis	Developmental disability (seizures in some patients)	↑ AP	Abnormal ApoCIII glycosylation	Liver transplantation has been successfully performed
	Cirrhosis	Cutis laxa	↓ Ceruloplasmin
	Hepatomegaly	X‐linked (females unaffected)	↑ Copper
	Possible liver failure at young age		↓ IgG
	Biopsy: hepatic copper accumulation, mild steatosis, or fibrosis
SLC37A4‐CDG	Severe hepatopathy	Facial dysmorphism	↑ TA	Type 2 CDT pattern	No specific treatment available
	Steatosis	Strabismus	↑ AP	De novo c.1267C>T (p.R423*) causes CDG (homozygous mutation causes GSD‐Ib)
	Biopsy: steatosis, increased hepatocyte volume	Failure to thrive	↑ GGT
			↑ aPTT
			↓ ATIII
			↓ Fibrinogen
			↓ Factors II, V, VII, XII
CDG with nonpredominant liver disease
PMM2‐CDG	Elevated TAs	Developmental disability (seizures in some patients)	↑ TAs	Type 1 CDT pattern (can rarely be normal)	No specific treatment available
	Hepatomegaly	Cerebellar hypoplasia	↓ ATIII	Deficient PMM2 enzyme activity in leukocytes
	Liver fibrosis	Pericardial effusion	↓ PT
	Liver steatosis	Inverted nipples	↓ Prothrombin
	Liver cirrhosis	Strabismus	↓ Protein C
	Ascites		↓ Protein S
	Biopsy: steatosis, fibrosis, cirrhosis, prominent cholestatic bile canaliculi, myelin‐like lysosomal inclusions in hepatocytes		↓ Factor IX
			↓ LDL‐cholesterol
			(↓ Albumin)
PGM1‐CDG	Hepatomegaly	Microretrognathia	↑ TA	Mixed type 1/type 2 CDT pattern	Galactose improves laboratory abnormalities, improves myopathic symptoms (complex carbohydrate‐rich diet)
	Hepatopathy	Cleft palate/bifid uvula	↓ ATIII	Deficient PGM1 enzyme activity in leukocytes/fibroblasts
	Biopsy: steatosis, cholestasis, mild fibrosis, glycogen accumulation	Pierre‐Robin sequence	↑ CK
		Cardiomyopathy
		Short stature
		Myopathy
		Hypoglycemia
ALG1‐CDG	Ascites	Developmental disability (seizures in some patients)	↑ TAs	Type 1 CDT pattern	No specific treatment available
	Cholestatic jaundice	Cardiomyopathy	↓ Albumin
	Portal hypertension
	Budd‐Chiari syndrome
ALG3‐CDG	Hepatomegaly	Developmental disability (seizures in some patients)	↑ TAs	Type 1 CDT pattern	No specific treatment available (ketogenic diet can improve seizures)
	Steatosis	Dysmorphic facial features	↓ Albumin
	Lobular structures on liver surface on liver US	Microcephaly
	Biopsy: steatosis, intrahepatic biliary fibroadenomatosis, including portal fibrosis and abnormal cystic and branched bile ducts on portal tracts, hepatocellular hemosiderosis	Arthrogryposis multiplex
ALG6‐CDG	Hepatomegaly	Developmental disability (seizures in some patients)	↑ TA	Type 1 CDT pattern	No specific treatment available
	Jaundice	Strabismus	↓ ATIII
			↓ LDL‐cholesterol
			↓ Factor XI
			↓ Protein C
			↓ Protein S
			↓ Albumin
ALG8‐CDG	PLE	Developmental disability (seizures in some patients)	↑ TAs	Type 1 CDT pattern	No specific treatment available
	Hepatomegaly		↓ ATIII
	Possible liver failure in infancy		↓ Albumin
	Biopsy: multiple cystic dilated intrahepatic and extrahepatic bile ducts
	Cholestasis
ALG9‐CDG	Liver cysts	Developmental disability (seizures in some patients)	↓ ATIII	Type 1 CDT pattern	No specific treatment available
	Hepato(‐spleno)megaly	Skeletal dysplasia	↓ Albumin
ALG13‐CDG	Hepatomegaly	Multisystem involvement in males	↑ TAs	Type 1 CDT pattern (frequently normal CDT, particularly for females)	No specific treatment available (ACTH, ketogenic diet can improve seizures)
		Primarily neurological involvement in females	↑ AP
		Developmental disability (seizures in some patients)
		X‐linked (de novo in females, can be inherited or de novo mosaic in males)
SRD5A3‐CDG	Elevated TAs Hepatosplenomegaly Biopsy: Inflammation, macro‐ and microvesicular steatosis	Developmental disability (seizures in many patients) Eye abnormalities (cataract, coloboma, optic disc dysplasia) Skin findings (ichthyosis)	↑ TA ↓ ATIII	Type 1 CDT pattern (but can be normal)	No specific treatment available
ATP6AP2‐CDG	Prolonged neonatal jaundice	Immunodeficiency	↑ TA	Type 2 CDT pattern	No specific treatment available
	Persistent hepatosplenomegaly	Cognitive impairment	↓ Albumin	Abnormal ApoCIII glycosylation
	Ascites	X‐linked	↓ IgG
COG‐CDG (COG1, COG4 COG5, COG6, COG7)	Hepato(spleno‐)megaly	Developmental disability (seizures in some patients)	↑ TA	Type 2 CDT pattern	No specific treatment available
	Steatosis	Multisystem involvement	↓ ATIII	Abnormal ApoCIII glycosylation
	Cirrhosis		↑ AP
	Jaundice		↑ GGT
	Cholestasis
CDG with isolated elevation of liver TAs
ALG12‐CDG	Only isolated elevated TAs described	Developmental disability (seizures in some patients)	↑ TA	Type 1 CDT pattern	No specific treatment available
		Immunodeficiency
		Skeletal dysplasia
SLC35A2‐CDG	Only isolated elevated TAs described	Developmental disability (seizures in some patients)	↑ TA	Type 2 CDT pattern (but often normal)	Galactose improves/normalizes glycosylation and improves TA seizures, growth, and motor skills
		Shortened extremities
		X‐linked (de novo in females, de novo mosaic in males)
SLC39A8‐CDG	Only isolated elevated TAs described	Developmental disability (seizures in some patients)	↑ TAs	Type 2 CDT pattern	Manganese corrects multiple biochemical abnormalities, including glycosylation, and improves development
		Skeletal abnormalities	↓ Manganese	Abnormal ApoCIII glycosylation	Galactose improves or normalizes glycosylation
		Immunodeficiency
TMEM165‐CDG	Only isolated elevated TAs described	Developmental disability	↑ TAs	Type 2 CDT pattern	Galactose improves glycosylation, biochemical, and clinical parameters, including ALT
		Endocrine symptoms	↑ CK
		Skeletal dysplasia

Of the CDG with predominant liver symptoms, recognizing MPI‐CDG (mannosephosphate isomerase‐CDG) is the most critical because it is effectively treated with dietary mannose supplementation to bypass the underlying enzyme defect, resulting in rapid clinical and biochemical improvement.³ Due to severe diarrhea and abdominal pain, MPI‐CDG is often initially misdiagnosed and investigated for celiac disease, cow milk allergy, or other GI disorders. MPI‐CDG may also demonstrate developmental abnormalities of the biliary tree, requiring liver transplantation despite mannose therapy.⁴ International consensus guidelines for the treatment and management of MPI‐CDG⁵ are summarized in Table 2.

TABLE 2.

Monitoring and Treatment Recommendations for CDG With Liver Involvement

CDG	Initial Evaluations	Treatment	GI Monitoring	Other Specialists
MPI‐CDG5	Diagnostic evaluation:	Oral mannose:	Follow‐up during oral mannose therapy:	Endocrinologist
	‐ CDT (serum or plasma)	‐ 150‐170 mg/kg/dose 4‐5 times a day (maximum 600 mg/kg/day; maximum 6 times a day)	‐ Every 3 months: unconjugated bilirubin, whole blood count, HbA1C, CDT	Geneticist
	‐ Genetic testing			Hematologist
	‐ Enzyme activity (leukocytes)	IV mannose:	Follow‐up of disease signs (with or without mannose therapy):	Neurologist
		‐ Only in life‐threatening conditions (when oral intake is not possible)	‐ Every 3 months:
	Baseline imaging:	‐ Up to 1 g/kg/day continuous infusion, combined with individualized IV glucose to prevent hypoglycemia	‐ Albumin (more often in case of severe PLE, every 6 months in the absence of PLE)
	‐ Liver US and elastography	‐ Monitor for severe hemolysis, severe neurological symptoms
	‐ Renal US		‐ Every 6 months (every 3 months in marked pathology):
	‐ Echocardiogram	Liver transplantation:	‐ Labs:
		‐ Consider in case of liver failure or portal hypertension with hepatopulmonary syndrome	‐ TA, GGT, bilirubin, AFP, PT
	Baseline labs:		‐ Liver US (eventually every 12 months, depending on severity of liver involvement)
	‐ CBC + differential	Additional measures:
	‐ Liver/GI tests: TAs, GGT, bilirubin, AFP, albumin, fecal A1AT	‐ Vaccination against hepatitis A and B	‐ Every 12 months:
	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S, factors II, V, VII, and X	‐ Avoidance of hepatotoxic drugs	‐ Liver elastography
	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins	‐ Alcohol abstinence	‐ Labs:
	‐ Endocrine: insulin, C peptide, cortisol, lactate, fatty acids, urinary ketones, TSH, T4, IGF1, IGFBP‐3, ALS, ALP, PTH, calcium, magnesium, phosphate	‐ Parenteral nutrition (in undernourished patients with chronic diarrhea or recurrent vomiting)	‐ Whole blood count plus differential
	‐ Renal function	‐ Albumin infusion (20% solution) in patients with serum albumin <2 g/dL and edema	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S (optional: factors II, V, VII, and X)
	‐ Immune: IgM, IgA, IgG		‐ Fecal A1AT
		Consider:	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
		In patients with portal hypertension with preserved hepatic function (normal PT, no hepatic encephalopathy):
		‐ Pharmacological therapy (e.g., nonselective beta‐blockers) or	‐ Patients with portal hypertension:
		‐ Shunting procedures (e.g., transjugular portosystemic shunt or distal splenorenal shunt)	‐ Esophageal endoscopy after 12 months (and then according to findings at least every 3 years)
			‐ Yearly checkup for extrahepatic complications:
			‐ Cardiac echography (portopulmonary hypertension)
			‐ Oximetry while lying down and standing, possibly with contrast cardiac US (hepatopulmonary syndrome)
			‐ Right away in case of imminent decompensation of coagulation (intercurrent infections, dehydration, severe PLE, before and after invasive procedures, etc.): basic coagulation parameters (PT, PTT, fibrinogen, factor XI, AT, protein C, protein S)
TMEM199‐CDG6	Diagnostic evaluation:	No specific therapy	Every 6‐12 months:	Geneticist
	‐ CDT (serum or plasma)		‐ Liver US
	‐ ApoCIII glycosylation	Additional measures:	‐ Liver elastography
	‐ Genetic testing	‐ Avoidance of hepatotoxic drugs	‐ Labs:
			‐ GI: TA, copper, ceruloplasmin, CDT, ApoCIII, ALP
	Baseline imaging:		‐ Coagulation parameters: PT, PTT, factor IX, factor XI, AT, protein C, protein S
	‐ Abdominal US and elastography		‐ Nutritional parameters: prealbumin, albumin, lipids, urea, creatinine, electrolytes
	Baseline labs:
	‐ CBC plus differential
	‐ Liver/GI tests: TA, GGT, CK, bilirubin, albumin, copper, ceruloplasmin
	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S, factors II, V, VII, and X
	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
	‐ Endocrine: cortisol, TSH, T4, ALP, PTH, calcium, magnesium, phosphate
	‐ Renal function
CCDC115‐CDG8	Diagnostic evaluation:	No specific therapy	Every 6‐12 months:	Geneticist
	‐ CDT (serum or plasma)		‐ Liver US	Neurologist
	‐ ApoCIII glycosylation	Liver transplantation:	‐ Liver elastography
	‐ Genetic testing	‐ Consider in case of liver failure	‐ Labs:
			‐ GI: TAs, copper, ceruloplasmin, CDT, ApoCIII, ALP, CK
	Baseline imaging:	Additional measures:	‐ Coagulation parameters: PT, PTT, factor IX, factor XI, AT, protein C, protein S
	‐ Abdominal US	‐ Avoidance of hepatotoxic drugs	‐ Nutritional parameters: prealbumin, albumin, lipids, urea, creatinine, electrolytes
	‐ Liver elastography
	Baseline labs:
	‐ CBC plus differential
	‐ Liver/GI tests: TAs, GGT, bilirubin, albumin, copper, ceruloplasmin, CK
	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S, factors II, V, VII, and X
	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
	‐ Endocrine: cortisol, TSH, T4, ALP, PTH, calcium, magnesium, phosphate
ATP6AP1‐CDG7	Diagnostic evaluation:	No specific therapy	Every 6‐12 months:	Cardiologist
	‐ CDT (serum or plasma)		‐ Liver US	Developmental pediatrician
	‐ ApoCIII glycosylation	Liver transplantation:	‐ Liver elastography	Geneticist
	‐ Genetic testing	‐ Consider in case of liver failure	‐ Labs:	Immunologist
			‐ GI: TAs; CK; fecal elastase; vitamins A, D, E, and K; ceruloplasmin; copper; fasting lipids; CDT; ApoCIII	Neurologist
	Baseline imaging:	Additional measures:	‐ Coagulation parameters: PT, PTT, AT
	‐ Abdominal US and liver elastography	‐ Avoidance of hepatotoxic drugs	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamin A, D, E, and K
	‐ Renal US
	‐ Echocardiogram
	Baseline labs:
	‐ GI: TA; CK; fecal elastase; vitamins A, D, E, and K; ceruloplasmin; copper; fasting lipids
	‐ Endocrine: am cortisol, ACTH, TBG, TSH, free T4, vitamin D, 25‐OH
	‐ Hematology: CBC with differential, PT/PTT, AT
	‐ Renal: urinalysis
	‐ Immunology: IgM, IgG, IgA, titers to vaccination
	Audiology evaluation
	Ophthalmology evaluation
	Neurologist developmental assessment
PMM2‐CDG9	Diagnostic evaluation:	No specific therapy	Every 6‐12 months:	Cardiologist
	‐ CDT (serum or plasma)		‐ Liver US	Developmental pediatrician
	‐ Genetic testing	Liver transplantation:	‐ Liver elastography	Endocrinologist
	‐ Enzyme activity (leukocytes)	Consider if cirrhosis develops	‐ Labs:	Geneticist
			‐ GI: TAs, CDT	Hematologist
	Baseline imaging:	Additional measures:	‐ Coagulation parameters: PT, PTT, factor IX, factor XI, AT, protein C, protein S	Neurologist
	‐ Liver US and elastography	‐ Avoidance of hepatotoxic drugs	‐ Nutritional parameters: prealbumin, albumin, lipids, urea, creatinine, electrolytes	Ophthalmologist
	‐ Renal US	‐ Supplemental enteral feeds in undernourished patients
	‐ Echocardiogram	‐ Parenteral nutrition (in undernourished patients with chronic diarrhea or recurrent vomiting)
	‐ MRI brain	‐ Albumin infusion (20% solution) in patients with serum albumin <2 g/dL and edema
		‐ Constipation management
	Baseline labs:
	‐ CBC plus differential	Additional note: liver biopsy rarely indicated
	‐ Liver/GI tests: TAs, GGT, bilirubin AFP, albumin, fecal A1AT
	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S
	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
	‐ Endocrine: cortisol, lactate, TSH, T4, TBG, IGF1, IGFBP‐3, calcium, magnesium, phosphate
	‐ Renal function
	Audiology evaluation
	Ophthalmology evaluation
	Neurologist developmental assessment
PGM1‐CDG11	Diagnostic evaluation:	Oral galactose:	Follow‐up during oral galactose therapy:	Cardiologist
	‐ CDT (serum or plasma)	1 g/kg/day (maximum 50 g/day) daily or divided into up to 4 doses (can be increased to up to 3 g/kg/day in infants)	Every 6 months: TAs, AT, CK, CDT, N‐glycan, Gal‐1‐P, urine galactitol	Craniofacial specialist
	‐ Genetic testing	Additional measures:		Developmental pediatrician
	‐ Enzyme activity (leukocytes)	Avoidance of hepatotoxic drugs	Every 12 months:	Endocrinologist
		Additional note:	‐ Liver US	Hematologist
	Baseline imaging:	Caution with anesthesia prior to surgeries because of possible malignant hyperthermia	‐ Liver elastography	Geneticist
	‐ Liver US and elastography		‐ Labs:	Neurologist
	‐ Renal US		‐ Tas	Ophthalmologist
	‐ Echocardiogram		‐ Whole blood count + differential	Otolaryngologist
			‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S
	Baseline labs:		‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
	‐ CBC plus differential
	‐ CK
	‐ Liver/GI tests: TA, GGT, bilirubin AFP, albumin, fecal A1AT
	‐ Coagulation parameters: PT, PTT, fibrinogen, factor VIII, factor IX, factor XI, AT, protein C, protein S, factors II, V, VII, and X
	‐ Nutritional parameters: prealbumin, lipids, urea, creatinine, electrolytes, mineral and trace elements, vitamins
	‐ Endocrine: glucose, insulin, C peptide, cortisol, ACTH, lactate, fatty acids, urinary ketones, TSH, T4, IGF1, IGFBP‐3, ALS, ALP, PTH, calcium, magnesium, phosphate
	‐ Renal function
	Audiology evaluation
	Ophthalmology evaluation
	Neurologist developmental assessment

The other CDG with predominant liver symptoms do not have specific therapies but will benefit from accurate diagnosis. Liver transplantation is an option to be considered in cases of liver failure. TMEM199‐CDG (transmembrane protein 199‐CDG) is a purely hepatic, adult‐onset CDG.⁶ CCDC115‐CDG (coiled‐coin domain‐containing protein 115‐CDG) and ATP6AP1‐CDG (ATPase, H+ transporting, lysosomal, accessory protein 1‐CDG) both present with hepatic copper accumulation, similar to Wilson disease.⁷, ⁸ In addition to the neurological features (developmental disability and, in some cases, seizures), which are present in both disorders, ATP6AP1‐CDG uniquely exhibits immunodeficiency and cutis laxa. Key features of these disorders are presented in Table 1. Suggestions for monitoring and management are summarized in Table 2.

Some CDG have multisystem involvement that includes liver dysfunction. Characteristic manifestations that may evoke the correct diagnosis are outlined in Table 1.

The most frequently encountered CDG is PMM2‐CDG (phosphomannomutase 2‐CDG). Although cases with severe liver involvement, including liver failure in early childhood, have been described,¹ liver dysfunction is usually mild, and almost all patients exhibit elevated TAs that slowly improve and ultimately normalize around 5 years of age. International consensus guidelines for the management of PMM2‐CDG⁹ are summarized in Table 2.

PGM1‐CDG (phosphoglucomutase 1‐CDG) is an important recognizable CDG that often presents with cleft palate, retrognathia, hypoglycemia, and liver dysfunction. Importantly, effective treatment is possible with galactose, which leads to rapid improvement of liver function, reduction of hypoglycemic events, and normalization of coagulation and endocrine abnormalities.¹⁰ International consensus guidelines for the treatment and management of PGM1‐CDG¹¹ are summarized in Table 2.

Monitoring and Management

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. Liver ultrasound (US) often shows a coarse liver echotexture suggestive of fibrosis or increased echogenicity as a result of steatosis. Liver elastography is more accurate at diagnosing liver fibrosis in CDG and is useful for noninvasive monitoring of disease progression. Expert consensus opinion recommends both US and elastography evaluation for regular, systematic screening and monitoring of fibrosis in CDG.²

Diagnosis

A high index of suspicion for CDG is necessary in the evaluation of patients with liver dysfunction, abnormal liver imaging, or abnormal histopathology. Laboratory abnormalities in multiple secreted proteins are also concerning for CDG, given the critical role of the liver in secreting glycoproteins into the blood. Frequently observed laboratory abnormalities in CDG include low coagulation factors or activity levels, hypoalbuminemia, low thyroxine (T4)‐binding globulin, low free T4, and hypocholesterolemia.

Biochemical screening for CDG analyzes transferrin glycosylation via mass spectrometry in specialized laboratories. An algorithm for efficient diagnosis based on abnormal transferrin screening is provided in Fig. 2. Transferrin analysis identifies characteristic patterns of glycosylation abnormalities corresponding to the subcellular localization of the disrupted glycosylation and guides diagnosis, as illustrated in Figs. 1 and 2. Type I defects showing loss of entire glycans correlate with disrupted glycan synthesis in the endoplasmic reticulum (ER). Type II defects exhibiting truncated glycans localize disrupted glycan maturation to the Golgi apparatus. Notably, liver dysfunction of any etiology may produce abnormalities in transferrin glycosylation,¹² thus necessitating caution in interpreting an abnormal result and requiring diagnostic confirmation with genetic testing.

FIG 2.

Algorithm for CDG diagnosis. Use of transferrin glycosylation analysis to prioritize further diagnostic investigations for CDG. Purple boxes indicate clinical assessments; blue boxes indicate laboratory testing; white boxes indicate results.

Conclusions

CDG should be considered in individuals with unusual or unexplained liver disease, particularly when there is multisystem involvement or a characteristic presentation. Known CDG patients require routine, systematic screening and monitoring of liver dysfunction using physical examination, laboratory investigations, and US liver imaging. Following international consensus guidelines will optimize management of these complex patients.