Exploration of Digestive Diseases

Table 1. Cirrhosis etiologies in children.

Category	Etiologies	Age at presentation	Hallmarks	Genetic tests	Red flags*
Cholestatic liver diseases	Biliary atresia	Within the first 2 weeks of life	Neonatal cholestasis + acholia + high γGT	ADD3 EFEMP1 GPC1	Kasai > 90 days Direct bilirubin > 34 µmol/L 3 months post-Kasai
	Alagille syndrome	Any age, most often the first 3 months	Cholestasis + high γGT + cardiopathy + triangular facies	JAG1 NOTCH2	Intractable pruritus Hepatocellular carcinoma
	Progressive familial intrahepatic cholestasis	First 3 months FIC-1 and BSEP deficiency, later in MDR3	Cholestasis + low γGT (except MDR3) High serum bile acids	ATP8B1 ABCB4 ABCB11 TJP2 NR1H4 MYO5B USP53 KIF12 LSR	Intractable pruritus Failure to thrive Hepatocellular carcinoma
	Cystic fibrosis	Neonatal if cholestasis, childhood/adolescence if steatosis	Cholestasis/Steatosis + high sweat chloride + failure to thrive + pulmonary disease	CFTR	Unmanageable variceal bleed Growth failure Liver failure
Hepatocellular diseases	Autoimmune liver diseases	Type 1: 10–20 years old, type 2: 6–7 years old	Increased total serum proteins or protein/albumin ratio + high IgG	HLA-DR3 and DR4	Liver failure
	Hepatitis B	Any age, median age at diagnosis 7 years old	HBsAG + HBV DNA	NA	Hepatocellular carcinoma Liver failure
	Hepatitis C	Any age, median age at diagnosis 8 years old	Anti-HCV + HCV DNA	NA	Hepatocellular carcinoma Liver failure
Metabolic and storage diseases	Wilson disease	Between 8 and 13 years	Low ceruloplasmin + high 24 h urinary Cu²⁺	ATP7B	Liver failure
	Alpha-1 antitrypsin deficiency	Before 24 months if cholestasis, later if not	Low alpha-1 antitrypsin	SERPINA	Liver failure
	Glycogen storage diseases (GSDs; I, III, IV, IX)	GSD I: 1.5 years old, GSD III: 2 years, GSD IV: childhood	Hypoglycemia + bland hepatomegaly + lactic acidosis GSD I: high triglycerides and uric acid + bleeding disorder GSD III: high triglycerides GSD IV: hard hepatomegaly + cardiac involvement	GSD I: G6PC1, SLC37A4 GSD III: AGL GSD IV: GBE1	Intractable metabolic decompensation Adenomatosis Hepatocellular carcinoma Liver failure (type IV)
	Niemann-Pick disease type C**	10 to 11 years old	Hepatosplenomegaly + ataxia + vertical supranuclear gaze palsy + developmental delay	NPC1 and NPC2	Liver failure Before advanced neurological disease
Other	Intestinal failure-associated liver disease	Variable depending on etiology	Abnormal liver tests + steatosis + parenteral nutrition	NA	Liver failure
Other	Fontan-associated liver disease	Between 10.5 and 17 years old	Fibrosis + high γGT	NA	Hepatocellular carcinoma

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*: In all cases, decompensated cirrhosis should prompt early evaluation for a possible liver transplantation. **: Liver transplantation for Niemann-Pick type C is still not widely adopted, and there is no formal indication to date. BSEP: bile salt export pump; MDR3: multidrug resistance protein 3; CFTR: cystic fibrosis transmembrane conductance regulator; HBsAg: surface antigen of Hepatitis B; HBV: hepatitis B virus; HCV: hepatitis C virus; Cu²⁺: copper; NA: not applicable.

Declarations

Author contributions

GAC: Conceptualization, Investigation, Writing—original draft, Writing—review & editing, Validation. FÁ: Conceptualization, Writing—original draft, Writing—review & editing, Supervision, Validation. Both authors read and approved the submitted version.

Conflicts of interest

GAC is a medical advisor for Mirum Pharmaceutics and Medison Pharma. GAC is also a PI in a clinical trial with Pfizer. FÁ has no conflicts of interest to declare.

Ethical approval

Not applicable.

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Funding

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