Table 1.
Summary of the differential diagnoses and diagnostic approaches.
| Disease | Diagnostic approach | Genetic analysis |
|---|---|---|
| BILE DUCT OBSTRUCTION | ||
| Structural | ||
| Biliary atresia | US, liver biopsy, ERCP, hepatobiliary scintigraphy, intraoperative cholangiogram | Wildhaber (71), Mieli-Vergani and Vergani (4) |
| Alagille syndrome | Typical facial features, chest x-ray (butterfly vertebrae), ophthalmology, echo, liver biopsy, cholesterol ↑ | JAG1, NOTCH2 genes; Vajro et al. (39), Turnpenny and Ellard (40), Kamath et al. (38) |
| Choledochal cyst | US, ERCP, MRCP | Todani et al. (41) |
| Caroli’s disease/syndrome | US (liver and kidneys), ERCP, MRCP if >1 year of age, PKHD1 gene (ARPKD) | Adeva et al. (72), Harring et al. (43), Krall et al. (73) |
| Gallstones or biliary sludge | US, ERCP | |
| Neonatal sclerosing cholangitis | ERCP, liver biopsy | Baker et al. (44), Girard et al. (45) |
| Hepatocellular | ||
| Idiopathic neonatal giant cell hepatitis (NGCH) | Histological diagnosis after exclusion of other causes | Torbenson (47) |
| Progressive familial intrahepatic cholestasis (PFIC) | Liver biopsy, genetic analysis | ABCB4, ABCB11, ATP8B1; Jacquemin (52), Kubitz et al. (54) |
| GGT (↓– → in types 1 + 2, ↑ in type 3) | ||
| METABOLIC DISORDERS, STORAGE DISEASES, AND OTHERS | ||
| Cystic fibrosis | Newborn screening (not in Germany), trypsinogen content in stool, genetic analysis | CFTR gene; Sokol and Durie (57) |
| A1AT deficiency | A1AT levels ↓ | SERPINA1 gene analysis for prenatal diagnosis; Perlmutter (59), Fregonese and Stolk (58) |
| PI analysis (type ZZ, SZ, MZ) | ||
| Inborn errors of bile acid synthesis | Urinary bile acid analysis, molecular–genetic analysis | Clayton et al. (66); BAAT and SLC27A5 gene, Setchell et al. (67) |
| Gaucher disease | AP ↑, β-glucocerebrosidase ↓, chitotriosidase ↑, BM biopsy: “crinkled paper” cytoplasm and glycolipid-laden macrophages, foam cells (Gaucher cells) | Rosenbloom et al. (69) |
| Niemann–Pick type C | Filipin positive reaction (detection of cholesterol in fibroblasts), genetic testing, chitotriosidase ↑ | NPC1, NPC2 gene; Patterson et al.(74) |
| Wolman disease, LAL deficiency | Lysosomal lipase acid ↓ ↓ in PBMC | LIPA gene; Zhang and Porto (75) |
| Mitochondrial disorders | Fasting and postprandial lactate, plasma lactate/pyruvate ratio >20, functional assays, genetics | SCO1, SUCLG1, BCS1L, POLG1, C10ORF2, DGUOK, and MPV17 gene mutations; Fellman and Kotarsky (76), Wong et al. (77) |
| Neonatal Intrahepatic cholestasis caused by citrin deficiency (NICCD) | Citrulline ↑, α-fetoprotein ↑, and ferritin ↑ | SLC25A13 gene; Lu et al. (78), Kimura et al. (79), Song et al. (80) |
| Peroxismal disorders (Zellweger’s spectrum and others) | Zellweger’s: Typical craniofacial dysmorphism, mental retardation, hepatomegaly, glomerulocystic kidney disease, cataracts, pigmentary retinopathy | Moser et al. (81, 82) |
| VLCFA ↑, pattern of plasmalogenes, phytanic acid, pristanic acid | ||
| Tyrosinemia | Newborn screening, urinary excretion of succinylacetone ↑, 4-hydroxy-phenylketones, and δ-aminolevulinic acid ↑ Cave: HCC (AFP ↑) (83) | FAH gene, de Laet et al. (84) |
| Classic galactosemia | Newborn screening, galactose-1-phosphate uridyl transferase activity in red blood cells ↓ ↓ | Mayatepek et al. (85) |
| Congenital disorders of glycosylation (CDG) | Dysmorphic facies, convergent strabism, inverted mammils, mental retardation, seizures, dystrophy, hepatomegaly, hepatic fibrosis/steatosis, cyclic vomiting and diarrhea, coagulopathy, protein losing enteropathy with hypoalbuminemia (CDG1b) | Jaeken (86), Freeze (87, 88), Linssen et al. (89) |
| Lab chemistry: Triglycerides ↑, ATIII ↓, factor XI ↓, protein C and S ↓, Transferrin IEF | ||
| ENDOCRINE DISORDERS | ||
| Hypothyroidism | Newborn screening (TSH ↑) | Hanna et al. (90) |
| Panhypopituitarism | Glucose ↓, Cortisol ↓, TSH ↓, fT4 ↓, IGF1 ↓, IGFBP ↓ | Binder et al. (91), Karnsakul et al. (92) |
| TOXIC OR SECONDARY DISORDERS | ||
| Parenteral nutrition-associated cholestasis (PNAC), drugs (e.g., anticonvulsants) | Exclusion of other causes | Hsieh et al. (93) |
| IMMUNOLOGICAL DISORDERS | ||
| Gestational alloimmune liver disease (GALD) | Ferritin ↑ ↑ (>1000 μg/L), buccal mucosal biopsy and liver biopsy (iron deposition?), MRI (extrahepatic iron deposition?) | Rand et al. (94) |
| Neonatal lupus erythematosus | Transplacental passage of ANA, anti-RoSSA, anti-La/SSB, anti-U1RNP antibodies | Hon and Leung (95) |
| Echo, ECG (congenital heart block) | ||
| Haemophagocytic lymphohistiocytosis (HLH) | Fever (>7 days), hepatosplenomegaly with liver dysfunction, pancytopenia, sCD25 (>2400μg/mL), ferritin (>500 μg/L), triglycerides (>3 mmol/L), hypofibrinogenemia (<150 mg/dL), serum cytokine levels of both IFNg (>75 pg/ml) + IL-10 (>60 pg/ml) ↑ | Lehmberg and Ehl (96), Xu et al. (97) |
| INFECTIOUS DISORDERS | ||
| Sepsis, urinary tract infections, TORCH, hepatitis A–E, EBV, HIV, Echo, adeno, coxsackie virus, Parvo B19, HHV6-8, VZV, syphilis, leptospirosis | PCR, microbiology, serology, ophthalmologic examination (toxoplasmosis, CMV, rubella) | Kosters and Karpen (98), Bellomo-Brandao et al. (99), Robino et al. (100) |
| VASCULAR MALFORMATIONS | ||
| Portosystemic shunts | US, MRI, LE ↑, unexplained galactosemia, hyperammonemia, manganemia | Bernard et al. (101) |
| Multiple hemangioma | US, MRI | Avagyan et al. (102), Horii et al. (103) |
| Congestive heart failure | Echo (heart anomalies, e.g., in Down syndrome), US, liver histology | Arnell and Fischler (104) |
| MISCELLANEOUS | ||
| Genetic disorders | Trisomy 21, Trisomy 18 | |
| ARC syndrome | Arthrogryposis multiplex congenita, facial dysmorphia, dystrophia, renal tubular acidosis, cholestasis, platelet dysfunction, ichthyosis | VPS33B gene; Smith et al. (105), Eastham et al. (106) |
| Aagenes syndrome | Lymphedema cholestasis syndrome 1 (LCS1) | Drivdal et al. (107) |
| Microvillus inclusion disease (MVID) | Life threatening congenital watery diarrhea of secretory type. Histology: microvillus atrophy, detection of PAS+ granules and CD10+ lining in LM and inclusion bodies in EM | MYO5B gene, Ruemmele et al. (108) |
| Neonatal leukemia | AML ≫ ALL | Van der Linden et al. (109) |
AFP, alpha-fetoprotein; ALP, alkaline phosphatase; BM, bone marrow; DD, differential diagnosis; ERCP, endoscopic retrograde cholangiopancreaticography; EM, electronmicroscopy; HCC, hepatocellular carcinoma; MRI, magnetic resonance imaging; LE, liver enzymes; LM, light microscopy; PBMC, peripheral blood mononuclear cell; US, ultrasound; VLCFA, very long chain fatty acids.