Patient 1 was a 5–year-and-11-month-old female referred to the First Affiliated Hospital, Jinan University due to abnormal liver function discovered for 5 years and 7 months. When aged 4 months, she was admitted to a hospital in Guangzhou due to jaundice for 3 months, where physical examination revealed an enlarged liver 4.0 cm below the right costal margin, and a liver function test revealed elevated serum levels of total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), alanine transaminase (ALT), aspartate transaminase (AST), γ-glutamyl transpeptidase (GGT), and alkaline phosphatase (ALP), indicating cholestatic jaundice (). Blood amino acid spectrum analysis by tandem mass spectrometry (MS-MS) revealed raised citrulline, methionine, arginine, and threonine, while large quantities of galactose, galactitol, galactonate, and 4-hydroxyphenyllactate (4HPL) were detected on urinary gas chromatography-mass spectrometry (GC-MS) analysis. Considering the above clinical and laboratory findings, NICCD was suspected, and breast-feeding was stopped while a lactose-free and medium-chain triglycerides (MCT)-enriched formula was introduced. When aged 4.9 months, SLC25A13 genetic analysis in our hospital unveiled a homozygote of the c.852_855del4 mutation () and the diagnosis of NICCD was hence made. Thereafter, besides feeding with the therapeutic formula, supplemental foods rich in protein were encouraged. As a result, her liver function indices got improved gradually and returned to normal by age 10.2 months. However, the hypercholanemia was refractory, with total bile acid (TBA) levels fluctuating from 27.6 µmol/L to 340.2 µmol/L (reference range: 0–10 µmol/L) (). After the age 2 years, the patient showed a fondness for foods rich in protein and fat while an aversion to carbohydrate-rich diets.\nAs the first product of a non-consanguineous couple, the child was delivered spontaneously at the gestational age of 38 weeks and 3 days after an uneventful pregnancy, with a birth weight of 3.0 kg and body length 50 cm. The parents were healthy, and there was no family history of any genetic or infectious diseases.\nPhysical examination revealed a body temperature (T) 36.5°C, heart rate (HR) 115 beats/min (bpm), respiratory rate (RR) 20 bpm, weight (WT) 18 kg, height 107.0 cm. No jaundice was observed in the skin and sclera. The lungs were clear. No murmurs or abnormal heart sounds were heard. There was no abdominal distention, and the liver and spleen were not enlarged. Physiological reflexes were normal and no pathological reflexes could be found on nervous system examination. The extremities were warm, and the distal perfusion was excellent.\nLaboratory investigation showed otherwise normal biochemical indices but a TBA level of 48.7 µmol/L. In view of the intractable hypercholanemia, NTCP deficiency was highly suspected, and SLC10A1 genetic analysis was performed. As a result, the patient was a homozygote, while the parents, carriers, of the reportedly pathogenic variant c.800C > T(p.Ser267Phe)(). NTCP deficiency was thus definitely diagnosed. No specific therapy was given but close clinic follow-up was underway.
Patient 2. A 5-day-old male infant was admitted to our Neonatal Section because of jaundice for 3 days. Mild jaundice appeared at age 2 days. At the 5th day after birth, the total bilirubin increased to 310.1 μmol/L. Then the infant was referred to our clinic, where a laboratory test revealed elevated TBA as well as indirect hyperbilirubinemia (Table ), and thus the infant was admitted for further management. As the first child of a non-consanguineous couple, the patient was delivered vaginally at the gestational age of 37 weeks with the birth weight 3050 g. The parents were both healthy. Family history of any genetic disease was denied.\nOn physical examination, the body weight was 2910 g, with T 36.2°C, HR 130 beats/min, and RR 43 breaths/min. Jaundiced skin and sclera were observed. The lungs were clear on auscultation, and no abnormal heart sound or murmur was heard. There was no abdominal distention, and the liver and spleen were not palpable. Primitive reflexes were normal and no pathological reflexes could be found on nervous system examination.\nThe patient underwent phototherapy for 3 days. As a result, his jaundice subsided, and he was discharged at age 9 days. No special treatment was given thereafter, and the jaundice did not reappear. However, his serum TBA levels kept high in the following 1 month, and hence SLC10A1 analysis was performed at age 33 days to evaluate the possibility of NTCP deficiency. On Sanger sequencing of the UGT1A1 gene, no pathogenic variant was detected but three benign SNPs in the 3ʹ UTR, i.e. rs10929303, rs1042640 and rs8330 [].