Serum matrix metalloproteinase-7 for discriminating biliary atresia: a diagnostic accuracy and validation study.

BACKGROUND: Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. METHODS: This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases (n = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients (n = 318, with 172 BA) and validated in a prospective cohort (n = 687, including 395 BA). RESULTS: The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946-0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5-97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0-90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9-93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6-96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0-30 days, which was 86.4% (95% CI: 75.0-94.0%), 95.5% (95% CI: 77.2-99.9%), 98.1% (95% CI: 89.7-100%), and 72.4% (95% CI: 52.8-87.3%), respectively. CONCLUSIONS: The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.

Efficacy of rituximab-containing regimens used as first-line and rescue therapy for giant cell hepatitis with autoimmune hemolytic anemia a retrospective study.

OBJECTIVE: To evaluate the efficacy of rituximab (RTX)-containing therapy as first-line as well as rescue treatment for giant cell hepatitis with autoimmune hemolytic anemia (GCH-AHA). METHODS: This retrospective study recruited patients diagnosed with GCH-AHA and treated with conventional immunosuppressor regimens consisting of prednisone or RTX-containing regimes consisting of RTX and prednisone, with or without another immunosuppressor. The primary outcomes were the complete remission (CR) rate and time-period required for CR. The secondary outcomes included relapses and adverse events. RESULTS: Twenty patients (8 females and 12 males; age range 1-26 months), 15 receiving conventional regimens and 5 receiving RTX-containing regimens, were included. The CR rates were 73.3 % (11/15) and 100 % (5/5) in the conventional and RTX-containing groups, respectively. The time-period required for CR was significantly shorter in the RTX-containing group than in the conventional group (6 (3-8) versus 14 (5-25) months, P = 0.015). Relapses occurred in 30.8 % (4/13) of patients in the conventional group; all achieved CR after adding RTX. Relapses occurred in 40.0 % (2/5) of patients in the RTX-containing group; both achieved CR after adding intravenous immune globulins or tacrolimus. Transient low immunoglobulin and infections were recorded in both groups. Treatment withdrawal was achieved in 73.3 % (11/15) and 60.0 % (3/5) of patients receiving conventional and RTX-containing regimens after 36 (2-101) and 22 (4-41) months, respectively. Two patients in conventional group died of disease progression and infection. CONCLUSIONS: RTX-containing first-line therapy achieves CR of GCH-AHA more quickly than the conventional therapy. RTX is efficacious when added to rescue therapy.

NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death.

BACKGROUND: Clinical studies on progressive familial intrahepatic cholestasis (PFIC) type 5 caused by mutations in NR1H4 are limited. METHODS: New patients with biallelic NR1H4 variants from our center and all patients from literature were retrospectively analyzed. RESULTS: Three new patients were identified to be carrying five new variants. Liver phenotypes of our patients manifests as low-γ-glutamyl transferase cholestasis, liver failure and related complications. One patient underwent liver transplantation (LT) and survived, and two other patients died without LT. Nine other patients were collected through literature review. Twelve out of 13 patients showed neonatal jaundice, with the median age of onset being 7 days after birth. Reported clinical manifestations included cholestasis (13/13, 100%), elevated AFP (11/11, 100%), coagulopathy (11/11, 100%), hypoglycemia (9/13, 69%), failure to thrive (8/13, 62%), splenomegaly (7/13, 54%), hyperammonemia (7/13, 54%), and hepatomegaly (6/13, 46%). Six of 13 patients received LT at a median age of 6.2 months, and only one patient died of acute infection at one year after LT. Other 7 patients had no LT and died with a median age of 5 months (range 1.2-8). There were 8 patients with homozygous genotype and 5 patients with compound heterozygous genotype. In total, 13 different variants were detected, and 5 out of 12 single or multiple nucleotides variants were located in exon 5. CONCLUSIONS: We identified three newly-diagnosed patients and five novel mutations. NR1H4-related PFIC typically cause progressive disease and early death. LT may be the only lifesaving therapy leading to cure.

Expanding the phenotype and metabolic basis of ATP6AP2-congenital disorder of glycosylation in a Chinese patient with a novel variant c.185G>A (p.Gly62Glu).

Background: A rare X-linked hereditary condition known as ATP6AP2-congenital disorder of glycosylation (ATP6AP2-CDG) is caused by pathogenic variants in ATP6AP2, resulting in autophagic misregulation with reduced siganling of mammalian target of rapamycin (mTOR) that clinically presents with aberrant protein glycosylation, hepatosteatosis, immunodeficiency, cutis laxa, and psychomotor dysfunction. To date, only two missense mutations have been reported in three patients from two unrelated families. Methods: In order to extend the profiles of phenotype and genotype associated with ATP6AP2-CDG, we assessed the clinical history, whole exome sequencing (WES), and liver histology as well as immunohistochemistry in a Chinese patient, and performed quantitative real-time polymerase chain reaction (qRT-PCR), Western blotting and untargeted metabolomics in genetic exogenously constructed cells. Results: The 11-month-old Chinese boy presented with recurrent jaundice, cutis laxa, cirrhosis, growth retardation, coagulopathy, anemia, and cardiomegaly, and underwent liver transplantation. A novel mutation, c.185G>A (p.Gly62Glu), was identified in exon 3 of ATP6AP2. The expression of ATP6AP2 was observed to remain unchanged in the liver sample of the patient as well as in HEK293T cells harboring the p.Gly62Glu. This missense mutation was found to dysregulate autophagy and mTOR signaling. Moreover, metabolomics analysis revealed that the exogenously introduced Gly62Glu mutant resulted in the downregulation of numerous metabolites involved in lipid metabolism pathway. Conclusion: This study may enable a more detailed exploration of its precise pathogenesis and potential therapeutic interventions.

Non-invasive biomarkers for identification of vanishing bile duct syndrome among children with acute cholestatic hepatitis.

Background: The identification of vanishing bile duct syndrome (VBDS) is still challenging before liver biopsy. This study tried to explore non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis. Methods: Between January 2017 and December 2021, 192 children underwent native-liver biopsy for acute cholestatic hepatitis with onset after 6 months of age. VBDS was diagnosed by liver biopsy. Differences of liver biochemical indices were compared between children with and without VBDS. Diagnostic performances for VBDS were tested by receiver operating characteristic (ROC) curve analyses. Results: Among the 192 patients, 24 (12.5%) were diagnosed with VBDS based on liver biopsy. At biopsy, their levels of total bilirubin (TB), direct bilirubin (DB), γ-glutamyl transpeptidase (GGT), total bile acid, triglyceride, and total cholesterol (TCH) were higher than patients without VBDS (all P<0.05). However, only GGT and TCH could distinguish patients with VBDS from patients without VBDS with an area under ROC curve (AUC) >0.850. Using GGT >446 U/L as a cut-off value, the sensitivity was 87.5%, the specificity was 91.6%, and the AUC was 0.948 (P<0.001). Using TCH >6.4 mmol/L as a cut-off value, the sensitivity was 100.0%, the specificity was 89.8%, and the AUC was 0.983 (P<0.001). A total of 28 patients had both GGT >446 U/L and TCH >6.4 mmol/L, including 21 patients with VBDS and 7 without VBDS (21/28 vs. 3/143, P<0.0001). Three patients with VBDS would be missed for GGT <446 U/L. Conclusions: Both GGT and TCH can be used as non-invasive biomarkers for identification of VBDS among children with acute cholestatic hepatitis.

Neonatal cholestasis as the onset symptom of McCune-Albright syndrome: case reports and a literature review.

Aim: This study aimed to summarize and show the characteristics and evolutionary process of neonatal cholestasis caused by McCune-Albright syndrome (MAS), as neonatal cholestasis may be the initial manifestation of MAS before other classic clinical features appear. Methods: The clinical characteristics, treatment methods, and outcomes of three neonatal cholestasis cases caused by MAS in our center were retrospectively studied. In addition, all the reported cases of MAS combined with cholestasis were reviewed and summarized to show the cholestatic features in them. Results: We have confirmed three MAS cases in our center, presenting onset symptoms of jaundice, pale stool, and neonatal cholestasis soon after birth. The cholestasis subsided spontaneously at around the sixth month. The literature review showed that the levels of total bilirubin, conjugated bilirubin, ALT, AST, and GGT in neonatal MAS cholestasis cases were 207 µmol/L (range 65-445 µmol/L), 162 µmol/L (range 46-412 µmol/L), 821 U/L (range 85-3,597 U/L), 532 U/L (range 127-3,633 U/L), and 244 U/L (range 79-3,800 U/L), respectively. Liver histology showed canalicular and hepatocellular cholestasis, giant hepatic cell transformation, and bile paucity. Extrahepatic manifestations such as café-au-lait pigmented skin lesions, Cushing's syndrome, hyperthyroidism, renal tubular dysfunction, and skeletal abnormalities could occur simultaneously when jaundice occurred. GNAS mutations had a high positive rate (83.3%-100%) in liver tissue with cholestasis. Neonatal cholestasis caused by MAS could be self-resolved, but hepatic lesions persist and have malignant potential. Conclusion: MAS can be one of the causes of neonatal cholestasis, which may be the first manifestation of the disease. Extrahepatic coexisting symptoms of MAS and liver histology can help to distinguish MAS from other etiology of cholestasis. Detecting GNAS mutations in liver tissue may shorten diagnostic time and is of particular interest in the partial and atypical forms of MAS with neonatal cholestasis. Neonatal cholestasis in children with MAS can self-resolve, but liver dysfunction and malignant lesions persist.

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A male infant, aged 1 month and 14 days, was admitted to the hospital due to abdominal distension lasting for 2 weeks and worsening for 3 days. The infant had a history of omphalitis. Physical examination revealed severe abdominal distension, prominent abdominal wall veins, hepatosplenomegaly, and massive ascites. There was a slight elevation in liver transaminase levels. Liver ultrasound and CT scans demonstrated the absence of visualization of the intrahepatic segment of the portal vein and the left, middle, and right veins of the liver, indicating occlusion of these vessels, along with surrounding fibrous hyperplasia. The clinical diagnosis was hepatic sinusoidal obstruction syndrome resulting from omphalitis. A large amount of bloody ascites developed after 12 days of hospitalization, resulting in hypovolemic shock and respiratory failure. The infant passed away following the family's decision to discontinue treatment. This article focuses on the diagnostic approach and multidisciplinary management of neonatal-onset hepatic sinusoidal obstruction syndrome, as well as provides insights into the differential diagnosis of hepatomegaly and ascites.

Recurrent AKR1D1 c.580-13T>A Variant: A Cause of Δ4-3-Oxosteroid-5ß-Reductase Deficiency.

Δ4-3-oxosteroid 5ß-reductase (AKR1D1) deficiency presents with neonatal cholestasis and liver failure in early infancy and features high levels of 3-oxo-Δ4-bile acids in urine. Genetic analysis is needed for definitive diagnosis, because in the neonatal period it can be difficult to distinguish a primary from a secondary enzyme deficiency. By re-analysis of the gene-sequencing data, one AKR1D1 noncanonical splice-site variant (NM_005989.4: c.580-13T>A) with controversial pathogenicity was discovered to be enriched in eight families with clinical and biochemically confirmed AKR1D1 deficiency. Further RNA sequencing of liver tissue suggested this variant causes complete degradation of mRNA. An in vitro minigene experiment indicated that this variant led to partial intron retention or exon jumping, which then leads to coding sequence frameshift and nonsense-mediated mRNA decay. Thus, AKR1D1 variant c.580-13T>A was considered pathogenic and, therefore, should be screened during genetic studies in infants with a suspicion of a congenital bile acid synthetic disorder.

Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome.

BACKGROUND: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers. METHODS: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 µmol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≥ 85.5 µmol/L at the last follow-up. RESULTS: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2ß,3α,7α,12α-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco- chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2ß,3α,7α,12α-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662-63.753), P = 0.002]. CONCLUSIONS: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes.

Neonatal cholestasis is an early liver manifestation of children with acid sphingomyelinase deficiency.

BACKGROUND: Patients with acid sphingomyelinase deficiency (ASMD) may be referred to a hepatologist for liver manifestations. This study summarized the liver manifestations of patients with ASMD in the early disease course. METHODS: This study enrolled ASMD patients diagnosed by genetic tests between July 2016 and December 2020 in a national pediatric liver center. The significance of low High-density lipoprotein cholesterol (HDL-C) for aid diagnosis of ASMD in infancy was explored by reviewing 160 consecutive infants with liver manifestations, who underwent both genetic tests and lipid profile studies, between January 2020 and December 2020. RESULTS: A total of 7 patients were diagnosed as ASMD, and 10 known disease-causing variants were identified. Hepatosplenomegaly, elevated transaminases, and liver foam cells were observed in all the 7 patients at age ranging from 4 to 31 months. Low HDL-C was detected in 5 patients, cherry red spot in 4 patients, development delay in 3 patients, and interstitial lung diseases in 1 patient. Three ASMD patients developed cholestasis around 1 month of age, and bilirubin levels normalized at age ranging from 3 to 10 months. They had persistently elevated transaminases and hepatosplenomegaly, and died within 4 years of age. Among the 160 infants with liver manifestations, 125 (78.1%) had low HDL-C. Fifty-four had both low HDL-C and splenomegaly, including 48 cholestatic infants, but only 1 (1.9%, 1/54) infant without cholestasis was diagnosed as ASMD. CONCLUSIONS: ASMD can manifest as neonatal cholestasis in the early disease course. Cholestasis is a pitfall when low HDL-C is used for aid diagnosis of ASMD in infants with splenomegaly.

Defining pathogenicity of NOTCH2 variants for diagnosis of Alagille syndrome type 2 using a large cohort of patients.

BACKGROUND AND AIMS: Alagille syndrome (ALGS) type 2 caused by mutations in NOTCH2 has genotypic and phenotypic heterogeneity. Diagnosis in some atypical patients with isolated hepatic presentation could be missed. METHODS: Using 2087 patients with paediatric liver manifestations, NOTCH2 allele frequencies, in-silico prediction, protein domains and clinical features were analysed to define the pathogenicity of NOTCH2 variants for diagnosis of ALGS type 2. RESULTS: Among 2087 patients with paediatric liver manifestations, significantly more NOTCH2 variants were absent in gnomAD in patients with elevated γ-glutamyltransferase (GGT) (p = .041). Significantly more NOTCH2 variants which were absent in gnomAD were located in protein functional domains (p = .038). When missense variants were absent in gnomAD and predicted to be pathogenic by at least three out of seven in-silico tools, they were found to be significantly associated with liver manifestations with elevated GGT (p = .003). Comparing this to patients with likely benign (LB) variants, the patients with likely-pathogenic (LP) variants have significantly more liver manifestations with elevated GGT (p = .0001). Significantly more patients with LP variants had extra-hepatic phenotypes of ALGS compared with those patients with LB variants (p = .0004). CONCLUSION: When NOTCH2 variants are absent in gnomAD, null variants and missense variants which were predicted to be pathogenic by at least three in-silico tools could be considered pathogenic in patients with high GGT chronic liver diseases.

The Presence of Vacuolated Kupffer Cells Raises a Clinical Suspicion of Niemann-Pick Disease Type C in Neonatal Cholestasis.

Early diagnosis of Niemann-Pick disease type C (NP-C) in neonatal cholestasis is still challenging because splenomegaly is non-specific and oxysterol profiling studies also have a relatively low specificity. This study explores a method for identifying infants with a high clinical suspicion of NP-C in neonatal cholestasis. We reviewed the clinical findings of 9 neonatal cholestatic infants with NP-C genetically diagnosed between January 2015 and December 2020. Seven underwent liver biopsy at ages ranging from 35 to 112 d. Foam cells were only detected in 2 (28.6%, 2/7) liver tissues obtained beyond 3 months of age. However, vacuolated Kupffer cells were detected in all 7 liver tissues. Their significance was explored by using 168 neonatal cholestatic infants, who underwent genetic tests and liver biopsy between January 2018 and December 2020. Of them, 26 detected vacuolated Kupffer cells. Six (23.1%, 6/26) were diagnosed as NP-C, comparing to none of the 142 neonatal cholestatic infants without vacuolated Kupffer cells (χ 2 = 33.983, p < 0.001). The ratio of positive diagnosis of NP-C was 31.6% (6/19) in neonatal cholestatic infants with both vacuolated Kupffer cells and splenomegaly. Therefore, we conclude that the presence of vacuolated Kupffer cells can raise a high clinical suspicion of NP-C in neonatal cholestatic infants, especially in those with splenomegaly.

Comparison of Two Donor Liver Procurement Methods for Treatment of Pediatric Acute Liver Failure.

Background: To evaluate the difference and efficacy of two donor liver procurement methods for treatment of pediatric acute liver failure (PALF) by living donor liver transplantation (LDLT). Methods: A total of 17 patients (12 men, 5 women) with PALF who underwent LDLT in our hospital between October 2016 and October 2020, and prognostic efficacy of donors and recipients using two donor liver procurement methods were analyzed. Results: The donors and recipients were both divided into laparoscopic (7 cases) and open (10 cases) donor liver procurement groups. In the recipients, two deaths occurred in the laparoscopic group and one in the open group, and there were three postoperative complications in the laparoscopic group and six in the open group. The cumulative 1-year and 3-year survival rates in the laparoscopic group and the open group were 80.0% and 85.7% separately. There was no difference in the postoperative survival and complications rates between the two groups. In the donors, the operation time, postoperative hospital stay, and blood loss of the laparoscopic group was significantly reduced compared with the open group (P ≤ 0.01). No death or serious complication occurred in either donor group. Conclusion: Laparoscopic donor liver procurement is worth recommending than open donor liver procurement for treatment of PALF combined with LDLT in qualified transplant centers.

MYO5B-associated diseases: Novel liver-related variants and genotype-phenotype correlation.

BACKGROUND & AIMS: Biallelic pathogenic variants in MYO5B cause microvillus inclusion disease (MVID), or familial intrahepatic cholestasis (FIC). The reported FIC patients are scarce and so the genotype-phenotype correlation has not been fully characterised. This study aimed to report more MYO5B-associated FIC patients and correlate genotypes to phenotypes in more detail. METHODS: The phenotype and genetic data of 12 newly diagnosed MYO5B-associated (including 11 FIC) patients, as well as 118 previously reported patients with available genotypes, were summarised. Only patients with biallelic MYO5B variants were enrolled. Nonsense, frameshift, canonical splice sites, initiation codon loss, and single exon or multiexon deletion were defined as null MYO5B variants. RESULTS: Phenotypically, 50 were isolated MVID, 47 involved both liver and intestine (combined), and 33 were isolated FIC (9 persistent, 15 recurrent, 3 transient, and 6 un-sub-classified) patients. The severity of intestinal manifestation was positively correlated to an increased number of null variants (ρ = 0.299, P = .001). All FIC patients carried at least one non-null variant, and the severity of cholestasis was correlated to the presence of a null variant (ρ = 0.420, P = .029). The proportion of FIC patients (16/29, 55%) harbouring missense/in-frame variants affecting the non-motor regions of MYO5B was significantly higher than that of MVID (3/25, 12%, P = .001) and combined patients (3/31, 10%, P = .000). 10 of the 29 FIC patients harboured missense/in-frame variants at the IQ motifs comparing to none in the 56 MVID and combined patients (P = .000). CONCLUSIONS: The phenotype of MYO5B deficiency was associated with MYO5B genotypes, the nullity or the domain affected.

Genetic spectrum and clinical characteristics of 3ß-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency in China.

BACKGROUND: Biallelic variants in HSD3B7 cause 3ß-hydroxy-Δ5-C27-steroid oxidoreductase (HSD3B7) deficiency, a life-threatening but treatable liver disease. The goal of this study was to obtain detailed information on the correlation between the genotype and phenotype of HSD3B7 deficiency and to report on responses to primary bile acid therapy. METHODS: The medical records of a cohort of 39 unrelated patients with genetically and biochemically confirmed HSD3B7 deficiency were examined to determine whether there exist genotype-phenotype relationships in this bile acid synthesis disorder. RESULTS: In all, 34 of the 44 variants identified in HSD3B7 were novel. A total of 32 patients presented early with neonatal cholestasis, and 7 presented after 1-year of age with liver failure (n = 1), liver cirrhosis (n = 3), cholestasis (n = 1), renal cysts and abnormal liver biochemistries (n = 1), and coagulopathy from vitamin K1 deficiency and abnormal liver biochemistries (n = 1). Renal lesions, including renal cysts, renal stones, calcium deposition and renal enlargement were observed in 10 of 35 patients. Thirty-three patients were treated with oral chenodeoxycholic acid (CDCA) resulting in normalization of liver biochemistries in 24, while 2 showed a significant clinical improvement, and 7 underwent liver transplantation or died. Remarkably, renal lesions in 6 patients resolved after CDCA treatment, or liver transplantation. There were no significant correlations between genotype and clinical outcomes. CONCLUSIONS: In what is the largest cohort of patients with HSD3B7 deficiency thus far studied, renal lesions were a notable clinical feature of HSD3B7 deficiency and these were resolved with suppression of atypical bile acids by oral CDCA administration.

Pediatric Wilson disease presenting as acute liver failure: Prognostic indices.

BACKGROUND: Acute liver failure (ALF) can be a primary presentation of Wilson disease (WD). Mortality rates are high in WD with ALF (WDALF). Predictions of mortality in WDALF vary by model and are sometimes contradictory, perhaps because few patients are studied or WD diagnoses are questionable. AIM: To determine the outcomes among well-documented WDALF patients and assess mortality model performance in this cohort. METHODS: We reviewed the medical records of our pediatric WDALF patients (n = 41 over 6-years-old, single-center retrospective study) and compared seven prognostic models (King's College Hospital Criteria, model for end-stage liver disease/pediatric end-stage liver disease scoring systems, Liver Injury Unit [LIU] using prothrombin time [PT] or international normalized ratio [INR], admission LIU using PT or INR, and Devarbhavi model) with one another. RESULTS: Among the 41 Han Chinese patients with ALF, WD was established by demonstrating ATP7B variants in 36. In 5 others, Kayser-Fleischer rings and Coombs-negative hemolytic anemia permitted diagnosis. Three died during hospitalization and three underwent liver transplantation (LT) within 1 mo of presentation and survived (7.3% each); 35 (85.4%) survived without LT when given enteral D-penicillamine and zinc-salt therapy with or without urgent plasmapheresis. Parameters significantly correlated with mortality included encephalopathy, coagulopathy, and gamma-glutamyl transpeptidase activity, bilirubin, ammonia, and serum sodium levels. Area under the receiver operating curves varied among seven prognostic models from 0.981 to 0.748 with positive predictive values from 0.214 to 0.429. CONCLUSION: WDALF children can survive and recover without LT when given D-penicillamine and Zn with or without plasmapheresis, even after enlisting for LT.

Biallelic loss-of-function ZFYVE19 mutations are associated with congenital hepatic fibrosis, sclerosing cholangiopathy and high-GGT cholestasis.

BACKGROUND: For many children with intrahepatic cholestasis and high-serum gamma-glutamyl transferase (GGT) activity, a genetic aetiology of hepatobiliary disease remains undefined. We sought to identify novel genes mutated in children with idiopathic high-GGT intrahepatic cholestasis, with clinical, histopathological and functional correlations. METHODS: We assembled a cohort of 25 children with undiagnosed high-GGT cholestasis and without clinical features of biliary-tract infection or radiological features of choledochal malformation, sclerosing cholangitis or cholelithiasis. Mutations were identified through whole-exome sequencing and targeted Sanger sequencing. We reviewed histopathological findings and assessed phenotypical effects of ZFYVE19 deficiency in cultured cells by immunofluorescence microscopy. RESULTS: Nine Han Chinese children harboured biallelic, predictedly complete loss-of-function pathogenic mutations in ZFYVE19 (c.314C>G, p.S105X; c.379C>T, p.Q127X; c.514C>T, p.R172X; c.547C>T, p.R183X; c.226A>G, p.M76V). All had portal hypertension and, at liver biopsy, histopathological features of the ductal plate malformation (DPM)/congenital hepatic fibrosis (CHF). Four children required liver transplantation for recurrent gastrointestinal haemorrhage. DPM/CHF was confirmed at hepatectomy, with sclerosing small-duct cholangitis. Immunostaining for two primary-cilium axonemal proteins found expression that was deficient intraluminally and ectopic within cholangiocyte cytoplasm. ZFYVE19 depletion in cultured cells yielded abnormalities of centriole and axoneme. CONCLUSION: Biallelic ZFYVE19 mutations can lead to high-GGT cholestasis and DPM/CHF in vivo. In vitro, they can lead to centriolar and axonemal abnormalities. These observations indicate that mutation in ZFYVE19 results, through as yet undefined mechanisms, in a ciliopathy.

A Novel, Recurrent, 3.6-kb Deletion in the PYGL Gene Contributes to Glycogen Storage Disease Type VI.

The PYGL gene is the only established gene known to cause glycogen storage disease type VI (GSD6), which is a rare autosomal recessive disorder associated with hepatomegaly, elevated levels of hepatic transaminases, and hypoglycemia. Extended bioinformatics analysis was performed on the exome sequencing data of 5 patients who were clinically diagnosed as having or highly suspected of having GSD, and a single heterozygous pathogenic or likely pathogenic or rare variant of uncertain significance single-nucleotide variant was identified on the PYGL gene. A recurrent, novel, 3.6-kb deletion involving exons 14 to 17 of PYGL was identified in three of the five patients. Together with the two novel and one established stop-gain SNVs, they were diagnosed as compounds heterozygous of PYGL variants and confirmed as GSD6. The detected 3.6-kb deletion was further screened in a Chinese cohort of 31,317 individuals without hepatic abnormalities, and 10 carriers were identified, showing an allele frequency of 0.016%. Compared with the previously established 47 PYGL pathogenic or likely pathogenic SNVs, the novel pathogenic deletion had the second highest allele frequency among the population. This recurrent, novel, 3.6-kb deletion improved the molecular diagnostic rate of the GSD6. The relatively high frequency of the variant suggests that it is a potential mutation hotspot in patients with GSD6.

Glycogen storage disease type VI can progress to cirrhosis: ten Chinese patients with GSD VI and a literature review.

Objectives The aim of our study is to systematically describe the genotypic and phenotypic spectrum of Glycogen storage disease type VI (GSD VI), especially in Chinses population.  Methods We retrospectively analyzed ten Chinese children diagnosed as having GSD VI confirmed by next generation sequencing in Children's Hospital of Fudan University and Jinshan Hospital of Fudan University. We described the genotypic and phenotypic spectrum of GSD VI through the clinical and genetic data we collected. Moreover, we conducted a literature review, and we compared the genotypic and phenotypic spectrum of GSD VI between Chinese population and non Chinese population.  Results For the first time, we found that four Chinese patients showed cirrhosis in liver biopsy characterized by the formation of regenerative nodules. In addition, c.772+1G>A and c.1900G>C, p.(Asp634His) were recurrent in three Chinese families and four European families respectively indicating that the genotypic spectrum of PYGL gene may vary among the population. Furthermore, we identified seven novel variants in PYGL gene.  Conclusions Our study enriched the genotypic and phenotypic spectrum of GSD VI, and provided a new clue for management of GSD VI.