[A case of neonatal liver failure]. / 新生儿肝衰竭1例.

The patient was a male infant, born full-term, admitted to the hospital at 28 days of age due to jaundice for 20 days and abdominal distension for 15 days. The patient developed symptoms of jaundice, hepatosplenomegaly, massive ascites, and progressively worsening liver function leading to liver failure, severe coagulation disorders, and thrombocytopenia one week after birth. Various treatments were administered, including anti-infection therapy, fluid restriction, use of diuretics, use of hepatoprotective and choleretic agents, intermittent paracentesis, blood exchange, and intravenous immunoglobulin, albumin, and plasma transfusions. However, the patient's condition did not improve, and on the 24th day of hospitalization, the family decided to discontinue treatment and provide palliative care. Sequencing of the patient's liver tissue and parental blood samples using whole-exome sequencing did not identify any pathogenic variants that could explain the liver failure. However, postmortem liver tissue pathology suggested congenital hepatic fibrosis (CHF). Given the rarity of CHF causing neonatal liver failure, further studies on the prognosis and pathogenic genes of CHF cases are needed in the future. This article provides a comprehensive description of the differential diagnosis of neonatal liver failure and introduces a multidisciplinary diagnostic and therapeutic approach to neonatal liver failure.

Dysregulation of the Scribble/YAP/ß-catenin axis sustains the fibroinflammatory response in a PKHD1-/- mouse model of congenital hepatic fibrosis.

Congenital hepatic fibrosis (CHF), a genetic cholangiopathy characterized by fibropolycystic changes in the biliary tree, is caused by mutations in the PKHD1 gene, leading to defective fibrocystin (FPC), changes in planar cell polarity (PCP) and increased ß-catenin-dependent chemokine secretion. In this study, we aimed at understanding the role of Scribble (a protein involved in PCP), Yes-associated protein (YAP), and ß-catenin in the regulation of the fibroinflammatory phenotype of FPC-defective cholangiocytes. Immunohistochemistry showed that compared with wild type (WT) mice, in FPC-defective (Pkhd1del4/del4 ) mice nuclear expression of YAP/TAZ in cystic cholangiocytes, significantly increased and correlated with connective tissue growth factor (CTGF) expression and pericystic fibrosis, while Scribble expression on biliary cyst cells was markedly decreased. Cholangiocytes isolated from WT mice showed intense Scribble immunoreactivity at the membrane, but minimal nuclear expression of YAP, which conversely increased, together with CTGF, after small interfering RNA (siRNA) silencing of Scribble. In FPC-defective cholangiocytes, inhibition of YAP nuclear import reduced ß-catenin nuclear expression, and CTGF, integrin ß6, CXCL1, and CXCL10 mRNA levels, whereas inhibition of ß-catenin signaling did not affect nuclear translocation of YAP. Notably, siRNA silencing of Scribble and YAP in WT cholangiocytes mimics the fibroinflammatory changes of FPC-defective cholangiocytes. Conditional deletion of ß-catenin in Pkhd1del4/del4  mice reduced cyst growth, inflammation and fibrosis, without affecting YAP nuclear expression. In conclusion, the defective anchor of Scribble to the membrane facilitates the nuclear translocation of YAP and ß-catenin with gain of a fibroinflammatory phenotype. The Scribble/YAP/ß-catenin axis is a critical factor in the sequence of events linking the genetic defect to fibrocystic trait of cholangiocytes in CHF.

Biliary sepsis complication with congenital hepatic fibrosis: an unexpected outcome.

BACKGROUND: CHF (Congenital hepatic fibrosis) is a rare hereditary disease characterized by periportal fibrosis and ductal plate malformation. Little is known about the clinical presentations and outcome in CHF patients with an extraordinary complication with biliary sepsis. Our case described a 23-year-old female diagnosed as CHF combined with biliary sepsis. Her blood culture was positive for KP (Klebsiella pneumoniae), and with a high level of CA19-9 (> 1200.00 U/ml, ref: <37.00 U/ml). Meanwhile, her imaging examinations showed intrahepatic bile duct dilatation, portal hypertension, splenomegaly, and renal cysts. Liver pathology revealed periportal fibrosis and irregularly shaped proliferating bile ducts. Whole-exome sequencing identified two heterozygous missense variants c.3860T > G (p. V1287G) and c.9059T > C (p. L3020P) in PKHD1 gene. After biliary sepsis relieved, her liver function test was normal, and imaging examination results showed no significant difference with the results harvested during her biliary sepsis occurred. CONCLUSION: The diagnosis of CHF complicated with biliary sepsis in the patient was made. Severely biliary sepsis due to KP infection may not inevitably aggravate congential liver abnormality in young patients. Our case provides a good reference for timely treatment of CHF patients with biliary sepsis.

Congenital Hepatic Fibrosis as an Early Sign of Presentation of ADPKD.

Autosomal dominant polycystic kidney disease (ADKPD) is the most frequent type of polycystic kidney disease. It is inherited through family members, with an incidence of approximately 1:400 to1:1000.Typically, individuals with ADKPD are identified between their fourth and fifth decade of life. ADKPD occurs as a results of mutation in one of the two genes, PDK1 and PDK2.Patients with PKD1 experience renal failure at an earlier onset than those with PKD2. We report on a 2 year-old-boy with hepatosplenomegaly and signs of portal hypertension. Both kidneys appeared normal until the age of 8, when multiple cysts developed, this being typical of ADKPD. Suspecting ADKPD, we performed whole exome sequencing, thereby confirming a mutation of c.6730 673del p.(Ser 2244Hisfs*17). The investigations of all family members found other individuals affected by ADKPD.

[Clinical and pathological features of 20 cases of congenital hepatic fibrosis].

Objective: To investigate the clinical and pathological features of congenital hepatic fibrosis (CHF). Methods: The clinical and pathological findings of 20 patients diagnosed with CHF from 2017 to 2023 were retrospectively analyzed. Results: Among the 20 patients, 8 were males and 12 were females with a median age of 21.5 years. Mostly patients were admitted to the hospital with cirrhosis, portal hypertension and upper gastrointestinal bleeding. Pathological features were diffuse fibrosis in the portal area, formation of fibrous septa of varying width, segmentation of the liver parenchyma, with hyperplasia of small bile ducts. Among them, 1 case (5%) was complicated with Caroli's disease, and 1 case (5%) was HNF1α hepatocellular adenoma. IHC GS showed that was positively expressed in acinar region 3 in 75% cases. Conclusion: CHF is mainly manifested by portal hypertension and its complications. Histopathology is the gold standard for diagnosis. The possibility of CHF should be considered first in children and adolescents with portal hypertension but no history of hepatitis, and complicated kidney disease. The positive pattern of acinus-3 region of GS in IHC is helpful for the diagnosis of CHF.

Association of novel TMEM67 variants with mild phenotypes of high gamma-glutamyl transpeptidase cholestasis and congenital hepatic fibrosis.

TMEM67 (mecklin or MKS3) locates in the transition zone of cilia. Dysfunction of TMEM67 disrupts cilia-related signaling and leads to developmental defects of multiple organs in humans. Typical autosomal recessive TMEM67 defects cause partial overlapping phenotypes, including abnormalities in the brain, eyes, liver, kidneys, bones, and so forth. However, emerging reports of isolated nephronophthisis suggest the possibility of a broader phenotype spectrum. In this study, we analyzed the genetic data of cholestasis patients with no obvious extrahepatic involvement but with an unexplained high level of gamma-glutamyl transpeptidase (GGT). We identified five Han Chinese patients from three unrelated families with biallelic nonnull low-frequency TMEM67 variants. All variants were predicted pathogenic in silico, of which p. Arg820Ile and p. Leu144del were previously unreported. In vitro studies revealed that the protein levels of the TMEM67 variants were significantly decreased; however, their interaction with MKS1 remained unaffected. All the patients, aged 7-39 years old, had silently progressive cholestasis with elevated GGT but had normal bilirubin levels. Histological studies of liver biopsy of patients 1, 3, and 5 showed the presence of congenital hepatic fibrosis. We conclude that variants in TMEM67 are associated with a mild phenotype of unexplained, persistent, anicteric, and high GGT cholestasis without typical symptoms of TMEM67 defects; this possibility should be considered by physicians in gastroenterology and hepatology.

Early clinical management of autosomal recessive polycystic kidney disease.

Autosomal recessive polycystic kidney disease (ARPKD) is a rare but highly relevant disorder in pediatric nephrology. This genetic disease is mainly caused by variants in the PKHD1 gene and is characterized by fibrocystic hepatorenal phenotypes with major clinical variability. ARPKD frequently presents perinatally, and the management of perinatal and early disease symptoms may be challenging. This review discusses aspects of early manifestations in ARPKD and its clincial management with a special focus on kidney disease.

Notch-Hes1 signaling activation in Caroli disease and polycystic liver disease.

The Notch signaling pathway plays a key role in the morphogenesis of the biliary tree, but its involvement in cystic biliary diseases, such as Caroli disease (CD) and polycystic liver disease (PLD), has yet to be determined. Immunostaining was performed using liver sections of CD and PLD, and the results were compared with those of congenital hepatic fibrosis (CHF) and von Meyenburg complex (VMC). The expression of Notch receptor 1 (Notch1) was increased in the nuclei of biliary epithelial cells in all cases of CD and PLD, whereas it remained at a low level in CHF and VMC. In addition, Notch2 and Notch3 were preferably expressed in the nuclei of biliary epithelial cells of PLD. Accordingly, the Notch effector Hes1 was highly expressed in biliary epithelial cells of CD and PLD, and the cell proliferative activity was significantly higher in CD and PLD. The expression of the Notch ligand Delta-like 1 was significantly increased in biliary epithelial cells of CD and PLD, which may be causally associated with the nuclear overexpression of Notch1 and Hes1. These results indicate that aberrant activation of the Notch-Hes1 signaling pathway may be responsible for the progression of biliary cystogenesis in CD and PLD.

Long term outcome of MPI-CDG patients on D-mannose therapy.

Mannose phosphate isomerase MPI-CDG (formerly CDG-1b) is a potentially fatal inherited metabolic disease which is readily treatable with oral D-mannose. We retrospectively reviewed long-term outcomes of patients with MPI-CDG, all but one of whom were treated with D-mannose. Clinical, biological, and histological data were reviewed at diagnosis and on D-mannose treatment. Nine patients were diagnosed with MPI-CDG at a median age of 3 months. The presenting symptoms were diarrhea (n = 9), hepatomegaly (n = 9), hypoglycemia (n = 8), and protein loosing enteropathy (n = 7). All patients survived except the untreated one who died at 2 years of age. Oral D-mannose was started in eight patients at a median age of 7 months (mean 38 months), with a median follow-up on treatment of 14 years 9 months (1.5-20 years). On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function. Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles. Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up. This study highlights (i) the efficacy and safety of D-mannose treatment with a median follow-up on treatment of almost 15 years (ii) the need for life-long treatment (iii) the risk of relapse with poor compliance, (iii) the importance of portal hypertension screening (iv) the need to be aware of venous and renal complications in adulthood.

Living donor liver transplantation for congenital hepatic fibrosis in children.

Congenital hepatic fibrosis (CHF) often accompanies autosomal recessive polycystic kidney disease (ARPKD), which stems from a PKHD1 gene mutation. The aim of this study was to clarify the prognosis of children with CHF who received living donor liver transplantation (LDLT) from donors who might be heterozygous carriers of a hepatorenal fibrocystic disease. Fourteen children with CHF who underwent LDLT at our center were enrolled. Eight and two patients had ARPKD and nephronophthisis, respectively. Eight of the donors were the recipients' fathers, and six donors were their mothers. We examined the histological and radiological findings of the donor livers and complications in the recipients following the liver transplantation. Seven of the donor livers presented morphological abnormalities of the bile ducts. Abdominal computed tomography revealed liver cysts in eight donors. One recipient underwent re-LT for graft failure due to rejection. Three patients presented with rejection, and one presented with sepsis. The overall survival rate was 100% and the original graft survival rate was 93%. In conclusion, the prognosis of recipients who received a LDLT from their parents for CHF was excellent. However, the morphology of half the donor livers was abnormal. Careful follow-up is needed to ensure long-term graft survival.

Deceased vs living donor grafts for pediatric simultaneous liver-kidney transplantation: A single-center experience.

INTRODUCTION: In conditions of limited experience of pediatric simultaneous liver-kidney transplantation (SLKT) using grafts from living and deceased donors, there is a certain need to validate the approach. PATIENTS: The retrospective study of 18 pediatric patients who received SLKT between 2008 and 2019. RESULTS: Grafts were obtained from both living and deceased donors. The patients' age ranged from 2 to 16 years (9 years ±4). The body weight of the children varied from 9.5 to 39 kg (22 kg ±9). The follow-up period lasted from 1 to 109 months (median 38 months ±35). The various graft combinations were used in both groups. There was no mortality during the follow-up. There was no significant difference in baseline parameters in recipients who received grafts from living and deceased donors except age (7.5 years ±2.2 vs 11.8 years ±4.1; P = .038). Rate of complications > grade II was higher among recipients of deceased donor SLKT (7.7% vs 60%; OR, 7.8; 95% CI, 1.04-58.48; P = .044). All the patients are alive with both grafts functioning. All the living donors returned to the normal life. CONCLUSION: SLKT is a safe and effective procedure for children with both simultaneous end-stage liver disease and end-stage renal disease. Both living donor partial liver and kidney transplantation and deceased donor liver-kidney transplantation can be considered as safe and feasible options.

Loss of fibrocystin promotes interleukin-8-dependent proliferation and CTGF production of biliary epithelium.

BACKGROUND & AIMS: Congenital hepatic fibrosis (CHF) is a genetic liver disease resulting in abnormal proliferation of cholangiocytes and progressive hepatic fibrosis. CHF is caused by mutations in the PKHD1 gene and the subsequent dysfunction of the protein it encodes, fibrocystin. However, the underlying molecular mechanism of CHF, which is quite different from liver cirrhosis, remains unclear. This study investigated the molecular mechanism of CHF pathophysiology using a genetically engineered human induced pluripotent stem (iPS) cell model to aid the discovery of novel therapeutic agents for CHF. METHODS: PKHD1-knockout (PKHD1-KO) and heterozygously mutated PKHD1 iPS clones were established by RNA-guided genome editing using the CRISPR/Cas9 system. The iPS clones were differentiated into cholangiocyte-like cells in cysts (cholangiocytic cysts [CCs]) in a 3D-culture system. RESULTS: The CCs were composed of a monolayer of cholangiocyte-like cells. The proliferation of PKHD1-KO CCs was significantly increased by interleukin-8 (IL-8) secreted in an autocrine manner. IL-8 production was significantly elevated in PKHD1-KO CCs due to mitogen-activated protein kinase pathway activation caused by fibrocystin deficiency. The production of connective tissue growth factor (CTGF) was also increased in PKHD1-KO CCs in an IL-8-dependent manner. Furthermore, validation analysis demonstrated that both the serum IL-8 level and the expression of IL-8 and CTGF in the liver samples were significantly increased in patients with CHF, consistent with our in vitro human iPS-disease model of CHF. CONCLUSIONS: Loss of fibrocystin function promotes IL-8-dependent proliferation of, and CTGF production by, human cholangiocytes, suggesting that IL-8 and CTGF are essential for the pathogenesis of CHF. IL-8 and CTGF are candidate molecular targets for the treatment of CHF. LAY SUMMARY: Congenital hepatic fibrosis (CHF) is a genetic liver disease caused by mutations of the PKHD1 gene. Dysfunction of the protein it encodes, fibrocystin, is closely associated with CHF pathogenesis. Using an in vitro human induced pluripotent stem cell model and patient samples, we showed that the loss of fibrocystin function promotes proliferation of cholangiocytes and the production of connective tissue growth factor (CTGF) in an interleukin 8 (IL-8)-dependent manner. These results suggest that IL-8 and CTGF are essential for the pathogenesis of CHF.

Ultrasound Elastography to Quantify Liver Disease Severity in Autosomal Recessive Polycystic Kidney Disease.

OBJECTIVES: To evaluate the diagnostic accuracy of ultrasound elastography with acoustic radiation force impulse (ARFI) to detect congenital hepatic fibrosis and portal hypertension in children with autosomal recessive polycystic kidney disease (ARPKD). STUDY DESIGN: Cross-sectional study of 25 children with ARPKD and 24 healthy controls. Ultrasound ARFI elastography (Acuson S3000, Siemens Medical Solutions USA, Inc, Malvern, Pennsylvania) was performed to measure shear wave speed (SWS) in the right and left liver lobes and the spleen. Liver and spleen SWS were compared in controls vs ARPKD, and ARPKD without vs with portal hypertension. Linear correlations between liver and spleen SWS, spleen length, and platelet counts were analyzed. Receiver operating characteristic analysis was used to evaluate diagnostic accuracy of ultrasound ARFI elastography. RESULTS: Participants with ARPKD had significantly higher median liver and spleen SWS than controls. At a proposed SWS cut-off value of 1.56 m/s, the left liver lobe had the highest sensitivity (92%) and specificity (96%) for distinguishing participants with ARPKD from controls (receiver operating characteristic area 0.92; 95% CI 0.82-1.00). Participants with ARPKD with portal hypertension (splenomegaly and low platelet counts) had significantly higher median liver and spleen stiffness than those without portal hypertension. The left liver lobe also had the highest sensitivity and specificity for distinguishing subjects with ARPKD with portal hypertension. CONCLUSIONS: Ultrasound ARFI elastography of the liver and spleen, particularly of the left liver lobe, is a useful noninvasive biomarker to detect and quantify liver fibrosis and portal hypertension in children with ARPKD.

Combination therapy for severe portopulmonary hypertension in a child allows for liver transplantation.

Severe PPHTN is a contraindication to liver transplantation and predicts an abysmal 5-year outcome. It is defined as a resting mPAP >45 mm Hg with a mean pulmonary artery wedge pressure of <15 mm Hg and pulmonary vascular resistance of >3 wood units in the setting of portal hypertension. There have been limited reports of successful treatment of PPHTN leading to successful liver transplantation in adults, and one reported use of monotherapy as a bridge to successful liver transplant in pediatrics. To our knowledge, we describe the first use of combination therapy as a successful bridge to liver transplantation in a pediatric patient with severe PPHTN. This report adds to the paucity of data in pediatrics on the use of pulmonary vasodilator therapy in patients with severe PPHTN as a bridge to successful liver transplantation. Early diagnosis in order to mitigate or avoid the development of irreversible pulmonary vasculopathy that would preclude candidacy for liver transplantation is crucial, but our report demonstrates that combination therapy can be administered safely, quickly, and may allow for successful liver transplantation in patients with severe PPHTN.

Congenital Hepatic Fibrosis in a Purebred Spanish Horse Foal: Pathology and Genetic Studies on PKHD1 Gene Mutations.

A 1-month-old Purebred Spanish Horse (PSH) foal presented with progressive hepatic failure culminating in death. Hepatic lesions were consistent with congenital hepatic fibrosis (CHF). Genetic studies in the PKHD1 gene in the affected foal revealed that it was heterozygous for the 2 previously described single-nucleotide polymorphisms (SNPs) linked to CHF in Swiss Franches-Montagnes (SFM) horses. In addition, 2 novel mutations were detected, the foal being homozygous for one of them and heterozygous for the other. Genetic studies in a healthy PSH population ( n = 35) showed a 3-fold higher genotypic frequency for PKHD1 SNP g.49,630,834G>A and a 5-fold higher genotypic frequency for PKHD1 SNP g.49,597,760A>T compared with those reported for SFM horses. SNPs in the PKHD1 gene in CHF-affected SFM horses might not fully explain the CHF observed in the PSH. Other mutations in the PKHD1 gene could play a more important role in the PSH.

B-type natriuretic peptide overexpression ameliorates hepatorenal fibrocystic disease in a rat model of polycystic kidney disease.

Polycystic kidney disease (PKD) involves progressive hepatorenal cyst expansion and fibrosis, frequently leading to end-stage renal disease. Increased vasopressin and cAMP signaling, dysregulated calcium homeostasis, and hypertension play major roles in PKD progression. The guanylyl cyclase A agonist, B-type natriuretic peptide (BNP), stimulates cGMP and shows anti-fibrotic, anti-hypertensive, and vasopressin-suppressive effects, potentially counteracting PKD pathogenesis. Here, we assessed the impacts of guanylyl cyclase A activation on PKD progression in a rat model of PKD. Sustained BNP production significantly reduced kidney weight, renal cystic indexes and fibrosis, in concert with suppressed hepatic cystogenesis in vivo. In vitro, BNP decreased cystic epithelial cell proliferation, suppressed fibrotic gene expression, and increased intracellular calcium. Together, our data demonstrate multifaceted effects of sustained activation of guanylyl cyclase A on polycystic kidney and liver disease. Thus, targeting the guanylyl cyclase A-cGMP axis may provide a novel therapeutic strategy for hepatorenal fibrocystic diseases.

Challenges in establishing genotype-phenotype correlations in ARPKD: case report on a toddler with two severe PKHD1 mutations.

BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) constitutes an important cause of pediatric end stage renal disease and is characterized by a broad phenotypic variability. The disease is caused by mutations in a single gene, Polycystic Kidney and Hepatic Disease 1 (PKHD1), which encodes a large transmembrane protein of poorly understood function called fibrocystin. Based on current knowledge of genotype-phenotype correlations in ARPKD, two truncating mutations are considered to result in a severe phenotype with peri- or neonatal mortality. Infants surviving the neonatal period are expected to carry at least one missense mutation. CASE-DIAGNOSIS/TREATMENT: We report on a female patient with two truncating PKHD1 mutations who survived the first 30 months of life without renal replacement therapy. Our patient carries not only a known stop mutation, c.8011C>T (p.Arg2671*), but also the previously reported c.51A>G PKHD1 sequence variant of unknown significance in exon 2. Using functional in vitro studies we have confirmed the pathogenic nature of c.51A>G, demonstrating activation of a new donor splice site in intron 2 that results in a frameshift mutation and generation of a premature stop codon. CONCLUSIONS: This case illustrates the importance of functional mutation analyses and also raises questions regarding the current belief that the presence of at least one missense mutation is necessary for perinatal survival in ARPKD.

Proposal for an algorithm for liver transplantation in Caroli's disease and syndrome: putting an uncommon effort into a common task.

Liver transplantation (LT) represents an uncommon indication for Caroli's disease (CD) or syndrome (CS). Excellent results of LT have been reported as shown by recent multicentric European and American registry reports. Clear therapeutic flowcharts to adopt in these diseases are still lacking. This review aims at analyzing highlighting recent transplant experiences in this field and also at focusing on the role of LT in case-specific comorbidities such as development of cholangiocellular cancer or renal failure are present.