先天性肝纤维化目前仍被认为是一种罕见的常染色体隐性遗传性疾病，该病与胆管板畸形所致的肝内胆管遗传发育障碍有关。现以1例多囊肾/多囊肝病变1基因突变致胆管炎型先天性肝纤维化患者为例，探讨该病发病原因、临床表现、诊断要点以及治疗进展，以期能够在一定程度上提高肝胆科医师对该病的认识，从而有效提高早期诊断率。.

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.
患儿男，足月儿，28日龄，因发现皮肤黄染20 d、腹胀15 d入院。患儿生后1周起病，以皮肤黄染、肝脾大、大量腹水、肝功能异常进行性加重至肝衰竭、严重凝血功能障碍、血小板减少为主要表现。给予抗感染、限液利尿、保肝利胆、间断放腹水、换血，以及静脉注射免疫球蛋白、白蛋白、血浆等多种血制品治疗，病情无好转，入院第24天家属决定放弃治疗行临终关怀。患儿肝组织和父母血家系全外显子组测序未找到可以解释患儿肝衰竭的致病变异，最终尸体解剖肝组织病理提示先天性肝纤维化（congenital hepatic fibrosis, CHF）。鉴于CHF导致新生儿肝衰竭罕见，今后仍需对CHF病例的转归及其致病基因进一步研究。该文对新生儿肝衰竭的鉴别诊断进行重点描述，并介绍其多学科诊疗思路。.

Congenital hepatic fibrosis (CHF) is considered to be a rare autosomal recessive hereditary fibrocystic liver disease, mainly found in children. However, cases of adult CHF with autosomal dominant polycystic kidney disease (ADPKD) caused by PKD1 gene mutation are extremely rare. We report a 31-year-old female patient admitted for esophageal and gastric variceal bleeding. Physical examination revealed significant splenomegaly, biochemical tests showed a slight increase in liver enzymes, and a decrease in platelet count. Imaging examinations showed significant dilatation of the common bile duct and intrahepatic bile ducts, as well as multiple renal cysts. Liver biopsy revealed enlarged portal areas, bridging fibrosis, and numerous variably shaped small bile ducts. Genetic testing identified two unique mutations in the PKD1 gene, identified as biallelic mutations compound heterozygous mutations composed of a mutation inherited from the father (c.8296 T > C) and one from the mother (c.9653G > C). Based on multiple test results, the patient was diagnosed with the portal hypertension type CHF associated with ADPKD. During her initial hospital stay, the patient underwent endoscopic treatment for gastrointestinal bleeding. To date, the patient has recovered well. Moreover, a significant reduction in varices was observed in a gastroscopy examination 18 months later.

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.
目的： 探讨先天性肝纤维化（CHF）的临床病理特征。 方法： 收集2017-2023年四川大学华西医院CHF病例20例，进行临床及病理特征分析。 结果： 20例患者中，男性8例，女性12例，中位发病年龄21.5岁。主要临床表现为肝硬化、门静脉高压及上消化道出血。病理学特征为汇管区弥漫性纤维化，形成宽窄不一的纤维间隔，分割肝实质，细胆管增生。1例（5%）并Caroli病，1例（5%）并HNF1α肝细胞腺瘤。免疫组织化学谷氨酰胺合成酶检测示75% CHF为腺泡3区的阳性表达。 结论： CHF主要临床表现为门静脉高压及其并发症，组织学检查是诊断金标准。对儿童或青少年发现门静脉高压症，但无肝炎病史，合并肾病者，应首先考虑CHF的可能性。谷氨酰胺合成酶免疫组织化学检查腺泡3区的阳性模式有助于CHF的诊断，对预后有一定的提示作用。.

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.
CONCLUSIONS: 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.

暂无摘要。

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.

暂无摘要。

先天性肝纤维化（CHF）是一种罕见的与胆管板畸形相关的肝内胆管遗传发育障碍疾病，无特异性临床表现，易误诊或漏诊。现报道1例误诊为肝硬化并发食管胃底静脉曲张破裂出血患者在行经颈静脉肝内门体分流术（TIPS）治疗时发现，最后经病理学检查确诊为CHF患者的临床资料，以期提高CHF的诊治水平。.

BACKGROUND: Congenital hepatic fibrosis (CHF) is a rare autosomal recessive disorder characterized by variable degrees of periportal fibrosis and malformation of bile ducts. CHF is generally accompanied by a variety of conditions or syndromes with other organ involvement.
METHODS: We report a 5-year-4-month-old Chinese boy with congenital hypothyroidism (CH) diagnosed with CHF. The patient was diagnosed with CH by a newborn screening test and has since been taking levothyroxine. He has developed normally without neurocognitive deficits. Abnormal liver function was observed in the patient at the age of 4 years and 11 mo, and elevated levels of liver function indices were persistent for 5 mo. Radiological imaging indicated hepatospleno-megaly without narrowing of the portal vein but dilated splenic vein. A liver biopsy confirmed the pathological features of CHF. Genetic testing revealed two novel homozygous mutations, namely, c.2141-3T>C variant in PKHD1 related to CHF and c.2921G>A (p.R974H) in DUOX2 related to CH. The patient was treated with compound glycyrrhizin tablet, ursodeoxycholic acid, and levothyroxine after diagnosis. The patient achieved a favorable clinical outcome during a follow-up period of over 2 years.
CONCLUSIONS: Herein, we report the first case of a Chinese boy with comorbidity of CHF and CH, carrying both PKHD1 gene and DUOX2 gene novel mutations. Liver biopsy and genetic testing should be considered for the diagnosis of coexistent liver disease in CH patients with unexplained abnormal liver function.