Intestinal failure (IF) is defined as the critical reduction of functional intestines below the minimum needed to absorb nutrients and fluids, so that intravenous supplementation with parenteral nutrition (PN) is required to maintain health and/or growth. Although the benefits are evident, patients receiving PN can suffer from serious cholestasis due to lack of enteral feeding and small intestinal bacterial overgrowth (SIBO). One such complication that may arise is intestinal failure-associated liver disease (IFALD). Evidences from recent studies suggest that alterations in the intestinal microbiota, as well as intraluminal bile acid driven signaling, may play a critical role in both hepatic and intestinal injury. Since Marshall first proposed the concept of the gut-liver axis in 1998, the role of gut-liver axis disorders in the development of IFALD has received considerable attention. The conversation between gut and liver is the key to maintain liver metabolism and intestinal homeostasis, which influences each other and is reciprocal causation. However, as a "forgotten organ" , intestinal microbiota on the pathogenesis of IFALD has not been well reflected. As such, we propose, for the first time, the concept of gut-microbiota-liver axis to emphasize the importance of intestinal microbiota in the interaction of gut-liver axis. Analysis and research on gut-microbiota-liver axis will be of great significance for understanding the pathogenesis of IFALD and improving the prevention and treatment measures.
Bacterial Infections/physiopathology* ; Bile Acids and Salts/physiology* ; Cholestasis/physiopathology* ; Enteral Nutrition ; Gastrointestinal Microbiome/physiology* ; Humans ; Intestinal Diseases/physiopathology* ; Intestines/physiopathology* ; Liver/physiopathology* ; Liver Diseases/physiopathology* ; Parenteral Nutrition/adverse effects* ; Short Bowel Syndrome/physiopathology* ; Signal Transduction

Congenital bile acid synthesis defect type 2 (CBAS2) is an autosomal recessive disorder caused by biallelic mutations of AKR1D1 gene, which encodes the Δ4-3-oxo-steroid 5β-reductase. Cholestatic jaundice is the main clinical manifestation, accompanied by malabsorption of fat and fat-soluble vitamins. This paper reported the clinical and genetic features of a CBAS2 patient definitely diagnosed by AKR1D1 genetic analysis. An 8-month-old male infant was referred to the hospital with the complaint of jaundiced skin and sclera over 7 months. On physical examination, growth retardation and malnutrition were discovered besides mild jaundice of the skin and sclera. The liver was palpable 8 cm below the right subcostal margin with medium texture, and the spleen was not enlarged. On liver function test, elevated levels of bilirubin (predominantly conjugated bilirubin) and transaminases were detected, but serum total bile acids and γ-glutamyl transpeptidase levels were within the normal ranges. Liver histopathologic analysis showed disorganized bile ducts, obvious multinucleated giant cells, significant cholestasis in hepatocytes, together with portal and interstitial fibrosis and lymphocytic infiltration. Via next generation sequencing analysis and Sanger sequencing confirmation, the infant proved to be a compound heterozygote of the AKR1D1 variants c.579+2delT and c.853C>T(p.Q285X), two novel mutations originated from his mother and father, respectively. CBAS2 was thus definitely diagnosed, and chenodeoxycholic acid was given orally. As a result, the abnormal liver function and hepatomegaly were improved gradually. On a follow-up 3 months later, a soft liver was palpable 2.5 cm below the right subcostal margin, and all liver function indices recovered to normal ranges.
Bile Acids and Salts ; blood ; Cholestasis ; blood ; genetics ; physiopathology ; therapy ; Humans ; Infant ; Liver ; physiopathology ; Male ; Mutation ; Oxidoreductases ; blood ; deficiency ; genetics ; Steroid Metabolism, Inborn Errors ; blood ; genetics ; physiopathology ; therapy

This study examined the effect of cholic acid (CA) on cultured cardiac myocytes (CMs) from neonatal rats with an attempt to explore the possible mechanism of sudden fetal death in intrahepatic cholestasis of pregnancy (ICP). Inverted microscopy was performed to detect the impact of CA on the beating rates of rat CMs. MTT method was used to study the effect of CA on the viability of CMs. CMs cultured in vitro were incubated with 10 μmol/L Ca(2+)-sensitive fluorescence indicator fluo-3/AM. The fluorescence signals of free calcium induced by CA were measured under a laser scanning confocal microscope. The results showed that CA decreased the beating rates of the CMs in a dose-dependent manner. CA could suppress the activities of CMs in a time- and dose-dependent manner. CA increased the concentration of intracellular free calcium in a dose-dependent manner. Our study suggested that CA could inhibit the activity of CMs by causing calcium overload, thereby leading to the sudden fetal death in ICP.
Animals ; Animals, Newborn ; Calcium ; metabolism ; Cells, Cultured ; Cholestasis, Intrahepatic ; complications ; metabolism ; physiopathology ; Cholic Acid ; metabolism ; pharmacology ; Death, Sudden ; etiology ; Dose-Response Relationship, Drug ; Female ; Fetal Death ; etiology ; Humans ; Microscopy, Confocal ; Myocardial Contraction ; drug effects ; Myocytes, Cardiac ; drug effects ; metabolism ; physiology ; Pregnancy ; Pregnancy Complications ; metabolism ; physiopathology ; Rats, Sprague-Dawley ; Time Factors

Cholestasis ; etiology ; Gestational Age ; Humans ; Hydrops Fetalis ; physiopathology ; Infant, Newborn ; Liver Function Tests ; Male ; Tachycardia, Paroxysmal ; complications ; embryology ; physiopathology ; Tachycardia, Supraventricular ; complications ; embryology ; physiopathology

OBJECTIVETo study the clinical features of children with 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency and review the literature.

METHODClinical features and treatment of one Chinese infant with 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency confirmed by HSD3B7 gene mutation analysis were retrospectively reviewed, and 51 cases of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency who were internationally reported since 2000 were also reviewed in this paper.

RESULT(1) A 3-month-old infant with neonatal cholestasis was admitted to our hospital because of hyperbilirubinemia and abnormal liver dysfunction (total bilirubin 110.7 µmol/L, direct bilirubin 74.5 µmol/L, γ-glutamyltransferase 24.4 IU/L, total bile acid 0.1 µmol/L).His jaundice disappeared within a few weeks, serum liver biochemistries improved and his growth in weight and height was excellent after oral cholic acid therapy.HSD3B7 gene analysis using peripheral lymphocyte genomic DNA from the patient identified compound heterozygous mutations. This child was confirmed as the most common inborn error of bile acid metabolism-3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency by molecular analysis.(2) Retrospective review of the literature showed that the clinical features of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency included neonatal cholestasis, some patients progressed to severe liver disease and needed liver transplantation without effective therapy; however, serum biochemical characteristics of normal γ-glutamyltransferase activity, normal or low total bile acid concentrations were not consistent with cholestasis, the replacement treatment with cholic acid produced a dramatic improvements in symptoms, biochemical markers of liver injury; 31 cases were diagnosed by HSD3B7 gene mutation analysis.

CONCLUSIONThe clinical characteristics of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency include neonatal cholestasis, normal serum γ-glutamyltransferase activity, and normal or low serum total bile acid concentration.Oral cholic acid replacement is an effective therapy; definitive diagnosis of 3β-hydroxy-Δ(5)-C27-steroid dehydrogenase deficiency can be identified by molecular genetic testing technology.

3-Hydroxysteroid Dehydrogenases ; deficiency ; genetics ; Administration, Oral ; Bile Acids and Salts ; biosynthesis ; blood ; Bilirubin ; blood ; Chenodeoxycholic Acid ; administration & dosage ; therapeutic use ; Cholestasis, Intrahepatic ; diagnosis ; drug therapy ; enzymology ; DNA Mutational Analysis ; Humans ; Infant ; Liver ; drug effects ; metabolism ; physiopathology ; Liver Function Tests ; Male ; Metabolic Diseases ; drug therapy ; physiopathology ; Molecular Sequence Data ; Mutation ; genetics ; Retrospective Studies

PURPOSE: We hypothesized that parenteral nutrition associated cholestasis (PNAC) would be more severe in small for gestational age (SGA) compared with appropriate for gestational age (AGA) very low birth weight (VLBW) infants. MATERIALS AND METHODS: Sixty-one VLBW infants were diagnosed as PNAC with exposure to parenteral nutrition with elevation of direct bilirubin > or =2 mg/dL for > or =14 days. Twenty-one SGA infants and 40 AGA infants matched for gestation were compared. RESULTS: Compared with AGA infants, PNAC in SGA infants was diagnosed earlier (25+/-7 days vs. 35+/-14 days, p=0.002) and persisted longer (62+/-36 days vs. 46+/-27 days, p=0.048). Severe PNAC, defined as persistent elevation of direct bilirubin > or =4 mg/dL for more than 1 month with elevation of liver enzymes, was more frequent in SGA than in AGA infants (61% vs. 35%, p=0.018). The serum total bilirubin and direct bilirubin levels during the 13 weeks of life were significantly different in SGA compared with AGA infants. SGA infants had more frequent (76% vs. 50%, p=0.046), and persistent elevation of alanine aminotransferase. CONCLUSION: The clinical course of PNAC is more persistent and severe in SGA infants. Careful monitoring and treatment are required for SGA infants.
Bilirubin/blood ; Case-Control Studies ; Cholestasis/diagnosis/epidemiology/*etiology ; Comorbidity ; Female ; Humans ; Infant, Newborn ; Infant, Premature, Diseases/epidemiology/etiology ; *Infant, Small for Gestational Age ; Infant, Very Low Birth Weight ; Liver/metabolism/physiopathology ; Male ; Parenteral Nutrition/*adverse effects

OBJECTIVETo study the effect of intrahepatic cholestasis of pregnancy (ICP) on the functions of the hypothalamic-pituitary-adrenocortical (HPA) axis and adrenal cortex in normal neonates.

METHODSDemographic characteristics, prenatal anxiety and depression, and perceived stress during delivery were investigated in 32 ICP women and 32 controls. The cord blood levels of cortisal, adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEAS) were measured by the radioimmunity technique in normal neonates immediately after birth.

RESULTSThe scores of prenatal anxiety and depression in ICP women were significantly higher than those in controls (p<0.05 and p<0.01, respectively). There were no significant differences in the perceived stress during delivery between the two groups. The cord blood levels of cortisol and ACTH in neonates from ICP women were significantly lower (p<0.01), while the DHEAS level was significantly higher (p<0.01) than in neonates from controls. The DHEAS/ACTH ratio was significantly higher (p<0.01), while the cortisol/DHEAS ratio was significantly lower in the ICP group (p<0.01) than in the control group. The glycocholic acid level in ICP women was positively correlated with the DHEAS level in neonatal cord blood (r=0.47, p<0.01).

CONCLUSIONSThere may be a dissociation between cortisol and DHEAS in neonates with normal birth outcome from ICP women. ICP may result in a decreased responsiveness of HPA axis and an increased secretion of DHEAS by adrenal cortex in these neonates. This suggests that there might be dysfunction of the fetal zones of the adrenal cortex.

Adrenal Cortex ; physiopathology ; Adrenocorticotropic Hormone ; blood ; Adult ; Cholestasis, Intrahepatic ; physiopathology ; Dehydroepiandrosterone Sulfate ; blood ; Female ; Humans ; Hydrocortisone ; blood ; Hypothalamo-Hypophyseal System ; physiopathology ; Infant, Newborn ; Pituitary-Adrenal System ; physiopathology ; Pregnancy ; Pregnancy Complications ; physiopathology

OBJECTIVETo investigate the effect and mechanism of emodin on acute intrahepatic cholestasis induced by alpha-naphthylisothiocyanate (ANIT) in rats.

METHODAcute cholestatic model in rats was induced by ANIT. Normal control group, emodin group without ANIT treatment, model group and emodin group with ANIT treatment were set up. Liver function and pathological changes of hepatic tissue were examined. Real-time fluorescent quantitative RT-PCR was used to detect the mRNA levels of the hepatic transport protein genes mdr1a (multidrug resistance protein 1a), mdr1b (multidrug resistance protein 1b) mdr2 (multidrug resistance protein 2), The expression of P-gp were determined by Western blotting analysis.

RESULTCompared to the model group, Emodin treatment resulted in significant reductions in serum total bilirubin (TBiL), direct bilirubin (DBiL), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), alkaline phosphatase (ALP), total bile acid (TBA) (P < 0.01 or P < 0.05). By examining the liver pathology, it was found that hepatic cellular change and necrosis, inflammatory cell infiltration and bile duct proliferation were notably alleviated in emodin model with ANIT treatment. Analysis of gene expression in livers from emodin-treated cholestatic rats revealed that mdr1a, mdr1b and mdr2 could be up-regulated (P < 0.01 or P < 0.05), expression of P-gp was increased in accordance with its mRNA (P < 0.05).

CONCLUSIONEmodin has a protective effect on hepatocytes and a restoring activity on cholestatic hepatitis. Mechanism of its action may be related to induce expression of the bile-metabolism-related transporter P-gp in the liver to prevent bile acids and other toxic compounds overaccumulation in hepatocytes and hepatic toxicity.

1-Naphthylisothiocyanate ; pharmacology ; ATP-Binding Cassette, Sub-Family B, Member 1 ; genetics ; Alanine Transaminase ; blood ; Alkaline Phosphatase ; blood ; Animals ; Aspartate Aminotransferases ; blood ; Bile Acids and Salts ; blood ; Bilirubin ; blood ; Cholestasis, Intrahepatic ; chemically induced ; drug therapy ; genetics ; metabolism ; Emodin ; pharmacology ; therapeutic use ; Gene Expression Regulation ; drug effects ; Liver ; drug effects ; metabolism ; pathology ; physiopathology ; Male ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the occurrence and progression of liver fibrosis induced by pig serum exposure and bile duct ligation, and analyze the relationship between hepatic inflammation and liver fibrosis.

METHODSChronically immune-mediated liver fibrosis was induced in rats by weekly injection of pig serum (IPS) into the peritoneal cavity at 3 ml/kg for 12 weeks. Cholestatic fibrosis was induced by common bile duct ligation (BDL). The Knodell score was used to evaluate the histological changes in the liver, and immunohistochemistry was performed using anti-SMA, anti-ED1, anti-CK7, and anti-CD45 antibodies. Quantitative real time PCR (qPCR) analysis was employed to quantify the mRNA expression of the genes related to inflammation, including interleukin-1beta (IL-1beta), IL-6, monocyte chemotactic protein-1, tumor necrosis factor-alpha, regulated upon activation normal T cell expressed and secreted (RANTES), transforming growth factor-beta, platelet-derived growth factor A, as well as the genes associated with fibrogenesis, namely collagen 1, alphaSMA, MMP-9 and TIMP-1.

RESULTSKnodell scores for periportal necrosis, intralobular degeneration and focal necrosis, and portal inflammation were all significantly higher in the BDL group than in the IPS group (P<0.01), whereas the scores for fibrosis was higher in the IPS group (P<0.05). Immunohistochemistry showed obvious inflammation with numerous alphaSMA-positive cells in the liver of the rats in BDL group; the liver of the rats in IPS group showed numerous alphaSMA-positive myofibroblasts with limited inflammatory cell infiltration. qPCR demonstrated a significant up-regulation of the genes related to extracellular matrix remodeling such as collagen 1 (P<0.01), alphaSMA (P<0.01), MMP-9 (P<0.01) and TIMP-1 (P<0.01) in the rat liver in IPS group compared with those in the normal control group, and the mRNA expressions of the inflammation-related cytokines, except for RANTES, were comparable with those in the control. In contrast, the BDL group showed a significant up-regulation of all the pro-inflammatory genes examined with also increased expression of the fibrogenesis-related genes (P<0.05).

CONCLUSIONLiver fibrosis induced by IPS is characterized by active ECM remodeling in the absence of obvious inflammation, indicating that chronic development of liver fibrosis can be independent of active hepatic inflammation. BDL-induced liver fibrosis highlights obvious inflammation and fibrous proliferation in the liver.

Animals ; Bile Ducts ; surgery ; Cholestasis ; complications ; physiopathology ; Ligation ; Liver Cirrhosis, Experimental ; etiology ; immunology ; pathology ; Male ; Rats ; Rats, Inbred F344 ; Serum ; immunology ; Swine

Cholestasis ; etiology ; physiopathology ; therapy ; Female ; Humans ; Liver Diseases ; drug therapy ; etiology ; physiopathology ; Male ; Neonatology ; Parenteral Nutrition, Total ; adverse effects ; S-Adenosylmethionine ; therapeutic use ; Ursodeoxycholic Acid ; therapeutic use