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

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

Cholestatic liver diseases are characterized by impairments of bile flows and accumulations of biliary constituents such as bile acids and bilirubin. The changes of phase I and II metabolism and the hepatobiliary transport system minimize cholestatic liver injury. These adaptive responses are transcriptionally regulated by several nuclear receptors. Recent studies have revealed that the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR) are key nuclear receptors for regulating many of the adaptive responses noted in cholestasis. PXR and CAR coordinately regulate not only bile acid metabolism and transport, but also bilirubin clearance. PXR and CAR ligands may be useful in the future for the treatment of cholestatic liver disease.
Transcription Factors/metabolism/*physiology ; Receptors, Steroid/metabolism/*physiology ; Receptors, Cytoplasmic and Nuclear/metabolism/*physiology ; Humans ; Cholestasis/metabolism/*physiopathology

OBJECTIVETo improve the diagnosis and management of primary biliary cirrhosis (PBC).

METHODSClinical data of 22 cases of PBC were reviewed including the clinical manifestation, laboratory test, and the response to therapy.

RESULTSThere were 20 female patients with an average of 50 years old in total of 22 PBC patients. The major symptoms were pruritus, fatigue, anorexia, and abdominal discomfort. The major signs included jaundice, hepatomegaly, splenmegaly, and ascites. Very high levels of serum alkaline phosphatase (ALP) and serum gamma glutamyl transpeptidase (GGT), hyperbilirubinemia and hypergammaglobulinemia were also detected in most of the patients. The aminotransferase level was only slightly elevated but the AST/ALT ratio was reversed. It took 8 months (ranging from 2 months to 5 years) to confirm the diagnosis after the clinical manifestation onset. Ursodeoxycholic acid could decrease the serum levels of ALP and bilirubin in 80% of the patients (12/15) and improve the symptom of pruritus and fatigue in 72.7% of the patients (11/15).

CONCLUSIONSPBC mainly affects middle-aged women and the main clinical manifestations are hepatosplenomegaly, jaundice, pruritus, and fatigue. Liver function test typically reveal a cholestatic pattern accompanied by hypergammagloblinemia and a positive antimitochondrial antibody (AMA) including M2 subtype (AMA-M2). Ursodeoxycholic acid could improve the abnormal liver function tests and clinical features in PBC patients

Alkaline Phosphatase ; Bilirubin ; Cholestasis ; Female ; Hepatomegaly ; Humans ; Liver Cirrhosis, Biliary ; metabolism ; physiopathology ; Liver Function Tests ; Male ; Middle Aged ; Ursodeoxycholic Acid

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

UNLABELLEDTo investigate the relationship between imbalance of cardiac autonomic nervous system and sudden death in fetuses of rats with intrahepatic cholestasis of pregnancy (ICP), the animal model of ICP was induced by hypodermic injection of 17-alpha-ethinylestradiol and progesterone. The electrocardiograms and frequency domain analysis of heart rate variability (HRV) including low frequency (LF), high frequency (HF) and the ratio between low and high frequencies (LF/HF) of fetal rats by the 21st day of gestation were evaluated with Chart 5 software of Powerlab biologic signal extracting and analyzing system.

RESULTS(1) The serum total bile acids (TBA) levels of pregnant rats were (78.5 +/- 4.5) micromol/L in Group ICP and (24.6 +/- 3.6) micromol/L in Group control; significant difference was noted between the two groups (P < 0.01). (2) In Group ICP, fetal rats arrhythmias appeared after (29.3 +/- 6.4) minutes' observation, and fetal rats died suddenly after (23.5 +/- 4.6) minutes' arrhythmias; However, the fetal rats in Group control all showed normal electrocardiograms over 90 minutes' continuous observation. (3) The values of LF and LF/HF of fetal rats in Group ICP within 20 minutes before fetal rats arrhythmias were significantly higher than those in Group control (LF 48.45 +/- 4.11 nu vs. 33.87 +/- 4.31 nu, and LF/HF 0.99 +/- 0.14 vs. 0.61 +/- 0.10, respectively, P < 0.01). (4) Dynamic power spectral analysis of HRV indicated that the values of LF and LF/HF of fetal rats in Group ICP increased progressively within 15 minutes before the sudden death of fetal rats. These demonstrated that autonomic imbalance in association with increased sympathetic activity has been strongly implicated in the pathophysiology of fetal arrhythmogenesis and sudden death in ICP. HRV analysis could be a useful tool for fetal surveillance, especially for ICP.

Animals ; Cholestasis, Intrahepatic ; physiopathology ; Death, Sudden ; etiology ; Electrocardiography ; Female ; Fetal Death ; etiology ; Heart Rate, Fetal ; Male ; Pregnancy ; Pregnancy Complications ; physiopathology ; Rats ; Rats, Sprague-Dawley

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

OBJECTIVETo explore the influence of vitamin E (VitE) concentration in serum on peripheral nerve conduction in patients with infantile hepatitis syndrome (IHS).

METHODSA retrospective study was carried out in 58 infants suffered from IHS without congenital biliary atresia and 31 of them were followed up. Thirty-two healthy infants were as control. The level of VitE in serum was detected with high performance liquid chromatography and nerve conduction was tested with surface electrodes along the nerves of limbs. The relationship between the level of VitE or total bilirubin (TB) or direct bilirubin (DB) and the nerve conduction velocity was analyzed comparatively.

RESULTS(1) The serum level of VitE was below the lower limit of 90% the normal value (13.78 micromol/L) in 71% (41/58) of patients, and was below the lower limit of 99% the normal level (9.17 micromol/L) in 48% (28/58) of patients. (2) The level of DB was more than 25.7 micromol/L in 86% (50/58) of the patients and was more than 102.6 micromol/L in 47% (27/58) of patients. Severe conjugated hyperbilirubinemia with cholestasis was demonstrated in most patients. (3) At least one abnormal parameter in nerve conduction test was found in 86% (50/58) patients. In 144 nerves tested, 60.4% (87/144) had at least one abnormal parameter. (4) Analysis for the association between bilirubin levels and VitE concentration in serum: in groups of DB > or = 25.7 micromol/L and DB < 25.7 micromol/L, the percentage of decreased VitE concentrations was 78% (39/50) and 25% (2/8), respectively, and the difference was significant (P < 0.01). Similar association between low VitE concentration and increased level of TB in serum could not be demonstrated. (5) Analysis for the association between abnormal nerve conduction and VitE concentration in serum: in the two groups with low and normal level of VitE, the percentage of abnormal nerve conduction was 93% (38/41) and 71% (12/17), respectively (chi(c)(2) = 4.93, P < 0.05). (6) Analysis for the association between abnormal nerve conduction and bilirubin in serum: There was no significant association between abnormal nerve conduction and serum level of either DB or TB. (7) Eight patients died and 9 patients had motor development delay in 31 patients during follow up. In these 17 patients with poor outcome, 88% (15/17) had very low VitE levels (< 9.17 micromol/L), which was markedly higher than the proportion of cases (43%, 6/14) with better prognosis (chi(c)(2) = 7.235, P < 0.01).

CONCLUSIONS(1) Low VitE serum levels were found in excess of the two thirds of patients with IHS and severely decreased levels in nearly a half of them. (2) A conjugated hyperbilirubinemia with cholestasis could be found in most patients (86%) suffered from IHS without congenital biliary atresia and about a half of them had serious cholestasis. (3) Conjugated hyperbilirubinemia with cholestasis could be the predominant cause of decreased serum VitE level in this study. (4) Abnormality of nerve conduction in patients with IHS might be related to VitE deficiency.

Bilirubin ; blood ; Cholestasis, Intrahepatic ; blood ; complications ; Female ; Follow-Up Studies ; Hepatitis ; blood ; complications ; Humans ; Infant ; Male ; Peripheral Nerves ; physiopathology ; Retrospective Studies ; Syndrome ; Vitamin E ; blood

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