Pharmacotherapy for primary biliary cholangitis: an assessment of medication candidacy and rates of treatment.

BACKGROUND: Ursodeoxycholic acid is the preferred first-line therapy for primary biliary cholangitis. Alternative therapies, such as obeticholic acid, are recommended for patients who cannot tolerate ursodeoxycholic acid or who have an inadequate response to ursodeoxycholic acid monotherapy. Prior investigations have suggested that as many as 30% of patients with primary biliary cholangitis may have never received treatment with ursodeoxycholic acid. No prior investigations have examined usage rates of obeticholic acid in the treatment of primary biliary cholangitis. METHODS: All patients with an ICD-10 diagnosis of primary biliary cholangitis who had any records within the health system were included. A review of medical records was performed to confirm the diagnosis of primary biliary cholangitis and determine which medications had been prescribed for treatment, as well as candidacy for second-line therapies. RESULTS: A total of 495 patients met inclusion criteria. Notably, 95% of patients were taking ursodeoxycholic acid for treatment of their primary biliary cholangitis, with 67% of patients having disease that was well-controlled on ursodeoxycholic acid monotherapy. In total, 8% of patients were taking obeticholic acid (either as combination or monotherapy). Only 3% would benefit from the addition of a second line therapy but had not yet been offered medication. Only 3% of patients were not on any medication for management of their primary biliary cholangitis. CONCLUSIONS: Ursodeoxycholic acid is a readily available and generally well-tolerated medication that should be offered to all patients with primary biliary cholangitis as first-line therapy. While prior investigations have suggested that up to 30% of patients with primary biliary cholangitis may never have received treatment for the disorder, the present study suggests that patients are generally being managed according to guidelines. Moreover, a significant proportion of patients with primary biliary cholangitis will qualify for second line therapies and prescribers should be aware of the indications to use these medications.

Gentianopsis metabolites and bioactivity: HPLC-PDA-ESI-tQ-MS/MS profiles, HPLC-UV quantification of Gentianopsis komarovii and Gentianopsis stricta, and choleretic potential.

Gentianopsis is a small gentianaceous genus with a known ethnopharmacological focus as hepatoprotectors containing two underestimated species that are scientifically unexplored: Gentianopsis komarovii (Grossh.) Toyok., which is typical of the Far East, and Gentianopsis stricta (Klotzsch) Ikonn., which is grown in Central Asia. Application of the HPLC-PDA-ESI-tQ-MS/MS technique led to the identification of 28 compounds, such as iridoid glycosides, flavones and xanthones, with loganic acid, sweroside, loganin, secologanin, isoorientin-7-O-glucoside, luteolin-7-O-gentiobioside, chrysoeriol-7-O-glucoside and acacetin-7-O-glucoside being found in the genus for the first time. The extracts of G. komarovii and G. stricta demonstrated choleretic potential, strengthening the bile flow and the total content of bile acids, bilirubin and cholesterol in the bile. The most pronounced effects were observed for luteolin-7-O-glucoside and gentiabavaroside (gentiacaulein-1-O-primveroside), establishing them as the principle choleretics of both herbs. Based on the results, G. komarovii, G. stricta and some phenolic metabolites are prospective new choleretic drugs.

Anti-inflammatory effect of polyherbal composition with hepatoprotective and choleretic properties on LPS-stimulated murine macrophages.

OBJECTIVES: A polyherbal formulation with hepatoprotective and choleretic properties combining pharmacological potential of eight medicinal plants was developed in Nargiz Medical center (Republic of Azerbaijan) for the use as herbal tea. To explore the effect of polyherbal composition on the metabolism of LPS-stimulated macrophages in vitro. METHODS: The qualitative and quantitative phytochemical analysis was conducted using specific color reactions and gas chromatography-mass spectrometry (GC-MS). Nitric oxide (NO) assay was determined using the Griess reaction. Reactive oxygen species (ROS) generation was measured using ROS-sensitive fluorescence indicator, H2DCFDA, by flow cytometry. Arginase activity was examined by colorimetric method. RESULTS: The studied polyherbal formulation exerted anti-inflammatory activity in LPS-stimulated macrophages which was evidenced by dose-dependent decrease of ROS generation and by shift of arginine metabolism to the increase of arginase activity and decrease of NO release. CONCLUSIONS: Our findings suggest that the herbal tea reduces macrophage inflammatory activity, that provide an important rationale to utilize it for the attenuation of chronic inflammation typical of hepatobiliary disorders.

Berberine Ursodeoxycholate for the Treatment of Primary Sclerosing Cholangitis: The Search for the Elusive Pharmacologic Holy Grail Will Need to Continue.

ABSTRACT: Effective pharmacologic treatment of primary sclerosing cholangitis (PSC) remains elusive. Ursodeoxycholic acid (UDCA) is known to improve liver biochemistry, specifically serum alkaline phosphatase, in patients with PSC but has not been shown to favourably alter the natural history. Similarly, many immunomodulatory medications have been studied for the treatment of PSC, but none has been demonstrated to be of unequivocal benefit. In this issue of the Journal, a pilot study of a ursodeoxycholate berberine salt vs placebo is reported. Although improvement in serum alkaline phosphatase is reported, without a control arm with UDCA monotherapy, it is not possible to determine whether this study drug is beneficial over UDCA by itself. More study in the PSC therapeutic arena is needed.

Postoperative pharmacotherapy for patients with biliary atresia in Japan.

BACKGROUND: Members of the Japanese Biliary Atresia Society were surveyed using questionnaires that assess their current practice regarding postoperative pharmacotherapy for outpatients with biliary atresia (BA). METHODS: In September 2018, questionnaires were sent to 100 member institutions of the Japanese Biliary Atresia Society. Questionnaires included the number of BA outpatients per institution and pharmacotherapy for outpatients with native liver. Pharmacotherapies were categorized into antibiotics, cholagogues, hepatoprotective agents, branched-chain amino acid supplement, Japanese Kampo medicine, probiotics, laxative, glycerin enema, and "others." In each category, the questionnaires asked about the medicine's details and the time of withdrawal of administration. RESULTS: Responses were collected from 58 of the 100 institutions. Fifty-four institutions (94.7%) had prescribed one or more medicines as postoperative pharmacotherapy, and three institutions (5.3%) did not prescribe any medicines. Fifty-three institutions (93.0%) had prescribed ursodeoxycholic acid (UDCA), and 32 (60.4%) of these continued prescribing UDCA as long as the condition of patients remained unchanged. Twenty-nine (50.9%) had prescribed Japanese Kampo medicines ("Inchinkoto" in all cases). Twenty-four (42.1%) had prescribed antibiotics, mainly trimethoprim-sulfamethoxazole, in 21 (87.5%). Twenty-three (40.4%) had prescribed probiotics. CONCLUSIONS: There were many variations of pharmacotherapy in BA outpatients with native liver in Japan, including antibiotic, probiotic, and Inchinkoto prescriptions. Of the various drugs, the most commonly administered was UDCA.

Dynamic Risk Prediction of Response to Ursodeoxycholic Acid Among Patients with Primary Biliary Cholangitis in the USA.

BACKGROUND: Ursodeoxycholic acid (UDCA) remains the first-line therapy for primary biliary cholangitis (PBC); however, inadequate treatment response (ITR) is common. The UK-PBC Consortium developed the modified UDCA Response Score (m-URS) to predict ITR (using alkaline phosphatase [ALP] > 1.67 times the upper limit of normal [*ULN]) at 12 months post-UDCA initiation). Using data from the US-based Fibrotic Liver Disease Consortium, we assessed the m-URS in our multi-racial cohort. We then used a dynamic modeling approach to improve prediction accuracy. METHODS: Using data collected at the time of UDCA initiation, we assessed the m-URS using the original formula; then, by calibrating coefficients to our data, we also assessed whether it remained accurate when using Paris II criteria for ITR. Next, we developed and validated a dynamic risk prediction model that included post-UDCA initiation laboratory data. RESULTS: Among 1578 patients (13% men; 8% African American, 9% Asian American/American Indian/Pacific Islander; 25% Hispanic), the rate of ITR was 27% using ALP > 1.67*ULN and 45% using Paris II criteria. M-URS accuracy was "very good" (AUROC = 0.87, sensitivity = 0.62, and specificity = 0.82) for ALP > 1.67*ULN and "moderate" (AUROC = 0.74, sensitivity = 0.57, and specificity = 0.70) for Paris II. Our dynamic model significantly improved accuracy for both definitions of ITR (ALP > 1.67*ULN: AUROC = 0.91; Paris II: AUROC = 0.81); specificity approached 100%. Roughly 9% of patients in our cohort were at the highest risk of ITR. CONCLUSIONS: Early identification of patients who will not respond to UDCA treatment using a dynamic prediction model based on longitudinal, repeated risk factor measurements may facilitate earlier introduction of adjuvant treatment.

Predicting Inchinkoto efficacy, in patients with obstructive jaundice associated with malignant tumors, through pharmacomicrobiomics.

Inchinkoto (ICKT) is a popular choleretic and hepatoprotective herbal medicine that is widely used in Japan. Geniposide, a major ingredient of ICKT, is metabolized to genipin by gut microbiota, which exerts a choleretic effect. This study investigates the relationship between stool genipin-producing activity and diversity of the clinical effect of ICKT in patients with malignant obstructive jaundice. Fifty-two patients with malignant obstructive jaundice who underwent external biliary drainage were included. ICKT was administered as three packets per day (7.5 g/day) for three days and 2.5 g on the morning of the fourth day. Stool samples were collected before ICKT administration and bile flow was monitored on a daily basis. The microbiome, genipin-producing activity, and organic acids in stools were analyzed. The Shannon-Wiener (SW) index was calculated to evaluate gut microbiome diversity. The stool genipin-producing activity showed a significant positive correlation with the SW index. Stool genipin-producing activity positively correlated with the order Clostridia (obligate anaerobes), but negatively correlated with the order Lactobacillales (facultative anaerobes). Moreover, stool genipin-producing activity was positively correlated to the concentration valeric acid, but negatively correlated to the concentration of lactic acid and succinic acid. The change of bile flow at 2 and 3 days after ICKT administration showed significant positive correlation with genipin-producing activity (correlation coefficient, 0.40 and 0.29, respectively, P < 0.05). An analysis of stool profile, including stool genipin-producing activity, may predict the efficacy of ICKT. Modification of the microbiome may be a target to enhance the therapeutic effect of ICKT.

Genipin induces developmental toxicity through oxidative stress and apoptosis in zebrafish.

Genipin, an iridoid substance, is mainly derived from Gardenia jasminoides Ellis of the traditional Chinese medicine and is widely used in raw materials for the food additive gardenia blue and biological materials. The developmental toxicity of genipin has not been investigated, and its underlying mechanism is unclear. Therefore, in this study we attempt to investigate the potential developmental toxicity of genipin in zebrafish embryos/larvae. The results showed zebrafish embryos treated with 50 µg/ml dose of genipin display inhibited hatching rates and body length. The pericardial edema was observed. It was also found that genipin could induce cardio-toxicity, hepatotoxicity and nephrotoxicity in zebrafish larvae. After genipin treatment, the suppression of antioxidant capacity and increase of oxidative stress were showed for the triggered generation of ROS and MDA, and decreased activity of SOD. Compared with the 0.5% DMSO group, a number of apoptotic cells in zebrafish were increased after genipin exposure. By measuring marker gene expression with the using of qRT-PCR, we proposed that developmental toxicity after genipin treatment might be associated with oxidative stress and apoptosis increase. Our research offers a better understanding for developmental toxicity of genipin.

Treatment of primary biliary cirrhosis with ursodeoxycholic acid combined with traditional Chinese medicine: A protocol for systematic review and meta analysis.

OBJECTIVE: Ursodeoxycholic acid is the priority drug of primary biliary cirrhosis (PBC) and is usually combined with traditional Chinese medicine. This study aimed to systematically evaluate the benefits of integrated Chinese and western interventions for PBC. METHODS: Searched the randomized controlled trials in PubMed, Web of Science, CNKI, CBM, Wanfang, VIP databases. The Cochrane risk of bias tool was used for methodological quality assessment and all data analysis was performed using Revman5.3 and Stata14.2 software. RESULT: 30 randomized controlled trials involving 10 interventions with a total of 1948 participants were included. Identified the direct and indirect evidence of trials, and used network meta analyses ranked the benefits of different interventions based on pairwise meta analysis. The primary outcom was clinical efficacy rate. Secondary outcome was liver function, including alkaline phosphataseand total bilirubin. CONCLUSION: The conclusion of this systematic review provide credible evidence - based for the relative advantages of integrated Chinese and western interventions for PBC.

Transcutaneous Neuromodulation improved inflammation and sympathovagal ratio in patients with primary biliary ssscholangitis and inadequate response to Ursodeoxycholic acid: a pilot study.

BACKGROUND: At present, ursodeoxycholic acid (UDCA) is internationally recognized as a therapeutic drug in clinic. However, about 40% Primary Biliary Cholangitis (PBC) patients are poor responders to UDCA. It has been demonstrated that Transcutaneous Neuromodulation (TN) can be involved in gut motility, metabolism of bile acids, immune inflammation, and autonomic nerve. Therefore, this study aimed to explore the effect of TN combined with UDCA on PBC and related mechanisms. METHODS: According to inclusion and exclusion criteria, 10 healthy volunteers and 15 PBC patients were recruited to control group and TN group, respectively. PBC patients were alternately but blindly assigned to group A (TN combined with UDCA) and group B (sham-TN combined with UDCA), and a crossover design was used. The TN treatment was performed via the posterior tibial nerve and acupoint ST36 (Zusanli) 1 h twice/day for 2 weeks. T test and nonparametric test were used to analyze the data. RESULTS: 1. TN combined with UDCA improved the liver function of PBC patients shown by a significant decrease of alkaline phosphatase and gamma-glutamyltransferase (γ-GT) (P < 0.05). 2. The treatment also decreased serum IL-6 levels (P < 0.05), but not the level of Tumor Necrosis Factor-α, IL-1ß or IL-10. 3. TN combined with UDCA regulated autonomic function, enhanced vagal activity, and decreased the sympathovagal ratio assessed by the spectral analysis of heart rate variability (P < 0.05). 4. There was no change in 13 bile acids in serum or stool after TN or sham-TN. CONCLUSIONS: TN cssombined with UDCA can significantly improve the liver function of PBC patients. It is possibly via the cholinergic anti-inflammatory pathway. TN might be a new non-drug therapy for PBC. Further studies are required. TRIAL REGISTRATION: The study protocol was registered in Chinese Clinical Trial Registry (number ChiCTR1800014633 ) on 25 January 2018.

Pharmacological interventions for treating intrahepatic cholestasis of pregnancy.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a liver disorder that can develop in pregnancy. It occurs when there is a build-up of bile acids in the maternal blood. It has been linked to adverse maternal and fetal/neonatal outcomes. As the pathophysiology is poorly understood, therapies have been largely empiric. As ICP is an uncommon condition (incidence less than 2% a year), many trials have been small. Synthesis, including recent larger trials, will provide more evidence to guide clinical practice. This review is an update of a review first published in 2001 and last updated in 2013. OBJECTIVES: To assess the effects of pharmacological interventions to treat women with intrahepatic cholestasis of pregnancy, on maternal, fetal and neonatal outcomes. SEARCH METHODS: For this update, we searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (13 December 2019), and reference lists of retrieved studies. SELECTION CRITERIA: Randomised or quasi-randomised controlled trials, including cluster-randomised trials and trials published in abstract form only, that compared any drug with placebo or no treatment, or two drug intervention strategies, for women with a clinical diagnosis of intrahepatic cholestasis of pregnancy. DATA COLLECTION AND ANALYSIS: The review authors independently assessed trials for eligibility and risks of bias. We independently extracted data and checked these for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included 26 trials involving 2007 women. They were mostly at unclear to high risk of bias. They assessed nine different pharmacological interventions, resulting in 14 different comparisons. We judged two placebo-controlled trials of ursodeoxycholic acid (UDCA) in 715 women to be at low risk of bias. The ten different pharmacological interventions were: agents believed to detoxify bile acids (UCDA) and S-adenosylmethionine (SAMe); agents used to bind bile acids in the intestine (activated charcoal, guar gum, cholestyramine); Chinese herbal medicines (yinchenghao decoction (YCHD), salvia, Yiganling and Danxioling pill (DXLP)), and agents aimed to reduce bile acid production (dexamethasone) Compared with placebo, UDCA probably results in a small improvement in pruritus score measured on a 100 mm visual analogue scale (VAS) (mean difference (MD) -7.64 points, 95% confidence interval (CI) -9.69 to -5.60 points; 2 trials, 715 women; GRADE moderate certainty), where a score of zero indicates no itch and a score of 100 indicates severe itching. The evidence for fetal distress and stillbirth were uncertain, due to serious limitations in study design and imprecision (risk ratio (RR) 0.70, 95% CI 0.35 to 1.40; 6 trials, 944 women; RR 0.33, 95% CI 0.08 to 1.37; 6 trials, 955 women; GRADE very low certainty). We found very few differences for the other comparisons included in this review. There is insufficient evidence to indicate if SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, Salvia, Yinchenghao decoction, Danxioling and Yiganling, or Yiganling alone or in combination are effective in treating women with intrahepatic cholestasis of pregnancy. AUTHORS' CONCLUSIONS: When compared with placebo, UDCA administered to women with ICP probably shows a reduction in pruritus. However the size of the effect is small and for most pregnant women and clinicians, the reduction may fall below the minimum clinically worthwhile effect. The evidence was unclear for other adverse fetal outcomes, due to very low-certainty evidence. There is insufficient evidence to indicate that SAMe, guar gum, activated charcoal, dexamethasone, cholestyramine, YCHD, DXLP, Salvia, Yiganling alone or in combination are effective in treating women with cholestasis of pregnancy. There are no trials of the efficacy of topical emollients. Further high-quality trials of other interventions are needed in order to identify effective treatments for maternal itching and preventing adverse perinatal outcomes. It would also be helpful to identify those women who are mostly likely to respond to UDCA (for example, whether bile acid concentrations affect how women with ICP respond to treatment with UDCA).

IgG4-related Autoimmune Hepatitis with a Suspected Drug-induced Etiology.

A 69-year-old man was referred to our department with acute hepatitis. He had been newly treated with benidipine hydrochloride for two months. His blood test results were as follows: aspartate aminotransferase, 1,614 IU/L; alanine aminotransferase, 1,091 IU/L and anti-smooth muscle antibody, ×80. Needle liver biopsy specimen showed interface hepatitis with mainly lymphocytic infiltration and bridging fibrosis in the periportal area. Immunohistochemistry revealed lymphocytic infiltration positive for IgG4. We diagnosed him with IgG4-related AIH with an etiology that was suspected of being drug-induced. Oral prednisolone was started and then tapered after achieving biochemical remission. Hepatitis recurred after the cessation of steroids; however, remission was achieved with ursodeoxycholic acid.

Therapeutic potential of genipin in various acute liver injury, fulminant hepatitis, NAFLD and other non-cancer liver diseases: More friend than foe.

Genipin is an aglycone derived from the geniposide, the most abundant iridoid glucoside constituent of Gardenia jasminoides Ellis. For decades, genipin is the focus of studies as a versatile compound in the treatment of various pathogenic conditions. In particularly, Gardenia jasminoides Ellis has long been used in traditional Chinese medicine for the prevention and treatment of liver disease. Mounting experimental data has proved genipin possesses therapeutic potential for cholestatic, septic, ischemia/reperfusion-triggered acute liver injury, fulminant hepatitis and NAFLD. This critical review is a reflection on the valuable lessons from decades of research regarding pharmacological activities of genipin. Of note, genipin represents choleretic effect by potentiating bilirubin disposal and enhancement of genes in charge of the efflux of a number of organic anions. The anti-inflammatory capability of genipin is mediated by suppression of the production and function of pro-inflammatory cytokines and inflammasome. Moreover, genipin modulates various transcription factor and signal transduction pathway. Genipin appears to trigger the upregulation of several key genes encoding antioxidant and xenobiotic-metabolizing enzymes. Furthermore, the medicinal impact of genipin extends to modulation of regulated cell death, including autophagic cell death, apoptosis, necroptosis and pyroptosis, and modulation of quality of cellular organelle. Another crucial effect of genipin appears to be linked to dual role in targeting uncoupling protein 2 (UCP2). As a typical UCP2-inhibiting compound, genipin could inhibit AMP-activated protein kinase or NF-κB in circumstance. On the contrary, reactive oxygen species production and cellular lipid deposits mediated by genipin through the upregulation of UCP2 is observed in liver steatosis, suggesting the precise role of genipin is disease-specific. Collectively, we comprehensively summarize the mechanisms and pathways associated with the hepatoprotective activity of genipin and discuss potential toxic impact. Notably, our focus is the direct medicinal effect of genipin itself, whereas its utility as a crosslinking agent in tissue engineering is out of scope for the current review. Further studies are therefore required to disentangle these complicated pharmacological properties to confer this natural agent a far greater potency.

Diagnosis and treatment of primary biliary cholangitis.

Primary biliary cholangitis is a cholestatic, chronic autoimmune liver disease with a wide individual variation in disease progression. The diagnosis is predominantly based on chronic elevation of alkaline phosphatase and the presence of anti-mitochondrial antibodies or other specific antinuclear antibodies (i.e. anti-gp210 and anti-sp100). Even in early-stage disease, health-related quality of life can be severely impaired by symptoms such as pruritus, fatigue, and sicca syndrome and metabolic bone disease should be assessed and treated. The prognosis of the disease is, however, largely determined by the development of cirrhosis and its complications. Ursodeoxycholic acid is associated with an improved prognosis and should be initiated and continued in all patients. Clinical outcome is related to the biochemical response to ursodeoxycholic acid, but the prognosis of those with an incomplete response is still better than those who remain untreated. Obeticholic acid was recently approved as second-line treatment and bezafibrate may serve as an adequate off-label alternative, particularly in patients with pruritus. Preliminary data suggest an additive effect of triple therapy with ursodeoxycholic acid, obeticholic acid, and bezafibrate, whereas other promising drugs are being evaluated in clinical trials.

The endoplasmic reticulum stress-autophagy pathway controls hypothalamic development and energy balance regulation in leptin-deficient neonates.

Obesity is associated with the activation of cellular responses, such as endoplasmic reticulum (ER) stress. Here, we show that leptin-deficient ob/ob mice display elevated hypothalamic ER stress as early as postnatal day 10, i.e., prior to the development of obesity in this mouse model. Neonatal treatment of ob/ob mice with the ER stress-relieving drug tauroursodeoxycholic acid (TUDCA) causes long-term amelioration of body weight, food intake, glucose homeostasis, and pro-opiomelanocortin (POMC) projections. Cells exposed to ER stress often activate autophagy. Accordingly, we report that in vitro induction of ER stress and neonatal leptin deficiency in vivo activate hypothalamic autophagy-related genes. Furthermore, genetic deletion of autophagy in pro-opiomelanocortin neurons of ob/ob mice worsens their glucose homeostasis, adiposity, hyperphagia, and POMC neuronal projections, all of which are ameliorated with neonatal TUDCA treatment. Together, our data highlight the importance of early life ER stress-autophagy pathway in influencing hypothalamic circuits and metabolic regulation.

[Advances in research of traditional Chinese medicine for promoting bile secretion and excretion].

Cholagogic traditional Chinese medicines refer to those that can promote bile secretion and excretion, strengthen gallbladder contraction and promote gallbladder emptying. They are mainly used to treat cholecystitis, gallstones, cholestasis, biliary tract infection, jaundice hepatitis and other diseases in clinical application. As a traditional medicine in our country, Chinese herbal medicines have many advantages, such as extensive resources, low cost, little or no toxic and side effects, and in addition, it is not easy for animals to produce drug resistance. With the progress of science and technology and the rapid development of traditional Chinese medicine, many achievements have been made in the research of cholagogic traditional Chinese medicines. Traditional Chinese medicine plays a cholagogic role mainly by promoting bile secretion, regulating SCP2 mRNA, FXR, BSEP and efflux transporter protein, dissolving cholesterol, promoting the relaxation of Oddi's sphincter and changing the composition of bile, etc. Traditional Chinese medicine decoction, traditional Chinese medicine preparation, Chinese medicine combined with acupuncture, ear acupoint pressing, soaking bath, western medicine and alike are often used to treat biliary system diseases in clinical practice. The effective rate of combination of traditional Chinese medicine and other methods was significantly higher than that of compound prescription, western medicine, acupuncture and soaking bath alone. General attack therapy and new therapies are also used in clinical treatment. The clinical effect of traditional Chinese medicine is remarkable. By means of literature review, the pharmacological effects, mechanism and clinical application of Chinese herbal medicines and compound prescriptions with gallbladder-promoting effect in the past 15 years were summarized in this paper. At the same time, some existing problems were found and prospects were expected.

Clinical effect of the extract of TCM Fructus akebiae combined with ursodeoxycholic acid on nonalcoholic fatty liver disease.

.Fructus akebiae extract (FAE) is a commonly used drug in the clinical treatment of liver cancer. FAE has many pharmacological activities, such as liver protection, anti-tumor, spasmolysis, pain relief and antifungal activity. Its clinical application is extensive, so far no toxic reports have been reported, and new drugs can be developed. This study was designed to investigate the therapeutic effect of predictor extract on non-alcoholic fatty liver disease (NAFLD). 180 patients with NAFLD were randomly divided into 2 groups. The control group was treated with ursodeoxycholic acid (UDCA), and the experimental group was treated with Fructus akebiae extract combined with ursodeoxycholic acid. The results showed that the comprehensive clinical efficacy of the treatment group was 95.56%, which was higher than that of the control group (93.33%), and P < 0.01. In the experimental group, 63 cases (70%) were improved after one course of treatment, main symptom score as (5.09 ±3.98), body mass index as (24.65±3.86), and liver CT value increased. It can be seen that the addition of FAE can significantly improve the clinical symptoms and serum biochemical indicators such as ALT, AST, TG and TC in patients with non-alcoholic fatty liver disease, which is supported by some histological evidence. These findings suggest that FAE combined with Ursodeoxycholic Acid is safe and effective in the treatment of fatty liver.

Kratom-Induced Cholestatic Liver Injury and Its Conservative Management.

Drug-induced liver injury (DILI) is a common cause of hepatotoxicity associated with prescription-based and over-the-counter exposure to medications and herbal supplements. Use of unapproved and inadequately tested herbal supplements can cause DILI. Therefore, thorough history-taking on exposure to herbal supplements must be an integral part of clinical evaluation of DILI. Kratom is an herbal supplement or remedy that has been known for its analgesic effects and has also been used for self-treatment of opiate withdrawals. A 52-year-old man was seen for evaluation of yellow discoloration of the eyes and skin. He reported taking kratom for right shoulder strain for at least a couple of months. On workup, his total bilirubin was noted to be 23.2 mg/dL, which peaked at 28.9 mg/dL. He was noted to have mild elevation of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase. Extensive laboratory tests were ordered and known causes of chronic liver disease ruled out. Magnetic resonance imaging of the abdomen was unremarkable without stigmata of portal hypertension or signs of chronic liver disease. He demonstrated no evidence of coagulopathy or hepatic encephalopathy during his illness. He underwent liver biopsy, which demonstrated histologic evidence of acute cholestatic hepatitis highly suspicious of DILI. He was advised to avoid kratom or other herbal supplements in future and prescribed ursodeoxycholic acid with significant improvement in his liver chemistries. Kratom is associated with significant liver enzymes derangements leading to DILI. Kratom is not approved for use in the United States and should be avoided.

Cholestasis affects enteral tolerance and prospective weight gain in the NICU.

BACKGROUND: Intestinal Failure-Associated Liver Disease is characterized by cholestasis and hepatic dysfunction due to parenteral nutrition (PN) therapy. We described key features of cholestatic infants receiving PN to assess overall outcomes in this population at our institution. METHODS: This is a retrospective single center study of 163 neonates grouped into cholestatic (n = 63) and non-cholestatic (n = 100) as defined by peak conjugated bilirubin of ≥2.0 mg/dL or < 0.8 mg/dL, respectively. Univariate and multiple regression models were used to study associations between variables and outcomes of interest. RESULTS: Lower Apgar scores (4 ± 3 vs. 6 ± 3, p-value = <0.005 at 1 min; 6 ± 2 vs. 7 ± 2, p < 0.005 at 5 min) and lower birth weight (adj ß [SE] = 0.62 [0.27], p-value = 0.024) were risk factors for developing cholestasis. Cholestatic infants were more likely to have had gastrointestinal surgery (31 [49%] vs. 15 [15%], p-value <0.005), received PN for a longer duration (40 ± 39 days vs. 11 ± 7 days, p-value <0.005), and started enteral feeds later in life (86 ± 23 days vs. 79 ± 20 days, p-value <0.005) when compared to non-cholestatic infants. Weight percentiles in cholestatic infants were lower both at hospital discharge (14 ± 19 vs. 24 ± 22, p-value <0.005) and at 6 months of age (24 ± 28 vs. 36 ± 31, p-value = 0.05). CONCLUSIONS: Cholestasis in the NICU is a multifactorial process, but it has a long lasting effect on prospective weight gain in infants who receive PN in the NICU. This finding highlights the importance of follow-up for adequate growth and the potential benefit from aggressive nutritional support.

Primary biliary cholangitis patients exhibit MRI changes in structure and function of interoceptive brain regions.

BACKGROUND: Many patients with primary biliary cholangitis (PBC) experience non-hepatic symptoms that are possibly linked to altered interoception, the sense of the body's internal state. We used magnetic resonance imaging (MRI) to determine if PBC patients exhibit structural and functional changes of the thalamus and insula, brain regions that process signals related to interoception. METHODS: Fifteen PBC patients with mild disease and 17 controls underwent 3 Tesla T1-weighted MRI, resting-state functional MRI, and quantitative susceptibility mapping (QSM), to measure thalamic and insular volume, neuronal activity and iron deposition, respectively. Group differences were assessed using analysis of covariance, and stepwise linear regression was used to determine the predictive power of clinical indicators of disease. RESULTS: PBC patients exhibited reduced thalamic volume (p < 0.01), and ursodeoxycholic acid (UDCA) non-responders exhibited lower left thalamus activity (p = 0.05). PBC patients also exhibited reduced anterior insula activity (p = 0.012), and liver stiffness positively correlated with MRI indicators of anterior insula iron deposition (p < 0.02). CONCLUSIONS: PBC affects structure and function of brain regions critically important to interoception. Moreover, these brain changes occur in patients with early, milder disease and thus may potentially be reversible.