Elevated Serum Bile Acid Levels Research Articles

Cholestasis gravidarum in women in the second and third trimester of gestation, clinical and specific pharmacological treatment and its benefits

Introduction: cholestasis gravidarum is a syndrome that usually occurs in pregnant women in the second or third trimester of pregnancy and ends in the puerperium. It is clinically characterized by the presence of predominantly nocturnal pruritus that is palmoplantar at first and then generalized. Alterations in liver function with or without jaundice and elevated serum bile acid levels, biochemical cholestasis is classified as mild to moderate in severity.This pathology does not have significant consequences for the mother, but it is associated with a high risk of affecting the newborn, such as premature delivery, fetal distress, fetal arrhythmias and intrauterine death. Objective: diagnostic methods and behaviors in their pharmacological treatments that provide the best results for those patients. Methods: systematic review with qualitative database from the PUBMED platform. The articles were downloaded from the PUBMED platform and Zotero was used to make the proper citations and references. In the investigation, the population will be composed of adult female patients who were admitted to any health care unit during the second and third trimesters. Results: the PUBMED database was used with the following MESH terms (cholestasis of pregnancy) that generated 2 597 results. 28 articles were analyzed in more depth, of which 12 articles were finally selected for the final analysis. Ursodeoxycholic acid (UDCA), a beta epimer of chenodeoxycholic acid, is a more polar bile acid than primary bile acids, with substantial choleretic and multiple other chemoprotective effects. The mechanism of action is not fully understood, but studies have shown that after treatment there is a reduction in total serum bile acids in both maternal and umbilical cord serum and a qualitative change in bile acid pool. serum. When compared to all controls, UDCA was also found to be associated with a decreased incidence of preterm birth, neonatal respiratory distress, and the number of neonatal intensive care unit admissions

Identification and validation of diagnostic biomarkers for intrahepatic cholestasis of pregnancy based on untargeted and targeted metabolomics analyses of urine metabolite profiles

BackgroundIntrahepatic cholestasis of pregnancy (ICP) is a prevalent pregnancy-specific complication that presents with maternal itching and elevated serum bile acid levels. ICP is associated with unfavorable pregnancy outcomes, severely decreasing the pregnant woman’s quality of life. Timely identification of ICP is crucial for effective management and improved outcomes.MethodsWe collected urine samples from 8 patients with ICP and 8 healthy individuals. We used Liquid Chromatography-Mass Spectrometry (LC-MS) to detect metabolite expression levels, then conducted a series of bioinformatic analyses to explore the potential biological meanings of differentially expressed metabolites, and preliminarily discovered several candidate biomarkers. To validate these candidate biomarkers, we performed Gas Chromatography-Mass Spectrometry (GC-MS) detection and analyzed their diagnostic values using receiver operating characteristic (ROC) curve.ResultsUntargeted metabolomics data showed that 6129 positive peaks and 6218 negative peaks were extracted from each specimen. OPLS-DA analysis and the heat map for cluster analysis showed satisfactory capability in discriminating ICP specimens from controls. Subsequent analysis extracted 64 significantly differentially expressed metabolites, which could be potential biomarkers for diagnosis of ICP. Based on the KEGG enrichment analyses, six candidate biomarkers were preliminarily identified. Two most promising biomarkers (3-hydroxypropionic acid and uracil) were validated by targeted metabolomics analyses with the area under the curve (AUC) of 0.920 and 0.850 respectively.ConclusionBased on preliminary screening from untargeted metabolomics and subsequent validation through targeted metabolomics, 3-hydroxypropionic acid and uracil were identified as promising diagnostic biomarkers for ICP.

Obeticholic acid alleviates intrauterine growth restriction induced by di-ethyl-hexyl phthalate in pregnant female mice by improving bile acid disorder.

Di-(2-ethylhexyl)-phthalate (DEHP) is a ubiquitous environmental pollutant and is widely used in industrial plastics. Intrahepatic cholestasis of pregnancy (ICP), distinguished by maternal pruritus and elevated serum bile acid levels, is linked to unfavorable pregnancy consequences. Few studies have investigated the potential effect of gestational DEHP exposure on the cholestasis in pregnant female mice, and the underlying mechanisms remain unclear. In the present study, a mouse model of cholestasis during pregnancy was established by DEHP exposure. We found that DEHP induces elevated bile acid levels by affecting bile acid synthesis and transporter receptor expression in the maternal liver and placenta of pregnant female mice, ultimately leading to intrauterine growth restriction (IUGR). In addition, DEHP changed the bile acid composition of maternal serum and liver as well as placenta and amniotic fluid in pregnant female mice; Importantly, we found that DEHP down-regulates the expression of farnesoid X receptor (FXR), which is considered to be a bile acid receptor. FXR agonist obeticholic acid (OCA) effectively alleviated the adverse effects of DEHP on pregnant female mice. While, OCA itself had no adverse effects on normal pregnant female mice. In summary, DEHP could induces bile acid disorder and IUGR in pregnant female mice by affect FXR, which was reversed by OCA.

Could real-time sonoelastography-measured placental strain ratio (PSR) value be a soft marker for the diagnosis of intrahepatic cholestasis of pregnancy?: A case-control study and short reviews.

Diagnosis of intrahepatic cholestasis of pregnancy (ICP) is often decided upon with typical pruritus supported by elevated serum bile acid levels. However, there is confusion regarding the absolute reference range for serum bile acid . To confirm the utility of Placental Strain Ratio (PSR) measurement as a marker for the diagnosis of ICP and to reveal the extent to which it is correlated with serum bile acid concentration. A case-control study was conducted. The case group included 29 patients who were admitted to our hospital in the second or third trimester of pregnancy with typical itching and were clinically diagnosed with ICP with >10 mmol/L serum bile acid. The first 45 pregnant women were assigned to a control group. Real-time tissue elastography software was used for ultrasound assessment of all pregnant placentas. Software was used to estimate the SR values. Biochemical liver function parameters, hemograms, serum bile acid levels, and SR values were compared between these groups. PSR was found to predict the development of cholestasis with poor discrimination (area under the curve [AUC] = 0.524; 95% CI = 0.399-0.646). The optimal threshold value with the best sensitivity and specificity rates was calculated to be 0.46 PSR. ICP developed significantly more frequently in the low PSR group than in the high PSR group (60% vs 29.3%, P = .05, odds ratios [OR] = 0.276, 95% CI = 0.069-1.105). No correlation was found between the PSR and bile acid levels (rho = -0.029, P = .816). PSR values can support the diagnosis of ICP, predict serum bile acid levels, and can be used as soft markers.

A comprehensive review of novel biomarkers in the diagnosis of intrahepatic cholestasis of pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) is a disease specific to pregnancy, featuring maternal itching and elevated serum bile acid levels. It leads to a series of adverse pregnancy outcomes as well as increased fetal mortality. Routine biochemical markers fail to fulfill the tremendous clinical requirements, thereby novel effective biomarkers are urgently desired. In our review, the potential novel biomarkers for ICP diagnosis are classified into four categories and elaborated in detail. The concrete diagnostic performances (sensitivity, specificityand area under the curve) of these biomarkers are demonstrated in tables. Moreover, the relationships between some biomarkers and ICP pathogenesis are briefly expounded. Nevertheless, only a few novel biomarkers are ideal, and their clinical applicability requires more evidence from larger multicenter trials.

Farnesoid X Receptor Activation Decreases Toll-like Receptor 2 Expression by Upregulating HBeAg Production

Background: Previous investigations have demonstrated that hepatitis B virus (HBV) infection leads to elevated serum bile acid levels, which is considered to cause liver damage. Thus, we suppose that bile acids may be of considerable significance in inducing immune tolerance. Methods: In this investigation, we explored the functions of the farnesoid X receptor (FXR), a nuclear receptor activated by bile acids, in modulating hepatitis B e antigen (HBeAg) production and toll-like receptor (TLR) expression in vitro and in vivo. Results: The results showed that FXR activation promoted secreted and intracellular HBeAg expression in HepG2 and HEK293T cells. However, FXR antagonist Z-guggulsterone (Z-g) decreased the bile acid-mediated HBeAg production. Meanwhile, TLR2 expression significantly reduced in HepG2 cells transfected with pAAV/HBV1.2 plasmid comprising whole HBV genome and treated with bile acids, but not with mutant pAAV/HBV1.2 plasmid with defected HBeAg product. In the hydrodynamic injection HBV mouse model, the level of serum HBeAg was decreased, but intrahepatic TLR2 expression was elevated in FXR-/- mice. Conclusions: In conclusion, FXR activation inhibits TLR2-mediated innate immunity by upregulating HBeAg production. Our data indicate that a mild elevation of serum bile acids may cause immune tolerance and lead to virus persistence in HBV-infected patients.

Obstetric outcome of elevated total serum bile acid levels in women with intrahepatic cholestasis of pregnancy

Obstetric outcome of elevated total serum bile acid levels in women with intrahepatic cholestasis of pregnancy

Cholestasis gravidarum in women in the second and third trimester of gestation, clinical and specific pharmacological treatment and its benefits. An evidence-based approach

Introduction: Cholestasis gravidarum is a syndrome that usually occurs in pregnant women in the second or third trimester of gestation and ends in the puerperium. It is clinically characterized by the presence of predominantly nocturnal pruritus that is initially palmo-plantar and then generalized. With alterations in liver function with or without jaundice and elevated serum bile acid levels, biochemical cholestasis is classified as mild to moderate severity. Objective: Diagnostic methods and pharmacological treatment approaches that provide the best results for these patients. Methods: Systematic review using the terms MESH (cholestasis of pregnancy) that generated 2597 results. Results: 28 papers were analyzed in more detail, of which 12 papers were finally selected for the final analysis. Treatment: Ursodeoxycholic acid (UDCA), a beta epimer of chenodeoxycholic acid, is a bile acid more polar than primary bile acids, with substantial choleretic and other multiple chemoprotective effects. The mechanism of action is not completely understood, but studies have shown that after treatment there is a reduction in total serum bile acids in both maternal and cord serum and a qualitative change in the serum bile acid pool. When compared with all controls, UDCA was also found to be associated with a decrease in the incidence of preterm birth, neonatal respiratory distress, and the number of neonatal admissions to intensive care units. Conclusions: The treatment of cholestasis gravidarum is oral administration of ursodeoxycholic acid is effective and safe in the treatment of patients with cholestasis gravidarum.

656 Intra-hepatic cholestasis of pregnancy: treatment and obstetric outcomes

ObjectiveIntrahepatic cholestasis of pregnancy (ICP) is a reversible condition and the most common pregnancy related liver disorder. Defined by significant pruritus and elevated serum bile acid (BA) and/or liver enzymes (LE) levels, it represents an increased risk for adverse maternal and fetal outcomes. Therefore, early recognition and treatment are imperative for success. Recent data claims that use of ursodeoxycholic acid (UDCA) may not be effective in the improvement of maternal and fetal outcomes. We aim to study maternal profile, behaviour of the disease and obstetric outcomes in patients diagnosed with intra-hepatic cholestasis of pregnancy (IHCP) who received UDCA. Study design: A retrospective, descriptive and analytic study was performed, including all pregnant women diagnosed with IHCP in the second or third trimester of pregnancy and who had labor in our center, between January and December of 2019. SPSS.25 was used for statistical analysis. Results: In 2019, twenty eight pregnant women (mean age 32,7±5,9 years) were diagnosed with IHCP (pruritus and/or increased LE), of which 23 had serum BA elevation. Mean gestacional age (GA) at diagnosis was 33±6,2 weeks. Serum BA concentration at diagnosis and after 3 days of treatment was significantly diferent (29,4±42,5 vs 17,9±20,1 mg/dl; p<.05). Reduction of serum BA and LE was not diferent regarding UDCA dose (250 or 500 mg, 8/8h), neither was occurrance of preterm labor. We had no maternal deaths or complications directly associated with IHCP. Two women with preexisting liver disease are still being studied and did not deliver yet. Conclusions: Despite being a controversial thopic, use of UDCA showed to be effective in decreasing symptoms, bile acids and liver enzyme levels in our population. We had no stillbirths, neonatal adverse outcomes neither maternal liver insuficiency. Multicentric, case-control studies can be valuable in establishing new guideline treatments.

English

BACKGROUND Intrahepatic cholestasis of pregnancy (ICP) is a multifactorial pregnancy specific liver disorder which is also known as obstetric cholestasis. The purpose of this study was to establish the value of maternal serum bile acid in diagnosis of ICP, evaluate the treatment of ICP with UDCA (ursodeoxycholic acid) and its influence on maternal and neonatal outcome. METHODS It was a cross-sectional study. 90 women diagnosed with ICP were studied for a period of 2 years and 3 months at tertiary care government hospital. Statistical analysis was performed using chi square test. ‘P’ value of &lt; 0.05 was considered as statistically significant in this observational study. RESULTS The present study evaluates that ICP is more common in multigravida and in age group of 26 years – 30 years. It recurs in subsequent pregnancies significantly. Itching, most common symptom is commenced at 34 weeks ± 2.85 weeks. Transaminases were normal with elevated serum bile acid levels in 32.33 % cases. The mean gestational age at delivery ranged between 35 to 39 weeks. Most common mode of delivery is lower segment caesarean section (LSCS) with commonest indication as meconium-stained amniotic fluid (MSAF) and 31 babies required neonatal intensive care unit (NICU). CONCLUSIONS Precise diagnosis, follow up, target medication and active management is required. Although maternal outcome for patients is good and without any long-term sequelae, fetal outcome can be devastating. Active management with close antenatal surveillance of the fetus is usually recommended for better perinatal outcome. KEYWORDS Intrahepatic Cholestasis of Pregnancy (ICP), Ursodeoxycholic Acid (UDCA), Neonatal Intensive Care Unit (NICU), Lower Segment Caesarean Section (LSCS)

Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.

Malnutrition, Frailty, and Sarcopenia in Patients With Cirrhosis: 2021 Practice Guidance by the American Association for the Study of Liver Diseases.

A Case Report of Severe Intrahepatic Cholestasis of Pregnancy with Severe Liver Damage as the Main Manifestation

Intrahepatic cholestasis of pregnancy (ICP) is the most common liver disorder during pregnancy [1]. Among these patients, bile cannot flow from the liver. The frequency of ICP varies widely between 0.1% and 25% with the specificity of ethnicity and geographic location. More cases about 0.8-1.46% were discovered in South Asian. The greatest prevalence was discovered in South American populations with up to 25% in women of Araucanian Indian. In China, the incidence has been reported be 0.8%-12%. ICP often appears in the late second or third trimester of pregnancy. It is a reversible form of cholestasis and tends to dissolve quickly after birth. Its characters involve pruritus, elevated serum bile acid levels, and abnormal liver function. It has been associated with sudden fetal death and fetal distress, stillbirth, and respiratory distress syndrome of newborn.

Case Report: A 31-year-old Post Cesarean Section Women with Intrahepatic Cholestasis of Pregnancy and Post Partum Bell’s Palsy

Intrahepatic cholestasis of pregnancy (ICP) is cholestasis condition characterized by pruritus, elevated serum aminotransferase and bile acid levels with onset in the second or third trimester of pregnancy. Estimated of ICP prevalence only 0.001% to 0.3%. Bell's Palsy is a neurological disorder that causes facial muscles on one side of the face to suddenly weaken or become paralyzed. Bell's Palsy is more common in young adults, older people, diabetics and pregnant women. A 31-year-old women with major complaint is yellow eyes. She got itching in all over the body. Patient was in second pregnancy with gestational age was 39-40 weeks. She suffered from unable to close her eyelid or blink. Patient was diagnosed with cholestasis intrahepatal in pregnancy and Bell’s palsy post partum. Diagnosis was established concluded from anamnesis, physical examination and hepar biopsy. The result of a liver biopsy showed intrahepatic cholestasis. From Fibroscan examination was visible with F2 category or Moderate Fibrosis. The main management of this patient is cesarean section with UDCA and corticosteroid therapy. Patient was administrated with antiviral therapy for her Bell’s Palsy condition. After 1 week hospitalization, patient was discharged with improvement of her major complaint.

Preclinical Development of U3-1784, a Novel FGFR4 Antibody Against Cancer, and Avoidance of Its On-target Toxicity.

The FGFR4/FGF19 signaling axis is overactivated in 20% of liver tumors and currently represents a promising targetable signaling mechanism in this cancer type. However, blocking FGFR4 or FGF19 has proven challenging due to its physiological role in suppressing bile acid synthesis which leads to increased toxic bile acid plasma levels upon FGFR4 inhibition. An FGFR4-targeting antibody, U3-1784, was generated in order to investigate its suitability as a cancer treatment without major side effects.U3-1784 is a high-affinity fully human antibody that was obtained by phage display technology and specifically binds to FGFR4. The antibody inhibits cell signaling by competing with various FGFs for their FGFR4 binding site thereby inhibiting receptor activation and downstream signaling via FRS2 and Erk. The inhibitory effect on tumor growth was investigated in 10 different liver cancer models in vivo The antibody specifically slowed tumor growth of models overexpressing FGF19 by up to 90% whereas tumor growth of models not expressing FGF19 was unaffected. In cynomolgus monkeys, intravenous injection of U3-1784 caused elevated serum bile acid and liver enzyme levels indicating potential liver damage. These effects could be completely prevented by the concomitant oral treatment with the bile acid sequestrant colestyramine, which binds and eliminates bile acids in the gut. These results offer a new biomarker-driven treatment modality in liver cancer without toxicity and they suggest a general strategy for avoiding adverse events with FGFR4 inhibitors.

Autotaxin, bile acid profile and effect of ileal bile acid transporter inhibition in primary biliary cholangitis patients with pruritus.

Pruritus is a common symptom in patients with primary biliary cholangitis (PBC) for which ileal bile acid transporter (IBAT) inhibition is emerging as a potential therapy. We explored the serum metabonome and gut microbiota profile in PBC patients with pruritus and investigated the effect of GSK2330672, an IBAT inhibitor. We studied fasting serum bile acids (BAs), autotaxin and faecal microbiota in 22 PBC patients with pruritus at baseline and after 2weeks of GSK2330672 treatment. Control group included 31 asymptomatic PBC patients and 18 healthy volunteers. BA profiling was done by ultra performance liquid chromatography coupled to a mass spectrometry (UPLC-MS). Faecal microbiomes were analysed by 16S ribosomal RNA gene sequencing. In PBC patients with pruritus, serum levels of total and glyco-conjugated primary BAs and autotaxin were significantly elevated. Autotaxin activity correlated significantly with tauro- and glyco-conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA), both at baseline and after GSK2330672. GSK2330672 significantly reduced autotaxin and all tauro- and glyco- conjugated BAs and increased faecal levels of CA (P=0.048) and CDCA (P=0.027). Gut microbiota of PBC patients with pruritus was similar to control groups. GSK2330672 increased the relative abundance of Firmicutes (P=0.033) and Clostridia (P=0.04) and decreased Bacteroidetes (P=0.033) and Bacteroidia (P=0.04). Pruritus in PBC does not show a distinct gut bacterial profile but is associated with elevated serum bile acid and autotaxin levels which decrease after IBAT inhibition. In cholestatic pruritus, a complex interplay between BAs and autotaxin is likely and may be modified by IBAT inhibition.

A Randomized, Controlled, Phase 2 Study of Maralixibat in the Treatment of Itching Associated With Primary Biliary Cholangitis.

Primary biliary cholangitis (PBC) is typically associated with elevated serum bile acid levels and pruritus, but pruritus is often refractory to treatment with existing therapies. This phase 2 study assessed the efficacy and safety of maralixibat, a selective, ileal, apical, sodium‐dependent, bile acid transporter inhibitor, in adults with PBC and pruritus. Adults with PBC and pruritus who had received ursodeoxycholic acid (UDCA) for ≥6 months or were intolerant to UDCA were randomized 2:1 to maralixibat (10 or 20 mg/day) or placebo for 13 weeks in combination with UDCA (when tolerated). The primary outcome was change in Adult Itch Reported Outcome (ItchRO™) average weekly sum score (0, no itching; 70, maximum itching) from baseline to week 13/early termination (ET). The study enrolled 66 patients (maralixibat [both doses combined], n = 42; placebo, n = 24). Mean ItchRO™ weekly sum scores decreased from baseline to week 13/ET with maralixibat (–26.5; 95% confidence interval [CI], –31.8, –21.2) and placebo (–23.4; 95% CI, –30.3, –16.4). The difference between groups was not significant (P = 0.48). In the maralixibat and placebo groups, adverse events (AEs) were reported in 97.6% and 70.8% of patients, respectively. Gastrointestinal disorders were the most frequently reported AEs (maralixibat, 78.6%; placebo, 50.0%). Conclusion: Reductions in pruritus did not differ significantly between maralixibat and placebo. However, a large placebo effect may have confounded assessment of pruritus. Lessons learned from this rigorously designed and executed trial are indispensable for understanding how to approach trials assessing pruritus as the primary endpoint and the therapeutic window of bile acid uptake inhibition as a therapeutic strategy in PBC.

Adenovirus-mediated human aquaporin-1 expression in hepatocytes improves lipopolysaccharide-induced cholestasis.

Lipopolysaccharides (LPS) are known to cause cholestasis in sepsis. There is evidence that a defective expression of canalicular aquaporin water channels contributes to bile secretory failure in LPS-induced cholestasis. Thus, we studied whether the hepatic adenovirus-mediated transfer of human aquaporin-1 gene (haqp1) can improve the cholestasis induced by LPS. Adenoviral vector encoding hAQP1 (AdhAQP1) or control vector was administered to rats by retrograde intrabiliary infusion. Hepatocyte canalicular hAQP1 expression was assessed by liver immunostaining and immunoblotting in purified plasma membranes. LPS reduced bile flow and biliary bile acid excretion by 30% and 45%, respectively. AdhAQP1-treatment normalized both bile flow and biliary bile acid excretion in LPS-induced cholestasis. Moreover, markedly elevated serum bile acid levels in cholestatic rats, were also normalized with the AdhAQP1 hepatic transduction. Bile flow and serum or biliary bile acids in normal rats were not significantly altered by AdhAQP1. AdhAQP1 delivery unaffected the downregulated protein expression of canalicular bile salt export pump (BSEP/ABCB11) in cholestasis, but improved its transport activity restoring reduced canalicular cholesterol content. Our data suggest that the adenovirus-mediated hepatocyte hAQP1 expression improves LPS-induced cholestasis in rats by stimulating the BSEP/ABCB11-mediated biliary bile acid excretion; a finding that might contribute to the understanding and treatment of sepsis-associated cholestatic diseases. © 2017 IUBMB Life, 69(12):978-984, 2017.

Intrahepatic Cholestasis of Pregnancy – Report of two Cases

Intrahepatic cholestasis of pregnancy (ICP) also known as obstetric cholestasis, is a cholestatic disorder characterized by pruritus, elevated serum aminotransferases and bile acid levels with gradual onset in the second or third trimester of pregnancy may lead to adverse fetal outcome, and spontaneous relief of signs and symptoms within two to three weeks after delivery.

Case Report: Intrahepatic Cholestasis of Pregnancy

AbstractIntrahepatic cholestasis of pregnancy (ICP) is a cholestatic disorder characterized by pruritus, elevated serum aminotransferases and bile acid levels with gradual onset in the second or third trimester of pregnancy, and spontaneous relief of signs and symptoms within two to three weeks after delivery.

The role of interleukin-17 in intrahepatic cholestasis of pregnancy

Objective: Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-specific liver disease, is characterized by pruritus, abnormal liver function and elevated serum bile acid levels. The main cause of ICP has not yet been identified. We aimed to provide a new perspective to the pathogenesis of by investigating the possible association of circulating interleukin-17 (IL-17) that is a recently discovered proinflammatory cytokine levels with ICP.Materials and methods: In this controlled cross-sectional study, maternal venous blood samples were obtained from 33 consecutive pregnant women with ICP (15 with mild and 18 with severe forms of the disease) and 25 healthy women with uncomplicated pregnancies (as the control group) and IL-17 levels were compared among the groups.Results: Although serum IL-17 levels were significantly higher in the severe ICP group than in the control group (p = 0.022), there were no significant differences between the mild and severe ICP groups or between the control and mild ICP groups.Conclusion: Explaining the mechanisms of hepatocyte injury might contribute to the existing therapeutic strategies for treating cholestatic diseases. Changes in IL-17 levels may shed light on the pathogenesis of ICP.