Biochemical Cholestasis Research Articles

Inflammation drives pathogenesis of early intestinal failure-associated liver disease

Patients with intestinal failure who receive long-term parenteral nutrition (PN) often develop intestinal failure-associated liver disease (IFALD). Although there are identified risk factors, the early pathogenesis is poorly understood and treatment options are limited. Here, we perform a transcriptomic analysis of liver tissue in a large animal IFALD model to generate mechanistic insights and identify therapeutic targets. Preterm Yorkshire piglets were provided PN or bottle-fed with sow-milk replacer for 14 days. Compared to bottle-fed controls, piglets receiving PN developed biochemical cholestasis by day of life 15 (total bilirubin 0.2 vs. 2.9 mg/dL, P = 0.01). RNA-Seq of liver tissue was performed. Ingenuity Pathway Analysis identified 747 differentially expressed genes (343 upregulated and 404 downregulated) with an adjusted P < 0.05 and a fold-change of > |1|. Enriched canonical pathways were identified, demonstrating broad activation of inflammatory pathways and inhibition of cell cycle progression. Potential therapeutics including infliximab, glucocorticoids, statins, and obeticholic acid were identified as predicted upstream master regulators that may reverse the PN-induced gene dysregulation. The early driver of IFALD in neonates may be inflammation with an immature liver; identified therapeutics that target the inflammatory response in the liver should be investigated as potential treatments.

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

Sarcopenia is associated with osteopenia and impaired quality of life in children with genetic intrahepatic cholestatic liver disease.

Sarcopenia occurs in pediatric chronic liver disease, although the prevalence and contributing factors in genetic intrahepatic cholestasis are not well-described. The objective of this study was to measure muscle mass in school-aged children with genetic intrahepatic cholestasis and assess relationships between sarcopenia, clinical variables, and outcomes. Estimated skeletal muscle mass (eSMM) was calculated on dual-energy x-ray absorptiometry obtained in a Childhood Liver Disease Research Network study of children with bile acid synthesis disorders(BASD) alpha-1 antitrypsin deficiency (a1ATd), chronic intrahepatic cholestasis (CIC), and Alagille syndrome (ALGS). Relationships between eSMM, liver disease, and transplant-free survival were assessed. eSMM was calculated in 127 participants (5-18y): 12 BASD, 41 a1ATd, 33 CIC, and 41 ALGS. eSMM z-score was lower in CIC (-1.6 ± 1.3) and ALGS (-2.1 ± 1.0) than BASD (-0.1 ± 1.1) and a1ATd (-0.5 ± 0.8, p < 0.001). Sarcopenia (defined as eSMM z-score ≤- 2) was present in 33.3% of CIC and 41.5% of ALGS participants. eSMM correlated with bone mineral density in the 4 disease groups (r=0.52-0.55, p < 0.001-0.07), but not serum bile acids, bilirubin, aspartate aminotransferase/platelet ratio index, or clinically evident portal hypertension. Of the 2 patients who died (1 with sarcopenia) and 18 who underwent liver transplant (LT, 4 with sarcopenia), eSMM z-score did not predict transplant-free survival. eSMM z-score correlated with the Physical Pediatric Quality of Life Inventory score (r=0.38-0.53, p = 0.007-0.04) in CIC and a1ATd. Severe sarcopenia occurs in some children with ALGS and CIC. The lack of correlation between eSMM and biochemical cholestasis suggests mechanisms beyond cholestasis contribute to sarcopenia. While sarcopenia did not predict transplant-free survival, LT and death were infrequent events. Future studies may define mechanisms of sarcopenia in genetic intrahepatic cholestasis.

A Medium-Chain Fatty Acid Analogue Prevents Intestinal Failure–Associated Liver Disease in Preterm Yorkshire Piglets

At least 20%-30% of patients with intestinal failure receiving long-term parenteral nutrition will develop intestinal failure-associated liver disease (IFALD), for which there are few therapeutic options. SEFA-6179 is a first-in-class structurally engineered medium-chain fatty acid analogue that acts through GPR84, PPARα, and PPARγ agonism. We hypothesized that SEFA-6179 would prevent biochemical and histologic liver injury in a preterm piglet model of IFALD. Preterm Yorkshire piglets were delivered by cesarean section, and parenteral nutrition was provided for 14 days via implanted central venous catheters. Animals were treated with either medium-chain triglyceride vehicle control or SEFA-6179. Compared to medium-chain triglyceride vehicle at day of life 15, SEFA-6179 prevented biochemical cholestasis (direct bilirubin: 1.9 vs <0.2 mg/dL, P= .01; total bilirubin: 2.7 vs 0.4 mg/dL, P= .02; gamma glutamyl transferase: 172 vs 30 U/L, P= .01). SEFA-6179 also prevented steatosis (45.6 vs 13.9 mg triglycerides/g liver tissue, P= .009), reduced bile duct proliferation (1.6% vs 0.5% area cytokeratin 7 positive, P= .009), and reduced fibrosis assessed by a masked pathologist (median Ishak score: 3 vs 1, P= 0.007). RNA sequencing of liver tissue demonstrated that SEFA-6179 broadly impacted inflammatory, metabolic, and fibrotic pathways, consistent with its invitro receptor activity (GPR84/PPARα/PPARγ agonist). In a preterm piglet model of IFALD, SEFA-6179 treatment prevented biochemical cholestasis and steatosis and reduced bile duct proliferation and fibrosis. SEFA-6179 is a promising first-in-class therapy for the prevention and treatment of IFALD that will be investigated in an upcoming phase II clinical trial.

A nordic multicenter study on contemporary outcomes of pediatric short bowel syndrome in 208 patients

Despite advances in the management of short bowel syndrome related intestinal failure (SBS-IF), large-scale contemporary pediatric studies are scarce. The aim of this multicenter study was to assess key outcomes and clinical prognostic factors in a recent Nordic pediatric SBS-IF population. Patients with SBS-IF treated during 2010-2019, whose parenteral support (PS) started at age <1 year and continued >60 consecutive days were included and retrospectively reviewed. All six participating centers followed multidisciplinary SBS-IF management. Risk factors for PS dependency, intestinal failure associated liver disease (IFALD) and mortality were assessed with Cox regression and Kaplan Meier analyses. IFALD was defined with serum liver biochemistry levels. Among 208 patients, SBS-IF resulted from NEC in 49%, gastroschisis w/wo atresia in 14%, small bowel atresia in 12%, volvulus in 11%, and other diagnoses in 14%. Median age-adjusted small bowel length was 43% (IQR 21-80%). After median follow up of 4.4 years (IQR 2.5-6.9), enteral autonomy was reached by 76%, none had undergone intestinal transplantation, and overall survival was 96%. Half of deaths (4/8) were caused by septic complications. Although biochemical cholestasis occurred only in 3% at latest follow-up and none of deaths were directly caused by IFALD, elevated liver biochemistry (HR 0.136; P=0.017) and shorter remaining small bowel (HR 0.941; P=0.040) predicted mortality. Shorter remaining small bowel and colon, and presence of end-ostomy were the main predictors of PS dependency, but not IFALD. Patients with NEC reached enteral autonomy more efficiently and had decreased incidence of IFALD compared to other etiologies. Although with current multidisciplinary management, prognosis of pediatric SBS is encouraging, septic complications and IFALD still associated with the remaining low mortality rate.

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.

Primary biliary cholangitis. Experience in 179 patients

Primary biliary cholangitis (PBC) is a chronic autoimmune cholestatic disease, which can progress to cirrhosis. It mainly affects middle-aged women. Its most frequent form of presentation is asymptomatic with biochemical cholestasis and the presence of antimitochondrial antibodies (AMA). To describe the epidemiological characteristics, clinical presentation and treatment for patients with PBC at a clinical hospital. Descriptive, observational, retrospective study, carried out between January 2015 and December 2020. 179 patients (158 women) were cared in the study period. At the time of diagnosis, the median age was 54 years (range 24-76), 55% of them were asymptomatic, 45% had fatigue and 28% had pruritus. Positive AMA were present in 65% of patients, antinuclear antibodies (ANA) in 51%, and anti-smooth muscle antibodies (ASMA) in 9%. Immunoglobulin M (IgM) was elevated in 30% of the patients and 50% of patients were biopsied. Splenomegaly and esophageal varices were present in 24 and 22% of patients, respectively. PBC was associated with Sjogren's syndrome in 15%, hypothyroidism in 14%, osteoporosis in 13%, and scleroderma in 8%. The epidemiological characteristics of our patients agree with those published abroad. Laboratory cholestasis associated with the presence of AMA, currently allows diagnosis without the need for histological study. Ursodeoxycholic acid (UDCA) is the first-line treatment for patients with PBC. The use of biochemical response criteria is essential to identify patients who require other UDCA alternatives for isolated or combined treatment.

P-75 UPDATE OF CLINICO-EPIDEMIOLOGICAL CHARACTERISTICS OF PRIMARY BILIAR CHOLANGITIS IN URUGUAY

Primary biliary cholangitis (PBC) is an autoimmune cholestatic liver disease of increasing prevalence, female-predominant, and usually diagnosed in the fifth decade of life. To update the description of clinico-epidemiological characteristics of a series of Uruguayan patients diagnosed with PBC. Descriptive, multi-centric study including Uruguayan patients diagnosed with PBC (at least two of the following criteria: biochemical cholestasis, autoantibodies —AMA, antinuclear with anticentromere, sp100, or gp210 patterns— and compatible liver biopsy). Age, sex, symptoms, associated diseases, laboratory, imaging, histological and elastography parameters were recorded in the diagnosis. One hundred twenty-nine patients (81 belonging to the first report), 93% female, with an average age of 57 years old (23 - 81) were included. Sixty-nine percent had at least one symptom and 59% had pruritus. Eighty-three percent were AMA-positive and in 41% of patients one or more associated diseases were confirmed. (Table). Histological studies were available in 40 patients (31%), 26 (65%) of which had advanced liver fibrosis or cirrhosis. Elastography was available in 6 patients, 2 of which (33%) were diagnosed with cirrhosis. Six patients (5%) were diagnosed with cirrhosis due to presence of ascites. The global survival rate was 84%. Survival depending on the presence or absence of symptoms was 251 months (95% CI, 229 - 274) and 241 months (95% CI, 238 - 275) respectively (p>0.05). Median survival for cirrhotic patients was 201 months (CI 95%, 160 – 242) versus 191 (CI 95%, 172 – 210) for non-cirrhotics (p>0.05). As previously reported, female prevalence and frequent association with other diseases –mainly autoimmune– remain. The presence of symptoms or cirrhosis showed no association with survival.

2811 Outcomes of Endoscopic Ultrasonography (EUS) in Patients Referred for Biliary Dilation Without Significant Biochemical Cholestasis

INTRODUCTION: The diagnostic yield of endoscopic ultrasound (EUS) in non-jaundiced patients with unexplained biliary dilation has been reported to be 6-33%. In our experience, patients with unexplained biliary dilation who use chronic narcotic analgesics might have an even lower diagnostic yield at EUS. However, this correlation has not been well-described as yet. METHODS: We reviewed electronic medical records of patients referred to our center for EUS for the primary indication of unexplained biliary dilation between July 2007 and June 2017. Our database search yielded 767 potential subjects. Exclusion criteria included pancreaticobiliary masses, stones, or calcific chronic pancreatitis seen on prior imaging, a total serum bilirubin &gt;3 mg/dl, or alkaline phosphatase (AP) &gt; 1.5x the upper limit of normal. Data were also separately abstracted on patients with liver tests exceeding the above criteria, yet who had no other exclusion criteria. RESULTS: 41 patients met all inclusion and exclusion criteria. The mean age was 62.4 ± 14.5 years, 37 (90.2%) were female, the mean bile duct diameter at EUS was 12.2 ± 3.8 mm, total bilirubin was 0.6 ± 0.3 mg/dL and AP was 112 ± 62.9 U/L. Most patients (33/41, 80.5%) were symptomatic, reporting abdominal pain or weight loss. A majority (29/41, 70.7%) of patients used oral narcotics. EUS demonstrated choledocholithiasis in 3/29 patients (10.3%) using narcotics and 1/12 (8.3%) not using narcotics. No masses or other relevant pathology was observed. This patient cohort was then combined with 39 additional patients with unexplained biliary dilation who had abnormal liver biochemical tests. Multivariable logistic regression analysis revealed that patients with abnormal liver biochemical tests were 3 times more likely to have positive EUS finding (OR 2.9, CI [1.5,5.7], P = 0.002). Patients using chronic narcotic analgesics were less likely to have positive EUS finding (OR 0.3, CI [0.1, 1.1], P = 0.06). CONCLUSION: A majority of patients referred for EUS to investigate biliary dilation without biochemical cholestasis were women using chronic narcotic analgesics. The diagnostic yield of EUS in this population was low (9.8%) and no neoplasia was found. In contrast, the yield of EUS in patients with biliary dilation and elevated liver tests was strikingly higher at 85%. Use of chronic narcotic analgesics appeared to predict a reassuring EUS examination.

Clinical and laboratory features of viral hepatitis B among HIV-patients in Zambia

Viral hepatitis B course in HIV patients in Zambia is still bad studied. At present, the study of the influence of immunosuppression on the clinical and laboratory features of viral hepatitis B acquires a special relevance. The aim of research is to investigate clinical and laboratory features of viral hepatitis B course among HIV-patients in Zambia. Epidemiological, descriptive, serological (HBV, HIV markers), biochemical (cytolysis and cholestasis syndromes’ indicators), statistic method for determining the reliability using average errors (m), t-criterion of the probability difference of the Student) methods are used. The results show HBV/HIV-positive Zambian patients reliably differ from HBV-monoinfected ones. As well, HBV/HIV-positive patients have significantly higher indexes of asteno-vegetatic, dyspeptic syndromes, hepato- and splenomegaly, cytolysis indexes (alanine aminotransferase, lactate dehydrogenase), which are associated with increase of HIV-infection’s stage. Hepatocellular deficiency’s indicators don’t differ reliably in comparison groups. Therefore, HBV/HIV-infected patients have more severe clinical and laboratory course than HBV-monoinfected ones.

Mixed Lipid, Fish Oil, and Soybean Oil Parenteral Lipids Impact Cholestasis, Hepatic Phytosterol, and Lipid Composition.

In parenteral nutrition-dependent infants and children, intestinal failure (IF)-associated liver disease (IFALD) remains an important problem. A comparative study was undertaken of parenteral mixed lipid (ML), ω-3 predominant fish oil (FO), and ω-6 predominant soybean oil (SO) emulsions in regards to hepatic phytosterol, neutral lipid, fatty acid (FA) content, and the relationship to cholestasis in piglets. Neonatal piglets received parenteral nutrition, varying in lipid dose (5 or 10 g· kg · day) and formulation: SO5 (n = 5), SO10 (n = 5), FO5 (n = 5), and ML10 (n = 5). On day 14, liver chemistry, bile flow, histology and neutral lipid staining were assessed. Hepatic triglyceride FA content was determined using thin layer and gas chromatography, and phytosterol content was assessed using gas chromatography-mass spectrometry. SO groups had higher prevalence of biochemical cholestasis (P < 0.04) and lower bile flow (P < 0.0001). Hepatic campesterol, stigmasterol, and β-sitosterol were highest in SO10 (P < 0.0001). Hepatic FA (P < 0.03) and ω-6/ω-3 FA ratio (P < 0.0001) were higher in the SO groups. Neutral lipid accumulation (P = 0.3) and liver histology (P = 0.16) were not different between groups. Univariate predictors of bile flow were: campesterol (r = -0.77, P = 0.001), β-sitosterol (r = -0.74, P = 0.002), stigmasterol (r = -0.74, P = 0.002), ω-6 FA (r = -0.72, P = 0.002), and ω-3 FA (r = 0.59, P = 0.02). Only campesterol independently predicted bile flow. ML and FO lipid emulsions reduce cholestasis in association with lowered hepatic phytosterol and lipid content. Lower hepatic phytosterol and ω-6 FA content, and higher ω-3 FA content are hepatoprotective. Multivariate analysis suggests reduced phytosterol accumulation may best explain the hepatoprotective effect of fish oil-containing lipids.

Parenteral Nutrition Associated Liver Toxicity: Prevention, Diagnosis and Management

Long-term parenteral nutrition (PN) treatment is limited by parenteral nutrition–associated liver disease (PNALD), which is characterized initially by intrahepatic cholestasis, typically defined as a direct bilirubin greater than 2 mg/dL in the absence of other causes of liver disease. PNALD is typically less common and less severe and progresses more slowly in older children and adults than in infants. The etiology of PNALD is multifactorial. Key factors include immature liver function, sepsis, and a lack of enteral nutrition. Additionally, nearly every component of PN has been attributed to or exacerbated hepatotoxicity. PN preparations must be carefully individualized and monitored to minimize hepatotoxicity from its various components. Although many hepatotoxic components or imbalances have been recognized, soybean oil–based lipid emulsions continue to be widely used as they are the only lipid emulsions currently approved for PN by the Food and Drug Administration. Fish oil–based lipid emulsions have been shown to reverse PNALD, with an associated decrease in mortality. As such, fish oil therapy should be considered early once biochemical cholestasis is detected in PN-dependent patients. Studies investigating the use of novel lipid emulsions for prevention and treatment of PNALD are ongoing. This review contains 5 figures, 5 tables, and 114 references.

Parenteral Nutrition Associated Liver Toxicity: Prevention, Diagnosis and Management

Long-term parenteral nutrition (PN) treatment is limited by parenteral nutrition–associated liver disease (PNALD), which is characterized initially by intrahepatic cholestasis, typically defined as a direct bilirubin greater than 2 mg/dL in the absence of other causes of liver disease. PNALD is typically less common and less severe and progresses more slowly in older children and adults than in infants. The etiology of PNALD is multifactorial. Key factors include immature liver function, sepsis, and a lack of enteral nutrition. Additionally, nearly every component of PN has been attributed to or exacerbated hepatotoxicity. PN preparations must be carefully individualized and monitored to minimize hepatotoxicity from its various components. Although many hepatotoxic components or imbalances have been recognized, soybean oil–based lipid emulsions continue to be widely used as they are the only lipid emulsions currently approved for PN by the Food and Drug Administration. Fish oil–based lipid emulsions have been shown to reverse PNALD, with an associated decrease in mortality. As such, fish oil therapy should be considered early once biochemical cholestasis is detected in PN-dependent patients. Studies investigating the use of novel lipid emulsions for prevention and treatment of PNALD are ongoing. This review contains 5 figures, 5 tables, and 114 references.

Novel Treatment Strategies for Primary Biliary Cholangitis.

Despite the presumed immunological pathogenesis of primary biliary cholangitis, no clear or even harmful consequences have resulted from treatments designed to modify the immunological condition. Ursodeoxycholic acid (13-16 mg/kg/d) has, however, clear favorable effects that not only improve biochemical cholestasis, but also delay histological progression. Long-term treatment with ursodeoxycholic acid is associated with excellent transplant-free survival in cases showing a biochemical response at 1 year. Data on the effects of obeticholic acid and fibrates are encouraging. Moreover, recent pilot studies evaluating several biological agents targeting immunity such as different monoclonal antibodies and other drugs that modulate cholestasis are under investigation, although with limited results at present.

Predictors of failure of fish-oil therapy for intestinal failure–associated liver disease in children ,

Background: Parenteral fish-oil (FO) therapy is a safe and effective treatment for intestinal failure–associated liver disease (IFALD). Patients whose cholestasis does not resolve with FO may progress to end-stage liver disease.Objective: We sought to identify factors associated with the failure of FO therapy in treating IFALD to guide prognostication and referral guidelines.Design: Prospectively collected data for patients treated with FO at Boston Children’s Hospital from 2004 to 2014 were retrospectively reviewed. Resolution of cholestasis was defined as sustained direct bilirubin (DB) <2 mg/dL, and treatment failure as liver transplantation or death while DB was >2 mg/dL as of July 2015. Demographics, laboratory values, and medical history at FO therapy initiation were compared between patients who achieved resolution of cholestasis and those who failed therapy.Results: Among 182 patients treated with FO, 86% achieved resolution of cholestasis and 14% failed therapy. Patients who failed therapy had median (IQR) lower birth weight [1020 g (737, 1776 g) compared with 1608 g (815, 2438 g); P = 0.03] and were older at FO initiation [20.4 wk (9.9, 38.6 wk) compared with 11.7 wk (7.3, 21.4 wk); P = 0.02] than patients whose cholestasis resolved. Patients who failed therapy had more advanced liver disease at therapy initiation than patients whose cholestasis resolved, as evidenced by lower median (IQR) γ-glutamyltransferase [54 U/L (41, 103 U/L) compared with 112 U/L (76, 168 U/L); P < 0.001], higher DB [10.4 mg/dL (7.5, 14.1 mg/dL) compared with 4.4 mg/dL (3.1, 6.6 mg/dL); P < 0.001], and a higher pediatric end-stage liver disease (PELD) score [22 (14, 25) compared with 12 (7, 15); P < 0.001]. A PELD score of ≥15, history of gastrointestinal bleeding, age at FO initiation ≥16 wk, presence of nongastrointestinal comorbidities, and mechanical ventilation at FO initiation were independent predictors of treatment failure.Conclusions: Most infants with IFALD responded to FO therapy with resolution of cholestasis, and liver transplantation was rarely required. Early FO initiation once biochemical cholestasis is detected in parenteral nutrition–dependent patients is recommended. This trial was registered at http://clinicaltrials.gov as NCT00910104.

Increased MMP-7 expression in biliary epithelium and serum underpins native liver fibrosis after successful portoenterostomy in biliary atresia.

The molecular mechanisms underlying progressive liver fibrosis following surgical treatment of biliary atresia (BA) remain unclear. Our aim was to address hepatic gene and protein expression and serum levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) after successful portoenterostomy (PE), and relate them to histological signs of liver injury, clinical follow‐up data and biochemical markers of hepatic function. LIver biopsies and serum samples were obtained from 25 children after successful PE at median age of 3.3 years. Serum MMP concentrations were determined by enzyme‐linked immune sorbent assay. Hepatic gene expression of MMPs and TIMPs was analyzed using real‐time reverse‐transcription PCR. Liver expression of MMP‐7 and cytokeratin‐7 was studied using immunohistochemistry. Despite effective clearance of biochemical and histological cholestasis following PE, BA patients showed increased hepatic gene expression of MMP‐7 (29‐fold, p < 0.001), MMP‐2 (3.1‐fold, p < 0.001), MMP‐14 (1.7‐fold, p = 0.007), and TIMP‐1 (1.8‐fold, p < 0.001), when compared to controls. Similar to a biliary epithelial marker cytokeratin‐7, expression of MMP‐7 localized in biliary epithelium of bile ducts and ductal proliferations and periportal hepatocytes and was increased (p < 0.001) in relation to controls. BA patients had 6‐fold higher serum levels of MMP‐7 (p < 0.001), which correlated positively with hepatic MMP‐7 gene (r = 0.548, p = 0.007) and protein (r = 0.532, p = 0.007) expression. Patients showed a positive correlation between biliary MMP‐7 expression and Metavir fibrosis stage (r = 0.605, p = 0.001) and portal fibrosis grade (r = 0.606, p = 0.001). Neither similarly increased MMP‐7 expression nor correlation with liver fibrosis was observed in patients with intestinal failure‐associated liver disease and comparable Metavir stage. In conclusion, our findings support an unique role of altered hepatic expression of MMP‐7 in the progression of liver fibrosis after successful PE and introduce a potential therapeutic target to pharmacologically extend native liver survival by inhibiting MMP‐7 hyperactivity. Serum MMP‐7 may be a valuable postoperative prognostic tool in BA.

Colangitis biliar primaria

DefinitionPrimary biliary cholangitis (cirrhosis) is a chronic cholestatic disease mainly observed in female. It is characterized by inflammation of the intrahepatic small and medium size bile ducts, that eventually results in cirrhosis. EtiopathogenesisUnknown, but of presumed autoimmune origin in genetic predisposed subjects. Clinical and analytical featuresMost patients are asymptomatic and are diagnosed fortuitously because of biochemical anicteric cholestasis with increased alkaline phosphatase. The presence of mitochondrial antibodies type M2 and specific antinuclear antibodies (gp210 and sp100) is characteristic of the disease. DiagnosisBiochemical cholestasis and positive antibodies are sufficient for the diagnosis, without needing liver biopsy. TreatmentUrsodeoxycholic acid is the specific treatment with an excellent response in more than 60% of patients. When optimal response is not observed, ursodeoxycholic acid can be combined with new agents, but those who have shown efficacy improving cholestasis are obeticholic acid and fibrates.

FRI-346 - Both Biochemical Hepatitis and Cholestasis at Six Months after Liver Transplantation Predict Recurrent Primary Biliary Cholangitis

FRI-346 - Both Biochemical Hepatitis and Cholestasis at Six Months after Liver Transplantation Predict Recurrent Primary Biliary Cholangitis

AIH Meets PSC: A Rare Twist in Hepatobiliary Disease

18% of patients with autoimmune hepatitis (AIH) present with a second auto-immune disease, which is termed “overlap syndrome.” Unlike AIH-primary biliary cirrhosis overlap syndrome, autoimmune hepatitis-primary sclerosing cholangitis (AIH-PSC) overlap syndrome is usually diagnosed in childhood. Limited data exist regarding adult diagnosis and treatment given the small number of cases in literature. Here we report a case of a young adult initially diagnosed with AIH. An otherwise healthy 24 year old male presented with right upper quadrant pain to our clinic. He denied jaundice, pruritis, fatigue, arthritis, prescription or OTC medications, dietary supplements and recent alcohol use. There was no known family history of liver or autoimmune disease. Serum tests were normal except for AST=319, AST=439, and ALP=794. ANA and ASMA titers found to be both positive at 1:160 and 1:40, respectively. An abdominal ultrasound showed a thickened gallbladder wall and sludge. Endoscopic ultrasound showed a normal common bile duct without gallstones. Steroid treatment was initiated for autoimmune hepatitis and his pain improved. However, with ALP's five fold elevation from normal, ursodiol was started and a cholangiogram was performed. Pathology showed small duct sclerosing cholangitis without plasma cells. Colonoscopy was negative for ulcerative colitis. Liver enzymes initially improved on steroids, but worsened with steroid taper. Given his high ANA titer, steroid-responsiveness and cholangiogram findings, our patient was diagnosed with AIH-PSC. Treatment with ursodiol, azithioprine and steroids resulted in improved symptoms and biochemical response. The pathogenesis of AIH-PSC overlap syndrome is poorly understood, but may be due to a shared genetic background. HLA-B8 and DR-3 have been reported in AIH-PSC. AIH-PSC also more commonly occurs in the presence of IBD, which our patient did not have. As in this case, patients with significant biochemical cholestasis should raise suspicion of AIH-PSC and prompt further investigation with a cholangiogram. The best indicators for differentiating PSC and AIH-PSC are IgG, gammaglobulins and the presence of ANA and ASMA. No standard of treatment has been established, but immunosuppression to decrease hepatic inflammation and cholestatic therapy may be beneficial. Half of adult patients can develop cirrhosis within only a few years of an AIH-PSC diagnosis, which indicates the need for early management. Further studies are necessary to help guide clinicians in their diagnosis and management.Figure 1Figure 2Figure 3

PTH-196 Chronic cholestasis and parenteral nutrition: prevalence and effect of bowel restoration surgery

<h3>Introduction</h3> Patients with mesenteric infarction can have intestinal failure due to a short bowel thereby needing parenteral nutrition. A short bowel and parenteral nutrition can increase the risk of chronic cholestasis. Restoring bowel continuity after a mesenteric infarction results in reduction or stopping parenteral nutrition requirements. The aims of this study are to determine the prevalence and the effect of restoring bowel continuity on chronic cholestasis. <h3>Method</h3> A retrospective review of patients with a short bowel due to mesenteric infarction from 2000–2012. We defined chronic cholestasis as two of bilirubin, alkaline phosphatase and gamma-glutamyl transferase being 1.5 times the upper limit of normal for more than 6 months. <h3>Results</h3> One hundred and four (55 females, median age 54 years) patients were identified. Seventy three (70%) patients had bowel continuity restored while 31 (30%) patients did not have bowel continuity restored. The prevalence of chronic cholestasis was 29%. Fifteen (21%) of 73 patients had chronic cholestasis. Following restoration of bowel continuity, 8 (53%) of 15 patients had a return of liver biochemistry to normal range within a year. Univariate analysis showed restoring bowel continuity (p = 0.002) was associated with a reduced risk of chronic cholestasis. Multivariate analysis showed cessation of PN was a significant factor in reducing chronic cholestasis (p = 0.02). <h3>Conclusion</h3> The prevalence of chronic cholestasis is 29% for patients with a short bowel receiving parenteral nutrition. Chronic cholestasis resolves in over half patients after continuity is restored. <h3>Disclosure of interest</h3> None Declared. <h3>References</h3> Cavicchi M, Beau P, Crenn P, <i>et al</i>. Prevalence of liver disease and contributing factors in patients receiving home parenteral nutrition for permanent intestinal failure. <i>Ann Intern Med</i>. 2000;132(7):525–32 Lloyd DAJ, Zabron AA, Gabe SM. Chronic biochemical cholestasis in patients receiving home parenteral nutrition: prevalence and predisposing factors. <i>Aliment Pharmacol Ther</i>. 2008;27(7):552–60 Nightingale JM. Management of patients with a short bowel. <i>World J Gastroenterol</i>. 2001;7(6):741–51 Salvino R, Ghanta R, Seidner DL, <i>et al</i>. Liver failure is uncommon in adults receiving long-term parenteral nutrition. <i>J Parenter Enter Nutr</i>. 2006;30(3):202–8