Diagnosis and management of benign recurrent intrahepatic cholestasis and psychosocial stressors in an adolescent:A case report

BACKGROUND Benign recurrent intrahepatic cholestasis(BRIC)is a rare autosomal recessive disorder,characterized by episodes of intense pruritus,elevated serum levels of alkaline phosphatase and bilirubin,and near-normal-glutamyl transferase.These episodes may persist for weeks to months before spontaneously resolving,with patients typically remaining asymptomatic between occurrences.Diagnosis entails the evaluation of clinical symptoms and targeted genetic testing.Although BRIC is recognized as a benign genetic disorder,the triggers,particularly psychosocial factors,remain poorly understood.CASE SUMMARY An 18-year-old Chinese man presented with recurrent jaundice and pruritus after a cold,which was exacerbated by self-medication involving vitamin B and paracetamol.Clinical and laboratory evaluations revealed elevated levels of bilirubin and liver enzymes,in the absence of viral or autoimmune liver disease.Imaging excluded biliary and pancreatic abnormalities,and liver biopsy demonstrated centrilobular cholestasis,culminating in a BRIC diagnosis confirmed by the identification of a novel ATP8B1 gene mutation.Psychological assessment of the patient unveiled stress attributable to academic and familial pressures,regarded as potential triggers for BRIC.Initial relief was observed with ursodeoxycholic acid and cetirizine,followed by an adjustment of the treatment regimen in response to elevated liver enzymes.The patient's condition significantly improved following a stress-related episode,thanks to a comprehensive management approach that included psychosocial support and medical treatment.CONCLUSION Our research highlights genetic and psychosocial influences on BRIC,emphasizing integrated diagnostic and management strategies.

Extrahepatic cholestasis associated with paracoccidioidomycosis:Challenges in the differential diagnosis of biliopancreatic neoplasia

BACKGROUND Paracoccidioidomycosis(PCM)may involve the hepatic pedicle and peripan creatic lymph nodes,cause damage to the bile duct and manifest,exceptionally,in combination with extrahepatic cholestasis(EHC),making investigation and treatment challenging.AIM To investigate the management of patients with visceral PCM admitted with EHC.METHODS All patients diagnosed with PCM treated in a public,tertiary teaching hospital between 1982 and 2020 were retrospectively evaluated.Those also identified with EHC were allocated to two groups according to the treatment approach for the purpose of comparing clinical,laboratory,and imaging findings,resources used for etiological diagnosis,treatment results,and prognosis.Statistical analyses were performed using the linear mixed-effects model(random and fixed effects),which was adjusted using the PROC MIXED procedure of the SAS®9.0 software,and Fisher’s exact test.RESULTS Of 1645 patients diagnosed with PCM,40(2.4%)had EHC.Of these,20(50.0%)lived in the rural area and 29(72.5%)were men,with a mean age of 27.1 years(3-65 years).Jaundice as first symptom and weight loss of at least 10 kg were observed in 16 patients(40.0%),and a mass in the head of the pancreas was observed in 8(20.0%).The etiological diagnosis was made by tissue collection during surgery in 4 cases(10.0%)and by endoscopic methods in 3 cases(7.5%).Twenty-seven patients(67.5%)received drug treatment alone(Group 1),whereas 13(32.5%)underwent endoscopic and/or surgical procedures in combination with drug treatment(Group 2).EHC was significantly reduced in both groups(40.7% in Group 1,with a mean time of 3 months;and 38.4% in Group 2,with a mean time of 7.5 months),with no statistically significant difference between them.EHC recurrence rates,associated mainly with treatment nonadherence,were similar in both groups:37% in Group 1 and 15.4% in Group 2.The mortality rate was 18.5% in Group 1 and 23% in Group 2,with survival estimates of 71.3% and 72.5%,respectively,with no statistically significant difference.CONCLUSION Although PCM-related EHC is rare,it needs to be included in the differential diagnosis of malignancies,as timely treatment can prevent hepatic and extrahepatic sequelae.

Expression and clinical significance of short-chain fatty acids in patients with intrahepatic cholestasis of pregnancy

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a pregnancy-specific liver condition that typically arises in the middle and late stages of pregnancy.Short-chain fatty acids(SCFAs),prominent metabolites of the gut microbiota,have significant connections with various pregnancy complications,and some SCFAs hold potential for treating such complications.However,the metabolic profile of SCFAs in patients with ICP remains unclear.AIM To investigate the metabolic profiles and differences in SCFAs present in the maternal and cord blood of patients with ICP and determine the clinical significance of these findings.METHODS Maternal serum and cord blood samples were collected from both patients with ICP(ICP group)and normal pregnant women(NP group).Targeted metabolomics was used to assess the SCFA levels in these samples.RESULTS Significant differences in maternal SCFAs were observed between the ICP and NP groups.Most SCFAs exhibited a consistent declining trend in cord blood samples from the ICP group,mirroring the pattern seen in maternal serum.Correlation analysis revealed a positive correlation between maternal serum SCFAs and cord blood SCFAs[r(Pearson)=0.88,P=7.93e-95].In both maternal serum and cord blood,acetic and caproic acids were identified as key metabolites contributing to the differences in SCFAs between the two groups(variable importance for the projection>1).Receiver operating characteristic analysis demonstrated that multiple SCFAs in maternal blood have excellent diagnostic capabilities for ICP,with caproic acid exhibiting the highest diagnostic efficacy(area under the curve=0.97).CONCLUSION Compared with the NP group,significant alterations were observed in the SCFAs of maternal serum and cord blood in the ICP group,although they displayed distinct patterns of change.Furthermore,the SCFA levels in maternal serum and cord blood were significantly positively correlated.Notably,certain maternal serum SCFAs,specifically caproic and acetic acids,demonstrated excellent diagnostic efficiency for ICP.

Liver stiffness in pregnant women with intrahepatic cholestasis of pregnancy:A case control study

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a rare but severe complication for both the mother and the unborn child.The diagnosis is primarily based on elevated serum levels of bile acids.In a large ICP cohort,we here study in detail liver stiffness(LS)using transient elastography(TE),now widely used to noninvasively screen for liver cirrhosis within minutes.AIM To specifically explore LS in a large cohort of women with ICP compared to a control group with uncomplicated pregnancy.METHODS LS and hepatic steatosis marker controlled attenuation parameter(CAP)were measured in 100 pregnant women with ICP using TE(Fibroscan,Echosens,Paris,France)between 2010 and 2020.In 17 cases,LS could be measured postpartum.450 women before and 38 women after delivery with uncomplicated pregnancy served as control group.Routine laboratory,levels of bile acids and apoptosis marker caspase-cleaved cytokeratin 18 fragment(M30)were also measured.RESULTS Women with ICP had significantly elevated transaminases but normal gammaglutamyl transferase(GGT).Mean LS was significantly increased at 7.3±3.0 kPa compared to the control group at 6.2±2.3 kPa(P<0.0001).Postpartum LS decreased significantly in both groups but was still higher in ICP(5.8±1.7 kPa vs 4.2±0.9 kPa,P<0.0001),respectively.In ICP,LS was highly significantly correlated with levels of bile acids and M30 but not transaminases.No correlation was seen with GGT that even increased significantly after delivery in the ICP group.Bile acids were mostly correlated with the liver apoptosis marker M30,LS and levels of alanine aminotransferase,aspartate aminotransferase,and bilirubin.In multivariate analysis,LS remained the sole parameter that was independently associated with elevated bile acids.CONCLUSION In conclusion,LS is significantly elevated in ICP which is most likely due to toxic bile acid accumulation and hepatocyte apoptosis.In association with conventional laboratory markers,LS provides additional non-invasive information to rapidly identify women at risk for ICP.

Effect of polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine on pregnancy outcomes in intrahepatic cholestasis

BACKGROUND Intrahepatic cholestasis of pregnancy(ICP)is a liver disorder that occurs in pregnant women and can lead to a range of adverse pregnancy outcomes.The condition is typically marked by pruritus(itching)and elevated levels of liver enzymes and bile acids.The standard treatment for ICP has generally been ursodeoxycholic acid and ademetionine 1,4-butanedisulfonate,but the efficacy of this approach remains less than optimal.Recently,polyene phosphatidylcholine has emerged as a promising new therapeutic agent for ICP due to its potential hepatoprotective effects.AIM To evaluate the effect of polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate on bile acid levels,liver enzyme indices,and pregnancy outcomes in patients with ICP.METHODS From June 2020 to June 2021,600 patients with ICP who were diagnosed and treated at our hospital were recruited and assigned at a ratio of 1:1 via randomnumber table method to receive either ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate(control group,n=300)or polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate(combined group,n=300).Outcome measures included bile acids levels,liver enzyme indices,and pregnancy outcomes.RESULTS Prior to treatment,no significant differences were observed between the two groups(P>0.05).Post-treatment,patients in both groups had significantly lower pruritus scores,but the triple-drug combination group had lower scores than the dual-drug combination group(P<0.05).The bile acid levels decreased significantly in both groups,but the decrease was more significant in the triple-drug group(P<0.05).The triple-drug group also exhibited a greater reduction in the levels of certain liver enzymes and a lower incidence of adverse pregnancy outcomes compared to the dual-drug group(P<0.05).CONCLUSION Polyene phosphatidylcholine/ursodeoxycholic acid/ademetionine 1,4-butanedisulfonate effectively relieves pruritus and reduces bile acid levels and liver enzyme indices in patients with ICP,providing a positive impact on pregnancy outcome and a high safety profile.Further clinical trials are required prior to clinical application.

Molecular overview of progressive familial intrahepatic cholestasis

Cholestasis is a clinical condition resulting from the imapairment of bile flow.This condition could be caused by defects of the hepatocytes,which are responsible for the complex process of bile formation and secretion,and/or caused by defects in the secretory machinery of cholangiocytes.Several mutations and pathways that lead to cholestasis have been described.Progressive familial intrahepatic cholestasis(PFIC)is a group of rare diseases caused by autosomal recessive mutations in the genes that encode proteins expressed mainly in the apical membrane of the hepatocytes.PFIC 1,also known as Byler’s disease,is caused by mutations of the ATP8B1 gene,which encodes the familial intrahepatic cholestasis 1 protein.PFIC 2 is characterized by the downregulation or absence of functional bile salt export pump(BSEP)expression via variations in the ABCB11 gene.Mutations of the ABCB4 gene result in lower expression of the multidrug resistance class 3 glycoprotein,leading to the third type of PFIC.Newer variations of this disease have been described.Loss of function of the tight junction protein 2 protein results in PFIC 4,while mutations of the NR1H4 gene,which encodes farnesoid X receptor,an important transcription factor for bile formation,cause PFIC 5.A recently described type of PFIC is associated with a mutation in the MYO5B gene,important for the trafficking of BSEP and hepatocyte membrane polarization.In this review,we provide a brief overview of the molecular mechanisms and clinical features associated with each type of PFIC based on peer reviewed journals published between 1993 and 2020.

Atypical causes of cholestasis

Cholestatic liver disease consists of a variety of disorders. Primary sclerosing cholangitis and primary biliary cirrhosis are the most commonly recognized cholestatic liver disease in the adult population, while biliary atresia and Alagille syndrome are commonly recognized in the pediatric population. In infants, the causes are usually congenital or inherited. Even though jaundice is a hallmark of cholestasis, it is not always seen in adult patients with chronic liver disease. Patients can have &#x0201c;silent&#x0201d; progressive cholestatic liver disease for years prior to development of symptoms such as jaundice and pruritus. In this review, we will discuss some of the atypical causes of cholestatic liver disease such as benign recurrent intrahepatic cholestasis, progressive familial intrahepatic cholestasis, Alagille Syndrome, biliary atresia, total parenteral nutrition induced cholestasis and cholestasis secondary to drug induced liver injury.

Biochemical characteristics of neonatal cholestasis induced by citrin deficiency

AIM:To explore differences in biochemical indices between neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and that with other etiologies. METHODS:Patients under 6 mo of age who were referred for investigation of conjugated hyperbiliru-binaemia from June 2003 to December 2010 were eligible for this study. After excluding diseases affecting the extrahepatic biliary system, all patients were screened for the two most common SLC25A13 mutations; the coding exons of the entire SLC25A13 gene was sequenced and Western blotting of citrin protein performed in selected cases. Patients in whom homo-zygous or compound heterozygous SLC25A13 mutation and/or absence of normal citrin protein was detected were defined as having NICCD. Cases in which no specific etiological factor could be ascertained after a com-prehensive conjugated hyperbilirubinaemia work-up were defined as idiopathic neonatal cholestasis (INC). Thirty-two NICCD patients, 250 INC patients, and 39 infants with cholangiography-confirmed biliary atresia (BA) were enrolled. Laboratory values at their first visit were abstracted from medical files and compared. RESULTS:Compared with BA and INC patients, the NICCD patients had significantly higher levels of total bile acid (TBA) [all measures are expressed as median (inter-quartile range):178.0 (111.2-236.4) μmol/L in NICCD vs 112.0 (84.9-153.9) μmol/L in BA and 103.0 (70.9-135.3) μmol/L in INC, P = 0.0001]. The NICCD patients had significantly lower direct bilirubin [D-Bil 59.6 (43.1-90.9) μmol/L in NICCD vs 134.0 (115.9-151.2) μmol/L in BA and 87.3 (63.0-123.6) μmol/L in INC, P = 0.0001]; alanine aminotransferase [ALT 34.0 (23.0-55.0) U/L in NICCD vs 108.0 (62.0-199.0) U/L in BA and 84.5 (46.0-166.0) U/L in INC, P = 0.0001]; aspartate aminotransferase [AST 74.0 (53.5-150.0) U/L in NICCD vs 153.0 (115.0-239.0) U/L in BA and 130.5 (81.0-223.0) U/L in INC, P = 0.0006]; albumin [34.9 (30.7-38.2) g/L in NICCD vs 38.4 (36.3-42.2) g/L in BA and 39.9 (37.0-42.3) g/L in INC, P = 0.0001]; glucose [3.2 (2.0-4.4) mmol/L in NICCD vs 4.1 (3.4-5.1) mmol/L in BA and 4.0 (3.4-4.6) mmol/L in INC, P = 0.0014] and total cholesterol [TCH 3.33 (2.97-4.00) mmol/L in N ICCD vs 4.57 (3.81-5.26) mmol/L in BA and 4.00 (3.24-4.74) mmol/L in INC, P = 0.0155] levels. The D-Bil to total bilirubin (T-Bil) ratio was significantly lower in NICCD patients [all measures are expressed as median (inter-quartile range):0.54 (0.40-0.74)] than that in BA patients [0.77 (0.72-0.81), P = 0.001] and that in INC patients [0.74 (0.59-0.80), P = 0.0045]. A much higher AST/ALT ratio was found in NICCD patients [2.46 (1.95-3.63)] compared to BA patients [1.38 (0.94-1.97), P = 0.0001] and INC patients [1.48 (1.10-2.26), P = 0.0001]. NICCD patients had significantly higher TBA/D-Bil ratio [3.36 (1.98-4.43) vs 0.85 (0.72-1.09) in BA patients and 1.04 (0.92-1.14) in INC patients, P = 0.0001], and TBA/TCH ratio [60.7 (32.4-70.9) vs 24.7 (19.8-30.2) in BA patients and 24.2 (21.4-26.9) in INC patients, P = 0.0001] compared to the BA and INC groups. CONCLUSION:NICCD has significantly different bio- chemical indices from BA or INC. TBA excretion in NICCD appeared to be more severely disturbed than that of bilirubin and cholesterol.

Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump

AIM： To study the association of three common ABCB11 and ABCC2 polymorphisms （ABCB11： 1331T〉C→V444A; ABCC2： 3563T〉A → V1188E and 4544G 〉A → C1515Y） with intrahepatic cholestasis of pregnancy （ICP） and contraceptive-induced cholestasis （CIC）. METHODS： ABCB11 and ABCC2 genotyping data were available from four CIC patients and from 42 and 33 ICP patients, respectively. Allele-frequencies of the studied polymorphisms were compared with those in healthy pregnant controls and Caucasian individuals. Furthermore, serum bile acid levels were correlated with the presence or absence of the 1331 C allele. RESULTS： The ABCB11 1331T〉C polymorphism was significantly more frequent in cholestatic patients than in pregnant controls： C allele 76.2% （CI, 58.0-94.4） vs 51.3% （CI 35.8-66.7）, respectively （P = 0.0007）; and CC allele 57.1% （CI 36.0-78.3） vs 20% （CI 7.6-32.4）, respectively （P = 0.0065）. All four CIC patients were homozygous carriers of the C allele. In contrast, none of the studied ABCC2 polymorphism was overrepresented in ICP or CIC patients. Higher serum bile acid levels were found in carriers of the 1331CC genotype compared to carriers of the TT genotype. CONCLUSION： Our data support a role for the ABCB11 1331T〉C polymorphism as a susceptibility factor for the development of estrogen-induced cholestasis, whereas no such association was found for ABCC2. Serum bile acid and 7-glutamyl transferase levels might help to distinguish ABCB4- and ABCB11-related forms of ICP and CIC.

ARC syndrome with high GGT cholestasis caused by VPS33B mutations

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome (OMIM 208085) is an autosomal recessive disorder that is caused by mutations in 2 interacting genes VPS33B and VIPAS39. Mutations in VPS33B gene account for most cases of ARC. As low or normal gamma-glutamyl transpeptidase (GGT) activity has been described in all patients with ARC syndrome identified so far, ARC syndrome is a possible diagnosis for low GGT cholestasis. Here we describe a Chinese patient with neonatal cholestasis and a high GGT level in three consecutive tests. She had other typical manifestations of ARC syndrome, including arthrogryposis multiplex congenita, renal involvement and ichthyosis. Genetic study of the VPS33B gene further confirmed the diagnosis by identification of compound heterozygosity of two known disease-causing mutations, c.403+2T &#x0003e; A and c.1509-1510insG. The mechanism of high GGT in this patient is unclear. Nevertheless, this case indicates that ARC syndrome cannot be excluded from the differential diagnosis of neonatal cholestasis even if high GGT activity is found.

Two novel VPS33B mutations in a patient with arthrogryposis,renal dysfunction and cholestasis syndrome in China's Mainland

Arthrogryposis, renal dysfunction and cholestasis (ARC) syndrome is a rare genetic disorder and has not been described in China. We present a female infant with neonatal intrahepatic cholestasis from a Chinese family with ARC syndrome. All 23 coding exons and flanking introns of the VPS33B gene were amplified and sequenced using peripheral lymphocyte genomic DNA of the patient and her parents. Genetic testing revealed two novel mutations (c.1033delA and c.1567C&#x0003e;T) in the VPS33B gene. The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.

Clinical Assessment of Differential Diagnostic Methods in Infants with Cholestasis due to Biliary Atresia or Non-Biliary Atresia

The different methods in differentiating biliary atresia(BA)from non-BA-related cholestasis were evaluated in order to provide a practical basis for a rapid,early and accurate differential diagnosis of the diseases.396 infants with cholestatic jaundice were studied prospectively during the period of May 2007 to June 2011.The liver function in all subjects was tested.All cases underwent abdominal ultrasonography and duodenal fluid examination.Most cases were subjected to hepatobiliary scintigraphy,magnetic resonance cholangiopancreatography(MRCP)and a percutaneous liver biopsy.The diagnosis of BA was finally made by cholangiography or histopathologic examination.The accuracy,sensitivity,specificity and predictive values of these various methods were compared.178 patients(108 males and 70 females with a mean age of 58±30 days)were diagnosed as having BA.218 patients(136 males and 82 females with a mean age of 61±24 days)were diagnosed as having non-BA etiologies of cholestasis jaundice during the follow-up period in which jaundice faded after treatment with medical therapy.For diagnosis of BA,clinical evaluation,hepatomegaly,stool color,serum gamma-glutamyltranspeptidase(GGT),duodenal juice color,bile acid in duodenal juice,ultrasonography(gallbladder),ultrasonography(griangular cord or strip-apparent hyperechoic foci),hepatobiliary scintigraphy,MRCP,liver biopsy had an accuracy of 76.0%,51.8%,84.3%,70.0%,92.4%,98.0%,90.4%,67.2%,85.3%,83.2%and 96.6%,a sensitivity of 83.1%,87.6%,96.1%,73.7%,90.4%,100%,92.7%,27.5%,100%,89.0%and 97.4%,a specificity of 70.2%,77.5%,74.8%,67.0%,94.0%,96.3%,88.5%,99.5%,73.3%,75.4%and 94.3%,a positive predictive value of 69.0%,72.6%,75.7%,64.6%,92.5%,95.7%,86.8%,98.0%,75.4%,82.6%and 98.0%,and a negative predictive value of 83.6%,8.5%,95.9%,75.7%,92.3%,100%,84.2%,93.7%,100%,84.0%and 92.6%,respectively.It was concluded that all the differential diagnosis methods are useful.The test for duodenal drainage and elements is fast and accurate.It is helpful in the differential diagnosis of BA and non-BA etiologies of cholestasis.It shows good practical value clinically.

Early treatment efficacy of S-adenosylmethionine in patients with intrahepatic cholestasis: A systematic review

BACKGROUND S-adenosylmethionine(AdoMet)is a metabolically pleiotropic molecule used to treat intrahepatic cholestasis(IHC)and chronic liver diseases.While the efficacy of AdoMet has been demonstrated previously,it has not been systematically investigated within the early weeks of treatment.AIM To systematically review the early treatment efficacy of AdoMet in adult patients with IHC.METHODS Studies reporting the efficacy of intravenous,intramuscular,or oral forms of AdoMet within 8 wk of treatment initiation were considered;three randomized and six non-randomized studies were eligible for inclusion(PROSPERO registration number CRD42018090936).Of the three randomized studies,two were double-blind and placebo-controlled,and one was comparator-controlled with unclear blinding and a relatively high risk of bias.Mean serum levels of alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),and gamma-glutamyl transferase(γGT)following AdoMet treatment vs placebo,comparator,or baseline were summarized to determine differences in liver enzymes.Changes in patient-reported clinical symptoms of cholestasis were also summarized.RESULTS Both placebo-controlled randomized studies reported significant reductions in serum ALT levels with AdoMet vs placebo within 2 wk.One of these also reported significant ALP reductions,and the other reported significant AST andγGT reductions within 2 wk.The comparator-controlled randomized study,which had a number of notable limitations,reported significant reductions in serum ALT and AST levels with AdoMet vs potassium magnesium aspartate within 4 wk,but not within2 wk.All of the non-randomized studies(4/4)that investigated ALT,AST,ALP and/orγGT reported significant reductions in at least two of these parameters within 2 wk.Of the five studies that evaluated fatigue,reductions were observed within 2 wk in one randomized and two nonrandomized studies.The remaining two non-randomized studies reported improvements in fatigue within 6 and 8 wk.Of the four studies reporting symptoms of depression,two non-randomized studies observed improvements within 2 wk and the other two observed improvements within 17 d and 8 wk.CONCLUSION Data from both randomized and non-randomized studies suggest that AdoMet improves some biochemical liver parameters and symptoms of cholestasis within 2 wk,with further improvements observed in some studies after 4 and 8 wk of treatment.

Novel ATP8B1 mutation in an adult male with progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation inATP8B1.We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years,in addition to cholestasis that eventually became fatal.Genetic sequencing studies of the entire coding(exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation(S1012I) and a synonymous 696T>C mutation in ATP8B1.The patient's progression was associated with not only impaired familial intrahepatic cholestasis 1(FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function.Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.

Induction of chronic cholestasis without liver cirrhosis-Creation of an animal model

To analyze time intervals of inflammation and regeneration in a cholestatic rat liver model.METHODSIn 36 Lewis rats, divided into six groups of 6 animals (postoperative observation periods: 1, 2, 3, 4, 6, 8 wk), the main bile duct was ligated with two ligatures and observed for the periods mentioned above. For laboratory evaluation, cholestasis parameters (bilirubin, γ-GT), liver cell parameters (ASAT, ALAT) and liver synthesis parameters (quick, albumin) were determined. For histological analysis, HE, EvG, ASDCL and HMGB-1 stainings were performed. Furthermore, we used the mRNA of IL-33, GADD45a and p-21 for analyzing cellular stress and regeneration in cholestatic rats.RESULTSIn chemical laboratory and histological evaluation, a distinction between acute and chronic cholestatic liver injury with identification of inflammation and regeneration could be demonstrated by an increase in cholestasis (bilirubin: 1-wk group, 156.83 ± 34.12 μmol/L, P = 0.004) and liver cell parameters (ASAT: 2-wk group, 2.1 ± 2.19 μmol/L.s, P = 0.03; ALAT: 2-wk group, 1.03 ± 0.38 μmol/L.s, P = 0.03) after bile duct ligation (BDL). Histological evaluation showed an increase of bile ducts per portal field (3-wk group, 48 ± 6.13, P = 0.004) during the first four weeks after bile duct ligation. In addition to inflammation, which is an expression of acute cholestasis, there was an increase of necrotic areas in the histological sections (2-wk group, 1.38% ± 2.28% per slide, P = 0.002). Furthermore, the inflammation could be verified by ASDCL (4-wk group, 22 ± 5.93 positive cells per portal field, P = 0.041) and HMGB-1 [2-wk group, 13 ± 8.18 positive cells per field of view (FoV), P = 0.065] staining. Therefore, in summary of the laboratory evaluation and histological studies, acute cholestasis could be found during the first four weeks after bile duct ligation. Subsequently, the described parameters declined so that chronic cholestasis could be assumed. For quantification of secondary biliary cirrhosis, eosin staining was performed, which did not reveal any signs of liver remodeling, thus precluding the development of a chronic cholestasis model. Additionally, to establish the chronic cholestasis model, we evaluated liver regeneration capacity through measurements of IL-33, p-21 and GADD45a mRNA.CONCLUSIONWe created a chronic cholestasis model. The point of inflammatory and regenerative balance was reached after four weeks. This finding should be used for experimental approaches dealing with chronic cholestatic liver damage.

Progressive familial intrahepatic cholestasis—farnesoid X receptor deficiency due to NR1H4 mutation:A case report

BACKGROUND Functioning farnesoid X receptor(FXR;encoded by NR1H4)is key to normal bile acid homeostasis.Biallelic mutations in NR1H4 are reported in a few children with intrahepatic cholestasis.We describe a boy with progressive familial intrahepatic cholestasis and homozygous mutation in NR1H4.CASE SUMMARY A boy had severe neonatal cholestasis with moderate hypercholanemia and persistently elevated alpha-fetoprotein.Despite medical treatment,coagulopathy was uncontrollable,prompting liver transplantation at age 8 mo with incidental splenectomy.The patient experienced catch-up growth with good liver function and did not develop allograft steatosis.However,1 year after transplant,he died from an acute infection,considered secondary to immunosuppression and asplenia.A homozygous protein-truncating mutation,c.547C>T,p.(Arg183Ter),was subsequently identified in NR1H4,and both parents were shown to be heterozygous carriers.Absence of FXR and of bile salt export pump expression was confirmed by immunostaining of explanted liver.CONCLUSION Severe cholestasis with persistently high alpha-fetoprotein and modest elevation of serum bile acid levels may suggest FXR deficiency.Some patients with FXR deficiency may not develop allograft steatosis and may respond well to liver transplantation.

Novel ABCB4 mutations in an infertile female with progressive familial intrahepatic cholestasis type 3:A case report

BACKGROUND Mutations that occur in the ABCB4 gene,which encodes multidrug-resistant protein 3,underlie the occurrence of progressive familial intrahepatic cholestasis type 3(PFIC3).Clinical signs of intrahepatic cholestasis due to gene mutations typically first appear during infancy or childhood.Reports of PFIC3 occurring in adults are rare.CASE SUMMARY This is a case study of a 32-year-old infertile female Chinese patient with a 15-year history of recurrent abnormal liver function.Her primary clinical signs were elevated levels of alkaline phosphatase andγ-glutamyl transpeptidase.Other possible reasons for liver dysfunction were eliminated in this patient,resulting in a diagnosis of PFIC3.The diagnosis was confirmed using gene detection and histological analyses.Assessments using genetic sequencing analysis indicated the presence of two novel heterozygous mutations in the ABCB4 gene,namely,a 2950C>T;p.A984V mutation(exon 24)and a 667A>G;p.I223V mutation(exon 7).After receiving ursodeoxycholic acid(UDCA)treatment,the patient's liver function indices improved,and she successfully became pregnant by in vitro fertilization.However,the patient developed intrahepatic cholestasis of pregnancy in the first trimester.Fortunately,treatment with UDCA was safe and effective.CONCLUSION These novel ABCB4 heterozygous mutations have a variety of clinical phenotypes.Continued follow-up is essential for a comprehensive understanding of PFIC3.

Review of a challenging clinical issue:Intrahepatic cholestasis of pregnancy

Intrahepatic cholestasis of pregnancy(ICP) is a reversible pregnancy-specific cholestatic condition characterized by pruritus, elevated liver enzymes, and increased serum bile acids. It commences usually in the late second or third trimester, and quickly resolves after delivery. The incidence is higher in South American and Scandinavian countries(9.2%-15.6% and 1.5%, respectively) than in Europe(0.1%-0.2%). The etiology is multifactorial where genetic, endocrine, and environmental factors interact. Maternal outcome is usually benign, whereas fetal complications such as preterm labor, meconium staining, fetal distress, and sudden intrauterine fetal demise not infrequently lead to considerable perinatal morbidity and mortality. Ursodeoxycholic acid is shown to be the most efficient therapeutic agent with proven safety and efficacy. Management of ICP consists of careful monitoring of maternal hepatic function tests and serum bile acid levels in addition to the assessment of fetal well-being and timely delivery after completion of fetal pulmonary maturity. This review focuses on the current concepts about ICP based on recent literature data and presents an update regarding the diagnosis and management of this challenging issue.

Different regional distribution of SLC25A13 mutations in Chinese patients with neonatal intrahepatic cholestasis

AIM: To investigate the differences in the mutation spectra of the SLC25A13 gene mutations from specific regions of China. METHODS: Genetic analyses of SLC25A13 mutations were performed in 535 patients with neonatal intrahepatic cholestasis from our center over eight years. Unrelated infants with at least one mutant allele were enrolled to calculate the proportion of SLC25A13 mutations in different regions of China. The boundary between northern and southern China was drawn at the historical border of the Yangtze River.RESULTS: A total of 63 unrelated patients (about 11% of cases with intrahepatic cholestasis) from 16 provinces or municipalities in China had mutations in the SLC25A13 gene, of these 16 (25%) were homozygotes, 28 (44%) were compound heterozygotes and 19 (30%) were heterozygotes. In addition to four well described common mutations (c.851_854del, c.1638_1660dup23, c.615+5G>A and c.1750+72_17514dup17insNM_138459.3:2667 also known as IVS16ins3kb), 13 other mutation types were identified, including three novel mutations: c.985_986insT, c.287T>C and c.1349A>G. According to the geographical division criteria, 60 mutant alleles were identified in patients from the southern areas of China, 43 alleles were identified in patients from the border, and 4 alleles were identified in patients from the northern areas of China. The proportion of four common mutations was higher in south region (56/60, 93%) than that in the border region (34/43, 79%, χ 2 = 4.621, P = 0.032) and the northern region (2/4, 50%, χ 2 = 8.288, P = 0.041). CONCLUSION: The SLC25A13 mutation spectra among the three regions of China were different, providing a basis for the improvement of diagnostic strategies and interpretation of genetic diagnosis.

Expanding etiology of progressive familial intrahepatic cholestasis

BACKGROUND Progressive familial intrahepatic cholestasis(PFIC)refers to a disparate group of autosomal recessive disorders that are linked by the inability to appropriately form and excrete bile from hepatocytes,resulting in a hepatocellular form of cholestasis.While the diagnosis of such disorders had historically been based on pattern recognition of unremitting cholestasis without other identified molecular or anatomic cause,recent scientific advancements have uncovered multiple specific responsible proteins.The variety of identified defects has resulted in an ever-broadening phenotypic spectrum,ranging from traditional benign recurrent jaundice to progressive cholestasis and end-stage liver disease.AIM To review current data on defects in bile acid homeostasis,explore the expanding knowledge base of genetic based diseases in this field,and report disease characteristics and management.METHODS We conducted a systemic review according to PRISMA guidelines.We performed a Medline/PubMed search in February-March 2019 for relevant articles relating to the understanding,diagnosis,and management of bile acid homeostasis with a focus on the family of diseases collectively known as PFIC.English only articles were accessed in full.The manual search included references of retrieved articles.We extracted data on disease characteristics,associations with other diseases,and treatment.Data was summarized and presented in text,figure,and table format.RESULTS Genetic-based liver disease resulting in the inability to properly form and secrete bile constitute an important cause of morbidity and mortality in children and increasingly in adults.A growing number of PFIC have been described based on an expanded understanding of biliary transport mechanism defects and the development of a common phenotype.CONCLUSION We present a summary of current advances made in a number of areas relevant to both the classically described FIC1(ATP8B1),BSEP(ABCB11),and MDR3(ABCB4)transporter deficiencies,as well as more recently described gene mutations--TJP2(TJP2),FXR(NR1H4),MYO5B(MYO5B),and others which expand the etiology and understanding of PFIC-related cholestatic diseases and bile transport.