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.

Presence of Obstetrics Cholestasis in Mothers Presenting with Pruritus in Pregnancy: In a Low Resource South Asian Setting

Obstetric cholestasis (also referred to as intrahepatic cholestasis of pregnancy—ICP) is a pruritic form of reversible cholestasis that is associated with significant fetal risks. There is a paucity of research regarding pregnancy outcomes of the mothers with obstetric cholestasis in the South Asian setting. Hence, the objective of this study was to determine the prevalence of obstetric cholestasis among mothers presenting with pruritus during pregnancy and to describe the characteristics and outcomes for those diagnosed with ICP in comparison with those with pruritus in the absence of ICP. Methods: All mothers presenting with pruritus to De Soyza Maternity hospital in Colombo Sri Lanka, between 1st January 2011 to 1st January 2014, were recruited for the study. A standard set of biochemical tests were used for diagnosis of ICP. An interviewer administered questionnaire and patient records were used for data collection. Presentation, characteristics and pregnancy outcomes were assessed and compared for mothers with ICP against those with pruritus in the absence of ICP. Results: The prevalence of ICP in the study population was found to be 27% (n = 27). Generalized pruritus with pruritus of the palms and soles was identified as the commonest pattern of pruritus for diagnosed with ICP. Delivery before 37 weeks (p = 0.001), meconium stained liquor (p = 0.004), placental abruption (p = 0.005), postpartum hemorrhage (p = 0.005), bleeding manifestation (p = 0.006), preterm labor (p = 0.031) and fetal distress (p = 0.035) were found to be significantly associated with the presence of ICP. Conclusions: Nearly 1/3 of mothers presenting with pruritus in pregnancy in Sri Lanka are affected by ICP which is associated with an increase in a wide range of adverse maternal and fetal outcomes compared to those with pruritus in the absence of ICP.

Intrahepatic cholestasis of pregnancy:When should you look further?

Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy(ICP),a condition associated with significant fetal complications.Although the etiology of ICP is unclear in many cases,certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect, which may not only affect subsequent pregnancies, but may be an indicator of more serious subsequent liver disease.We report a kindred of Anglo-Celtic descent,among whom many members present with ICP,gallstones or cholestasis related to use of oral contraception.Genetic studies revealed a novel mutation in the ABCB4 gene,which codes for a phospholipid transport protein.The clinical significance of this mutation and the importance of identifying such patients are discussed.

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.

Mother’s intrahepatic cholestasis does not affect her daughter’s health

Objective: To establish whether a mother’s intrahepatic cholestasis of pregnancy (ICP) has connections to her daughter’s health. Design: A retrospective study of daughters to ICP mothers. Setting: The region of Tampere University Hospital in Finland. Subjects: The study population comprised 575 women diagnosed with ICP during at least one pregnancy in the obstetric department of Tampere University Hospital in the period 1969-1988, and two controls chosen for each. Questionnaires were sent to these women and to their daughters: 305 daughters to ICP mothers and 642 to controls in autumn 2010. Eventually 187 daughters to ICP mothers responded (61.3%) and 373 to controls (58.1%). Main Outcome Measures: Evaluated health, symptoms and complaints, diagnosed diseases, mental health and use of medicines. Results: Only minor differences were detected between the two groups regarding the majority of items inquired. The only prominent difference between daughters to ICP mothers and those to controls concerned epilepsy, which was significantly more frequent among ICP mothers’ daughters, the prevalence being fourfold (3.2% vs 0.8%, p = 0.033). Conclusion: A mother’s ICP does not generally affect her daughter’s health. This can be considered an encouraging new finding for mothers with ICP in primary health care.

Prolonged cholestasis following successful removal of common bile duct stones:Beware patients on estrogen therapy

有在成年人的长期的胆汁郁积的黄疸的各种各样的很好描述的形式，例如自体免疫的胆管炎，导致药的胆管炎和怀孕的肝内胆汁郁积。我们在场胆石在的延长胆汁郁积追随者移动的二个盒子内视镜后退 cholangiopancreatography (ERCP ) 和随后的清楚的胆管造影术。两个病人在表示的时候正在拿口头的雌激素，它随后被撤退。第一个盒子对皮质甾治疗很快作出回应，并且第二个盒子与 ursodeoxycholic 酸有一个慢得多的决定。两个盒子与延长黄疸追随者 ERCP 和 intra-ductal 石头的移动在女病人加亮导致雌激素的胆汁郁积的意义。在口头的雌激素被中止以后，类固醇的一堂短功课需要被考虑。

Analysis on Therapeutic Effect of Western and Chinese Drug in Treating Intrahepatic Cholestasis of Pregnancy

Objective: To evaluate the therapeutic effect of Yinchenghao decoction (YCHD, 茵陈蒿汤) and S-adenosy-L-methionine (SAM) in treating intra-hepatic cholestasis of pregnancy (TCP) and improving prognosis of perinatal newborn babies. Methods: Sixty in-patients of TCP were randomly divided into two groups, the group A treated with YCHD and the group B treated with SAM. The symptom of itching and serum biochemical indexes, including glycocholic acid, bilirubin and transaminase, were observed after 3 weeks treat-ment, and the prognosis of perinatal newborn babies between the two groups was compared after delivery. Results: After treatment, the symptom of itching, serum levels of glycocholic acid, bilirubin and transaminase improved significantly (P< 0.05) in both groups, and the prognosis of newborn in the two groups was similar (P>0. 05). Conclusion: Both YCHD and SAM could effectively treat ICP. The former is rather cheaper, so it is more feasible for spreading.Original article on CJITWM (Chin) 2004 ;24(4): 309

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.

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.

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.

Novel mutation in a Chinese patient with progressive familial intrahepatic cholestasis type 3

Genotyping is conclusive for the diagnosis of progressive familial intrahepatic cholestasis type 3(PFIC3). Here we report a Chinese patient of PFIC3 with compound mutations in the ABCB4 gene. Liver biopsy was performed on a 17-year-old male patient with intrahepatic cholestasis of unknown etiology. Liver histology findings are indicative of intrahepatic cholestasis with extensive fibrosis. Genotyping revealed c.175C>T(p.L59L) mutation in exon 4, c.504C>T(p.N168N) mutation in exon 6, c.711A>T(p.I237I) mutation in exon 8, c.874A>T(p.K292X) in exon 9 and a novel mutation, c.1804G>T(p.G602W) in exon 15. Based on these findings, the patient was diagnosed with PFIC3. The novel mutation p.G602 W in exon 15 was predicted as probably damaging by Poly Phen-2 with a score of 0.986(sensitivity: 0.54; specificity: 0.94) and was predicted to affect protein function with a SIFT score of 0.01.

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.Key words

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>T)in the VPS33B gene.The patient is a compound heterozygote and her parents were heterozygous for each of the mutations.

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>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.

Xanthogranulomatous cholecystitis mimicking gallbladder cancer and causing obstructive cholestasis

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is a destructive inflammatory disease of the gallbladder that can mimic gallbladder carcinoma. METHODS: We present the case of a 35-year-old Hispanic male complaining of right upper quadrant pain and jaundice for 2 months prior to admission. He denied a history of fever, nausea/ vomiting, and weight loss. The past medical history was relevant only for diabetes. He had no previous history of jaundice or previous operations. RESULTS: CA19-9 was slightly elevated (52 U/mL). Abdominal ultrasonography showed an irregular thickening of the gallbladder wall and no gallstones were detected. CT scan also revealed an irregular thickening of the wall of the gallbladder body suggestive of malignancy. At laparotomy, the mass was adherent to the duodenum and colon, and although the frozen section biopsy was negative, the intraoperative findings were suggestive of malignancy, and the patient underwent left liver trisegmentectomy, resection of the common bile duct and Roux-en-Y hepaticojejunostomy. Pathological examination unexpectedly revealed XGC without malignancy. CONCLUSIONS: Preoperative and intraoperative differential diagnosis of XGC from gallbladder carcinoma remains a challenge when it is associated with inflammatory involvement of surrounding tissues. Since gallbladder carcinoma and XGC may coexist, radical resection is justified when malignancy cannot be completely ruled out.

Most common SLC25A13 mutation in 400 Chinese infants with intrahepatic cholestasis

AIM:To establish the real time fluorescence polymerase chain reaction(RT-PCR) with dual labeled probes for fast detection of SLC25A13 gene mutation 851del4.METHODS:Four hundred infants(< 1 year of age) with unexplained intrahepatic cholestasis from 18 provinces or municipalities in China were enrolled in this study for detecting their SLC25A13 gene mutation 851del4.Suitable primers and fluorescence-labeled probes for detecting SLC25A13 gene mutation 841del4 were designed.Normal and mutant sequences were detected by PCR with two fluorescence-labeled probes.After a single RT-PCR,results were obtained by analyzing the take-off curves.Twenty-four positive and 14 negative samples were retested by direct sequencing.RESULTS:Eight homozygous and 30 heterozygous mutations were detected in 46 mutant alleles with a 851del4 mutation rate of 5.8%(46/800).Twenty-six and 20 mutant alleles were observed respectively,in 474 and 242 alleles from the intermediate and southern areas of China.No mutant allele was detected in 84 alleles from northern China.Twenty-four positive samples including 4 homozygous and 20 heterozygous mutations,and 14 negative samples were retested by direct sequencing,which confirmed that the accuracy of RTPCR was 100%.CONCLUSION:RT-PCR can detect the mutation 851del4 in infants with intrahepatic cholestasis with an accuracy of 100%.

Progressive familial intrahepatic cholestasis

BACKGROUND:Three types of progressive familial intrahepatic cholestasis(PFIC)have been identified,but their etiologies include unknown mechanisms. DATA SOURCES:A PubMed search on'progressive familial intrahepatic cholestasis'and'PFIC'was performed on the topic,and the relevant articles were reviewed. RESULTS:The etiologies of the three PFIC types still include unknown mechanisms.Especially in PFIC type 1,enterohepatic circulation of bile acid should be considered.Ursodeoxycholic acid,partial external biliary diversion and liver transplantation have been used for the treatment of PFIC patients according to disease course. CONCLUSIONS:Since the etiologies and disease mechanisms of PFIC are still unclear,detailed studies are urgently required. Strategies for more advanced therapies are also needed.These developments in the future are indispensable,especially for PFIC type 1 patients.

Computed tomography findings for predicting severe acute hepatitis with prolonged cholestasis

AIM: To evaluate the significance of computed tomography (CT) findings in relation to liver chemistry and the clinical course of acute hepatitis. METHODS: Four hundred and twelve patients with acute hepatitis who underwent enhanced CT scanning were enrolled retrospectively. Imaging findings were analyzed for the following variables: gallbladder wall thickness (GWT), arterial heterogeneity, periportal tracking, number and maximum size of lymph nodes, presence of ascites, and size of spleen. The serum levels of alanine aminotransferase, alkaline phosphatase, bilirubin, albumin, and prothrombin time were measured on the day of admission and CT scan, and laboratory data were evaluated every 2-4 d for all subjects during hospitalization. RESULTS: The mean age of patients was 34.4 years, and the most common cause of hepatitis was hepatitis A virus (77.4%). The mean GWT was 5.2 mm. The number of patients who had findings of arterial heterogeneity, periportal tracking, lymph node enlargement > 7 mm, and ascites was 294 (80.1%), 348 (84.7%), 346 (84.5%), and 56 (13.6%), respectively. On multivariate logistic regression, male gender [odds ratio (OR) = 2.569, 95%CI: 1.477-4.469, P = 0.001], toxic hepatitis (OR = 3.531, 95%CI: 1.444-8.635, P = 0.006), level of albumin (OR = 2.154, 95%CI: 1.279-3.629, P = 0.004), and GWT (OR = 1.061, 95%CI: 1.015-1.110, P = 0.009) were independent predictive factors for severe hepatitis. The level of bilirubin (OR = 1.628, 95%CI: 1.331-1.991, P < 0.001) and GWT (OR = 1.172, 95%CI: 1.024-1.342,P = 0.021) were independent factors for prolonged cholestasis in multivariate analysis. CONCLUSION: In patients with acute hepatitis, GWT on CT scan was an independent predictor of severe hepatitis and prolonged cholestasis.