Infant cholestasis patient with a novel missense mutation in the AKR1D1 gene successfully treated by early adequate supplementation with chenodeoxycholic acid: A case report and review of the literature

Steroid 5β-reductase [aldo-keto reductase family 1 member D1(AKR1D1)] is essential for bile acid biosynthesis. Bile acid deficiency caused by genetic defects in AKR1D1 leads to life-threatening neonatal hepatitis and cholestasis. There is still limited experience regarding the treatment of this disease. We describe an infant who presented with hyperbilirubinemia and coagulopathy but normal bile acid and γ-glutamyltransferase. Gene analysis was performed using genomic DNA from peripheral lymphocytes from the patient, his parents, and his elder brother. The patient was compound heterozygous for c.919CT in exon 8 and exhibited a loss of heterozygosity of the AKR1D1 gene, which led to an amino acid substitution of arginine by cysteine at amino acid position 307(p.R307C). Based on these mutations, the patient was confirmed to have primary 5β-reductase deficiency. Ursodeoxycholic acid(UDCA) treatment did not have any effect on the patient. However, when we changed to chenodeoxycholic acid(CDCA) treatment, his symptoms and laboratory tests gradually improved. It is therefore crucial to supplement with an adequate dose of CDCA early to improve clinical symptoms and to normalize laboratory tests.     

Protective effects of ursodeoxycholic acid on chenodeoxycholic acid-induced liver injury in hamsters

AIM To investigate the effects of ursodeoxycholic acid (UDCA) on chenodeoxycholic acid (CDCA)-induced liver injury in hamsters, and to elucidate a correlation between liver injury and bile acid profiles in the liver.METHODS Liver injury was induced in hamsters by administration of 0.5% (w/w) CDCA in their feed for 7 d.UDCA (50 mg/kg and 150 mg/kg) was administered for the last 3 d of the experiment.RESULTS At the end of the experiment, serum alanine aminotransferase (ALT) increased more than 10 times and the presence of liver injury was confirmed histologically. Marked increase in bile acids was observed in the liver. The amount of total bile acids increased approximately three-fold and was accompanied by the increase in hydrophobic bile acids, CDCA and lithocholic acid (LCA). UDCA (50 mg/kg and 150 mg/kg) improved liver histology, with a significant decrease (679.3 ±77.5 U/L vs 333.6 ± 50.4 U/L and 254.3 ± 35.5 U/L, respectively, P ＜ 0.01) in serum ALT level. UDCA decreased the concentrations of the hydrophobic bile acids, and as a result, a decrease in the total bile acid level in the liver was achieved.CONCLUSION The results show that UDCA improves oral CDCA-induced liver damage in hamsters. The protective effects of UDCA appear to result from a decrease in the concentration of hydrophobic bile acids, CDCA and LCA, which accumulate and show the cytotoxicity in the liver.     

Suppression of bile acid synthesis by thyroid hormone in primary human hepatocytes

AIM: It is known that thyroid hormones alter the bile acid metabolism in humans, however the effect on individual enzymes has been difficult to elucidate. This is mainly due to the lack of human liver cell lines producing bile acids. We used cultures of primary human hepatocytes to study the effects of triiodothyronine (T3) on bile acid synthesis. METHODS: Primary hepatocytes were isolated from liver tissue obtained from three different patients undergoing liver resection due to underlying malignancy. The hepatocytes were cultured under serum-free conditions and treated from d 1 to d 5 with culture containing 0.1 -1000 nmol/L of T3. Bile acid formation and mRNA levels of key enzymes were analysed. RESULTS: The lowest concentration of T3 decreased cholic acid (CA) formation to 43%-53% of controls and chenodeoxycholic acid (CDCA) to 52%-75% of controls on d 5. The highest dose further decreased CA formation to 16%-48% of controls while CDCA formation remained at 50%-117% of controls. Expression of mRNA levels of cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) dose-dependently decreased. Sterol 27-hydroxylase (CYP27A1) levels also decreased, but not to the same extent. CONCLUSION: T3 dose-dependently decreased total bile acid formation in parallel with decreased expression of CYP7A1 and CYP8B1. CA formation is inhibited to a higher degree than CDCA, resulting in a marked decrease in the CA /CDCA ratio.     

Fenofibrate for patients with asymptomatic primary biliary cirrhosis

AIM:Primary biliary cirrhosis (PBC) is a chronic, cholestatic disease of autoimmune etiology,the histology of which shows a destruction of the intrahepatic bile duct and portal inflammation. Ursodeoxycholic acid (UDCA) is now used as a first-line drug for asymptomatic PBC (aPBC) because it is reported that UDCA decreases mortality and prolongs the time of liver transplantation.However, only 20-30% of patients respond fully to UDCA.Recently,lipoprotein-lowering agents have been found to be effective for PBC.The aim of this study was to examine the safety and efficacy of fenofibrate, a member of the fibrate class of hypolipidemic and anti-inflammatory agent via peroxysome proliferatory-activated receptor α,in patients with aPBC.METHODS:Fenofibrate was administered for twelve weeks in nine patients with aPBC who failed to respond to UDCA.UDCA was used along with fenofibrate during the study.The data from aPBC patients were analyzed to assess the biochemical effect of fenofibrate during the study.RESULTS: The serum levels of alkaline phosphatase (ALP)(285±114.8IU/L) and immunoglobulin M (IgM) (255.8±85.9mg/dl) significantly decreased to 186.9±76.2IU/L and 192.9±67.5mg/dL respectively, after fenofibrate treatment in patients with aPBC (P<0.05). Moreover,the titer of antimitochondrial antibody (AMA) also decreased in 4 of 9 patients with aPBC. No adverse reactions were observed in any patients.CONCLUSION:Fenofibrate appears to be significantly effective in treating patients with aPBC who respond incompletely to UDCA alone.Although the mechanism of fenofibrate on aPBC has not yet been fully clarified,combination therapy using fenofibrate and UDCA might be related to the anti-immunological effects, such as the suppression of AMA production as well as its antiinflammatory effect.     

Ursodeoxycholic acid therapy in gallbladder disease,a story not yet completed

Gallstone disease represents an important issue in the healthcare system.The principal non-invasive nonsurgical medical treatment for cholesterol gallstones is still represented by oral litholysis with bile acids.The first successful and documented dissolution of cholesterol gallstones was achieved in 1972.Since then a large number of investigators all over the world,have been dedicated in biochemical and clinical studies on ursodeoxycholic acid(UDCA),demonstrating its extreme versatility.This editorial is aimed to provide a brief review of recent developments in UDCA use,current indications for its use and,the more recent advances in understanding its effects in terms of an antiinflammatory drug.     

Ursodeoxycholic acid treatment of vanishing bile duct syndromes

Vanishing bile duct syndromes (VBDS) are characterized by progressive loss of small intrahepatic ducts caused by a variety of different diseases leading to chronic cholestasis, cirrhosis, and premature death from liver failure. The majority of adult patients with VBDS suffer from primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). Ursodeoxycholic acid (UDCA), a hydrophilic dihydroxy bile acid, is the only drug currently approved for the treatment of patients with PBC, and anticholestatic effects have been reported for several other cholestatic syndromes. Several potential mechanisms of action of UDCA have been proposed including stimulation of hepatobiliary secretion, inhibition of apoptosis and protection of cholangiocytes against toxic effects of hydrophobic bile acids.     

Low-dose tacrolimus ameliorates liver inflammation and fibrosis in steroid refractory autoimmune hepatitis

AIM: To determine the eff icacy of tacrolimus on clinical status, histopathological status and biochemical markers in patients with steroid refractory autoimmune hepatitis (AIH). METHODS: Retrospectively, clinical parameters, biochemistry and histology were obtained from patient records. RESULTS: Nine patients [8 females/1 male, median age 32 (range 16-64) years] were identified to have received tacrolimus for a median duration of 18 (12-37) mo. Before initiation of tacrolimus treatment the patients were maintained on a prednisolone dose of 20 mg daily (range 20-80 mg/d), which was tapered to 7.5 (5-12.5) mg/d (P = 0.004). Alanine aminotransferase and immunoglobulin-G concentrations decreased from 154 (100-475) to 47(22-61) U/L (P = 0.007), and from 16 (10-30.2) to 14.5 (8.4-20) g/L (P = 0.032), respectively. All patients showed improvement of the liver inflammatory activity, as determined by the Ishak score (P = 0.016), while the degree of f ibrosis tended to decrease (P = 0.049). CONCLUSION: The use of low dose tacrolimus can lead to biochemical and histologic improvement of inflammation with no progression of the stage of f ibrosis in patients with steroid refractory AIH. Low dose tacrolimus therapy also allows substantial reduction of prednisone dose.     

Effect of Zimian Formula combined with ursodeoxycholic acid in the treatment of primary biliary cholangitis patients with Gan-Shen Yin deficiency syndrome:a randomized controlled trial

<正>Objective To observe the clinical efficacy and safety of Zimian Formula(ZMF) combined with ursodeoxycholic acid(UDCA) in the treatment of primary biliary cholangitis(PBC) patients with Gan-Shen yin deficiency syndrome(GSYDS).Methods Totally 73 PBC patients with GSYDS in line with the inclusion criteria were assigned to the control group(37 cases) and the treatment group(36 cases) according to random number table.Patients in the control group took UDCA,while those in the treatment group ...     

Chemoprotective effects of curcumin in esophageal epithelial cells exposed to bile acids

AIM:To investigate the ability of curcumin to counteract the impact of bile acids on gene expression of esophageal epithelial cells.METHODS:An esophageal epithelial cell line(HET1A)was treated with curcumin in the presence of deoxycholic acid.Cell proliferation and viability assays were used to establish an appropriate dose range for curcumin.The combined and individual effects of curcumin and bile acid on cyclooxygenase-2(COX-2)and superoxide dismutase(SOD-1 and SOD-2)gene expression were also assessed.RES...     

Endoscopic management of postoperative bile leaks

BACKGROUND: Significant bile leak as an uncommon complication after biliary tract surgery may constitute a serious and difficult management problem. Surgical management of biliary fistulae is associated with high morbidity and mortality. Biliary endoscopic procedures have become the treatment of choice for management of biliary Gstulae. METHODS: Ninety patients presented with bile leaks after cholecystectomy ( open cholecystectomy in 45 patients, cholecystectomy with common bile duct exploration in 20 and laparoscopic cholecystectomy in 25). The presence of bile leaks was confirmed by ERCP and the appearance of bile in percutaneous drainage of abdominal collections. Of the 90 patients with postoperative bile leaks, 18 patients had complete transaction of the common bile duct by ERCP and were subjected to bilioenteric anastomosis. In the remaining patients after cholangiography and localization of the site of bile leaks. therapeutic procedures like sphinctero-tomy, biliary stenting and nasobiliary drainage ( NBD ) were performed. If residual stones were seen in the common bile duct, sphincterotomy was followed by stone extraction using dormia basket. Nasobiliary drain or stents of 7F size were placed according to the standard techniques. The NBD was removed when bile leak stopped and closure of the fistula confirmed cholangiographically. The stents were removed after an interval of 6-8 weeks. RESULTS: Bile leaks in 72 patients occurred in the cystic duct (38 patients), the common bile duct (30 ), and the right hepatic duct (4). Of the 72 patients with post-operative bile leak, 24 had associated retained common bile duct stones and 1 had ascaris in common bile duct. All the 72 patients were subjected to therapeutic procedures including sphincterotomy with stone extraction followed by biliary stenting (24 patients), removal of ascaris and biliary stenting (1), sphincterotomy with biliary stenting (18), sphincterotomy with NBD (12), biliary stenting alone (12), and NBD alone (5). Bile leaks stopped in all patients at a median interval of 3 days (range 3-16 days) after endoscopic in- terventions. No difference was observed in efficacy and in time for the treatment of bile leak by sphincterotomy with endoprosthesis or endoprosthesis alone in patients with bile leak after surgery. CONCLUSIONS: Post-cholecystectomy bile leaks occur most commonly in the cystic duct and associated common bile duct stones are found in one-third of cases. Endoscopic therapy is safe and effective in the management of bile leaks and fistulae after surgery. Sphincterotomy with endoprosthesis or endoprosthesis alone is equally effective in the management of postoperative bile leak.     

Fenofibrate for patients with asymptomatic primary biliary cirrhosis

AIM:Primary biliary cirrhosis(PBC)is a chronic,cholestaticdisease of autoimmune etiology,the histology of whichshows a destruction of the intrahepatic bile duct and portalinflammation.Ursodeoxycholic acid(UDCA)is now used asa first-line drug for asymptomatic PBC(aPBC)because it isreported that UDCA decreases mortality and prolongs thetime of liver transplantation.However,only 20-30% ofpatients respond fully to UDCA.Recently,lipoprotein-lowering agents have been found to be effective for PBC.The aim of this study was to examine the safety and efficacyof fenofibrate,a member of the fibrate class of hypolipidemicand anti-inflammatory agent via peroxysome proliferatory-activated receptor α,in patients with aPBC.METHODS:Fenofibrate was administered for twelve weeksin nine patients with aPBC who failed to respond to UDCA.UDCA was used along with fenofibrate during the study.The data from aPBC patients were analyzed to assess thebiochemical effect of fenofibrate during the study.RESULTS:The serum levels of alkaline phosphatase(ALP)(285±114.8 IU/L)and immunoglobulin M(IgM)(255.8±85.9mg/dl)significantly decreased to 186.9±76.2 IU/L and192.9±67.5 mg/dL respectively,after fenofibrate treatmentin patients with aPBC(P<0.05).Moreover,the titer ofantimitochondrial antibody(AMA)also decreased in 4 of 9patients with aPBC.No adverse reactions were observed inany patients.CONCLUSION:Fenofibrate appears to be significantlyeffective in treating patients with aPBC who respondincompletely to UDCA alone.Although the mechanism offenofibrate on aPBC has not yet been fully clarified,combination therapy using fenofibrate and UDCA might berelated to the anti-immunological effects,such as thesuppression of AMA production as well as its anti-inflammatory effect.     

Effects of long term hydrophilic bile acid therapy on in vitro contraction of gallbladder muscle strips in patients with cholesterol gallstones

AIM:To evaluate ursodeoxycholic acid (UDCA) therapy on the in vitro contraction of gallbladder smooth muscle strips from cholesterol gallstone patients. METHODS:The contraction forces of gallbladder smooth muscle strips from 28 patients with cholesterol gallstones treated with UDCA were compared with contraction forces from 14 untreated patients. The strips were stimulated with increasing concentrations of cholecystokinin-8 (CCK-8). RESULTS:Although the contraction forces that developed in response to CCK-8 were higher in strips from specimens of UDCA treated patients compared to untreated patients,longer treatment periods (6-wk) caused more contraction responses than the short treatment period of 3-wk (F = 19.297,1.85 ± 0.22 g vs 1.70 ± 0.10 g,P < 0.01). Contraction forces developed with maximal stimulation with KCl in the 6-wk treatment group were also higher than contraction forces in the untreated group (F = 4.274,3.77 ± 0.45 g vs 3.30 ± 0.30 g,P < 0.05). CONCLUSION:Six-week UDCA treatment caused an increase in contractions of muscle strips from patients with cholesterol gallstones when compared to shorter treatment administration or controls. We suggest that extending UDCA treatment periods may cause more effective contractions in the gallbladder,and thereby increase the rate of response to treatment.     

熊去氧胆酸及其联合激素和免疫抑制剂治疗原发性胆汁性肝硬化的临床观察

目的 观察熊去氧胆酸(UDCA)、UDCA联合泼尼松龙、UDCA联合硫唑嘌呤3种方案治疗对原发性胆汁性肝硬化(PBC)的疗效,并评价影响疗效的危险因素.方法 82例初诊PBC患者随机分为单用UDCA(U组,28例)、UDCA联合泼尼松龙(UP组,27例)、UDCA联合硫唑嘌呤(UA组,27例)3个治疗组,在治疗第0、3、6、12个月采集临床、实验室资料及药物不良反应.主要采用重复测量的方差分析和COX回归进行统计学处理.结果 UP组患者较U组及UA组在乏力和瘙痒程度上有明显改善(P=0.015和P=0.037),U组、UA组无改善.3组患者治疗后丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)、碱性磷酸酶(ALP)、谷氨酰转肽酶(GGT)、总胆红素、直接胆红素(DBIL)和IgM均下降,组内比较差异有统计学意义(P＜0.05),3组间比较差异无统计学意义(P＞0.05).发生疾病进展的患者Mayo危险性评分高(P=0.018)、凝血酶原时间(PT)延长(P=0.042).UP组血糖升高2例、满月脸5例、多毛1例;UA组白细胞下降2例,胆绞痛1例,U组未出现药物不良反应.ALP、GGT、总胆固醇基线水平高是生化缓解的危险因素(P=0.015).总胆红素、DBIL、总胆汁酸增高、PT延长不利于肝生化缓解(P=0.075).结论 3种方案对PBC患者肝脏生化指标、IgM的改善作用相近,UDCA联合泼尼松龙方案可减轻乏力、瘙痒症状,单用UDCA方案不良反应发生率最低.Mayo危险性评分高、PT延长的患者疾病易进展;高水平的ALP、GGT、总胆固醇是生化缓解的危险因素;高水平的总胆红素、DBIL、总胆汁酸、PT不利于生化缓解.

Abstract：

Objective The aims of this study were to compare the clinical and laboratory responses to ursodeoxycholic acid (UDCA) monotherapy with the combination therapy of UDCA plus prednisolone/azathioprine in primary biliary cirrhosis(PBC),and to investigate the risk factors affecting the therapeutic responses.Methods Eighty-two patients with untreated PBC were divided randomly into three groups.Group U (28 patients) received UDCA alone,group UP(27 patients) received UDCA and pr ednisolone,while group UA (27 patients ) received UDCA and azathioprine.The clinical and laboratory data were recorded after treated for 3,6 and 12 months.Repeated measures ANOVA and COX regression model were used for statistical analysis.Results Fatigue and pruritus were improved only in group UP(P=0.015 and P=0.037 respectively).Alanine aminotransferase(ALT),aspartate aminotransferase(AST),alkaline phosphatase(ALP),gamma-glutamyl transferase (GGT),total bilirubin (TBIL),direct bilirubin (DBIL) and IgM in the 3 groups were decreased (P＜0.05),while there was no statistical significant difference between the three groups (P＞0.05).The patients with disease progression had higher Mayo risk score (MRS) (P=0.018) and prolonged prothrombin time (PT)(P=0.042).In group UP,side-effect associated with glucocorticosteroids occurred in eight patients while there was no side-effect in group U.High baseline levels of ALP、GGT and CHO were risk factors for biochemical remission(P=0.015).The increase of DBIL,TBIL,total bile acid(TBA) and PT did not contribute to the prediction of biochemical remission ( P=0.075 ).Conclusion There are no differences among the three groups in the improvement of hepatic biochemical data and IgM.The combination therapy of UDCA with prednisolone could relieve fatigue and itching.The disease of patients with higher Mayo risk score and prolonged PT tend to progress.High baseline levels of ALP,GGT and CHO are risk factors for biochemical remission.High baseline levels of TBIL,DBIL,TBA and PT could not predict biochemical remission.The incidence of adverse effect is lowest when treated with UDCA alone.     

Anemia in inflammatory bowel disease: A neglected issue with relevant effects

Anemia,a common complication associated with inflammatory bowel disease(IBD),is frequently overlooked in the management of IBD patients.Unfortunately,it represents one of the major causes of both decreased quality of life and increased hospital admissions among this population.Anemia in IBD is pathogenically complex,with several factors contributing to its development.While iron deficiency is the most common cause,vitamin B12and folic acid deficiencies,along with the effects of pro-inflammatory cytokines,hemolysis,drug therapies,and myelosuppression,have also been identified as the underlying etiology in a number of patients.Each of these etiological factors thus needs to be identified and corrected in order to effectively manage anemia in IBD.Because the diagnosis of anemia in IBD often presents a challenge,combinations of several hematimetric and biochemical parameters should be used.Recent studies underscore the importance of determining the ferritin index and hepcidin levels in order to distinguish between iron deficiency anemia,anemia due to chronic disease,or mixed anemia in IBD patients.With regard to treatment,the newly introduced intravenous iron formulations have several advantages over orally-administerediron compounds in treating iron deficiency in IBD.In special situations,erythropoietin supplementation and biological therapies should be considered.In conclusion,the management of anemia is a complex aspect of treating IBD patients,one that significantly influences the prognosis of the disease.As a consequence,its correction should be considered a specific,first-line therapeutic goal in the management of these patients.     

Prevalence of bile reflux in gastroesophageal reflux disease patients not responsive to proton pump inhibitors

AIM： To determine the prevalence and characteristics of bile reflux in gastroesophageal reflux disease （GERD） patients with persistent symptoms who are nonresponsive to medical therapy. METHODS： Sixty-five patients （40 male, 25 female; mean age, 50±7.8 years） who continued to report symptoms after 8 wk of high-dose proton pump inhibitor （PPI） therapy, as well as 18 patients with Barrett＇s esophagus, were studied. All patients filled out symptom questionnaires and underwent endoscopy, manometry and combined pH-metry and bilimetry. RESULTS： There were 4 groups of patients： 22 （26.5%） without esophagitis, 24 （28.9%） grade A-B esophagitis, 19 （22.8%） grade C-D and 18 （21.6%） Barrett＇s esophagus. Heartburn was present in 71 patients （85.5%） and regurgitation in 55 （66.2%）, with 44 （53%） reporting simultaneous heartburn and regurgitation. The prevalence of pathologic acid reflux in the groups without esophagitis and with grades A-B and C-D esophagitis was 45.4%, 66.6% and 73.6%, respectively. The prevalence of pathologic bilirubin exposure in these 3 groups was 53.3%, 75% and 78.9%, respectively. The overall prevalence of bile reflux in non-responsive patients was 68.7%. Pathologic acid and bile reflux was observed in 22.7% and 58.1% of non-esophagitic patients and esophagitic patients, respectively.CONCLUSION： The high percentage of patients poorly responsive to PPI therapy may result from poor control of duodenogastroesophageal reflux. Many patients without esophagitis have simultaneous acid and bile reflux, which increases with increasing esophagitis grade.     

Retrospective study of steroid therapy for patients with autoimmune pancreatitis in a Chinese population

AIM:To explore the optimal steroid therapeutic strategy for autoimmune pancreatitis(AIP).METHODS:This study was conducted retrospectively in two large institutions in China.Patients with clinically,radiologically and biochemically diagnosed AIP were enrolled.The performed radiological investigations and biochemical tests,the regimen of the given steroid treatment,remission and relapse whether with and without steroid therapy were analyzed.RESULTS:Twenty-eight patients with AIP received steroid treatment,while 40 patients were treated surgically by pancreatoduodenectomy,distal pancreatectomy and choledochojejunostomy,radiofrequency ablation for the enlarged pancreatic head,percutaneous transhepatic biliary drainage and endoscopic biliary drainage.The starting oral prednisolone dose was 30 mg/d in 18(64.3%) patients and 40 mg/d in 10(35.7%) patients administered for 3 wk.The remission rate of AIP patients with steroid treatment(96.4%) was significantly higher than in those without steroid treatment(75%).Maintenance therapy(oral prednisolone dose 5 mg/d) was performed after remission for at least 6-12 mo to complete the treatment course.Similarly,the relapse rate was significantly lower in AIP patients with steroid treatment(28.6%) than in those without steroid treatment(42.5%).Steroid re-treatment was effective in all relapsed patients with or without steroid therapy.CONCLUSION:Steroid therapy should be considered in all patients with active inflammatory phase of AIP.However,the optimal regimen still should be trailed in larger numbers of patients with AIP.     

Sequential changes of serum ferritin levels and their clinical significance in lamivudine-treated patients with chronic viral hepatitis B

AIM: To study the sequential changes of serum ferritin levels in lamivudine-treated patients with chronic viral hepatitis B and the clinical implications. METHODS: Thirty-eight patients with chronic viral hepatitis B were prospectively studied during their treatment with lamivudine. Each patient received 100 mg oral lamivudine daily for 12 mo, and was observed and tested for blood biochemistry and hepatitis B virus (HBV) DNA levels and serum ferritin levels at baseline and at 3, 6 and 12 mo during the treatment. Serum HBV DNA levels were quantitatively determined using fluorescent quantitative polymerase chain reaction (FQ-PCR), and serum ferritin levels were measured by radioimmunoassay. The sequential changes of serum ferdtin levels and their relationships with virological, serological and biochemical responses in the patients were analyzed. RESULTS: All the patients had a baseline HBV DNA level higher than 1&#215;10^7 copies/L as determined by FQ-PCR and positive HBsAg and HBeAg and abnormal ALT levels. At the end of the 12-mo treatment, 19 of the 38(50.00%) patients had undetectable serum HBV DNA levels by FQ-PCR, and 12(31.58%) became negative for serum HSeAg and 10(26.32%) had seroconversion from HBeAg to HBeAb. Nineteen out of the 38(50.00%) patients had biochemically normal ALT levels after 12-mo lamivudine treatment. Sequential determination showed bhat lamivudine treatment significantly reduced ferritin levels in chronic hepatitis B patients. When the patients were divided into different groups according to their posttreatment virological, serological and biochemical responses for analysis of the sequential changes of ferritin levels, it was found bhat the decrease of ferritin levels in HBV DNA-negative group was significantly more obvious than that in HBV DNApositive group at 6 mo during the treatment (P=-0.013). Consecutive comparisons showed that ferritin levels at 3 mo of treatment were obviously decreased as compared with the baseline levels (P&lt;0.05) in HBeAg-negative group, and the decrease of serum ferritin levels in patients with normalized ALT was more significant than that in patients with abnormal ALT at the end of the 12-mo treatment (P=0.048). CONCLUSION: Lamivudine treatment can reduce the serum ferritin levels in chronic viral hepatitis B patients and decreases of ferdtin levels can be more significant in patients exhibiting virological, serological and biochemical responses, indicating that dynamic observation of serum ferritin levels in patients with chronic viral hepatitis B during lamivudine treatment might be helpful for monitoring and predicting patients‘ responses to the therapy.     

Gallbladder bile composition in patients with Crohn＇s disease

AIM:To further elucidate the pathogenesis andmechanisms of the high risk of gallstone formation inCrohn's disease.METHODS:Gallbladder bile was obtained from patientswith Crohn's disease who were admitted for electivesurgery (17 with ileal/ileocolonic disease and 7 withCrohn's colitis).Fourteen gallstone patients servedas controls.Duodenal bile was obtained from tenhealthy subjects before and after the treatment withursodeoxycholic acid.Bile was analyzed for biliary lipids,bile acids,bilirubin,crystals,and crystal detection time(CDT).Cholesterol saturation index was calculated.RESULTS:The biliary concentration of bilirubin wasabout 50% higher in patients with Crohn's disease thanin patients with cholesterol gallstones.Ten of the patientswith Crohn's disease involving ileum and three of thosewith Crohn's colitis had cholesterol saturated bile.Fourpatients with ileal disease and one of those with colonicdisease displayed cholesterol crystals in their bile.About1/3 of the patients with Crohn's disease had a shortCDT.Treatment of healthy subjects with ursodeoxycholicacid did not increase the concentration of bilirubin induodenal bile.Several patients with Crohn's disease,with or without ileal resection/disease had gallbladderbile supersaturated with cholesterol and short CDT andcontained cholesterol crystals.The biliary concentrationof bilirubin was also increased in patients with Crohn'scolitis probably not due to bile acid malabsorption.CONCLUSION:Several factors may be of importance forthe high risk of developing gallstones of both cholesteroland pigment types in patients with Crohn's disease.     

FOLFOX/FOLFIRI pharmacogenetics:The call for a personalized approach in colorectal cancer therapy

While 5-fluorouracil used as single agent in patients with metastatic colorectal cancer has an objective response rate around 20%,the administration of combinations of irinotecan with 5-fluorouracil/folinic acid or oxaliplatin with 5-fluorouracil/folinic acid results in significantly increased response rates and improved survival.However,the side effects of systemic therapy such as myelotoxicity,neurotoxicity or gastrointestinal toxicity may lead to life-threatening complications and have a major impact on the quality of life of the patients.Therefore,biomarkers that would be instrumental in the choice of optimal type,combination and dose of drugs for an individual patient are urgently needed.The efficacy and toxicity of anticancer drugs in tumor cells is determined by the effective concentration in tumor cells,healthy tissues and by the presence and quantity of the drug targets.Enzymes active in drug metabolism and transport represent important determinants of the therapeutic outcome.The aim of this review was to summarize published data on associations of gene and protein expression,and genetic variability of putative biomarkers with response to therapy of colorectal cancer to 5-fluorouracil/leucovorin/oxaliplatin and 5-fluorouracil/leukovorin/irinotecan regimens.Gaps in the knowledge identified by this review may aid the design of future research and clinical trials.     

Stimulating erythropoiesis in inflammatory bowel disease associated anemia

Anemia is a frequent complication in patients with inflammatory bowel disease (IBD), and is associated with decreased quality of life and increased rate of hospitalization. The primary therapeutic targets of IBD- associated anemia are iron deficiency and anemia of chronic disease. An important prognostic parameter of the success or failure of therapy is the outcome of the underlying disease. Iron deficiency should be appropriately managed with iron supplementation. However, the use of oral iron therapy is limited by several problems, the most important being gastrointestinal side effects leading occasionally to disease relapse and poor iron absorption. Intravenous iron preparations are more reliable, with iron sucrose demonstrating the best efficacy and tolerability. Treatment with erythropoietin or darbepoetin has been proven to be effective in patients with anemia, who fail to respond to intravenous iron. Patients with ongoing inflammation have anemia of chronic disease and may require combination therapy comprising of intravenous iron sucrose and erythropoietin. After initiating treatment, careful monitoring of hemoglobin levels and iron parameters is needed in order to avoid recurrence of anemia. In conclusion, anemia in the setting of IBD should be aggressively diagnosed, investigated, and treated. Future studies should define the optimal dose and schedule of intravenous iron supplementation and appropriate erythropoietin therapy in these patients.