Scintigraphic documentation of an improvement in hepatobiliary excretory function after treatment with ursodeoxycholic acid in patients with cystic fibrosis and associated liver disease.

We have previously documented that ursodeoxycholic acid exerts a beneficial effect on liver function and bile acid metabolism in patients with cystic fibrosis. We hypothesized that the mechanism of action may be related in part to the choleretic properties of the administered bile acid. We therefore compared hepatobiliary scintigraphic images obtained before and 1 yr after initiation of ursodeoxycholic acid therapy to document an improvement in bile flow in 13 patients with cystic fibrosis and hepatobiliary involvement. Before therapy, hepatobiliary scintigraphy documented biliary stasis with retention of the isotope in intrahepatic and extrahepatic bile ducts in nine patients; during therapy, duct dilatation decreased substantially in eight patients, with decreased intrahepatic retention and more rapid biliary outflow of the tracer. The time of appearance of isotope in the intestine decreased (from a mean of 36.9 +/- 17.8 min to 18.8 +/- 9.0 min; p less than 0.01) in all patients in whom it had been abnormal, and the half-time of hepatic washout decreased from a mean of 35 +/- 20.7 min to 26 +/- 15.6 min (p less than 0.05). During ursodeoxycholic acid administration enrichment of bile was achieved, with the mean ursodeoxycholic acid percent composition increasing from 5.8% +/- 2.9% to 35.7% +/- 8.5%. Ursodeoxycholic acid became the predominant bile acid in serum. Liver function improved in all 10 of the patients with abnormal values at baseline. We conclude that hepatobiliary scintigraphy is of value in monitoring the therapeutic responses of cystic fibrosis patients with liver disease to ursodeoxycholic acid therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy.

The efficacy and safety of ursodeoxycholic acid in the treatment of intrahepatic cholestasis of pregnancy was investigated in an open pilot study. Five patients received 1 gm/day of ursodeoxycholic acid during 20 days and another three patients received two identical periods of treatment separated by a 14-day interval free of the drug. Pruritus and serum levels of total bile salts and glutamic-pyruvic transaminase improved significantly during treatment with ursodeoxycholic acid. In the three patients who received two periods of treatment with ursodeoxycholic acid, pruritus and the laboratory alterations relapsed in the second week after the drug was discontinued, but they improved again when ursodeoxycholic acid was readministered. No adverse reactions were detected in the mothers or in their babies. All newborns were thriving normally during a follow-up period that lasted 5 mo after delivery. It is concluded that UDCA appears to be safe when administered in late pregnancy; its promising efficacy in the treatment of intrahepatic cholestasis of pregnancy should now be confirmed in controlled clinical trials.     

Endogenous ursodeoxycholic acid and cholic acid in liver disease due to cystic fibrosis

Focal biliary cirrhosis causes significant morbidity and mortality in cystic fibrosis (CF). Although the mechanisms of pathogenesis remain unclear, bile acids have been proposed as potential mediators of liver injury. This study examined bile acid composition in CF and assessed altered bile acid profiles to determine if they are associated with incidence and progression of liver injury in CF-associated liver disease (CFLD). Bile acid composition was determined by gas-liquid chromatography/mass spectrometry in bile, urine, and serum samples from 30 children with CFLD, 15 children with CF but without liver disease (CFnoLD), and 43 controls. Liver biopsies from 29 CFLD subjects were assessed histologically by grading for fibrosis stage, inflammation, and disruption of the limiting plate. A significantly greater proportion of endogenous biliary ursodeoxycholic acid (UDCA) was demonstrated in CFnoLD subjects vs. both CFLD subjects and controls (2.4- and 2.2-fold, respectively; ANOVA, P =.04), and a 3-4 fold elevation in endogenous serum UDCA concentration was observed in both CFLD subjects and CFnoLD subjects vs. controls (ANOVA, P <.05). In CFLD, there were significant correlations between serum cholic acid and hepatic fibrosis, inflammation, and limiting plate disruption as well as the ratio of serum cholic acid/chenodeoxycholic acid to hepatic fibrosis, inflammation, and limiting plate disruption. In conclusion, elevated endogenous UDCA in CFnoLD suggests a possible protective role against liver injury in these patients. The correlation between both cholic acid and cholic acid/chenodeoxycholic acid levels with histological liver injury and fibrosis progression suggests a potential monitoring role for these bile acids in CFLD.     

熊去氧胆酸联合脂溶性维生素注射液治疗酒精性肝病伴肝内胆汁淤积患者疗效观察

目的 探讨熊去氧胆酸（UDCA）联合脂溶性维生素注射液治疗酒精性肝病（ALD）伴肝内胆汁淤积患者的疗效。方法 2015年 1月~2016年 1月我院收治的75例ALD伴肝内胆汁淤积患者被随机分为试验组43例,给予UDCA联合脂溶性维生素注射液治疗,对照组32例只接受UDCA治疗,均治疗4 w。结果 在治疗4 w结束时,试验组和对照组AST为[（46.2±17.2）U/L 和（96.4±37.3）U/L,P<0.05],GGT为[（78.9±19.1）U/L 和（123±54.5）U/L,P<0.05],TBIL为[（44.8±20.7） μmol/L 和（85.3±29.6）μmol/L,P<0.05],ALP 为[（79.6±22.3）U/L 和（101±29.7）U/L,P<0.05],APTT 为[（46.4±14.2）s和（58.8±14.9）s,P<0.05],TBA 为[（47.7±19.3）μmol/L和（111.2±36.3）μmol/L,P<0.05]。结论 UDCA联合脂溶性维生素治疗ALD伴肝内胆汁淤积患者近期疗效确切。     

熊去氧胆酸治疗妊娠期肝内胆汁淤积症患者疗效研究*

目的 探讨应用熊去氧胆酸（UDCA）治疗妊娠期肝内胆汁淤积症（ICP）患者的疗效及其安全性。方法 2015年3月~2018年4月我院收治的ICP患者70例,被随机分为观察组35例和对照组35例,分别给予常规治疗和UDCA治疗4周。采用高效液相色谱串联质谱法检测血清胆汁酸谱,包括石胆酸（LCA）、UDCA、鹅去氧胆酸（CDCA）、胆酸（CA）、甘氨胆酸（GCA）、牛磺石胆酸（TLCA）和总胆酸（TCA）。结果 在治疗结束时,观察组和对照组瘙痒评分分别为（1.1±0.3）对（2.3±0.8）,差异显著（P<0.05）;血清ALT水平分别为（25.7±10.0） U/L对（85.1±24.3） U/L,AST分别为（22.6±10.3） U/L对（84.3±11.3） U/L,TBIL分别为（21.6±3.8） μmol/L对（30.5±5.4）μmol/L,差异显著（P<0.05）;血清UDCA分别为（3.2±0.1） μmol/L对（2.5±0.2） μmol/L,CA水平分别为（1.2±0.1） μmol/L对（2.4±0.2） μmol/L,GCA分别为（1.6±0.2） μmol/L对（2.8±0.5） μmol/L,TCA分别为（1.2±0.3） μmol/L对（4.2±0.9） μmol/L,差异显著（P<0.05）;观察组早产、产后出血和新生儿窒息等不良结局发生率显著低于对照组（17.1%对51.4%,P<0.05）。结论 应用UDCA治疗ICP患者能显著减轻症状,改善肝功能指标,且无明显的不良后果。     

Ursodeoxycholic acid treatment in patients with cystic fibrosis at risk for liver disease

BackgroundMeconium ileus has been detected as a risk factor for development of liver disease in cystic fibrosis, with influence on morbidity and mortality.AimsTo evaluate the effect of early treatment with ursodeoxycholic acid in patients with cystic fibrosis and meconium ileus to prevent chronic hepatic involvement and to explore the potential role of therapy on clinical outcomes.Methods26 cystic fibrosis patients with meconium ileus (16 M, mean age 8,4 years, range 3,5–9) were assigned to two groups: group 1 (14 patients) treated early with ursodeoxycholic acid (UDCAe); group 2 (12 patients) treated with ursodeoxycholic acid at the onset of cystic fibrosis liver disease (UDCAd). Anthropometric data, pulmonary function tests, pancreatic status, complications such as diabetes, hepatic involvement and Pseudomonas aeruginosa colonisation were compared among groups.ResultsA higher prevalence of cystic fibrosis chronic liver disease was observed in the UDCAd group with a statistically significant difference at 9 years of age (p < 0.05). Chronic infection by P. aeruginosa was found in 7% of UDCAe and 33% of UDCAd (p < 0.05). No differences were observed in nutritional status and other complications.ConclusionsEarly treatment with ursodeoxycholic acid may be beneficial in patients at risk of developing cystic fibrosis chronic liver disease such as those with meconium ileus. Multicentre studies should be encouraged to confirm these data.     

The benign course of liver disease in adults with cystic fibrosis and the effect of ursodeoxycholic acid

Background and Aims: The life expectancy of patients with cystic fibrosis (CF) has been increasing and the associated liver disease has emerged as a significant medical issue. Our aim was to describe the clinical features, course and effect of ursodeoxycholic acid (UDCA) on liver disease in an adult CF population. Study: From 1983 to 2005, 278 patients with CF were followed up at the Alfred Hospital, an adult tertiary referral centre. Twenty‐seven patients (9.7%) satisfied the criteria for liver disease and their clinico‐pathological features were assessed. The effect of UDCA on hepatobiliary symptoms and biochemical parameters was determined. Results: The mean age at liver disease diagnosis was 23 years (range 8–47 years). Portal hypertension was present in 18 (67%) patients. During a median follow‐up of 7 years (range 1.5–15), variceal haemorrhage occurred in two patients and ascites in three (one spontaneously). Nine (33%) patients died and five (19%) underwent lung transplantation. There was no encephalopathy, liver transplantation or liver‐related deaths. UDCA was taken by 22 patients and was associated with a significant improvement in hepatobiliary symptoms [11/22 (50%) in the pre‐UDCA period vs 1/22 (4%) in the post‐UDCA period; P=0.0003] and a significant reduction in aspartate aminotransferase (P=0.005); alanine aminotransferase (P<0.001); γ‐glutamyltranspeptidase (P=0.021); and alkaline phosphatase (P<0.001). Conclusions: Liver disease in adults with CF is commonly complicated by portal hypertension, but morbidity and mortality associated with this in our small patient population were low. UDCA is associated with improvement in hepatobiliary symptoms and liver function tests.     

Efficacy and safety of ursodeoxycholic acid in patients with intrahepatic cholestasis of pregnancy

Background and aims. Patients with intrahepatic cholestasis of pregnancy (ICP) benefit from ursodeoxycholic acid (UDCA) treatment. Since there is still certain reluctance to use UDCA in pregnant women, mainly due to warnings in the official SPC information in respective drug leaflets, our objective was to assess the efficacy and safety of UDCA during pregnancy.Material and methods. Our retrospective multicentric study was performed on 191 consecutive pregnant women with ICP treated with UDCA. Any maternal and/or fetal complications of the UDCA treatment were searched for; healthy pregnant women (n = 256) served as controls.Results. The UDCA treatment improved liver disease status in the majority of the affected women (86.1%). This treatment was well tolerated, with only negligible skin reactions (0.5%) and mild diarrhea (4.7%). No complications attributable to UDCA treatment were detected during the fetal life, delivery, or the early neonatal period.Conclusion. We confirmed the good efficacy and safety of UDCA treatment in pregnancy for both mothers and fetuses/neonates.     

Delayed intestinal visualization at hepatobiliary scintigraphy is associated with response to long-term treatment with ursodeoxycholic acid in patients with cystic fibrosis-associated liver disease.

BACKGROUND/AIMS: Abnormalities of biliary drainage have been documented at hepatobiliary scintigraphy in many but not all patients studied with cystic fibrosis-associated liver disease. Ursodeoxycholic acid was shown to be beneficial in this disease, mainly by improving biliary secretion. Therefore, patients with impaired biliary drainage are expected to obtain the greatest benefit from this treatment. METHODS: We evaluated the effects of long-term treatment with ursodeoxycholic acid in 36 patients with cystic fibrosis-associated liver disease, and compared the response in patients presenting a normal (n=18) or delayed time of intestinal visualization (n=18) at baseline hepatobiliary scintigraphy. RESULTS: The mean treatment duration was 58+/-26 (S.D.) months and 63+/-29 months in the groups with normal or delayed time of intestinal visualization, respectively. The time of intestinal visualization decreased (57+/-23%, p<0.001) from baseline in patients with initially abnormal values and became normal in four (22%). Treatment failure, i.e. lack of sustained normalization of serum liver enzymes or the occurrence of a clinically relevant adverse event, was more frequently observed in patients with a normal time of intestinal visualization at baseline (OR, 5.50; 95% CI, 1.32-22.7). When only clinically relevant adverse events were considered, they occurred in six of the latter patients (liver transplantation in one case, development of ultrasographic or endoscopic signs of portal hypertension in six cases), but in only one patient (development of portal hypertension) in the group with delayed time of intestinal visualization (OR, 10.82; 95% CI, 1.17-100.4). CONCLUSIONS: Delayed intestinal visualization at hepatobiliary scintigraphy in patients with cystic fibrosis-associated liver disease seems to predict a better response to ursodeoxycholic acid.     

Use of ursodeoxycholic acid in patients with liver disease

Ursodeoxycholic acid (UDCA), the 7β-epimer of chenodeoxycholic acid, has multiple hepatoprotective activities. UDCA modifies the bile acid pool, decreasing levels of endogenous, hydrophobic bile acids while increasing the proportion of nontoxic hydrophilic bile acids. UDCA has a choleretic effect, increasing hepatocellular bile acid excretion, as well as cytoprotective, antiapoptotic, and immunomodulatory properties. UDCA has been shown to delay development of gastroesophageal varices and progression to cirrhosis as well as to improve long-term survival in patients with primary biliary cirrhosis. Significant improvement of abnormal liver tests may be achieved during UDCA therapy in patients with primary sclerosing cholangitis, intrahepatic cholestasis of pregnancy, cystic fibrosis-associated liver disease, nonalcoholic fatty liver disease, graft-versus-host disease of the liver, total parenteral nutrition-induced cholestasis, and in some pediatric cholestatic liver diseases. However, unlike the effecs of UDCA in primary biliary cirrhosis, the long-term effects of UDCA in disease progression and survival in these other conditions remain to be established.     

Pancreatic morphology and function in adult patients with cystic fibrosis.

To determine the relation between pancreatic morphology and pancreatic exocrine and endocrine function, we have studied 8 adult cystic fibrosis patients and 14 normal control subjects by ultrasonography and pancreatic function testing. In the patients with cystic fibrosis the maximum anteroposterior diameter of the pancreatic head was significantly increased over that in control subjects (p less than 0.01), whereas the maximum diameter of the body was significantly decreased (p = 0.05). Increased echogenicity of the pancreatic body was observed in most patients. In the cystic fibrosis patients postprandial insulin secretion was reduced in the 1st h (p less than 0.005 versus control), whereas pancreatic polypeptide secretion was virtually abolished for at least 3 h (p less than 0.01 versus control). All cystic fibrosis patients had evidence of exocrine pancreatic dysfunction as reflected by a diminished urinary para-aminobenzoic acid excretion. Intraduodenal enzyme and bicarbonate output in response to secretin-cholecystokinin was reduced in all of three patients studied. It is concluded that loss of endocrine and exocrine pancreatic function in adult cystic fibrosis patients is accompanied by a small and echo-dense pancreatic body relative to a large pancreatic head.     

熊去氧胆酸联合腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症临床分析

目的评价熊去氧胆酸联合腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症患者的临床疗效。方法2011年10月至2014年10月我院收治的130例妊娠期肝内胆汁淤积症患者被随机分为观察组和对照组,每组各65例。给予观察组熊去氧胆酸联合腺苷蛋氨酸治疗1周,对照组只接受熊去氧胆酸治疗1周。结果观察组治疗后血清ALT为（116.56±12.27） IU/L,AST为（108.73±13.01） IU/L,总胆红素为（13.04±1.89）μmol/L,总胆汁酸为（15.86±2.23）μmol/L,瘙痒评分为（1.1±0.6）分,改善程度明显优于对照组【分别为（153.71±13.34） IU/L、（136.24±12.89） IU/L、（21.65±2.52）μmol/L、（23.15±3.17）μmol/L和（2.3±0.9）分,P<0.05】;观察组早产（6.15%）、剖宫产（23.08%）、羊水污染（16.92%）和胎儿窘迫发生率（18.47%）均低于对照组（分别为16.92%、44.62%、30.77%、43.08%）,差异有统计学意义（P<0.05）。结论熊去氧胆酸联合腺苷蛋氨酸治疗妊娠期肝内胆汁淤积症能缓解皮肤瘙痒症状,减轻肝脏损伤,改善妊娠结局。     

Respiratory muscle function in patients with cystic fibrosis

Respiratory muscle function in patients with cystic fibrosis (CF) can be assessed by measurement of maximal inspiratory pressure (Pi_max), maximal expiratory pressure (Pe_max), and pressure–time index of the respiratory muscles (PTI_mus). We investigated the differences in maximal respiratory pressures and PTI_mus between CF patients with no gross hyperinflation and healthy controls and described the effects of pulmonary function and nutrition impairment on respiratory muscle function in this group of CF patients. Forced expiratory volume in 1 sec (FEV₁), forced vital capacity (FVC) and maximal expiratory flow between 25% and 75% of VC (MEF_25–75), body mass index (BMI), upper arm muscle area (UAMA), Pi_max, Pe_max, and PTI_mus were assessed in 140 CF patients and in a control group of 140 healthy subjects matched for age and gender. Median Pi_max and Pe_max were significantly lower in CF patients compared to the controls [Pi_max = 74 (57–94) in CF vs. 84 (66–102) in controls, P = 0.009], [Pe_max = 71 (50–95) in CF vs. 84 (66–102) in controls, P < 0.001]. Median PTI_mus in CF patients compared to controls was significantly increased [PTI_mus = 0.110 (0.076–0.160) in CF vs. 0.094 (0.070–0.137) in controls, P = 0.049] and it was significantly higher in CF patients with impaired pulmonary function. In CF patients, PTI_mus was significantly negatively related to upper arm muscle area (r = 0.184, P = 0.031). These findings suggest that CF patients with no severe lung disease compared to healthy subjects exhibit impaired respiratory muscle function, while CF patients with impaired pulmonary function and nutrition indices exhibit higher PTI_mus values. Pediatr Pulmonol. 2013; 48:865–873. © 2012 Wiley Periodicals, Inc.     

Muscular strength and function in patients with cystic fibrosis

BACKGROUND: For 20 years, physical activity has been an important component in the treatment of cystic fibrosis (CF) patients in Sweden. Data concerning physical performance in terms of muscular strength in these patients are limited OBJECTIVE: To compare muscular strength and function in patients with CF with those aspects in a healthy control group (CG). DESIGN: Thirty-three patients with CF (16 women) aged 16 to 35 years and 20 healthy individuals matched for age and gender were included in the study. All participants had undertaken regular physical training two to three times per week. The following tests were performed: vertical jumping ability; hand-grip strength; abdominal strength; arm/shoulder strength; quadriceps muscle strength; and a functional test of leg muscle endurance. RESULTS: Patients with CF showed decreased muscle strength and function compared to control subjects (women: maximal hand-grip strength in the right [p = 0.02] and the left hand [p = 0.001]; sustained hand-grip strength in the left hand [p = 0.002]; and in leg muscle endurance [p = 0.02]; men: the number of sit-ups performed within 30 s [p = 0.03]; and left leg isokinetic quadriceps strength at 180 degrees per second [p = 0.02]). The differences were not related to pancreatic or pulmonary function. There was no significant difference between the CF group and the CG in any other test results. CONCLUSIONS: Our study showed few differences in muscular performance between patients with CF and healthy control subjects. Both groups had regular moderate-to-high activity levels. Further studies are needed to evaluate whether the small but significant differences might be related to metabolic abnormalities in skeletal muscles in CF patients.     

Pancreatic exocrine function in patients with cystic fibrosis

Pancreatic insufficiency in cystic fibrosis (CF) is associated with more severe disease and requires replacement therapy. Outcome measures such as growth and number of stools, frequency of abdominal pain, and flatulence have often been used to identify pancreatic-insufficient patients and to adjust the dose of replacement enzymes. Unfortunately, some patients with CF are misclassified, and approximately 9% do not receive therapy appropriate for their pancreatic exocrine functional status. Growth, number of stools, frequency of abdominal pain, and flatulence cannot be used to adjust enzyme doses.     

Pulmonary function and morbidity in 40 adult patients with cystic fibrosis.

Pulmonary function and cardiopulmonary complications were studied in a group of 40 patients with cystic fibrosis who reached the age of 25 years. Mean values for vital capacity (VC), functional residual capacity, residual volume (RV), the ratio of RV over total lung capacity (RV/TLC), conductance, and the ratio of the forced expiratory volume in one second over VC were abnormal. There was a variable pattern of progression from patient to patient. The men differed from the women only in that they had a significantly larger TLC and inspiratory capacity than the women. The resultant preservation of VC may have an advantage for survival in those patients in whom it is observed. Pseudomonas aeruginosa was encountered with increasing frequency with age. Massive hemoptysis did not result in early death. The occurrence of rightsided heart failure secondary to cor pulmonale, with or without respiratory failure, was a poor prognostic sign.     

Expression of cystic fibrosis transmembrane conductance regulator in liver tissue from patients with cystic fibrosis

The authors examined the expression of cystic fibrosis transmembrane conductance regulator (CFTR) and its relationship to histopathological changes in cystic fibrosis (CF) liver tissue. Immunohistochemistry was used to examine expression of CFTR, intercellular adhesion molecule-1 (ICAM-1) and liver cell-type markers in liver cryosections in 11 patients with CF-associated liver disease, and non-CF controls with (n = 17) and without (n = 3) liver disease. In CF patients prominent inflammatory infiltrates were not found, yet hepatic stellate cells were identified within fibrotic areas around bile ducts. Proliferating bile ducts displayed ICAM-1 immunoreactivity in 3 cases, but bile ducts were otherwise negative. In 2 patients homozygous for R764X and for 1112delT no CFTR immunoreactivity was detected. Bile-duct epithelial cells in patients carrying the DeltaF508 mutation displayed aberrant cytoplasmic immunolocalization of CFTR, as determined with confocal laser scanning microscopy, in contrast to the distinct CFTR expression at the luminal surface seen in controls. No clear relationship between CFTR expression and fibrosis or inflammation was evidenced in CF patients. In conclusion, these findings are consistent with an impairment of DeltaF508 CFTR processing in intrahepatic biliary epithelium. ICAM-1 expression on bile-duct epithelial cells and inflammatory infiltrates were rare findings in CF liver tissue, indicating that immunological mechanisms are unlikely to be involved in initiation of CF-associated liver disease.