Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is characterized by pruritus, intrahepatic cholestasis, low serum gamma-glutamyltransferase levels, and characteristic "Byler bile" on electron microscopy. Many patients require liver transplantation, but partial external biliary diversion (PEBD) has shown therapeutic promise. However, the effect of PEBD on liver morphology and bile composition has not been evaluated. METHODS: We reviewed liver biopsy specimens from 3 children with low gamma-glutamyltransferase PFIC before and after PEBD. Follow-up liver biopsies were performed 9-60 months after PEBD. Light and electron microscopic features were scored blindly. Biliary bile acid composition was analyzed by gas chromatography-mass spectrometry before and after PEBD in 1 patient and after PEBD in 2 patients. RESULTS: Following PEBD, all patients improved clinically. Preoperative biopsy specimens showed characteristic features of PFIC, including portal fibrosis, chronic inflammation, cholestasis, giant cell transformation, and central venous mural sclerosis. Ultrastructural findings included coarse, granular canalicular Byler bile, effaced canalicular microvilli, and proliferative pericanalicular microfilaments. Following diversion, histology showed almost complete resolution of cholestasis, portal fibrosis, and inflammation with resolution of ultrastructural abnormalities. Biliary bile acids before PEBD consisted predominantly of cholic acid. After PEBD, the proportion of chenodeoxycholic acid increased significantly in 1 patient and was above the PFIC range in a second patient. CONCLUSIONS: The resolution of hepatic morphologic abnormalities following PEBD supports PEBD as an effective therapy for PFIC. The improved biliary bile acid composition suggests enhanced bile acid secretion after PEBD, perhaps by induction of alternative canalicular transport proteins.     

Successful pregnancy after ileal exclusion in progressive familial intrahepatic cholestasis type 2

Progressive familial intrahepatic cholestasis type 2 (PFIC 2) results from mutations in ABCB11 gene coding bile salt export pump (BSEP). Medical treatment is usually unsuccessful and surgery intervention is necessary. Partial external biliary diversion (PEBD) is regarded as the first choice of surgical treatment. Ileal exclusion (IE) is an alternative operation if external stoma is not tolerated; however, a favorable outcome is uncertain. In chronic liver diseases pregnancy brings additional risk of deterioration of liver function and generally is not recommended. We present the first case report of successful pregnancy in a genetically confirmed PFIC 2 patient after surgical conversion from PEBD to IE.     

Genetic cholestasis: lessons from the molecular physiology of bile formation.

Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT) activity, whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2, respectively. The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids, respectively. Benign recurrent intrahepatic cholestasis (BRIC) is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be difficult to differentiate from these transport defects. Intrahepatic cholestasis of pregnancy (ICP) appears to be related to these cholestatic diseases. For example, heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in families with BRIC. In Dubin-Johnson syndrome there is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is affected. This, therefore, is a mild disease, and patients have a normal lifespan.     

Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion

Background  

Partial External Biliary Diversion (PEBD) is a surgical intervention to treat children with Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille syndrome (AGS). PEBD can reduce disease progression, and examining the alterations in biliary lipid composition may be a prognostic factor for outcome.     

Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome

Alagille syndrome (AGS) causes intractable pruritus and disfiguring xanthomas because of retained bile acids and cholesterol. This study was performed to determine whether partial external biliary diversion (PEBD) is effective for relief of pruritus and xanthomas in AGS patients who fail conventional medical therapy. Between the years 1985 and 2001, 9 AGS patients underwent PEBD. Complete follow-up data were available for all patients. The average age at PEBD was 4.8 (range 1.4-10) years. The average duration of follow-up was 7.5 (range 0.5-16.0) years. All 9 patients had severe, mutilating pruritus (grade 4) prior to diversion. At 1 year post-PEBD, the average pruritus score was 1.1; 8 patients had only mild scratching when undistracted. Three patients with extensive xanthomas prior to PEBD had complete resolution within 1 year. Mean serum bile salt levels (n = 5) decreased from 136.5 to 37.1 micromol/L and mean cholesterol (n = 7) from 724 to 367 mg/dL 1 year after PEBD. A single 21-year-old patient with PEBD for 14 years experienced an increase in pruritus from grade 1 to grade 4 within 2 months of elective reversal of PEBD. In conclusion, PEBD is effective for treating severe pruritus and hypercholesterolemia in AGS patients without cirrhosis who did not respond to medical therapy. PEBD should be considered as a therapeutic option for these patients before referral for liver transplantation because of morbid complications.     

Partial external biliary diversion in bile salt export pump deficiency: Association between outcome and mutation

AIM To investigate the relation of two different mutations to the outcome of partial external biliary diversion(PEBD)in severe bile salt export pump(BSEP) deficiency.METHODS Mutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney(HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatographytandem mass spectrometry. Wild-type and mutant BSEP transport of [~3H]-labeled taurocholate(TC) and taurochenodeoxycholate(TCDC) was assessed by vesicular transport assays.RESULTS A girl(at 2 mo) presented with pruritus, jaundice and elevated serum bile salts(BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919 del and the nonsense mutation p.R1235 X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy(age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032 R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives( 5%). The patients' native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919 del and p.G1032 R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute, respectively.CONCLUSION In summary, our findings suggest that residual function of BSEP as well as substrate specificity influence the therapeutic effectiveness of PEBD in progressive familial intrahepatic cholestasis type 2(PFIC-2).     

Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2

OBJECT: The authors report the case of a boy with PFIC type 2 or BRIC type 2 who suffered from liver dysfunction at 2 months after birth. METHODS AND RESULTS: A liver biopsy specimen revealed mild liver cirrhosis, and the findings resembled those observed in Byler disease. Genetic examination revealed a normal familial intrahepatic cholestasis-1 gene, but a heterozygous mutation for the ABCB11, C1620A (F540L), was observed. Therefore, the patient was initially diagnosed with PFIC type 2. For 3 years after the diagnosis, he had severe pruritus, an increased serum bile acid, and normal serum values of gamma-glutamyl transaminase. At the age of 2, treatment with administration of ursodeoxycholic acid was started; subsequently, a gradual improvement in his liver function was observed. At the age of 3, he suffered from massive intestinal and pulmonary hemorrhage, which improved immediately after the administration of vitamin K. He was then admitted to our hospital for liver transplantation. At 1 month after the admission, his liver dysfunction showed further improvement, except for a mild increase in the serum bile acid level. This condition did not show any change during the 5-year follow-up period. In addition, the patient showed severe growth failure and was diagnosed with growth hormone deficiency. Hence, he receives growth hormone administration. CONCLUSION: The patient could be genetically diagnosed with bile salt export pump disease of PFIC type 2 or BRIC type 2. Various clinical features are observed in PFIC or BRIC patients with ABCB11 mutation.     

血清胆红素与不稳定型心绞痛的关系探讨

目的　探讨血清胆红素与不稳定型心绞痛 (UAP)发病的关系。方法　对符合 WHO U AP标准的 40 2例不稳定型心绞痛患者 (UAP组 )和 76 6例冠状动脉造影正常者 (对照组 )测定清晨空腹血清总胆红素浓度。比较两组间临床特征及实验室指标的差异 ,对血清总胆红素浓度与 U AP之间的关系进行单因素及多元逐步 L ogistic回归分析。结果　 U AP组血清总胆红素浓度显著低于对照组 (12 .7± 5 .2 μm ol/ L vs16 .0± 5 .7μmol/ L,P<0 .0 1) ;单因素分析显示血清总胆红素浓度越低 ,UAP发病率越高 (P<0 .0 1)。多元逐步 L ogistic回归发现 :血清总胆红素浓度与 U AP的发生显著负相关 (X2 wald =5 4.2 313,P=0 .0 0 0 1,OR=0 .899) ,血清总胆红素浓度减低是 U AP的独立危险因子。血清总胆红素浓度每减少一个等级 ,UAP的发病增加 10 .1%。结论　血清总胆红素浓度减低可能在UAP的发病中具有一定作用     

Progressive familial intrahepatic cholestasis: partial biliary diversion normalizes serum lipids and improves growth in noncirrhotic patients

OBJECTIVES: Progressive familial intrahepatic cholestasis (PFIC) usually presents with pruritus, jaundice, hepatomegaly, and growth failure. A group of PFIC is recognized by marked elevation of total serum bile acids, decreased serum apolipoprotein A-1, and high-density lipoprotein, but normal gamma-glutamyltranspeptidase and cholesterol. Although medical therapy generally fails, partial external biliary diversion (DIV) has been used with promising results for cholestasis. However, little has been reported of its effect on linear growth, synthetic liver function, and lipid metabolism. METHODS: DIV was performed on six noncirrhotic children with PFIC, all suffering from severe pruritus and cholestasis, refractory to medical treatment. Stature was below -1 (median, -2.3) standard deviation score (SDS) for height in all cases. All patients had markedly enhanced bile acids (307 +/- 72 microl/L), markedly decreased high-density lipoprotein (20 +/- 7 mg/dl), and apolipoprotein A-1 (58 +/- 37 mg/dl), but normal gamma-glutamyltranspeptidase and cholesterol. In addition, cholinesterase activity, monoethylglycinexylidide test, and Fischer's ratio indicated a significantly reduced synthetic liver function in all children but the youngest. RESULTS: After DIV, all patients were consistently relieved of pruritus, and experienced normalization of all liver function tests, including cholinesterase activity, monoethylglycinexylidide test, and Fischer's ratio, as well as the serum lipid profile within 1 yr. In addition, a marked catch-up growth (median, +/- 1.3 SDS) was evident after 1 yr in all cases. CONCLUSIONS: This report shows an excellent result of DIV in noncirrhotic PFIC patients and compares favorably with other reports. All patients experienced complete remission, including normalization of synthetic liver function and lipid metabolism. For the first time we have shown that DIV can also be associated with an accelerated growth in these patients.     

Hereditäre Defekte hepatobiliärer Transportproteine

Defects in transport proteins that are expressed at the hepatocyte canalicular membrane can cause severe impairment of hepatobiliary transport processes. Progressive familial intrahepatic cholestasis (PFIC) typically manifests in early childhood. Genetic variants in the aminophospholipid transporter FIC1 (ATP8B1 gene) cause PFIC1, characterized by elevated serum bile acids but normal or only mildly elevated gamma-GT levels. Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is also caused by ATP8B1 mutations. Defects in the function of the bile salt efflux pump (BSEP; ABCB11) cause PFIC2 or BRIC2, depending on the degree of BSEP impairment. A common BSEP variant, the V444A polymorphism, is commonly found in various types of cholestatic liver injury, including drug-induced liver injury. Finally, dysfunction of the multidrug resistance gene product MDR3 (ABCB4) leads to PFIC3, characterized by low biliary phospholipids and high gamma-GT levels in serum due to bile duct injury. All three transporter genes are also associated with intrahepatic cholestasis of pregnancy. Treatment options include ursodeoxycholic acid for milder forms and liver transplantation for severe pediatric cases.     

血清胆红素水平与女性冠心病关系的探讨

目的：探讨血清胆红素水平与女性冠心病的关系。方法：109例女性患者按冠状动脉造影结果分为冠心病组（74例）和非冠心病组（35例）。同时测定血清胆红素及各项生化指标。冠状动脉狭窄程度用冠状动脉狭窄计分表示。结果：女性冠心病组血清总胆红素、直接胆红素和间接胆红素水平均显著低于非冠心病组（P〈0．01）。相关分析显示，女性冠心病组直接胆红素与总胆固醇（TC）和甘油三酯（TG）呈显著负相关（r1=-0．398，r2=-0．405，P均〈0．01）。三种胆红素水平与冠状动脉病变积分均不呈负相关。结论：低血清胆红素水平是冠状动脉粥样硬化的危险因素。     

Relationships between serum bilirubins and production and conjugation of bilirubin. Studies in Gilbert's syndrome, Crigler-Najjar disease, hemolytic disorders, and rat models

The pattern of serum bilirubins was determined in serum of humans and rats with unconjugated hyperbilirubinemia due to increased pigment load or defective hepatic conjugation. Bilirubin ester conjugates were present in all serum samples tested and were identified as bilirubin 1-O-acyl glucuronides. In Gilbert's syndrome, the concentration of total conjugates was comparable to the values in healthy control subjects. Because the concentration of unconjugated pigment was increased, the fraction of conjugated relative to total bilirubins was markedly decreased. Sera from patients with Crigler-Najjar disease differed from those with Gilbert's syndrome by the higher unconjugated bilirubin levels and the undetectability of diconjugated bilirubins. A striking finding was that in hemolytic disease, the concentration of both monoconjugates and diconjugates was enhanced in parallel with the increase of unconjugated pigment. Therefore, the fraction of conjugated relative to total bilirubins remained within the normal range. As in Gilbert's syndrome, heterozygote R/APfd-j/+ rats with impaired hepatic bilirubin conjugation exhibit an increased unconjugated bilirubin level in serum, whereas the concentration of total conjugates was comparable to the values in normal rats. In serum of normal rats loaded intraperitoneally with unconjugated bilirubin, both unconjugated and mono- and diconjugated bilirubins were increased in parallel so that the ratio of unconjugated to esterified pigment remained unaffected. Decreased hepatic conjugation or increased bilirubin load was associated with a lower percentage of diconjugates relative to total conjugates both in human and rat serum. The present results are consistent with a compartmental model in which there is bidirectional transfer across the sinusoidal membrane for unconjugated bilirubin as well as for the bilirubin glucuronides. Because typical patterns of serum bilirubins are found in Gilbert's syndrome and patients with hemolytic hyperbilirubinemia, determination of esterified bilirubins in serum is of value to study the pathophysiology and the differential diagnosis of unconjugated hyperbilirubinemia.     

血清胆红素和血脂的综合指数与冠心病的关系研究

目的探讨血清胆红素与血脂的综合指数与冠心病(CHD)的关系.方法将80名行冠状动脉造影术的患者分为2组:CHD组与对照组(冠状动脉正常).测定血清总胆红素水平(TBIL),总胆固醇(TC),高密度脂蛋白胆固醇(HDL-C),低密度脂蛋白胆固醇(LDL-C),计算出其综合指数:LDL-C/(HDL-C TBIL)和TC/(HDL-C TBIL),分析其与CHD之间的关系.结果CHD患者血清TBIL水平明显低于非冠心病患者(P＜0.05).CHD患者总胆固醇(TC),低密度脂蛋白胆固醇(LDL-C),LDL-C/(HDL-C TBIL)比值,TC/(HDL-C TBIL)比值水平明显高于冠状动脉正常组(P＜0.05).进行Logistic回归分析,TC,LDL-C,LDL-C/(HDL-C TBIL),TC/(HDL-C TBIL)可引入Logistic回归模型,它们为CHD的危险因素.结论CHD的发生与TBIL的降低有一定的相关性,综合考虑血脂、血清胆红素与血脂的综合指数有助于CHD的诊断.     

Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis

BACKGROUND & AIMS: Progressive familial intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patients with normal gamma-glutamyltransferase activity have mutations of the FIC1 locus on chromosome 18q21 or mutations of the BSEP gene on chromosome 2q24. Also, patients with bile acid synthesis defects have low gamma-glutamyltransferase activity. We investigated expression of the bile salt export pump (BSEP) in liver samples from patients with a PFIC phenotype and correlated this with BSEP gene mutations. METHODS: BSEP and multidrug resistance protein 2 (MRP2) expressions were studied by immunohistochemistry in liver specimens of 28 patients and BSEP gene mutation analysis in 19 patients. Bile salt kinetics were studied in 1 patient. RESULTS: Sixteen of 28 liver samples showed no canalicular BSEP staining. Staining for MRP2 showed a normal canalicular pattern in all but 1 of these samples. Ten of 19 patients showed BSEP gene mutations; BSEP protein expression was lacking in all 10 patients. No mutations were found in 9 of 19 patients, and in all except 1, BSEP protein expression was normal. Bile salt concentration in bile of BSEP-negative/MRP2-positive PFIC patients was 0.2 +/- 0.2 mmol/L (n = 9; <1% of normal) and in BSEP-positive PFIC patients 18.1 +/- 9.9 mmol/L (n = 3; 40% of normal). The kinetic study confirmed the dramatic decrease of bile salt secretion in BSEP-negative patients. CONCLUSIONS: The findings show a close correlation between BSEP gene mutations and canalicular BSEP expression. Biliary secretion of bile salts is greatly reduced in BSEP-negative patients.     

血清总胆红素浓度与动脉粥样硬化性血栓性脑梗死的关系

目的　探讨血清总胆红素浓度在动脉粥样硬化性血栓性脑梗死发病中的作用。方法　选择动脉粥样硬化性血栓性脑梗死患者 32 7例和对照组 380例 ,并将病例与对照配对 93对。采清晨空腹肘静脉血测定血清总胆红素浓度 ,比较两组间血清总胆红素浓度的差异 ,并进一步利用病例对照配对研究 ,对低浓度血清总胆红素与动脉粥样硬化性血栓性脑梗死的关系进行分析。结果　病例组血清总胆红素浓度显著低于对照组 (u =5 5 7,P <0 0 1) ;病例组和对照组血清总胆红素低、中、高浓度构成不同 ,病例组低浓度的比例高于对照组 ,高浓度的比例低于对照组 (x2 =6 6 0 1,P <0 0 1) ;病例对照配对分析表明 ,低浓度血清总胆红素与动脉粥样硬化性血栓性脑梗死有关 ,与非低浓度组相比 ,低浓度可使动脉粥样硬化性血栓性脑梗死的危险性增加 1 0 5倍 (OR =2 0 5 ,x2 =6 2 2 ,P <0 0 5 )。结论　低浓度血清总胆红素可能与动脉粥样硬化性血栓脑梗死的发病之间存在相关性     

血清胆红素与冠心病的关系

目的 :探讨血清胆红素与冠心病的发病关系。方法 :将入选 2 19例患者行冠状动脉造影 ,依据造影结果分为两组 :主要冠状动脉狭窄≥ 5 0 %为冠心病组 ,共 12 6例 ,冠状动脉造影正常者为对照组 ,共 93例 ,两组均采空腹静脉血测定血清总胆红素 ,比较两组间血清总胆红素浓度变化。结果 :冠心病组血清总胆红素水平显著低于对照组 ,且胆红素浓度与冠心病发病呈负相关。结论 :低血清胆红素水平可能是导致冠心病的危险因素之一     

不稳定型心绞痛与血胆红素的关系

目的:探讨血清胆红素水平与不稳定型心绞痛的关系。方法:心内科住院患者98例,经冠状动脉造影分成两组,冠心病(CHD)组65例,其中不稳定型心绞痛(UAP)组35例,稳定型心绞痛(SAP)组30例;非CHD组33例。均采用2,4-二氯苯胺重氮盐(DCA)比色法测定血清胆红素水平。结果:UAP组血清总胆红素(15.17±4.10)μmol/L、间接胆红素(11.31±3.12)μmol/L水平明显低于SAP组[(18.69±5.48)μmol/L,(14.27±4.06)μmol/L]和对照组[(17.86±3.53)μmol/L,(14.08±2.58)μmol/L,P0.01],而SAP组与对照组相比无显著性差异(P0.05)。结论:血清胆红素水平与不稳定型心绞痛有关,有可能成为评价不稳定型心绞痛患者的生化标志物。     

吸烟对血清总胆红素浓度的影响及其致冠心病作用

目的:探讨吸烟对血清总胆红素(TB)浓度的影响及其在致冠心病中的作用。方法:将符合条件的154例行冠脉造影术的病人分为吸烟组(81例)与不吸烟组(73例),测定血清总胆红素浓度,分析组间血清TB水平差异。按冠脉造影的结果将此154例病人重新分组:冠脉造影正常组(63例),冠脉造影中度狭窄组(21例),冠脉造影高度狭窄组(70例),分析组间血清TB水平差异。结果:吸烟组血清TB浓度显著低于不吸烟组(P<0.05)。冠脉高度狭窄组及冠脉中度狭窄组的TB水平显著低于冠脉造影正常组(P<0.05-<0.01)。结论:吸烟可显著降低血清总胆红素水平,从而增加冠心病发病危险。     

胆总管结石对血清CA19-9的影响

目的:探讨胆总管结石对血清CEA、CA19-9的影响.方法:回顾经ERCP或手术证实、治疗的胆总管结石患者68例,分析血清CEA,特别是血清CA19-9与胆总管结石患者总胆红素、直接胆红素的相关性:并对20例血清CA19-9值超过正常上限两倍以上的患者统一时间进行随访,分析治疗前后血清CA19-9变化值与总胆红素、直接胆红素变化值的相关性.结果:血清CA19-9与总胆红素、直接胆红素存在明显相关性(r=0.813,0.786,均P=0.000);血清CEA与总胆红素、直接胆红素不存在相关性;治疗前后血清CA19-9变化值与总胆红素、直接胆红素变化值存在明显相关性(r=0.787,0.806,均P=0.000).结论:胆总管结石合并阻塞性黄疸时,可导致血清CA19-9升高,此时血清CA19-9作为肿瘤标志物的特异性差.     

Progressive familial intrahepatic cholestasis and inborn errors of bile acid synthesis

Progressive familial intrahepatic cholestasis (PFIC), types 1, 2 and 3, are due to defects in genes involved in bile secretion (FIC1, BSEP, MDR3). PFIC and inborn errors of bile acid synthesis (IEBAS) often present in infancy with cholestasis. The distinctive feature of PFIC 1 and 2 and IEBAS is a normal level of GGT, while IEBAS are suspected in patients with low plasma bile acids concentration. Molecular testing, urinary bile acid analysis (IEBAS), liver biopsy and immuno-staining are used for the diagnosis. Some patients with PFIC can be successfully treated with ursodeoxycholic acid or partial external biliary diversion. IEBAS is treated with cholic acid. Liver transplantation is required for cirrhosis with liver failure. Hepatocarcinoma has been reported in PFIC2.