Evidence for defective primary bile acid secretion in children with progressive familial intrahepatic cholestasis (Byler disease)

To clarify the relationship of progressive familial intrahepatic cholestasis (Byler disease) to bile acid metabolism, we analysed, by high performance liquid chromatography, the bile acid composition of serum and bile in seven children with Byler disease and in eight control children with other cholestatic diseases. In serum, total bile acid concentration was increased in patients with Byler disease (0.30±0.05 mmol/l) and in control patients (0.21±0.08 mmol/l). Cholate (C) and chenodeoxycholate (CDC) cornprised the major proportion of total bile acids in patients with Byler disease as in control patients. Hyocholate (HC) was only detected in patients with Byler disease and lithocholate was only present in control children. In bile, total bile acid concentration was very low in patients with Byler disease (1.1±1.4 mmol/l) compared to control patients (88.9±83.2 mmol/l). C and CDC were the major bile acids in control patients, whereas C and HC comprised the major proportion of bile acids in patients with Byler disease. These results suggest the existence of a defect of primary bile acid secretion in Byler disease characterized by the presence of high concentration of bile acids in serum and absence or very low concentration of bile acids in bile.     

Liver retransplantation with external biliary diversion for progressive familial intrahepatic cholestasis type 1: a case report

Abstract:  PFIC1, originally described as "Byler disease," is characterized by cholestatic feature and chronic diarrhea. Many patients require LT for the cure, but intractable diarrhea and prolonged growth retardation after LT are serious complications limiting the ultimate outcome of LT for this disease. EBD has recently been shown to be a promising and effective treatment. Recently, we successfully treated a five-yr-old boy with PFIC1 employing EBD after re-transplantation. The patient received LDLT at the age of one yr. Six months after initial transplantation, he developed repeated attacks and diarrhea followed by the development of liver dysfunction and ascites. Liver biopsy at three yr after LDLT revealed the features of chronic graft rejection. With a diagnosis of chronic graft rejection with liver failure, we performed a repeat LDLT with EBD in which the jejunal loop used for hepaticojejunostomy was taken out of the body surface through the abdominal wall. Ten months after surgery, he is doing well, having no attack of diarrhea.     

Hepatoblastoma in a child with progressive familial intrahepatic cholestasis

End-stage liver cirrhosis because of metabolic or infectious diseases predisposes to hepatic malignancies like hepatocellular carcinoma. We report the first case of hepatoblastoma incidentally detected in the explanted liver of a 2-yr-old child undergoing liver transplantation for cirrhosis because of progressive familial intrahepatic cholestasis (PFIC). The diagnosis was difficult to obtain. The hepatoblastoma was not seen on ultrasound examination of the cirrhotic liver. As we could confirm retrospectively, alpha fetoprotein (AFP) was found elevated prior to transplantation. Two years after successful transplantation, there are no signs of malignancy detectable by clinical and radiological methods. We conclude from this case that PFIC may induce hepatoblastoma and that children with liver cirrhosis should undergo routine screening of serum AFP concentration.     

熊脱氧胆酸治疗早产儿胃肠外营养相关性胆汁淤积症的疗效

目的探讨熊脱氧胆酸(UDCA)对早产儿胃肠外营养相关性胆汁淤积(PNCA)的疗效。方法选取给予胃肠外营养并PNAC的早产儿65例为研究对象,根据不同UDCA治疗剂量,将其分成低剂量治疗组、高剂量治疗组、对照组。其中高剂量治疗组24例。UDCA 20 mg.kg-1.L-1,分2、3次服用。治疗前ALT(73.5±31.9)U.L-1,谷氨酰转肽酶(GGT)(107.5±27.9)U.L-1,总胆红素(TBIL)(217.0±24.3)μmol.L-1,结合胆红素(DBIL)(71.8±18.8)μmol.L-1,总胆汁酸(TBA)(61.5±18.2)μmol.L-1。低剂量治疗组18例。UDCA 10 mg.kg.L-1,分2、3次服用。ALT(76.8±32.1)U.L-1,GGT(116.8±29.8)U.L-1,TBIL(207.7±20.8)μmol.L-1,DBIL(71.0±20.1)μmol.L-1,TBA(63.9±19.8)μmol.L-1。对照组23例采用综合治疗,但未服用UDCA。ALT(70.3±33.8)U.L-1,GGT(108.3±30.8)U.L-1,TBIL(220.0±25.8)μmol.L-1,DBIL(67.9±19.7)μmol.L-1,TBA(63.5±22.6)μmol.L-1。治疗2～4周比较3组肝功能指标改善情况。结果高剂量治疗组3例因不能耐受高剂量转为低剂量治疗,统计时将其剔除。其他UDCA治疗患儿均未观察到有变应性皮疹、腹泻、血糖升高、白细胞升高等UDCA的不良反应。治疗前3组肝功能指标差异均无统计学意义(Pa>0.05),治疗2周、4周,高剂量治疗组与对照组ALT、GGT、TBIL、DBIL、TBA比较差异均有统计学意义(Pa<0.05),肝功能指标明显降低;低剂量治疗组与对照组指标比较差异均有统计学意义(Pa<0.05),肝功能指标明显降低;高、低剂量治疗组间各指标比较差异均无统计学意义(Pa>0.05)。结论各剂量UDCA治疗早产儿PNCA疗效显著且安全。     

Successful pregnancy after liver transplantation in progressive familial intrahepatic cholestasis,type 1

Cash WJ, Knisely AS, Waterhouse C, Iqbal M, Stokes V, Byrne B, McCormick PA. Successful pregnancy after liver transplantation in progressive familial intrahepatic cholestasis, type 1.
Pediatr Transplantation 2011: 15: E174–E176. © 2010 John Wiley & Sons A/S. Abstract: A woman who had undergone liver transplantation for genetically documented ATP8B1 disease/progressive familial intrahepatic cholestasis, type 1, successfully conceived, carried, and was delivered of a healthy child. The pregnancy and its management are described; implications are discussed.     

Ursodeoxycholic acid therapy in children with cholestatic liver disease

The beneficial effect of ursodeoxycholic add have been documented in adults but experience with this agent is limited in the pediatric population. The objective of this study was to evaluate ursodeoxycholic acid treatment in children with cholestatic liver disease. Twenty-four patients with intrahepatic cholestasis (neonatal hepatitis 7, Byler disease 7, idiopathic intrahepatic cholestasis 10) whose ages ranged from 1.5 months to 15 years were treated with ursodeoxycholic acid (15-20 mg/kg/day) for 12 months. Liver biopsy was performed initially on all patients and on 17 at the end of the twelve months. The outcome was evaluated by monitoring clinical and biochemical markers of cholestasis, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase, cholesterol, total serum tasting bile acids and total and conjugated bilirubin at entry and every three months of treatment. Pruritus was ameliorated in all patients; there was complete disappearance of itching in 16.7 percent. There were significant decreases in mean serum levels of alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin and gamma-glutamyl transpeptidase. Liver biopsy specimens showed a significant improvement in the cholestasis but not in fibrosis. No adverse effects of therapy were noted. The improvements in the clinical and biochemical parameters and tolerability of the drug suggest that ursodeoxycholic acid is a safe and effective treatment in children with intrahepatic cholestasis.     

Total internal biliary diversion during liver transplantation for type 1 progressive familial intrahepatic cholestasis: a novel approach

LT for PFIC type 1 is often complicated by postoperative diarrhea and recurrent graft steatosis. A 26‐month‐old female child with cholestatic jaundice, pruritus, diarrhea, and growth retardation revealed total bilirubin 9.1 mg/dL, gamma‐glutamyl transpeptidase 64 IU/L, and TBA 295.8 μmol/L. Genetic analysis confirmed ATP8B1 defects. A LT (segment 2, 3 graft) from the heterozygous father was performed. Biliary diversion was performed by a 35‐cm jejunum conduit between the graft hepatic duct and the mid‐transverse colon. Stools became pigmented immediately. Follow‐up at 138 days revealed resolution of jaundice and pruritus and soft‐to‐hard stools (6–8 daily). Radioisotope hepato‐biliary scintigraphy (days 26, 68, and 139) confirmed unobstructed bile drainage into the colon (t_1/2 34, 27, and 19 minutes, respectively). Contrast meal follow‐through at day 62 confirmed the absence of any colo‐jejuno‐hepatic reflux. At 140 days, contrast follow‐through via the biliary stent revealed patent jejuno‐colonic anastomosis and satisfactory transit. Graft biopsy at LT, 138 days, and 9 months follow‐up revealed comparable grades of macrovesicular steatosis (<20%). TIBD during LT may be a clinically effective stoma‐free biliary diversion and may prevent recurrent graft steatosis following LT for PFIC type 1.     

进行性家族性肝内胆汁淤积症2例临床及遗传学分析

目的探讨进行性家族性肝内胆汁淤积症(PFIC)的临床及遗传学特征。方法回顾分析2例PFIC患儿的临床资料和基因检测结果。结果例1,女性,15岁,临床表现以黄疸、皮肤瘙痒、白色黏稠便为主,伴脾大;例2,男性,3岁6月龄,表现为黄疸、皮肤瘙痒。全外显子测序发现,例1的ATP8B1基因存在c.2652GC和c.1573CT复合杂合变异,其中c.2652GC变异遗传自父亲,c.1573CT变异遗传自母亲,c.2652GC是既往未见报道的新变异位点。例2的ABCB11基因存在c.2606AC纯合错义变异,来源于父母。结论基因检测有助于PFIC的明确诊断及治疗。此研究丰富了ATP8B1致病变异谱。     

Safety of living-related liver transplantation for progressive familial intrahepatic cholestasis

Progressive familial intrahepatic cholestasis (PFIC) is a severe cholestatic liver disease of early life often requiring liver transplantation. Organ shortage leads to consider living-related liver transplantation. Because of possible partial metabolic defect in heterozygotes, the use of familial donors might be questionable. We therefore evaluated the safety of this procedure, for both donors and recipients. We compared a series of seven parental-children pairs, having participated in the living related liver transplant program for PFIC between 1994 and 2001, with that of a series of seven parental-children pairs, performed for biliary atresia (BA) during the same period. No primary graft dysfunction was observed. There was no difference in the course of transaminases, gamma-glutamyl transpeptidase and bilirubin levels after transplantation in both donor and recipient series. Thirteen recipients and 14 donors are alive and well 3-10 yr post-surgery. One PFIC recipient died nine months post-orthotopic liver transplantation from sepsis. We conclude that PFIC heterozygote status of the donor does not increase the risk of liver dysfunction in either recipients or donors, with a similar course compared with BA recipients and donors.     

低血清谷氨酸转肽酶进行性家族性肝内胆汁淤积症23例临床分析

目的 总结以低血清谷氨酸转肽酶（GGT）为特征的进行性家族性肝内胆汁淤积症(PFIC)各型的临床特征,提高对该病的认识。方法 回顾性分析2004年1月至2007年6月在复旦大学附属儿科医院临床诊断为低血清GGT的PFIC患儿的临床症状、实验室检查、肝脏组织病理学检查和随访等资料,根据ATP8B1和ABCB11全部基因外显子测序结果分为PFIC-Ⅰ、PFIC-Ⅱ和未分型3组,分析3组间临床特征的差异。结果 23例低血清GGT的PFIC患儿进入分析,PFIC-I、PFIC-Ⅱ和未分型组分别为9、7和7例。23例PFIC患儿出生体重均正常,以黄疸、瘙痒和肝功能损害起病。中位发病年龄40 d（0 d至7个月）,中位就诊年龄6（2～36）个月。①13例（56.5%）病程中出现过白陶土样大便,有明显腹泻症状3例。6例（26.1%）有营养不良、佝偻病和生长发育落后。2例（8.7%）随访中发现胆结石。②15例肝组织病理活检示：7例（46.7%）肝细胞多核巨细胞样转化,14例（93.3%）肝细胞和毛细胆管胆汁淤积明显,未发现脂肪变性病例。③未分型组ALT水平较PFIC-Ⅰ型和PFIC-Ⅱ型组显著升高（P<0.05）; PFIC-Ⅱ型组ALT、TBA水平显著高于PFIC-Ⅰ型组（P<0.05）;PFIC-Ⅱ型和未分型组肝细胞多核巨细胞转化发生率显著高于PFIC-Ⅰ型组（P<0.05）。结论 低血清GGT的PFIC患儿以黄疸、瘙痒和肝功能损害为主要临床表现,PFIC-Ⅰ型肝穿刺病理活检未见肝细胞多核巨细胞转化,PFIC-Ⅱ型血清ALT、TBA水平明显高于PFIC-Ⅰ型,有助于临床分型和治疗方法的选择。     

Ursodeoxycholic acid's role in avoiding diversionary surgery in idiopathic fibrosing pancreatitis

Obstructive jaundice in childhood is rare but a cause of great concern and warrants aggressive investigation into its aetiology. Idiopathic fibrosing pancreatitis (IFP) is a rare cause of this phenomenon and is presently a diagnosis of exclusion with lymphoma a main differential diagnosis. IFP appears to be a self limiting occurrence and as a result the previous gold standard of therapy of surgical diversion may ultimately be unnecessary. We describe ursodeoxycholic acid as a useful adjunct to treatment allowing more time for clinicians to evaluate the nature of the underlying disease process without hastily moving towards invasive surgery until clearly indicated.     

Progressive idiopathic cholestasis presenting with profuse watery diarrhoea and recurrent infections (Byler''s disease)

The second child of healthy unrelated parents presented with chronic diarrhoea since the age of two months, initially associated with non-characteristic liver involvement. Recurrent infections, severe failure to thrive and various metabolic deficiencies complicated the further course, as well as profuse watery diarrhoea with elevated regulatory gut peptides, responding only to somatostatin analog treatment. At 22 months of age, intermittent cholestasis with permanently normal serum gamma-glutamyltransferase was evident. The child died of fulminant purulent meningitis at the age of three years six months. Liver histology showed intrahepatic cholestasis, bile duct paucity with focal proliferation as well as slight portal and intralobular fibrosis. The clinical, biochemical and histopathological findings were indicative of Byler's disease.     

Common bile duct stones in infancy: a medical approach

Abstract: Symptomatic choledocholithiasis in infancy is not common. It usually presents with jaundice and acholic stools and is diagnosed on abdominal ultrasonography. Favourable outcome of conservative management has been reported, but specific management guidelines are not well defined in the literature. We describe three cases using a combination of ursodeoxycholic acid and antibiotics as a treatment paradigm, which could potentially negate more invasive treatment. All three patients had ultrasonography proven choledocholithiasis with concomitant obstructive liver function test. They were treated with a combination of ursodeoxycolic acid and antibiotics. Patient 1 had an Escherichia coli urinary tract infection and was treated with oral bactrim. Intravenous amoxicillin, gentamicin and metronidazole were used for the other two patients. All three patients responded with a return to normal‐coloured stools within 48 h of combination treatment. Repeat ultrasonography done within 11 days after the first study for all three patients confirmed complete resolution of choledocholithiasis. It is postulated that this improvement is as a result of a reduction in inflammation and oedema, associated with a low‐grade cholangitis, following antibiotic treatment. This is coupled with improved bile flow with ursodeoxycholic acid therapy. The findings suggest the potential application of this safe, non‐invasive therapeutic strategy as initial management in infants with this condition. A follow‐up prospective randomised controlled trial may be an answer to prove the validity of this observation but due to the rarity of this problem, it would be a challenge to recruit sufficient number of patients.     

Biliary lipid metabolism in children with chronic intrahepatic cholestasis

Biliary lipid composition, standard liver function tests, serum lipids and faecal fat excretion were studied in 15 children with chronic intrahepatic cholestasis (severe intrahepatic cholestasis, n=6; paucity of intralobular bile ducts, n=4; benign recurrent cholestasis, n=5) and compared to 15 children without gastrointestinal diseases. Severe and benign intrahepatic cholestasis were associated with normal or moderately elevated serum lipids. Biliary lipid concentrations were extremely reduced, bile acid concentrations were below the critical micellar concentration. This may account for the high incidence of gallstone formation in these patients. Remission periods in patients with benign recurrent cholestasis were not followed by complete normalisation of biliary lipid concentrations, indicating a primary defect in hepatic excretory function. Children with paucity of intralobular bile ducts showed markedly increased serum lipids, but only a two-fold reduction in biliary lipid concentrations. Cholic acid was the predominant bile acid in bile of all cholestatic children even during remission. Neither increased levels of monohydroxy bile acids nor unusual bile acids could be identified in notable amounts.