Surgical treatment of biliary atresia in the liver transplantation era

Biliary atresia (BA) still remains one of the most intractable gastrointestinal diseases in infancy despite the concerted efforts of pediatric surgeons all over the world. The introduction of liver transplantation has revolutionized the protocols for the treatment of this condition. In this editorial, the role of hepatic portoenterostomy (the Kasai procedure) in the surgical treatment of BA in the "transplantation era" will be discussed.     

Improved survival in biliary atresia patients in the present era of liver transplantation

Therapy for patients with biliary atresia (BA) has become controversial, with orthotopic liver transplantation (OLTx) suggested in place of portoenterostomy. This is based on the unpredictable success of portoenterostomy, and the increased difficulty of the OLTx procedure following prior extensive liver surgery. The survival rate reported here for infants transplanted after unsuccessful portoenterostomy does not support this approach. OLTx was undertaken in 37 patients when end-stage liver failure followed primary portoenterostomy. Recipient age ranged from 6 months to 14 years (median, 13 months), and weight ranged from 5 to 45 kg (median, 8 kg) at the time of OLTx. Reduced-size allografts were used as the primary allograft in 25 patients (23 left lobe), and 12 received whole-organ allografts. Retransplantation was required in 5 patients, each received a reduced-size allograft. There was no increased incidence of vascular complications, primary nonfunction, irreversible rejection, intestinal perforation, biliary complications, sepsis, or lymphoma comparing the BA patients with all other non-BA patients who had undergone OLTx (all P = .16). There was no statistically significant difference in mean operative blood loss between BA patients (EBL = 1.99 BV) and non-BA patients (1.50 BV) (P = .14). Actuarial survival for the series of BA patients was 89% at 1 year, and 80% at 2 years. Following the introduction of reduced-size allografts, donor organs were selected for use with a priority on donor stability. The actuarial survival for BA patients during this time has improved to 96% at 1 year, and 91% at 2 years.(ABSTRACT TRUNCATED AT 250 WORDS)     

Medical informatics in perinatology project AGUSTINA in Argentina

Biliary atresia, a progressive obliterative process involving the bile ducts, has its onset in the newborn period. It is characterized by worsening cholestasis, hepatic fibrosis, and cirrhosis, which lead to portal hypertension and a decline in hepatic synthetic function. Untreated, the outcome is uniformly fatal. The two major milestones toward improved treatment of this disease have been the Kasai portoenterostomy and orthotopic liver transplantation. There has been discussion regarding transplantation as primary therapy, but portoenterostomy remains the standard of care as first-line intervention. Hepatic transplantation, done more frequently for biliary atresia than for any other cause of liver failure in the pediatric population, offers improved survival and quality of life to those for whom the Kasai operation fails. The etiology of biliary atresia remains poorly understood. Working toward a better understanding of this disease, recent investigations target more precise characterization of the hepatic pathology and seek to identify possible causative agents and predictors of favorable outcome. Recent advances in the understanding of biliary atresia published between December 1995 and November 1996 are the focus of this review.     

Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association

Biliary atresia is a disorder of infants in which there is obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow. Untreated, the resulting cholestasis leads to progressive conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. Biliary atresia has an incidence of approximately one in 10,000 live births worldwide. Evidence to date supports a number of pathogenic mechanisms for the development of biliary atresia. An infectious cause, such as by a virus, would seem most pausible in many cases. The clinical observation that biliary atresia is rarely encountered in premature infants would support an agent acting late in gestation. However, no infectious or toxic agent has been conclusively implicated in biliary atresia. Genetic mechanisms likely play important roles, even regarding susceptibility to other specific causes, but no gene whose altered function would result in obstruction or atresia of the biliary tree has been identified. The variety of clinical presentations support the notion that the proposed mechanisms are not mutually exclusive but may play roles individually or in combination in certain patients. Biliary atresia, when untreated, is fatal within 2 years, with a median survival of 8 months. The natural history of biliary atresia has been favorably altered by the Kasai portoenterostomy. Approximately 25 to 35% of patients who undergo a Kasai portoenterostomy will survive more than 10 years without liver transplantation. One third of the patients drain bile but develop complications of cirrhosis and require liver transplantation before age 10. For the remaining one third of patients, bile flow is inadequate following portoenterostomy and the children develop progressive fibrosis and cirrhosis. The portoenterostomy should be done before there is irreversible sclerosis of the intrahepatic bile ducts. Consequently, a prompt evaluation is indicated for any infant older than 14 days with jaundice to determine if conjugated hyperbilirubinemia is present. If infectious, metabolic, endocrine disorders are unlikely and if the child has findings consistent with biliary atresia, then exploratory laparotomy and intraoperative cholangiogram should be done expeditiously by a surgeon who has experience doing the Kasai portoenteostomy. Biliary atresia represents the most common indication for pediatric liver transplantation, representing more than 50% of cases in most series. Transplantation is indicated when symptoms of end stage liver disease occur, including recurrent cholangitis, progressive jaundice, portal hypertension complications, ascites, decreased synthetic function, and growth/nutritional failure.     

Evidence of peripheral axonal neuropathy in primary restless legs syndrome

The aim of this study was to assess the risk and prognostic factors of gut perforation after orthotopic liver transplantation in children with biliary, atresia using univariate and stepwise regression analysis. Among 51 pediatric recipients who underwent transplantation because of biliary atresia after failure of portoenterostomy, 10 patients (20%) had 19 episodes of gut perforations after 14 transplantations. The median delay between transplantation and perforation was 13 days. These perforations were treated either by suture (n = 21) or ostomy (n = 11). The study of preoperative and perioperative variables showed that children with gut perforation were in surgery for a significantly longer period of time including a longer period of receiving hepatectomy and undergoing portal venous clamp. These children also needed large amounts of blood transfused during hepatectomy. After transplantation there was no difference regarding total steroid doses and early occurrence of cytomegalovirus disease between the two groups. Stepwise regression analysis identified three factors associated with the occurrence of gut perforation: duration of transplant operation, posttransplant intra-abdominal bleeding requiring reoperation, and early portal vein thrombosis. During the postoperative course, severe fungal infections were significantly more frequent in the gut perforation group. The 3-year patient survival rate was 70% in the group with gut perforation and was not different from the group without perforation (80%). This study shows that children with previous portoenterostomy carry a high risk of developing gut perforation after liver transplantation. This is especially true for those patients with the most difficult hepatectomies, which are responsible for the iatrogenic injury of the bowel. Other risk factors pointed out in this study were splanchnic congestion in case of prolonged portal venous clamp time or early portal vein thrombosis and repeated trauma of the bowel caused by reoperations. On the other hand, other well known risk factors, such as steroid therapy and viral diseases, were not involved in the occurrence of gut perforations in this study. Besides emergent surgical treatment, this type of complication requires aggressive therapy against fungal infections.     

Total anomalous pulmonary venous return complicating portoenterostomy for biliary atresia

Cardiovascular anomalies such as absent inferior vena cava and preduodenal portal vein are reported in cases of biliary atresia and make hepatic portoenterostomy a technical challenge. The authors present the case of a severe cardiac anomaly that significantly altered the functional outcome of a Kasai procedure. Baby M., an 8-week-old boy born with total anomalous pulmonary venous return (TAPVR), underwent hepatic portoenterostomy for biliary atresia. Over the next 3 months he remained icteric and febrile, and failed to gain weight. After multiple antibiotic treatments for suspected cholangitis, he underwent reexploration of the portoenterostomy, with no improvement in his overall condition. His prognosis was considered dismal because correction of the cardiac anomaly is associated with a high mortality rate (> 90%). The cardiac surgeon agreed to attempt a cure of the TAPVR, provided liver transplantation is contemplated if the patient survived. Within 48 hours postoperatively, his hepatic function had improved drastically. He became afebrile, had an improved appetite and weight gain, and was finally discharged 203 days after admission. One year later, he is thriving and remains anicteric. The exact reason for this drastic improvement is not well understood, but the right-sided cardiac failure caused by the TAPVR had a significant effect on the functional outcome of the portoenterostomy.     

Surgical and nonsurgical management of primary and metastatic liver tumors

The medical records of 267 patients who had liver tumors, primary and metastatic, from 1988 to 1995 were retrospectively reviewed. Two hundred thirteen patients (80%) had metastatic disease, and 54 patients (20%) had primary liver disease. Their clinical manifestations and laboratory values were evaluated as factors predictive of diagnosis and survival. There was a significant increase in the occurrence of upper abdominal pain, weight loss, extrahepatic symptoms due to the metastatic origin, and hepatomegaly. Metastases from colorectal primary lesions were synchronous in 34 patients and metachronous in 31 patients. Stomach, lung, and pancreatic primaries were more commonly synchronous. Breast metastases were more commonly metachronous. Elevated serum glutamic-oxaloecetic transaminase and alkaline phosphatase and decreased albumin were the most common liver test abnormalities at diagnosis. Carcinoembryonic antigen values were elevated in the majority of colon cancer patients. Eighty-one percent of patients with primary liver cancer had elevated levels of alpha-fetoprotein, 40 per cent were seropositive for hepatitis B, and 23 per cent were seropositive for hepatitis C. Seventy-nine patients (30%) underwent surgery for their cancer, 37 (47%) had resections, 38 (48%) were unresectable, and 4 (5%) underwent liver transplantation. The patients who underwent surgery had a 32 per cent 5-year survival rate compared to a 0 per cent 5-year survival in the patients who did not have surgery (p = 0.0001). The patients who had resections had a better survival rate than those deemed unresectable at surgery (62% versus 0% at 5-years with p = 0.0008). The perioperative morbidity rate was 16 per cent, with lobectomies having the best rate and trisegmentectomies having the worst. Perioperative mortality rate was zero for all liver resections. Hepatic resection and, in selected patients, liver transplantation are the only two available therapeutic modalities that produce long-term survival with a possible cure in patients with primary and metastatic liver tumor.     

Early stopping of a clinical trial when there is evidence of no treatment benefit: protocol B-14 of the National Surgical Adjuvant Breast and Bowel Project

In patients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), risk score models that reflect disease severity have been developed and can serve as an objective measurement to assess and evaluate the effect of the severity of liver disease on the outcome of liver transplantation. Thus, using the established Mayo risk scores for PBC and PSC, one not only can estimate survival for the individual patient but can measure disease activity as well. Indeed, several studies have suggested that the optimal timing of liver transplantation with use of the Mayo PBC model may be an important tool to improve survival, decrease morbidity, and decrease overall related costs. Likewise, studies in patients with PSC have yielded similar results. This review explores how prognostic mathematical survival models for PBC and PSC might be applied to individual patients in need of liver transplantation. The following question is addressed: How can the timing of liver transplantation be optimized to increase survival, decrease postoperative morbidity, and ultimately, decrease the overall resource utilization involved in this procedure?     

Changes of hepatic volume after successful Kasai operation

The number of long term survivors who have undergone Kasai operation for biliary atresia is increasing, but some have a hepatic dysfunction likely to require liver transplantation in the near future. Hepatic volume possibly reflects whole liver function, and our objective was to assess the changes of hepatic volume after Kasai operation. Ten patients were studied. Ages ranged from 3 to 27 years. They underwent Kasai operation at ages ranging from 50 to 80 days. Liver areas (cm2) on CT images were measured with an image processing and analysis program (NIH Image 1.57). Hepatic volume (cm3) was calculated by summing up the areas of each image and multiplying by slice thickness (cm). After Kasai operation, the size of the liver increased to 1.7-1.9 times the standard volume, and then reduced to normal size around 5 years of age. In the teens, hepatic volume decreased below the standard volume. Segmental hypertrophy accompanying atrophy of other hepatic segments was observed in 9 out of 10 patients; right lobe hypertrophy: 6, medial segment: 2, and lateral segment: 1. Therefore, progressive hepatic atrophy begins in the teens, but is compensated for by segmental hypertrophy.     

Liver transplantation: experiences and results of a program at the University of Liege

The orthotopic liver transplantation (OLT) program of the University of Liège was initiated in 1986. Between 1986 and December 1998, 150 adult OLT have been performed in our institution, including 18 liver retransplantations, 1 combined heart and liver transplantation and 3 combined liver and kidney transplantations. The aim of this study was to report the last 3 years of our experience. From January 1996 to November 1998, we performed 50 OLT on 49 patients. Three were retransplantations and two were combined liver and kidney transplantations. Fourty-three patients were transplanted for chronic liver disease and 6 for acute or subacute hepatopathy. Mean waiting time on the list was 4 weeks. Immunosuppression was based on triple therapy (cyclosporin A/tacrolimus, steroids, azathioprine), with steroid and azathioprine withdrawal in most of the patients after 3 months. In the chronic liver disease group, operative (< 30 days) survival was 95% (peroperative myocardial infarction in 2 patients). In the acute liver disease group, postoperative survival was 66%. No perioperative death occurred in 1997 and 1998. Actuarial one year survival was 87%. In our experience, OLT has become a safe procedure.     

Alcohol use following liver transplantation for alcoholic cirrhosis

Due to the significant increase in the number of patients with alcoholic liver cirrhosis being referred for liver transplantation, studies to determine recidivism rates and influential factors affecting those rates have become increasingly crucial. Between 12/85 and 12/91, 67 patients diagnosed with alcohol related end-stage liver disease underwent orthotopic liver transplantation at Baylor University Medical Center. A 3-8 year follow-up study was conducted wherein surviving patients were contacted by phone to evaluate subsequent alcohol consumption following transplantation (with the exception of two patients whose primary physicians were contacted). Of the 67 patients transplanted, 18 had expired, 7 were alive but unavailable, and 1 had been lost to follow-up. Of the remaining 41 patients interviewed, 21 had remained abstinent, while the other 20 had returned to some form of drinking. Of patients with less than 6 months of pretransplant abstinence, only 30% remained abstinent, while the other 70% had resumed drinking. Regarding patients with at least 6 months of pretransplant abstinence, 58% had remained abstinent, while the other 42% had resumed drinking. In both groups, nearly 1/3 of those who had admitted to posttransplant drinking reported themselves as again abstinent and recommitted to sobriety when interviewed. In conclusion, 49% of patients interviewed had resumed some type of drinking following transplantation-- however, this appears not to have affected compliance or survival potential. Only 2 (4.8%) of the 41 patients interviewed had returned to excessive drinking. Thus, our findings support the use of orthotopic liver transplantation for patients with alcohol related end-stage liver disease.     

Structure of CheA, a signal-transducing histidine kinase

BACKGROUND/AIMS: After liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown. METHODS: In this retrospective study we reviewed the clinical course of 25 patients transplanted for autoimmune hepatitis and followed for a mean of 5.3 years (2-8.5 years). RESULTS: The actuarial 5-year patient and graft survival rates were 91% (+/-6%) and 83% (+/-8%). The actuarial 1-year rate of acute rejection was 50% (+/-10.2%), which was comparable to that of patients transplanted for primary biliary cirrhosis and primary sclerosing cholangitis. Autoantibodies persisted in 77% of patients, at a lower titer than before liver transplantation. Ten patients were excluded from the study of autoimmune hepatitis recurrence, one because of an early postoperative death and nine because of hepatitis C virus infection acquired before or after liver transplantation. In the remaining 15 patients, who were free of hepatitis C virus infection, 5-year patient and graft survivals were 100% and 87%, respectively. Despite triple immunosuppressive therapy, three patients (20%) developed chronic hepatitis with histological and serological features of autoimmune hepatitis in the absence of any other identifiable cause. The disease was severe in two patients, leading to graft failure and asymptomatic in another, despite marked histological abnormalities. In one of these three patients, autoimmune hepatitis recurred on the second liver graft as well. CONCLUSIONS: Patients undergoing liver transplantation for autoimmune hepatitis have an excellent survival rate although severe primary disease may recur, suggesting the need for stronger post-operative immunosuppressive therapy.     

Liver disease in ulcerative colitis: an epidemiological and follow up study in the county of Stockholm

In an epidemiological study of the incidence of ulcerative colitis (UC) in the county of Stockholm between 1955 and 1979, 1274 patients with UC were discovered. Almost all these patients had regularly been investigated with liver function tests; 142 (11%) of them showed signs of hepatobiliary disease. A follow up study on all 142 patients with abnormal liver function and UC was made between 1989 and 1991 to evaluate the cause of the liver abnormality and to find out if the liver disease had affected the survival rates. At follow up, eight patients were reclassified as having Crohn's disease, 60 had developed normal liver function as judged from test results, while the remaining 74 still had signs of hepatobiliary disease. The most common explanation for a transient abnormality in liver function was active colitis. The temporary signs of liver injury were not associated with changes in survival rates for these patients. Infections, especially those because of hepatitis B and C virus transmitted by blood transfusions accounted for the abnormalities in liver function in 21 patients, nine of which had a chronic, but non-fatal course. Twenty nine (2.3%) of the patients developed primary sclerosing cholangitis (PSC), and 12 of them died during the study period four because of cholangiocarcinoma and eight because of hepatic failure; one patient had a transplant. The estimated median time of survival from the first presentation of evidence of a liver function, compatible with the diagnosis of PSC, to death or liver transplantation was 21 years. A comparison of survival rates in patients with UC and patients with UC and concurrent PSC showed, a significant reduction in survival in the PSC group (p<0.0001). The number of patients with UC who developed PSC remained constant during the study period. Thus, although evidence of abnormal liver function is a common finding in UC, a spontaneous return to normal levels is common. In this study, which did not have a selection bias, the median time of survival among PSC patients was far longer than previously described although development of PSC among patients with UC does significantly reduce the estimated median time of survival.     

Hepatocellular carcinoma outcomes based on indicated treatment strategy

Hepatocellular carcinoma (HCC) in Western populations historically has been associated with poor survival. In this study, we conducted a 7-year retrospective analysis of patients evaluated at our institution with HCC to determine the effects of newer treatment strategies on outcome. During the period of study, 117 patients [86 (74%) male; mean age, 59 years (range, 16-85)] were evaluated with treatment as follows: surgical resection in 22 (19%), chemoembolization with or without systemic chemotherapy in 40 (35%), systemic treatment alone in 16 (13%), orthotopic liver transplantation in 8 (7%), and supportive care only in 31 (26%). Sixty-nine patients (59%) had documented cirrhosis, with hepatitis C being the most common cause in 27 of 69 (39%). In patients receiving no treatment, median survival was just under 3 months, with only two 1-year survivors. Patients with orthotopic liver transplantation had 1-, 2-, and 3-year survival rates of 87, 87, and 58 per cent compared with 69, 52, and 43 per cent in surgically resected patients. Survival after chemoembolization was 35, 20, and 11 per cent at 1, 2, and 3 years, whereas survival after systemic chemotherapy was 30 and 15 per cent at 1 and 2 years, respectively. One-year survival was improved in noncirrhotic patients compared with cirrhotics (47% vs 29%; P < 0.05) but was no different in patients younger than 55 years compared with older patients (38% vs 38%). When possible, surgical treatment strategies offer superior survival.     

Gastrointestinal immune responses in HIV infected subjects

Biliary atresia (BA) is characterized by luminal obstruction of the extrahepatic bile duct with fibrous remnants. The authors reviewed ultrasonographic examinations of the fibrous tissue in the bifurcation of the portal vein at the porta hepatis and identified the triangular- or tubular-shaped echogenic density, the so-called "triangular cord" (TC), in the vicinity of the portal vein on a transverse or longitudinal scan. In this prospective study, the authors investigated whether TC was useful in the noninvasive diagnosis of biliary atresia in 18 infants who had persistent neonatal jaundice. This was done by comparing the ultrasonographic examination with the histopathologic examination (HPE) of liver specimens obtained from a needle biopsy. The TC was identified in nine patients, all of whom were confirmed to have BA by HPE. The TC was not observed in the other nine patients, who had neonatal hepatitis (NH). The mean size of the TC was 13 mm (wide) x 6 mm (thick) (width range, 5 to 21 mm; thickness range, 4 to 12 mm). The diagnosis of BA was confirmed at the time of Kasai hepatoportojejunostomy in eight of the nine patients whose TC was noted by ultrasonography (US). The other patient was discharged because his parents refused the operation; he died of liver failure at 15 months of age. The nine patients with absent TC were treated medically for NH. Eight of them improved clinically. The other, diagnosed to have NH by needle and wedge liver biopsies, was reexamined 40 days after the initial examination because of worsening jaundice. A 18 x 12-mm TC was visualized ultrasonographically. Additionally, a percutaneous liver biopsy specimen showed BA with severe portal fibrosis and ductal proliferation. The patient underwent a Kasai hepatoportoenterostomy. On the basis of these results, the authors conclude that TC is a very specific ultrasonographic finding, representing the fibrous cone at the porta hepatis, and is a useful tool in the noninvasive diagnosis of BA. However, early exploration or close US follow-up is recommended for any patient suspected of having BA clinically, even if a liver biopsy confirms the NH.     

Efficacy of combination therapy (hepatectomy and prophylactic arterial chemoinfusion) for liver metastases of colorectal cancer

From 1979 to 1997, 146 patients had hepatectomy for metastases of colorectal cancer (curative B: 122; curative C: 24). We categorized the severity of liver metastases as follows, H1: one lobe; H2: bilateral but less than five, and H3: bilateral with five or more lesions. In H1 and H2 patients, we compared the survival rate after resection alone (including repeat hepatectomy) with that after combination therapy (resection and prophylactic arterial chemoinfusion of 12-24 g of 5-FU). In H1 patients, the 3-year survival rate of the resected group (n = 74) and combination group (n = 6) was 47.2 and 53.3, respectively. In H2 patients, the resected group (n = 16) and combination group (n = 7) had survival rates of 34.5 and 100%, respectively. In H1 cases, the 3-year recurrence rate in the remnant liver was 63.4 versus 16.7% and in H2 cases it was 58.0 versus 0%. H3 patients received one week of continuous prophylactic arterial chemoinfusion [total dose of 5-FU = 6 g]. All four patients in the H3 combination group are alive at 20, 13, 13, and 12 months after resection, while the median survival of the resection only group (n = 4) was 12.5 months. We suggest that our combination therapy may be applicable to all patients with liver metastases of colorectal cancer.     

The prevalence of hepatitis C virus (HCV) in infants and children after liver transplantation

Hepatitis C virus (HCV) is an important cause of liver injury following liver transplantation in adults. We hypothesized that the prevalence of HCV infection in children following liver transplantation would be lower than the prevalence in adults after liver transplantation because HCV-related liver disease leading to liver transplantation in children is low and children require less blood products than adults during transplantation. We therefore performed a cross-sectional study to determine the prevalence of HCV infection in children who had undergone liver transplantation. Serum samples were obtained from 62 of 65 (95.4%) consecutive patients surviving for more than six months after transplantation. Using a second-generation enzyme-linked, immunosorbent assay (ELISA-2) and a second-generation recombinant immunoblot assay (RIBA-II), antibodies to HCV were detected in 5.1% (3 of 59) of the subjects. Using a single-step, polymerase chain reaction (PCR), HCV RNA was detected in 6.2% (4 of 62). All HCV-positive children had undergone liver transplantation before the initiation of routine screening for HCV in blood donors; overall 30 patients were transplanted prior to routine screening of blood products for HCV. The prevalence of HCV in infants and children after liver transplantation in our study is substantially less than the rates reported in adults. This difference may be due, in part, to the lower volume of blood product exposure and to the fact that children, as opposed to adults, rarely have chronic HCV infection as a cause of end-stage liver disease.     

Clinical significance of plasma endothelin levels in patients with biliary atresia

Biliary atresia (BA) is the end-result of a destructive inflammatory process that affects intra- and extrahepatic bile ducts, leading to fibrosis and obliteration of the biliary tracts with the development of biliary cirrhosis and portal hypertension (PH). Endothelins (ET) are 21-amino-acid peptides of endothelial origin with potent vasoconstrictor activity that bind to various cells of the liver. Nothing is presently known about plasma ET levels in BA. The aim of this study was to determine the clinical significance of plasma ET levels in patients with BA after hepatic portoenterostomy (Kasai's procedure) and to correlate these with liver function tests (LFT) and PH. We measured plasma concentrations of ET in 19 patients with BA (5 boys and 14 girls; mean age 11.6 +/- 5.5 years) after portoenterostomy and 10 age-matched controls. Patients were grouped according to outcome based on LFT: group A consisted of 9 patients with an "unfavorable outcome" and Group B 10 patients with a "favorable outcome". The plasma ET levels were measured using a highly sensitive and specific enzyme immunometeric assay (EIA). No patient had ascites or hepatorenal syndrome. Plasma ET levels were significantly higher in patients with BA than in controls (3.42 +/- 0.42 vs 1.75 +/- 0.39 pg/ml, respectively; P < 0.01) and in patients in group A than in group B. (3.75 +/- 0.25 vs 3.06 +/- 0.23 pg/ml, respectively; P < 0.01). In group A, plasma ET levels were higher in patients with PH (n = 4) than in those without PH (n = 5) (3.99 +/- 0.06 vs 3.64 +/- 0.22 pg/ml, respectively; P < 0.05). We conclude that plasma ET levels are high in patients with BA, especially those with severe biliary cirrhosis, and that ET may partially contribute to development of PH in BA. The results of the present study also suggest that plasma ET concentrations may be a useful marker in the follow-up of patients with BA.     

Using ethnography to investigate life scientists'' information needs

Although several liver diseases of childhood, particularly biliary atresia (BA) and cystic fibrosis (CF) liver disease (CFLD) are characterized by hepatic fibrosis, the pathogenesis of this process is incompletely understood. The cytokine transforming growth factor-beta1 (TGF-beta1) has been implicated in hepatic fibrosis in experimental animals, in which both the hepatic expression and plasma concentration of this cytokine are increased. The objective of our study was to determine whether there are similar alterations of TGF-beta1 in patients with hepatic fibrosis secondary to either BA and/or CFLD. The study design was as follows. In study 1, plasma TGF-beta1 was assessed by ELISA in 9 children with BA undergoing liver transplantation, 11 patients with CFLD, and appropriate control subjects. In study 2, hepatic expression of TGF-beta1 protein (assessed immunohistochemically) and hepatic fibrosis were scored semiquantitatively, on a 1-3 scale, by blinded investigators, in archival liver biopsy specimens from 10 children with BA, 10 with CFLD, and from 10 older children with normal hepatic histology, as well as in 4 patients with liver diseases of various etiologies. Simultaneous plasma and liver TGF-beta1 studies were performed in 8 patients with liver disease. Results were as follows. Plasma TGF-beta1 values were inversely correlated with age in healthy subjects (r=-0.54, p < 0.0001). The plasma TGF-beta1 protein of children with BA was decreased (13+/-2 ng/mL) compared with values for healthy children (42+/-6 ng/mL, n=10, p < 0.005). Similarly, the plasma TGF-beta1 concentration in patients with CFLD was also decreased compared with values for children with CF and normal serum liver profiles (n=14) (2+/-1 ng/mL versus 12+/-1, p < 0.05). However, the plasma TGF-beta1 concentration was increased in two patients with other types of liver disease. The hepatic expression of TGF-beta1 was increased in the presence of hepatic fibrosis in all types of liver diseases studied. Forty-six percent of patients had both marked hepatic fibrosis and marked TGF-beta1 labeling; 86% of samples without fibrosis showed no TGF-beta1 labeling, p=0.007. In conclusion, these studies have established the association of hepatic TGF-beta1 protein and hepatic fibrosis in several common liver diseases of childhood. Our data also suggest that, in children, plasma TGF-beta1 does not appear to be a useful marker of hepatic expression of this cytokine.     

Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis

BACKGROUND & AIMS: Long-term ursodeoxycholic acid (UDCA) therapy slows the progression of primary biliary cirrhosis. This study examined the effect of UDCA therapy on survival free of liver transplantation in a large group of patients. METHODS: Data from three clinical trials were combined in which patients with primary biliary cirrhosis were randomly assigned to receive UDCA (n = 273) or placebo (n = 275). After 2 years, patients from French and Canadian studies received UDCA for up to 2 years. Patients from the American study remained on their assigned treatment for up to 4 years. RESULTS: Survival free of liver transplantation was significantly improved in the patients treated with UDCA compared with the patients originally assigned to placebo (P < 0.001; relative risk, 1.9; 95% confidence interval, 1.3-2.8). Subgroup analyses showed that survival free of liver transplantation was significantly improved in medium- and high-risk groups (serum bilirubin level, 1.4 to 3.5 or > 3.5 mg/dL; P < 0.0001 and P < 0.03, respectively) and histological stage IV subgroup (P < 0.01). CONCLUSIONS: Long-term UDCA therapy improves survival free of liver transplantation in patients with moderate or severe disease. An effect in patients with mild disease is probably not found because they do not progress to end-stage disease in 4 years.