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.     

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 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.     

Biliary atresia and biliary cysts

The authors present a review of the classification, aetiology, presentation, treatment and long-term outcome of children and adults with biliary atresia and choledochal cyst disease. Biliary atresia should be suspected in any infant with jaundice beyond the second week of life. Although the aetiology and pathogenesis remain unclear, early management with portoenterostomy has significantly improved the course of this disease. Recent advances in immunosuppression have made liver transplantation a valuable and necessary adjunct to biliary bypass. With choledochal cyst disease, adults, unlike children, often present with acute biliary tract symptoms or pancreatitis. The treatment of choice remains extrahepatic cyst excision and biliary bypass. This treatment has excellent long-term results that minimize the development of malignancy.     

Current concept of the treatment of biliary atresia

Hepatic portoenterostomy (Kasai operation) for the patient with biliary atresia (BA) can restore the bile flow in approximately 80% of children operated on before 60 days of life [1]. However, in terms of long-term survival, according to a recent nationwide survey among the major pediatric centers in Japan, only 325 of 2013 patients had more than 10 years' survival, and only 157 patients (7.8%) remained jaundice-free with normal liver function [2]. About 20% of BA cases without jaundice are generally able to survive for long periods; and most of those patients have portal hypertension or abnormal liver function [3-5]. As the results of liver transplantation have improved, controversy has arisen over the optimal care of these children [4, 6, 7]. Some investigators have claimed that transplantation is the favored primary therapy for most patients with BA [8]. We are thus at a turning point concerning the primary therapy of BA, which makes it necessary to determine the exact indications for the Kasai portoenterostomy and the timing of liver transplantation. This paper describes our strategy for the optimal treatment of BA patients based on our 117 patients who have had various form of portoenterostomy.     

Current status of 21 patients who have survived more than 20 years since undergoing surgery for biliary atresia

Between 1952 and 1993, 289 patients with biliary atresia underwent surgery at the authors' institution. Twenty-two of them survived more than 20 years; one has since died of hepatic failure (at age 28 years). Of the 21 current survivors (age range, 20 to 39 years), 13 underwent hepatic portoenterostomy; the others had hepaticoenterostomy. None of these patients has undergone liver transplantation. Sixteen patients have led near-normal lives. This includes three married women, one of whom has given birth to a healthy baby boy. Of the six patients who had portal hypertension, three underwent both splenectomy and proximal splenorenal shunting in or before 1985. None of these patients has required additional treatment for portal hypertension. The quality of life of one patient has been severely affected by an unrelated condition (Turner's syndrome). A 22-year-old man was diagnosed as having intrahepatic stones 3 years ago. In another 22-year-old man, hepatic dysfunction developed after frequent episodes of cholangitis. He is now being considered for liver transplantation. The majority of the long-term survivors have good quality of life. However, a few continue to suffer from complications including recurrent cholangitis. Close long-term postoperative follow-up is required for patients with biliary atresia.     

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.     

Anatomic anomalies in neonatal cholestatic jaundice

Disorders of the biliary tree are an important cause of cholestatic jaundice in infancy. For the most frequent diseases in this group, biliary atresia and choledochal cyst, prognosis is strongly dependent on timely diagnosis and treatment. In biliary atresia the bile flow is obstructed due to obliteration of the extrahepatic bile ducts. Construction of an hepatic portoenterostomy before 60 days of age will result in restoration of bile flow in the vast majority of patients. When failed, the disease is progressive and ultimately fatal, unless a liver transplantation is performed. For those patients in which restoration of the bile flow succeeds, the subsequent course is strongly dependent on the occurrence of cholangitis. For all patients fat-soluble vitamins should be supplemented and caloric intake should be carefully monitored. Presentation of a choledochal cyst can be either before or after the first year of life. It is mostly characterized by jaundice, with or without abdominal pain. Therapy consists of resection of the cyst, followed by a hepatico-jejunostomy. Paucity of bile ducts is an intrahepatic disorder, in which--almost--no bile ducts can be found in the portal tracts. This anomaly is frequently found in combination with a typical facies, a pulmonary stenosis and vertebral anomalies, a combination which is called Alagille syndrome. Prognosis is generally good.     

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.     

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)     

Dissociation between anxiolytic and hypomnestic effects for combined extracts of zingiber officinale and ginkgo biloba, as opposed to diazepam

Extrahepatic biliary atresia is a severe neonatal liver disease resulting from a sclerosing cholangiopathy of unknown etiology. Although biliary obstruction may be surgically corrected by a "Kasai" hepatoportoenterostomy, most patients still develop progressive hepatic fibrosis, although the source of increased collagen deposition is unclear. This study examined the role of hepatic stellate cells (HSCs) and assessed the source of transforming growth factor-beta (TGF-beta) production in hepatic fibrogenesis in patients with biliary atresia. Liver biopsies from 18 biliary atresia patients (including 5 pre- and post-Kasai) were subjected to immunohistochemistry for alpha-smooth muscle actin and in situ hybridization for either procollagen alpha1 (I) mRNA or TGF-beta1 mRNA. Sections were also subjected to immunohistochemistry for active TGF-beta1 protein. The role of Kupffer cells in TGF-beta1 production was assessed by immunohistochemistry for CD68. Procollagen alpha1 (I) mRNA was colocalized to alpha-smooth muscle actin-positive HSCs within the region of increased collagen protein deposition in fibrotic septa and surrounding hyperplastic bile ducts. The number of activated HSCs was decreased in only one post-Kasai biopsy. TGF-beta1 mRNA expression was demonstrated in bile duct epithelial cells and activated HSCs and in hepatocytes in close proximity to fibrotic septa. Active TGF-beta1 protein was demonstrated in bile duct epithelial cells and activated HSCs. This study provides evidence that activated HSCs are responsible for increased collagen production in patients with biliary atresia and therefore play a definitive role in the fibrogenic process. We have also shown that bile duct epithelial cells, HSCs, and hepatocytes are all involved in the production of the profibrogenic cytokine, TGF-beta1.     

Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy

BACKGROUND: In transplantation, novel methods are required to augment the supply of donor organs. We report the first domino liver transplant in which a patient with familial amyloid polyneuropathy (FAP) received an orthotopic split liver graft, and her explanted liver was donated to another patient. Three successful liver transplants were thus achieved from the one cadaver liver. PATIENTS AND METHODS: A cadaveric donor liver was split and the left lobe was grafted into a child with biliary atresia. The right lobe was transplanted into a woman with FAP associated with the transthyretin Met30 variant. Her own otherwise healthy liver was donated to a patient with cirrhosis and hepatocellular carcinoma. RESULTS: Fifteen months after transplantation, all three recipients are well with normal liver function. The domino recipient developed inferior vena cava stricturing at the level of anastomosis after surgery with resultant ascites, requiring dilatation and LeVeen shunt insertion. Serum amyloid P component scintigraphy showed amyloid regression in the domino donor and to date has not identified any amyloid deposits in the recipient, who also remains free of tumor recurrence. CONCLUSIONS: Domino transplantation using the livers from patients with FAP may be justified for patients whose disease condition precludes a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation rather than long-term cure is the aim.     

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.     

Use of external conduit impairs liver function in patients with biliary atresia

An external conduit (stoma) for patients with biliary atresia has been used to prevent postoperative cholangitis. Thirty-two patients with biliary atresia who had hepatic portoenterostomies with external conduits were studied retrospectively with respect to frequency and severity of postoperative cholangitis or stoma bleeding. Changes in their liver enzyme levels, and total bilirubin (TB) levels were measured before and after closure of the stoma. Cholangitis was observed in 20 patients (62.5%), and major hemorrhage from the stoma site was seen in 14 patients (43.8%) prior to closure. Levels of liver enzymes such as glutamic oxaloacetic transaminase (SGOT), glutamic pyruvic transaminase (SGPT), gamma-glutamyl transpeptidase (gamma-GTP), and alkaline phosphatase (ALP) improved significantly within 1 month after closure of the stoma, and remained low thereafter. The TB concentration was the only liver function that did not change significantly following closure. In summary, the authors do not recommend an external conduit in patients with biliary atresia because it is not an effective way of reducing the incidence of postoperative cholangitis, and it may be deleterious to liver function.     

The new age of liver transplantation

The advent of cyclosporin A for immunosuppression (IS) in liver transplantation (LTx) in the early 1980s heralded a new age for LTx, resulting in widespread application, rapidly expanding indications, relaxation of restrictions in donor selection and advances in the preservation of liver grafts and management of LTx operations. Liver transplantation, together with the transplantation of other organs (kidney, pancreas, heart, heart-lung, intestine), became possible. In Australia, around 125 LTx (22% in children) are performed each year. Indications are: primary sclerosing cholangitis; primary biliary cirrhosis; auto-immune hepatitis; chronic viral hepatitis; biliary atresia; metabolic disorders; fulminant hepatic failure (FHF); alcoholic cirrhosis; and malignancy (cancer, CA). Since 1965, 810 patients underwent LTx and 70 (9%) re-Tx. Patient survivals at 1, 5 and 9 years post-Tx are 80, 74 and 66%, respectively. Patients with primary diseases that recur in the LTx (hepatitis B and CA) do less well following LTx, with 5-year survival rates of 55 and 40%, respectively). Recent developments include: increasing the availability of donor organs by the use of living donors, 'split' cadaveric donor (CD) grafts, 'marginal' and non-heart-beating CD grafts and xenografts; expanding the indications for LTx; development of effective liver support systems for patients with FHF; the treatment of diabetics with liver failure with islet Tx (at the time of LTx); more effective immunosuppression; and methods to diminish recurrent disease in LTx. Some understanding of the unique 'tolerogenic' capabilities of the liver has come with the recognition of 'two-way microchimerism'. The satisfactory 5-9 year outcomes for patients underline the cost-effectiveness of LTx.     

Do cold agglutinins have any impact on the outcome of liver transplantation?

Cold agglutinins, IgM red blood cell autoantibodies, cause cold agglutinin disease with hemolysis and microvascular occlusion. Cold preservation of kidneys during renal transplantation in the presence of cold agglutinins can cause graft malfunction. However, the impact of cold agglutinins on the outcome of liver transplantation is unknown. We measured the pretransplant presence and titer of cold agglutinins in 327 primary liver allograft recipients and analyzed their relationship to outcome after transplant. Thirty-three percent of pretransplant patients had cold agglutinins. Cold agglutinins were more common in patients with viral-related liver diseases (49%) compared with those with nonviral-related liver disease (32%). There was no difference between recipients with and without cold agglutinins in usage of blood products, postoperative day 2 aminotransferase levels, acute rejection at day 7, the development of hepatic artery thrombosis, nonanastomotic biliary strictures, or 4-month allograft survival. In conclusion, cold agglutinins are common in liver transplant patients before surgery, especially those with viral-related liver diseases. However, the presence of cold agglutinins does not impact on outcome after liver transplantation.     

Sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a chronic, progressive cholestatic liver disease whose aetiopathogenesis is unknown. PSC is frequently associated with inflammatory bowel disease, in particular chronic ulcerative colitis, is most commonly observed in young males and is clinically characterized by fatigue, pruritus and jaundice. The diagnosis is supported by a cholestatic biochemical profile and histological abnormalities, and confirmed by visualization of an abnormal biliary tree. The natural history of the disease is currently being evaluated but is generally recognized to be slowly progressive, leading to complications of chronic cholestasis, portal hypertension and biliary cirrhosis. There is no specific medical treatment, and orthotopic liver transplantation remains the only definitive treatment for patients with end-stage PSC. A more rational approach to medical therapy will ensue upon a better understanding of the aetiopathogenesis of this disease.     

Hibernating myocardium: a hypometabolic state for energy conservation

Because of the anatomical features associated with situs inversus, technical difficulties will be encountered during orthotopic liver transplantation. This report describes the case of a patient with situs inversus totalis and end-stage liver disease from biliary atresia who was treated by segmental orthotopic liver transplantation. The segmental graft was safely placed in the left subphrenic space, and a suitable orientation was obtained for anastomoses of the hilar vessels. Chronic rejection necessitated retransplantation, by the same method, 19 months later. This technique has potential advantages in coping with anatomical obstacles encountered in patients with situs inversus.     

Usefulness of liver biopsy in the study of the pediatric patient. Review of 145 cases

There were reviewed 145 cases of children in which hepatic biopsy was done at the Hospital Infantil del Estado de Sonora, from 1978 to 1990. The larger age group were infants and preschool children (74.3 percent) males being predominant; signs and symptoms were related with hepatic illness, as well as the admission diagnoses. The indication of biopsy was for confirmation of liver disease in more than 50 percent, 37.1 percent for unknown diagnoses and 20.6 percent to look for liver disease by a systemic illness. The most usual procedure was percutaneous biopsy with Vim-Silverman needle in 111 cases (76.5 percent), in 23 percent, the biopsy was done by major surgical method. Nine percent of the children needed open surgical method after percutaneous biopsy. The time from the admission to biopsy performance in patients with neonatal hepatitis vs biliary atresia was 14 days. In other type of illness the time was 25 days. The morbidity was 1 percent. There was no mortality. The histopathologic diagnosis of liver diseases was done in 96 cases (66.7 percent) by this method in 31 children (21.3 percent) with investigation of jaundice (neonatal hepatitis vs biliary atresia). The diagnostic mistake in tissues obtained by percutaneous needle, was statistically significant (p < 0.05). Average hospitalization stay was less than two months in 70 percent of the cases.     

Physiologic studies of spinal inhibitory circuits in patients with stiff-person syndrome

Human protoporphyria results from mutations in the ferrochelatase gene. Heritable deficiency of ferrochelatase causes overproduction of protoporphyrin IX, principally in the erythron. Photosensitivity is a universal feature of protoporphyria but hepatic clearance of the hydrophobic protoporphyrin molecule with excretion in bile may lead to precipitation within biliary pathways. Thus cholestatic injury and protoporphyrin gallstones occur. Minor hepatic abnormalities are frequent, but at least 30 patients have been reported with a progressive liver disease that requires transplantation. Fulminant hepatic disease appears to be recessively inherited in some pedigrees. Hazards of liver transplantation include tissue photolysis, hemolysis, and an unexplained neurological syndrome, but most of the 15 patients reported after transplantation have survived for several months to > 6 years. Aspects of protoporphyria, its pathogenesis and contemporary therapeutic strategies are considered, with emphasis on hepatic sequelae.