Paucity Of Bile Ducts Research Articles

Abnormal hepatic expression of fibrillin-1 in children with cholestasis.

Fibrillin-1, one of the main constituents of microfibrils, is present in normal adult liver and overexpressed in fibrotic area around cirrhotic nodules and hepatocellular carcinoma. In this work fibrillin-1 expression was studied by immunohistochemistry in liver samples from children with various cholestatic diseases corresponding to paucity of intrahepatic bile ducts, biliary atresia, congenital hepatic fibrosis, Byler's disease, mitochondrial cytopathy, sclerosing cholangitis, or choledochal cyst. As controls, histologically normal liver samples were used. In control liver, as in adult, fibrillin-1 was expressed in vessel walls, sinusoids, and portal connective tissue, particularly at the interface with the limiting hepatocytic plate and close to the basement membrane of bile ducts. In paucity of intrahepatic bile ducts without fibrosis, the fibrillin-1 distribution was similar to controls. In cholestatic diseases associated with severe fibrosis, such as biliary atresia, congenital hepatic fibrosis, Byler's disease, mitochondrial cytopathy, or sclerosing cholangitis, an enhanced deposition of fibrillin-1 was observed in portal connective tissue and fibrous septa. The strong fibrillin-1 expression close to the basement membrane of biliary structures was lost in cholestatic diseases, except biliary atresia. Finally, in normal and pathologic tissues, fibrillin-1 was co-localized with its putative receptor alphaVbeta3 in sinusoids but not around biliary structures.

Pathology of lethal fetal growth retardation syndrome with aminoaciduria, iron overload, and lactic acidosis (GRACILE).

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q33-37. The basic defect of the disease remains unknown.

Atypical Morphologic Presentation of Biliary Atresia and Value of Serial Liver Biopsies

ABSTRACTBackgroundLiver biopsy findings are important in diagnosing extrahepatic biliary atresia. Diffuse ductular proliferation is a characteristic finding. We describe four patients with conjugated hyperbilirubinemia in whom the initial liver biopsy findings showed a lack of ductular proliferation, despite subsequent development of biliary atresia.ResultsOn initial biopsy, paucity of intrahepatic bile ducts was present in three of four patients, with a bile duct to portal space ratio of 0.3 to 0.4 (normal, 0.9–1.8). A normal bile duct to portal space ratio of 1.0 was observed in the fourth patient. Ductular proliferation became apparent in three subjects between 9 and 12 weeks of age, and biliary atresia was noted at the time of a Kasai portoenterostomy. The fourth child had well‐developed biliary cirrhosis at liver transplantation.ConclusionsChanges characteristic of biliary atresia may appear even after 9 weeks of age. Bile duct paucity and normal bile duct to portal space ratio do not preclude the subsequent development of biliary atresia. Infants with unexplained conjugated hyperbilirubinemia and acholic stools should undergo sequential liver biopsies until clinical improvement occurs or until biliary atresia can be excluded from the differential diagnosis.

PATHOLOGY OF LETHAL FETAL GROWTH RETARDATION SYNDROME WITH AMINOACIDURIA, IRON OVERLOAD, AND LACTIC ACIDOSIS (GRACILE)

Autopsy study of 17 newborn infants with lethal autosomal recessive disease presenting as growth retardation with lactic acidosis, Fanconi aminoaciduria, and hepatic hemosiderosis is reported. The patients succumbed between day 1 and 4 months of life; 9 patients died within the first month. All patients showed severe pathologic changes of liver with cholestasis in all livers. Extensive accumulation of stainable iron of the hepatocytes was present in 9/17 autopsy tissues and in two biopsy specimens. Moderate to abundant iron storage in the Kupffer cells was seen in all liver specimens. The amount of hepatocytic iron was high in livers up to 1 month of age and decreased thereafter. The general features and liver findings of this disorder suggest the name Growth Retardation Aminoaciduria Cholestasis Iron Overload, Lactacidosis and Early Death (GRACILE, OMIM 603358). Calcified concrements were seen in the medulla of 13/16 kidney specimens. Pancreas of 13/14 patients showed interstitial fibrosis and exocrine atrophy. Various pathologic findings such as renal tubular dysgenesis, paucity of hepatic bile ducts and iron storage in the macrophages of spleen and pulmonary alveoli were observed in some cases. Previous extensive clinical genetic and laboratory investigations have revealed that the patients had a previously unrecognized genetic disease. It is inherited as an autosomal recessive trait. The gene locus is 2q 33-37. The basic defect of the disease remains unknown.

Hemodynamic response to continuous infusion of dobutamine in Alagille's syndrome.

Alagille's syndrome is a rare condition that is characterized by paucity of interlobular bile ducts and peripheral pulmonary artery stenosis. Liver transplantation in the setting of peripheral pulmonary stenosis and right ventricular hypertension seems to be associated with a higher mortality, which raises the concern that these patients are unable to increase their cardiac output in the immediate posttransplantation period to meet the demands of reperfusion and early graft dysfunction and cope with further increases in pulmonary vascular resistance. Cardiac catheterization was performed in 15 children with Alagille's syndrome and peripheral pulmonary artery stenosis to measure the cardiac output response to dobutamine infusion. The cardiac output was measured before and during each increment of infusion of dobutamine at 10 microg/kg/min and 20 microg/kg/min by using a thermodilution catheter placed in the pulmonary artery. There was a significant change in the baseline cardiac index (P<0.001) with an infusion of 20 microg/kg/min of dobutamine with an increase from 4.4(1.0) L/min/m2 to 6.4(1.5) L/min/m2. There was, however, a wide variation between individuals in the increase in cardiac index, ranging from 7.3-95%. There was no correlation between the baseline systolic right ventricular/aortic pressure ratios and the increase in cardiac index (r=0.1086). The increase in cardiac index, in response to dobutamine in patients with Alagille's syndrome, is independent of the more conventional measurement of the right ventricular pressure. This method of producing a hemodynamic response is closer to the response that results after liver transplantation, and thus, it may be a better way of predicting the outcome of liver transplantation in these patients.

Nutritional Management of Neonatal and Infant Liver Disease

After completing this article, readers should be able to: 1. Describe the caloric requirements of a neonate who has chronic liver disease. 2. Identify the vitamin and mineral deficiencies associated with cholestasis and the methods used to correct these deficits. 3. Describe the relationship between total parenteral nutrition and the development of chronic liver disease. 4. Delineate the relationship between malnutrition at the time of liver transplantation and subsequent morbidity and mortality. 5. List the best measurements of nutrition assessment in infants who have chronic liver disease. The liver is involved in many of the body’s metabolic processes, including: regulation of protein, fat, and carbohydrate metabolism; vitamin storage and activation; and detoxification and excretion of waste products. The healthy liver synthesizes and excretes bile salts. With cholestatic liver diseases, poor bile flow results in fat malabsorption because micelles, which solubilize long-chain fatty acids, cannot form without bile salts. Fat malabsorption results in enteric losses of the fat-soluble vitamins A, D, E, and K. Impaired liver function can lead to nutrient deficiencies and eventually protein-energy malnutrition. All of these factors, combined with the common symptoms of anorexia and poor dietary intake, make malnutrition common in chronic liver disease, particularly if it occurs in infants, who are more vulnerable to the debilitating effects of malnutrition because of their higher energy and growth requirements. A wide range of deficits occurs in most chronic liver diseases of children (Table 1⇓ ). Malnutrition itself may induce further derangements of liver function because the liver requires energy for a number of synthetic, storage, and detoxification functions. View this table: Table 1. Nutritional Risk Factors in Acute and Chronic Liver Disease The need for aggressive, early nutrition support in neonates has been well established and discussed extensively. Some centers routinely use a “standardized” approach to nutrition support; we use a “tailored” approach that entails parenteral or …

Evaluation of the triangular cord sign in the diagnosis of biliary atresia.

Infantile cholestasis continues to represent a diagnostic challenge. It is very important to diagnose surgically correctable disorders, such as biliary atresia, in a timely manner to prevent progressive damage to the liver. It has been recently suggested that the triangular cord (TC) sign is a simple and useful tool in the diagnosis of biliary atresia. We prospectively studied 65 infants presenting with conjugated hyperbilirubinemia (age range: 32-161 days). All patients underwent ultrasonographic examination with a 7.0-MHz transducer (Acuson, Mountain View, CA). The TC was defined as a triangular, or tubular, echogenic density seen immediately cranial to the portal vein bifurcation. The TC sign was identified in 25 infants, and all of them had histologic features suggestive of biliary atresia; the diagnosis was confirmed at surgery by gross morphology of hepatobiliary system, and liver biopsy, with or without intraoperative cholangiogram. Among the 40 patients who did not have the TC sign, 6 had paucity of the intrahepatic bile ducts. Three had alph-1-antitrypsin deficiency, and 31 had neonatal hepatitis. None of the 40 patients who did not have the TC sign developed acholic stools. Seven patients with biliary atresia were followed by ultrasonographic examination for 6 months after the Kasai procedure. The TC sign disappeared in all patients after the surgery; however, the TC sign reappeared in 3 patients who developed progressive cholestasis after the procedure. The TC sign is a simple, timesaving, and reliable diagnostic tool in the evaluation of infants with infantile cholestasis. The TC sign may also prove to be helpful in following patients after hepatoportoenterostomy. We suggest a new diagnostic strategy for patients suspected to have biliary atresia. When the TC sign is visualized, the patient should undergo intraoperative cholangiogram to confirm the diagnosis of biliary atresia, reserving percutaneous liver biopsy for those patients in whom the TC sign could not be detected.

The DSL domain in mutant JAG1 ligand is essential for the severity of the liver defect in Alagille syndrome.

Alagille syndrome (AGS) is a congenital multi-system anomaly mainly characterized by paucity of intrahepatic bile ducts caused by haploinsufficiency of the Jagged 1 gene (JAG1). To explore the relationship between genotype and phenotype, we analyzed the JAG1 gene in 25 Japanese AGS families at the genomic DNA level and identified 15 point mutations and one large deletion. Analysis of the genotype and phenotype strongly indicated that the Delta/Serrate/Lag-2 (DSL) domain in JAG1 protein played an essential role in determining the severity of the liver disorder. In four sporadic cases, missing an entire DSL domain in mutant JAG1 resulted in progressive liver failure and all 4 patients needed a liver transplant at a very young age. This correlation was further confirmed by statistical analysis (chi2=9.143, p<0.001). Our finding demonstrated that the DSL domain in JAG1 appears to be essential for normal liver development and function.

Successful heterotopic segmental liver transplantation from a live donor to a patient with Alagille syndrome

Alagille syndrome is characterized by a paucity of bile ducts in the liver. The syndrome is associated with some or all the features of chronic cholestasis, cardiac disease, skeletal abnormalities, ocular defects and a distinctive facial appearance. The most common finding is chronic cholestasis, which causes intractable pruritus, xanthoma, deficiency of certain metabolic nutrients and growth retardation. Cardiac abnormalities are the most common cause of death in these patients. It is unusual to see the clinical picture of hepatic failure resulting in cirrhosis and requiring transplantation, but liver transplantation is indicated in Alagille syndrome patients who have chronic cholestasis. If the disease is diagnosed in childhood, transplantation can improve significantly the patient's prognosis and the quality of life. In recent years, auxiliary liver transplantation has gained popularity for treating both acute and chronic liver disease. Heterotopic segmental liver transplantation is an alternative treatment modality for patients who do not require native liver removal. Individuals with Alagille syndrome are good candidates for this type of treatment. J Pediatr Surg 36:667-671. Copyright © 2001 by W.B. Saunders Company.

Alagille Syndrome and the Jagged1 Gene

Since the first descriptions of Alagille syndrome (syndromic bile duct paucity) 30 years ago, our appreciation of the clinical variability and complexity of this disorder has grown. In addition to the liver, Alagille syndrome is associated with abnormalities that involve the heart, eye, skeleton, kidneys, and the increasing importance of abnormalities of the central nervous system is being recognized. The developmental nature of the disorder has been proven with the identification of the disease-causing gene, Jagged1. Jagged1 is a cell surface protein that functions in an embryologically important signaling pathway, known as the Notch signaling pathway. Identification of the role of Jagged1 (JAG1) in the etiology of Alagille syndrome has improved diagnosis for this variably expressed disorder. In this review, we summarize information on the range of clinical abnormalities of the liver and other affected organs in affected individuals. Genetic studies have demonstrated the range of defects in JAG1 that cause Alagille syndrome. Mutations in JAG1 can be identified in 70% of Alagille syndrome patients, and they are inherited in 30-50%. These mutations include total gene deletions as well as mutations (frameshift, missense, and nonsense) in almost all regions of the 26 exons of the Jagged1 gene. This review focuses on clinical and genetic features of Alagille syndrome.

A Case of Nonsyndromic Intrahepatic Bile Duct Paucity with Congenital Bilateral Vocal Cord Paralysis and 13q Deletion

A Case of Nonsyndromic Intrahepatic Bile Duct Paucity with Congenital Bilateral Vocal Cord Paralysis and 13q Deletion

ALAGILLE SYNDROME: The Widening Spectrum of Arteriohepatic Dysplasia

Alagille syndrome was described more than 35 years ago as a genetic entity characterized by five major features: chronic cholestasis resulting from paucity of interlobular bile ducts, peripheral pulmonary stenosis, butterflylike vertebral arch defect, posterior embryotoxon, and peculiar facies. Recently, JAGGED1 has been identified as a responsible gene by demonstration of mutations in AGS patients. Studies of the JAGGED1 expression pattern demonstrate that minor features and almost all the elements in the long list of manifestations described in AGS patients are not coincidental. This finding suggests that the definition of AGS may be reconsidered in the light of JAGGED1 mutations.

JAGGED1 Gene Expression During Human Embryogenesis Elucidates the Wide Phenotypic Spectrum of Alagille Syndrome

Mutations of the JAGGED1 gene, encoding a NOTCH receptor ligand, cause Alagille syndrome (AGS), a complex malformative disorder affecting mainly the liver, heart, vertebrae, eye, and face. Minor and occasional features involving kidney, pharynx, systemic arteries, skeleton, and ear are in some cases associated with the syndrome. To describe the expression of JAGGED1 during human embryogenesis and to study its relationship with all the features of AGS, we performed in situ hybridization studies on human embryos and fetal tissue sections. JAGGED1 was mainly expressed in the cardiovascular system. In the liver,JAGGED1 transcripts were only detected in blood vessels.JAGGED1 was also expressed in other structures of mesenchymal origin (distal mesenchyme of limb buds; mesonephric and metanephric tubules of the kidney) and in epithelial structures including the ciliary margin of the retina and the posterior part of the lens, the ventral epithelium of the otic vesicle, the neurosensory epithelium of the ear vestibule, the epithelium of pharyngeal arches, and the developing central nervous system. The strongJAGGED1 expression during human embryo- and feto-genesis both in the vascular system and in other mesenchymal and epithelial tissues implicates abnormal angiogenesis in the pathogenesis of Alagille syndrome and particularly the paucity of interlobular bile ducts. However, it is probably not the only mechanism of the disease. Except for the central nervous system, there is a strong correlation between JAGGED1 expression and all the features of AGS. This implies that the features occasionally associated with the syndrome are not coincidental.(Hepatology 2000;32:574-581.)

Echocardiographic Features of Genetic Diseases: Part 7. Complex Genetic Disorders

Alagille syndrome, or arteriohepatic dysplasia, is a well-defined genetic disorder affecting the liver, heart, face, eyes, and vertebrae.An autosomal dominant mode of transmission with reduced penetrance has been suggested.1,2 The Alagille syndrome gene has been localized to chromosome 20p12.2 This syndrome includes a paucity of interlobular bile ducts with associated cholestasis.3 Peripheral pulmonary artery stenosis or other complex cardiovascular malformations are estimated to occur in 85% of patients.3

The role of endoscopic retrograde cholangiopancreatography in infants with cholestasis

Background/Purpose: Endoscopic retrograde cholangiopancreatography (ERCP) was assessed in the diagnosis of cholestatic liver disease in infants. Methods: ERCP was performed in 50 infants who had prolonged cholestasis. Their ages ranged from 25 to 274 days (mean, 69 days), and their weight ranged from 2.6 to 6.7 kg (mean, 4.7 kg). Incomplete visualization of the biliary tree or visualization of only the pancreatic duct was followed by exploratory laparotomy. In those in whom the biliary tree was visualized completely, the caliber of the bile duct was compared with that of the pancreatic duct. Results: ERCP was completed in 43 patients (success rate, 86%) without complications. In the 7 patients in whom ERCP failed, 6 had biliary atresia (BA) diagnosed by exploratory laparotomy. The other patient had congenital biliary dilatation (CBD). In 29 of the 43 patients, the biliary tree was seen partially or only the pancreatic duct was visualized. These patients had BA diagnosed by laparotomy. Complete visualization of the biliary tree was obtained in 14 patients. Of these, 9 had neonatal hepatitis (NH), 2 had a paucity of intrahepatic bile ducts (PIBLD), and 3 had CBD. In all of the patients with NH, cholestasis improved spontaneously. The 2 patients with PIBLD had biopsy-proven disease. The caliber of the bile duct was larger than that of the pancreatic duct in NH. This relationship was not observed in PIBLD. Conclusions: ERCP is safe in infants. It is useful in the diagnosis of prolonged cholestasis. J Pediatr Surg 35:545-549. Copyright © 2000 by W.B. Saunders Company.

Severe hepatic involvement in visceral larva migrans

Because of its anatomical position, the liver may be involved in many protozoan and helminthic gastrointestinal infections. Visceral larva migrans caused by Toxocara canis is rarely taken into account in adult patients with cholestatic syndrome, especially when liver disease is not associated with hypereosinophilic reaction. We report on a 74-year-old immunocompetent woman who presented with fever, bronchospasm, erythema nodosum, weight loss and progressive jaundice. A liver biopsy showed caseating granulomatous hepatitis with secondary portal fibrosis and paucity of interlobular bile ducts. A step-by-step search for aetiological factors led us to a diagnosis of toxocariasis (positive enzyme-linked immunosorbent assay IgG test). An excellent clinical response to combined treatment with steroid and diethylcarbamazine, and a reduction in the antibody level against T. canis supported the diagnosis. Computed tomography and laparoscopy demonstrated multiple small mass lesions and fibrous perihepatitis. This report shows that visceral larva migrans may be a cause of prostrating chronic liver disease and should be suspected in every febrile patient with cryptogenic cholestatic hepatitis.

Clinical and molecular genetics of Alagille syndrome.

Alagille syndrome (AGS) is a dominantly inherited disorder characterized by bile duct paucity and resultant liver disease in combination with cardiac, skeletal, ocular, and facial abnormalities. Jagged1 (JAG1) has been identified as the AGS disease gene. It encodes a ligand in the Notch signaling pathway that is involved in cell fate determination. AGS is the first developmental disorder to be associated with this pathway. It shows highly variable expressivity, and diagnosis in mildly affected persons can be difficult without molecular analysis. Currently, JAG1 mutations are detected in about 70% of patients with AGS and include total gene deletions as well as protein truncating, splicing, and missense mutations. Mutations are located across the gene within the evolutionarily conserved motifs of the protein. There is no phenotypic difference between patients with deletion of the entire JAG1 gene and those with intragenic mutations. This suggests that haploinsufficiency for JAG1 is a mechanism causing AGS.

The use of hepatocyte extraction fraction to evaluate neonatal cholestasis.

Hepatobiliary scintigraphy is used routinely to evaluate infants with neonatal cholestasis. Hepatobiliary scintigraphy determines biliary patency by detecting radioactivity in the bowel on imaging, in duodenal and gastric aspirates, or all of these. During hepatobiliary scintigraphy, the hepatocyte extraction fraction (HEF) is calculated by deconvolution analysis. Normal values of HEF are more than 90%. It is believed that HEF may predict hepatic dysfunction, because, during hepatobiliary scintigraphy, the radiopharmaceutical used in this test is extracted by the hepatocytes from the blood stream. Therefore, a low value of HEF is seen with more severe hepatocellular disease. The goal of this study was to determine whether HEF has any correlation with synthetic liver function, whether HEF can differentiate obstructive from nonobstructive lesions that cause neonatal cholestasis, and whether HEF can predict the outcome of the different causes of neonatal cholestasis. A retrospective analysis of 68 hepatobiliary scintigraphy results was done in patients with neonatal cholestasis for a period covering 6 years. The HEF was available in 67 of these 68 patients, with a median value of 25% (range, 3.3% to 100%). The results of synthetic liver function tests (i.e., albumin and prothrombin time) were normal in all infants with neonatal cholestasis. No significant correlation was detected between HEF and the serum levels of total and direct bilirubin, albumin, alkaline phosphatase, and prothrombin time by exploratory data analysis (R = 0.08; small, P > 0.2). The HEF values in different causes of neonatal cholestasis were compared: extrahepatic biliary atresia, neonatal hepatitis, and a miscellaneous category consisting of alpha1-antitrypsin deficiency, ischemic hepatitis, paucity of bile ducts, and others. The outcomes of these diseases were assessed as resolution, continuing disease, transplantation, or death, but no predictive correlation was found with HEF. A single determination of HEF is of no value in assessing synthetic liver function (as assessed by albumin and prothrombin time), specific diagnoses, and outcomes in patients with neonatal cholestasis. Therefore, a low isolated value of HEF should not be considered suggestive of poor prognosis and outcome in these patients.

Expression of collagens type I and IV, osteonectin and transforming growth factor beta-1 (TGFβ1) in biliary atresia and paucity of intrahepatic bile ducts during infancy

Background/Aims: Biliary atresia and paucity of intrahepatic bile ducts are the main causes of neonatal cholestasis leading to hepatic fibrosis. Fibrotic evolution is slow in paucity of bile ducts as compared to the rapid progression to biliary cirrhosis in biliary atresia when cholestasis persists despite hepatoportoenterostomy. Our aim was to compare the expression of collagens type I and IV,α-smooth muscle actin, osteonectin and transforming growth factor β1 in biliary atresia and paucity of bile ducts. Methods: Liver biopsies were obtained in 12 children with biliary atresia and in five with paucity of bile ducts. Collagens type I and IV, α-smooth muscle actin were detected with immunostaining. Collagens type I and IV, osteonectin and transforming growth factor β1 mRNAs were detected by in situ hybridization. Results: Expression of mRNA and proteins was roughly parallel. In ductular proliferation areas of biliary atresia: (1) the expression of collagens type I and IV and osteonectin was increased, and was localized to periductular myofibroblasts; (2) transforming growth factor β1 was expressed around biliary ductules, probably in inflammatory cells, and also in biliary cells. Osteonectin expression was also increased in the lobules. In paucity of bile ducts, there was no overexpression of collagens type I and IV and transforming growth factor β1, except in the only child with marked fibrosis. However, osteonectin expression was enhanced at the periphery of the lobules, even when fibrosis was mild or absent. Conclusions: These findings suggest that in biliary atresia ductular proliferation areas are the site of a marked production of extracellular matrix proteins in periductular myofibroblasts, probably secondary to transforming growth factor β1 production by inflammatory cells and by biliary cells. The weak expression of transforming growth factor β1 could explain the slow progression of fibrosis in paucity of bile ducts.

Clinical and biochemical expression of the histopathological lesions of primary biliary cirrhosis

Background/Aims: This study aimed to assess the relationships which may link elementary histological lesions with symptoms and biochemistries in primary biliary cirrhosis. Methods: We studied 103 patients with primary biliary cirrhosis who participated in a double-blind, placebo-controlled trial of UDCA treatment and in whom liver biopsy specimens obtained at entry were reassessed. Relationships between histological features, fatigue, pruritus and biochemistries were calculated by using exact tests for 2 ordinal variables. Results: The degrees of severity of fatigue and pruritus were significantly and exclusively related to the presence of florid interlobular bile duct lesions ( p<0.01 and p<0.02, respectively). The only laboratory parameter associated with the presence of interlobular bile duct florid lesion was IgM level. The most discriminant biochemical test for interlobular bile duct paucity was gamma glutamyltranspeptidase activity. The degree of severity of both lymphocytic hepatocellular piecemeal necrosis and lobular inflammation and necrosis was mainly associated with increased gammaglobulin and IgG levels and to a lesser extent with increased IgM and aspartate aminotransferase levels. The extent of fibrosis was mainly associated with gammaglobulin levels and to a lesser degree with serum albumin, bilirubin and IgG levels. Conclusions: Symptoms and biochemistries classically used to assess primary biliary cirrhosis reflect in part the degree of severity of the main elementary histological lesions. We propose that the picture of primary biliary cirrhosis results from the clinical and biochemical expression of three distinct processes, e.g., bile duct inflammation and destruction, parenchymal inflammation and necrosis, and fibrosis. The various combinations of these processes may explain why the spectrum of primary biliary cirrhosis varies from typical primary biliary cirrhosis to mixed type of primary biliary cirrhosis and autoimmune hepatitis and suggests that the response to therapies may depend on the predominance of each process in a given patient.