Paucity Of Intrahepatic Bile Ducts Research Articles

Immunoreactivity of neoplastic and non-neoplastic hepatocytes for CD68 and with 3A5, Ki-M1P, and MAC387 light- and electron-microscopic findings

The immunohistochemical finding that the macrophage markers KP1, PG-M1 (both CD68) and Ki-M1P occasionally stain epithelial cells prompted a systematic immunohistochemical investigation of liver tissue with these and other macrophage markers. The material investigated comprised normal and cirrhotic liver, four hepatocellular carcinomas, including one fibrolamellar carcinoma, and liver specimens from two cases of extrahepatic biliary atresia and one case of paucity of intrahepatic bile ducts. The macrophage markers KP1, PGM1, Ki-M1P, 3A5, MAC387 and anti-lysozyme were employed. Two cases (one each of extrahepatic biliary atresia and cirrhosis) were investigated by immunoelectron microscopy to determine the subcellular site of reactivity. In the normal liver, only the Kupffer cells reacted with the macrophage markers. However, in neoplastic and non-neoplastic hepatic disorders, all the antibodies (with the exception of anti-lysozyme) stained hepatocytes in at least one case. KP1 produced particularly strong staining. Electron microscopy revealed the reaction product here to be related to lysosome-like granules in the hepatocytes. Therefore, when immunohistochemical investigation of liver biopsy specimens reveals reactivity with macrophage markers, it should be borne in mind that hepatocytes may also be reactive.

Resolution of nonsyndromic paucity of intrahepatic bile ducts in infancy

Resolution of nonsyndromic paucity of intrahepatic bile ducts in infancy

Growth hormone insensitivity associated with elevated circulating growth hormone-binding protein in children with Alagille syndrome and short stature.

The purpose of this study was to assess GH sensitivity in children with Alagille syndrome (syndromic intrahepatic bile duct paucity) by examining their response to short term administration of recombinant human GH (rhGH). Serum levels of insulin-like growth factor-I (IGF-I) were low despite elevated overnight integrated serum GH concentrations. Administration of rhGH (0.05 mg/kg.day for 3 days) to four growth-retarded children with Alagille syndrome did not significantly alter the serum concentrations of IGF-I and insulin, blood urea nitrogen, or urinary calcium excretion. In contrast, circulating IGF-I increased 2-fold in two children with Alagille syndrome and normal stature. In the control group, consisting of seven prepubertal children with GH deficiency, the predicted changes in response to rhGH in serum concentrations of IGF-I and insulin, urea nitrogen, and urinary calcium excretion were observed. Serum GH-binding protein levels, measured by a ligand-mediated immunofunctional assay, were significantly higher in children with Alagille syndrome than in children with cirrhosis or GH deficiency. We conclude that growth-retarded children with Alagille syndrome are insensitive to GH. The growth disturbances and metabolic defects may be due in part to failure to increase IGF-I concentrations in response to GH, implying that growth-retarded children with Alagille syndrome may benefit from IGF-I treatment.

Abnormalities of intrahepatic bile ducts in extrahepatic biliary atresia

The infantile cholangiopathies are a group of conditions associated with neonatal jaundice, which include extrahepatic biliary atresia, paucity of intra-hepatic bile ducts and disorders associated with persistence of fetal biliary structures, the so-called ductal plate malformations. Although previously regarded as distinct entities, it has recently been suggested that they may represent parts of a disease spectrum in which the principal process is one of bile duct destruction, the morphological manifestations in individual cases being influenced by the stage of intra-uterine development at which such injury occurs and by the site within the biliary system at which there is maximum damage. To further examine this concept, we have studied liver biopsy specimens from 37 neonates with extrahepatic biliary atresia, with particular reference to abnormalities of the intrahepatic bile ducts. Paucity of intrahepatic ducts, defined as a bile duct: portal tract ratio of less than 0.9, was identified in six cases (16.2%). In eight cases (21.6%) we found concentric tubular ductal structures similar to those observed in ductal plate malformations. In one case, both abnormalities could be demonstrated. Our findings support the concept that there is overlap between the various types of infantile cholangiopathy.

Essential Fatty Acid Deficiency Mimicking Porphyria Cutanea Tarda in a Patient with Chronic Cholestasis

Essential fatty acid deficiency was documented in a 3-year-old boy with chronic cholestasis secondary to paucity of intrahepatic bile ducts (Alagille's syndrome). Dietary management had consisted almost exclusively of a proprietary formula with over 80% of the fat as medium-chain triglycerides. The bullous lesions involved mostly sun-exposed areas and were diagnosed initially as being compatible with acquired porphyria cutanea tarda. Improvement followed correction of the fatty acid abnormalities with a polyunsaturated fat supplement administered orally. We postulate that the association of fatty acid deficiency and abnormal vitamin E status contributed to skin damage, possibly involving photosensitizing compounds poorly cleared by the markedly cholestatic liver.

Essential Fatty Acid Deficiency Mimicking Porphyria Cutanea Tarda in a Patient with Chronic Cholestasis

Essential fatty acid deficiency was documented in a 3‐year‐old boy with chronic cholestasis secondary to paucity of intrahepatic bile ducts (Alagille's syndrome). Dietary management had consisted almost exclusively of a proprietary formula with over 80% of the fat as medium‐chain triglycerides. The bullous lesions involved mostly sun‐exposed areas and were diagnosed initially as being compatible with acquired porphyria cutanea tarda. Improvement followed correction of the fatty acid abnormalities with a polyunsaturated fat supplement administered orally. We postulate that the association of fatty acid deficiency and abnormal vitamin E status contributed to skin damage, possibly involving photosensitizing compounds poorly cleared by the markedly cholestatic liver.

Syndromic Paucity of Intrahepatic Bile Ducts

Syndromic Paucity of Intrahepatic Bile Ducts

Prognosis of Nonsyndromic Paucity of Intrahepatic Bile Ducts

Prognosis of Nonsyndromic Paucity of Intrahepatic Bile Ducts

Idiopathic adulthood ductopenia: A cause of chronic cholestatic liver disease and biliary cirrhosis

We describe three adult patients who had chronic cholestatic liver disease associated with unexplained loss of interlobular bile ducts; two of these patients eventually required orthotopic liver transplantation. We have named this condition 'idiopathic adulthood ductopenia' because (1) the etiology is unknown, (2) the age of the patients may be the only distinguishing feature between this newly described condition and neonatal or infantile nonsyndromatic paucity of intrahepatic bile ducts, and (3) morphologic demonstration of ductopenia is an indispensable finding. Our three patients, all males, had a negative drug history, absence of antimitochondrial antibodies, normal cholangiographic findings, and no evidence of inflammatory bowel disease. Idiopathic adulthood ductopenia may be a representation of (1) late onset of infantile paucity of intrahepatic bile ducts, (2) destructive viral cholangitis, and (3) isolated small-duct primary sclerosing cholangitis - that is, 'pericholangitis' unassociated with inflammatory bowel disease.

Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver.

Morphologic findings of the liver in syndromatic paucity of intrahepatic bile ducts (SPIHBD) during infancy include paucity of interlobular bile ducts, features of "giant cell hepatitis," dilated lymphatics and veins in the portal tract, perisinusoidal fibrosis, and bile duct epithelial changes with a concentric layering of mesenchymal cells around bile ducts reminiscent of renal dysplasia. The latter change is characteristic of SPIHBD. Although the disease is characterized by paucity of bile ducts, morphometric studies show paucity of interlobular bile ducts in less than half of the patients during infancy. Reduced numbers of portal tracts and increased percentage of portal tracts devoid of bile ducts are more constant findings. It was impossible to predict from the early biopsy which patients would develop more severe portal fibrosis. Later in the disease portal fibrosis is variable and unevenly distributed, being more severe near the hilum regardless of the prior performance of a Kasai-type operation or the state of patency of the extrahepatic bile ducts. Hypoplasia of the extrahepatic bile ducts is the usual finding in SPIHBD, but if atresia of extrahepatic bile ducts is associated with intrahepatic paucity of bile ducts, the hepatic histopathology is that of PIHBD. Recognition of PIHBD would avoid unwarranted surgical procedures.

Diagnostic utility of hepatobiliary scintigraphy with 99mTc-DISIDA in neonatal cholestasis

We retrospectively evaluated the utility of hepatobiliary scintigraphy and various clinical factors in differentiating intrahepatic cholestasis from biliary atresia in 28 consecutive infants with neonatal cholestasis. One millicurie of technetium-labeled diisopropyliminodiacetic acid (DISIDA) was administered intravenously, and images were obtained for up to 24 hours or until gastrointestinal excretion was noted. Nine separate studies in seven infants with biliary atresia were correctly interpreted as showing no gastrointestinal excretion of radionuclide. Of the 21 patients with intrahepatic cholestasis, only nine had gastrointestinal excretion on the first study; in eight without excretion, a second study was done, and five of these showed gut excretion. All infants with either neonatal hepatitis (six) or inspissated bile syndrome (three) had demonstrable gastrointestinal excretion either on the first or second DISIDA study. However, five of six infants with paucity of intrahepatic bile ducts, two of six infants with cholestasis secondary to total parenteral nutrition, and one infant with cholangiolitis did not show evidence of gastrointestinal excretion. The mean birth weight, mean gestational age, and mean weight at study were significantly greater (P less than 0.005) for infants with biliary atresia without excretion than for infants with intrahepatic cholestasis without excretion. The mean direct bilirubin concentration was 6.0 mg/dL for both infants with biliary atresia and infants with intrahepatic cholestasis without excretion; however, infants with excretion had a significantly lower (P less than 0.02) mean direct bilirubin value of 3.4 mg/dL. Excretion was noted in four infants with total bilirubin values greater than 10.0 mg/dL. The absence of gut excretion on the first DISIDA study was 100% sensitive but only 43% specific for biliary atresia. In infants without gut excretion of DISIDA, birth weight greater than 2200 g was 100% sensitive and 92% specific for biliary atresia. We conclude that DISIDA scanning, together with clinical data, is useful in differentiating extrahepatic from intrahepatic cholestasis. The absence of gut excretion on the first DISIDA study does not necessarily indicate extrahepatic obstruction; the study should be repeated if the diagnosis is not clear.

Familial intrahepatic cholestatic syndromes.

This discussion has illustrated the enormous variety found within the category of familial intrahepatic cholestasis. It has also demonstrated how much more there is to learn about these fascinating disorders, which may be examples of experiments in nature on bile formation. This analysis should be recognized to be the author's own, and there is much debate about this classification. For example, some workers in this field contend that North American Indian cholestasis is in reality Byler's syndrome. Such an identity seems unlikely, given the differences between the two syndromes (Table 2). This is a field that is changing rapidly. Recently, a new cholestatic syndrome, bearing some similarities to benign recurrent intrahepatic cholestasis, but dissimilar in several ways, has been reported. There is evidence that cholestasis of pregnancy may be inherited as an autosomal dominant, sex-limited trait. If further studies confirm a genetic etiology, this syndrome would be the most common form of familial intrahepatic cholestasis. The assessment of any individual case remains difficult, particularly early in the course. Table 2 can serve as a guide to the differential diagnosis of these conditions. When faced with a neonate with jaundice, all of the usual causes must be ruled out first. The pattern of bile acids in serum is useful for ruling out Zellweger's syndrome. A good family history and physical examination, particularly of the heart, are important. An ophthalmologic examination by a specialist, often under anesthesia, and a spine radiograph can be useful in confirming a diagnosis of Alagille's syndrome. A liver biopsy, carefully interpreted with input from the clinician, is useful in pointing toward one direction or another. Often a firm conclusion cannot be reached, or is reached prematurely, so the clinician would be advised to inform the parents of all diagnostic possibilities in order to avoid false hopes or unwarranted depression. The diagnostic pitfalls to be avoided in this evaluation are many. No histologic findings are clearly pathognomonic for one syndrome or another. Giant cell transformation and paucity of intrahepatic bile ducts may be found in several syndromes. Biliary atresia, or at least failure to demonstrate a patent biliary tree from the liver to the cystic duct, may be present in patients with Alagille's syndrome. In that syndrome, the eye findings, particularly the posterior embryotoxon, may not be appreciated except on extensive ophthalmologic testing, including gonioscopy. Butterfly vertebrae may not be visible at birth and may be no longer evident in adulthood.(ABSTRACT TRUNCATED AT 400 WORDS)

Syndromatic paucity of intrahepatic bile ducts — A rare differential diagnosis of intrahepatic cholestasis

Syndromatic paucity of intrahepatic bile ducts — A rare differential diagnosis of intrahepatic cholestasis

Possible defect in the bile secretory apparatus in arteriohepatic dysplasia (Alagille's syndrome): a review with observations on the ultrastructure of liver.

Ultrastructural observations on 12 liver biopsies from 10 patients with arteriohepatic dysplasia syndrome (Alagille's syndrome) are reported. The electron microscopic changes in the liver in this condition are different from those seen in other forms of chronic intra- and extrahepatic cholestasis. In particular, the bile canalicular and pericanalicular changes classically observed in cholestasis are infrequently seen. When compared with other forms of intrahepatic cholestasis including syndromes associated with paucity of intrahepatic bile ducts, the ultrastructural changes in Alagille's syndrome appear to be distinctive. Bile pigment retention is found in the cytoplasm especially in lysosomes and in vesicles of the outer convex face of the Golgi apparatus (cis-Golgi), but rarely in bile canaliculi or the immediate pericanalicular region. These results suggest a block in the Golgi apparatus or in the pericanalicular cytoplasm.

Manifestations of nonsuppurative cholangitis in chronic hepatobiliary diseases: morphologic spectrum, clinical correlations and terminology.

The features of nonsuppurative cholangitis were studied in liver biopsy specimens from 185 patients with chronic active hepatitis (CAH), 280 patients with primary biliary cirrhosis (PBC), and 55 patients with primary sclerosing cholangitis (PSC). Specimens from patients with other liver diseases in which the presence of nonsuppurative cholangitis had been recorded were also studied. We identified four types of nonsuppurative cholangitis: granulomatous cholangitis, lymphoid cholangitis, fibrous cholangitis, and pleomorphic cholangitis. Granulomatous cholangitis almost always seemed to be destructive; the other types were either destructive or nondestructive. Granulomatous cholangitis was, for all practical purposes, diagnostic of PBC and the obliterative form of fibrous cholangitis was similarly diagnostic for the hepatic manifestations of PSC in adults and paucity of intrahepatic bile ducts in infants. All other types of cholangitis were found in CAH, PBC, PSC, and other liver diseases. Thus, the term "nonsuppurative cholangitis" describes a spectrum of morphologic lesions that differ in incidence, morphogenesis, usefulness for liver biopsy diagnosis, and, probably, pathogenesis.

RENAL INVOLVEMENT IN ARTERIOHEPATIC DYSPLASIA (AHD)

The syndrome of AHD consists of cholestasis secondary to paucity of intrahepatic bile ducts, pulmonic stenosis, vertebral abnormalities, mental retardation, and a characteristic facies. Although renal involvement has been infrequently reported, a spectrum of changes including congenital small kidney with renal failure, cystic kidney disease, tubulointerstitial nephropathy and renal lipidosis have been noted. To better define renal functions in AHD, we evaluated 8 children(2M,6F;ages2-16yr). Glomerular filtration rate (GFR) was reduced in 2/5(<10%;<50%). One of 2 pts with proteinuria had nephrotic syndrome and reduced GFR; 1 had mild proteinuria and normal GFR. Proximal and distal renal tubular functions including concentration and acidifiation tests were normal(5/5). Initially serum electrolytes, calcium, magnesium, uric acid and acid-base status were normal, but hyperchloremic metabolic acidosis developed with cholestyramine therapy in 3. Rickets developed in 1. Blood pressure was normal in all. Renal tissue(1 biopsy, 3 postmortem) examination showed normal kidney(1), glomerulosclerosis(1), calcium deposits(1) and renal lipidosis(1). On electron microscopic examination, the lipid deposits showed granular and lamellar electron-dense bodies, while X-ray dispersive analysis showed them to be rich in chromium, silicon, calcium, phosphorus and iron. Conclusions: 1) A spectrum of renal changes are found in AHD. 2) Renal functions may be variably reduced. 3) Renal lipidosis may be related to long standing hyperlipidemia as a result of intrahepatic cholestasis. 4) Trace elements are accumulated in electron-dense bodies.

Obliterative cholangitis due to cytomegalovirus: A possible precursor of paucity of intrahepatic bile ducts

A fetus at 24 weeks' gestation was found to have ascites and abdominal calcifications by ultrasonography. Pathologic examination after prostaglandin termination of pregnancy two weeks later revealed disseminated cytomegalovirus infection with inclusions in the lung, pancreas, kidney, and liver. A mononuclear inflammatory reaction was present in the portal areas of the liver and in the kidney, and gliosis was diffuse in the brain. The liver lesions were of greatest interest because most portal areas had no bile ducts. In other portal areas there was a combination of inclusions in epithelial cells of the few remaining interlobular ducts and intense duct-oriented inflammation. Thus, in fetuses surviving intrauterine cytomegalovirus infection, inflammatory destruction of intrahepatic bile ducts could manifest as chronic cholestasis and paucity of bile ducts later in infancy.

Arteriohepatic dysplasia in infancy and childhood: a longitudinal study of six patients.

Arteriohepatic dysplasia (syndromatic ductular hypoplasia, Alagille syndrome) is a condition of chronic cholestasis dating from infancy accompanied by characteristic facies, pulmonic stenosis, and other somatic abnormalities. The pathologic hallmark of arteriohepatic dysplasia is a paucity or absence of intrahepatic bile ducts, wildely regarded as a congenital deficiency. We present a longitudinal study of six infants and children with arteriohepatic dysplasia, stressing evolution of the characteristic pathology on liver biopsy. All patients were biopsied twice. All five liver biopsies performed during infancy (&lt;6 months old) showed intrahepatic cholestasis and portal inflammation, and two infants had, in addition, giant cell transformation. No infant showed congenital absence of interlobular bile ducts. Three of five infants had normal numbers of interlobular bile ducts (0.5 to 1.0 interlobular bile ducts per triad) and two infants had a paucity of interlobular bile ducts (&lt;0.5 per triad). Three infants showed focal destructive inflammation of interlobular bile ducts. All biopsies performed later in childhood, between 3 and 20 years of age, showed a paucity or absence of interlobular bile ducts. At this time cholestasis and inflammation had largely resolved but some fibrosis persisted. The number of interlobular bile ducts decreased with age in each patient but there was no characteristic age at which interlobular bile ducts disappeared completely. The presence of interlobular bile ducts in infancy followed later in childhood by paucity or absence of interlobular bile ducts, suggests that intrahepatic bile duct deficiency in some patients with arteriohepatic dysplasia is acquired rather than congenital. The mechanism of bile duct disappearance in these patients may have been destructive inflammation of duct epithelium. Histopathologic diagnosis of arteriohepatic dysplasia may be difficult or impossible in infancy since interlobular bile ducts may be present at that time. However, arteriohepatic dysplasia should be considered in the differential diagnosis of all infants with cholestasis and such infants should have careful clinical evaluation for the syndromatic features of arteriohepatic dysplasia. Evaluation of their liver biopsies should include specific morphometric assessment of interlobular bile ducts.

The Rose Bengal test in neonatal cholestasis: diagnostic and prognostic value.

131I Rose Bengal(131IRB) studies were performed in 73 infants with extrahepatic biliary atresia (EHBA) and in 37 with intrahepatic cholestasis of various origins. Fecal 131IRB excretion of less than 10% ("complete' cholestasis) was observed in EHBA but also in some patients with either paucity of intrahepatic bile ducts (syndromatic type) or with alpha-1-antitrypsin deficiency. Seventy one 131IRB tests were also performed 3 to 8 weeks postoperatively in children operated on for EHBA. Fecal 131IRB excretion more than 15% was present in 27 out of 34 cases who were later completely jaundice free and in only one out of 37 cases where no bile flow restoration occurred. These results indicate that complete cholestasis in infants can be observed in some types of intrahepatic cholestasis, as well as in EHBA, and show that a post-operative 131IRB test is a reliable means of predicting complete restoration of bile flow in EHBA.

Questions Regarding Neonatal Hepatitis

Lawson and Boggs1 reported the results of long-term follow-up of 23 patients with "neonatal hepatitis." The authors state that "familial neonatal hepatitis had significantly more serious morbidity and mortality than the sporadic disease, whether or not surgically treated." It is difficult to see how this conclusion was reached on the basis of a total of five cases from two families, without a control group of unoperated familial cases. Moreover, the two families are put forward as examples of familial neonatal hepatitis, whereas they appear to represent two distinct types of liver disease: family S is subject to a chronic hepatocellular process characterized by relatively elevated bilirubin, transaminase, and prothrombin values and normal alkaline phosphatase values, which terminates fatally in biliary cirrhosis; in family McK, hepatic excretory function appears primarily affected, resulting in pruritus, elevated alkaline phosphatase values, hypercholesterolemia, and progression to chronic cholestasis, presumably reflecting paucity of intrahepatic bile ducts.