Management of paucity of interlobular bile ducts

Two types of paucity of interlobular bile ducts (PIBD) may be observed in children with chronic cholestasis. The syndromatic type (80 cases) is the most frequent. The non-syndromatic type (32 cases) is the most severe and half of the patients in this group died from liver failure in the first years of life. The main therapeutic point is that patients with PIBD should not be operated on. The only treatment available is symptomatic medical treatment: the main helpful possibilities concern feeding of medium-chain triglycerides, large supplementation of liposoluble vitamins (A, D, E and K) given intramuscularly, phenobarbital and cholestyramine when there is severe pruritus. The place of the liver transplantation will be clarified in the near future.     

Non-syndromic paucity of interlobular bile ducts.

A 3 1/2-month-old male infant presented with cholestatic jaundice. Peroperative cholangiogram showed a gall bladder and small but patent extrahepatic bile ducts. Liver histology showed paucity of interlobular bile ducts. The child is being treated medically for his symptoms.     

Fatty acid content in lymphocytes from children with syndromic paucity of interlobular bile ducts,Alagille syndrome

Summary Fatty acid (FA) concentrations were studied in lymphocytes isolated from children with syndromic paucity of interlobular bile ducts (PILBD), Alagille syndrome. The aim of this study was to assess whether the specific FA changes previously observed in fibroblast cultures from such patients were also present in other tissues. Lymphocyte FA, obtained both from controls and patients were studied under two experimental conditions, either after separation of the mononuclear cells or after 48 hours of culture. Freshly isolated lymphocytes from patients presented few FA changes compared to the controls. However, when patient lymphocytes were placed in culture medium for 47 hours, FA changes were amplified compared to those observed in controls; the decrease in the sum of saturated andn-6 polyunsaturated FA of total lipids was significant only in patients, and then-3 FA of phospholipids was strikingly increased in patients (p≤0.001), compared to controls. These results are related to those previously observed in fibroblast cultures and suggest that placing cells in culture could reveal a pre-existing cellular abnormality in patients with PILBD.     

2-Deoxy-d-glucose uptake and fatty acid content in fibroblast cultures from children with syndromic paucity of interlobular bile ducts (alagille syndrome)

Summary 2-Deoxy-d-glucose (2-DOG) uptake was studied in skin fibroblast cultures from control children and children with Alagille syndrome or syndromic paucity of interlobular bile ducts (PILBD). No significant differences in uptake were observed between patients and controls. However, as the scatter of the results was larger in the fibroblasts from patients, we attempted to establish for these patients a relationship between 2-DOG uptake and some biochemical parameters. We observed an inverse relationship between this uptake and the levels of plasma cholesterol and phospholipids (r=–0.85). Compared to controls, 2-DOG uptake was significantly lower in cultures from patients who had very high levels of cholesterol (P2 group), but not in cultures from patients with moderately increased levels of cholesterol (P1 group). The level of total cellular cholesterol in cultured cells from the P1 and P2 groups was not significantly different from the control level, but we found marked differences between the concentrations of fatty acids. In the cultures from patients (especially the P2 group), we observed a significant increase in total fatty acids; among the saturated fatty acids, this increase chiefly concerned the 18:0 (14%) and among the polyunsaturated then –3 fatty acids (55%). The high concentrations of 20:5, 22:5 and 22:6, which enhance membrane fluidity, might explain the decrease in 2-DOG uptake found in the cultures from patients (P2 group) with PILBD. The nature of these abnormalities might be connected with the genetic origin of Alagille syndrome     

Case report: Paucity of interlobular bile ducts in Chinese children

Sixteen Chinese children with cholestasis since early infancy were diagnosed to have paucity of interlobular bile ducts (PILBD) or its equivalent. Twelve children belonged to the syndromic group of PILBD and four children belonged to the non-syndromic group. A definite histological diagnosis of bile duct paucity was established in only two children (aged 4 and 9 months) during the first percutaneous needle biopsy. In the remaining 14 children a varying degree of bile duct destruction was evident in the follow up percutaneous or wedge liver biopsies. The evolving changes were characterized by inflammatory infiltration near or at the ductal wall, the presence of dysmorphic ductules, the degeneration of ductal epithelia and a progressive decrease of interlobular bile ducts. Of 10 children who underwent laparotomy for definite diagnosis, kasai operation was performed in two of them. In the syndromic PILBD group, all children, including two paired siblings, had at least three of five major clinical features. Hypoplasia of the extrahepatic biliary tree was found in five children and atresia of the extrahepatic bile duct was found in one. Three of six children studied were shown, by polymerase chain reaction, to have cytomegalovirus infection in the liver. This study demonstrates that bile duct paucity is a result of progressive bile duct destruction. A definitive diagnosis is difficult to make in early infancy. Thus, the careful evaluation of extrahepatic features in cholestatic children and follow-up liver biopsies are indicated. Although the pathogenetic mechanism of PILBD is unknown, bile duct destruction is the common pathway leading to paucity of bile ducts irrespective of syndromic or non-syndromic types.     

Nonsyndromatic paucity of interlobular bile ducts: light and electron microscopic evaluation of sequential liver biopsies in early childhood

Liver biopsies and/or autopsy specimens from 17 children (ages 1 week to 5 years) with nonsyndromatic paucity of the interlobular bile ducts were studied by light and electron microscopy. Initial biopsies were obtained before 90 days of age from all patients, and two or more specimens were available from nine. No specific underlying condition was found in nine infants. The remaining cases were associated with Down's syndrome (n = 2), hypopituitarism (n = 2), cystic fibrosis (n = 1), alpha 1-antitrypsin deficiency (n = 1), cytomegalovirus (n = 1) and Ivemark syndrome (n = 1). Before 90 days of age, portal changes included duct paucity and fibrosis. Lobular changes were nonspecific, consisting of cholestasis, giant cell transformation, extramedullary hematopoiesis and perisinusoidal fibrosis. Duct paucity, portal fibrosis and perisinusoidal fibrosis persisted after 90 days. Cholestasis was mild or no longer apparent. Portal changes before 90 days of age appear to be sufficiently distinctive to microscopically distinguish nonsyndromatic from syndromatic paucity. Electron microscopic findings suggest that paucity in nonsyndromatic patients may result from a primary ductal insult: ultrastructural studies revealed bile duct destruction characterized by undulation and breaks in the basal lamina and infiltration of the epithelium by lymphocytes. Bile canalicular dilatation with blunting of microvilli and electron-dense material in the lumen, predominantly seen before 90 days, also reinforces the hypothesis of a primary ductal defect.     

Cholesterol and prostaglandin synthesis by cultured human skin fibroblasts in the alagille syndrome involving paucity of interlobular bile ducts

Summary Children with Alagille syndrome show high serum cholesterol (15–20 mmol/L). To establish correlation of this unusual level of cholesterol with the regulation of cholesterol metabolism, 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) activity and synthesis of cholesterol, fatty acids and acidic steroids from [¹⁴C]acetate were determined in cultured skin fibroblasts from 2–3-year old children. Prostaglandin E₂ (PGE₂) synthesis and nucleic acid synthesis were determined in cells when they were growing in medium containing normal, Alagille or fetal bovine serum. These values were similar to values of controls.HMGR activity was found to be similar in cells of control and children with the syndrome, whether the cells were incubated in lipoprotein-deficient or normal medium. Incorporation of acetate into cholesterol was inhibited to a greater extent by lipoprotein-containing medium in control than in children with the syndrome. Fatty acid synthesis was similar in all conditions. 1–7% of the recovered lipid radioactivity in cells and medium separated as acidic steroids.Serum from a donor patient, when included in the medium, did not affect PGE₂ or nucleic acid synthesis compared with normal human or fetal bovine serum. The data suggest that cells of children with Alagille syndrome may have a membrane defect of transfer of cholesterol (LDL receptor defect) leading to excessive cholesterol synthesis. Also, synthesis of acidic steroids (bile acid-like material) and their secretion into the medium occurs in normal fibroblasts and those from children with the syndrome.Journal Paper No. J-13160 of the Iowa Agriculture and Home Economics Experiment Station, Ames, Iowa: Project No. 2728.     

Scavenger cells with gram-positive bacterial lipoteichoic acid infiltrate around the damaged interlobular bile ducts of primary biliary cirrhosis

BACKGROUND/AIMS: Gram-positive bacterial DNA is frequently detectable in gallbladder bile of primary biliary cirrhosis (PBC) patients. To advance these findings, lipoteichoic acid (LTA) of gram-positive bacteria with high antigenicity was examined in liver specimens and bile from PBC patients and controls. METHODS: LTA was examined by Western blotting in the gallbladder bile from 15 PBC, 11 cholecystolithiasis and six normal subjects, and by immunohistochemistry in liver specimens from 16 PBC, six primary sclerosing cholangitis (PSC), eight chronic viral hepatitis C (CVH-C) and five normal subjects. RESULTS: In the gallbladder bile, there was no significant difference in the positive rate of LTA between PBC and controls. LTA-containing mononuclear cells were frequently detected in the portal tracts, particularly around the bile ducts and in hepatic sinusoids in PBC, while they were infrequent or occasional in control livers. These LTA-containing cells were sinusoidal endothelial cells and Kupffer cells, and portal monocytes, which frequently expressed scavenger receptor class B type 1. CONCLUSIONS: LTA derived from bacterial fragments may reach the bile, not only in the diseased state but also under normal conditions. Such LTA may be involved in the development and progression of portal tract lesions, particularly bile duct lesions, in PBC.     

Plasma lipid fatty acid composition, desaturase activities and insulin sensitivity in Amerindian women

Background and aimsTwo Amerindian populations – Shuar women living in the Amazonian rain forest under traditional conditions and urbanized women in a suburb of Lima were studied. The fatty acid composition in plasma lipids and the relationships between fatty acid composition and metabolic variables were studied, as well as in a reference group of Swedish women.Methods and resultsFasting plasma was used for analyses of glucose, insulin, leptin and fatty acid composition. Women in Lima had more body fat, higher fasting insulin and leptin and lower insulin sensitivity than the Shuar women, who had insulin sensitivity similar to Swedish women. Shuar women had very high proportions (mean; SD) of palmitoleic (13.2; 3.9%) and oleic (33.9; 3.7%) acids in the plasma cholesteryl esters with very low levels of linoleic acid (29.1; 6.1 3%), as expected on a low fat, high carbohydrate diet. The estimated activity of delta 9 (SCD-1) desaturase was about twice as high in the Shuar compared with Lima women, suggesting neo lipogenesis, while the delta 5 desaturase activity did not differ. The Lima women, as well as the Swedish, showed strong positive correlations between SCD-1 activity on the one hand and fasting insulin and HOMA index on the other. These associations were absent in the Shuar women.ConclusionsThe high SCD-1 activity in the Shuar women may reflect increased lipogenesis in adipose tissue. It also illustrates how a low fat diet rich in non-refined carbohydrates can be linked to a good metabolic situation.     

Plasma fatty acid composition in patients with ileal dysfunction

Chemical signs of essential fatty acid deficiency (EFD) were studied in 31 patients who has undergone an ileal resection on an average 7 years earlier by determining fatty acid composition in serum lipids. The subjects were divided into two groups in accordance with the presence (greater than 7 g/day) or absence (less than 7 g/day) of fat malabsorption. The two groups were matched for age, nutritional status, and essential fatty acid intake, but the patients with steatorrhea had higher levels of fecal bile acids and serum triglycerides and lower levels of serum cholesterol than those without steatorrhea. The contents of linoleic acid (LA; 18:2,n-6), the sum of n-6 polyunsaturated fatty acids, and eicosapentaenoic acid levels were lower, whereas those of the C 14-18 saturated and monoenoic fatty acids and eicosatrienoic fatty acid (ETA; 20:3,n-9), a characteristic fatty acid of EFD, were higher in the serum lipids of the patients with fat malabsorption. The LA of cholesterol esters, the ETA of phospholipids, and the ETA to arachidonic acid ratio of phospholipids were closely correlated with the amount of fecal fat, less significantly with the composition of dietary fat or the length of excluded intestine, and not at all with relative body weight or the amount of fecal bile acids. Changes in fatty acid patterns, considered characteristic of EFD, were found for almost a third of the patients with fat malabsorption; yet no clinical evidence of EFD was documented. Thus, the results demonstrate that chemical signs of EFD are common in patients with fat malabsorption after gut resections despite the good nutritional status. The findings suggest that, for preventive purposes, patients with gut resections should increase their dietary intake of polyunsaturated fatty acids in proportion to the amount of fecal fat.     

Biliary lipid composition in idiopathic bile acid malabsorption

Background—Chronic diarrhoea is the clinicalhallmark of patients presenting with idiopathic bile acidmalabsorption. Its pathogenesis is unknown; colonic water secretion canbe induced by dihydroxy bile acids, but it is not known whetherenrichment of the bile acid pool with these bile acids occurs in suchpatients. Furthermore, bile acid malabsorption is known to affectbiliary lipid composition, but no information is available for theidiopathic type.
Aims—To verify: (a) whetherdiarrhoea in patients with idiopathic bile acid malabsorption isassociated with enrichment of the bile acid pool with dihydroxy bileacids; and (b) whether supersaturation with cholesterol ofduodenal bile occurs in such patients as a result of chronic bile acid depletion.
Patients—Thirteen patients with idiopathic bileacid malabsorption diagnosed according to abnormal ⁷⁵SeHCATtest and absence of other organic diseases, and 23 control subjects.
Methods—Bile rich duodenal fluid was collectedduring intravenous ceruletide infusion in the fasting state. Biliarylipids were analysed by enzymatic assays and bile acids by highperformance liquid chromatography.
Results—Patients with idiopathic bile acidmalabsorption had a cholesterol saturation index similar to controls.Bile acid composition showed only a decrease in percentage cholic acid(29(2)% versus 36 (2)%; p<0.05); the dihydroxy:trihydroxy bile acid ratio was similar to controls.
Conclusions—Patients with idiopathic bile acidmalabsorption do not have an increased risk of forming cholesterolgallstones. The mechanism of diarrhoea does not seem to depend on anenrichment of the bile acid pool with dihydroxy bile acids.

Keywords:primary bile acid malabsorption; bile acids; diarrhoea; ⁷⁵SeHCAT; biliary lipids; cholesterol saturationindex

     

Effect of ursodeoxycholic acid on biliary bile acid and bile lipid composition in gallstone patients

In five patients with radiolucent gallstones, the effect of ursodeoxycholic acid (Urso) in doses of 250, 500, 750, 1,000, and 1,250 mg per day on biliary lipid and bile acid composition was studied. Biliary cholesterol decreased from 8.8 +/- 0.8 mole% to 4.4 +/- 0.2 mole% at 500 mg Urso per day (7.1 mg per kg) and to 4.2 +/- 0.3 mole% at 750 mg Urso per day (10.7 mg per kg). Administration of 1,000 or 1,250 mg Urso per day produced no further decrease of biliary cholesterol. The biliary content of phospholipids and total bile acids remained unchanged. During Urso treatment, the relative amounts of glyco-Urso and tauro-Urso in bile increased. Glyco-Urso reached a plateau at 49.1 +/- 2.1% of total bile acids during treatment with 1,000 mg Urso per day, and tauro-Urso increased up to 4.3 +/- 1.5% of total bile acids at 250 mg Urso per day. Simultaneously cholic acid, chenodeoxycholic acid, deoxycholic acid, and lithocholic acid decreased. The data indicate that Urso treatment reduces biliary cholesterol efficiently already at a dose of 500 mg per day; biliary bile acid composition changes up to 1,000 mg Urso per day. Doses greater than 1,000 mg per day produced no additional alterations in bile composition.     

Bile lipid composition and bile acid pool size in diabetes

Since the prevalence of gallstones is higher in diabetics than in controls and since cholelithiasis is often associated with supersaturated bile, we measured bile lipid composition and bile acid pool size in 8 patients with juvenile diabetes, 16 with maturity-onset diabetes, and 10 control subjects. Bile lipid composition was expressed as “saturation index.” In the maturity-onset diabetics the saturation index (1.60:±0.45SDM) was significantly higher (P<0.005) than that in the controls (0.82±0.20) and in patients with juvenile diabetes (0.75±0.24). The absolute values for biliary bile acid concentration were significantly lower (P<0.01) in the maturity-onset diabetics than in the other two groups. There were no differences in either the proportion of the individual biliary bile acids or the size of the bile acid pool between the three groups. The results suggest that the incidence of cholelithiasis in diabetes is associated with the secretion of a supersaturated bile only in the maturity-onset subgroup.     

Effect of ursocholic acid on bile lipid secretion and composition

To further clarify the relationship between physical-chemical characteristics of bile acids and biliary lipid secretion, we investigated the effect of ursocholic acid, the 7 beta-hydroxyepimer of cholic acid, on bile lipid secretion and composition. The study included acute duodenal infusion (1 g/h for 5 h) of ursocholic acid contrasted with a less hydrophilic bile acid, ursodeoxycholic acid, in 3 T-tube patients and short-term oral administration (2 wk) of ursocholic acid (10-15 mg/kg X day) to 10 gallstone patients. Following acute infusion, ursocholic acid, similarly to ursodeoxycholic acid, accounted for greater than 80% of the biliary bile acids. However, ursocholic acid induced (per micromole of secreted bile acid) a significantly lower (p less than 0.01) secretion of cholesterol (0.013 mumol) and phospholipids (0.054 mumol) than that induced by ursodeoxycholic acid (0.034 mumol of cholesterol and 0.138 mumol of phospholipids). Biliary alkaline phosphatase activity during ursocholic acid administration was significantly lower (p less than 0.01) than during ursodeoxycholic acid administration. After short-term oral administration, ursocholic acid, undetectable before treatment, constituted 20.50% +/- 8.60% of the biliary bile acids. The percentage of deoxycholic acid increased from 32.35% +/- 18.79% to 47.53% +/- 16.19% (p less than 0.05). Mean saturation index decreased from a pretreatment value of 1.23 +/- 0.22 to 0.99 +/- 0.17 (p less than 0.05), but only in 4 of 10 subjects did bile become undersaturated. It is concluded that ursocholic acid, due to its higher hydrophilicity, stimulates a lower cholesterol and phospholipid output than ursodeoxycholic acid. Consequently, despite the low enrichment of the biliary bile acids with ursocholic acid, oral administration of ursocholic acid induces a reduction of bile cholesterol saturation.     

Effect of endoscopic sphincterotomy on bile acid pool size and bile lipid composition in man

The effect of endoscopic sphincterotomy on bile acid pool size and lipid composition was studied in 3 patients with an intact gallbladder and in 7 patients who had previous cholecystectomy. Measurements were made at two time intervals after endoscopic sphincterotomy, early (3-9 days) and late (6-9 months). Patients with an intact gallbladder showed a marked reduction in their total bile acid pool during follow-up examinations (95.3 +/- SD 14.0 vs. 18.6 +/- 8.1 mumol/kg), whereas in the cholecystectomized patients the pool size showed no significant change (29.4 +/- 13.4 vs. 26.6 +/- 11.4 mumol/kg). The reduction in bile acid pool size caused by sphincterotomy in patients with an intact gallbladder did not increase the degree of cholesterol saturation in hepatic bile.     

Effect of chronic ursocholic acid administration on bile lipid composition and bile acid pool size in gallstone patients

We assessed the effect of chronic (4-6 weeks) administration of ursocholic acid (UCA) (15 mg/kg/day), a natural bile acid with poor detergent capacity, on biliary lipid composition of gallbladder bile (n = 26) and bile acid pool size (n = 5) in gallstone patients. During treatment the biliary molar percentage UCA increased from trace values to 28% (p less than 0.001). This effect was accompanied by an increase in molar percentage deoxycholic acid from 16% to 33% (p less than 0.001). Total bile acid pool size remained unchanged during UCA administration; cholic acid and chenodeoxycholic acid pool sizes decreased from 1.0 to 0.6 mmol (p less than 0.05) and from 1.6 to 0.9 mmol (p less than 0.05), respectively. The molar percentage cholesterol of gallbladder bile decreased from 9.8% to 7.0% (p less than 0.001) during UCA, but bile remained supersaturated with cholesterol in 21 patients. The weak effect on biliary lipid composition and the increase of potentially toxic deoxycholic acid in bile suggest that UCA is unlikely to replace ursodeoxycholic and chenodeoxycholic acid for medical treatment of gallstones.