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1. Pruritus was assessed in 19 patients by measurement of nocturnal limb movement. 2. Serum (nine pruritic, ten non-pruritic) and interstitial fluid (five pruritic, three non-pruritic) bile acids were fractionated according to their mode of conjugation by using DEAP-Sephadex LH-20 and measured by gas chromatography—mass spectrometry. 3. No correlation was found between serum or interstitial fluid total bile acid or individual bile acid concentrations and pruritus. Bile acid profiles in the two groups of patients were similar and there was no correlation between pruritus and the conjugation pattern. 4. The bile acid profile of interstitial fluid reflected that of serum and a linear relationship was found between serum and interstitial fluid bile acid concentrations (r = 0·95, P < 0·001). 5. The proportion of bile acid sulphate in interstitial fluid was significantly smaller than that in serum (P < 0·025), where sulphates accounted for up to 46% of the total bile acids. 6. In three patients, a decrease in serum bile acid concentrations achieved by percutaneous transhepatic biliary drainage had little or no effect on pruritus. 7. These findings suggest that bile acids do not have a causative role in the pruritus of cholestatic liver disease.

The time course of gamma-glutamyl transpeptidase (GGTP) was traced during a number of weeks after birth in 31 apparently healthy low birth weight infants. Also glutamic-pyruvic transaminase (GPT), 5'-nucleotidase (5 'ND) and alkaline phosphatase (AP) were determined in most of the same samples. In many of the prematures, but not in all, the GGTP showed a transient elevation, reaching maximal levels up to 150 I.U. Most values of GPT and 5'ND, however, were within the normal range, whereas for AP rather large variations were found. No age dependency could be established for the appearance of the GGTP maximum; neither the period of its occurrence nor its height showed a correlation to birth weight and to the degree of prematurity. The significance of transient GGTP activity in prematures is discussed. The results of our investigations suggest that in such infants increased values of GGTP have to be interpreted very carefully. Other enzyme and chemical parameters have to be considered simultaneously in order to establish cholestatic liver disease.

Diet selection was investigated in an animal model of cholestatic liver disease produced by bile duct ligation. Animals self-selected diets from separate sources of macronutrients (protein, fat, carbohydrate). Diet selection was evaluated when the fat source was comprised of either a primarily medium-chain fat (coconut oil) or a primarily long-chain fat (Crisco vegetable shortening). Relative to intakes of control animals, bile duct ligated (BDL) animals consuming the long-chain fat decreased fat intake, decreased protein intake, and increased carbohydrate intake. Consumption of the fat source was decreased in BDL rats fed the medium-chain fat relative to intakes of control animals, however carbohydrate and protein intakes were not affected. Total caloric intake was comparable to control intakes by day 16 post-ligation in BDL rats fed the long-chain fat and by day 11 in BDL rats fed the medium-chain fat. Body weight gain was significantly greater in BDL rats fed the medium-chain fat than in those fed the long-chain fat. Mortality was 44% in BDL animals fed the long-chain fat, and 0% in those fed the medium-chain fat. The results suggest that BDL animals make dietary selections which may decrease the severity of liver disease. Differences between ligated animals consuming either medium- or long-chain fats suggest that some fat sources may be more beneficial during cholestasis.

In 1975 Alagille described in the English literature a syndromatic form of intrahepatic biliary hypoplasia associated with characteristic facial features (prominent forehead, deep-set eyes, mild hypertelorism, straight nose, and small pointed chin). To test the specificity of the facies for Alagille syndrome, close-up facial photographs of 15 children and young adults with various forms of intrahepatic cholestasis (including seven with Alagille syndrome) were examined by 13 pediatric hepatologists from the United States and Canada and by Dr. Alagille and eight of his co-workers from France, without knowledge of the individual diagnoses. Each examiner was asked to identify the patients with facies characteristic for Alagille syndrome. Fifty-one percent of the U.S./Canadian group's matchings and 49% of the French group's matchings of facies to underlying liver disease (presence or absence of Alagille syndrome) were incorrect. The sensitivity of the facies for diagnosing Alagille syndrome was 54% and 32%, the specificity 44% and 68%, and the predictive value 46% and 47% based on the U.S./Canadian and French groups, respectively. "Cholestasis facies" does not appear specific for Alagille syndrome; rather, it seems to be a general feature of congenital intrahepatic cholestatic liver disease.

The hepatic clearance of unconjugated bilirubin-14C from the plasma of 5 patients with cholestatic liver disease was normal when compared with values obtained in healthy young adults. In 1 patient with benign recurrent cholestasis, clearance was the same during an attack of cholestasis (serum bilirubin concentration 25.7 mg/100 ml) as when the patient was in remission (serum bilirubin concentration 0.65 mg/100 ml). We conclude that the hepatic clearance of unconjugated bilirubin may not be altered in hepatic disorders where cholestasis is the predominant feature and that other explanations should be considered when patients with these disorders manifest an increased plasma concentration of unconjugated bilirubin.

The enzyme alkaline phosphatase is an important serum analyte and its elevation in serum is correlated with the pressure of bone, liver, and other diseases. The analysis of the isoenzymes of alkaline phosphatase is an aid in diagnosing liver and/or bone disease, especially the high molecular weight isoenzymes that appear in cholestatic liver disease.

Liver transplantation has provided individuals with cholestatic disorders a chance for long-term near-normal quality and quantity of survival. The experience at the University of Pittsburgh with hepatic transplantation for chronic cholestatic liver disease is presented in brief in this article.

A 15-yr-old patient with chronic cholestatic liver disease associated with haloperidol therapy is presented. Emphasis is placed on the pattern of biochemical abnormalities and on the histologic features observed in the four serial biopsies which demonstrated a pronounced injury to the bile duct epithelium, correlating well with the clinical and biochemical abnormalities. During the early stage of illness, the clinicopathologic features simulated obstructive jaundice, whereas a resemblance to chronic chlorpromazine-induced cholestasis or primary biliary cirrhosislike syndrome was striking as the chronicity developed. Comparison is made of the features in our patient with those in 2 patients with biopsy-documented, acute haloperidol-induced liver disease reported for the first time in 1977. Despite the lack of concrete evidence, both the clinical and morphologic features, and the close temporal relationship between the medication and onset of illness in this patient led to the reasonable inference that haloperidol was responsible for the chronic cholestatic reaction on a hypersensitivity basis.

A relatively rapid and specific method for the estimation of serum individual bile acids, conjugated and free, in small volumes (1 ml) of sera from patients with liver disease has been developed. This method has been applied to a study of 25 patients with liver disease. Cholestatic liver disease has been found to be associated with an increase in serum monohydroxy bile acids which appear to be of an unsaturated nature. No association was found between the concentration of any particular bile acid and the presence or absence of pruritus.

Autoimmune cholangitis (AIC) was first described in 1987 as immunocholangitis in three women who presented with signs and symptoms of primary biliary cholangitis (PBC), but who were antimitochondrial (AMA) negative and antinuclear antibodies (ANA) positive, and responded to immunosuppressive therapy with azathioprine and prednisolone (1). AIC is a rare chronic cholestatic inflammatory disease characterized by the presence of high ANA or smooth muscle antibodies (SMA) but AMA seronegativity. Histologically, AIC exhibits bile duct injury (2). In terms of therapeutics, in addition to response to ursodeoxycholic acid, a prompt response to corticosteroids has also been reported in earlier stages, distinguishing it from PBC. Herein the authors describe two cases with mixed signs of PBC and autoimmune hepatitis (AIH). The diagnostic differentiation between these diseases (AIC, PBC and AIH) is essential because of the different therapeutic strategies. Our cases highlight the importance of clinician awareness of the autoimmune spectrum of liver diseases.

Paucity of interlobular bile ducts is a common feature of cholestatic liver disease in premature infants. Whereas a bile duct to portal space ratio of 0.9 to 1.8 is cited by Alagille as the norm for children, there are no data regarding the normal bile duct to portal space ratio in preterm infants. In this study, by examining liver tissue obtained from autopsied fetuses and infants, we have determined that the bile duct to portal space ratio increases as a function of postconceptional age. After 38 weeks postconception, a ratio equal to or greater than 0.9 was seen in eight of nine subjects. Therefore, in evaluating premature infants for duct paucity, liver biopsies should be obtained only after 38 weeks. Prior to 38 weeks postconception, a bile duct to portal space ratio less than 0.9 may be physiologic.

We describe a 14-year-old boy who was severely debilitated by the neurological syndrome associated with vitamin E deficiency secondary to chronic cholestatic liver disease. In addition to the usual neurological deficits described with this deficiency, the patient had severe bulbar weakness and vision loss which we attribute to the degree and duration of his vitamin E deficiency. Vitamin A deficiency may have contributed to his visual disturbance. Early recognition of vitamin E deficiency is important, as the neurological and visual disorders which result are treatable.

The developmental metabolism of bile acids can be partly studied by the analysis of bile acid patterns in meconium. Employing modern analytical techniques, it has been found that besides the main bile acids of humans (cholic, chenodexoycholic, deoxycholic, and lithocholic acids) several "atypical" bile acids occur in meconium. It is unlikely that these "atypical+ bile acids are derived from materno--fetal transfer, and they therefore probably reflect a special fetal bile acid metabolism. Hydroxylations at positions 1 and 6 of the steroid skeleton are regularly encountered. These hydroxylations, as well as the occurrence of 3 beta-hydroxy-delta 5 compounds and of bile acids of the 5 alpha series, suggest that fetal bile acid synthesis differs markedly from that of the adult. These observations are of interest in relation to the origin of unusual bile acids found in the cholestatic condition of the adult. It appears that a resurgence of the fetal biosynthetic patterns takes place under the conditions of cholestatic liver disease.

The presentations in this section addressed some of the potentially harmful effects of human milk upon the recipient infant. These included: transmission of viral infection via milk; transmission of drugs via milk; deposition in developing tissues of the trans-fatty acids present in most milks; sensitization of the infant secondary to transfer of foreign antigens via milk; vitamin K deficiency and hemorrhagic disease of the newborn secondary to the low vitamin K content of human milk.

Jaundice in infancy may be physiologic or due to a pathologic cause. Fractionation of the serum bilirubin level is the first step in the evaluation. Unconjugated hyperbilirubinemia if left untreated may reach toxic levels. Primary hepatobiliary disorders, as well as infectious, toxic, genetic, and metabolic diseases, may manifest with conjugated hyperbilirubinemia. A carefully organized diagnostic evaluation in a timely fashion allows early identification of treatable disorders. Medical management of the complications of cholestatic liver disease remains a major challenge. Early surgical intervention for biliary atresia and significant advances in hepatic transplantation offer the opportunity for long-term survival for infants with previously fatal liver disorders.

Relationships between biliary bilirubin and lipid secretions were studied in patients with chronic cholestatic liver disease, mainly primary biliary cirrhosis. The bilirubin secretion rate in the patients was not significantly different from that in the controls. However, the bilirubin output per phospholipids, per bile acids, and per phospholipids plus bile acids was high, especially at low bile acid secretion rates. Thus, the bile of the patients with chronic cholestatic liver disease appears to be frequently ‘supersaturated’ with bilirubin. This metabolic abnormality may be associated with an increased risk of pigment stone formation in patients with cirrhosis.

In conclusion, cholestatic liver disease is a frequent complication in low birthweight infants who receive parenteral nutrition. The etiology of this disorder is probably multifactorial. Although the composition of parenteral nutrition solutions may play a role in the development of cholestasis, at this time, there are limited data to suggest how to change parenteral solutions to alter the course of this disease. Further work is necessary to elucidate therapies to prevent and treat this disorder.

A case is reported of hypertrophic osteoarthropathy with recovery after a liver graft in a young man with end stage cholestatic cirrhosis related to non-Wilsonian copper overload. To our knowledge this is the first case in the literature illustrating the curative role of liver grafting on hypertrophic osteoarthropathy associated with chronic cholestatic liver disease.

"Direct reacting bilirubin" in serum of patients with cholestatic liver disease and in serum of bile duct-ligated rats consists of a complex mixture of bilirubin metabolites. These metabolites were studied by means of high-pressure liquid chromatography. Bilirubin glucuronides in normal bile are beta-glycosidic 1-O-acyl conjugates which are completely hydrolyzed on incubation with beta-glucuronidase. Cholestatic serum contains glucuronide and non-glucuronide bilirubin metabolites. The glucuronides were only partially hydrolyzable with beta-glucuronidase. Compernolle et al. [11] showed that the 1-O-acyl bond of bilirubin glucuronides is labile and prone to migrate from the C1 position at the glucuronosyl residue to positions C2, C3 and C4. The isomerisation products are non-beta-glycosidic, beta-glucuronidase-resistant conjugates. The main beta-glucuronidase-resistant conjugates in cholestatic serum were characterized as: non-beta-glycosidic bilirubin monoglucuronide, non-beta-glycosidic diglucuronide and a diglucuronide isomer with beta-glycosidic and non-beta-glycosidic glucuronosyl groups. Moreover, a substantial amount of bilirubin monoglucoside monoglucuronide was detected in cholestatic human serum.

SUMMARY Assessment for both trabecular and cortical osteoporosis was carried out in 36 unselected patients with chronic cholestatic liver disease of whom a number had received corticosteroids during the course of their illness. Symptoms suggestive of osteoporosis were present in 42 per cent of patients of whom 11 per cent had evidence of one or more wedged or collapsed vertebrae. There was a highly significant decrease in the cortical area (total area ratio of the second metacarpal ( p = 0.05), bone mineral content at the metaphyseal site of the radius ( p = 0.01) and the total trabecular bone volume of the iliac crest biopsies ( p = 0.005) in the 31 female patients when compared with age and sex-matched healthy controls). There was a nonsignificant decrease in total trabecular bone volume of the iliac crest and bone mineral content of the radial metaphysis in the males compared with age and sex-matched controls but the cortical plate thickness of the iliac crest ( p = 0.005) and bone mineral content of the radial diaphysis ( p = 0.02) were significantly higher. In total, 42 per cent of patients had evidence of either excessive cortical (28 per cent) and/or trabecular (36 per cent) bone loss as judged by radiological and histological criteria. Only the total trabecular bone volume of the iliac crest, of all the parameters measured was significantly ( p = 0.02) lower in patients with backache compared with those without back pain. Significantly greater bone loss was demonstrated at all sites measured in those patients that were receiving or had received corticosteroids in the past.

We performed eye examinations in neonates to determine whether pigmented corneal rings were present in infants with hepatic disease, as in adults. None of 16 control infants had pigmented corneal rings, but 10 (71%) of 14 infants with cholestatic liver disease had such rings. Most rings could be seen without slit lamp by direct inspection of the cornea. Furthermore, the rings appeared to resolve over time. Liver dysfunction tended to be more severe in patients with corneal rings. We speculate that abnormal tissue accumulation of copper may be present in many infants with cholestatic liver disease. Ophthalmologic examination for pigmented corneal rings or determination of serum copper levels may need to be performed in patients at high risk with hepatic disease to monitor for excessive copper accumulation.

Direct visualization of the extrahepatic biliary tree is difficult in infants and young children without resorting to an intraoperative cholangiogram. Small size and lack of dilated intrahepatic ducts especially in infants with cholestatic jaundice often preclude using the techniques of percutaneous transhepatic cholangiography or endoscopic retrograde cholangiopancreatography. We studied the feasibility of ultrasound-guided percutaneous cholecystocholangiography (US-guided PCC) in differentiating extrahepatic from intrahepatic causes of cholestatic jaundice in four infants. Clinical, laboratory, radiographic, and histologic criteria had not conclusively excluded extrahepatic obstruction prior to the use of this technique. Four infants, between 4 and 10 weeks of age, were studied without complications. In one patient, biliary atresia was diagnosed at 4 weeks of age; in another, aspirated bile was cultured leading to a specific diagnosis of bacterial cholangitis; and, in two others, intrahepatic cholestasis was confirmed by the demonstrated patency of the extrahepatic biliary tree. In infants and young children in whom a gallbladder lumen can be seen, US-guided PCC offers a potential rapid, nonoperative means of differentiating intrahepatic and extrahepatic causes of cholestatic jaundice, defining the anatomy of the extrahepatic biliary tree, and directly sampling gallbladder bile.

The natural history of cholestatic syndromes in infancy remains largely unclarified for lack of sufficient data. Newborn and premature infants are particularly vulnerable to cholestasis because of immaturities in bile-forming mechanisms. Until recently, two broad categories of etiologic factors have been thought to be associated with cholestasis in early infancy: mechanical obstruction (almost always extrahepatic), and hepatocellular damage (the "neonatal hepatitis" group). Although in both groups specific etiologic factors have been identified, the majority of cases are currently of unknown etiology.Problems in differential diagnosis are reviewed. In the neonatal period, laboratory screening procedures usually do not uncover cholestatic liver disease until the infants become icteric. It is important to note that patients with liver dysfunction may remain anicteric or become anicteric while cholestasis persists. It is, therefore, important that biochemical markers of cholestasis other than conjugated bilirubin be found.

Monozygotic twins were found concordant for gout and liver disease. Chronic ulcerative colitis was present in 1 twin but had not developed in his sibling during the 6-year period he was under observation. These findings suggest that the potential to develop liver disease and ulcerative colitis may be inherited separately and need not be related to the presence of disease within the bowel.

In Reply.— We agree with Aballi that a combination of factors placed our patient1 at high risk for vitamin K deficiency during her first month of life. These factors include decreased intestinal absorption of vitamin K due to the cholestatic liver disease of α-1-antitrypsin deficiency and a diet consisting solely of breast milk which is known to have little vitamin K. Aballi correctly points out the lack of data on the role of vitamin K in preventing late-onset hemorrhagic disease.

A child is reported whose alpha-1 -antitrypsin phenotype is SZ and who has chronic cholestatic liver disease that began in the neonatal period. Liver biopsy demonstrated paucity of the interlobular bile ducts, marked hepatocellular deposition in periportal areas of PAS-positive, diastase-resistant granules, and bridging portal fibrosis. The association of paucity of the interlobular bile ducts with SZ phenotype alpha-1-antitrypsin deficiency has not been reported previously.

Correspondence pertaining to material published in theJournalwill be published, if found suitable, as space permits. Submit double-spaced copy clearly marked "For publication" and signed by all authors; references should conform toJournalformat; maximum length: 500 words. Copyright assignment signed by all authors is required. The Editor reserves the right to edit such letters, which should be received within six weeks of publication of theJournalarticle in question. Sir.— We read with interest the report by Rosenthal et al (Journal133:1195-1196, 1979) concerning infantile cholestatic liver disease associated with alpha 1 -antitrypsin deficiency and the Pi-SZ phenotype. We have seen a similar patient who at 1 month of age had failure to thrive and conjugated hyperbilirubinemia. The only other clinical abnormality was a cholesterol level of 415 mg/dL. Rose bengal sodium I 131 did not enter the intestine. An operative cholangiogram and open biopsy were performed before the

In Reply .—We are gratified that Drs Harris and Beatty have seen a case that resembles the one reported by us. It was our intent to point out that PAS-positive, diastase-resistant granules may be observed during the first two months in periportal hepatocytes and in Kupffer cells of patients heterozygous for alpha-1-antitrypsin deficiency. As indicated in our article, examination with the electron microscope demonstrated that these deposits were located in the rough endoplasmic reticulum of hepatocytes. In contrast, in patients with cholestasis due to other causes, PAS-positive, diastase-resistant granules may be seen in damaged hepatocytes not usually confined to peripheral regions of lobules, and concentrated in lysosomes rather than in expanded regions of the rough endoplasmic reticulum. The deposits of lipofuscin-melanin pigment observed in Dubin-Johnson syndrome, to which Drs Harris and Beatty refer, are panlobular in distribution and have a dark brown color that may be readily distinguished from the

Using adequate analytical techniques, which included capillary column gasliquid chromatography and mass-spec trometry, detailed bile acid (BA) profiles were obtained from 23 fetal bile samples, collected after legal aborption performed between the 14th to 20th week of gestation. Qualitatively, all fetal bile samples were similar:the predominant BA were chenodeoxycholic (CDCA)and cholic (CA) acids. The presence of variable amounts of deoxycholic and lithocholic acids suggested placental transfer of these BA from the maternal circulation;3s-hydroxy-5-cholenoic acid was bearly detectable. A conspicous feature of the profiles was the presence of BA with hydroxyl groups in position C1, C2, C6, indicating fetal hepatic synthesis via pathways different from those normally seen in adults. Quantitatively, total biliary BA concentrations were extremely low(less than 0.1mM/L) before week 17 of gestation,but thereafter concentrations rapidly increased (greater than 10 fold), reflecting a surge in BA synthesis. However the ratio of CDCA to CA remained relatively constant over this period (mean 1.5) and different from normal adult (0.9). These data indicate an immaturity in hepatic 12-α-hydroxylation of BA during development and that other synthetic pathways are active at this stage of life. It is of interest that BA metabolism in the adult with severe cholestatic liver disease shows striking similarities to that seen in this study on the fetus.

Hyaluronic acid (HA) is cleared from the circulation specifically by hepatic endothelial cells. To assess whether measurement of serum HA may give information about hepatic function not provided by conventional liver function tests, we have measured serum HA in 48 infants who presented with cholestatic liver disease in the first 6 months of life (25 extra-hepatic biliary atresia [EHBA], 13 alpha-1 antitrypsin deficiency [α1-ATD], 10 idiopathic hepatitis of infancy [IHI] and 51 age-matched healthy infants.)

Results so far suggest that liposomes can promote absorption of lipid-soluble vitamins in bile-duct-obstructed and normal animals. This approach may benefit human subjects who are at present given regular intramuscular injections of vitamin E. The absorption of liposomal preparations of vitamin E which only contain natural ingredients should be compared with that of water-soluble tocopheryl polyethylene glycol succinate which has recently been given successfully to children with chronic cholestatic liver disease (Sokol et al., 1987). Combination of vitamins in liposomes may also enable mixtures of the lipid-soluble vitamins to be administered together in a single dose.

Mn, like copper, is an essential trace element that is excreted almost entirely via the bilary tract. Copper accumulation occurs when bile flow is compromised but similar data for Mn are not available. The objective of this study was to determine serum Mn concentrations in a patient with cholestatic liver disease who was receiving TPN. The subject was a 16 month old female, weighing 10.5 kg, with intractable diarrhea who had been receiving TPN since 1 week of age. Despite repeated attempts at partial enteral feeding, she developed progressive cholestatic liver disease. At the time of this study, liver function tests included: bilirubin 10.4 mg/dl, AST 424 IU/l, alk phos 264 IU/l. She had been receiving 2.4 mcgMn/day added to her TPN infusate. The table gives serum Mn levels determined by flameless atomic absorption spectrophotometry before and at progressive intervals after Mn was withheld from the infusate: Two additional patients, aged 9 and 15 months, who had also been receiving Mn in long-term TPN but had not developed significant cholestasis both had serum Mn of 1.0 ng/ml. It is suggested that intravenous Mn, as a component of TPN, be administered in reduced quantities to children with cholestatic liver disease.

Liver disease in infants with alpha1-antitrypsin deficiency was first reported by Freier et al in 1968.1This type of infantile liver disease has been observed almost exclusively in association with the ZZ phenotype for the protease inhibitor system.2Alpha1-antitrypsin deficiency with liver disease has also been described in heterozygous adults with phenotype SZ, but has been rarely implicated as a cause of neonatal hepatitis and subsequent chronic liver disease in childhood.3.4In addition, the characteristic hepatocellular PAS-positive granules observed in the liver biopsy specimens of pediatric patients with ZZ phenotype have been infrequently observed in other phenotypes.5We are reporting a case of alpha1-antitrypsin deficiency in an infant with SZ phenotype associated with severe cholestatic liver disease and parenchymal deposition of PAS- positive material. Report of a Case.—A male infant weighing 1,600 g was delivered by cesarean section at 31 to