Bone disease in infants and children with hepatobiliary disease

Radiological studies of bone were performed in infants and children with hepatobiliary disease. Rickets was found in 23 out of 39 patients (59%) with surgically unrepaired biliary atresia, in 4 out of 15 (27%) with surgically repaired biliary atresia, in 11 out of 21 (52%) with neonatal hepatitis, and in 2 out of 4 (50%) with intrahepatic cholestasis. Osteoporosis was found in 23 out of 39 (59%) with unrepaired biliary atresia, in 3 out of 15 (20%) with repaired biliary atresia, in 5 out of 21 (24%) with neonatal hepatitis, and in 1 out of 4 (25%) with intrahepatic cholestasis. 2 girls with Byler disease and 1 infant with choledochal cyst showed no radiological evidence of bone disease.In unrepaired biliary atresia comparative studies of biochemical data in the groups with and without bone disease showed the following. Serum calcium levels were reduced in the patients with bone disease compared with those in the group without it. Serum magnesium levels were markedly reduced in the groups with and without bone disease. The product of serum calcium and phosphorus was reduced in the group with osteoporosis compared with that in the group without it. The raised levels of serum alkaline phosphatase were unrelated to the presence or absence of bone disease.     

Intestinal absorption of calcium and magnesium in hepatobiliary disease in infancy

The intestinal absorption of calcium and magnesium was measured by metabolic balance studies in 6 normal infants, 13 infants with biliary atresia, 5 infants with successfully repaired biliary atresia, 7 infants with neonatal hepatitis, and 2 infants with choledochal cyst. The absorption of both elements was impaired in these disorders. The malabsorption of these elements was most marked in biliary atresia. In successfully repaired biliary atresia the absorption was increased to the normal levels. In neonatal hepatitis the degree of the malabsorption was variable in individual cases. In choledochal cyst the reduction of the absorption was less marked than in biliary atresia and neonatal hepatitis. In biliary atresia parenteral vitamin D increased moderately the absorption of both elements, though oral vitamin D had little effect. In infants with biliary atresia receiving a milk containing medium-chain triglycerides the absorption was moderately raised. There was a clear relation between the absorption of calcium and that of magnesium: the per cent. absorption of magnesium was almost the same as that of calcium in most cases. The serum calcium level determined during the studies was within the normal ranges in hepatobiliary diseases. The serum magnesium level was, however, found to be generally reduced in these conditions. It was greatly reduced in the patients with biliary atresia.     

Serum 25-hydroxy-vitamin D in hepatobiliary disease in infancy.

Serum 25-hydroxy-vitamin D (25-OHD) concentrations were measured in 49 patients with hepatobiliary disease in infancy. Low mean values were found in groups of patients with biliary atresia, neonatal hepatitis, choledochal cyst, and chronic intrahepatic cholestatic syndrome. In the group of patients with surgically repaired biliary atresia, the mean value did not differ from normal. Parenteral vitamin D increased 25-OHD in serum in patients with biliary atresia, but did not do so in one patient with neonatal hepatitis. In contrast, oral vitamin D did not increase serum 25-OHD concentrations in patients with biliary atresia. It is concluded that the reduction of serum 25-OHD seen in biliary atresia was largely due to the malabsorption of vitamin D, while in neonatal hepatitis it was due to impairment of 25-hydroxylation of the vitamin.     

Hepatobiliary scintigraphy and the string test in the evaluation of neonatal cholestasis

We evaluated [99mTc]diisopropylphenyl-carbamoylmethylimidodiacetic acid ([99mTc]DISIDA) cholescintigraphy with measurement of duodenal fluid radioactivity collected by the string test in patients with neonatal cholestasis. Twenty-six infants with prolonged jaundice and acholic stools were studied prospectively. Twelve patients had neonatal hepatitis, 12 biliary atresia, and one each Alagille syndrome and alpha 1-antitrypsin deficiency liver disease. All infants except the biliary atresia patients and four of the neonatal hepatitis patients revealed bowel activity on scan 6 h after tracer administration. At 24 h, three of these latter patients with neonatal hepatitis and two of the patients with biliary atresia revealed bowel activity. String radioactive counts for neonatal hepatitis ranged from 99,574 to 967,205 cpm (374,504 +/- 232,210 cpm; mean +/- SD) and for biliary atresia from 8,342 to 370,346 cpm (117,149 +/- 98,698 cpm; mean +/- SD). While neither test alone was capable of correctly differentiating among all patients, those patients with biliary atresia had either a negative hepatobiliary scan at 24 h or string radioactive count below 197,007 cpm. Disparity between the hepatobiliary scan and the string radioactive counts mandates further diagnostic investigation. These data suggest that simultaneous administration of the string test with hepatobiliary scintigraphy is advantageous in the evaluation of infants with cholestatic jaundice.     

Studies on the Enterohepatic Circulation of Bile Acids in Infancy and Childhood

To elucidate the enterohepatic circulation of bile acids in hepatobiliary disorders, the present author measured the fasting cholic acid levels in serum and followed up the changes of the levels after MCT milk administration. The subjects were 17 cases of neonatal hepatitis, 24 cases of congenital biliary atresia (CBA), 19 cases of other hepatobiliary disorders and 117 normal children. The serum cholic acid levels in the neonatal period were significantly high, which suggested a physiological cholestasis in neonates which gradually decreased with age. The mean level in CBA was rather higher than that in neonatal hepatitis but showed overlap of the levels. The patterns of changes of serum cholic acid levels in MCT milk test were classified into 6 types which were respectively characteristic of each disorders according to varied disturbance of the enterohepatic circulation of bile acids. This MCT milk test may be useful in making a differential diagnosis of various hepatobiliary disorders, especially neonatal hepatitis and CBA.     

Alpha1-fetoprotein in neonatal hepatobiliary disease.

It has been suggested that the quantitative estimation of serum alpha-1-fetoprotein may help in distinguishing the neonatal hepatitis syndrome from biliary atresia. We measured the serum AFP concentration in 52 neonates and infants with various hepatobiliary disorders, including neonatal hepatitis syndrome (group I), biliary atresia (group II), and other hepatopathies such as choledochal cyst (group III). The mean serum AFP concentration in patients with neonatal hepatitis was significantly greater than the mean concentration in the other two groups. There was no significant difference between the mean serum AFP concentrations in patients with biliary atresia and in group III patients. Patient age was noted to be an important factor: Serum AFP levels greater than 35 microgram/ml in infants one to four months of age suggpst the diagnosis of neonatal hepatitis syndrome. Serum AFP levels below 10 microgram/ml in infants less than four months of age suggest the diagnosis of biliary atresia or hepatopathies other than neonatal hepatitis. However, the variable and significant overlapping of serum AFP values between 10 and 35 microgram/ml limit the diagnostic value of this test.     

Lack of correlation between infection with reovirus 3 and extrahepatic biliary atresia or neonatal hepatitis

Infection with reovirus 3 (Reo-3) has been suggested as the cause of extrahepatic biliary atresia and idiopathic neonatal hepatitis, but confirmation has been lacking. Therefore we have searched for a specific anti-Reo-3 antibody response in the sera of patients with biliary atresia or neonatal hepatitis and for Reo-3 antigens in their hepatobiliary tissues. Sera from 23 infants with extrahepatic biliary atresia, 12 with neonatal hepatitis, 30 age-matched control patients with other liver diseases, and 55 control patients without liver disease were tested by an enzyme-linked immunosorbent assay for total (IgA, IgG, and IgM) anti-Reo-3 antibodies; sera of infants younger than 6 months of age were tested also for IgM anti-Reo-3 antibodies alone. There was no difference between either total or IgM anti-Reo-3 antibody levels in infants with extrahepatic biliary atresia or neonatal hepatitis and levels in control infants. Reo-3 antigens were not detected in the hepatobiliary tissues of 19 infants (18 with biliary atresia, one with neonatal hepatitis) by an immunoperoxidase method that readily demonstrated Reo-3 in control infected HEp-G2 cells. Our data do not support a relationship between neonatal liver diseases and infection with Reo-3.     

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.     

Bile acids in serum and bile of infants with cholestatic syndromes

The concentration of individual bile acids in serum was measured in 18 neonates and infants with various cholestatic conditions (extrahepatic biliary atresia, neonatal hepatitis syndrome, chronic intrahepatic cholestasis and posthemolytic cholestasis). The cholate/chenodeoxycholate ratio in serum was smaller than one in all patients with neonatal hepatitis syndrome or extrahepatic biliary atresia, cholestatic conditions which were accompanied by signs of liver cell injury. It was greater than one in the patients with chronic intrahepatic cholestasis. Administration of cholestyramine to patients with patent extrahepatic bile ducts decreased the total concentration bile acids in serum and elevated the cholate/chenodeoxycholate ratio. Thus, cholestyramine administration may be of diagnostic value for evaluation of bile duct patency in cholestasis of infancy. Differences between the bile acid pattern in serum and bile were observed. Thus, the cholate/chenodeoxycholate ratio was always higher in bile than in serum. 3beta-hydroxy-5-cholenoic acid found in serum was not detectable in bile. This finding suggests that impairment of biliary excretion rather than increased hepatic synthesis is responsible for elevation of this monohydroxy bile acid in serum.     

Unconjugated, Glycine-conjugated, Taurine-conjugated Bile Acid Nonsulfates and Sulfates in Urine of Young Infants with Cholestasis

ABSTRACT. A direct assay system for conjugated bile acids using an enzymatic procedure and high-performance liquid chromatography was used for the analysis of urinary bile acid profiles in young infants with intrahepatic cholestasis (idiopathic neonatal hepatitis syndrome) or extra-hepatic biliary atresia. The major urinary bile acids were cholate and chenodeoxycholate conjugates, but a small amount of deoxycholate and 3β-hydroxy-5-cholenate conjugates were detected. Although there was no significant difference in total bile acid excretion between patients with intrahepatic cholestasis and extrahepatic biliary atresia, mean ratios of cholate to chenodeoxycholate and sulfated to total urinary bile acids were different between the two groups examined (5.63±2.83 vs. 2.50±1.25, p <0.05, 15.8±9.9 vs. 34.5±9.9%, p < 0.005). The proportion of taurine-conjugated chenodeoxycholate in the sulfate fraction to the total bile acid was lower in intrahepatic cholestasis, compared with that in biliary atresia (7.7±7.5 vs. 22.7±7.8 %, p < 0.005). The greater ratio of cholate to chenodeoxycholate and the reduced excretion of sulfated urinary bile acids in intrahepatic cholestasis was due to decreased taurine-conjugated chenodeoxycholate sulfate excretion.     

Phenobarbital-enhanced hepatobiliary scintigraphy in the diagnosis of biliary atresia: two decades of experience at a tertiary center

Background

Hepatobiliary scintigraphy is highly sensitive for diagnosing biliary atresia; however, its specificity has varied in the literature from 35% to 97%.

Objective

The purpose of this study was to re-evaluate the accuracy of phenobarbital-enhanced hepatobiliary scintigraphy in differentiating biliary atresia from other causes of neonatal cholestasis.

Materials and methods

We retrospectively reviewed all hepatobiliary scans of infants with cholestasis at our institution from December 1990 to May 2011. Per our routine protocol the scans were obtained after pretreatment with phenobarbital (5 mg/kg/day for 5 days) to achieve a serum level of ≥15 mcg/ml. Normal hepatic uptake with no biliary excretion by 24 h was considered consistent with biliary atresia.

Results

One hundred eighty-six infants with 210 hepatobiliary scans composed the study group. Forty-three (23%) infants had the final diagnosis of biliary atresia. Hepatobiliary scintigraphy was 100% sensitive, 93% specific and 94.6% accurate in diagnosing biliary atresia. Of the 186, 39/111 (35.1%) term and 2/68 (2.9%) preterm infants had biliary atresia; two of seven children with unknown gestational age also had biliary atresia. Other diagnoses included neonatal hepatitis, total parenteral nutrition cholestasis, Alagille syndrome, cystic fibrosis, choledochal cyst, hypothyroidism, alpha-1 antitrypsin deficiency and persistent cholestasis of unknown etiology.

Conclusion

Phenobarbital-enhanced hepatobiliary scintigraphy is highly accurate in differentiating biliary atresia from other causes of neonatal cholestasis. Biliary atresia is rare in premature infants.     

Investigation of serum bile acids; seven patients with Alagille syndrome

To clarify whether an abnormal bile acid pattern has a role in the pathogenesis of Alagille syndrome, we compared serum bile acid patterns in seven with Alagille syndrome with those of patients with congenital biliary atresia (CBA), neonatal hepatitis (NH) and normal infants.Of the seven patients with Alagille syndrome, four patients were younger and three were older than 1 year. The mean total serum bile acid level in the infants was higher than in older subjects. There was a dissociation between the levels of serum total bile acid and bilirubin in three of the seven cases. The mean total bile acid levels in serum were in the following decreasing order: CBA, Alagille syndrome, NH and controls.The ratio of cholate to chenodeoxycholate in the younger patients with Alagille syndrome was significantly higher than CBA (P<0.001). However, no specific bile acid pattern was found in Alagille syndrome by high-performance liquid chromatography (HPLC).Abbreviations TBA total bile acids - FBA free bile acids - conj-BA conjugated bile acids - C/CDC ratio of cholate to chenodeoxycholate - G/T ratio of glycine conjugates to taurine conjugates - GPT glutamic pyruvic transaminase - CBA congenital biliary atresia - NH neonatal hepatitis - HPLC high performance liquid chromatography - GCA glycocholate - TCA taurocholate - GCDCA glycochenodeoxycholate - TCDCA taurochenodeoxycholate     

IMMUNE RESPONSES IN PATIENTS WITH OBSTRUCTIVE JAUNDICE OF INFANCY

ABSTRACT. To investigate possible involvement of immune responses in the pathogenesis of obstructive jaundice in infancy we measured antibody to liver specific lipoprotein (LSP) by radio immunoassay and immune complexes by their ability to bind Clq in sera from 16 patients with extrahepatic biliary atresia and 16 with neonatal hepatitis and 13 age matched controls. Anti-LSP was present in 6 of 16 with preoperative biliary atresia and 6 of 16 with hepatitis. Mean percentage Clq bound was higher in hepatitis (22 SD 15 %) than preoperative biliary atresia (11.1 SD 2.3 %). Nine of 16 hepatitis patients had elevated Clq binding as compared with 1 of 16 with biliary atresia. The highest value for anti-LSP and Clq binding were found in sera from patients with histologically severe hepatitis and hepotitis associated with specific viral or bacterial causes. Anti-LSP was significantly raised 5 months post-operatively in all of 6 patients with biliary atresia and poor biliary drainage but only 2 of 5 survivors. Elevated Clq binding was detected in 6 of 7 with poor drainage and 1 of 7 survivors at the same stage. Anti-LSP and Clq binding fell in 4 patients with neonatal hepatitis on recovery. These findings suggest that immunological mechanisms, possibly involving antibody to hepatocyte membrane components and immune complexes, may be involved in the pathogenesis of progressive liver disease in biliary atresia.     

Expression of osteopontin correlates with portal biliary proliferation and fibrosis in biliary atresia

The acquired or perinatal form of biliary atresia is a Th1 fibro-inflammatory disease affecting both the extrahepatic and intrahepatic bile ducts. Osteopontin (OPN) is a Th1 cytokine implicated in several fibro-inflammatory and autoimmune diseases. We examined the expression of OPN in acquired biliary atresia in comparison to normal liver and several pediatric cholestatic liver diseases. We also assessed OPN expression by cultured human bile duct epithelial cells. We found that liver OPN mRNA and protein expression were significantly increased in biliary atresia versus normal and other cholestatic diseases. OPN expression in biliary atresia was localized to epithelium of proliferating biliary structures (ductules and/or ducts) and bile plugs contained therein. No portal biliary OPN expression could be demonstrated in normal liver, syndromic biliary atresia, biliary obstruction not due to biliary atresia, and idiopathic neonatal hepatitis. OPN expression by human bile duct epithelial cells in culture was responsive to IL-2 and TNF-alpha. Our results demonstrate an up-regulation of OPN expression by interlobular biliary epithelium in biliary atresia, which correlates with biliary proliferation and portal fibrosis. These findings suggest a role for OPN in the pathogenesis of biliary atresia.     

Unconjugated, glycine-conjugated, taurine-conjugated bile acid nonsulfates and sulfates in urine of young infants with cholestasis

A direct assay system for conjugated bile acids using an enzymatic procedure and high-performance liquid chromatography was used for the analysis of urinary bile acid profiles in young infants with intrahepatic cholestasis (idiopathic neonatal hepatitis syndrome) or extra-hepatic biliary atresia. The major urinary bile acids were cholate and chenodeoxycholate conjugates, but a small amount of deoxycholate and 3 beta-hydroxy-5-cholenate conjugates were detected. Although there was no significant difference in total bile acid excretion between patients with intrahepatic cholestasis and extrahepatic biliary atresia, mean ratios of cholate to chenodeoxycholate and sulfated to total urinary bile acids were different between the two groups examined (5.63 +/- 2.83 vs. 2.50 +/- 1.25, p less than 0.05, 15.8 +/- 9.9 vs. 34.5 +/- 9.9%, p less than 0.005). The proportion of taurine-conjugated chenodeoxycholate in the sulfate fraction to the total bile acid was lower in intrahepatic cholestasis, compared with that in biliary atresia (7.7 +/- 7.5 vs 22.7% +/- 7.8%, p less than 0.005). The greater ratio of cholate to chenodeoxycholate and the reduced excretion of sulfated urinary bile acids in intrahepatic cholestasis was due to decreased taurine-conjugated chenodeoxycholate sulfate excretion.     

Hepatobiliary effects of cholic and lithocholic acids: experimental study in hamsters

Etiopathogenesis of biliary atresia remains unknown. Among several theories, one proposes that the disorder may be caused by the toxic effect of monohydroxy bile acids on fetal and neonatal hepatobiliary system. In this paper we evaluated toxic effects produced by ingestion of cholic acid, a trihydroxy bile acid, and lithocholic acid, a monohydroxy bile acid in the hepatobiliary system of a hamster during gestational and perinatal periods. A diet composed by 0.5% cholic acid and 0.25% lithocholic acid was administrated to pregnant hamsters. Liver and bile ducts of the adult and newborn animals were analyzed to point out the changes induced by these acids after birth. Because hamsters and humans have a similar bile metabolism, these animals were eligible for the study. The ingestion of 0.5% lithocholic acid, during hamster’s gestation, caused maternal intense ductal/ductular proliferation, inflammatory signs, hepatic cells degeneration and regeneration, hyperplasia of extra hepatic ducts epithelium, and abortion. Both 0.5% cholic acid and 0.25% lithocholic acid ingested by pregnant hamsters, caused ductal/ductular proliferation and hepatobiliary inflammatory damage in a different degree of intensity in adult animals and mild intensity in the young; and also the number of the young was reduced in the litter. We found that the ingestion of these bile acids by hamsters, during gestational period caused different degrees of toxicity on maternal and neonatal hepatobiliary systems. The histopathologic findings observed in biliary atresia patients could not be found in newborn hamsters. New experimental models are needed in the attempt to establish a correlation of these acids with neonatal cholestatic diseases.     

Hepatobiliary scintigraphy in arteriohepatic dysplasia (Alagille's syndrome)

Hepatobiliary scintigraphy has proven to be of great utility in distinguishing biliary atresia from other causes of neonatal cholestasis. Arteriohepatic dysplasia (Alagille's syndrome) is an uncommon entity characterized by typical facial features, pulmonary artery stenosis, and a liver disorder which presents during the neonatal period as progressive jaundice. Two neonates, who were later shown to have Alagille's syndrome, underwent hepatobiliary scintigraphy to rule out biliary atresia. Findings on the hepatobiliary scans from the two patients were similar to those usually associated with biliary atresia and both finally required surgical exploration to rule out biliary atresia. The findings on hepatobiliary scans in these patients with Alagille's syndrome are discussed and compared with those associated with other forms of neonatal cholestasis.     

Apparent gut excretion of Tc-99m-DISIDA in a case of extrahepatic biliary atresia

Our patient had DISIDA scan at 39 days of age to exclude biliary atresia. Gut excretion was seen 18h after injection and the diagnosis of neonatal hepatitis was made. Because of continued elevated liver function values, liver biopsy was performed and demonstrated findings consistent with biliary atresia. Exploratory laparotomy performed 8 days after the scan showed patent cystic duct, bile duct, and gall-bladder, but an atretic common hepatic duct. This case is an example of documented biliary atresia demonstrating gut excretion on the DISIDA scan.     

URINARY MONOHYDROXY BILE ACIDS IN YOUNG INFANTS WITH OBSTRUCTIVE JAUNDICE

ABSTRACT. Using an aluminum oxide column, we fractionated and quantitatively determined urinary monohydroxy bile acids in young infants. For comparison purposes, monohydroxy bile acids were also measured in urine from older children and adults with obstructive jaundice. Lithocholic acid was not found in any specimens of the young infants examined, while 3β-hydroxy-5-cholenoic acid was detected in all. In the biliary atresia group, 3β-hydroxy-5-cholenoic acid excreted was 0.45 ± 0.28 μmol per day ( n = 7), and in the neonatal hepatitis group, 0.48 ± 0.44 μmol per day ( n = 9). The mean rate of 3β-hydroxy-5-cholenoic acid to total urinary bile acids in the biliary atresia group was 2.1%, and 1.3% in the neonatal hepatitis group. In the older children and adults with obstructive jaundice ( n =6), 3β-hydroxy-5-cholenoic acid was excreted at a mean rate of 3.9% of total urinary bile acids, ranging from 0.63 to 14.81 mol per day. The excretion rate of 3β-hydroxy-5-cholenoic acid was related to that of chenodeoxycholic acid ( p <0.05) in infants, while it was related to that of both chenodeoxycholic acid ( p <0.01) and cholic acid ( p <0.05) in older children and adults.     

Serum alpha-fetoprotein levels in extrahepatic biliary atresia, idiopathic neonatal hepatitis and alpha-1-antitrypsin deficiency (PiZ).

Serum alpha-fetoprotein levels were measured using a sensitive radioimmunoassay in 77 infants presenting with persistent conjugated hyperbilirubinaemia. A breed range of alpha-fetoprotein concentrations occurred in both the 23 infants with extrahepatic biliary atresia and the 35 with idiopathic neonatal hepatitis but the 13 with alpha-1-antitrypsin deficiency had uniformly low levels. High alpha-fetoprotein concentrations (above 10 000 mug/1) favoured the diagnosis of neonatal hepatitis especially in the first ten weeks of life, but the overlap between neonatal hepatitis and extrahepatic biliary atresia was large and alpha-fetoprotein determination cannot be recommended as a reliable method for distinguishing the two conditions. Serial alpha-fetoprotein values showed no consistent relationship with standard liver function tests and gave no guide to prognosis. There was an association between alpha-fetoprotein production and needle biopsy evidence of hepatic giant cell transformation. The uniformly low alpha-fetoprotein levels in alpha-1-antitrypsin deficient infants with neonatal hepatitis is a new observation and possible mechanisms for disordered glycoprotein release are discussed.