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Cholestatic Disorders of Infancy
Pediatric Gastroenterology II
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Cholestatic Disorders of Infancy
Joseph F. Fitzgerald, MD
Obstructive liver disease of infancy, a familiar term to physicians of my vintage, has given way to the terms neonatal cholestasis and cholestatic disorders of infancy. The term cholestasis was coined by Popper and is preferred because it acknowledges that the pathology may be functional and at the level of the hepatocyte, instead of a mechanical obstruction. 47 Yet, occasional use of "obstructive liver disease ofinfancy" allows reflection on the past and illumination of the inroads that have been made in neonatal hepatology in the past score of years. How well I recall my anxiety in the mid-1960s when asked to examine an icteric 5- to 6-week old infant. It was commonly recognized that children with congenital infections and metabolic disorders tended to appear sick, while those with extrahepatic biliary atresia (it was thought that there was an intrahepatic form) were well, overall. A deep inner sadness would consume me as I examined the healthy, tan, 6week-old infant with icteric sclerae, hepatomegaly, a full spleen tip, and acholic stools. The diagnosis of biliary atresia was likely, which meant that this infant would melt away before his parents' eyes and succumb before his first birthday. It was commonplace for these infants to be sent to our colleagues in surgery who would perforrri diagnostic laparotomies. Causes other than biliary atresia were found on rare occasion, which, appropriately, led to concern that the underlying condition might be affected negatively by the surgical procedure. Indeed, it was reasoned that if we had nothing to offer the patient with biliary atresia, and if we might be harming infants with other causes of cholestasis by subjecting them to a surgical procedure, why operate on any of these infants? Various tests were touted as the tool which could separate the completely obstructed infant (i.e., with biliary atresia) from the others, but none was found to have 100 per cent specificity. The scene changed dramatically following the report of Kasai et al. in the Journal of Pediatric Surgery in 1968. 34 Interestingly, their report was received with some temperance in North America. Several pediatric surgeons of high stature in the United States traveled to Japan to investigate the experience and returned with glowing support for the procedure(s) *Professor of Pediatrics, Indiana University School of Medicine; Gastroenterologist, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
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espoused. These surgeons taught these procedures to others, and this type of neonatal biliary surgery became commonplace in the United States. 2B This allowed us to offer some hope to these families. We were aware of the fact that some of the patients who were not completely obstructed, that is, who had normally pigmented stools or a patent biliary tree at surgery, progressed to end-stage cirrhosis. Many of these infants with "neonatal hepatitis" probably had a metabolic disease such as a-I-antitrypsin deficiency. Occasionally, more than one infant in a family demonstrated similar findings and a course resulting in death. I once reviewed records of four children born around 1950 who had progressive neonatal liver disease leading to cirrhosis and death in the first year of life. Many of these familial defects in bile movement have now been identified. Landing37 carefully pointed out the histologic similarities of neonatal hepatitis, biliary atresia, and choledochal cyst, and suggested that these entities were separate points on a continuum. The continuum/spectrum was designated "infantile obstructive cholangiopathy." N ewer diagnostic techniques have improved selection of patients for surgical management, and advanced surgical techniques have improved the number of infants with hepatic bile drainage. Improvements in nutritional monitoring and the availability of unique nutritional solutions have greatly increased prolonged survival in this patient population. Finally, the coming of the cyclosporine era in orthotopic hepatic transplantation has provided another dimension in the management of the infant with a progressive hepatopathy. I must confess to more than a little excitement as I recount the experience of the last 20 years.
PATHOPHYSIOLOGY OF CHOLESTASIS Cholestasis indicates impaired bile formation and excretion, and the retention of biliary constituents in the liver and blood. 45 , 47 In spite of the progress made in our understanding of cholestasis, complete understanding of the physiochemistry of bile flow is still lacking. Bile flow is dependent on hepatocellular uptake of plasma constituents, transhepatic transport and metabolic processing of these constituents, the activity of the bile secretory apparatus, involvement of the cytoskeleton, the fluidity and permeability of membranes, the paraductular pathway of bile formation, and ductular modifications of canalicular bile. 45 Many of these biologic steps in bile flow are incompletely developed in the neonate. 17 Bile acid synthesis, uptake, excretion, and ileal reabsorption have been shown to be decreased in the neonate compared to adult levels. Total bile acid pool size in newborns is approximately 50 per cent of the pool size of adults; it is further reduced in prematurely born infants. Balistreri5 has pointed out that newborns have a cholestatic propensity. This is attributed to immaturity of hepatic excretory function, inborn errors of bile acid metabolism resulting in hepatic dysfunction, and an inherent susceptibility to viral or toxic insult, which produces an exaggerated and stereotypic response in the immature liver. The more interested reader should treat him- or herself to the thorough reviews of the ontogeny of hepatic bile acid metabolism and transport,62
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and inborn errors of bile acid synthesis, 52 recently published in Seminars in Liver Disease. PRESENTATION AND DIFFERENTIAL DIAGNOSIS Infants with cholestatic disorders are often asymptomatic and come for evaluation when direct hyperbilirubinemia persists beyond the first 3 weeks of life. Some, however, especially those with congenital infections, are of concern early because they are small for gestational age, often microcephalic, and have splenomegaly as well as hepatomegaly.67 Infants with bacterial infections and metabolic hepatopathies usually appear ill at presentation. 21, 67 The differential diagnosis is of some length (Table 1), and it is fluid, with new causes added each year. It has been pointed out that the neonatal liver is uniquely susceptible to a wide variety of injuries that may result in a similar response, that is, giant cell transformation, inflammation, hepatocellular necrosis, extramedullary hematopoiesis, and the development of fibrosis. 6 It should not be surprising then that the entities comprising the continuum designated generically as "infantile obstructive cholangiopathy" account for three quarters of the cases of neonatal cholestasis. a-I-Antitrypsin deficiency and arteriohepatic dysplasia (Alaqille's syndrome) account for an additional 10 to 15 per cent. INFANTILE OBSTRUCTIVE CHOLANGIOPATHY These conditions had been recognized individually for decades before Landing37 suggested a responsive relationship and that atresia of extrahepatic and intrahepatic bile ducts was not due to defective development but to progressive destruction of bile ducts. It has been learned that fibrous obliteration of the bile ducts is only one histologic aspect of the cholangiopathy, and that additional histopathologic features (e.g., necrosis, inflammation, and periductal fibrosis) are also observed. 11 Various observers noted clustering of cases of biliary atresia over the years and considered the possible influences of infectious agents and environmental toxins on this developmental condition. I saw three infants with biliary atresia from the same area of southwestern Indiana over a 2month period in 1970. Strickland and Shannon61 studied 30 cases of biliary atresia from north Texas and found that a preponderance of affected infants were from rural counties, and that they presented during the late summer/ early fall (August-October). Two studies of twins, which included some who were monozygotic, led to a conclusion that biliary atresia was not inherited but acquired. 31,60 The above observations created an environment which was desperate for direction. This has, perhaps, been provided by Glaser, Morecki, and coinvestigators. 7, 22-24, 42, 49 They recalled the early report of Stanley et al. 58 who described intrahepatic lesions in newborn mice infected with reovirus 3 and designed similar experiments but focused on morphologic changes at
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Table 1. Neonatal Cholestasis: Etiologic Classification I. Extrahepatic Disorders A. Biliary atresia B. Biliary hypoplasia C. Bile duct stenosis D. Anomalies of choledochal-pancreatico-ductal junction E. Spontaneous perfuration of bile duct F. Mass (neoplasia, stone) G. Bile/mucous plug II. Intrahepatic Disorders A. Idiopathic: 1. Idiopathic neonatal hepatitis 2. Intrahepatic cholestasis, persistent a. Arteriohepatic dysplasia (Alagille syndrome) b. Byler disease (severe intrahepatic cholestasis with progressive hepatocellular disease) c. Trihydroxycoprostanic acidemia (defective bile acid metabolism and cholestasis) d. Zellweger syndrome (cerebrohepatorenal syndrome) e. Nonsyndromic paucity of intrahepatic ducts (apparent absence of bile ductules) 3. Intrahepatic cholestasis, recurrent (syndromic?) a. Familial benign recurrent cholestasis b. Hereditary cholestasis with lymphedema (Aagenaes) B. Anatomic: 1. Disorders of amino acid metabolism 2. Caroli's disease (cystic dilation of intrahepatic ducts) C. Metabolic disorders: 1. Disorders of amino acid metabolism a. Tyrosinemia 2. Disorders of lipid metabolism a. Wolman's disease b. Niemann-Pick disease c. Gaucher's disease 3. Disorders of carbohydrate metabolism: a. Galactosemia b. Fructosemia c. Glycogenosis IV 4. Metabolic disease in which the defect is uncharacterized a. a-I-Antitrypsin deficiency b. Cystic fibrosis c. Idiopathic hypopituitarism d. Hypothyroidism e. Neonatal iron storage disease f. Infantile copper overload g. Multiple acyl-CoA dehydrogenation deficiency (glutaric acid type II) h. Familial erythrophagocytic lymphohistiocytosis D. Hepatitis: 1. Infectious: a. Cytomegalovirus b. Hepatitis B virus (non-A, non-B virus?) c. Rubella virus d. Reovirus type 3 e. Herpesvirus f. Varicella virus g. Coxsackie virus h. Echovirus i. Toxoplasmosis j. Syphilis k. Tuberculosis I. Listeriosis 2. Toxic: a. Cholestasis assocmted with parenteral nutrition b. Sepsis with possible endotoxemia (urinary tract infection, gastroenteritis) E. Genetic or chromosomal: 1. Trisomy E 2. Down's syndrome 3. Donahue's syndrome (Leprechaunism) F. Miscellaneous: 1. Histiocytosis X 2. Shock or hypoperfusion 3. Intestinal obstruction 4. Polysplenia syndrome
From Balistreri WF: Semin Liver Dis 7, 1987.
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the porta hepatis (i. e., similar in location to available tissue from infants with biliary atresia who had undergone portoenterostomy). They noted extensive epithelial cell necrosis and acute inflammation of the extrahepatic bile ducts 1 week after injection. Segmental obliterative fibrosis was observed 2 to 3 weeks after inoculation. Some animals were clinically icteric by that time. Interestingly, complete regeneration occurred in the mice allowed to live longer than 21 days. These investigators carried their study a step further and tested paired sera obtained from babies with biliary atresia and age-matched controls for neutralizing antibodies to reovirus 3. Two (of twenty) affected infants and no controls had elevated antibody titers in their first sera. These two demonstrated a significant increase in titer in subsequent samples. These investigators developed a sensitive and specific indirect immunofluorescent antibody test and have reported their study of 100 infants younger than 6 months of age with varied cholestatic syndromes and 81 age-matched controls. Fifty to sixty per cent of infants with biliary atresia and neonatal hepatitis had antibodies to reovirus 3, while only 7 to 10 per cent of controls and infants with other forms of cholestasis were antibody positive. French investigators, however, found no difference in the rate of antibody positivity in infants with biliary atresia, neonatal hepatitis, and in controls.14 They found antibody to reovirus 3 in 50 per cent of their control infants under 4 months of age and suggested the likelihood that the antibodies to reovirus 3 were passively acquired from the mother. They expressed their reluctance to accept reovirus 3 as an important cause of infantile obstructive cholangiopathy in European countries. Glaser and Morecki24 feel that their observations implicate reovirus 3 as an important agent in the etiology of infantile obstructive cholangiopathy. Their current work is directed toward stimulating regeneration of bile ducts. 23
METABOLIC DISEASES Perusal of Table 1 allows appreciation of the large number of metabolic disorders which can cause infantile cholestasis. I want to make comment on three of these disorders, namely, cystic fibrosis, rr-l-antitrypsin deficiency, and idiopathic hypopituitarism. Cystic Fibrosis This entity has been an extremely uncommon cause of neonatal jaundice in my experience. I suspect that many of these infants have elevated serum bile acid levels but it is unusual for them to present for medical evaluation because of persistent jaundice. Perkins et al. 43 reported two infants with cystic fibrosis and prolonged cholestasis who were initially thought to have biliary atresia. Interestingly, one was a black infant who received a portoenterostomy. The second infant had meconium ileus. Another infant with meconium ileus and sonographically demonstrated inspissated choledochal bile has been reported recently. 10 There have been reports of familial, progressive intrahepatic cholestasis associated with elevated sweat electrolytes. 29, 40 These patients did not have pancreatic
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insufficiency nor pulmonary dysfunction. They all developed an organized cirrhosis. Alpha-I-Antitrypsin Deficiency Liver Disease Balistreri constructed a table of relative frequency of the various forms of neonatal cholestasis based on published series encompassing over 500 cases. 6 Seven to ten per cent of all cases were attributed to a-I-antitrypsin deficiency; the estimated frequency was found to be 0.25 per 10,000 live births. We have found the assay for a-I-antitrypsin to be quite reliable. Infants who are homozygous for protease inhibitor (Pi) ZZ have a-Iantitrypsin levels that are less than 25 per cent of normal. lIeterozygotes (PiMZ) have levels that are 50 to 60 per cent of normal. Only a few of all infants with a-I-antitrypsin deficiency will present with infantile cholestasis. 15 Only 11 per cent of 125 children with homozygous deficiency, based on prospective screening, developed neonatal cholestasis. 63 An additional 6 per cent demonstrated varied manifestations of liver dysfunction while the remaining 83 per cent were healthy. This underscores the need to confirm the disorder histologically. I have seen a patient with PiZZ phenotype and neonatal hepatitis who was assigned a poor prognosis attendant with the diagnosis of a-I-antitrypsin deficiency liver disease. Our biopsy, however, revealed giant cell transformation without PAS-positive paraportal inclusions, and the patient's hepatopathy resolved. The pathogenesis of a-I-antitrypsin deficiency liver disease remains obscure. It seems unlikely that disturbed antiprotease-protease balance is a major factor. 15 More likely is the concept that the accumulation of coreglycosylated, biologically active a-I-antitrypsin in the endoplasmic reticulum somehow irreversibly injures hepatocytes. 1s A recent retrospective analysis of a small series of a-I-antitrypsin deficient children with documented liver disease suggested that breast feeding may offer some protection against early progression of the hepatopathy. 64 All who participate in the evaluation and management of these patients should read Sharp's superb review of this subject in Seminars in Liver Disease from 1982.53 Idiopathic Hypopituitarism Cholestatic liver disease has been reported in association with idiopathic hypopituitarism and septo-optic dysplasia. 35 The patient most commonly presents with icterus, moderate hepatomegaly, and acholic stools. A history of hypoglycemia or seizures, and the physical finding of wandering nystagmus would suggest this diagnosis. 16 It is terribly rare, in my experience, to see profound hypoglycemia with other causes of neonatal cholestasis. We recently managed a 2-month-old patient with liver failure and hypoglycemia of such profundity that we had to provide glucose in a concentration of 25 gm per dl through a central venous catheter to maintain normoglycemia. He displayed mild penile hypoplasia. He had depressed serum thyroxine, TSH, cortisol, and growth hormone levels. Hepatic biopsy revealed profound giant cell transformation. There was intense cholestasis characterized by granular bile pigment in many hepatocytes and canalicular
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Table 2. Infectious Diseases Manifesting Neonatal Cholestasis I. Bacterial A. Gram-negative sepsis, especially E. coli B. Urinary tract infections C. Gram-positive infection, e.g. Listeria monocytogenes D. Tuberculosis E. ? Clostridial infections II. Viral A. Cytomegalovirus B. Hepatitis viruses, e.g. HAV, HBV, and NANBVs C. Herpesvirus D. Rubella E. Coxsackie B F. Echovirus III. Other A. Syphilis B. Toxoplasma gondii
plugging. Electron microscopy revealed liver cells with coalescent cytoplasmic membranes and marked glycogen depletion. The canaliculi were disrupted. There was a marked decrease of endoplasmic reticulum and the mitochondria appeared deformed. Bile concretions and occasional lipid vacuoles were noted. Biopsy tissue obtained 3 months after replacement therapy was instituted revealed clearing of the cholestasis and a decrease in the proportion of giant cells. Mild portal fibrosis was noted. One patient reviewed by Kaufman et al. 35 displayed persistent hepatomegaly and was found to have micronodular cirrhosis at age 2 years. Growth hormone deficiency has not been a universal finding in these patients, which has led some to postulate that cortisol insufficiency, secondary to inadequate ACTH stimulation, might be the primary endocrine abnormality responsible for both the hypoglycemia and the hepatopathy. 38 Others have found ACTH deficiency to be an inconsistent finding,9 which underscores the opinion that the precise mechanism of the cholestasis associated with hypopituitarism remains undefined at this time.
INFECTIOUS DISEASES
The infectious causes of neonatal cholestasis have been relatively constant during the past decade (Table 2). Infection may be acquired in utero, during the birthing process, or postnatally. Findings at the time of presentation usually point toward an infectious process. Bacterial Infections Icterus may be the only manifestation of sepsis in an otherwise healthy appearing infant.67 Serum bilirubin levels can exceed 10 mg per dl, and are predominantly direct reacting. Gram-negative bacteria, especially Escherichia coli, are most often isolated. It had been determined early that a large proportion of neonatal bacterial infections arise from the urinary tract. 16 Circulating endotoxin from cell walls of gram-negative bacteria have been
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causally implicated in the hepatic dysfunction. It has been demonstrated that endotoxin reduces bile How in isolated rat liver preparations. 65 It is suggested that the neonatal liver might be especially sensitive to this pathophysiologic action. Although gram-positive infections are common in neonates, associated hepatic manifestations are distinctly uncommon; infection with Listeria monocytogenes is a noteworthy exception. Affected infants are critically ill. Viral Infections Congenital cytomegalovirus infection occurs in 0.3 to 2.0 per cent of neonates born around the world. 26 It can be transmitted in breast milk. Only 5 to 10 per cent of infants who are congenitally infected with CMV demonstrate clinical symptoms. The classic symptom complex of congenital CMV infection is well known to all pediatricians. 16. 67 The hepatitis viruses, that is, A, B and non-A non-B, rarely cause neonatal cholestasis in my experience. I have, however, participated in the unsuccessful management of a few infants with hepatitis A virus disease who presenteq under 6 months of age with fulminant hepatitis. My recollectioll is that none survived, even though their aminotransferases were only in the 700 to 1000 IU per liter range. Some of the highest aminotransferase levels that I have seen (12,000 and 15,000 IU per liter) have been in infants with herpesvirus hepatitis. Symptoms of this infection may arise in the immediate perinatal period or as long as3 weeks after birth. The average age at onset of symptoms is 6 days.67 The finding of necrotic, ulcerative, or vesicular lesions on the skin or mucous membranes should suggest the diagnosis. The prognosis is poor. 27 Neonates infected with coxsackie B may present with hepatitis, myocarditis, meningoencephalitis, and pancreatitis. Hepatomegaly is common but only a small proportion are icteric. Fatal massive hepatic necrosis has been observed, however, in infants infected with coxsackie B. Toxoplasma gondii
Maternal infection during gestation is necessary for the offspring to develop congenital toxoplasmosis. 59 Many maternal infections are without apparent symptoms, or are mild, which accounts for the estimated 3000 cases of congenital toxoplasmosis in the United States annually. Seventyfive per cent of infected newborns are asymptomatic. 16 Only 10 per cent have serious disease with central nervous system or hepatic involvement in the newborn perioq. The Sabin-Feldman dye test is the diagnostic standard. High titers of IgG anti-Toxoplasma antibody should be followed by more specific tests, e.g., IgM-ELISA or IgM-immunoHuorescent antibody tests. 4 ARTERIOHEPATIC DYSPLASIA This entity, also referred to as Alagille syndrome, is the diagnosis in 5 to 6 per cent of infants with neonatal cholestasis. 6 We recognized these
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patients in the late 1960s because of their associated facial appearance, cardiovascular manifestations, and profound hypercholesterolemia. The first infant in my memory was small and had a facial appearance that suggested Hallermann-Streiff syndrome. I especially recall the benign appearance of the hepatic biopsy. We examined the tissue with electron microscopy for membrane ATP-ase and found this enzyme to be present. I biopsied this patient on four occasions during her first 3 years of life and noted a progressive disappearance of intraportal bile ducts and cholestasis without the development of significant fibrosis. The patient became normobilirubinemic while we were observing a disappearance of intrahepatic bile ducts. We "wondered where the yellow went?" This patient is now 19 years old. The next patient was admitted for biopsy. I was upset with a house officer for obtaining electrolytes without justification. The serum sodium was 128 mEq per liter. We had to repeat it-127 mEq per liter. Urine sodium was 39 mEq per liter. Serum lipids were obtained and the serum cholesterol was 1300 mg per dl. A subsequent patient had a serum cholesterol value of 1900 mg per dl. Most of our patients have had mild heart disease, most commonly peripheral pulmonic stenosis. We have had patients with coarctation of the aorta and, recently, tetralogy of Fallot. We have found evidence of renal dysfunction more often in the patients with significant cardiovascular disease. Eye and bone manifestations are now well established. The classic paper of Alagille et al. in 1975,2 which should be in the files of every pediatrician, stressed the association of retarded physical, mental, and sexual maturation with the arteriohepatic dysplasia and unusual facial appearance. The unusual facial appearance is characteristic but not pathognomonic, as clearly demonstrated by Sokol et al. 56 The facial appearance is hard to describe but major features are deep-set eyes with a prominent protruding nasal bridge, prominent glabella, and pointed chin. There is extreme variability in severity in affected family members. 54 Recent work suggests that the hepatic manifestations of arteriohepatic dysplasia result from a block in the Golgi apparatus, or in the pericanalicular cytoplasm. 66 Sequential hepatobiliary morphology has been carefully described by Kahn and co-workers. 33 Riely recently reviewed familial intrahepatic cholestatic syndromes. 48 It is an excellent, highly readable review that I recommend to the interested reader.
EVALUATION
The infant with direct hyperbilirubinemia persisting beyond 2 to 3 weeks of life deserves attention. The medical history is rarely helpful, but a history of maternal infection during the last trimester, hemolytic disease in the early newborn period, or family history of metabolic disease carries weight. Physical examination, with careful plotting of growth parameters, has significant diagnostic value. Septic infants, as well as those with tyrosinemia, fructose intolerance, and galactosemia, appear ill. Infants with congenital infections and Alaqille's syndrome are small. An enlarged spleen
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is more consistent with congenital infection, storage diseases, and hemolytic disease. Rashes direct the observer toward congenital infection, storage diseases, histiocytosis, and metabolic disorders. I consider stool examination part of the physical examination. Beige or white stool indicates high-grade obstruction and is found most often in otherwise healthy, though icteric, infants. One must insist that the infant receive formula only in the observation period since coloring in solids/oral medicines may confuse the examiner. Needless to say, more than one stool should be examined. I must confess to the reader that I make decisions based on history, physical examination, initial laboratory data, and examination of the stool. I do not intubate the duodenum for fluid collection. Greene and coworkers 25 popularized the 24-hour collection of duodenal fluid for the presence of bile. They positioned an 8 French radiopaque feeding tube in the second and third portions of the duodenum. Fluid was collected by gravity drainage into glass tubes for visual inspection. If no bile pigment was observed in 12 hours, the infant was fed 2 ounces of glucose/electrolyte solution every 2 hours and the fluid collection continued for another 12 hours. Absence of yellow, bilious fluid was interpreted as being consistent with complete obstruction (i.e., biliary atresia). I personally found no advantage of this test over my visual inspection of the stool. British and Chinese investigators have modified this test by examining the fluid for bile acids and Tc-99m DISIDA, respectively, which they suggest further increases the accuracy of the test. 32, 69 Other investigators employ the "string test" and find it to be simpler and as accurate. 50 Our initial tests (Table 3) include CBC, electrolytes, bilirubin with fractions, and hepatic enzymes (SGOT, SGPT, and gamma glutamyl transferase). A direct-reacting bilirubin less than 4 mg per dl is not consistent with complete obstruction. An SGOT/SGPT which is elevated tenfold or greater, especially when associated with a GGT that is less than fivefold increased, supports hepatocellular rather than biliary tract disease. Conversely, an SGOT less than fivefold elevated with a GGT greater than fivefold elevated suggests biliary tract disease, although infants with a-Iantitrypsin deficiency disease often have markedly elevated GGT levels. 18, 46,50 The reader must realize, however, that a low GGT does not exclude biliary atresia. 50 Data obtained to this point dictates further evaluation. Additional laboratory studies often include sweat iontophoresis, a-I-antitrypsin, TORCH and HBV serology, IgM, urine examination for CMV, RBC galactose-I-phosphate uridyl transferase activity, and examination of the urine for reducing substances. Abdominal ultrasonography, performed after a 3- to 4-hour fast, allows evaluation of the liver and biliary tract. Abnormal dilation of the bile duct is readily discerned, and failure to visualize the gallbladder lends weight to a suspicion of biliary atresia. A recent report describes the sonographic features of the "bile plug" syndrome. 14 There has been a large amount of enthusiastic ink extolling hepatobiliary scintigraphy,l. 13.20,36 and with some merit. Certainly biliary patency can be documented and abnormal dilation of the bile duct defined. Failure
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Table 3. Evaluation of the Infant with Persistent Cholestasis I. History/Physical Examination A. Stool Examination II. Initial Laboratory Studies A. CBC, reticulocyte count, platelet count B. Electrolytes, BUN, creatinine C. Hepatic enzymes, e.g., SGOT/SGPT, GGT D. Prothrombin time, APTT E. Protein electrophoresis F. Calcium, phosphorus, alkaline phosphatase III. Specific Tests A. Sweat iontophoresis B. a-I-Antitrypsin C. TORCH, IgM D. Urine exam/culture for CMV E. HBsAgianti-HBc-IgM, ? anti-HAV-IgM F. Urine for reducing substances G. Galactose-I-phosphate uridyl transferase IV. Hepatobiliary Ultrasonography V. Tests for Biliary Patency A. Duodenal intubation: 1. Examination for bile acids 2. Examination for Tc-99m DISIDA 3. String test B. Tc-99m hepatobiliary scintigraphy VI. Hepatic Biapsy VII. Exploratory Laparotomy A. Intraoperative cholangiogram B. Hepatic biopsy C. Portoenterostomy
to detect radionuclide in the intestine or biliary tract, however, cannot be absolutely equated with complete obstruction. I place all infants with acholic stools on phenobarbital (5 mg per kg per day) 3 days before obtaining a fasting (3 to 4 hours) scintiscan. 41 I perform a percutaneous hepatic biopsy when hepatobiliary scintigraphy confirms biliary patency. Possible exceptions might be confirmed cystic fibrosis or congenital infection. Many notable gastroenterologists recommend biopsy of patients with complete obstruction on hepatobiliary scintigraphy as well. It is well accepted that hepatic histology revealing widened portal areas with bile duct proliferation in a jaundiced infant I month old or older is highly suggestive, if not diagnostic, of biliary atresia. I do not perform a percutaneous hepatic biopsy on all icteric infants, however. I recommend laparotomy for the infant passing acholic stools with a direct bilirubin fraction greater than 4 mg per dl, a GGT greater than fivefold elevated, a normal a-I-antitrypsin level, and nonvisualization of the intestine on hepatobiliary scintigraphy. The gallbladder of most of these infants cannot be identified on fasting abdominal ultrasonography. Hepatic tissue obtained by either closed or open techniques are studied by both light and electron microscopy.
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MANAGEMENT
Surgical The surgeon is prepared to perform a portoenterostomy when exploratory laparotomy is elected. I cannot recall sending a single patient for exploratory laparotomy who did not have biliary atresia. The technical aspects of the hepatoportal reconstructive surgery performed at my institution have been reviewed,68 and, to be candid, are beyond my expertise and the intention of this treatise. The reader is further referred to other current reviews of surgical management by deVries and COX,12 Howard,30 and a ven' recent, in-depth, nicely illustrated review of the surgical technique by Ryckman and Noseworthy.51 Most gastroenterologists consider hepatoportoenterostomy a temporizing measure, althoug)1 we, like others, have more than a few patients who are over 5 years of age and are anicteric, without a hint of hepatic failure. These patients (it is hoped) will never require transplantation but they are now of sufficient size and age that transplantation is likely to be successful, should it become a necessary consideration. We would seem to be in agreement with the recent position statement of Lilly, Hall, and Altman 39 in this regard. We always hope that drainage following portoenterostomy will be sufficient to defer hepatic failure until after the first year of life, at the very least. We refer patients with chronic liver disease for transplantation when it is clear that the patient's liver is failing progressively, in spite of optimal medical therapy. Medical The medical management of the infant with chronic liver disease depends on specific diagnosis. 57 Management of the patient with chronic cholestasis demands certain knowledge and skills. Inadequate bile How results in insufficient delivery of bile salts to the proximal small bowel, leading to malabsorption of fat and fat-soluble vitamins. Retention of bile acids and other substances normally secreted in bile causes progressive liver damage culminating in end-stage cirrhosis. The consequences of cholestasis must be kept in mind when monitoring the patient and planning medical strategy (Table 4). Efforts are directed toward stimulating or enhancing bile How and preventing the nutritional deficiencies that logically accompany prolonged intraluminal bile salt insufficiency. An excellent, indepth review of the medical management of the infant with chronic cholestasis has been published recently. 57 The reader will note that I prefer to offer my infants a low-fat, elemental formulation (Vital HN, Ross Laboratories, Columbus, Ohio) at a caloric density of 0.67 kcal per ml, recognizing that iron and calcium supplementation is necessary. This formula provides 9.4 per cent of its calories as fat, 5 per cent as linoleic acid, which considers malabsorption in meeting the essential fatty acid requirement of 2.7 per cent of total calories. The remaining 4 per cent is in the form of medium-chain triglycerides (MCT). It does not provide a significant load of long-chain triglycerides to these infants, which, in the face of bile salt deficiency, would result in steatorrhea with its attendant consequences. I do not recommend Portagen (Mead
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Table 4. Medical Management of the Infant with Persistent Cholestasis I. Formula: A. Viral HN, 0.67 kcallml, 1.25 x calculated caloric need II. Vitamins: A. Water-soluble: twice the recommended daily allowance B. Fat-soluble: 1. Vitamin A: aquasol A, 10,000 to 15,000 IV/day 2. Vitamin 0: cholecalciferol, 1200 to 5000 IV/day 3. Vitamin E: Alpha-tocopherol, 100 to 400 IV/day 4. Vitamin K: water-soluble derivative of menadione, 2.5 to 5 mg on alternate days III. Micronutrients: A. Calcium: elemental, 25 to 100 mg/kg B. Phosphorus: 25 to 50 mg/kg/day C. Zinc: zinc sulfate solution, 1 mg/kg/day IV. Choleretic Agents: A. Phenobarbital, 5 mg/kg/day B. Cholestyramine, 0.25 gm/kg/day, given in 3 doses, with feedings V. Management of Ascites: A. Spironolactone, 3 to 5 mg/kg/day B. Furosemide, 1 to 2 mg/kg every other day to twice daily C. Sodium restriction, 1 mEq/kg/day, if feasible
Johnson, Evansville, Indiana) because this formula provides only 2.5 per cent of its total calories as linoleic acid, and I strongly doubt that all of the calories provided as MCT are utilized because they are not stored. Furthermore, it is conceivable that the underutilized metabolites of MCT may have a deleterious effect on body chemistry (e.g., acid-base balance). Infants with neonatal cholestasis develop fat-soluble vitamin deficiencies in spite of the provision of these vitamins in usual dosage. These infants must be monitored closely and supplemented appropriately. We monitor vitamin E status in our infants by measuring both the serum vitamin E level and erythrocyte peroxide hemolysis (EPR), which correlates with erythrocyte membrane vitamin E levels. Erythrocyte peroxide hemolysis less than 20 per cent always equates with vitamin E sufficiency, in our experience. 8 I am often unable to accomplish vitamin E sufficiency with massive dosages of standard vitamin E. These patients acquire normal vitamin E levels and EPR less than 20 per cent when administered the investigational water-soluble preparation, o-a-tocopherol polyethylene glycol-lOOO succinate (TPGS) in a dosage of 20 IV per kg per day. Studies are being conducted to ensure the safety of this preparation. I often find it necessary to administer parenteral vitamin K to these infants, usually at biweekly intervals. I have not found it necessary to provide vitamin A parenterally, although this has been recommended. 3 Severely obstructed infants almost always fail to maintain normal serum vitamin D levels and normal calcium homeostasis with oral cholecalciferol and require or~l 25-hydroxyvitamin D (3-5 I-Lg per kg per day) or 1,25 dihydroxyvitamin D (0.05-0.2 I-Lg per kg per day). Enteral supplementation of elemental calcium (25-100 mg per kg per day) and phosphorus (25 to 50 mg per kg per day) may be necessary to correct bone demineralization. 57 I administer phenobarbital (5 mg per kg per day) to stimulate bile acidindependent bile flow, and cholestyramine (0.25 gm per kg per day) to stimulate bile acid-dependent bile flow in patients with intrahepatic cho-
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lestasis. I do not administer cholestyramine to the infant with a portoenterostomy. Transplantation Unfortunately, many infants with persistent cholestasis develop progressive hepatic fibrosis/cirrhosis, ending in hepatic failure, despite our best efforts. Orthotopic hepatic transplantation is then the only remaining consideration. 19 I defer transplantation until I am unable to control the clinical manifestations ofliver failure. I hope to delay referral to a transplant center for at least 1 year, but this is not always possjble. Orthotopic hepatic transplantation has been uniformly successful in recent years in our patients over 1 year of age at the time of transplantation. One patient with neonatal hepatitis, with profound giant cell transformation, developed a similar pathologic process in the implant leading to hepatic failure and death. Our experience with infants less than 1 year of age has been uniformly dismal.
SUMMARY We no longer view the infant with persistent cholestasis with a "wait and see" strategy. Identification of the cause of "neonatal hepatitis" may allow specific treatment. Improved surgical techniques for portoenterostomy have provided early hope for patients with biliary atresia. Rapidly advancing nutritional strategies allow many portoenterostomy failures an additional further option, that is, hepatic transplantation. I express my thanks to the many investigators who have contributed and are continuing to advance the progress recounted in this review. Perusal of the references cited in this review makes clear the identity of these investigators. ACKNOWLEDGMENT I express my gratitude to Vicki Havilaqd for her assistance in the prepation of this article.
REFERENCES 1. Abramson SJ, Treves S, Littlewood-Teele R: The infant with possible biliary atresia: Evaluation by ultrasound and nuclear medicine. Pediatr RadioI12:1, 1982 2. Alagille D, Odievre M, Gautier M et al: Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental and sexual development, and cardiac murmur. J Pediatr 86:63, 1975 3. Alagille D: Management of chronic cholestasis in childhood. Sem Liver Dis 5:254, 1985 4. Alpert G, Plotkin SA: A practical gUide to the diagnosis of cougenital infections in the newborn infant. Pediatr Clin North Am 33:465, 1986 5. Balistreri WF: Neonatal cholestasis. J Pediatr 106:171, 1985 6. Balistreri WF: Neonatal cholestasis: Lessons from the past, issues for the future. Semin Liver Dis 7:Foreword, 1987 7. Bangaru B, Morecki R, Glaser JH et al: Comparative studies of biliary atresia in the human newborn and reovirus-induced cholangitis in weanling mice. Lab Invest 43:456, 1980 8. Clark JH, Nagamori KE, Ellett ML et al: Vitamin E suffiCiency in children with cholestasis:
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a comparison between erythrocyte peroxide hemolysis and serum a-tocopherol. Clin Chim Acta 153:117, 1985 Copeland KC, Franks RC, Ramamurthy R: Neonatal hyperbilirubinemia and hypoglycemia in congenital hypopituitarism. Clin Pediatr 20:523, 1981 Davies MB, Daneman A, Stringer DA: Inspissated bile in a neonate with cystic fibrosis .. J Ultrasound Med 5:335, 1986 Desmet VJ: Cholangiopathies: Past, present and future. Semin Liver Dis 7:67, 1987 deVries PA, Cox KL: Surgical treatment of congenital and neonatal biliary obstruction. Surg Clin North Am 61:987, 1981 Dick MC, Mowat AP: Biliary scintigraphy with DISIDA. Arch Dis Child 61:191, 1986 Dussaix E, Hadchouel M, Tardieu M et al: Biliary atresia and reovirus 3 infection. N Engl J Med 310:658, 1984 . Eriksson SG: Liver disease in alpha-I-antitrypsin deficiency. Scand J GastroenteroI20:907, 1985 . Felber S, Sinatra F: Systemic disorders associated with neonatal cholestasis. Semin Liver Dis 7:108, 1987 Freese D: Intracellular cholestatic syndromes of infancy. Semin Liver Dis 2:255, 1982 Fung KP, Lau SP: Gamma glutamy transpeptidase activity and its serial measurement in differentiation between extrahepatic biliary atresia and neonatal hepatitis. J Pediatr Gastroenterol Nutr 4:208, 1985 Gartner JC Jr, Zitelli BJ, Malatack JJ ei: al: Orthotopic liver transplantation in children: Two-year experience with 47 patients. Pediatrics 74:140, 1984 Gerhold JP, Klingensmith WC, Kuni CC et al: Diagnosis of biliary atresia with radionuclide imaging. Radiology 146:499, 1983 Ghishan FK, Greene HL: Inborn errors of metabolism that lead to permanent liver injury. In Zakin D, Boyer TD (eds): Hepatology. Philadelphia, WB Saunders, 1982, p 1084 Glaser JH, Balistreri WF, Morecki R: Role of reovirus type 3 in persistent infantile cholestasis. J Pediatr 105:912, 1984 Glaser JH, Morecki R, Fallon-Friedlander Set al: An extrahepatic bile duct growth factor: In vivo effect and preliminary characterization. Hepatology 7:272, 1987 Glaser JH, Morecki R: Reovirus type 3 and neonatal cholestasis. Serilin Liver Dis 7:100, 1987 Greene HL, Helinek GL, Moran R: A diagnostic approach to prolonged obstructive jaundice by 24-hour collection of duodenal fluid. J Pediatr 95:412, 1979 Griffiths PD: Cytomegalovirus and the liver. Semin Liver Dis 4:307, 1984 Hamory BH, Luger A, Kobberman T: Herpesvirus hominis hepatitis of mother and newborn infant. South Med J 74:992, 1981 Hays DM: Differences in attitude toward the management of biliary atresia among surgeons in Japan and in North America. J Pediatr Surg 4:580, 1979 Hillemeier AC, Hen J, Riely CA et al: Meconium peritonitis and increasing sweat chloride determinations in a case of familial progressive intrahepatic cholestasis. Pediatrics 69:325, 1982 Howard ER: Extrahepatic biliary atresia: A review of current management. Br J Surg 70:193, 1983 Hyams JS, Glaser JH, Leichtner AM et al: Discordance for biliary atresia in two sets of monozygotic twins. J Pediatr 107:420, 1985 Jaw T-S, Wu C-C, Ho Y-H et al: Diagnosis of obstructive jaundice in infants: Tc-99m DISIDA in duodenal juice. J Nucl Med 25:360, 1984 Kahn EI, Daum F, Markowitz J et al: Arteriohepatic dysplasia. II. Hepatobiliary morphology. Hepatology 3:77, 1983 Kasai M, Kimura S, Asakura Y et al: Surgical treatment of biliary atresia. J Pediatr Surg 3:665,1968 Kaufman FR, Costin G, Thomas DW et al: Neonatal cholestasis and hypopituitarism. Arch Dis Child 59:787, 1984 Kirks DR, Coleman RE, Filston HC et al: An imaging approach to persistent neonatal jaundice. Am J RadioI142:461, 1984 Landing BH: Considerations on the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst: The concept ofinfantile obstructive cholangiopathy. Prog Pediatr Surg 6:113,1974
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38. Leblanc A, Odievre M, Hadchouel M et al: Neonatal cholestasis and hypoglycemia: possible role of cortisol deficiency. J Pediatr 99:577, 1981 39. Lilly JR, Hall RJ, Altman RP: Liver transplantation and Kasai operation in the first year of life: therapeutic dilemma in biliary atresia. JPediatr 110:561, 1987 40. Lloyd-Still JD: Familial cholestasis, with elevated sweat electrolyte concentrations. J Pediatr 99:580, 1981 41. Majd M, Reba RC, Altman RP:Hepatobiliary scintigraphy with 99m Tc-PIPIDA in evaluation of neonatal jaundice. Pediatrics 67:140, 1981 42. Morecki R, Glaser JH, Cho S et al: Biliary atresia and reovirus type 3 infection. N Eng! J Med 307:481, 1982 43. Perkins WG, Klein GL, Beckerman RC: Cystic fibrosis mistaken for idiopathic biliary atresia. Clin Pediatr 24:107, 1985 44. Pfeiffer WR, Robinson LH, Balsara VJ: Sonographic features of bile plug syndrome. j Ultrasourtd Med 5:161, 1986 45. Phillips MJ, Poucell S, Oda M: Biology of disease: Mechanisms of cholestasis. Lab Invest 54:593, 1986 46. Platt MS, Potter JL, Boeckman CR et al: Elevated GGTP/SGOT ratio. Am J Dis Child 135:834, 1981 47. Reichen J, Simon FR: Mechanisms of cholestasis. Internat Rev Exp Bioi 26:231, 1984 48. Riely CA: Familial intrahepatic cholestatic syndromes. Semin Liver Dis 7:119, 1987 49. Rosenberg DP, Morecki R, Lollini 0 et al: Extrahepatic biliary atresia in a rhesus monkey (Macaca mulatta). Hepatology 3:577, 1983 50. Rosenthal P, Liebman WM, Sinatra F et al: String test in evaluation of cholestatic jaundice of infancy. J l'ediatr 107:253, 1985 51. Ryckman FC, Noseworthy J: Neonatal cholestatic conditions requiring surgical reconstruction. Semin Liver Dis 7:134, 1987 52. Setchell KD, Street JM: Inborn errors of bile acid synthesis. Semin Liver Dis 7:85, 1987 53. Sharp HL: Alpha-I-antitrypsin: An ignored protein iiI understanding liver disease. Semin Liver Dis 2:314, 1982 54. Shulman SA, Hyams JS, Gunta R et al: Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Gen 19:325, 1984 55. Sinatra F: The role of gamma g!utamyl transpeptidase in the preoperative diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 4:167, 1985 56. Sokol RJ, Heubi JE, Balistreri WF: Intrahepatic "cholestasis facies": is it specific for Alagille syndrome? J Pediatr 103:205, 1983 57. Sokol RJ: Medical management of the infant or child with chronic liver disease. Semin Liver Dis 7:155, 1987 58. Stanley NF, Dorman PC, Ponsford J: Studies on the pathogenesis of a hitherto undescribed virus (hepatoencephalomyelitis) producing unusual symptoms in suckling mice. Aust J Exp Bioi Med Sci 31:147, 1953 59. Stray-Pedersen B: Infants potentially at risk for congenital toxoplasmosis. Am J Dis Child 134:638, 1980 60. Strickland AD, Shannon K, Coin CD: Biliary atresia in two sets of twins. J Pediatr 107:418, 1985 61. Strickland AD, Shannon K: Studies in the etiology of extrahepatic biliary atresia: time clustering. J Pediatr 100:749, 1982 62. Suchy FJ, Bucuvalas JC, Novak DA: Determinants of bile formation during development: Ontogeny of hepatic bile acid metabolism and transport. Semin Liver Dis 7:77, 1987 63. Sweger T: Liver disease in alpha-I-antitrypsin deficiency detected by screening of 200,000 infants. N Eng! J Med 294:13i6, 1976 64. Udall IN, Dixon M, Newman AP, et al: Liver disease in alpha-I-antitrypsin deficiency: a retrospective analysis of the influence of early breast, vs bottle-feeding. JAMA 253:2679, 1985 65. Utili R, Abernathy CO, Zimmerman HJ: Cholestatic effects of Escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 70:248, 1976 66. Valencia-Majoral P, Weber J, Cutz E et al: Possible defect in the bile secretory apparatus in arteriohepatic dysplasia (Alagille's syndrome): A review with observations on the ultrastructure of liver. Hepatology 4:691, 1984 67. Watkins J, Sunaryo FP, Berezin SH: Hepatic manifestations of congenital and perinatal disease. Clin Perinatol 8:467, 1981
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68. Weber TR, Grosfeld JL: Contemporary management of biliary atresia. Surg Clin North Am 61:1079, 1981 69. Yamashiro Y, Robinson PG, Lari J et al: Duodenal bile acids in diagnosis of biliary atresia. J Pediatr Surg 18:278, 1983 James Whitcomb Riley Hospital for Children 702 Barnhill Drive Indianapolis, Indiana 46223
0031-3955/88 $0.00
+ .20
Cholestatic Disorders of Infancy
Joseph F. Fitzgerald, MD
Obstructive liver disease of infancy, a familiar term to physicians of my vintage, has given way to the terms neonatal cholestasis and cholestatic disorders of infancy. The term cholestasis was coined by Popper and is preferred because it acknowledges that the pathology may be functional and at the level of the hepatocyte, instead of a mechanical obstruction. 47 Yet, occasional use of "obstructive liver disease ofinfancy" allows reflection on the past and illumination of the inroads that have been made in neonatal hepatology in the past score of years. How well I recall my anxiety in the mid-1960s when asked to examine an icteric 5- to 6-week old infant. It was commonly recognized that children with congenital infections and metabolic disorders tended to appear sick, while those with extrahepatic biliary atresia (it was thought that there was an intrahepatic form) were well, overall. A deep inner sadness would consume me as I examined the healthy, tan, 6week-old infant with icteric sclerae, hepatomegaly, a full spleen tip, and acholic stools. The diagnosis of biliary atresia was likely, which meant that this infant would melt away before his parents' eyes and succumb before his first birthday. It was commonplace for these infants to be sent to our colleagues in surgery who would perforrri diagnostic laparotomies. Causes other than biliary atresia were found on rare occasion, which, appropriately, led to concern that the underlying condition might be affected negatively by the surgical procedure. Indeed, it was reasoned that if we had nothing to offer the patient with biliary atresia, and if we might be harming infants with other causes of cholestasis by subjecting them to a surgical procedure, why operate on any of these infants? Various tests were touted as the tool which could separate the completely obstructed infant (i.e., with biliary atresia) from the others, but none was found to have 100 per cent specificity. The scene changed dramatically following the report of Kasai et al. in the Journal of Pediatric Surgery in 1968. 34 Interestingly, their report was received with some temperance in North America. Several pediatric surgeons of high stature in the United States traveled to Japan to investigate the experience and returned with glowing support for the procedure(s) *Professor of Pediatrics, Indiana University School of Medicine; Gastroenterologist, James Whitcomb Riley Hospital for Children, Indianapolis, Indiana
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espoused. These surgeons taught these procedures to others, and this type of neonatal biliary surgery became commonplace in the United States. 2B This allowed us to offer some hope to these families. We were aware of the fact that some of the patients who were not completely obstructed, that is, who had normally pigmented stools or a patent biliary tree at surgery, progressed to end-stage cirrhosis. Many of these infants with "neonatal hepatitis" probably had a metabolic disease such as a-I-antitrypsin deficiency. Occasionally, more than one infant in a family demonstrated similar findings and a course resulting in death. I once reviewed records of four children born around 1950 who had progressive neonatal liver disease leading to cirrhosis and death in the first year of life. Many of these familial defects in bile movement have now been identified. Landing37 carefully pointed out the histologic similarities of neonatal hepatitis, biliary atresia, and choledochal cyst, and suggested that these entities were separate points on a continuum. The continuum/spectrum was designated "infantile obstructive cholangiopathy." N ewer diagnostic techniques have improved selection of patients for surgical management, and advanced surgical techniques have improved the number of infants with hepatic bile drainage. Improvements in nutritional monitoring and the availability of unique nutritional solutions have greatly increased prolonged survival in this patient population. Finally, the coming of the cyclosporine era in orthotopic hepatic transplantation has provided another dimension in the management of the infant with a progressive hepatopathy. I must confess to more than a little excitement as I recount the experience of the last 20 years.
PATHOPHYSIOLOGY OF CHOLESTASIS Cholestasis indicates impaired bile formation and excretion, and the retention of biliary constituents in the liver and blood. 45 , 47 In spite of the progress made in our understanding of cholestasis, complete understanding of the physiochemistry of bile flow is still lacking. Bile flow is dependent on hepatocellular uptake of plasma constituents, transhepatic transport and metabolic processing of these constituents, the activity of the bile secretory apparatus, involvement of the cytoskeleton, the fluidity and permeability of membranes, the paraductular pathway of bile formation, and ductular modifications of canalicular bile. 45 Many of these biologic steps in bile flow are incompletely developed in the neonate. 17 Bile acid synthesis, uptake, excretion, and ileal reabsorption have been shown to be decreased in the neonate compared to adult levels. Total bile acid pool size in newborns is approximately 50 per cent of the pool size of adults; it is further reduced in prematurely born infants. Balistreri5 has pointed out that newborns have a cholestatic propensity. This is attributed to immaturity of hepatic excretory function, inborn errors of bile acid metabolism resulting in hepatic dysfunction, and an inherent susceptibility to viral or toxic insult, which produces an exaggerated and stereotypic response in the immature liver. The more interested reader should treat him- or herself to the thorough reviews of the ontogeny of hepatic bile acid metabolism and transport,62
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and inborn errors of bile acid synthesis, 52 recently published in Seminars in Liver Disease. PRESENTATION AND DIFFERENTIAL DIAGNOSIS Infants with cholestatic disorders are often asymptomatic and come for evaluation when direct hyperbilirubinemia persists beyond the first 3 weeks of life. Some, however, especially those with congenital infections, are of concern early because they are small for gestational age, often microcephalic, and have splenomegaly as well as hepatomegaly.67 Infants with bacterial infections and metabolic hepatopathies usually appear ill at presentation. 21, 67 The differential diagnosis is of some length (Table 1), and it is fluid, with new causes added each year. It has been pointed out that the neonatal liver is uniquely susceptible to a wide variety of injuries that may result in a similar response, that is, giant cell transformation, inflammation, hepatocellular necrosis, extramedullary hematopoiesis, and the development of fibrosis. 6 It should not be surprising then that the entities comprising the continuum designated generically as "infantile obstructive cholangiopathy" account for three quarters of the cases of neonatal cholestasis. a-I-Antitrypsin deficiency and arteriohepatic dysplasia (Alaqille's syndrome) account for an additional 10 to 15 per cent. INFANTILE OBSTRUCTIVE CHOLANGIOPATHY These conditions had been recognized individually for decades before Landing37 suggested a responsive relationship and that atresia of extrahepatic and intrahepatic bile ducts was not due to defective development but to progressive destruction of bile ducts. It has been learned that fibrous obliteration of the bile ducts is only one histologic aspect of the cholangiopathy, and that additional histopathologic features (e.g., necrosis, inflammation, and periductal fibrosis) are also observed. 11 Various observers noted clustering of cases of biliary atresia over the years and considered the possible influences of infectious agents and environmental toxins on this developmental condition. I saw three infants with biliary atresia from the same area of southwestern Indiana over a 2month period in 1970. Strickland and Shannon61 studied 30 cases of biliary atresia from north Texas and found that a preponderance of affected infants were from rural counties, and that they presented during the late summer/ early fall (August-October). Two studies of twins, which included some who were monozygotic, led to a conclusion that biliary atresia was not inherited but acquired. 31,60 The above observations created an environment which was desperate for direction. This has, perhaps, been provided by Glaser, Morecki, and coinvestigators. 7, 22-24, 42, 49 They recalled the early report of Stanley et al. 58 who described intrahepatic lesions in newborn mice infected with reovirus 3 and designed similar experiments but focused on morphologic changes at
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Table 1. Neonatal Cholestasis: Etiologic Classification I. Extrahepatic Disorders A. Biliary atresia B. Biliary hypoplasia C. Bile duct stenosis D. Anomalies of choledochal-pancreatico-ductal junction E. Spontaneous perfuration of bile duct F. Mass (neoplasia, stone) G. Bile/mucous plug II. Intrahepatic Disorders A. Idiopathic: 1. Idiopathic neonatal hepatitis 2. Intrahepatic cholestasis, persistent a. Arteriohepatic dysplasia (Alagille syndrome) b. Byler disease (severe intrahepatic cholestasis with progressive hepatocellular disease) c. Trihydroxycoprostanic acidemia (defective bile acid metabolism and cholestasis) d. Zellweger syndrome (cerebrohepatorenal syndrome) e. Nonsyndromic paucity of intrahepatic ducts (apparent absence of bile ductules) 3. Intrahepatic cholestasis, recurrent (syndromic?) a. Familial benign recurrent cholestasis b. Hereditary cholestasis with lymphedema (Aagenaes) B. Anatomic: 1. Disorders of amino acid metabolism 2. Caroli's disease (cystic dilation of intrahepatic ducts) C. Metabolic disorders: 1. Disorders of amino acid metabolism a. Tyrosinemia 2. Disorders of lipid metabolism a. Wolman's disease b. Niemann-Pick disease c. Gaucher's disease 3. Disorders of carbohydrate metabolism: a. Galactosemia b. Fructosemia c. Glycogenosis IV 4. Metabolic disease in which the defect is uncharacterized a. a-I-Antitrypsin deficiency b. Cystic fibrosis c. Idiopathic hypopituitarism d. Hypothyroidism e. Neonatal iron storage disease f. Infantile copper overload g. Multiple acyl-CoA dehydrogenation deficiency (glutaric acid type II) h. Familial erythrophagocytic lymphohistiocytosis D. Hepatitis: 1. Infectious: a. Cytomegalovirus b. Hepatitis B virus (non-A, non-B virus?) c. Rubella virus d. Reovirus type 3 e. Herpesvirus f. Varicella virus g. Coxsackie virus h. Echovirus i. Toxoplasmosis j. Syphilis k. Tuberculosis I. Listeriosis 2. Toxic: a. Cholestasis assocmted with parenteral nutrition b. Sepsis with possible endotoxemia (urinary tract infection, gastroenteritis) E. Genetic or chromosomal: 1. Trisomy E 2. Down's syndrome 3. Donahue's syndrome (Leprechaunism) F. Miscellaneous: 1. Histiocytosis X 2. Shock or hypoperfusion 3. Intestinal obstruction 4. Polysplenia syndrome
From Balistreri WF: Semin Liver Dis 7, 1987.
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the porta hepatis (i. e., similar in location to available tissue from infants with biliary atresia who had undergone portoenterostomy). They noted extensive epithelial cell necrosis and acute inflammation of the extrahepatic bile ducts 1 week after injection. Segmental obliterative fibrosis was observed 2 to 3 weeks after inoculation. Some animals were clinically icteric by that time. Interestingly, complete regeneration occurred in the mice allowed to live longer than 21 days. These investigators carried their study a step further and tested paired sera obtained from babies with biliary atresia and age-matched controls for neutralizing antibodies to reovirus 3. Two (of twenty) affected infants and no controls had elevated antibody titers in their first sera. These two demonstrated a significant increase in titer in subsequent samples. These investigators developed a sensitive and specific indirect immunofluorescent antibody test and have reported their study of 100 infants younger than 6 months of age with varied cholestatic syndromes and 81 age-matched controls. Fifty to sixty per cent of infants with biliary atresia and neonatal hepatitis had antibodies to reovirus 3, while only 7 to 10 per cent of controls and infants with other forms of cholestasis were antibody positive. French investigators, however, found no difference in the rate of antibody positivity in infants with biliary atresia, neonatal hepatitis, and in controls.14 They found antibody to reovirus 3 in 50 per cent of their control infants under 4 months of age and suggested the likelihood that the antibodies to reovirus 3 were passively acquired from the mother. They expressed their reluctance to accept reovirus 3 as an important cause of infantile obstructive cholangiopathy in European countries. Glaser and Morecki24 feel that their observations implicate reovirus 3 as an important agent in the etiology of infantile obstructive cholangiopathy. Their current work is directed toward stimulating regeneration of bile ducts. 23
METABOLIC DISEASES Perusal of Table 1 allows appreciation of the large number of metabolic disorders which can cause infantile cholestasis. I want to make comment on three of these disorders, namely, cystic fibrosis, rr-l-antitrypsin deficiency, and idiopathic hypopituitarism. Cystic Fibrosis This entity has been an extremely uncommon cause of neonatal jaundice in my experience. I suspect that many of these infants have elevated serum bile acid levels but it is unusual for them to present for medical evaluation because of persistent jaundice. Perkins et al. 43 reported two infants with cystic fibrosis and prolonged cholestasis who were initially thought to have biliary atresia. Interestingly, one was a black infant who received a portoenterostomy. The second infant had meconium ileus. Another infant with meconium ileus and sonographically demonstrated inspissated choledochal bile has been reported recently. 10 There have been reports of familial, progressive intrahepatic cholestasis associated with elevated sweat electrolytes. 29, 40 These patients did not have pancreatic
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insufficiency nor pulmonary dysfunction. They all developed an organized cirrhosis. Alpha-I-Antitrypsin Deficiency Liver Disease Balistreri constructed a table of relative frequency of the various forms of neonatal cholestasis based on published series encompassing over 500 cases. 6 Seven to ten per cent of all cases were attributed to a-I-antitrypsin deficiency; the estimated frequency was found to be 0.25 per 10,000 live births. We have found the assay for a-I-antitrypsin to be quite reliable. Infants who are homozygous for protease inhibitor (Pi) ZZ have a-Iantitrypsin levels that are less than 25 per cent of normal. lIeterozygotes (PiMZ) have levels that are 50 to 60 per cent of normal. Only a few of all infants with a-I-antitrypsin deficiency will present with infantile cholestasis. 15 Only 11 per cent of 125 children with homozygous deficiency, based on prospective screening, developed neonatal cholestasis. 63 An additional 6 per cent demonstrated varied manifestations of liver dysfunction while the remaining 83 per cent were healthy. This underscores the need to confirm the disorder histologically. I have seen a patient with PiZZ phenotype and neonatal hepatitis who was assigned a poor prognosis attendant with the diagnosis of a-I-antitrypsin deficiency liver disease. Our biopsy, however, revealed giant cell transformation without PAS-positive paraportal inclusions, and the patient's hepatopathy resolved. The pathogenesis of a-I-antitrypsin deficiency liver disease remains obscure. It seems unlikely that disturbed antiprotease-protease balance is a major factor. 15 More likely is the concept that the accumulation of coreglycosylated, biologically active a-I-antitrypsin in the endoplasmic reticulum somehow irreversibly injures hepatocytes. 1s A recent retrospective analysis of a small series of a-I-antitrypsin deficient children with documented liver disease suggested that breast feeding may offer some protection against early progression of the hepatopathy. 64 All who participate in the evaluation and management of these patients should read Sharp's superb review of this subject in Seminars in Liver Disease from 1982.53 Idiopathic Hypopituitarism Cholestatic liver disease has been reported in association with idiopathic hypopituitarism and septo-optic dysplasia. 35 The patient most commonly presents with icterus, moderate hepatomegaly, and acholic stools. A history of hypoglycemia or seizures, and the physical finding of wandering nystagmus would suggest this diagnosis. 16 It is terribly rare, in my experience, to see profound hypoglycemia with other causes of neonatal cholestasis. We recently managed a 2-month-old patient with liver failure and hypoglycemia of such profundity that we had to provide glucose in a concentration of 25 gm per dl through a central venous catheter to maintain normoglycemia. He displayed mild penile hypoplasia. He had depressed serum thyroxine, TSH, cortisol, and growth hormone levels. Hepatic biopsy revealed profound giant cell transformation. There was intense cholestasis characterized by granular bile pigment in many hepatocytes and canalicular
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Table 2. Infectious Diseases Manifesting Neonatal Cholestasis I. Bacterial A. Gram-negative sepsis, especially E. coli B. Urinary tract infections C. Gram-positive infection, e.g. Listeria monocytogenes D. Tuberculosis E. ? Clostridial infections II. Viral A. Cytomegalovirus B. Hepatitis viruses, e.g. HAV, HBV, and NANBVs C. Herpesvirus D. Rubella E. Coxsackie B F. Echovirus III. Other A. Syphilis B. Toxoplasma gondii
plugging. Electron microscopy revealed liver cells with coalescent cytoplasmic membranes and marked glycogen depletion. The canaliculi were disrupted. There was a marked decrease of endoplasmic reticulum and the mitochondria appeared deformed. Bile concretions and occasional lipid vacuoles were noted. Biopsy tissue obtained 3 months after replacement therapy was instituted revealed clearing of the cholestasis and a decrease in the proportion of giant cells. Mild portal fibrosis was noted. One patient reviewed by Kaufman et al. 35 displayed persistent hepatomegaly and was found to have micronodular cirrhosis at age 2 years. Growth hormone deficiency has not been a universal finding in these patients, which has led some to postulate that cortisol insufficiency, secondary to inadequate ACTH stimulation, might be the primary endocrine abnormality responsible for both the hypoglycemia and the hepatopathy. 38 Others have found ACTH deficiency to be an inconsistent finding,9 which underscores the opinion that the precise mechanism of the cholestasis associated with hypopituitarism remains undefined at this time.
INFECTIOUS DISEASES
The infectious causes of neonatal cholestasis have been relatively constant during the past decade (Table 2). Infection may be acquired in utero, during the birthing process, or postnatally. Findings at the time of presentation usually point toward an infectious process. Bacterial Infections Icterus may be the only manifestation of sepsis in an otherwise healthy appearing infant.67 Serum bilirubin levels can exceed 10 mg per dl, and are predominantly direct reacting. Gram-negative bacteria, especially Escherichia coli, are most often isolated. It had been determined early that a large proportion of neonatal bacterial infections arise from the urinary tract. 16 Circulating endotoxin from cell walls of gram-negative bacteria have been
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causally implicated in the hepatic dysfunction. It has been demonstrated that endotoxin reduces bile How in isolated rat liver preparations. 65 It is suggested that the neonatal liver might be especially sensitive to this pathophysiologic action. Although gram-positive infections are common in neonates, associated hepatic manifestations are distinctly uncommon; infection with Listeria monocytogenes is a noteworthy exception. Affected infants are critically ill. Viral Infections Congenital cytomegalovirus infection occurs in 0.3 to 2.0 per cent of neonates born around the world. 26 It can be transmitted in breast milk. Only 5 to 10 per cent of infants who are congenitally infected with CMV demonstrate clinical symptoms. The classic symptom complex of congenital CMV infection is well known to all pediatricians. 16. 67 The hepatitis viruses, that is, A, B and non-A non-B, rarely cause neonatal cholestasis in my experience. I have, however, participated in the unsuccessful management of a few infants with hepatitis A virus disease who presenteq under 6 months of age with fulminant hepatitis. My recollectioll is that none survived, even though their aminotransferases were only in the 700 to 1000 IU per liter range. Some of the highest aminotransferase levels that I have seen (12,000 and 15,000 IU per liter) have been in infants with herpesvirus hepatitis. Symptoms of this infection may arise in the immediate perinatal period or as long as3 weeks after birth. The average age at onset of symptoms is 6 days.67 The finding of necrotic, ulcerative, or vesicular lesions on the skin or mucous membranes should suggest the diagnosis. The prognosis is poor. 27 Neonates infected with coxsackie B may present with hepatitis, myocarditis, meningoencephalitis, and pancreatitis. Hepatomegaly is common but only a small proportion are icteric. Fatal massive hepatic necrosis has been observed, however, in infants infected with coxsackie B. Toxoplasma gondii
Maternal infection during gestation is necessary for the offspring to develop congenital toxoplasmosis. 59 Many maternal infections are without apparent symptoms, or are mild, which accounts for the estimated 3000 cases of congenital toxoplasmosis in the United States annually. Seventyfive per cent of infected newborns are asymptomatic. 16 Only 10 per cent have serious disease with central nervous system or hepatic involvement in the newborn perioq. The Sabin-Feldman dye test is the diagnostic standard. High titers of IgG anti-Toxoplasma antibody should be followed by more specific tests, e.g., IgM-ELISA or IgM-immunoHuorescent antibody tests. 4 ARTERIOHEPATIC DYSPLASIA This entity, also referred to as Alagille syndrome, is the diagnosis in 5 to 6 per cent of infants with neonatal cholestasis. 6 We recognized these
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patients in the late 1960s because of their associated facial appearance, cardiovascular manifestations, and profound hypercholesterolemia. The first infant in my memory was small and had a facial appearance that suggested Hallermann-Streiff syndrome. I especially recall the benign appearance of the hepatic biopsy. We examined the tissue with electron microscopy for membrane ATP-ase and found this enzyme to be present. I biopsied this patient on four occasions during her first 3 years of life and noted a progressive disappearance of intraportal bile ducts and cholestasis without the development of significant fibrosis. The patient became normobilirubinemic while we were observing a disappearance of intrahepatic bile ducts. We "wondered where the yellow went?" This patient is now 19 years old. The next patient was admitted for biopsy. I was upset with a house officer for obtaining electrolytes without justification. The serum sodium was 128 mEq per liter. We had to repeat it-127 mEq per liter. Urine sodium was 39 mEq per liter. Serum lipids were obtained and the serum cholesterol was 1300 mg per dl. A subsequent patient had a serum cholesterol value of 1900 mg per dl. Most of our patients have had mild heart disease, most commonly peripheral pulmonic stenosis. We have had patients with coarctation of the aorta and, recently, tetralogy of Fallot. We have found evidence of renal dysfunction more often in the patients with significant cardiovascular disease. Eye and bone manifestations are now well established. The classic paper of Alagille et al. in 1975,2 which should be in the files of every pediatrician, stressed the association of retarded physical, mental, and sexual maturation with the arteriohepatic dysplasia and unusual facial appearance. The unusual facial appearance is characteristic but not pathognomonic, as clearly demonstrated by Sokol et al. 56 The facial appearance is hard to describe but major features are deep-set eyes with a prominent protruding nasal bridge, prominent glabella, and pointed chin. There is extreme variability in severity in affected family members. 54 Recent work suggests that the hepatic manifestations of arteriohepatic dysplasia result from a block in the Golgi apparatus, or in the pericanalicular cytoplasm. 66 Sequential hepatobiliary morphology has been carefully described by Kahn and co-workers. 33 Riely recently reviewed familial intrahepatic cholestatic syndromes. 48 It is an excellent, highly readable review that I recommend to the interested reader.
EVALUATION
The infant with direct hyperbilirubinemia persisting beyond 2 to 3 weeks of life deserves attention. The medical history is rarely helpful, but a history of maternal infection during the last trimester, hemolytic disease in the early newborn period, or family history of metabolic disease carries weight. Physical examination, with careful plotting of growth parameters, has significant diagnostic value. Septic infants, as well as those with tyrosinemia, fructose intolerance, and galactosemia, appear ill. Infants with congenital infections and Alaqille's syndrome are small. An enlarged spleen
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is more consistent with congenital infection, storage diseases, and hemolytic disease. Rashes direct the observer toward congenital infection, storage diseases, histiocytosis, and metabolic disorders. I consider stool examination part of the physical examination. Beige or white stool indicates high-grade obstruction and is found most often in otherwise healthy, though icteric, infants. One must insist that the infant receive formula only in the observation period since coloring in solids/oral medicines may confuse the examiner. Needless to say, more than one stool should be examined. I must confess to the reader that I make decisions based on history, physical examination, initial laboratory data, and examination of the stool. I do not intubate the duodenum for fluid collection. Greene and coworkers 25 popularized the 24-hour collection of duodenal fluid for the presence of bile. They positioned an 8 French radiopaque feeding tube in the second and third portions of the duodenum. Fluid was collected by gravity drainage into glass tubes for visual inspection. If no bile pigment was observed in 12 hours, the infant was fed 2 ounces of glucose/electrolyte solution every 2 hours and the fluid collection continued for another 12 hours. Absence of yellow, bilious fluid was interpreted as being consistent with complete obstruction (i.e., biliary atresia). I personally found no advantage of this test over my visual inspection of the stool. British and Chinese investigators have modified this test by examining the fluid for bile acids and Tc-99m DISIDA, respectively, which they suggest further increases the accuracy of the test. 32, 69 Other investigators employ the "string test" and find it to be simpler and as accurate. 50 Our initial tests (Table 3) include CBC, electrolytes, bilirubin with fractions, and hepatic enzymes (SGOT, SGPT, and gamma glutamyl transferase). A direct-reacting bilirubin less than 4 mg per dl is not consistent with complete obstruction. An SGOT/SGPT which is elevated tenfold or greater, especially when associated with a GGT that is less than fivefold increased, supports hepatocellular rather than biliary tract disease. Conversely, an SGOT less than fivefold elevated with a GGT greater than fivefold elevated suggests biliary tract disease, although infants with a-Iantitrypsin deficiency disease often have markedly elevated GGT levels. 18, 46,50 The reader must realize, however, that a low GGT does not exclude biliary atresia. 50 Data obtained to this point dictates further evaluation. Additional laboratory studies often include sweat iontophoresis, a-I-antitrypsin, TORCH and HBV serology, IgM, urine examination for CMV, RBC galactose-I-phosphate uridyl transferase activity, and examination of the urine for reducing substances. Abdominal ultrasonography, performed after a 3- to 4-hour fast, allows evaluation of the liver and biliary tract. Abnormal dilation of the bile duct is readily discerned, and failure to visualize the gallbladder lends weight to a suspicion of biliary atresia. A recent report describes the sonographic features of the "bile plug" syndrome. 14 There has been a large amount of enthusiastic ink extolling hepatobiliary scintigraphy,l. 13.20,36 and with some merit. Certainly biliary patency can be documented and abnormal dilation of the bile duct defined. Failure
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Table 3. Evaluation of the Infant with Persistent Cholestasis I. History/Physical Examination A. Stool Examination II. Initial Laboratory Studies A. CBC, reticulocyte count, platelet count B. Electrolytes, BUN, creatinine C. Hepatic enzymes, e.g., SGOT/SGPT, GGT D. Prothrombin time, APTT E. Protein electrophoresis F. Calcium, phosphorus, alkaline phosphatase III. Specific Tests A. Sweat iontophoresis B. a-I-Antitrypsin C. TORCH, IgM D. Urine exam/culture for CMV E. HBsAgianti-HBc-IgM, ? anti-HAV-IgM F. Urine for reducing substances G. Galactose-I-phosphate uridyl transferase IV. Hepatobiliary Ultrasonography V. Tests for Biliary Patency A. Duodenal intubation: 1. Examination for bile acids 2. Examination for Tc-99m DISIDA 3. String test B. Tc-99m hepatobiliary scintigraphy VI. Hepatic Biapsy VII. Exploratory Laparotomy A. Intraoperative cholangiogram B. Hepatic biopsy C. Portoenterostomy
to detect radionuclide in the intestine or biliary tract, however, cannot be absolutely equated with complete obstruction. I place all infants with acholic stools on phenobarbital (5 mg per kg per day) 3 days before obtaining a fasting (3 to 4 hours) scintiscan. 41 I perform a percutaneous hepatic biopsy when hepatobiliary scintigraphy confirms biliary patency. Possible exceptions might be confirmed cystic fibrosis or congenital infection. Many notable gastroenterologists recommend biopsy of patients with complete obstruction on hepatobiliary scintigraphy as well. It is well accepted that hepatic histology revealing widened portal areas with bile duct proliferation in a jaundiced infant I month old or older is highly suggestive, if not diagnostic, of biliary atresia. I do not perform a percutaneous hepatic biopsy on all icteric infants, however. I recommend laparotomy for the infant passing acholic stools with a direct bilirubin fraction greater than 4 mg per dl, a GGT greater than fivefold elevated, a normal a-I-antitrypsin level, and nonvisualization of the intestine on hepatobiliary scintigraphy. The gallbladder of most of these infants cannot be identified on fasting abdominal ultrasonography. Hepatic tissue obtained by either closed or open techniques are studied by both light and electron microscopy.
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MANAGEMENT
Surgical The surgeon is prepared to perform a portoenterostomy when exploratory laparotomy is elected. I cannot recall sending a single patient for exploratory laparotomy who did not have biliary atresia. The technical aspects of the hepatoportal reconstructive surgery performed at my institution have been reviewed,68 and, to be candid, are beyond my expertise and the intention of this treatise. The reader is further referred to other current reviews of surgical management by deVries and COX,12 Howard,30 and a ven' recent, in-depth, nicely illustrated review of the surgical technique by Ryckman and Noseworthy.51 Most gastroenterologists consider hepatoportoenterostomy a temporizing measure, althoug)1 we, like others, have more than a few patients who are over 5 years of age and are anicteric, without a hint of hepatic failure. These patients (it is hoped) will never require transplantation but they are now of sufficient size and age that transplantation is likely to be successful, should it become a necessary consideration. We would seem to be in agreement with the recent position statement of Lilly, Hall, and Altman 39 in this regard. We always hope that drainage following portoenterostomy will be sufficient to defer hepatic failure until after the first year of life, at the very least. We refer patients with chronic liver disease for transplantation when it is clear that the patient's liver is failing progressively, in spite of optimal medical therapy. Medical The medical management of the infant with chronic liver disease depends on specific diagnosis. 57 Management of the patient with chronic cholestasis demands certain knowledge and skills. Inadequate bile How results in insufficient delivery of bile salts to the proximal small bowel, leading to malabsorption of fat and fat-soluble vitamins. Retention of bile acids and other substances normally secreted in bile causes progressive liver damage culminating in end-stage cirrhosis. The consequences of cholestasis must be kept in mind when monitoring the patient and planning medical strategy (Table 4). Efforts are directed toward stimulating or enhancing bile How and preventing the nutritional deficiencies that logically accompany prolonged intraluminal bile salt insufficiency. An excellent, indepth review of the medical management of the infant with chronic cholestasis has been published recently. 57 The reader will note that I prefer to offer my infants a low-fat, elemental formulation (Vital HN, Ross Laboratories, Columbus, Ohio) at a caloric density of 0.67 kcal per ml, recognizing that iron and calcium supplementation is necessary. This formula provides 9.4 per cent of its calories as fat, 5 per cent as linoleic acid, which considers malabsorption in meeting the essential fatty acid requirement of 2.7 per cent of total calories. The remaining 4 per cent is in the form of medium-chain triglycerides (MCT). It does not provide a significant load of long-chain triglycerides to these infants, which, in the face of bile salt deficiency, would result in steatorrhea with its attendant consequences. I do not recommend Portagen (Mead
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Table 4. Medical Management of the Infant with Persistent Cholestasis I. Formula: A. Viral HN, 0.67 kcallml, 1.25 x calculated caloric need II. Vitamins: A. Water-soluble: twice the recommended daily allowance B. Fat-soluble: 1. Vitamin A: aquasol A, 10,000 to 15,000 IV/day 2. Vitamin 0: cholecalciferol, 1200 to 5000 IV/day 3. Vitamin E: Alpha-tocopherol, 100 to 400 IV/day 4. Vitamin K: water-soluble derivative of menadione, 2.5 to 5 mg on alternate days III. Micronutrients: A. Calcium: elemental, 25 to 100 mg/kg B. Phosphorus: 25 to 50 mg/kg/day C. Zinc: zinc sulfate solution, 1 mg/kg/day IV. Choleretic Agents: A. Phenobarbital, 5 mg/kg/day B. Cholestyramine, 0.25 gm/kg/day, given in 3 doses, with feedings V. Management of Ascites: A. Spironolactone, 3 to 5 mg/kg/day B. Furosemide, 1 to 2 mg/kg every other day to twice daily C. Sodium restriction, 1 mEq/kg/day, if feasible
Johnson, Evansville, Indiana) because this formula provides only 2.5 per cent of its total calories as linoleic acid, and I strongly doubt that all of the calories provided as MCT are utilized because they are not stored. Furthermore, it is conceivable that the underutilized metabolites of MCT may have a deleterious effect on body chemistry (e.g., acid-base balance). Infants with neonatal cholestasis develop fat-soluble vitamin deficiencies in spite of the provision of these vitamins in usual dosage. These infants must be monitored closely and supplemented appropriately. We monitor vitamin E status in our infants by measuring both the serum vitamin E level and erythrocyte peroxide hemolysis (EPR), which correlates with erythrocyte membrane vitamin E levels. Erythrocyte peroxide hemolysis less than 20 per cent always equates with vitamin E sufficiency, in our experience. 8 I am often unable to accomplish vitamin E sufficiency with massive dosages of standard vitamin E. These patients acquire normal vitamin E levels and EPR less than 20 per cent when administered the investigational water-soluble preparation, o-a-tocopherol polyethylene glycol-lOOO succinate (TPGS) in a dosage of 20 IV per kg per day. Studies are being conducted to ensure the safety of this preparation. I often find it necessary to administer parenteral vitamin K to these infants, usually at biweekly intervals. I have not found it necessary to provide vitamin A parenterally, although this has been recommended. 3 Severely obstructed infants almost always fail to maintain normal serum vitamin D levels and normal calcium homeostasis with oral cholecalciferol and require or~l 25-hydroxyvitamin D (3-5 I-Lg per kg per day) or 1,25 dihydroxyvitamin D (0.05-0.2 I-Lg per kg per day). Enteral supplementation of elemental calcium (25-100 mg per kg per day) and phosphorus (25 to 50 mg per kg per day) may be necessary to correct bone demineralization. 57 I administer phenobarbital (5 mg per kg per day) to stimulate bile acidindependent bile flow, and cholestyramine (0.25 gm per kg per day) to stimulate bile acid-dependent bile flow in patients with intrahepatic cho-
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lestasis. I do not administer cholestyramine to the infant with a portoenterostomy. Transplantation Unfortunately, many infants with persistent cholestasis develop progressive hepatic fibrosis/cirrhosis, ending in hepatic failure, despite our best efforts. Orthotopic hepatic transplantation is then the only remaining consideration. 19 I defer transplantation until I am unable to control the clinical manifestations ofliver failure. I hope to delay referral to a transplant center for at least 1 year, but this is not always possjble. Orthotopic hepatic transplantation has been uniformly successful in recent years in our patients over 1 year of age at the time of transplantation. One patient with neonatal hepatitis, with profound giant cell transformation, developed a similar pathologic process in the implant leading to hepatic failure and death. Our experience with infants less than 1 year of age has been uniformly dismal.
SUMMARY We no longer view the infant with persistent cholestasis with a "wait and see" strategy. Identification of the cause of "neonatal hepatitis" may allow specific treatment. Improved surgical techniques for portoenterostomy have provided early hope for patients with biliary atresia. Rapidly advancing nutritional strategies allow many portoenterostomy failures an additional further option, that is, hepatic transplantation. I express my thanks to the many investigators who have contributed and are continuing to advance the progress recounted in this review. Perusal of the references cited in this review makes clear the identity of these investigators. ACKNOWLEDGMENT I express my gratitude to Vicki Havilaqd for her assistance in the prepation of this article.
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38. Leblanc A, Odievre M, Hadchouel M et al: Neonatal cholestasis and hypoglycemia: possible role of cortisol deficiency. J Pediatr 99:577, 1981 39. Lilly JR, Hall RJ, Altman RP: Liver transplantation and Kasai operation in the first year of life: therapeutic dilemma in biliary atresia. JPediatr 110:561, 1987 40. Lloyd-Still JD: Familial cholestasis, with elevated sweat electrolyte concentrations. J Pediatr 99:580, 1981 41. Majd M, Reba RC, Altman RP:Hepatobiliary scintigraphy with 99m Tc-PIPIDA in evaluation of neonatal jaundice. Pediatrics 67:140, 1981 42. Morecki R, Glaser JH, Cho S et al: Biliary atresia and reovirus type 3 infection. N Eng! J Med 307:481, 1982 43. Perkins WG, Klein GL, Beckerman RC: Cystic fibrosis mistaken for idiopathic biliary atresia. Clin Pediatr 24:107, 1985 44. Pfeiffer WR, Robinson LH, Balsara VJ: Sonographic features of bile plug syndrome. j Ultrasourtd Med 5:161, 1986 45. Phillips MJ, Poucell S, Oda M: Biology of disease: Mechanisms of cholestasis. Lab Invest 54:593, 1986 46. Platt MS, Potter JL, Boeckman CR et al: Elevated GGTP/SGOT ratio. Am J Dis Child 135:834, 1981 47. Reichen J, Simon FR: Mechanisms of cholestasis. Internat Rev Exp Bioi 26:231, 1984 48. Riely CA: Familial intrahepatic cholestatic syndromes. Semin Liver Dis 7:119, 1987 49. Rosenberg DP, Morecki R, Lollini 0 et al: Extrahepatic biliary atresia in a rhesus monkey (Macaca mulatta). Hepatology 3:577, 1983 50. Rosenthal P, Liebman WM, Sinatra F et al: String test in evaluation of cholestatic jaundice of infancy. J l'ediatr 107:253, 1985 51. Ryckman FC, Noseworthy J: Neonatal cholestatic conditions requiring surgical reconstruction. Semin Liver Dis 7:134, 1987 52. Setchell KD, Street JM: Inborn errors of bile acid synthesis. Semin Liver Dis 7:85, 1987 53. Sharp HL: Alpha-I-antitrypsin: An ignored protein iiI understanding liver disease. Semin Liver Dis 2:314, 1982 54. Shulman SA, Hyams JS, Gunta R et al: Arteriohepatic dysplasia (Alagille syndrome): extreme variability among affected family members. Am J Med Gen 19:325, 1984 55. Sinatra F: The role of gamma g!utamyl transpeptidase in the preoperative diagnosis of biliary atresia. J Pediatr Gastroenterol Nutr 4:167, 1985 56. Sokol RJ, Heubi JE, Balistreri WF: Intrahepatic "cholestasis facies": is it specific for Alagille syndrome? J Pediatr 103:205, 1983 57. Sokol RJ: Medical management of the infant or child with chronic liver disease. Semin Liver Dis 7:155, 1987 58. Stanley NF, Dorman PC, Ponsford J: Studies on the pathogenesis of a hitherto undescribed virus (hepatoencephalomyelitis) producing unusual symptoms in suckling mice. Aust J Exp Bioi Med Sci 31:147, 1953 59. Stray-Pedersen B: Infants potentially at risk for congenital toxoplasmosis. Am J Dis Child 134:638, 1980 60. Strickland AD, Shannon K, Coin CD: Biliary atresia in two sets of twins. J Pediatr 107:418, 1985 61. Strickland AD, Shannon K: Studies in the etiology of extrahepatic biliary atresia: time clustering. J Pediatr 100:749, 1982 62. Suchy FJ, Bucuvalas JC, Novak DA: Determinants of bile formation during development: Ontogeny of hepatic bile acid metabolism and transport. Semin Liver Dis 7:77, 1987 63. Sweger T: Liver disease in alpha-I-antitrypsin deficiency detected by screening of 200,000 infants. N Eng! J Med 294:13i6, 1976 64. Udall IN, Dixon M, Newman AP, et al: Liver disease in alpha-I-antitrypsin deficiency: a retrospective analysis of the influence of early breast, vs bottle-feeding. JAMA 253:2679, 1985 65. Utili R, Abernathy CO, Zimmerman HJ: Cholestatic effects of Escherichia coli endotoxin on the isolated perfused rat liver. Gastroenterology 70:248, 1976 66. Valencia-Majoral P, Weber J, Cutz E et al: Possible defect in the bile secretory apparatus in arteriohepatic dysplasia (Alagille's syndrome): A review with observations on the ultrastructure of liver. Hepatology 4:691, 1984 67. Watkins J, Sunaryo FP, Berezin SH: Hepatic manifestations of congenital and perinatal disease. Clin Perinatol 8:467, 1981
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68. Weber TR, Grosfeld JL: Contemporary management of biliary atresia. Surg Clin North Am 61:1079, 1981 69. Yamashiro Y, Robinson PG, Lari J et al: Duodenal bile acids in diagnosis of biliary atresia. J Pediatr Surg 18:278, 1983 James Whitcomb Riley Hospital for Children 702 Barnhill Drive Indianapolis, Indiana 46223