Abstract
Jaundice sometimes appears at birth, indicated by the dark yellow color of the countenance and arising from obstructions of the liver. Cases are generally incurable.
Cholestatic Liver Disease
Jaundice sometimes appears at birth, indicated by the dark yellow color of the countenance and arising from obstructions of the liver. Cases are generally incurable.
Introduction
Cholestasis may be defined physiologically as a measurable decrease in bile flow, pathologically as the histologic presence of bile pigment in hepatocytes and bile ducts, and clinically as the accumulation in blood and extrahepatic tissues of substances normally excreted in bile (e.g., bilirubin, bile acids, and cholesterol). The process occurs as a result of impaired bile formation by the hepatocyte or from obstruction to the flow of bile through the intrahepatic and extrahepatic biliary tree [2, 3]. In the neonate, the clinical and laboratory features of the many liver diseases presenting with cholestasis are quite similar. An important focus of the pediatric hepatologist is to differentiate intrahepatic from extrahepatic cholestasis and, if possible, establish a specific diagnosis [4]. Strategies for the treatment of metabolic or infectious liver disease and for the surgical management of biliary anomalies require early diagnosis. Even when treatment is not available or effective, infants with progressive liver disease usually benefit from optimal nutritional support and medical management of complications of cholestasis and possibly cirrhosis until liver transplantation is performed.
This chapter presents an overview of the approach to the infant with cholestatic liver disease. The diagnostic evaluation of these patients is emphasized. The incidence and scope of the problem are placed in perspective, and the differential diagnosis is reviewed, but the large numbers of specific disorders are not discussed here in detail. These disorders are covered comprehensively in subsequent chapters.
Incidence
The overall incidence of neonatal liver disease, most cases manifesting clinical or biochemical evidence of cholestasis, may be as high as 1 in 2,500 live births [5, 6]. Of the many conditions that cause neonatal cholestasis, biliary atresia accounts for approximately 25%, genetic disorders for another 25%, metabolic disease for 20%, idiopathic neonatal hepatitis for 15%, α1-antitrypsin deficiency for 10%, and viral illness for 5% [7]. So-called idiopathic neonatal hepatitis was the most common diagnosis in older series, with a reported incidence of 1 in 4,800–9,000 live births [8, 9]. However, with the advent of new more accurate diagnostic methods that allow for diagnosis of disorders of bile acid synthesis, disorders of canalicular transport, storage diseases, mitochondrial diseases, and infectious diseases, the incidence of what was once called “idiopathic neonatal hepatitis” has decreased. The estimated incidence of biliary atresia ranges from 1 in 5,000 to 1 in 21,000 live births, with cases occurring more frequently in Far Eastern than in Western countries [10]. In a retrospective study utilizing data from the triennial Health Cost and Utilization Database from 1997 to 2002, the incidence of biliary atresia in the USA was 4.47 per 100,000 and was higher in females (RR 1.43), Asian/Pacific Islanders (RR 1.89) and blacks (RR 1.3) compared with whites [11].
Differential Diagnosis of Neonatal Cholestasis
Liver dysfunction in the neonate, regardless of the etiology, is commonly associated with a failure of bile secretion and conjugated hyperbilirubinemia [12]. Jaundice is a frequent and early presenting feature of liver disease during early life rather than a late manifestation of advanced disease, as is seen in the older child or adult [12]. Owing to an immaturity of hepatic excretory function, a susceptibility to infection during the perinatal period, and the initial effects of congenital malformations and inborn errors of metabolism, the number of distinct disorders presenting with cholestasis is greater in the neonate than at any other time of life. A conceptually useful overview of the differential diagnosis of neonatal cholestasis is presented in Table 8.1. Although the origin or the predominating form of liver damage may be traced primarily to the level of the hepatocyte or to the biliary apparatus, there is considerable overlap between disorders in their clinical features as well as in the subsequent sites of injury. For example, injury to the biliary epithelium may be a prominent finding in neonatal infection with cytomegalovirus, α1-antitrypsin deficiency, and some inborn errors of bile acid metabolism. Moreover, mechanical obstruction of the common bile duct invariably results in liver dysfunction and intrahepatic injury, which may include in the neonate significant giant cell transformation of hepatocytes. It is unclear in this setting whether giant cells, which appear to be a frequent, non-specific manifestation of neonatal liver injury, reflect the noxious effects of biliary obstruction or whether the hepatocytes as well as the biliary epithelium are damaged by a common insult such as a virus or toxin with tropism for both types of cells.
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* For genetic and metabolic causes, the affected gene(s) is listed in parenthesis when known.
The term neonatal hepatitis refers to the histologic finding of extensive giant cell transformation of hepatocytes. The term is misleading because it implies an infectious process involving the liver (such as the numerous forms of viral hepatitis), but it has been used to describe virtually all forms of liver disease after structural disorders of the biliary tree, such as biliary atresia and choledochal cysts, have been excluded. Because of improved imaging techniques, advances in virology, and the application of sophisticated biochemical and molecular methods to the diagnosis of inborn errors of metabolism, there are fewer infants whose liver disease may be classified as idiopathic or cryptogenic. A disorder should now be designated as hepatitis only if an infectious agent can be documented or suspected based on other clinical features associated with congenital infection. An increasing number of infections have been associated with neonatal hepatitis, including parvovirus B19, human herpesvirus 6, and HIV. The percentage of cases that can be classified as idiopathic will also be influenced by referral patterns, the prevalence of certain infections within a population, and the availability of specialized diagnostic techniques and biochemical assays.
In a review of 62 liver biopsies at two tertiary centers with a diagnosis of neonatal giant cell hepatitis, the average age at liver biopsy was two months (73% male)[13]. Giant cell transformation affected an average of 36% of hepatocytes (range, 5–90%). Extramedullary hematopoiesis (both myelopoiesis and erythropoiesis) was found in 74% of the children. An actual “hepatitis” characterized by portal and lobular inflammation was mild to absent in 95%. Mild to moderate lobular cholestasis with a predominately canalicular distribution occurred in 84%. Bile ducts were hypoplastic in 32% but were not absent or reduced in number. Mild focal ductular proliferation was found in another 18% of biopsies. Portal or pericellular fibrosis was found in 30% and was advanced in 8%. A cause for cholestasis could not be established in 49% of patients. In the remaining patients, the specific diagnoses were hypopituitarism (16%), biliary atresia (8%), Alagille syndrome (6%), bile salt defects (6%), and several other disorders present at 5% or less. Histological features did not readily distinguish among the various etiologies, with the unexpected exception that bile duct hypoplasia was more common in hypopituitarism [13].
Spontaneously resolving forms of neonatal cholestasis may result from several factors including immaturity of bile secretion and perinatal disease leading to hepatic hypoxia or ischemia [14]. In one study of 70 infants with moderate portal and lobular fibrosis, multinucleated giant hepatocytes, and hematopoietic foci, 15 children had follow-up liver biopsies that were normal or improved [14]. The occurrence of so-called neonatal hepatitis in babies with other serious disorders, such as Down syndrome, hemolytic disease of the newborn, ischemic injury, or congenital heart disease, also suggests that systemic disease may either increase susceptibility to agents capable of causing hepatitis or further exacerbate an under- lying immaturity of hepatic excretory function to the point of producing pathologic cholestasis.
Approximately 25% of cholestatic infants have evidence of an inherited molecular defect that leads to abnormalities in metabolism and substrate transport. Defects in bile acid transport, phospholipid transport, bile acid synthesis, and abnormal embryogenesis have been identified with variable presentations and prognoses [7]. The genes for several forms of progressive familial intrahepatic cholestasis (PFIC) have been identified and encode proteins critically important for bile formation [15–17]. Giant cell transformation of hepatocytes is the predominant histologic feature in type 2 PFIC because of mutations in the gene encoding the bile salt excretory pump [18].
Another feature often accompanying neonatal cholestasis is bile ductular paucity, a histologic finding implying a diminution in the number of interlobular bile ducts. The abnormality may be of primary importance in patients with so-called syndromic paucity of interlobular bile ducts (Alagille syndrome) but also may occasionally occur in other disorders including cytomegalovirus and rubella infections, α1-antitrypsin deficiency, chromosomal monosomy and trisomy, cystic fibrosis, and bile acid synthesis defects [19]. The finding may not be present or may be difficult to recognize in the neonate; however, serial liver biopsies may demonstrate injury to bile ductular epithelial cells, a variable amount of associated inflammation, and a progressive decrease in the number of bile ductules per portal tract.
Manifestations of Cholestatic Liver Disease in the Neonate
Jaundice is the most overt physical sign of liver disease and occurs more commonly in the neonatal period than at any other time of life [20]. Unconjugated hyperbilirubinemia in the older patient is usually harmless, but in the neonate with an immature blood–brain barrier, it may be associated with deposition of free bilirubin in neuronal tissue and subsequent brain damage. In contrast, conjugated bilirubin is not toxic, but an elevated level is the most common presenting feature of liver disease in the neonate. Unconjugated jaundice is first appreciated in the head and progresses caudally to the palms and soles as the serum bilirubin increases. Jaundice becomes clinically apparent in the older child when the serum bilirubin concentration reaches 2–3 mg/dL, but the neonate may not appear icteric until the bilirubin level is >5 mg/dL. A serum conjugated (direct) bilirubin concentration of >1 mg/dL with a total bilirubin of <5 mg/dL, or over 20% of the total bilirubin concentration if the total is >5 mg/dL, is abnormal and requires evaluation [21]. Many clinical laboratories now employ the Ektachem method, which specifically measures direct bilirubin. A serum conjugated bilirubin concentration >1 mg/dL is abnormal using this assay.
The majority of infants with cholestatic liver disease present during the first month of life [12]. Differentiation of cholestatic jaundice from the common physiologic hyperbilirubinemia of the neonate or the prolonged jaundice occasionally associated with breast-feeding is essential. The initial goal of the physician must be to exclude rapidly life-threatening but potentially treatable disorders such as gram-negative infection, endocrinopathies (such as panhypopituitarism), galactosemia, and inborn errors of bile acid metabolism. Prompt identification of cholestatic infants is also required to minimize the risk of hemorrhage from vitamin K deficiency. Because of early hospital discharges, some cholestatic infants may escape detection until the first well-baby examination at six to eight weeks of age. The possibility of liver or biliary tract disease must be considered in any neonate jaundiced beyond two weeks of age. Between 2.4% and 15% of newborns will still be jaundiced at two weeks of age; the majority are breast-fed. These infants should be evaluated for cholestasis by measurement of total and conjugated serum bilirubin. However, with reliable follow-up, this testing may be deferred until three weeks of age in jaundiced breast-fed infants if stool color, urine color, and physical examination are normal.
The spectrum of illness is remarkably wide in infants with cholestatic jaundice [4]. Acholic stools are a cardinal feature of biliary obstruction but may also occur as a result of severe bile secretory failure at the level of the hepatocyte [22]. The affected infant may appear remarkably well, particularly during the evolution of biliary obstruction, or may manifest hepatic failure at birth. These infants also may be small for gestational age and fail to thrive. Congenital infection may be associated with low birth weight, microcephaly, purpura, and chorioretinitis. Dysmorphic facies may be observed in association with chromosomal aberrations and with syndromic paucity of interlobular bile duct [23]. Congenital malformations, including cardiac anomalies, polysplenia, intestinal malrotation, and situs inversus viscerum may be found in almost a third of infants with biliary atresia [24]. Hepatomegaly is often a presenting feature of neonatal liver disease; if there is large duct obstruction, the liver is firm or even hard to palpation. In the polysplenia syndrome, a midline liver may be palpable in the hypogastrium. The spleen may be enlarged with infection or as a result of advanced prenatal liver disease and fibrosis, but it is usually of normal size early in the course of biliary tract disease. A mass in the right upper quadrant may be felt in approximately 50% of patients with a choledochal cyst. Pruritus and xanthomata, cutaneous manifestations of chronic cholestasis, are not observed in the neonate.
Irritability, poor feeding, vomiting, and lethargy are frequent symptoms in metabolic disorders such as galactosemia and tyrosinemia [25]. Ascites, edema, and coagulopathy may be present at birth or evolve rapidly during the first weeks of life after massive loss of hepatocytes through necrosis or apoptosis. A profound impairment of hepatic synthetic function, often in excess of that expected for the degree of cholestasis, may be an early indication of metabolic liver disease, such as neonatal iron storage disease or tyrosinemia. Neurologic abnormalities in the infant with liver disease may be primary symptoms, as found in mitochondrial disorders and Zellweger syndrome, or they may be secondary to hypoglycemia, hyper-ammonemia, or intracranial hemorrhage [26].
The vast majority of infants with biliary atresia appear entirely well during the first four to six weeks of life apart from mild jaundice. However, the apparent well-nourished appearance of infants with biliary atresia may be a factor in a delay of diagnosis. Thorough anthropometric studies show that infants with biliary atresia have significantly decreased fat stores and lean body mass [22]. The added weight of an enlarged liver and spleen and the occasional finding of subclinical ascites may account for a relatively normal weight for age and weight for length on standardized growth curves [27]. Stools of a patient with biliary atresia are acholic, but early in the course of incomplete or evolving obstruction, stools may appear normally pigmented or only intermittently pigmented. Similarly, fluctuating levels of serum bilirubin do not exclude biliary atresia [28]. Liver disease also must be suspected in a jaundiced infant whose urine is dark yellow as opposed to colorless.
Unfortunately, late recognition of neonatal cholestasis remains a problem. Despite attempts to educate providers, the median age of hepatoportoenterostomy in the USA has not shown any improvement over the past 15 years [11]. The median age for diagnosis of biliary atresia remains ≥60 days in the USA, Canada and France [11, 29, 30]. Reasons for late diagnosis of biliary atresia include early hospital discharge of newborn infants, lack of standard one-month well-child visits, inadequate follow-up of persistent jaundice, misdiagnosis of breast milk jaundice, and false reassurance of providers by pigmented stools or decreasing total serum bilirubin levels [6, 31, 32]. Increased age at Kasai operation has been shown to be associated with worse survival, independent of other prognostic factors [33]. In a study of 695 patients with biliary atresia who underwent the Kasai procedure in France, survival with native liver was best in children operated on in the first 30 days of life [30].
Evaluation of the Cholestatic Neonate
General Approach
An algorithm for the investigation of the cholestatic infant is presented in Figure 8.1. The order in which this assessment proceeds may vary depending on the clinical findings that may strongly suggest a diagnosis. Box 8.1 lists the individual studies that are often used in this evaluation [34, 35]. The optimal diagnostic strategy demands a cooperative medical and surgical effort at a center prepared to investigate and manage potentially correctable abnormalities of the biliary tree as well as hepatocellular disorders [22]. The initial assessment should confirm rapidly that cholestasis is present, provide a baseline assessment of the severity of liver dysfunction, and exclude potentially treatable infectious, endocrine, and metabolic disorders. Next, in order to establish a specific diagnosis, a comprehensive plan for investigation is outlined, which should be guided by the initial history and physical examination. Because of the frequent lack of specific clinical features and overlap of many diagnostic studies, most cholestatic infants require a stepwise comprehensive evaluation. However, at any point during the process, a serologic test or imaging study may establish the probable cause of the liver disease. For example, ultrasonography may promptly demonstrate a choledochal cyst in a jaundiced infant, obviating the need to search for an infectious or metabolic basis for the liver disease. Increasing numbers of infants will be identified because of neonatal screening programs. Some US states are using mass spectroscopy in tandem with other methods to detect as many as 40 inherited disorders, some of which may present as cholestasis in the neonate, including hypothyroidism, cystic fibrosis, and galactosemia [36].
Related posts:
Chapter 5 – Cirrhosis and Chronic Liver Failure in Children
Chapter 12 – Neonatal Jaundice and Disorders of Bilirubin Metabolism
Chapter 16 – Diseases of the Gallbladder in Infancy, Childhood, and Adolescence
Chapter 26 – Cystic Fibrosis Liver Disease in Children
Chapter 32 – Lysosomal Storage Disorders in Children
Chapter 43 – Liver Transplantation in Children: Indications and Surgical Aspects
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