Introduction

Jaundice, which is observed in almost every newborn, is termed “physiologic” because it clears within a few days, after activation of bilirubin conjugation. This phenomenon reflects a unique feature of prenatal life: Many functions of the liver that are required after birth for nutrition, metabolic balance, and detoxification and excretion of endogenous chemicals are provided to the developing fetus by the placenta and the mother. “Pathologic” jaundice is the most frequent indication for liver biopsy in children, especially infants, because functional immaturity is not limited to glucuronidation, and intrinsic defects in many processes and structures lead to cholestasis. This is even more evident in premature infants. Not only do the first challenges to hepatobiliary function account for liver diseases that “adult” pathologists encounter very rarely, but maternal-fetal interactions are not always beneficial. Certain infections and immunologically mediated injuries are observed only in infants.

This chapter focuses on constitutional deficiencies of the liver that necessitate examination of tissue for diagnosis and treatment. Myriad chromosomal imbalances and heritable mutations that manifest with dysmorphism and multisystem disease, such as Down syndrome, may affect the liver but can be diagnosed clinically; they are included in this chapter only if they offer a challenge to diagnosis. Anatomic and synthetic defects, such as clotting factor deficiencies that do not lead to hepatobiliary dysfunction, are covered in other publications.^1,2

We have incorporated a practical approach to liver biopsy that is derived from Jevon and Dimmick’s classification of the histologic pattern of pediatric liver biopsies, which identify six dominant patterns.³ Finally, the progress made during the past decade with regard to decoding the genetic basis of disease has resulted in improved therapeutics as well as reclassification and renaming of disease entities, genes, and proteins. In the preparation of this chapter, we have benefited from Online Mendelian Inheritance in Man (OMIM; www.omim.org), an online compendium of human genes and phenotypes maintained by the Johns Hopkins University and developed by the National Center for Biotechnology Information (NCBI). This searchable database provides a unique accession number for each entity and incorporates all alternative disease names and gene nomenclature. Throughout the text and in the tables, we have provided OMIM numbers for heritable conditions that may be beneficial to readers.

Other than prior liver or bone marrow transplantation (see Chapter 42), the most common indications for liver biopsy in the pediatric age group are conjugated hyperbilirubinemia in young infants (Table 54.1); tumor diagnosis (see Chapter 55); and assessment of liver injury, inflammation, and fibrosis. Metabolic diseases may manifest with fetal demise immediately after birth or at any age thereafter (Table 54.2).

Pediatric Liver Biopsy Specimen

Because of the broad range of diseases in children, evaluation of liver biopsies in these patients is distinct from that in adults. To perform all potentially necessary tests on a liver biopsy specimen, prior arrangements should be in place to ensure adequate specimen processing (Table 54.4).

Normal and Potentially Misleading Features of the Liver in Infants and Children

Some key features in the liver of infants and children differ from those in adult liver (Table 54.5). Variations occur in architecture, specific cell populations, content of hepatocytes, and response to injury.

Architecture

The liver undergoes substantial growth after birth. It normally doubles in weight within the first month of life, doubles again during the first year of life, and does not reach its mature size until late adolescence. The portal tract system grows in parallel with the liver. Therefore, the most peripheral aspects of the liver may exhibit developmental residua of fetal histology. For instance, residual bile duct plates may rim the portal tracts, and the latter contain a more cellular mesenchyme and a centrally placed portal vein (Fig. 54.1).⁴ The dimensions of hepatic lobules remain constant with growth. However, hepatocyte cords may remain two cells thick well into the fourth postnatal year. This should not be misinterpreted as regenerative hyperplasia in response to tissue injury.

Approach to the Diagnosis of Pediatric Liver Disorders in Liver Biopsies

When evaluating pediatric liver biopsy specimens, a careful review of patient age at disease onset (see Table 54.2), clinical manifestations, and routine laboratory workup findings is essential (Table 54.7). If the presentation includes hepatomegaly, awareness of extrahepatic involvement is also helpful (Table 54.8). It is useful to initially classify the histologic pattern of disease into one of the six patterns of injury described initially by Jevon and Dimmick.³ Although these patterns often overlap, it is usually possible to define the predominant pattern in an individual case.¹¹ This section describes an algorithmic approach to the diagnosis of liver disorders, beginning with the histologic patterns of tissue injury (see Boxes 54.1 through 54.6). A detailed description of the major entities is found later in the chapter.

CBC Diff, Complete blood cell count with differential; GCT, giant cell transformation; TORCH, toxoplasmosis, other agents, rubella, cytomegalovirus, and herpes simplex.

Cholestatic Pattern

The differential diagnosis of cholestatic disease in childhood is extremely broad and includes extrahepatic biliary obstruction (EHBA, choledochal cyst), infections, immune regulatory defects such as Langerhans cell histiocytosis, genetic disorders, metabolic disorders, total parenteral nutrition (TPN) and toxin exposures (see Table 54.1). Liver biopsies to determine the cause of cholestasis should be performed only after completion of a thorough radiologic and laboratory workup, including ultrasonography, hepatobiliary scintigraphy, viral serology, Pi typing for A1AT deficiency, and sweat chloride testing to rule out the more common causes of cholestasis in this age group.¹²

When confronted with a predominantly cholestatic pattern of liver injury in a biopsy specimen, a useful starting point is the serum level of γ-glutamyltransferase (GGT) (Box 54.1). Serum levels of GGT, a canalicular membrane protein, are usually low in disorders of defective bile acid synthesis or bile salt secretion. These entities (Table 54.9) are discussed later in the chapter. Although the histologic features differ among some of these entities (e.g., lack of giant cells in progressive familial intrahepatic cholestasis type 1 [PFIC1] compared with PFIC2 and PFIC3), ultrastructural examination, specialized enzymatic assays, and genetic testing are crucial in diagnosing these disorders. Among the cholestatic disorders with normal or low serum GGT, congenital defects in bile acid synthesis are commonly diagnosed by urinary mass spectrometry. Peroxisomal biogenesis disorders, such as Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease, typically manifest with cholestasis, necrosis, and siderosis. These disorders are caused by mutations in multiple peroxin (PEX) genes¹³ and are usually diagnosed by measurement of very-long-chain fatty acids in plasma and erythrocyte plasmalogen.¹⁴

Two rare disorders of ductal plate malformation—congenital hepatic fibrosis and Caroli disease—deserve mention here. Both manifest with cholestasis and cholangitis but often with portal hypertension.¹⁵ Both are associated with autosomal recessive polycystic kidney disease (ARPKD), and both carry mutations in PKHD1 (fibrocystin), the that is gene defective in ARPKD,¹⁶ in approximately 30% of cases.

Steatotic Pattern

A steatotic pattern of injury is present when there is a prominent and diffuse distribution of fat vacuoles within hepatocytes. Steatosis is a common histopathologic finding in several types of inherited disorders that affect the liver; those in which other histologic features predominate are discussed separately. When one is considering the differential diagnosis of a primary steatotic pattern of liver injury, the most useful feature is the type of fat accumulation: microvesicular, macrovesicular, or mixed microvesicular and macrovesicular (Box 54.2).

Microvesicular steatosis results from perturbation of mitochondrial metabolism, fatty acid β-oxidation (FAO), or electron transport chain function, through either genetic defect or drug-induced¹⁷ inhibition of the pathways. The latter mechanism may result from a variety of drugs, including aspirin, ibuprofen, valproate, and zidovudine (see Chapter 48