Inherited Metabolic and Developmental Disorders of the Pediatric and Adult Liver

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Chapter 54

Inherited Metabolic and Developmental Disorders of the Pediatric and Adult Liver

Angshumoy Roy

James M. Crawford

Milton J. Finegold


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;, 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.

Pediatric Liver Biopsies

Indications for Liver Biopsy in Children

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).

Table 54.1

Liver Disease in Infants


Table 54.2

Presentation of Metabolic Diseases That Involve the Liver

Age Hepatic Failure Encephalopathy (±Bleeding) Jaundice (Hepatitis) Failure to Thrive and/or Hepatomegaly Portal Hypertension (Ascites, Bleeding, Splenomegaly)
(Hypoglycemia) (Normal Sugar)
Newborn Galactosemia, mitochondriopathies, urea cycle defects, glutaric aciduria II Crigler-Najjar syndrome type I Leprechaunism, fructose 1.6 diphosphatase deficiency
First 2 mo Wolman disease, tyrosinemia, perinatal hemochromatosis α1-Antitrypsin deficiency, NPD type C GSD 1a, Ib Zellweger syndrome GSD IV
First 6 mo Hereditary fructose intolerance, LCAD deficiency, carnitine deficiency, propionic acidemia Byler disease, Alagille syndrome, THCA, 3β-HSD, isomerase deficiency GSD III Lysinuric protein intolerance, MPS, other storage diseases
First 2 yr MCAD deficiency, mitochondriopathies Cystic fibrosis, Rotor syndrome GSD VI and IX, congenital disorder of glycosylation type Ib, glycoprotein
Up to 6 yr Reye syndrome Cholesterol ester storage, NPD types A and B, cystinosis, hereditary fructose intolerance
Puberty/and adolescence Wilson disease, erythropoietic porphyria Gilbert syndrome, Wilson disease, Dubin-Johnson syndrome α1-Antitrypsin deficiency, Wilson disease, lipoatrophic diabetes
Adults Gaucher disease, citrullinemia, hemochromatosis


GSD, Glycogen storage disorder; 3β-HSD, 3β-hydroxysteroid dehydrogenase; LCAD, long-chain acyl-coenzyme A dehydrogenase; MCAD, medium chain acyl-coenzyme A dehydrogenase; MPS, mucopolysaccharidoses; NPD, Niemann-Pick disease; THCA, trihydroxycholestanoic acid.

For young infants with conjugated hyperbilirubinemia, extrahepatic biliary atresia (EHBA) is the one condition that is amenable to surgical treatment. Choledochal cysts and other rare causes of duct obstruction that lead to jaundice shortly after birth are rare and are typically diagnosed by imaging studies rather than liver biopsy. Biliary atresia must be recognized quickly if surgical hepatic portoenterostomy is to be successful in reestablishing biliary drainage. Biopsy specimens from these patients are often obtained before the results of noninvasive studies, such as protease inhibitor typing, are available. Even in infants with probable biliary atresia, a liver biopsy may be performed to exclude other potential causes of jaundice. Therefore, clinical management decisions rely heavily on morphologic assessment of liver biopsy specimens (Table 54.3). After exclusion of biliary atresia and infections, consideration should be given to the possibility of an inherited disease as the cause of the patient’s illness.

In older children, hepatomegaly, liver tumors, or chronic liver disease may prompt a liver biopsy. When liver disease appears after the neonatal period, clinical studies are typically used to identify the specific cause of the disease. Clinically diagnosed disorders include hepatitis B virus (HBV) and hepatitis C virus (HCV) infection, Wilson disease, reticuloendothelial storage disorders, steatosis, drug-induced hepatitis, autoimmune hepatitis, and cholangiopathy. Unusual causes include Alagille syndrome and metabolic storage disorders. On occasion, liver tissue may be obtained from a child with portal hypertension in whom none of these conditions is suspected. In such cases, congenital vascular anomalies (see Chapter 51) and congenital hepatic fibrosis should be considered. Liver biopsies are used to assess the severity of disease and the response to treatment in all of these disorders.

Formalin-fixed specimens should be processed for routine light microscopy. Serial sections should be obtained. For example, a ribbon of 20 sections may be placed on 10 slides, with two tissue sections per slide. The first and last slides should be stained with hematoxylin and eosin (H&E). Periodic acid–Schiff (PAS) stain with and without diastase digestion, trichrome stain, Perls iron stain, and reticulin techniques may be used on intervening slides. The remaining slides may be held for possible future use.

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.


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.

Cell Populations

Hematopoietic elements are commonly present in liver biopsy specimens obtained during the postnatal months. Granulopoiesis predominates in portal tracts, whereas erythropoiesis is common in the parenchyma.

Hepatocyte Content

Until a postnatal age of approximately 3 months, hepatocytes normally contain copper-binding protein and copper (demonstrable by orcein and rhodanine techniques, respectively) and granules of hemosiderin, particularly in periportal hepatocytes. These deposits are considered to be physiologic and disperse with time. Conversely, hepatocyte alterations characteristic of various storage disorders may be inconspicuous in early infancy because of the time required to accumulate abnormal substances, such as α1-antitrypsin (A1AT). One dramatic exception to the concept of physiologic iron deposition occurs in newborns who exhibit liver failure at birth, which is usually attributable to severe liver injury in utero. In this scenario, marked iron deposits may be present in hepatocytes at birth, giving rise to the term neonatal iron storage disease, or perinatal hemochromatosis.5 A severe degree of necrosis and fibrosis is also present in patients with this condition. The extrahepatic reticuloendothelial system does not exhibit iron accumulation, a fact that highlights the primacy of the liver injury.6 The finding of severe perinatal hepatic siderosis is nonspecific and indicates the development of liver injury during gestation.7 A lesser degree of hemosiderosis, with reticuloendothelial system deposits, may be seen in cases of maternal-fetal blood group incompatibility with significant hemolysis.

Response to Injury

Giant, multinucleated hepatocytes, with or without bile pigment, are commonly present in infants with liver disease, regardless of the etiology. This change is considered nonspecific and reactive. Multinucleated hepatocytes are formed by syncytial breakdown of cell–cell borders but with partial preservation of the canalicular aspects of the cell membrane.8 The canalicular remnants, with retained bile, may be observed within the cytoplasm. Giant cells exhibit multiple nuclei, either scattered throughout the cytoplasm or clustered toward one pole of the cell. This reaction may persist well into childhood if the inciting disorder is not resolved. Multinucleated giant cell change is unusual in older children and adults, but it may occur in some disorders, such as autoimmune hepatitis and paramyxovirus hepatitis.9,10

The histologic spectrum of neonatal hepatitis includes giant cell change in hepatocytes, intralobular cholestasis, necrosis of hepatocytes, and intrahepatic hematopoiesis. All of these features are nonspecific events in infancy and can be observed in EHBA, A1AT storage disorder, and many other conditions (Table 54.6). With advances in biochemistry and molecular genetics, many conditions formerly grouped within the category of neonatal giant cell hepatitis can now be specifically diagnosed, including progressive familial cholestasis types 2 and 3 and various bile salt synthetic defects.


* Prompt medical intervention is possible and can be lifesaving, protect the central nervous system, and avert transplantation.

 Medical intervention is possible.

ARC, Arthrogryposis, renal dysfunction, and cholestasis; BSEP, bile salt export pump; GGT, γ-glutamyltransferase; PFIC, progressive familial intrahepatic cholestasis.

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.


* Acute presentation: bleeding, seizures, and vomiting.

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

Box 54.1

Diagnostic Algorithm for Cholestatic Pattern

High-GGT Cholestasis

EM, Electron microscopy; GGT, γ-glutamyltransferase; GRACILE, growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, and early death; PAS, periodic acid–Schiff; RER, rough endoplasmic reticulum.

Box 54.3

Diagnostic Algorithm for Storage Pattern

Box 54.5

Diagnostic Algorithm for Cirrhotic Pattern

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

Table 54.9

Genetic Defects and Available Testing for Inherited Disorders That Manifest with a Cholestatic Pattern

Disorder Gene Protein Inheritance Secondary Pattern Confirmatory Testing
Progressive Familial Intrahepatic Cholestasis (PFIC) Syndrome
PFIC1 (allelic disorder: BRIC)
(OMIM 211600)
ATP8B1 ATPase, class I, type 8B, member 1 AR Cirrhotic Gene sequencing
(OMIM 601847)
ABCB11 ATP-binding cassette, subfamily B, member 11 AR Hepatitic
Gene sequencing
(OMIM 602347)
ABCB4 (MDR3) ATP-binding cassette, subfamily B, member 4 AR Cirrhotic Serum LPX, genotyping
Congenital Bile Acid Synthetic (CBAS) Defects
(OMIM 607765)
HSD3B7 3β-Hydroxy-Δ5-C27-steroid dehydrogenase AR Hepatitic Blood spot ESI-MS or urine MS
(OMIM 235555)
AKR1D1 Δ4-3-Oxosteroid 5β-reductase AR Hepatitic
Blood spot ESI-MS or urine MS
North American Indian childhood cirrhosis
(OMIM 604901)
CIRH1A Cirhin AR Cirrhotic R565W (c.1741C→T) genotyping
Alagille syndrome
(OMIM 118450; 610205)
JAG1; NOTCH2 Jagged1; Notch-2 AD Cirrhotic
Gene sequencing
Niemann-Pick disease type C
(OMIM 257220, 601015)
NPC1; NPC2 Niemann-Pick disease types C1 and C2 AR Hepatitic
Filipin staining in fibroblasts
Peroxisomal Biogenesis Disorders
Zellweger syndrome
(OMIM 214100)
PEX genes Peroxisomal biogenesis factors AR Hepatitic
↑ Plasma VLCFA by GC
Neonatal adrenoleukodystrophy
(OMIM 202370)
PEX Peroxisomal biogenesis factors AR ↑ Plasma VLCFA by GC
Infantile Refsum disease
(OMIM 266510)
PEX Peroxisomal biogenesis factors AR ↑ Plasma VLCFA by GC


AD, Autosomal dominant; AR, autosomal recessive; ATP, adenosine triphosphate; ATPase, adenosine triphosphatase; BRIC, benign recurrent intrahepatic cholestasis; ESI, electrospray ionization; GC, gas chromatography; LPX, lipoprotein X; MS, mass spectrometry; OMIM, Online Mendelian Inheritance in Man (; VLCFA, very-long-chain fatty acids.

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

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