Rarely, metabolic diseases that affect the liver are pure functional disorders with minimal or absent histological changes (Table 13.2). In certain circumstances, such a liver may be utilized for transplantation (Popescu and Dima 2012). Examples of metabolic diseases due to abnormal liver metabolism that consistently lack morphological abnormalities are primary oxalosis, acute intermittent porphyria, maple syrup urine disease, and homozygous hypercholesterolemia. Also lacking progressive liver disease are disorders of bilirubin conjugation (Gilbert syndrome, Crigler-Najjar syndrome types I and II), in which diminished or absent glucuronosyltransferase activity results in indirect-reacting hyperbilirubinemia without hemolysis (Sampietro and Iolascon 1999). Bilirubin encephalopathy is a hazard in the severe form of this disease. In Dubin-Johnson syndrome, mutations in the MRP2 gene impair secretion of conjugated bilirubin across the canalicular membrane into bile causing mild conjugated hyperbilirubinemia without liver disease. A melanin-like lipofuscin pigment accumulates in the apical region of zones 2–3 hepatocytes and secondarily in Kupffer cells, without further histological or functional consequences (Fig. 13.1).

Idiopathic neonatal hepatitis (INH) is an umbrella term originally devised for transient nonobstructive cholestatic liver disease in the first several months of life. Histological features are lobular cholestasis, giant cell transformation of variable extent, persistent extramedullary hematopoiesis, mild inflammation, minimal or absent changes in bile ducts, and little or no fibrosis (Fig. 13.2). Modern advances in understanding of the etiology of cholestatic liver disease in infants with direct hyperbilirubinemia indicate the lesion of INH exists in numerous contexts and is often the initial histological diagnosis in an infant who develops progressive liver disease due to a specific metabolic disease (Table 13.3). Despite these advances, experience indicates that INH continues to have multiple etiologies including perinatal virus infection, immunopathy such as hemophagocytic lymphohistiocytosis (HLH), presumably undiscovered disorders of bile formation and transport, and as a transient expression of immaturity of the infant liver under stress. Histological features that suggest that an INH-like disorder may have a specific, underlying metabolic etiology are prevalence of pseudoacini, excessive giant cell necrosis, excessive inflammation, intralobular (pericellular) fibrosis, steatosis, prominent vacuolation of Kupffer cells, and prevalence of injury to small bile ducts. Liver ultrastructure in INH demonstrates nonspecific features of lobular cholestasis (Fig. 13.3) and may help identify specific metabolic diseases that cause direct hyperbilirubinemia in infants.

Portal and lobular inflammation, other than extramedullary hematopoiesis, is usually a minor feature in INH and may be absent in many metabolic disorders that affect the liver of infants. The explanation may be lack of metabolic by-products that are toxic to the affected cells; or a toxic effect may be easily compensated by replacement of injured cells or organelles without permanent injury to the liver. On the other hand, some metabolic diseases of the liver are commonly accompanied by inflammatory changes, such as alpha-1-antitrypsin deficiency, tyrosinemia, and several bile acid synthetic defects, that may mimic chronic viral hepatitis or drug-induced hepatitis or autoimmune hepatitis. The common denominator in metabolic disorders consistently presenting as “hepatitis” seems to be accumulation of toxic metabolites that stress hepatocytes or small bile ducts. An alternate explanation is that inflammation incidental to intercurrent events such as viremia, sepsis, systemic inflammatory disease, or drug exposure may be poorly tolerated in metabolic disease. Examples of metabolic liver diseases with propensity to inflammation and/or cirrhosis and long-term liability to neoplasia are listed in Table 13.4.

Canalicular cholestasis and cytoplasmic chole-stasis regularly occur in INH and in certain metabolic diseases. Disruption of the canalicular network as a result of necrosis or extensive giant cell transformation may contribute to nonobstructive cholestasis. Examples are tyrosinemia, alpha-1-antitrypsin storage disease, perinatal iron storage disorder, galactosemia, and some mitochondriopathies. Another group includes disorders in which the synthesis or transport of bile acids is abnormal. In both, lobular cholestasis is severe, but in synthetic defects, toxic hydrophobic monohydroxy bile acids may injure bile canaliculi and ductules as well as hepatocytes. Bile ducts are spared and serum gamma glutamyl transferase is typically normal. A third group with cholestasis are genetic metabolic diseases that are characterized by progressive cholangiopathy affecting bile ducts such as Alagille syndrome, Zellweger disease, cystic fibrosis, and one form of progressive familial intrahepatic cholestasis, PFIC3. In this group are those few infants with alpha-1-antitrypsin storage disease who have early-onset cholestasis with progressive small bile duct injury potentially resulting in paucity. Serum gamma glutamyl transferase is typically elevated in cholangiopathies.

Paucity of interlobular bile ducts is by definition a feature of Alagille syndrome. Nonsyndromatic paucity has been reported rarely in a host of other metabolic, genetic, and acquired diseases such as alpha-1-antitrypsin deficiency, PFIC2, bile acid synthetic defects, congenital panhypopituitarism, or conditions such as Zellweger disease, Down syndrome, and arthrogryposis-renal-cholestasis syndrome. Paucity may be due to bile duct destruction with or without sclerosis or delays in small bile duct formation (Kahn et al. 1986; Sinha et al. 2007).

Recognition of the difference between proliferation of interlobular bile ducts and reactive bile ductules is important for distinguishing a true cholangiopathy such as biliary atresia from the common periportal ductular reaction (DR). The latter occurs in diverse liver diseases (viral, autoimmune, drug induced, and metabolic) that are not primary diseases of bile ducts (Fig. 13.4a–c). Persistent ductular reaction is a sign of injury to bile ductules and zone 1 hepatocytes. Metabolic diseases such as tyrosinemia, galactosemia, alpha-1-antitrypsin deficiency, and the more hepatotoxic bile acid synthetic defects are regularly accompanied by ductular reaction and progressive periportal fibrosis. Ductular reaction in Alagille syndrome and Zellweger syndrome may hinder recognition of paucity of interlobular bile ducts.

True cholangiopathies are characterized by primary injury to intra- and/or extrahepatic bile ducts and are often accompanied by a persistent DR with progressive periportal fibrosis. DR and proliferation of interlobular bile ducts often coexist in large duct cholangiopathies, e.g., extrahepatic biliary atresia, ABCB4 disease (PFIC3), Langerhans cell histiocytosis, and primary sclerosing cholangitis.

Bile duct epithelium usually is not involved in metabolic storage diseases that affect Kupffer cells and/or hepatocytes. Exceptions include some lysosomal storage diseases (type II glycogenosis, GM1 gangliosidosis, mucolipidoses) and cystic fibrosis. In perinatal hemochromatosis (PH), hemosiderin deposits in duct epithelium may be observed possibly reflecting the general deposition of hemosiderin in extrahepatic parenchymal cells.

Fatty change in the liver of infants and children is usually acquired but may be a manifestation of an underlying rare genetic metabolic disease such as a defect in beta oxidation of lipids, mtDNA depletion, disorder of specific electron transport proteins, urea cycle defect (UCD), organic acidemia, or an aminoacidopathy. Accumulation of lipid in hepatocytes without inflammation, hepatocyte necrosis or other abnormalities of liver cells, or evidence of fibrosis, is simple steatosis (Fig. 13.5a). Simple steatosis may be seen with cystic fibrosis, Wilson disease, celiac disease, protein avoidance in urea cycle defects, corticosteroid therapy, certain drug reactions, hypertriglyceridemia, after gastric bypass surgery and portocaval shunts, and with blind loop and short gut syndromes. Simple steatosis is characterized by large vacuoles of neutral lipid that displace the nucleus to the periphery (Fig. 13.5a). This change commonly is limited to periportal hepatocytes (zone 1) but may be panlobular, or limited to zone 3 in certain circumstances related to gastrointestinal dysfunction (Fig. 13.5b). A form of simple steatosis is readily acquired in infants and children during periods of temporary caloric deprivation. Simple histiocytosis is common at autopsy of critically ill children who die in hospital intensive care units and occurs in a minority of infants who are diagnosed with sudden infant death syndrome. In these circumstances, lipid droplets are of small to medium size, often panlobular, and tend not to displace hepatocyte nuclei (Fig. 13.5c). Because coalescence of lipid into visible medium- and large-sized vacuoles is a dynamic process, hepatocytes containing medium- and large-sized lipid droplets often coexist. Nonetheless, the predominant physical form of lipid vacuoles provides a clue, albeit an imperfect one, to the tempo and the underlying cause of lipid accumulation.

Inflammation and fibrosis typically are absent in simple steatosis except in cystic fibrosis where focal obstructive cholangiopathy may coexist. Because lipid has been extracted during processing, it can only be presumptively identified in paraffin sections based upon the sharp interface with surrounding hepatocyte cytoplasm. Storage lysosomes may have a similar sharp interface by light microscopy, but ultrastructure discloses a limiting membrane.

Simple steatosis may be the only change in nonalcoholic fatty liver disease (NAFLD), or these patients may have steatohepatitis (SH) (Schwimmer et al. 2005). NAFLD is linked to obesity, type 2 diabetes mellitus, and insulin resistance. Obese children who develop transaminasemia are commonly subjected to liver biopsy for the purpose of staging and grading the liver lesion (Kleiner et al. 2005; Brunt et al. 2011). SH usually can be distinguished from simple steatosis or steatosis due to a genetic defect in lipid metabolism by subtle lobular inflammation and active hepatocyte injury. Findings in SH in addition to macro- and microsteatosis include multifocal lobular inflammation, ballooned degenerate hepatocytes, and, especially in children, portal inflammation (Fig. 13.6). Mallory-Denk bodies are more common in adults than children with SH. Ultrastructural changes in NAFLD are more commonly observed in SH than with simple steatosis. Excess smooth and rough endoplasmic reticulums are common but nonspecific. An array of focal mitochondrial changes presumably due to oxidative stress includes pleomorphism, matrix crystalloids, and occasional megamitochondria (Fig. 13.7). Persistent hepatocyte injury in NAFLD carries risk for progressive fibrosis but is reversible.

More than a dozen disorders of in fatty acid oxidation (FAO) have been recognized (Vockley and Whiteman 2002; Saudubray et al. 1999). Morbidity/mortality is highest during infancy. A metabolic crisis with hepatomegaly and nonketotic hypoglycemia is a typical presentation in medium-chain acyl-coenzyme A (CoA) dehydrogenase deficiency (MCAD), the most common FAO, but true hepatic failure is rare. Progressive cardiomyopathy and episodic rhabdomyolysis are less common presentations of FAO.

MCAD is the most common of the defects in FAO. The incidence is about 1/10,000 live births in Caucasians but is much less common in Asians based upon data from newborn screening programs (Horvath et al. 2008). Newborns with high C8-acylcarnitine levels have an increased frequency of the common 985A > G mutation. Early detection by screening improves outcome because it highlights the vulnerability to fasting and need for preventative measures, particularly during the first several years of life. However, genetic variants of uncertain significance have emerged from the screening data, and genotype-phenotype correlation remains uncertain (Lindner et al. 2010). In MCAD, an acute metabolic crisis with nonketotic hypoglycemia is precipitated by a febrile illness that causes loss of appetite, exposing the inability of affected children to metabolize lipid during brief starvation. MCAD is also associated with cardiac arrhythmias and sudden death, accounting for a small percentage of neonatal and unexplained infant deaths. FAO disorders may mimic epidemic post-viral Reye syndrome (RS) in clinical presentation, although the affected age groups substantially differ. Morphological manifestations may provide a basis for differentiation if liver tissue is available for both light and electron microscopy (Treem et al. 1986).

Long-chain acyl-CoA dehydrogenase deficiency results in progressive liver fibrosis, often with cardiomyopathy, myopathy, or pigmentary retinopathy. FAO defects or lipid transport defects may result in a metabolic crisis in the immediate newborn period before feeding is initiated, as in the infantile forms of carnitine palmitoyltransferase two deficiency and carnitine-acylcarnitine translocase deficiency (Chalmers et al. 1997). Many cases of acute fatty liver of pregnancy are a manifestation of recessively inherited FAO defects in the fetus, the most common being mitochondrial trifunctional protein defect that impairs oxidation of long-chain fatty acids (Ibdah et al. 1999; Yang et al. 2002).

Several FAO defects, including medium-chain acyl-CoA dehydrogenase, long-chain acyl-CoA dehydrogenase, carnitine transporter defect, and carnitine translocase defect, have been implicated in a small number of sudden deaths in infancy and childhood.

Based upon observations in liver biopsies and autopsy material, infants and children with defective FAO accumulate neutral lipid in organs most dependent upon FAO such as the liver, heart, proximal renal tubules, and type 1 skeletal muscle fibers. The lipid accumulation occurs predominantly in the form of microvesicular steatosis in which the lipid vacuoles indent but do not displace the nucleus (Fig. 13.9a, b); coexistent large droplet lipid is usually associated, but often a lesser component. In MCAD, the accumulation of lipid in hepatocytes may be transient and may abate or disappear without permanent liver injury when homeostasis is restored. Analysis of urine for acylcarnitine compounds and establishment of a fibroblast culture are essential supplements to appropriate tissue samples when clinical suspicion is high. Limited published observations on antemortem liver samples suggest that ultrastructure of mitochondria in FAO are not distinctive in comparison to mitochondrial alterations in primary disorders of electron transport, mitochondrial DNA (mDNA) depletion, and epidemic Reye Syndrome.

Diagnosis is usually based upon a characteristic abnormal urine acylcarnitine profile determined by high-performance liquid chromatography (HPLC) and plasma acylcarnitine profile determined by fast atom bombardment mass spectrometry from Guthrie card bloodspots, organic acid profiles, and studies of fatty acid processing performed on cultured fibroblasts. Mutation analysis is available for the most common mutations in MCAD.

Mitochondriopathies are abnormalities of energy metabolism caused either by nuclear DNA mutations or mtDNA mutations/deletions that impair oxidative phosphorylation (OXPHOS) (Finsterer 2004; Dimauro 2011). Clinical manifestations in infants or children may involve one or more organs, often in clinically recognizable patterns, but the spectrum differs somewhat from those that affect adults (Bernier et al. 2002). Though enigmas remain, understanding continues to evolve as knowledge and experience expand and the difference between primary and secondary mitochondrial dysfunction due to other metabolic disturbances is clarified.

Mitochondriopathies first recognized, such as those characterized by ragged-red muscle fibers, usually do not affect the liver. Most are caused by maternally inherited mtDNA mutations that typically affect one particular component of OXPHOS system. Clinical manifestations are usually delayed until the proportion of abnormal mitochondria in a given organ, usually skeletal muscle, exceeds a critical threshold that varies with metabolic demand. Large deletions in mtDNA cause Kearns-Sayre syndrome, a myopathy in which the liver is rarely involved, and Pearson marrow-pancreas syndrome. Pearson syndrome, the more common of the two in infants and young children, causes anemia, both exocrine and endocrine pancreas dysfunction, and liver disease that may be clinically significant (Williams et al. 2012). Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a multisystem disease that affects young adults but may begin in childhood; the liver is not usually involved (Garone et al. 2011).

Nuclear DNA (nDNA) mutations may affect one particular enzyme in the Krebs citric acid cycle, one subunit of the OXPHOS system, or generally impair mtDNA synthesis resulting in multiple defects in OXPHOS. The liver may be affected alone or in various combinations with brain, heart, kidney, skeletal muscle, or gastrointestinal tract.

Acute liver failure due to mitochondriopathy is rare and usually manifest in infants, many of whom have or will develop significant brain disease (Sarzi et al. 2007). One cause, deficiency of cytochrome oxidase (complex IV), associates with many phenotypes, one of which is congenital lactic acidosis, a systemic disease with devastating clinical manifestations that suggest multiorgan dysfunction. Another phenotype, GRACILE syndrome (intrauterine growth restriction, aminoaciduria, cholestasis, hepatic iron overload, and lactic acidosis), is due to mutation in BCS1L, a chaperon protein for complex III, that results in reduced levels of this electron transporter. Still another phenotype, Wolcott-Rallison syndrome, consists of neonatal-infantile diabetes mellitus, skeletal dysplasia, growth retardation, and intermittent liver failure. In these infants, complex I is deficient due to mutation in a nuclear gene, PRK-like ER kinase. Recent studies show that infant liver failure is often caused by another mechanism, mtDNA depletion, that results from mutations in nuclear genes that control synthesis of most subunits of the OXPHOS system (Fellman and Kotarsky 2011). Examples of mutations in nuclear genes or nuclear-coded proteins that are reported to cause progressive hepatic or hepatocerebral mitochondriopathy in infancy are deoxyguanosine kinase, POLG1, SUCLG1, and MPV17. The phenotypic spectrum of MPV17 mutation-related disease includes the Navajo neurohepatopathy (Holve et al. 1999; Karadimas et al. 2006).

Most, if not all, of the valproic acid-associated cases of acute liver failure in infants or children with seizures have an underlying mitochondriopathy that affects both liver and brain. Such patients are exceptionally vulnerable to valproic acid because it interferes with mitochondrial oxidation of fatty acids (Silva et al. 2008). Most cases of Alpers-Huttenlocher syndrome are mitochondriopathies in which brain involvement leads to early presentation as a seizure disorder (Gordon 2006). The well-known association of progressive liver and brain mitochondriopathy is the basis for the warning to avoid liver transplants in infants or children with liver failure unless brain involvement can reasonably be excluded.

Mitochondrial hepatotoxicity of nucleoside reverse transcriptase inhibitors of DNA polymerase gamma may cause steatosis and lactic acidemia. These complications of therapy for chronic viral infections are rare in children perhaps because long-term exposure is necessary, but have been reported in infants exposed during pregnancy.

Liver histological features at the time of liver failure due to a primary mitochondriopathy vary depending on the age of onset and stage of the disorder. Typical changes in older infants at the time of liver failure include patchy, sometimes extensive micro- and macrovesicular steatosis, intralobular cholestasis, finely granular bright red hepatocytes isolated or clumped in groups that contain excessive numbers of mitochondria, swollen hepatocytes that lack lipid droplets, scattered necrotic hepatocytes, foci of intralobular regeneration and collapse, and mixed portal/lobular inflammation accompanied by progressive portal fibrosis (Fig. 13.10a–d). Oxidative enzyme histochemistry applied to cryostat sections of the liver may be helpful in recognition of mitochondriopathy. Selective reduction or hyperintensity of histochemical reactions for cytochrome oxidase and succinic dehydrogenase, normally uniform in cryostat sections of liver, may be observed (Ibdah et al. 1999). In the liver, as well as in organs such as the heart, mitochondriopathy may induce generalized proliferation of mitochondria despite functional deficiency. The generic histological phenotype described above may be absent in fulminant mitochondriopathies that cause lethal lactic acidosis in the newborn period (Fig. 13.10e). Immunohistochemical stains may be useful to demonstrate mitochondrial hyperplasia.

Distinctive ultrastructural mitochondrial abnormalities are reported in many infants and young children with proven mitochondriopathy (Mandel et al. 2001; Labarthe et al. 2005; Wong et al. 2007). These include pleomorphism of size and shape, increased or decreased numbers of mitochondria per hepatocyte, bizarre dilatation of cristae, and expansion of matrix that displaces cristae as it accumulates causing mitochondrial enlargement that may be spectacular. Matrix may be pale or dense (Fig. 13.11a–d). Similar morphological changes occur in acute liver failure associated with what formerly were called “idiosyncratic” drug reactions to valproic acid used to treat seizures in infants or in older children. Many of these patients have an unrecognized genetic mitochondriopathy that causes mDNA depletion. Curiously, intra-cristal paracrystalline inclusions of the type that are common in the ragged-red fibers of mitochondrial myopathy are rarely, if ever seen in mitochondrial hepatopathy. Whether mitochondrial ultrastructural changes may be specific for particular defects requires more observation.

The range of ultrastructural changes in primary mitochondriopathy appears to differ from changes due to nonspecific oxidative metabolic stress that accompany ethanolism, nonalcoholic steatohepatitis, urea cycle disorders, bile acid synthesis defects, extrahepatic portal vein obstruction, and rarely in glycogenosis. These changes include normal mitochondria with mild pleomorphism, scattered pale swollen mitochondria, paracrystalline matrix inclusions, and megamitochondria (Figs. 13.7 and 13.14d).

Criteria for clinical and laboratory diagnosis of mitochondriopathy in the context of neuromuscular disease with or without multiorgan involvement are not perfect (Gordon 2006). These criteria are even less helpful when mitochondrial disease primarily affects one or more visceral organs such as the liver. Skeletal muscle is commonly affected in multiorgan mitochondriopathies but does not always exhibit diagnostic changes by light or electron microscopy. Nonetheless, muscle biopsy is convenient and, properly triaged and processed, has a reasonably high yield as a screening test for biochemical and molecular genetic disorders (nDNA or mtDNA). Muscle biopsy may be useful when clinical signs indicate primary liver involvement alone or in conjunction with central nervous system disease.

Light and electron microscopic findings in needle biopsy samples of the liver often create suspicion for mitochondrial hepatopathy and may occasionally be diagnostic though not specific for a particular genetic entity. mtDNA content may be assessed in a needle biopsy specimen. Specific mutations in nDNA that cause mtDNA depletion and liver failure in infants or young children can now be assayed in blood leukocyte DNA. However, open liver biopsy may be needed for a complete assessment that includes light and electron microscopy, measurement of electron transport activities, mDNA content, and search for mDNA deletions or point mutations. With the advent of mitoexome and whole genome sequencing, DNA from the liver, cultured fibroblasts and leukocytes will modify the role of liver biopsy.

RS is an acute liver dysfunction with encephalopathy and fatty degeneration of the liver. RS occurs in two clinical guises. One form affects older, previously well children, peaked between 1970 and 1985 and has almost disappeared. The other form mainly affects infants and young children, as a complication of an underlying metabolic disorder. The former was a transient post-viral acute encephalopathy associated with fatty degeneration of hepatocytes in which microvesicular steatosis developed in the wake of a viral illness along with signs of brief transient failure of hepatic synthetic function, hyperammonemia, and mild to moderate elevation of serum aminotransferases. Clear evidence of association of RS with epidemics of chicken pox and influenza B was followed by epidemiological evidence linking the syndrome to low-therapeutic levels of salicylate. Mortality and long-term morbidity due to brain injury was about 5 %. Both light and electron microscopy of liver tissue obtained early in the course of the disease were distinctive and established the basis as a hyperacute emergence (phanerosis) of microvesicular fat as a marker for acute liver failure due to a transient reversible mitochondriopathy (Partin et al. 1971; Bove et al. 1975). Concomitant glycogen depletion was often severe, accounting for hypoglycemia. The hepatocytes in the early phase are swollen and contained few visible lipid droplets in paraffin sections (Fig. 13.12). However, abundant microvesicular lipid, apparently concealed during rapid evolution of the hepatopathy, was demonstrable in fat stains on frozen sections. Zonal necrosis was absent, but apoptosis was often seen. Histochemical studies showed depletion of succinic dehydrogenase and cytochrome oxidase. Ultrastructural changes in mitochondria were distinctive and remain so in retrospect, suggesting kinship to the “membrane permeability transition” pathway. The biology of the relationship of RS to low blood levels of salicylate remains mysterious, and the validity of the statistical link, though generally accepted, has been questioned.

With decline of aspirin usage as an antipyretic in children, RS has almost, but not completely, disappeared in the United States (Belay et al. 1999) except in the context of acute decompensation of an underlying metabolic disorder of energy metabolism typically in infants or very young children. In such cases, the distinctive ultrastructural changes of mitochondria in epidemic RS are absent (Garone et al. 2011). Skepticism about the existence of RS except in the context of a specific metabolic disorder is based upon advances over the past 30 years in diagnostic techniques that were not available at the height of the epidemic. However, this argument is unconvincing given the prevalence of epidemic RS in older children and rarity of second episodes in the vast majority who survived.

WD is an autosomal recessive disorder of copper transport due to mutations in the ATP7B gene that results in copper overload in the liver, progressive liver disease, and degeneration of central brain nuclei often with onset in childhood. Laboratory criteria for diagnosis are low serum ceruloplasmin, elevated 24-h urine copper, and high hepatic tissue copper levels, but may not be definitive (Nicastro et al. 2010). Early signs in children such as elevated serum transaminases and/or hepatomegaly or acute onset of liver failure may prompt an investigation that includes liver biopsy. Liver histology ranges from normal to chronic hepatitis with or without steatosis, often prominent nuclear glycogenation, or submassive necrosis. The rhodanine copper stain identifies copper within secondary lysosomes and is widely used but not specific, because copper accumulates nonuniformly in WD and may also be detected in other conditions, particularly if cholestasis is a confounding factor. Liver ultrastructure may be helpful showing prominent mitochondrial changes such as tubular dilatation of cristae and matrix inclusions, as well as unusually complex membrane-bound insoluble lipid inclusions, dubbed lipolysosomes (Fig. 13.13a, b). The mitochondrial changes in Wilson disease overlap with those seen in primary mitochondriopathies and also with those seen in acquired conditions such as steatohepatitis where oxidative stress may be causative. Evidence from humans and animal models of genetic and acquired copper toxicity suggests that copper localizes in and promotes oxidant injury to mitochondria thereby playing an essential role in progressive liver and brain damage in Wilson disease (Sokol et al. 1994; Zischa et al. 2011).

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