Definitions and Epidemiology
Metabolic liver disease has traditionally referred to diseases that result from inborn errors of metabolism. These disorders are due to a single enzyme defect that affects the synthesis or catabolism of a carbohydrate (CHO), protein, or lipid. These defects in metabolism can result in either liver failure or cirrhosis, with or without injury to other tissues, or relative sparing of the liver with primary toxicity to other organ systems (Table 28–1). Metabolic disorders that arise in the liver with primary toxicity to other organ systems are not addressed in this chapter. This chapter approaches metabolic-induced liver disease not only from the traditional approach, those resulting from a single enzyme defect, but also as a genetic susceptibility induced by a trigger, such as a drug or a metabolic derangement associated with visceral obesity (nonalcoholic fatty liver disease (NAFLD)).
|Fructose dysphosphatase||Hereditary fructose intolerance (HFI)|
|Glucose-6-phosphatase||Glycogen storage disease type 1 (GSD-I)|
|Debranching enzyme||Glycogen storage disease type 3 (GSD=III)|
|Branching enzyme||Glycogen storage disease type 4 (GSD-IV)|
|Fumarylacetoacetate hydrolase||Hereditary tyrosinemia type 1 (TT1)|
|Lysosomal acid lipase||Wolman’s/cholesterol ester storage|
|Cholesterol transport||Niemann–Pick type C (NPC)|
|Bile acid disorders|
|Bile acid synthesis|
|Sterol nucleus modification||3B hydroxy, 5B reductase, 7a hydroxylase|
|Side-chain shortening||Zellweger, Refsum, neonatal ALD|
|Bile acid transport|
|Alpha-1-antitrypsin deficiency||Chapter 26|
|Cystic fibrosis||Chapter 32|
|Nonalcoholic fatty liver disease (NAFLD)|
|Wilson’s disease||Chapter 25|
Taken individually, single enzyme defects are rare, although as a group they constitute at least 10% of pediatric liver transplantations. Wilson’s disease, alpha-1-antitrypsin deficiency (A1AT), and cystic fibrosis are the most common inherited metabolic conditions that affect the liver and are discussed individually in this textbook. Fortunately, in children most drug-induced liver disease (DILI) remains uncommon, although certain pediatric patient populations are at increased risk. NAFLD is becoming a worldwide problem of childhood and is the most common cause of liver disease in this age group. The increase in prevalence parallels the epidemic of obesity.1 This chapter will address the following three categories of metabolic liver disease in separate sections: inherited metabolic-induced liver disease, DILI, and obesity-induced NAFLD.
Inherited Metabolic-Induced Liver Disease
Enzymatic disorders that cause liver disease include disorders of CHO, protein, lipid/microsomal, and bile acid synthesis. Because the pathogenesis of these disorders is directly related to the metabolic pathway where the defect occurs, each class of disorders is addressed separately.
Clinical manifestations of inherited metabolic liver disease result from the location of the enzyme defect, by either the loss of substrate or accumulation of abnormal byproducts. The approach to the child with a suspected metabolic defect is guided by the age of presentation, physical exam, and biochemical abnormalities. Patients can present acutely with evidence of liver failure or as a chronic presentation of liver dysfunction (Tables 28–2 and 28–3). Defects that present as a life-threatening event are more common in the neonate, but can present in infancy or childhood. The importance of the onset of neurologic deterioration in a newborn infant has been categorized by Saudubray et al.2 In the neonate, neurologic symptoms resulting rapidly after a variable symptom-free period indicate a toxic cause. Alternatively, the absence of a symptom-free period associated with delayed evolution of coma suggests an energy-deficient type of defect. Symptoms are protean and can mimic a variety of disorders. Unexplained symptoms or failure to respond to routine measures should raise the suspicion of a metabolic disease.
|• Acute liver failure|
|Acute or chronic presentation|
|• Failure to thrive|
|• Acute liver failure|
|• Chronic seizures|
|• Development delay|
|• Growth failure|
|• Mental retardation|
|• Recurrent liver failure|
|• Recurrent sepsis|
|• Recurrent/cyclic vomiting|
Diet is one of the most important historical facts to ascertain, and should include current diet, recent changes, introduction of new foods, or avoidance of a particular food. In addition, the frequency of feeds and length of fasting should be explored. Associated signs and symptoms may include vomiting, diarrhea, lethargy, seizures, growth failure, and recurrent infections. Family history of spontaneous abortions, stillbirth, early childhood death, developmental delay, or mental retardation is worrisome for metabolic liver disease.
Most patients with metabolic liver disease will have some degree of hepatomegaly, with or without splenomegaly. Depending on the disorder there may be jaundice, or hepatic synthetic dysfunction with ascites and a coagulopathy. Most patients will have some degree of growth failure. Neurologic status will depend on the particular enzymatic defect.
|Acute liver failure|
|Cerebral vascular accident|
|Congenital heart disease|
|• Necrotizing enterocolitis (NEC)|
|Sudden infant death|
|Cerebral vascular accident|
|Cyclic vomiting syndrome|
Suspicion of a metabolic condition is the key to diagnosis. In all children who present with unexplained liver dysfunction, a sample of blood and urine should be obtained at presentation. Serum and urine samples can be stored to be analyzed at a later date, as indicated by the patient’s clinical course. Key laboratory studies need to be obtained at presentation, when the patient is ill, as many laboratory values will normalize with supportive treatment (Tables 28–6 and 28–7).
|• Prothrombin time (PT)/international normalized ratio (INR)|
|• Blood gas|
|• Uric acid|
|• Lactic dehydrogenase (LDH)|
|• Creatinine phosphokinase (CPK)|
|• Lactic/pyruvic acid ratio (L:P)|
|• Serum ketone bodies|
|• Stored specimen|
|• Reducing substance|
|• Stored specimen|
|• Quantitative amino acids|
|• Carnitine/acylcarnitine profile|
|• Lipid profile|
|• Free fatty acids|
|• Quantitative amino acids|
|• Organic acids|
|• Succinyl acetone|
Disorders of Carbohydrate Metabolism
There are many known disorders of carbohydrate metabolism, but only three classes of these cause significant liver injury. These include disorders of fructose and galactose metabolism and certain glycogen storage diseases (GSDs) (Figure 28–1). All are inherited in an autosomal recessive mode. As opposed to disorders of lipid and protein metabolism, disorders of CHO can be either prevented by prenatal diagnosis or treated with modest dietary restriction.3
There are three disorders of galactose metabolism that have traditionally been referred to as galactosemia. Each disorder is a result of a specific enzyme deficiency. Transferase deficiency and epimerase deficiency result in liver disease. Consequences of transferase deficiency are more severe than the relatively rare epimerase deficiency. Galactokinase deficiency results in cataracts, but does not cause liver disease.
Transferase deficiency galactosemia was first described in 1935 and affects 1 in 30,000–50,000 live births. Symptoms result from a deficiency of the enzyme galactose-1-phosphate uridyl transferase (GALT), which catalyzes conversion of galactose-1-phosphate (Gal-1-P) to uridine diphosphate galactose (UDP-galactose) and glucose-1-phosphate (Figure 28–1). UDP-galactose is then converted to UDP glucose by UDP-galactose-4-epimerase. The gene is mapped to chromosome 9p18, and >150 mutations have been identified. Toxicity has been attributed to the metabolic byproducts of galactose: Gal-1-P and galactitol. Although the exact mechanism is unknown, liver toxicity has been attributed to the accumulation of Gal-1-P, while accumulated galactitol causes cataract formation.
Patients with GALT deficiency present in early infancy. Some patients present within the first day or two of life with a severe, fulminant illness. The most common presentation is a subacute illness with vomiting, diarrhea, and growth failure within a few days after the infant has received breast milk or a lactose-containing formula. This is followed by jaundice and hepatomegaly. Some patients are identified while being evaluated for obstructive jaundice. The liver disease is progressive and patients can present with liver failure. Hemolytic anemia has also been observed. There is a strong association of E. coli sepsis and galactosemia, such that this diagnosis should be considered in any infant with E. coli sepsis, and galactose should be removed from the diet until the diagnosis has been excluded. Cataracts may be present at birth if the mother has consumed a large amount of milk products during pregnancy, or may develop postnatally. Commercially available formula preparations that are lactose-free may mask the symptoms until months or years later when cataracts, developmental delay, or hepatomegaly develop.
Laboratory findings include hypoglycemia, hyperchloremic acidosis, and elevated blood and urine galactose levels. A positive urine reducing substance in the absence of glucosuria is suggestive but is neither sensitive nor specific. False-negative results can occur if there is inadequate lactose intake. Reducing substances will clear from the urine within days after lactose has been removed or intravenous hydration has been administered. False positives can occur with severe liver dysfunction and some medications. Various degrees of liver dysfunction, aminoaciduria, and proteinuria have been identified. Diagnosis is made by measuring GALT activity in red blood cells. Prenatal diagnosis can be made by measuring enzymatic activity cells obtained by amniocentesis. Most patients are detected by newborn screening programs.
Treatment is elimination of all dietary galactose. This is a lifelong task and older patients need to pay attention to additives in prepared foods. Sources of hidden galactose include soybeans, legumes, tomatoes, coffee, and processed meats or organ meats such as liver, kidney, and brain. Fruit or fruit juices made from apples, oranges, kiwi, or watermelons also contain galactose. Galactose-free diet results in reversal of acute symptoms, normal growth, and recovery of liver function. Long-term intellectual development is unclear with many patients developing various degrees of learning disabilities, and neurologic defects.
Ovarian failure has been described in up to 65% of women with galactosemia. As a result of dietary restrictions and ovarian failure, osteoporosis is also a frequent complication.
UDP galactose-4-epimerase deficiency galactosemia is a rare disorder that was discovered incidentally from screening programs in Switzerland. Patients have elevated levels of Gal-1-P, but normal levels of GALT. The clinical presentation varies from a benign condition to that similar to GALT galactosemia.4
There are three disorders of fructose metabolism: hereditary fructose intolerance (HFI), fructose diphosphatase deficiency, and essential fructosuria, of which only the first two cause hepatic injury (Figure 28–1). The initial step in fructose metabolism is the phosphorylation of fructose to fructose-1-phosphate by fructokinase. Absence of this enzyme results in benign essential fructosuria.
HFI occurs in about 1 in 20,000 live births. First recognized in 1957, it is caused by a deficiency of fructose-1-phosphate aldolase (aldolase B). Aldolase B is present in liver, kidneys, and muscle. There are two other isoenzymes, aldolase A in muscle and aldolase C in brain, which are unaffected in this disorder. Aldolase B has been sequenced and mapped to chromosome 9q13-32. More than 20 mutations have been described. Aldolase B is the second step in fructose metabolism catalyzing the conversion of fructose-1-phosphate to produce d-glyceraldeyde and dihydroxyacetone phosphate (triose-phosphate). Accumulation of fructose-1-phosphate results in hypoglycemia secondary to impaired glycogenolysis (inhibition of glycogen phosphorylase) and impaired gluconeogenesis as the triose-phosphates is not produced for substrate. Additionally, formation and accumulation of fructose-1-phosphate results in ATP and GTP depletion, impairing protein synthesis.
Patients with HFI remain completely asymptomatic on breast milk or sucrose-free formula. Symptoms occur with the introduction of sucrose-containing formulas, sucrose- or fructose-containing foods, or medications prepared in a sucrose base. Symptoms vary depending on the amount, duration, and age of exposure. Infants most commonly have poor feeding, vomiting, sweating, and hypoglycemia. A large exposure may result in signs of liver failure (hepatomegaly, ascites, and coagulopathy) and renal tubular dysfunction (renal tubular acidosis and hypophosphatemia). Occasionally, older children may be diagnosed due to a profound aversion to dietary “sweets.”
Laboratory abnormalities include hypoglycemia, hypophosphatemia, hypokalemia, hypoalbuminemia, and elevated aminotransferase and prothrombin time. Anemia, thrombocytopenia, and hyperuricemia may be present while serum ammonia is usually normal. Urinalysis reveals increased reducing substances, proteinuria, aminoaciduria, organic aciduria, and fructosuria.
Diagnosis can be made by enzyme analysis of intestinal or preferably liver tissue or targeted DNA analysis. Negative results from targeted sequencing do not completely eliminate the diagnosis; however, targeted DNA sequencing is a useful tool to screen siblings. Complete gene sequencing is available as a research tool.
Initial treatment is supportive care. Long-term treatment is based on dietary restriction with complete avoidance of fructose and sucrose with special attention to food additives and medications. Sorbitol should be avoided, as it is metabolized to fructose. Lifelong abstinence of these sugars results in normal intelligence with reversal of growth failure and organ dysfunction, although hepatomegaly may persist.
Fructose-1,6-biphosphate deficiency (FDP) was first described in 1970. FDP deficiency is a heterogeneous disorder of gluconeogenesis. FDP catalyzes the conversion of fructose-1,6-biphosphate to triphosphates, as a substrate for gluconeogenesis. Patients with FDP differ from those with HFI, as their symptoms (hypoglycemia and lactic acidosis) can be precipitated not only by fructose consumption, but also with fasting. Euglycemia depends on appropriate glucose intake or adequate hepatic glycogen stores. In periods of prolonged fasting, or limited hepatic glycogen, as in the neonate, gluconeogenic precursors will accumulate and hypoglycemic lactic acidosis will occur.
Symptoms usually occur in the first few days of life with hypoglycemia, hyperventilation, and metabolic acidosis. Irritability, seizures, coma, hypotonia, and hepatomegaly are often observed. Abnormal laboratory studies include elevated serum lactate, ketones, alanine, and uric acid. In contrast to HFI, liver and kidney abnormalities are not observed. The fasting-induced hypoglycemia can be confused with GSD type Ib. Diagnosis is based on measuring enzymatic activity in liver tissue. Treatment focuses on avoiding prolonged fasting. Fructose, sucrose, and sorbitol should be avoided, but strict dietary avoidance is not required.
GSD is a group of disorders first described by von Gierke in 1929. Ten types of GSD have been described based on a specific enzyme deficiency in glycogen synthesis or degradation. Type I, III, IV, VI, and IX primarily affect the liver, but only I, III, and IV cause significant hepatic injury (Figure 28–1). In most types of GSD, there is increased glycogen content in liver, muscle, or both. In some cases, the glycogen content may be normal or less than normal; however, the molecular structure may be altered. Although each type of GSD results from a specific enzyme defect, determination of the specific type cannot be made by clinical presentation alone.
Glycogen metabolism is controlled by two enzymes, glycogen synthetase and phosphorylase, both of which exist in active and inactive states. Glycogen synthesis is inhibited by phosphorylase and cyclic AMP (cAMP). Following a meal, increased blood glucose inactivates phosphorylase, halting glycogenolysis and stimulating glycogen production. During periods of fasting, glucagon-mediated increases in cAMP result in activation of phosphorylase and deactivation of glycogen synthesis, stimulating glycogenolysis (Figure 28–2).
Glycogen storage disease type I (GSD-I) is also referred to as von Gierke’s disease and results from a deficiency of glucose-6-phosphatase. Glucose-6-phosphatase is located in the endoplasmic reticulum and catalyzes the terminal step in both glycogenolysis and gluconeogenesis (Figure 28–1). GSD-I is estimated to occur in approximately 1 in 100,000 live births and accounts for 25% of all GSDs. GSD I has three different clinical forms: type Ia, Ib, and Ic. GSD-Ib and -Ic are clinically similar to GSD-Ia, but, during testing of tissue extracts, have normal glucose-6-phosphatase activity in disrupted microsomes but not in intact microsomes.
The enzyme is composed of a catalytic subunit and three transporter subunits, T1, T2, and T3. Defects in the catalytic unit result in GSD-Ia. The gene has been mapped to chromosome 17q21 and is found in the liver, kidney, and intestine. GSD-Ib results from a defect in transporter subunit T1, which has been localized to chromosome 11q23.3. The gene product is microsomal glucose-6-phosphate translocator, which is found in liver, kidney, and leukocytes. GSD-Ic results from defects in transporter subunit T2 that is a microsomal phosphate and pyrophosphate transporter localized to chromosome 11q23.3-24.2. It is found in liver, kidney, and pancreas.
GSD-Ia is considered the classic form of the disease, representing 90% of all GSD-I cases. Patients present with severe hypoglycemia and hepatomegaly, and because the enzyme is also found in the kidney, renal enlargement may be noted. This defect affects both glycogenolysis and gluconeogenesis; thus, symptoms occur when fasting >3–4 hours. Symptoms may occur in the first few weeks of life or later, when feeding frequency decreases. It often presents when infants begin to sleep through the night or when fasting is caused by illness. When infants are fed on demand rather than on a rigid schedule, the diagnosis may be delayed. In addition to hepatomegaly, these children have growth failure, Cushingoid facies, and delayed motor development. Laboratory tests reveal profound hypoglycemia, metabolic acidosis, and elevated serum lactic and uric acid. Triglycerides are markedly elevated, up to 6000 mg/dL, while serum aminotransferases are modestly elevated and bilirubin is normal. There may be hypophosphatemia, dyslipidemia, and platelet dysfunction. Adolescent and adult patients may develop hepatic adenomas or carcinomas, nephrolithiasis, nephropathy, and gouty arthritis.