Metabolic Liver Disease in Children Part 1

1. James Squires, MD James Heubi, MD Cincinnati Children’s Hospital Medical Center Reviewed by Sunny Hussain, MD of the Professional Education Committee Metabolic Liver Disease in ChildrenPart 1

2. Part 1 • Disorders of Bilirubin Metabolism • Disorders of Carbohydrate Metabolism

3. Introduction • The liver has expansive role in synthesis, degradation, and regulation of pathways involved in the metabolism of carbohydrates, proteins, lipids, trace elements, and vitamins • Abnormalities that affect these pathways as well as specific enzyme deficiencies often affect the liver commonly via accumulation of metabolites resulting in a spectrum of liver injury • Clinical presentations of children vary from acute life threatening illness to a more indolent chronic disease • A detailed history can often elicit the possibility of a metabolic dysfunction and assist in the guidance of further clinical investigations while treatment is dependent of the particular metabolic defect that is identified

4. Disorders of Bilirubin Metabolism - Introduction • Bilirubin is formed by the breakdown of heme containing products (RBCs ) • Subsequent degradation of heme produces carbon monoxide and biliverdin • Biliverdin is then metabolized to bilirubin by the enzyme biliverdin reductase • Majority of bilirubin is bound to albumin and transported to the liver.

5. Disorders of Bilirubin Metabolism - Introduction • Bilirubin bound to albumin is taken up by hepatocytes and is conjugated via uridine diphosphogluconurate glucuronosyltransferase (UGT) to be secreted into the biliary ductal system • Majority of neonatal jaundice is non-pathologic and is due to changes in bilirubin metabolism resulting in: • Increased production, • Decreased clearance, and • Increased entero-hepatic circulation

6. Disorders of Bilirubin Metabolism -Breast Milk Jaundice • Jaundice that results from the normal physiologic mechanisms contributing to elevated circulating indirect bilirubin levels • Etiology not clearly understood, several proposed mechanisms: • Increased bilirubin production resulting from the increased breakdown and turnover of RBCs • Decreased activity and/or inhibition of UGT • Responsible for bilirubin conjugation and subsequent secretion into the biliary system • Increased entero-hepatic circulation: • Relative sterility of the neonatal gut • Increased content of beta glucuronidase activity in breast milk

7. Disorders of Bilirubin MetabolismBreast Milk Jaundice – Clinical Presentation & Diagnosis • Yellowing of the skin and sclera becomes clinically evident as production begins to exceed the clearance of bilirubin • Breastfeeding jaundice: • Manifests after the first 24 hours of life • Accentuated by breastfeeding • Suboptimal milk production and/or intake • Suboptimal caloric intake • True breast milk jaundice (BMJ) manifests after the first 4-7 days of life. • A second peak in serum bilirubin level may be seen around 14 days of life. • Serum bilirubin levels plotted on nomogram to differentiate physiologic vs pathologic jaundice • Jaundice progression: • Cephalocaudal: Jaundice evident first over the head and progressing to the palms and soles • Rough estimation of bilirubin level: Face ̴ 5 mg/dL; mid abdomen ̴15 mg/dL; soles ̴ 20 mg/dL

8. Disorders of Bilirubin MetabolismBreast Milk Jaundice – Treatment and Outcomes • Treatment protocol based on serum bilirubin level • Serum bilirubin levels 17-25 mg/dL necessitate initiation of phototherapy • Most rapid way to reduce serum bilirubin levels: • Interrupt breastfeeding for 24 hours, • Feed with formula, • Add phototherapy • Prognosis is excellent • Jaundice in breastfed infants may persist for up to 12 weeks

9. Disorders of Bilirubin MetabolismGilbert’s Syndrome - Pathogenesis • The most common inherited (autosomal recessive) disorder of bilirubin glucuronidation • Characterized by chronic and recurrent elevations in serum unconjugated bilirubin levels • Decreased UGT activity (Uridinediphosphoglucuronate glucuronosyltransferase) often due to mutations in the promoter region of gene encoding UGT

10. Disorders of Bilirubin MetabolismGilbert’s Syndrome - Clinical Presentation & Diagnosis • Presents in adolescence or young adulthood with mild, intermittent elevations in unconjugated bilirubin levels without evidence additional liver disease or dysfunction • Unconjugated bilirubin levels seldom rise above 4 mg/dL • Commonly episodes of icterus associated with precipitating factors • Dehydration, Fasting, Intercurrent illness, Menstrual periods, Stressors such as trauma and overexertion • Physical exam: • May exhibit only mild scleral icterus, yellowing of the skin is rarely present • A presumptive diagnosis can be made when patients exhibit : • Unconjugated hyperbilirubinemia on repeat testing • Normal CBC, peripheral smear, and reticulocyte count • No evidence of liver dysfunction • Remember: Critical to the diagnosis of GS is clinician’s suspicion and thus avoidance of unnecessary invasive and investigatory testing

11. Disorders of Bilirubin MetabolismGilbert’s Syndrome - Treatment and Outcomes • Reassurance • GS is a benign condition with no evidence of long term potential for hepatic dysfunction • No specific treatment is necessary • Most important aspect of management is the recognition of the disorder and the understanding of its favorable outcomes

12. Disorders of Bilirubin MetabolismCrigler-Najjar Syndrome - Pathogenesis • Rare autosomal recessive disease characterized by significantly elevated unconjugated bilirubin levels • Patients with CN thus have a profound inability to conjugate and subsequently excrete bilirubin in the bile • Result from defects in UGT activity • Two distinct forms of the disease based on severity of UGT1A1 enzyme dysfunction • Type 1 (CN1): complete absence of UGT enzymatic activity • Type 2 (CNII): Markedly reduced UGT activity

13. Disorders of Bilirubin MetabolismCrigler-Najjar Syndrome- Clinical Presentation & Diagnosis • Presentation: First few days of life with jaundice and profound elevation in serum bilirubin levels (often > 20 mg/dL) • Bilirubin induced brain dysfunction, or kernicterus, is always a concern in children with CN • Bilirubin deposition in the grey matter of various central nervous system structures can result in a myriad of acute symptoms including: • Lethargy, decreased feeding, hypo- or hypertonia, high-pitched cry, fever, seizures, and death • Genetic testing can be performed to assess UGT1A1 mutations and liver biopsy can be used to obtain tissue for UGT1A1 function assays

14. Disorders of Bilirubin MetabolismCrigler-NajjarSyndrome - Treatment and Outcomes • Treatment: Early initiation of phototherapy or plasmapheresis to lower serum bilirubin levels and thus preventing possibility of future neurological sequelae • Additional therapeutic options: • Cholestyramine, agar, or calcium phosphate: act as binding agents and traps unconjugated bilirubin in the gut and prevents enterohepatic recirculation • Phenobarbital: May be useful in patients with CNII • Liver synthetic function is preserved in children with CN making them ideal candidates for orthotopic liver transplantation • The effects of elevated bilirubin concentrations on the central nervous system and the development of kernicterus remains the most important indicator of patient outcome

15. Disorders of Bilirubin MetabolismRotor Syndrome - Pathogenesis • Benign, autosomal recessive disorder resulting in chronic elevations of both conjugated and unconjugated bilirubin levels without evidence of hemolysis • Exact abnormality remains unknown • Primary deficiency is thought to be related to a defective intracellular storage capacity of liver for binding anions involved in the excretion of conjugated bilirubin

16. Disorders of Bilirubin MetabolismRotor Syndrome – Clinical Presentation & Diagnosis • Should be suspected in children presenting with jaundice and scleral icterus in the setting of normal liver function tests and no evidence of biliary obstruction or hemolysis • Total bilirubin levels generally reside in the 2 to 7 mg/dL with the conjugated bilirubin fraction over half of the total serum bilirubin concentration • A confirmatory diagnosis can be made when urinary coproporphyrin levels are measured to be 2.5 to 5 times higher than normal

17. Disorders of Bilirubin MetabolismRotor Syndrome – Treatment and Outcomes • Patients with Rotor’s syndrome do not require any specific therapy

18. Disorders of Carbohydrate MetabolismIntroduction • Liver plays a primary role in the management of glucose homeostasis • Glucose production can occur through a variety of metabolic pathways including gluconeogenesis as well as degradation of glycogen (glycogenolysis) • Glucose along with galactose and fructose are the major dietary carbohydrates that are absorbed and processed for energy generation necessary for sustaining cellular function

19. Disorders of Carbohydrate Metabolism -Galactosemia • Autosomal recessive • Incidence: 1:60,000 live births • Enzymatic deficiency in one of three proteins in the metabolic pathway through which galactose is converted to glucose: • Galactokinase (GALK), • Galactose-1-phosphate uridyl transferase (GALT), and • Uridine diphosphate galactose-4-epimerase (GALE)

20. Disorders of Carbohydrate MetabolismGalactosemia – Clinical Presentation & Diagnosis • Classically presents in the first few weeks of life after ingestion of breast milk or milk based formulas containing lactose (glucose+galactose) • Failure to thrive and jaundice are the most common presenting symptoms • Clinical presentation ranging from an acute, life threatening decompensation often associated with E. coli sepsis to a more subtle non-specific manifestations • Physical exam: • Jaundice with hepatomegaly, ascites, edema, excessive bruising, hypotonia, and a full fontanelle • Laboratory investigations: • Multi-system abnormalities with direct hyperbilirubinemia, elevated transaminases, hypoalbuminemia and coagulopathy • Diagnosis: • Complete absence of GALT activity via a quantitative assay remains to be the gold standard

21. Disorders of Carbohydrate MetabolismGalactosemia – Treatment and Outcomes • Management: • Immediate removal of galactose from the diet • Switch to soy based formula • Further acute management aimed at treating co-morbidities present at diagnosis – such as jaundice, infection, coagulopathy, and acidosis • Antibiotics, intravenous fluids, blood products, and vitamin K are often needed • Referral to a dietician • Patients with galactosemia should be followed to ensure dietary compliance and assess end organ damage • Most affected children will have some degree of intellectual deficit with speech and language delays

22. Disorders of Carbohydrate MetabolismHereditary Fructose Intolerance- Pathogenesis • Autosomal recessive • Incidence: 1:20,000 • Deficiency of enzyme fructose-1-phosphate aldolase (aldolase B)

23. Disorders of Carbohydrate MetabolismHereditary Fructose Intolerance- Clinical Presentation & Diagnosis • Children with HFI are healthy until they ingest fructose and/or sucrose • Presentation: • Vomiting, hepatomegaly, decreased oral intake, and failure to thrive • A detailed nutritional history is critical as symptom onset frequently correlates with intake of fructose containing foods • Laboratory investigations: • May reveal evidence of acute liver failure, proximal renal tubular dysfunction, and hypoglycemia • Reducing substances in urine due to fructosuria • Diagnosis: • Patients with HFI can be diagnosed with non-invasive DNA amplification with a limited number of allele-specific oligonucleotides

24. Disorders of Carbohydrate MetabolismHereditary Fructose Intolerance – Treatment and Outcomes • Treatment: • Removal of fructose and sucrose from the diet • Optimal levels of restriction have not been established and while some patients are able to demonstrate normalization of hepatic and renal function with low fructose intake, others may suffer with chronic, non-specific symptoms despite treatment • Once appropriate dietary restriction is implemented, clinical progression is rarely encountered and the majority of children exhibit normal growth and intellectual development

25. Disorders of Carbohydrate MetabolismGlycogen Storage Diseases (GSD) - Introduction • Glycogen is a polysaccharide that constitutes the primary carbohydrate storage compound and is the principal source of energy providing substrates for the generation of ATP • The complexity of this process is underscored by the multitude of enzymes involved, deficiencies in which result in the 12 recognized forms of glycogen storage diseases (GSD) • The overall incidence of GSD is estimated 1:20,000-40,000 cases per live birth

26. Disorders of Carbohydrate MetabolismGSD I (von Gierke’s Disease) - Pathogenesis • Autosomal recessive] • Several enzymatic defects involved, resulting in further classification of GSD I • GSD Ia: • Complete absence of glucose-6-phosphatase, an enzyme involved in the final process of both gluconeogenesis and glycogenolysis • GSD Ib: • Defect in the enzyme glucose-6-phosphatase translocase which transports glucose-6-phosphatase from the cytoplasm into the microsomes

27. Disorders of Carbohydrate MetabolismGSD I (von Gierke’s Disease) – Clinical Presentation & Diagnosis • GSD1 typically present in early infancy with profound hepatomegaly and fasting hypoglycemia • Other presenting signs and symptoms: • Protruding abdomen, metabolic derangements, seizures, growth failure, recurrent infections, muscular hypotonia, epistaxis, and delayed psychomotor development • Laboratory findings: • Hypoglycemia, lactic acidosis, hyperuricemia, hypophosphatemia, hyperlipidemia, and platelet dysfunction • Neutropenia is a unique manifestation of GSD Ib • Diagnosis: • DNA testing for common mutations confirms the diagnosis • In the absence of identifiable genetic abnormality, liver enzyme activity on biopsy sample can be measured

28. Disorders of Carbohydrate MetabolismGSD I (von Gierke’s Disease) – Treatment and Outcomes • Treatment goal is maintenance of euglycemia and correct metabolic abnormalities • A carbohydrate-balanced diet with frequent day time feedings paired with continuous nocturnal feeds and/or the addition of uncooked cornstarch are the mainstays of treatment • Management of GSD Ib is similar to GSD Ia except the need for granulocyte colony-stimulating factor (G-CSF) administration in GSS 1b • Patients with GSD I to survive well into the third decade of life with normal growth and pubertal development • Increased risk for development of Hepatocellular adenomas with possible malignant degeneration has been reported • Annual serum alpha-fetoprotein levels and liver ultrasounds are recommended • While adequate metabolic control can result in normal neurological development, repeated episodes of hypoglycemia and lactic acidosis can also result in mental handicaps

29. Disorders of Carbohydrate MetabolismGSD III (Forbes Disease, Cori Disease, Glycogen Debrancher Deficiency) – Pathogenesis • Autosomal recessive • Resulting from mutations in the gene encoding amylo-1, 6-glucosidase – glycogen debranching enzyme • 2 main sub-classifications • GSD IIIa: • Involves both the liver and muscle • GSD IIIb • Affects primarily the liver

30. Disorders of Carbohydrate MetabolismGSD III - Clinical Presentation & Diagnosis • Clinical presentation: • Hepatomegaly, hypoglycemia, hyperlipidemia, and acidosis • Muscular involvement: • Weakness, muscle wasting, and cardiac dysfunction • Elevated creatinine kinase levels seen in GSD IIIa • Children with GSD IIIbno muscular involvement as the affected RNA isoform is expressed only in the liver • Diagnosis: • Confirmed with direct measurement of amylo-1, 6-glucosidase activity in liver (IIIa/b) and muscle (IIIa) tissue samples

31. Disorders of Carbohydrate MetabolismGSD III – Treatment and Outcomes • Treatment: • Directed toward avoidance of hypoglycemia • Hepatic involvement in GSD III is considered mild, self-limiting, and improves with age usually resolves by the second decade of life • Hepatocellular carcinoma and cirrhosis have been reported • Monitor annually with serum alpha-fetoprotein and liver ultrasound

32. Disorders of Carbohydrate MetabolismGSD IV (Andersen Disease, Glycogen Branching Enzyme Deficiency ) – Pathogenesis • Autosomal recessive • Mutations in the gene encoding the glycogen branching enzyme (GBE) • GBE catalyzes the attachment of glucosyl chains to glycogen • Deficiency of GBE results in abnormal glycogen structure

33. Disorders of Carbohydrate MetabolismGSD IV – Clinical Presentation & Diagnosis • Four main phenotypic variants based on age of presentation • Perinatal form: presents with fetal akinesia deformation sequence (FADS) characterized by contractures, hydrops fetalis, cardiac dysfunction, and death • Congenital form: presents as hypotonia, muscle atrophy, cardiomyopathy and rapid progression to death • Juvenile variant: has been described with muscular cardiomyopathy • Adult form: described primarily with neuromuscular manifestations; myopathy, upper and lower neuron dysfunction, and dementia • GSD IV is a unique disorder of glycogenolysis in that hypoglycemia is uncommon • Diagnosis: • GSD IV is confirmed by the demonstration of absent branching enzyme activity in skin fibroblasts

34. Disorders of Carbohydrate MetabolismGSD IV– Treatment and Outcomes • Liver transplantation is the sole medical treatment for patients with GSD IV • Without prompt diagnosis and transplant, most patients rapidly progress to end stage liver disease, cirrhosis, and death by the third year of life