Higado 2

SECTION
6Ni
Bile Acid Synthetic Defects

Table of Contents
6Ni
Einar Hafberg, MD
439
Kevin Bove, MD
Alexander Miethke, MD
Previous edition authors: Khyati Mehta, MD and James Heubi, MD
I. Overview
A. Bile acids (BAs) are synthesized in hepatocytes from cholesterol through 14

enzymatic steps that comprise the BA synthetic pathway
B. 9 congenital defects in humans have been described
C. Incidence is not known but thought to be 1–9/1,000,000
II. Pathophysiology
A. Humans make 2 primary BAs: cholic acid (3α, 7α, 12α, trihydroxy-5 β
cholanoic acid) and chenodeoxycholic acid (3α, 7 α–dihydroxy-5β-cholanoic
acid)
B. These BAs are extensively conjugated to the amino acids glycine and taurine
C. The primary BAs enter the intestine and colon, where a portion are
deconjugated and dehydroxylated by bacterial enzymes to produce the
secondary BAs, deoxycholic and lithocholic acid
1. Secondary BAs are highly insoluble, so most are excreted in feces while
some are carried back to the liver
D. BAs perform several important functions
1. Major catabolic pathways for elimination of cholesterol from the body
2. Provide the primary driving force for the promotion and secretion of
bile
3. Essential biliary excretory route for the elimination of endogenous and
exogenous toxic substances, including bilirubin and drug metabolites
4. Within the intestinal lumen, the detergent action of BAs facilitates the
absorption of fats and fat-soluble vitamins
5. Recently discovered to be signaling molecules in metabolic processes,
including preservation of body mass and glucose metabolism
E. There are 9 identified enzyme defects in the BA synthetic pathway resulting
in:
1. Blocked production of normal BAs
2. Creation of hepatotoxic BA intermediaries
3. Accumulation of unusual BAs and intermediary metabolites
4. Reduced bile flow
5. Decreased intraluminal solubility of fat and fat-soluble vitamins
SECTION 6: Liver
III. Clinical presentation
A. BA synthetic defects should be considered in all cholestatic infants

B. Clinical suspicion should be raised in particular if:
1. Total serum BAs are low or normal, as they are usually high in
Table of Contents
cholestatic infants 6Ni

2. α-glutamyltransferase (GGT) is normal or minimally elevated (usually
high in cholestatic infants) 440
3. Absence of pruritus (a common and distressing component of most
cholestatic disorders)
IV. Diagnosis
A. Requires high index of suspicion

B. If serum BAs are normal or low, urine BAs should be measured by fast atom
bombardment ionization mass spectrometry (FABMS)
1. FABMS can be complemented by gas chromatography-mass
spectrometry of urine, bile, and serum to establish absence or
reduction of primary BAs in conjunction with the presence of atypical
BA and sterols that are synthesized as a result of enzymatic deficiency
C. Liver biopsy may demonstrate suggestive features
V. Treatment
A. Give BAs to activate negative feedback mechanism and hinder further

production of toxic metabolites
B. Nutritional support, including fat-soluble vitamins and medium-chain
triglyceride-containing formula
C. Liver transplant may be an option in some cases
VI. β-hydroxy C-27 steroid oxidoreductase/dehydrogenase

deficiency (3βHSD)
A. Most commonly reported defect in BAs
B. 3βHSD catalyzes the conversion of 7α hydroxyl cholesterol to 7α
hydroxyl-4-cholesten-3-one
C. Presents in neonates with progressive jaundice; increased aminotransferases
D. History of consanguinity common
E. Normal GGT, conjugated hyperbilirubinemia, and low-to-normal serum total
BAs
F. Hepatomegaly with or without splenomegaly, malabsorption with
steatorrhea and fat-soluble vitamin deficiency, and rickets
G. Urine BA profile shows decreased primary BAs and increased di- and
trihydroxy cholenoic acids
H. Liver biopsy: giant cell hepatitis/portal inflammation, perilobular fibrosis, and
canalicular bile plugs
I. Genetic testing available
6Ni. Bile Acid Synthetic Defects

J. Treatment with cholic acid (Cholbam®) can improve liver function and resolve
jaundice if fibrosis has not yet occurred
VII. Oxysterol 7α hydroxylase deficiency

Table of Contents
A. Part of the acidic pathway and demonstrates the importance of this pathway 6Ni
in early life
B. Few (<5) cases reported 441
C. Clinical presentation of severe progressive liver failure, cholestasis, and
hepatosplenomegaly
D. Urine BAs show absent primary BAs and increased sulfate and glycosulfate
conjugates of 3 beta-delta 5-monohydroxy BAs
E. Liver biopsy shows lobular disarray, giant cell transformation, and moderate
portal inflammation
VIII. Δ4-3 oxosteroid 5β reductase deficiency
A. Δ4-3 oxosteroid 5β reductase catalyzes conversion of the intermediates 7α

hydroxyl 4-cholesten-3-one and 7α, 12α-dihydroxy-4-cholesten-3-one to their
corresponding 3-oxo-5β (H) intermediates
B. Present with neonatal cholestasis, increased aminotransferases, conjugated
hyperbilirubinemia, coagulopathy, and normal GGT
C. Liver biopsy typical of neonatal hepatitis
D. Enzyme not expressed in fibroblasts or leukocytes
E. Diagnosis must be made by FABMS, which shows increased 3-oxo-7α BAs.
Urine and serum concentration of normal BAs are low. Accumulated
Δ4-3-oxo-7α BAs cause hepatotoxicity.
F. Treatment with cholic acid (Cholbam®), as it suppresses endogenous
synthesis of BAs and accumulation of toxic metabolites
IX. Cerebrotendinous xanthomatosis
A. A defect in BA side chain modification

B. Slowly progressive disease of lipid accumulation, characterized in adults
by progressive neurologic dysfunction, dementia, ataxia, cataracts, and
xanthomata in the brain and tendons
C. Liver disease is not generally a feature of this condition, but a self-limiting
neonatal cholestasis may occur
1. ↑ alanine transaminase, aspartate aminotransferase, conjugated
bilirubin, and normal α-glutamyl transpeptidase and liver enzymes;
usually resolves by 6 months of age because of ↑ cholic acid production
by compensatory alterative 25 hydroxylation pathway
D. Without treatment, tendinous and central nervous system xanthomata occur,
with neurologic dysfunction in adulthood
E. Treatment with chenodeoxycholic acid or cholic acid (Cholbam®) is
recommended, plus a statin to suppress cholesterol synthesis
SECTION 6: Liver
X. Alpha methylacyl-coenzyme A (CoA) racemase deficiency
A. Defect results in inhibition of cholesterol side chain oxidation

B. Key enzyme required for racemization of trihydroxycholestanoic acid and
pristanic acid into their stereoisomers
Table of Contents
C. Present with cholestatic liver disease, severe fat-soluble vitamin deficiencies, 6Ni
and coagulopathy. If undiagnosed in infancy, may later present as adults with
peripheral neuropathy. 442
D. Urine BAs show decreased primary BAs and increased trihydroxycholestanoic
(also found in alligator bile) and pristanic acids
E. Liver biopsy shows neonatal hepatitis with giant cell transformation. Electron
microscopy shows decreased numbers of peroxisomes.
F. Treatment options include cholic acid and, with severe presentation, liver
transplant
XI. BA conjugation (amidation) defects
A. Conjugation of cholic and chenodeoxycholic acid into taurine and glycine is

the final step in primary BA synthesis
B. The enzymes that catalyze this conjugation are the rate-limiting CoA ligase
and CoA: amino acid N-acyltransferase
C. Patients have symptoms of malabsorption and fat-soluble vitamin deficiency
D. May have conjugated hyperbilirubinemia, severe cholestasis, and liver failure
E. Diagnosis is based on urine FABMS, with complete absence of usual glycine
and taurine-conjugated BA
F. Treatment with oral primary conjugated BAs and fat-soluble vitamins
Recommended Reading
Chong CP, Mills PB, McClean P, et al. Bile acid-CoA ligase deficiency--a new inborn error
of bile acid metabolism. J Inherit Metab Dis. 2012;35:521-530.
Clayton PT. Disorders of bile acid synthesis. J Inherit Metab Dis. 2011;34:593-604.
Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 4th ed. New York, NY:
Cambridge University Press; 2014.
Sundaram SS, Bove KE, Lovell MA, et al. Mechanisms of disease: inborn errors of bile
acid synthesis. Nat Clin Pract Gastroenterol Hepatol. 2008;5:456-468.
6Ni. Bile Acid Synthetic Defects

SECTION
6Nii
Disorders of Carbohydrate
Table of Contents
6Nii
Metabolism (Glycogen Storage) 443
Einar Hafberg, MD
Kevin Bove, MD
Previous edition authors: Maria Perez, DO and Carol Potter, MD
I. Overview
A. Main carbohydrates are glucose, galactose, and fructose
B. Cardinal function of the liver is to maintain glucose homeostasis though
storage of glucose as glycogen until needed and the releases of glucose via
glycogenolysis
1. Glucose is stored as branched glucose polymer (glycogen) in the liver
and in muscle (for local use)
C. Main symptoms of inborn errors of carbohydrate metabolism include
hypoglycemia, acidosis, growth failure, and hepatic dysfunction
D. In the neonatal period, the symptoms are more dramatic compared with
older children, where they may debut after acute illness or prolonged fasting
II. Galactosemia
A. There are 4 main enzymes that metabolize galactose
FIGURE 1 Galactose Metabolization

*
Galactose
1
Galactose 1-phosphate
2
UDP-Galactose
3
UDP-Glucose
4
Glucose 1-phosphate
1: Galactokinase
2: Galactose 1-phospate uridyltransferase
3: Uridine diphosphate galactose 4-epimarase
4: Uridine diphosphate glucose pyrophosphorylase
SECTION 6: Liver
B. All defects in galactose metabolism are autosomal recessive (AR)
C. Classic galactosemia
1. Overview
a. The most common defect (incidence is 1:10,000–70,000 live
births) is deficiency of galactose 1-phosphate uridyltransferase
Table of Contents
(GALT) 6Nii
b. Neonates present in the first days of life after milk has been
introduced with hypoglycemia, vomiting, diarrhea, poor weight 444
gain, seizures, hepatomegaly, jaundice, and liver failure
c. Hemolytic anemia and tubular dysfunction can be seen
d. Neonatal E. coli sepsis, which should always prompt evaluation
for galactosemia
e. Most significant long-term consequence is mental retardation and
correlates with dietary control
f. Premature ovarian failure (hypergonadotropic hypogonadism)
g. Cataract due to accumulation of galactitol
2. Diagnosis
a. Most patients are diagnosed via the newborn screen
b. Positive urinary reducing substances, without glucosuria
c. ↓ GALT activity in red blood cells
1) Prior transfusion may interfere with test
3. Treatment
a. Elimination of dietary galactose
b. Switch infants to soy or protein hydrolysate formula
c. Older children and adults should avoid products that contain milk
and milk products
d. Beans such as garbanzo and black beans should also be avoided
because they contain high increased amounts of galactose
e. Calcium and vitamin D supplementation is recommended
f. Annual ophthalmologic examinations and neurodevelopmental
assessments are recommended
D. Duarte galactosemia
1. A benign form with residual enzyme activity of more than 50%
2. Most are asymptomatic and need no dietary restrictions
E. Uridine diphosphate galactose epimerase deficiency
1. Similar to classical galactosemia
F. Galactokinase deficiency
1. Rapid progressive cataract in the 1st week of life
2. Glucose in urine
3. Lactose-free diet
4. No liver pathology
III. Hereditary fructose intolerance

A. Fructose is the monosaccharide found in fruit and honey and in the
disaccharide sucrose (fruc+gluc)
B. AR; incidence 1:20,000
C. Classical form is caused by aldolase B (fructose 1,6 bisphosphate
6Nii. Disorders of Carbohydrate Metabolism (Glycogen Storage)

aldolase isoenzyme B) deficiency that catalyzes fructose 1-phosphate to
dihydroxyacetone phosphate
D. Causes lack of adenosine triphosphate (ATP) intracellularly as a result of
accumulated of fructose 1-phosphate and depletion inorganic phosphate
E. Fructose 1-phosphate is an inhibitor of gluconeogenesis and glycogenolysis
Table of Contents
F. Aldolase B is expressed in liver, kidney, and small intestine 6Nii

G. Liver takes up about 75% of absorbed fructose
H. Symptoms include: 445
1. Initially vomiting, nausea, restlessness, pallor, sweating, lethargy,
coagulation disturbances, and in some cases, apathy, coma, jerks, and
convulsions
2. Chronic failure to thrive (FTT), hepatomegaly, jaundice, steatosis,
edema, ascites, and signs of proximal renal tubular dysfunction
develop later on
I. Laboratory evaluation may show:
1. Hypophosphatemia, ↑ aminotransferases (elim serum),
hyperbilirubinemia, and abnormal clotting factors; proteinuria,
aminoaciduria, and metabolic acidosis
2. Tissue enzyme activity or genetic analysis (95% diagnostic)
J. Treatment is strict elimination of any fructose from diet
IV. Fructose 1,6-bisphosphatase deficiency

A. An AR condition resulting in impaired gluconeogenesis
B. A slight female predominance exists (1.5:1)
C. Symptoms develop when glycogen stores are low (such as in newborns or in
periods of prolonged fasting or illness)
D. Approximately 50% of affected patients will develop symptoms shortly after
birth, including hypoglycemia, hyperventilation, and metabolic acidosis
E. Definitive diagnosis is made by liver biopsy or genetic testing
F. Treatment includes avoidance of prolonged periods of fasting and limitation
of dietary fructose and sucrose
V. Glycogen storage disease (GSD)

A. Caused by deficiencies of specific enzymes in the glycogen metabolism
pathway
B. 12 different types have been identified and present either with pathological
glycogen storage and dysfunction of the corresponding organ or with
hypoglycemia
1. 6 types primarily affect the liver (I, IIIb, IV, VI, IX, and XI)
2. 2 types have mixed hepatic and myopathic presentation (II and IIIa)
3. 9 (including all types affecting the liver) of the 12 types can be
diagnosed prenatally
C. Diagnosis is based on genetic testing or biopsy with enzyme activity studies
D. All GSDs are AR
1. Except alpha form of IX, which is X-linked recessive (XR)
E. Early diagnosis is essential to minimize organ damage and to prolong life
SECTION 6: Liver
TABLE 1 Review of Glycogen Storage Disease
Affected Inheritance
Type Enzyme Defect Clinical Features
Tissue
Table of Contents
Hypoglycemia and metabolic

acidosis 3–4 hours postmeal; 6Nii
hepatomegaly with protuberant
Ia Glucose Liver and
abdomen and lordosis; elevated 446
von 6-phosphatase kidney
AR triglycerides; doll facies and
Gierke xanthomas; impaired platelet
function/bleeding; ↑ uric acid;
hepatic adenomas as long-term
complication
Ib Glucose Ib—neutropenia and recurrent

von 6-phosphatase Liver AR infections; association with
Gierke translocase colitis
Ic Phosphatase
von translocase
Liver AR Ic—impaired insulin secretion
Gierke
II Alpha 1-4-glucosidase
Heart,
Cardiorespiratory failure and
Pompe (acid maltase)
muscle, AR
cardiomyopathy
disease and liver
Milder than GSD I; tolerate

longer fasting, usually without
IIIa-b Liver, hypoglycemia; develop
Cori, Debranching enzymes muscle, and AR hepatomegaly and growth
Forbes heart failure; hepatic fibrosis;
disease ↑ transaminases; lactic acid
and uric acids usually normal
Classic progressive liver

cirrhosis 3–15 months old;
IV Branching enzyme
FTT, abdominal distention, and
Andersen (α-1,4-glucan 6 Liver AR
hepatosplenomegaly early; no
disease glucosyltransferase)
hypoglycemia until end-stage
liver disease
Mennonite community;
VI hepatomegaly; growth
Hers Liver phosphorylase E Liver AR retardation; microsteatosis;
disease hypoglycemia with prolonged
fasting
Most commonly present 1–5

years old; hepatomegaly, growth
Liver phosphorylase Liver and retardation, motor skill delay,
IX (alpha) kinase muscle
XR/AR
and hypotonia ↑ transaminases,
cholesterol, and lipids; fasting
hyper ketosis and hypoglycemia
Hepatomegaly;
hypergalactosemia; postprandial
Liver and hyperglycemia; hyperlipidemia
XI GLUT2 transporter
kidney
AR
and cholesterolemia;
hypophosphatemic rickets; moon
facies

FIGURE 2 Hematoxylin and Eosin Staining from a Child with GSD Type I
*
A B
Table of Contents
6Nii
447
Expanded glycogen-rich cytoplasm of hepatocytes is sufficient to compress sinusoids and also contains random
lipid droplets. Glycogenated nuclei (arrows) are common in GSD types I and III but also occur in Wilson disease,
nonalcoholic fatty liver disease, and diabetes mellitus.
Recommended Reading
Hicks J, Wartchow E, Mierau G. Glycogen storage diseases: a brief review and update on
clinical features, genetic abnormalities, pathologic features, and treatment. Ultrastruct
Pathol. 2011;35:183-196.
SECTION 6: Liver
Table of Contents
6Nii
448

SECTION
6Niii
Disorders of Amino Acid Metabolism

Table of Contents
6Niii
Einar Hafberg, MD
449
Kevin Bove, MD
Previous edition authors: Maria E. Perez, DO and Carol Potter, MD
I. Overview
A. Multisystem disease that primarily affects the liver, kidney, and nervous
system
B. Defect in fumarylacetoacetate hydrolase (FAH)
1. Last step in tyrosine degradation
2. Enzyme is mainly expressed in hepatocyte and the proximal tubules
of the kidney but also in lymphocytes, erythrocytes, fibroblasts, and
chorionic villa
C. Other conditions causing elevation of blood tyrosine are transient
tyrosinemia of the newborn (most common cause of hypertyrosinemia,
resulting from immaturity of the liver and the enzymes required for tyrosine
degradation); any severe hepatocellular dysfunction; and congenital
deficiencies or dysfunction of enzymes related to tyrosine metabolism,
hyperthyroidism, and vitamin C deficiency
II. Hepatorenal tyrosinemia (hereditary tyrosinemia type 1)

A. Epidemiology/pathogenesis
1. Autosomal-recessive condition
2. Defect in FAH, resulting in accumulation of fumarylacetoacetate and
maleylacetoacetate and their derivatives, succinylacetoacetone and
succinylacetone (SA)
3. Incidence of 1 in 20,000–100,000; higher incidence in Scandinavians
(1 in 8,000) and in Saguenay-Lac Saint-Jean area in North Quebec,
Canada (1 in 1,846)
4. Maleylacetoacetate induces renal Fanconi syndrome
5. Maleylacetoacetate and fumarylacetoacetate are reactive, unstable
compounds that may form glutathione adducts, which allow free
radical formation
a. May be the source of DNA damage and the ↑ risk of
hepatocellular carcinoma (HCC)
6. SA inhibits synthesis of porphobilinogen from δ-aminolevulinic acid
(δ-ALA)
7. Newborn screening is succinylacetone on dried filter paper
8. Serum tyrosine leads to high false positive due to transient tyrosinemia
SECTION 6: Liver
B. Clinical features
1. Acute
a. Acute liver failure with vomiting, diarrhea, hepatosplenomegaly,
edema, ascites, mild elevations of bilirubin and transaminases,
and severe hepatic synthetic dysfunction—producing
Table of Contents
coagulopathy, hypoglycemia, and hypoalbuminemia 6Niii

b. The coagulopathy is UNRESPONSIVE to vitamin K with low normal
factor V 450
1) Very low vitamin-K-dependent factors II, VII, IX, X, and
normal VIII
c. Should be suspected in any infant with abnormal coagulation
2. Chronic
a. Growth failure
b. Renal tubular dysfunction from Fanconi syndrome with
phosphaturia and renal rickets, resulting from maleylacetoacetate
accumulation
c. Neurological crises, pain with paresthesias, and posturing result
from δ-ALA accumulation
1) Can last up to a week
2) May progress to flaccid paralysis and respiratory failure,
resembling acute intermittent porphyria
3) Infection is often the cause
d. Main causes of death are liver failure, recurrent bleeding, and
neurological crises
e. HCC may be a long-term complication occurring in less than 1/4
of patients
1) Abdominal ultrasound or computed tomography
2) α-fetoprotein
C. Diagnosis
1. Elevated urine succinyl acetone is most diagnostic
2. Urine δ-ALA also elevated but is less specific as it is also elevated in
other disorders
3. Coagulopathy (with normal factors V and VIII), hypoalbuminemia, and
hypoglycemia out of proportion to milder elevation of bilirubin and
transaminases
4. Hemolytic anemia
5. Renal tubular dysfunction (Fanconi) (phosphaturia, glucosuria,
proteinuria, and aminoaciduria)
6. Liver biopsy
a. Acute: lobular cholestasis, hemosiderin, pseudo acini, giant-cell
transformation, fatty focal changes, and excessive inflammation
with necrosis
b. Chronic: multilobular cirrhosis, bile duct proliferation, and
regenerative nodules
D. Management/treatment
1. Coagulopathy is NOT responsive to vitamin K
2. Dietary restriction of phenylalanine and tyrosine
a. In infants, Tyrex® or Tyros® formula is used
6Niii. Disorders of Amino Acid Metabolism

3. Nitisinone®: 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione-
NTBC
a. Inhibits 4-hydroxyphenylpyruvate dioxygenase (4HpPD) (2nd step
in tyrosine degradation)
b. >95% of patients respond with significant hepatic and renal
Table of Contents
improvement 6Niii
c. Need frequent monitoring, including liver function tests and urine
SA 451
d. Recurrent ophthalmological evaluations due to risk of corneal
crystals
4. Serum α-fetoprotein every 6–12 months
5. Nitisinone started early may ↓ the incidence of HCC, but careful
monitoring is still required for all cases of type I
6. Liver transplantation ± kidney transplantation
a. Reserved for those patients who do not respond to medical
therapy
b. Reported 1-year survival is high: >90%
c. Renal tubular dysfunction, renal rickets, and poor growth may
persist after transplantation
III. Other forms of tyrosinemia
A. Liver failure: nonspecific elevation of many urine and serum amino acids,
including tyrosine
B. Transient tyrosinemia of the newborn: immaturity of 4HpPD causes self-
limited elevation of tyrosine. Treat with lower protein diet and vitamin C.
C. Vitamin C deficiency: vitamin C is a cofactor for 4HpPD
D. Hp type III: congenital defect in 4HpPD
E. Hp type II (oculocutaneous tyrosinemia) autosomal-recessive deficiency
of tyrosine aminotransferase. Hyperkeratosis of palms and soles, corneal
thickening, and developmental delay with normal hepatic and renal
functions.
Recommended Reading
Hoffmann GF, Zschocke J, Nyhan WL, eds. Inherited Metabolic Diseases: A Clinical
Approach. Berlin Heidelberg: Springer; 2010.
SECTION 6: Liver
Table of Contents
6Niii
452
6Niii. Disorders of Amino Acid Metabolism

SECTION
6Niv
Disorders of Lipid Metabolism

Table of Contents
6Niv
Einar Hafberg, MD
453
Kevin Bove, MD
I. Overview
A. About 80% of energy used by skeletal and heart muscles is derived from β
fatty acid oxidation (FAO)
1. Essential role in maintaining blood glucose levels during fasting
B. About 22 different defects in the FAO pathway have been described
1. Phenotype is variable and ranges from severe to mild
2. Severe phenotype tends to present in infancy while milder forms in
late childhood to adulthood
3. Hypoketotic hypoglycemia is a hallmark of most FAO disorders
C. During the normal fed state, metabolism of glucose raises the concentration
of malonyl-coenzyme A (CoA), which inhibits carnitine-palmitoyltransferase 1
(CPTI)—the 1st and rate-limiting step in FAO
D. FAO leads to the production of ketone bodies, which are an important
secondary energy source for many tissues, including the brain, when glucose
supplies are low
E. This is particularly important in childhood when glycogen stores are limited
F. The initial step in fatty acid metabolism is lipolysis, in response to fasting,
resulting in free fatty acids (FFAs)
G. All lengths of FFAs are transported across the plasma membrane and are
esterified to CoA by the enzyme acyl-CoA synthetase to form acyl-CoA esters
before entry into the mitochondria for further metabolism
1. Long-chain fatty acids (LCFAs) require the carnitine cycle and
transesterification to acylcarnitines to cross the mitochondrial
membrane
2. Enzymes responsible for long-chain metabolism (e.g., very-long-chain
acyl-CoA dehydrogenase [VLCAD], long-chain 3-hydroxyacyl-CoA
dehydrogenase [LCHAD], and LKAT) are associated with the inner
mitochondrial membrane
3. Medium-chain fatty acids and short-chain fatty acids can traverse the
mitochondrial membrane without conversion to acylcarnitines
a. Enzymes responsible for short- and medium-chain metabolism
(e.g., medium-chain acyl-CoA dehydrogenase [MCAD], short-chain
acyl-CoA dehydrogenase [SCAD], medium-chain 3-hydroxyacyl-
CoA dehydrogenase [MCHAD], short-chain 3-hydroxyacyl-CoA
SECTION 6: Liver
dehydrogenase [SCHAD], and medium-chain 3-ketoacyl-CoA
thiolase [MCKAT]) are associated with the mitochondrial matrix
H. Within the mitochondria, the acyl-CoA esters enter the β-oxidation cycle and
carnitine is shuffled back across the inner mitochondrial membrane to bring
more LCFAs across the membrane
Table of Contents
I. The β-oxidation cycle is a 4-enzyme-step cyclical process, involving 2 6Niv

oxidation steps, a hydration step, and a thiolysis step
1. Each turn of the β-oxidation cycle results in the cleavage of two carbon 454
fragments from the original LCFA in the form of acetyl-CoAs that are
then directed into ketone body synthesis or Krebs cycle
a. An important byproduct of the β-oxidation cycle is the production
of electrons for the electron transport chain
2. There are 4 major enzyme families responsible for each turn of the
β-oxidation cycle
a. Acyl-CoA dehydrogenases (ACADs)
b. Enoyl-CoA hydratases
c. 3-hydroxyacyl-CoA dehydrogenases
d. 3-ketoacyl-CoA thiolases
e. The rate-limiting step in the β-oxidation cycle is the 1st reaction
catalyzed by the family of acyl-CoA dehydrogenases
1) Riboflavin (vitamin B2) is a precursor to these enzymes
3. The following are the recognized defects in FAO; many have unique
acylcarnitine profiles and urine organic acids
a. 2,4-dienoyl-CoA reductase (2,4-Di) deficiency
b. Carnitine acylcarnitine translocase (CAT) deficiency
c. CPTII deficiency
d. CPTI deficiency
e. Carnitine uptake defect
f. LCHAD deficiency
g. MCKAT deficiency
h. MCAD deficiency
i. MCHAD deficiency
j. SCHAD deficiency
k. Multiple acyl-CoA dehydrogenase deficiency
l. SCAD deficiency
m. Trifunctional protein deficiency
n. VLCAD deficiency
o. 3-hydroxy-3-methylglutaryl (HMG)-CoA synthase deficiency
p. HMG-CoA lyase deficiency
q. ACAD9 deficiency
II. Epidemiology/genetics
A. Incidence of approximately 1 in 9,300
1. Lower in Asians
B. Autosomal recessive
C. MCAD deficiency is the most common and best studied FAO disorder
1. 1 point mutation accounting for about 70%–80% of cases
6Niv. Disorders of Lipid Metabolism

III. Clinical features/associations
A. In general, the more proximal the defect in the FAO pathway, the earlier the
clinical presentation and the more severe the clinical course
B. Most symptoms appear after a period of fasting and/or vomiting, typically
Table of Contents
associated with an acute infection or illness 6Niv

C. Hypoketotic hypoglycemia is a hallmark of most FAO disorders
D. Symptoms at presentation include: 455
1. Vomiting
2. Lethargy
3. Apnea
4. Seizures
5. Encephalopathy
6. Respiratory arrest
E. May also present with a metabolic crisis, cardiac arrhythmia, and skeletal or
muscle myopathy/rhabdomyolysis
IV. Physical examination

A. Marked hepatomegaly but NO splenomegaly, hypotonia, and a gallop rhythm
and poor perfusion if the heart is affected
B. Jaundice is rare
C. One-third of patients will have a family history significant for sudden infant
death syndrome (5% due to an underlying FAO disorder), Reye syndrome,
sudden cardiac decompensation, or early infant death due to acute liver
failure or sepsis
D. Acute liver failure is overall an uncommon presentation for FAO disorders.
However, several cases of LCHAD, CAT, ACAD9, and MCKAT have presented
this way.
E. Some patients with SCAD deficiency may have persistent vomiting, GERD, and
failure to thrive
F. Mild types of MCAD and SCAD may have a cyclic-vomiting-syndrome-like
presentation
G. Several cases of LCHAD and CPTII deficiencies have been linked to repeated
episodes of pancreatitis
H. Pregnancy and FAO disorders: well-documented association between FAO
disorders and complications, such as acute fatty liver of pregnancy (AFLP)
and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome,
particularly in those women carrying LCHAD-deficient fetuses
1. A common homozygous mutation G1528C in the gene HADHA encoding
LCHAD has been found in offspring of women who develop these
3rd trimester complications, and the infants should be screened for this
mutation
2. AFLP
a. Disorder with significant morbidity and mortality in women during
the third trimester of pregnancy
b. Women typically present with nausea, vomiting, and abdominal
pain and quickly progress to fulminant hepatic failure with
coagulopathy and encephalopathy
SECTION 6: Liver
c. Liver histology reveals microvesicular hepatic steatosis and
mitochondrial disruption
d. Management includes prompt delivery
3. HELLP syndrome—complication of pre-eclampsia that occurs in the
3rd trimester
Table of Contents
a. Better prognosis than AFLP 6Niv

b. Liver histology reveals periportal hemorrhage and fibrin
deposition 456
c. Management includes prompt delivery
V. Diagnosis
A. Newborn screening using a tandem mass spectrometric acylcarnitine profile

is the most common way of diagnosis
B. Urine organic acids and serum acylcarnitine profile have the best
diagnostic yield
C. Labs significant for:
1. ↑ ammonia
2. Mild ↑ in transaminases
3. Normal or very mild ↑ in bilirubin
4. Mild to moderate ↑ in blood urea nitrogen, uric acid, and creatine
phosphokinase
5. Urinary ketones during a metabolic crisis may be useful
6. Serum FFAs and β-hydroxybutyrate (↑ FFA concentrations in FAO
disorders)
7. Tissue assays (liver, muscle, and skin fibroblasts) to measure enzyme
activity
8. Genetic screening
VI. Management/treatment
A. Acute
1. Reverse hypoglycemia with dextrose infusions
2. Dextrose also raises insulin levels and inhibits FAO and lipolysis
3. Avoid drugs that inhibit FAO (e.g., valproic acid, nonsteroidal anti-
inflammatory drugs, and salicylate) and drugs that increase the release
of FFA (e.g., epinephrine)
4. Avoid fat emulsions
5. Carnitine (IV or enteral) particularly for those with a carnitine transport
defect
B. Chronic
1. AVOID fasting. A low-fat, high-carbohydrate diet is recommended.
Overnight nasogastric or gastrostomy tube feeding may be helpful.
2. Carnitine supplementation for long-chain defects
3. Daily carnitine supplementation (100 mg/kg/day) for those with
carnitine transport defects
C. Riboflavin supplementation (100 mg/day) for those with defects in the first
steps of the β-oxidation cycle or ACAD9 deficiency

VII. Prognosis
A. Those who present in neonatal period have a poor prognosis

1. Mortality rate as high as 60% by age 4–5 years
B. If diagnosis can be made early, then appropriate measures can be taken to
Table of Contents
prevent acute episodes 6Niv
457
Recommended Reading
Bastin J. Regulation of mitochondrial fatty acid β-oxidation in human: what can we
learn from inborn fatty acid beta-oxidation deficiencies? Biochimie. 2014;96:113-120.
Olpin SE. Pathophysiology of fatty acid oxidation disorders and resultant phenotypic
variability. J Inherit Metab Dis. 2013;36:645-658.
SECTION 6: Liver
Table of Contents
6Niv
458

SECTION
6Nv
Mitochondrial Disorders
Table of Contents
6Nv
Einar Hafberg, MD
459
Kevin Bove, MD
I. Overview
A. Mitochondrial disease has an estimated prevalence of 1:7,634 live births
1. 20% have a liver phenotype
B. Mitochondrial hepatopathies are categorized by phenotype or genotype
1. 2 main phenotypes: primary and secondary
a. Secondary are conditions where mitochondrial dysfunction
has been suggested as a key component in theses syndrome;
however, not an intrinsic mitochondrial defect per se
b. Primary
1) Respiratory chain defects
2) Complex I, III (BCS1L), and IV (SCO1)
3) Neonatal liver failure
a) mtDNA depletion syndrome (MDS) (DGUOK,
MPV17, POLG1, and SULG1)
4) Electron transfer flavoprotein deficiencies
5) Glycine cleavage enzymes deficiency
6) Citrin deficiency
c. Secondary
1) Reye syndrome
2) Copper overload
3) Iron overload
4) Drugs/toxins
II. Genetics
A. The mitochondrial genome is mostly in the cell nucleus
1. 228 genes encoded by nuclear DNA (nDNA) and 13 genes encoded by
mitochondrial DNA (mtDNA)
B. The respiratory chain
1. Located on inner membrane of mitochondria
2. 5 complexes which are critical for:
a. Adenosine triphosphate generation
b. Metabolism of pyruvate, glutamine, and fatty acids
C. Most mitochondrial proteins/enzymes are coded by nuclear genes
1. Normal Mendelian inheritance
SECTION 6: Liver
2. Mutations in genes coding for mtDNA replication or translation may
cause MDS or translational disorder
D. Some respiratory chain subunits, the ribosomal RNAs, and the transfer RNAs
(tRNAs) are encoded by mitochondrial genes
1. Maternal inheritance
Table of Contents
2. Lacks protective histones 6Nv

3. Exposed to radicals from oxidative phosphorylation (OXPHOS)
460
A. Overview
1. Mitochondrial hepatopathies can present at any age
a. Infancy most present as acute liver failure (ALF), whereas in older
children the disease may progress slowly and lead to chronic liver
disease
b. Multisystem involvement raises the suspicion for a mitochondrial
hepatopathy, especially if central nervous system (CNS), cardiac,
or renal disease precedes the onset of liver disease
c. Mitochondrial depletion syndrome (MDS) is tissue specific
1) 3 types of MDS: hepatocerebral, myopathic, and
encephalomyopathic
d. Depletion syndromes can affect one particular enzyme of the
tricarboxylic acid cycle, one subunit of OXPHOS, or multiple
1) Complex II is only encoded by nDNA, and its activity is not
reduced in MDS, as opposed to the complexes I, III, and
IV, which may show variable reduction in activity, typically
below 40% in order to meet diagnostic criteria (Figure 1B)
2. Infants
a. Presentation
1) Poor feeding, hypotonia (poor suck), lethargy, and seizures
2) Mild liver dysfunction → liver failure
3) Occurs in the first weeks to months of life
b. Most frequent causes in this age group are respiratory chain
defects, with MDS as the underlying cause
c. Laboratory
1) ↑ lactate >2.5 mM
2) ↑ lactate/pyruvate >25
3) Hypoglycemia (ketotic)
4) ↑ prothrombin time
5) +/– ↑ of aspartate aminotransferase, alanine
transaminase, and bilirubin
d. Deoxyguanosine kinase deficiency (DGUOK) shares clinical
features with gestational alloimmune liver disease (previously
called neonatal hemochromatosis) including hyperferritinemia
e. Histology
1) Micro- and macrovesicular steatosis with absent or
minimal inflammation; canalicular cholestasis; bile duct
thrombi; ductular proliferation; hepatocytes clumped
6Nv. Mitochondrial Disorders

FIGURE 1 Mitochondrial Liver Disease - Oxidative Phosphorylation
*
A H+ H+ H+
Table of Contents
Cytocr C
Co Q 6Nv
l lll IV V
461
ll
FADH2 FAD + 2H+ H+
NADH NAD+ + H+ ADP+P ATP
B
Gene Complex I Complex II Complex III Complex IV Complex V
Location
Mitoc. 7 0 1 3 2
Nucleus 36 4 10 10 14
A: The oxidative phosphorylation chain.

B: Location of genes involved in complex assembly. Note that complex II
is solely encoded by nuclear genes; used as a reference in diagnosis of
global mtDNA depletion syndrome.
highly eosinophilic; progressive portal fibrosis; electron

microscopy (EM) shows great variation in size, number,
and cristae morphology
f. Outcome
1) Poor prognosis; some have recurrent ALF, depending on
genotype
2) Most have neurological manifestation; hence, this
disease represents a relative contraindication to liver
transplantation
3. Older children
a. Alpers-Huttenlocher syndrome (POLG1)
1) Bimodal age distribution 3 months–8 years; 17–24 years
a) 80% before age 2 years
2) In most children, liver failure is proceeded by neurological
symptoms
3) GERD; intractable vomiting
4) Reduced activity of complex I, III, and IV in respiratory
chain activity assays on muscle or liver tissue
5) Brain magnetic resonance imaging shows cerebral volume
loss
6) Some have loss of synthetic function (low factor V and VII
and albumin; ↑ international normalized ratio)
SECTION 6: Liver
7) Biopsy: microvesicular steatosis; portal fibrosis
8) Seizures: seizure medication, especially valproic acid, may
trigger liver failure or abnormal lab work
b. Pearson syndrome (mtDNA deletion)
1) Caused by 4,000- to 5,000-bp deletion in mtDNA; one of
Table of Contents
the few diseases related to alterations in mtDNA and not 6Nv

the nuclear genome, which affects the liver
a) Mostly sporadic cases; during oogenesis 462
b) Mostly affecting complex I
i. Subunits of complex V and IV are also affected
as are 5 tRNAs
2) Affects the bone marrow (typically sideroblastic anemia
with vacuolization of marrow precursors), pancreas, and
liver
a) Some advance to cirrhosis before age of 4 years
3) Adrenal insufficiency; renal Fanconi; diabetes mellitus;
proximal muscle weakness
4) Muscle spared
5) Some have partial small intestine villous atrophy diagnosis
with point mutation/deletion analysis of mitochondrial
genome
c. Navajo neurohepatopathy (MPV17)
1) An autosomal recessive disease with ↑ incidence among
Navajo children
2) Sensorimotor neuropathy
3) Weakness; hypotonia; areflexia; acral mutilation; serious
systemic infections
4) 3 forms of liver disease
a) Infantile: fatal by 2 years of age; jaundice, failure to
thrive, and progressive liver failure;
± neurological findings
b) Childhood: presents between 1 and 5 years of age;
rapid liver failure
c) Classical: progressive neurological symptoms with
moderate liver involvement
5) Caused by mutation in MPV17
6) Affects complexes I, III, and IV
7) Liver disease can present acutely, as chronic liver disease,
or as liver disease with other organ involvement (CNS,
heart, and muscle)
IV. Evaluation
A. When mitochondrial liver disease is suspected, a tiered approach is currently
recommended
1. Tier 1: early screening
a. Lactate/pyruvate (best 1 hr after feeding), ammonia,
α-fetoprotein, creatine phosphokinase, serum ketone bodies,
and acylcarnitine profile; serum-free and total carnitines, urine

organic acids, urine and plasma ketone bodies, and serum amino
acids (alanine > 600 µM)
2. Tier 2: genetic testing for more common genes
a. Panels commercially available to evaluate OXPHOS mutations
with next-generation sequencing. Consider at least survey for
Table of Contents
biallelic mutations in the genes DGUOK, POLG1, and MPV 17, as 6Nv
they are associated with a poor prognosis. If clinical symptoms
of MELAS or Pearson disease (see above), consider deletion/ 463
duplication assay for mtDNA.
3. Tier 3: tissue evaluation
a. Liver biopsy
1) Light microscopy, EM, Oil Red O stain for fat, and iron stain
2) Frozen tissue for respiratory chain analysis and DNA
(mtDNA/nDNA) quantification
b. Skin biopsy: fibroblast culture
c. Muscle biopsy: if neuromuscular symptoms, light microscopy, EM,
and respiratory chain analysis
4. Tier 4: further molecular and biochemical evaluation: targeted gene
analysis for genes associated with mtDNA depletion (SCO1 and
TWINKLE) or fatty acid oxidation defects (ACAD9)
Hematoxylin and Eosin Stain of a Liver Biopsy from a 2-Month-Old Male

FIGURE 2
with MPV17 Mitochondriopathy, mtDNA Depletion, and ALF
*
Notable are lobular collapse due to aggregates of atrophic eosinophilic hepatocytes (black arrows)
intermixed with swollen hepatocytes that contain coarse cytoplasmic granules and lipid droplets.
SECTION 6: Liver
Recommended Reading
Koopman WJ, Willems PH, Smeitink JA. Monogenic mitochondrial disorders. N Engl J
Med. 2012;366:1132-1141.
Table of Contents
Molleston JP, Sokol RJ, Karnsakul W, et al. Evaluation of the child with suspected 6Nv
mitochondrial liver disease. J Pediatr Gastroenterol Nutr. 2013;57:269-276.
464
Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 4 ed. New York, NY:
th

SECTION
6Nvi
Urea Cycle Defects

Table of Contents
6Nvi
Einar Hafberg, MD 465

Kevin Bove, MD
I. Overview
A. Urea cycle processes waste nitrogen and disposes of it safely in the form of
urea
1. 6 primary enzymes and 2 transporters of the mitochondrial membrane
2. Ammonia is a byproduct of the amino acid (AA) catabolism
3. Ammonia is highly neurotoxic and does cause damage to the blood
brain barrier
B. Increased ammonia production during:
1. Fasting
2. Stress
C. Normal blood ammonia levels are 30 µmol/L; portal blood has
100–300 µmol/L
1. 75% or urea is excreted via kidneys
2. 25% in the gut
a. Bacteria transform some urea back to ammonia again, which is
reabsorbed
D. Causes of hyperammonemia
1. Urea cycle defects (UCDs) (↑ ammonia, NO metabolic acidosis, and
metabolic alkalosis)
2. Fatty acid oxidation (FAO) disorders (↑ ammonia, + metabolic acidosis,
↑ anion gap, and NO ketones in urine)
3. Organic acidemias (↑ ammonia, + metabolic acidosis, ↑ anion gap, and
↑ ketones in urine)
4. Transient hyperammonemia of the newborn (rapid postnatal
neurological deterioration)—premature newborns
5. Reye’s syndrome (hypoglycemia and coagulopathy)
6. Liver failure
7. Severe systemic illness
8. Pyruvate carboxylase deficiency (lactic acidosis and
↓ aspartate/↑ alanine)
9. Lysinuric protein intolerance (postprandial hyperammonemia with
↓ lysine and arginine ornithine and ↑ urine AA)
10. Drugs (valproate and cyclophosphamide)
SECTION 6: Liver
TABLE 1 Laboratory Abnormalities
Laboratory Abnormalities
Ammonia Acidosis Anion Gap U-Ketones Other
Table of Contents
No (metabolic
Low blood 6Nvi
UCD High N/A N/A urea nitrogen
alkalosis)
(BUN)
466
Disorder Almost
High Yes Yes
of FAO always absent
Organic
High Yes Yes Elevated
acidemias
II. Urea cycle defect

A. 6 enzymes and 2 transporters involved are:
1. Enzyme defects
a. Carbamoyl phosphate synthetase (CPS)
1) Diagnosis: orotic acid ↑ in urine and serum citrulline low
2) Newborn screen: ↓ serum citrulline
b. Ornithine transcarbamylase (OTC)
1) Also known as ornithine carbomyltransferase
c. Argininosuccinate (AS) synthetase 1—citrullinemia
1) Diagnosis: ↑ serum citrulline; ↓ arginine
2) Newborn screen: high citrulline
d. AS lyase (AS-L)
1) Diagnosis: ↑ citrulline and argininosuccinic acid; ↓ arginine
2) Newborn screen: high citrulline
e. Arginase-1
1) Diagnosis: ↑ arginine
2) Newborn screen: ↑ arginine
f. N-acetylglutamate synthetase
1) Diagnosis: orotic acid and ↓ citrulline
2) Newborn screen: ↓ citrulline
2. Transporter defects
a. Mitochondrial ornithine transporter
1) Diagnosis: orotic acid and homocysteine elevated
2) Newborn screen: unknown
b. Citrin (transporter)
1) Citrulline and threonine/serine ratio ↑
2) Newborn screen: sometimes ↑ citrulline
III. Clinical features

A. Patients with OTC, CPS, N-acetyl glutamate synthetase, and AS deficiencies
most often present clinically in similar fashion
B. Neonatal presentation, usually normal at birth; 48–72 hr later develop a
sepsis-like picture; lethargy rapidly progresses to coma
6Nvi. Urea Cycle Defects

C. All are autosomal recessive except for OTC, which is X-linked
D. Liver histology shows pale and swollen hepatocytes; histology can be normal.
Hepatic fibrosis can be found in OTC and particularly in AS-L deficiencies.
IV. Diagnosis
Table of Contents
6Nvi
A. Clinical suspicion, especially in the neonatal period
B. Elevated ammonia levels and ± low BUN. (Remember: hyperammonemia is 467
not only present in UCD but also in organic acidemias and FAO defects.)
C. Citrulline level (low in OTC and CPS deficiencies; high in AS deficiency)
D. ↑ in transaminases and prothrombin time during acute exacerbations
E. Diagnosis is confirmed by the measurement of tissue enzyme activity or
genetic testing
V. Ornithine transcarbamylase deficiency
A. Expressed in liver and intestinal mucosa

B. Affected males have virtually absent enzyme activity
C. Females are heterozygous but can be affected
1. Often present later with hyperammonemic encephalopathy and
vomiting following protein-rich meals
VI. Management/treatment
A. Urea cycle disorder consortium protocols
(www.rarediseasesnetwork.org/cms/UCDC)
1. Acute
a. Reduce serum ammonia levels
b. Discontinue all protein intake
c. Prevent catabolism by IV glucose and insulin ± fatty acids
d. Fluid resuscitate gently for risk of exacerbation of cerebral edema
e. Provide alternatives for nitrogen excretion
1) Sodium benzoate (1 mole of nitrogen excreted for each
mole of benzoate given)
2) Phenylbutyrate (2 moles of nitrogen excreted for each
mole of phenylbutyrate given)
3) Dialysis and hemofiltration
2. Chronic
a. Dietary
1) Protein restriction (<700 mg/kg/day)
2) Cyclinex® (free nonessential AA formula)
3) Arginine supplementation (except for those with arginase
deficiency)
4) Citrulline supplementation (excretes additional nitrogen)
for OTC and CPS deficiencies
5) Some may require anticonvulsants (avoid valproate)
6) Regular monitoring of serum ammonia and AAs
7) Caution during periods of fasting, illness, infections,
SECTION 6: Liver
anesthesia, or surgery
8) Transplantation should be considered as a treatment
choice; playing a larger role in management. 100% 5-year
survival in recent report of 23 patients at a single center.
9) Avoid systemic steroids (increases catabolism)
Table of Contents
6Nvi
VII. Outcomes
468
A. Duration of hyperammonemia and number of hyperammonemic episodes
are related to neurodevelopmental outcomes
B. Severity of hyperammonemia is not related to developmental outcomes
VIII. Hyperornithinemia-hyperammonemia-homocitrullinuria
syndrome
A. Caused by defect in mitochondrial ornithine transporter encoded by the gene

SLC25A15
B. Metabolic triad establishes the diagnosis
1. Persistent hyperornithinemia
2. Postprandial hyperammonemia
3. Urinary excretion of homocitrulline
C. Clinical symptoms
1. Chronic neurodevelopmental delay
2. Ataxia
3. Cognitive deficit
4. Acute encephalopathy
5. Due to hyperammonemic crisis
6. Chronic liver disease
7. Elevation of liver function tests
8. ± mild coagulopathy
D. Treatment
1. Same as UCD (see above)
2. In addition, citrulline supplementation
Recommended Reading
Hoffmann GF, Zschocke J, Nyhan WL, eds. Inherited Metabolic Diseases: A Clinical
Approach. Berlin Heidelberg: Springer; 2010.
6Nvi. Urea Cycle Defects

SECTION
6Nvii
Alpha-1-Antitrypsin Deficiency
Table of Contents
6Nvii
Einar Hafberg, MD
469
Kevin Bove, MD
Previous edition authors: Christine Waasdorp Hurtado, MD and Michael Narkewicz, MD
I. Overview
A. The most common genetic liver disease in infants and children

B. Should be considered in all infants with cholestasis and children and adults
with chronic hepatitis or cirrhosis of unknown etiology
C. α1-antitrypsin (A1AT) deficiency (A1ATD) is associated with chronic liver
disease in 10% of affected adults and 10%–15% of affected children
D. A1AT is an acute phase protein
II. Genetics and function

A. A1AT is an inhibitor of neutrophil proteases and elastases
B. A1ATD is an autosomal codominant disorder affecting 1 in 12,000 live births
C. Gene is located on the long arm of chromosome 14 q31-32.2
D. There are more than 100 allelic variants of A1AT
E. Not all variants are associated with clinical disease
F. Major genotypes are M, Z, and S
1. PiMM (protease inhibitor [PI]), the normal phenotype that is present in
95% of the population and is associated with normal serum levels of
A1AT
G. The Z A1AT protein is caused by a single nucleotide substitution (Glu to Lys)
1. The gene is most common in those of northern European descendants
2. PiZZ and PiSZ phenotypes are associated with severe deficiency and
liver disease
3. PiMZ and PiSS phenotype leads to an intermediate deficiency without
liver disease

A. A1ATD predisposes children and adults to liver and pulmonary disease
B. Affected infants have a tendency to be small for gestational age
C. Liver involvement
1. First identified in the newborn period due to persistent direct
hyperbilirubinemia
a. The jaundice generally clears
2. 10%–15% of PiZZ individuals present with liver disease in the 1st years
of life
SECTION 6: Liver
3. 10%–30% of those presenting with neonatal liver disease develop
moderate to severe liver disease with coagulopathy, poor growth,
portal hypertension, and ascites in childhood
4. ↑ serum aminotransferase levels, alkaline phosphatase, and GGT
5. Deficiency can lead to cirrhosis and hepatocellular carcinoma
Table of Contents
D. Emphysema is not seen in children; develops in 60%–70% of A1ATD adults 6Nvii

with the peak in the 4th and 5th decades
E. Absence of antitrypsin function and polymers of A1AT promoting 470
a proinflammatory state and neutrophil dysfunction predispose to
antineutrophil-cytoplasmic-antibody-positive vasculitis, glomerulonephritis,
neutrophilic panniculitis, and chronic pancreatitis
IV. Pathogenesis and diagnosis
A. Accumulation of A1AT protein in the hepatocyte due to protein misfolding

and lack of autophagy, leading to cellular injury
B. Defective autophagy (the method used by cells to dispose of polymers
and A1AT aggregates) leads to accumulation of the mutant protein in the
endoplasmic reticulum with resultant hepatotoxicity
C. Far fewer patients exhibit liver and lung disease associated with A1ATD than
estimated by population human genetic estimations, suggesting genetic and/or
environmental modulating factors in the development of tissue damage
D. Other inherited traits for protein degradation and environmental factors
(viral hepatitis and alcohol) may ↑ accumulation of the defective protein and
result in increased liver injury
E. Histology
1. Periodic acid-Schiff (PAS)-positive, diastase-resistant globules in the
periportal region
2. Globules have clear halo surrounding them in zone 1
3. Can be hard to find in the 1st months of live, when A1ATD does mimic
idiopathic neonatal hepatitis
F. Laboratory
1. Serum levels are typically decreased; however, it is an acute phase
reactant
a. Rarely above 50–60 mg/dL in PiZZ patients
2. Phenotype
V. Treatment
A. Infants with cholestasis may benefit from:
1. Fat-soluble vitamin supplements (vitamins A, D, E, and K) and infant
formula containing medium-chain triglyceride oil
2. Ursodeoxycholic acid may increase bile flow and reduce liver injury
associated with cholestasis, although there is no evidence of direct
long-term benefit
B. Currently, no specific treatments are commercially available
C. Carbamazepine has been shown to ↑ autophagy and AT disposal in mouse
models; clinical trials in patients >14 years of age are currently underway
6Nvii. Alpha-1-Antitrypsin Deficiency

D. Clinical trials are currently underway on RNA treatment in adults
E. Avoidance of cigarette smoking (including secondhand smoke) and
environmental pollution exposure is mandatory in order to slow the
progression of lung disease
F. Orthotopic liver transplantation is the treatment for A1ATD-associated end-
Table of Contents
stage liver disease and liver failure 6Nvii

1. The recipient assumes the donor PI phenotype and is no longer at risk
for emphysema 471
G. Screening is recommended for all relatives of patients with A1ATD to identify
PiZZ or PiSZ family members and is mandatory for siblings of affected
patients
H. Newborn screening has not been instituted
Liver Biopsy from an 18-Month-Old Female with Minimally Active Liver

FIGURE 1
Disease Secondary to A1ATD
*
A B
(A) Shows PAS-positive, diastase-resistant globules in zone 1 hepatocytes. Globules represent condensed misfolded
protein. (B) Zone 3 contains swollen hepatocytes with dilated endoplasmic reticulum that contains early
accumulation of ZZ protein that is nonreactive with PAS stain, underlining the importance of Zone 1 evaluation.
SECTION 6: Liver
Recommended Reading
Maurice N, Perlmutter DH. Novel treatment strategies for liver disease due to α1-
antitrypsin deficiency. Clin Transl Sci. 2012;5:289-294.
Table of Contents
Russo P, Ruchelli ED, Piccoli DA, eds. Pathology of Pediatric Gastrointestinal and Liver
6Nvii
Disease, 2nd ed. Berlin Heidelberg: Springer-Verlag; 2014.
472
6Nvii. Alpha-1-Antitrypsin Deficiency

SECTION
6Nviii
Wilson Disease
Table of Contents
6Nviii
Einar Hafberg, MD
473
Kevin Bove, MD
Previous edition authors: Isabel Rojas, MD and Norberto Rodriguez-Baez, MD
I. Overview
A. Wilson disease (WD), also known as hepatolenticular degeneration, is caused
by copper accumulation in various tissues of the body
1. ↓ secretion of copper into the bile, which is the body’s main route of
elimination
2. Liver is primarily affected
3. Basal ganglia, cornea, thyroid, and kidney also affected
B. Autosomal recessive condition with incidence 1:7,000–1:30,000
C. The gene ATP7B is located on chromosome 13 (>500 mutations documented)
1. Poor phenotype genotype correlation indicates importance of other
modulator genes
D. ATP7B is a P-type ATP expressed mainly in hepatocytes but also in kidney,
lung placenta, and brain
1. Functions to export copper into bile and to incorporate it into
ceruloplasmin
2. Defect in this protein causes
a. Accumulation of copper in hepatocytes and brain tissue
b. ↓ synthesis of ceruloplasmin
E. Accumulation of copper causes oxidative stress leading to:
1. Mitochondrial damage
2. Changes in antiapoptotic proteins, leading to lower threshold for cell
death
3. Inhibited polymerization of tubulin
4. Collagen gene expression and fibrosis
F. Ceruloplasmin is an iron transporter and acute phase protein
1. No direct role in the pathophysiology of WD
G. Ceruloplasmin can be normal in up to 30% of pediatric patients with WD
II. Clinical manifestations

A. Clinical features rarely present prior to 3 years of age
B. Presentation varies by age; in children, usually presents as liver disease: 1st
decade: 75% hepatic; 2nd decade: 50% liver and 50% neuropsychiatric; >3rd
decade: 75% neuropsychiatric
C. WD should be suspected in any age group with undiagnosed liver disease,
especially if more than 1 organ system is involved
SECTION 6: Liver
III. Hepatic manifestations
A. May vary from mild elevation of the transaminases to acute liver failure
B. Commonly present as acute hepatitis with jaundice and anorexia but
can also present as cirrhosis with portal hypertension, chronic hepatitis,
Table of Contents
steatohepatitis, gallstones, or hepatocellular carcinoma 6Nviii

C. Liver biopsy may show cirrhosis, periportal glycogenated nuclei, and micro-
or macrovesicular steatosis (see Figure 1) 474
FIGURE 1 Liver Biopsy from a 9-Year-Old Male with Severe Neurological WD

*
A B
(A) Trichrome stain shows nodular cirrhosis with bridging fibrosis. (B) Hematoxylin and eosin stain shows focal
macrovesicular steatosis with prominent interface chronic inflammatory infiltrate.
IV. Neurologic manifestations
A. Usually occur in 2nd–3rd decade of life

B. Basal ganglia and cerebellum mainly affected with corticobulbar and
corticospinal pathways
C. Motor symptoms are most prominent and include dystonia, worsening of
handwriting, ataxia, tremor, and dysarthria
D. Intelligence and sensory function unaffected
E. Behavior can be affected and ranges from organic depression to frank
psychosis
F. Other manifestation
1. Heme—Coombs negative hemolysis (~15% of cases of acute liver
failure [fulminant Wilson])
2. Renal—proximal tubular defect
3. Cardiac—cardiac arrhythmias, left ventricular hypertrophy, and carditis
4. Bone—bone demineralization, rickets, osteomalacia, and stiffness of
larger joints
5. Endocrine—sex hormone dysfunction and thyroid dysfunction
6Nviii. Wilson Disease

V. Diagnosis
A. No single test to establish the diagnosis

B. Classically aspartate aminotransferase (AST) > alanine transaminase (ALT)
and low alkaline phosphatase (ALP)
Table of Contents
1. The indices of AST/ALT > 2.2 and ALP/total bilirubin < 4 are particularly 6Nviii
useful for considering the working diagnosis of fulminant Wilson (see
below; King’s College criteria). 475
C. 24-hour urine copper > 100 μg/24 hours is typically found in symptomatic
patients (>40–50 μg/24 hours requires additional/repeat testing)
D. Ceruloplasmin < 20 mg/dL is an important screening test
1. Falsely elevated by acute inflammation, malignancy, estrogen therapy,
protein-losing enteropathy, and malnutrition
2. 10%–30% of children have normal ceruloplasmin levels at diagnosis
E. Hepatic copper concentration >250 µg dry weight
1. Falsely elevated in other cholestatic diseases
F. Serum copper usually low
1. Can be high in acute hepatitis
G. Genetic testing is available and should be done if diagnosis is questioned and
for the purpose of screening of family members, especially siblings who have
a 25% risk of being affected
VI. Management
A. Chelating agents
1. D-penicillamine
a. Chelates copper and induces cupruria
1) Needs supplementation with pyridoxine (vitamin B6)
b. Adverse effects include fever, skin rash, lupus, lymphadenopathy,
and thrombocytopenia and nephrotoxicity
2. Trientine
a. Chelates copper and induces cupruria
b. Safe during pregnancy
3. Ammonium tetrathiomolybdate
a. Blocks copper absorption
4. Zinc
a. Interferes with the uptake of copper from the GI and induces
enterocyte metallothionein, which binds copper and traps in the
enterocyte
b. Poor efficacy in children with moderate liver disease; role as
monotherapy is questioned by many clinicians
c. Often added to treatment, especially since prolonged chelation
therapy leads to zinc deficiency
5. Antioxidants
a. Vitamin E may have a role, does interfere with vitamin K-
dependent clotting factor synthesis, and needs to be monitored if
used
SECTION 6: Liver
B. Dietary avoidance of food with high copper content
1. Shellfish, nuts, chocolate, mushrooms, and organ meats
C. Liver transplant
1. Patients in liver failure or decompensated liver disease unresponsive to
treatment benefit from liver transplantation
Table of Contents
6Nviii
VII. Fulminant Wilson disease
476
A. Typically present with acute liver failure
1. Vitamin-K-resistant coagulopathy
2. Mildly elevated serum aminotransferases compared with the degree of
hyperbilirubinemia
3. ↓ ALP levels (ALP/total bilirubin < 20)
4. Coombs negative hemolytic anemia
5. Kayser-Fleischer rings in 50% of cases
6. Acute renal failure is a particular concern, which may benefit from early
plasmapheresis
B. Suspicion for acute decompensation of WD is based on the clinical
presentation, as described above, and needs to prompt consideration of
early listing for liver transplant as status 1A, even before confirmation by
results from 24-hour urine copper quantification and other definitive studies
Recommended Reading
European Association for Study of Liver. EASL clinical practice guidelines: Wilson
disease. J Hepatol. 2012;56:671-685.
Roberts EA, Schilsky ML, American Association for Study of Liver Diseases (AASLD).
Diagnosis and treatment of Wilson disease: an update. Hepatology. 2008;47:2089-2111.
6Nviii. Wilson Disease

SECTION
6O
Peroxisomal Disorders
Table of Contents
6O
Lynette Gillis, MD
477
Yumirle P. Turmelle, MD
Previous edition author: Lynette Gillis, MD
I. Functions of peroxisomes
A. Peroxisomes are present in all cells except erythrocytes, with the highest
concentration in liver and kidneys
B. Catabolic functions
1. β-oxidation of very-long-chain fatty acids (VLCFAs)
2. Oxidation of phytanic acid, pipecolic, pristanic, and many other
dicarboxylic acids
3. Degradation of hydrogen peroxide
C. Anabolic functions
1. Biosynthesis of ether lipids, isoprenoids, cholesterol, and bile acids
II. Epidemiology and classification

A. Incidence estimated to be 1–5/10,000 live births
B. Over 20 disorders have been described
C. Classified into two main groups
1. Disorders of peroxisome biogenesis
a. Zellweger syndrome (ZWS)
b. Neonatal adrenoleukodystrophy (NALD)
c. Infantile Refsum disease (IRD)
d. Rhizomelic chondrodysplasia punctata type 1 (RCDP1)
2. Deficiency of a single peroxisomal enzyme-multiple disorders classified
(e.g., Refsum disease, acyl-coenzyme A [CoA] oxidase deficiency, etc.)
III. General clinical features of peroxisomal disorder: varies by age

A. Neurological—encephalopathy, hypotonia, seizures, and deafness
B. Skeletal—short limbs, calcific stippling, and craniofacial abnormalities
C. Ocular—retinopathy, corneal clouding, cataract, and blindness
D. Hepatic—neonatal hepatitis, hepatomegaly, cholestasis, and cirrhosis
IV. Diagnostic evaluation

A. Abnormal alanine transaminase/aspartate aminotransferase ± elevated
bilirubin
SECTION 6: Liver
B. Serum VLCFA: ↑ (C26 et al.) in nearly all peroxisomal disorders
C. Serum cholesterol: normal or low (in setting of cholestasis)
D. Serum pristanic acid: ↑ in disorders of peroxisome biogenesis
E. Serum phytanic acid: ↑ in disorders of peroxisome biogenesis and Refsum
disease
Table of Contents
F. Erythrocyte plasmalogens: ↓ in disorders of peroxisome biogenesis 6Nviii

G. Bile acid intermediates (urine/serum) are typically abnormal
H. Skin fibroblast or genetic testing may be necessary to confirm the diagnosis 478
V. Disorders of peroxisome biogenesis
A. Zellweger (cerebro-hepato-renal syndrome): autosomal recessive

1. Clinical presentation
a. Usually identified as newborns with hypotonia, poor feeding,
distinct facies (wide fontanelle, prominent forehead, midface
hypoplasia, and epicanthal folds), seizures, and hepatic
dysfunction
b. Older children: retinal dystrophy, sensorineural hearing loss,
developmental delay with hypotonia, and liver dysfunction
c. Characteristic bony stippling (chondrodysplasia punctata) of the
patella(e) and other long bones may occur
d. Overall, the hepatic involvement is overshadowed by the
neurological symptoms
e. Usually fatal in the first 2 years of life
2. Liver findings
a. ↓ production of normal bile acids and increase in abnormal di-
and trihydroxy bile acids
b. Ultrastructure reveals absence of peroxisomes; usually overall
intact pericanalicular tight junctions with focal loss of integrity of
pericanalicular tight junctions with dilation of the lateral spaces
3. Diagnosis
a. ↑ plasma VLCFA levels
b. ↑ concentrations of phytanic acid, pristanic acid, and pipecolic
acid in plasma and fibroblasts
c. ↓ erythrocyte concentration of plasmalogen
d. Mutations in 12 different PEX genes that encode peroxins
(proteins required for normal peroxisome assembly) identified
1) Mutations in PEX1 the most common
2) Sequence analysis is available clinically for the following
14 genes: PEX1, PEX2, PEX3, PEX5, PEX6, PEX7, PEX10, PEX12,
PEX13, PEX14, PEX16, PEX19, PEX26, and PHYH
4. Management
a. Symptomatic therapy may include:
1) Gastrostomy to provide adequate calories
2) Vitamin supplementation
3) Reduce exposure to phytanic acid
4) Genetic counseling is very important
6O. Peroxisomal Disorders

B. Nonalcoholic fatty liver disease
1. Autosomal recessive
2. Most have mutations in either the PEX1 or PEX6 genes that encode
ATPases needed to import protein into peroxisomes
3. Midface hypoplasia, adrenal insufficiency, and behavioral problems
Table of Contents
4. Neurologic features include weakness, hypotonia, seizures, and 6O

progressive visual and auditory dysfunction. Liver disease is usually
mild or absent. 479
5. Labs—same biochemical abnormalities as seen in ZWS
6. Most children die by 5 years
C. Immune restoration disease
1. Autosomal recessive
2. Most have mutations in either the PEX1 or PEX6 genes
3. Least severe presentation: typically at 1–6 months with dysmorphic
features, hypotonia, visual and auditory abnormalities, retinitis
pigmentosa, polyneuropathy, cerebellar ataxia, deafness, anosmia,
ichthyosis, skeletal and cardiac symptoms, and normal intelligence
quotient
4. May not be diagnosed until later in life because of very mild features
5. May present with vomiting, diarrhea, and malabsorption
6. Most have hepatomegaly with cirrhosis
7. Labs—similar biochemical abnormalities as seen in ZWS
D. Rhizomelic chondrodysplasia punctata type 1
1. Due to mutation in PEX7
2. Clinical presentation includes profound mental retardation,
dysmorphic facies, and unique severe short statue
a. Also seen: proximal limb shortening, microcephaly, contractures,
spasticity, cataracts, and ichthyosis
3. Diagnosis: VLCFA not ↑, ↓ plasmalogens, ↑ phytanic acid, and
↓ pristanic acid
4. Therapy: restrict phytanic acid (benefit in some)
VI. Deficiency of a single peroxisomal enzyme
A. There are multiple disorders described, all autosomal recessive. 2 of the

more common examples are described below.
1. Refsum disease—also known as hereditary motor and sensory
neuropathy IV and heredopathia atactica polyneuritiformis
a. Mutations in the gene (PhyH) encoding the enzyme phytanoyl-
CoA hydroxylase
b. Different from other peroxisomal disorders since responds to
dietary treatment
c. Clinical presentation usually in adolescence
1) Retinitis pigmentosa, anosmia, sensorineural hearing loss,
ataxia, peripheral polyneuropathy, ichthyosis, and cardiac
conduction defects
2) Cognitive function is normal
SECTION 6: Liver
d. Treatment
1) Dietary restriction to eliminate phytol-containing foods,
such as meat or fats from ruminating animals and dairy
products
2) Goal of dietary reduction of phytanic acid to <10 mg daily
Table of Contents
3) Avoidance of rapid weight loss or fasting conditions, which 6Nviii

stimulate lipolysis
4) Phytanic acid concentration can also be reduced by 480
plasmapheresis—which halts progression of the disease
but does not completely reverse neurologic abnormalities
2. Acyl-CoA oxidase deficiency—also known as pseudo-NALD
a. Clinical presentation includes neonatal hypotonia, seizures,
hearing impairment, diarrhea, retinitis pigmentosa, and
hepatomegaly
b. Diagnosis: elevated VLCFA and normal pristanic acid and bile acid
intermediates
Recommended Reading
Braverman NE, D’Agostino MD, Maclean GE. Peroxisome biogenesis disorders:
biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev.
2013;17:187-196.
Farrell DF. Neonatal adrenoleukodystrophy: a clinical, pathologic, and

biochemical study. Pediatr Neurol. 2012;47:330-336.
Fidaleo M. Peroxisomes and peroxisomal disorders: the main facts. Exp Toxicol
Pathol. 2010;62:615-625.
Van Veldhoven PP. Biochemistry and genetics of inherited disorders of

peroxisomal fatty acid metabolism. J Lipid Res. 2010;51:2863-2895.
6O. Peroxisomal Disorders

SECTION
6P
Familial Hepatocellular Cholestatic

Table of Contents
6P
Disorders 481
Gillian Noel, MD
Shikha Sundaram, MD, MSCI
Previous edition author: Karan McBride Emerick, MD
I. Progressive familial intrahepatic cholestasis (PFIC)
A. Heterogeneous group of autosomal recessive (AR) genetic disorders that

lead to disruption of bile formation and progressive cholestasis
B. PFIC type 1
1. AR disorder, chromosome 18q21-22, gene ATP8B1/FIC1
2. Located on apical membranes of hepatocytes, colon, intestine, and
pancreas
3. Histology: bland cholestasis with coarse granular canalicular bile
(“Byler bile”) on electron microscopy (EM)
4. Laboratory: normal or low serum γ-glutamyltransferase (GGT), ↑ serum
bile acids, and ↓ biliary bile acids
5. Clinical characteristics: progressive cholestasis, severe pruritus,
diarrhea, steatorrhea, pancreatic involvement, growth failure, and
hearing loss
6. Treatment: supportive care, antipruritic agents, biliary diversion,
internal ileal exclusion, and liver transplant
a. Biliary diversion—a procedure that interrupts the enterohepatic
circulation and ↓ the load of bile salts to liver by diverting bile
from the gallbladder through a jejunal loop that connects the
gallbladder to skin
7. Can distinguish PFIC-1 from other PFIC types using genetic testing
C. PFIC type 2
1. AR, chromosome 2q24, gene ABCB1/bile salt export protein (BSEP)
2. Located on the canalicular membranes of hepatocytes
3. Histology: neonatal giant cell hepatitis and amorphous canalicular bile
on EM
4. Laboratories: normal or ↓ serum GGT, ↑ serum bile acids, and ↓ biliary
bile acids
5. Clinical characteristics: rapidly progressing cholestatic giant cell
hepatitis, pruritus, growth failure, and severe fat-soluble vitamin
deficiency
6. Risk of portal hypertension: PFIC-2 > PFIC-1
7. Risk of hepatocellular carcinoma or cholangiocarcinoma
SECTION 6: Liver
8. Treatment: supportive care, antipruritic agents, biliary diversion, and
liver transplant
9. Can distinguish PFIC-2 from other PFIC types using genetic testing
D. PFIC type 3
1. AR disorder, chromosome 7q21, gene ABCB4/MDR3
Table of Contents
2. Located on the canalicular membrane of hepatocytes 6P

3. Histology: bile duct proliferation and periportal bile on EM
4. Laboratories: ↑ serum GGT and normal biliary bile acid concentrations 482
5. Clinical characteristics: onset of cholestasis later than PFIC-1/PFIC-2,
minimal pruritus, portal hypertension, and gallstones
6. Treatment: ursodeoxycholic acid and liver transplant
E. Newly described PFIC-associated gene
1. AR inheritance, chromosome 9q21, gene TJP2
2. Histology: tight junctions between hepatocytes and biliary canaliculi
elongated and lacking densest part of zona occludens on EM
3. Clinical: early onset cholestasis with severe liver disease and end-stage
liver disease before adulthood
4. Treatment: supportive care, antipruritic agents, and liver transplant
F. Findings consistent amongst PFIC diseases
1. Absence of xanthomas
2. Near normal serum cholesterol
3. Severe fat-soluble vitamin deficiency
4. Growth failure
5. Progression to cirrhosis
II. Benign recurrent intrahepatic cholestasis (BRIC)

A. Hereditary disorder characterized by intermittent, recurrent episodes of
cholestasis
B. AR disorder, chromosome 18q21-31, gene ATP8B1 and chromosome 2q24,
gene ABCB1/BSEP
C. Located on apical membranes of hepatocytes, colon, intestine, and pancreas
and canalicular membranes of hepatocytes
D. Histology: centrilobular cholestasis and canalicular cholestasis
E. Laboratories: normal serum GGT and ↑ serum bile acids
F. Clinical characteristics: intermittent cholestasis, intermittent pruritus,
asymptomatic between episodes, and no cirrhosis
G. Treatment: antipruritic agents and supportive care
III. Alagille syndrome (see Section 6Cii. Cholestasis in Older Children)
IV. Congenital disorders of glycosylation (CDG)

A. Phenotypically diverse disorders of synthesis and attachment of glycans to
proteins. CDG should be considered in any patient with unexplained liver
dysfunction.
1. Defects in N-glycosylation and/or O-glycosylation, lipid glycosylation,
and multiple gene defects
6P. Familial Hepatocellular Cholestatic Disorders

B. Histology variable: steatosis, expanded portal tracts, and hamartomatous
collections of bile ducts
C. Laboratory: variable range of biochemical abnormalities
D. Diagnosis: transferrin isoelectric-focusing electrophoresis (abnormal patterns
due to altered N-glycosylation) and gene sequencing
Table of Contents
E. Clinical: highly variable and affects multiple systems: neurologic, 6P

musculoskeletal, cardiac, gastrointestinal, endocrinologic, and hematologic.
The most commonly involved is neurologic. Some noted clinical characteristics are 483
detailed below.
1. Neurologic: developmental and intellectual delay, seizures, neuropathy,
hypotonia, and strabismus
2. Cardiac: ventricular septal defect, cardiomyopathy, and aortic
insufficiency
3. Skeletal: arachnodactyly, skeletal dysplasia, microcephaly, and
adducted thumbs
4. Gastrointestinal: obesity, gastroesophageal reflux, diarrhea, and
hepatopathy
5. Skin: cutis laxa
6. Hematologic: thrombosis and bleeding diathesis
F. Treatment: phosphomannose isomerase deficiency treated with enteral
mannose and no treatment for other forms of CDG
Recommended Reading
Freeze HH, Eklund EA, Ng BG, et al. Neurological aspects of human glycosylation
disorders. Annu Rev Neurosci. 2015;38:105-125.
Hartley JL, Gissen P, Kelly DA. Alagille syndrome and other hereditary causes of
cholestasis. Clin Liver Dis. 2013;17:279-300.
Sambrotta M, Strautnieks S, Papouli E, et al. Mutations in TJP2 cause progressive

cholestatic liver disease. Nature Genet. 2014;46:326-328.
Scott K, Gadomski T, Kozicz T, et al. Congenital disorders of glycosylation: new defects

and still counting. J Inherit Metab Dis. 2014;37:609-617.
SECTION 6: Liver
Table of Contents
6P
484
6P. Familial Hepatocellular Cholestatic Disorders

SECTION
6Q
Drug-Induced Liver Injury

Table of Contents
6Q
Alisha Mavis, MD
485
Saeed Mohammad, MD
Previous edition authors: Henry Lin, MD and Adam Davis, MD
I. Overview
A. Drug-induced liver disease rare in children

B. Adverse drug reactions (not necessarily hepatotoxic) more frequent in very
young children and children with cancer
C. About 1/6 of all drug-related deaths in children are due to acute liver failure
and usually associated with antiepileptic or antineoplastic drugs
II. Hepatic drug metabolism

A. Activation (phase I): transformation of drug into a more polar or reactive
metabolite
1. Cytochrome P450 enzymes are associated with most phase I reactions:
hydroxylation, dealkylation, and dehalogenation
2. Cytochromes P450
a. Mono-oxygenases (insert molecular oxygen into substrate)
b. Have overlapping substrate specificity
c. Are inducible
3. Cytochromes P450 in 1A, 2B, 2C, 2D, 2E, and 3A subfamilies are
particularly important in human hepatic drug metabolism
B. Detoxification (phase II): formation of a polar conjugate that can be readily
excreted in urine or bile
1. Phase II enzymes: glutathione S-transferases, uridine diphosphate-
glucuronosyltransferases, epoxide hydrolases, sulfotransferases,
N-acetyltransferases, and enzymes responsible for glycine conjugation
C. Polymorphisms in these enzymes make individuals either rapid or slow
metabolizers and are important factors in drug hepatotoxicity
III. Drug hepatotoxicity

A. Drug-induced liver disease is mostly cytotoxic and usually targets hepatocytes
1. Zonal hepatocellular necrosis implies that the production of toxic
metabolites are actively involved in pathogenesis
a. Hepatocytes in zone 3 of the Rappaport acinus have the greatest
potential for producing toxic metabolites because of the highest
concentration of cytochromes P450
B. Drug hepatotoxicity classified by duration
SECTION 6: Liver
1. Acute: develops over days to weeks without histological features of
chronicity
2. Subacute: lesions develop over weeks to months with areas of fibrosis
and possible regeneration
3. Chronic: lesions develop over months with fibrosis or cirrhosis, bile
Table of Contents
duct paucity (ductopenia), vascular changes, and neoplasia 6Q

C. Drug hepatotoxicity classified by clinical features
1. Hepatitic: symptoms of hepatitis (fatigue, anorexia, nausea, or 486
vomiting) and isolated ↑ aminotransferases
2. Cholestatic: jaundice, pruritus, significantly ↑ alkaline phosphatase,
bilirubin, and γ-glutamyltransferase; and mildly ↑ aminotransferases
3. Mixed hepatitic-cholestatic: elements of both hepatitis and cholestasis
4. Drug hypersensitivity syndrome (drug rash with eosinophilia and
systemic symptoms syndrome): fever, inflammation of various organ
systems (hepatitis, Stevens-Johnson syndrome, renal dysfunction,
or myocarditis), lymphadenopathy, eosinophilia, and atypical
lymphocytosis
5. Chronic active hepatitis (autoimmune hepatitis [AIH]-like): subacute
or chronic course with fatigue, anorexia, variable extrahepatic
findings (lupoid rash and arthralgias), ↑ serum immunoglobulin G, and
detectable nonspecific autoantibodies (i.e., antinuclear antibody)
D. Drug hepatotoxicity classified by predictability (combines mechanistic and
clinic considerations)
1. Intrinsic hepatotoxin: true toxin/poison; causes predictable hepatic
damage in everyone in a dose-related manner
2. Contingent hepatotoxin: unpredictable; causes hepatotoxicity in
susceptible individuals when hepatic biotransformation is abnormal
(acquired or genetic)
3. Immunoallergic response: hepatotoxicity eliciting immunoallergic
response (includes drug hypersensitivity syndrome, hepatic
granulomatosis, and chronic active hepatitis)
IV. Drugs commonly associated with liver injury

(refer to livertox.nih.gov for specific drug-induced injuries)
A. Acetaminophen
1. Primary cause of acute liver failure due to drug-induced liver injury but
rarely fatal in children and adolescents
2. Minimum toxic doses
a. Doses >350 mg/kg: nearly all patients develop severe liver toxicity
b. Acute ingestion: 150 mg/kg once or >12 grams in 24 hours
c. Chronic ingestion: 150–175 mg/kg per 24 hours over 2–4 days
3. Clinical manifestations
a. Stage I (<24 hours): nausea, vomiting, pallor, lethargy, and malaise
followed by an asymptomatic period
b. Stage II (24–72 hours): abdominal pain, ↑ alanine transaminase
(ALT)/aspartate aminotransferase (AST), coagulopathy, jaundice,
and, in severe cases, nephrotoxicity and/or pancreatitis
6Q. Drug-Induced Liver Injury

TABLE 1 Summary of Histology Findings for Hepatotoxic Agents
Finding Causative Agent

Acetaminophen, isonicotinic acid
Table of Contents
Acute hepatitis 6Q
hydrazide, and halothane
Minocycline, nitrofurantoin, and
AIH-like 487
infliximab
Cyclosporine, estrogens/oral
Acute cholestasis contraceptives, Augmentin™, and
haloperidol
Insulin, mycophenolate mofetil,
Cytoplasmic inclusions
diazepam, steroids, and tacrolimus
Gallstones Ceftriaxone
Carbamazepine, sulfonamides, penicillin,

Granulomatosis
phenytoin, diazepam, and isoniazid
Estrogens/oral contraceptives and
Hepatic vein thrombosis
decarbazine
Estrogens/oral contraceptives and
Liver cell adenoma
anabolic steroids
Macrovesicular steatosis L-asparaginase
Macrovesicular steatosis and fibrosis Methotrexate
Microvesicular steatosis Valproic acid and tetracycline
Mixed hepatitis-cholestasis Erythromycin and azathioprine
Nodular regenerative hyperplasia Azathioprine and 6-thioguanine
Peliosis Estrogens and androgens
Phospholipidosis Amiodarone
Steatohepatitis Amiodarone and irinotecan
Stellate cell lipidosis Retinoids and hypervitaminosis A
6-thioguanine, busulfan, oxaliplatin, and

Veno-occlusive disease
bush tea (pyrrolizidine alkaloids)
Zonal liver cell necrosis Acetaminophen
SECTION 6: Liver
c. Stage III (72–96 hours): ALT/AST peak; can progress to liver failure
and multiorgan failure
d. Stage IV (4–24 days): recovery with normalization of labs and
resolution of symptoms
4. Histopathology: zonal hepatocellular necrosis in a centrilobular pattern
Table of Contents
(zone 3) with minimal to no inflammatory response 6Q

5. Treatment
a. N-acetylcysteine is accepted antidote for acetaminophen 488
1) Restores hepatic glutathione stores to reduce the toxic
intermediate metabolites of acetaminophen
b. Most effective if given within 8–10 hours of ingestion
c. 72-hour oral regimen and 20-hour IV regimen have same efficacy
d. Good prognosis if coagulopathy and aminotransferases are
normal or near normal after 48 hours of treatment
B. Antiepileptics
1. Carbamazepine/oxcarbazepine
a. Usually associated with drug hypersensitivity syndrome
b. Immunogenetics influence susceptibility to liver injury
2. Phenobarbital
a. Jaundice, hepatitis, rash, fever, and eosinophilia usually present
within 8 weeks of starting the drug
b. Fulminant liver failure has been reported in children
3. Phenytoin
a. Incidence 2–4:100,000 exposures
b. Hepatitis, jaundice, fever, rash, lymphadenopathy, leukocytosis,
and eosinophilia
c. Histology: spotty necrosis of hepatocytes, occasional granulomas,
and cholestasis
d. Consider steroid therapy in severe cases
4. Valproic acid
a. 2 patterns of liver injury
1) Dose-responsive hepatitis that resolves when the dose is
decreased
2) Liver failure that progresses despite stopping the drug
a) Resembles Reye syndrome clinically and cannot be
predicted based on monitoring labs
b) Hepatitic prodrome with malaise, anorexia, nausea,
and vomiting
b. Histopathology: microvesicular steatosis and zonal hepatocellular
necrosis
C. Antimicrobials
1. Trimethoprim/sulfamethoxazole
a. Idiosyncratic hypersensitivity reaction; may have eosinophilia
b. Typically cholestatic; may be prolonged and lead to liver failure
2. Macrolides
a. Cholestatic liver injury
3. Minocycline
a. AIH-like liver injury: hepatitis, jaundice, and positive
autoantibodies

b. Histopathology resembles AIH: interface hepatitis, inflammatory
cell infiltrate, fibrosis, and bridging necrosis
c. May require treatment with steroids
4. Penicillins
a. Amoxicillin-clavulanic acid (Augmentin™)
Table of Contents
1) Cholestasis or a mixed hepatitic-cholestatic reaction 6Q

2) Can cause ductopenia with prolonged cholestasis
b. Cholestasis: oxacillin, cloxacillin, and flucloxacillin 489
D. Antineoplastic drugs
1. General hepatic injury with ↑ aminotransferases but otherwise
asymptomatic
a. 6-mercaptopurine, cis-platinum, cytosine arabinoside,
nitrosoureas, and dacarbazine most frequently produce hepatitis
b. Adriamycin, dactinomycin, and vinca alkaloids infrequently cause
hepatotoxicity
2. Cyclophosphamide may cause dose-related hepatitis
3. 6-mercaptopurine and carmustine may cause a mixed hepatic-
cholestatic injury with severe cholestasis
4. L-asparaginase associated with severe steatosis, hepatocellular
necrosis, and fibrosis
a. Usually reverses after L-asparaginase stopped
5. Veno-occlusive disease (sinusoidal obstruction syndrome)
a. Presents with enlarged, tender liver, ascites or unexplained
weight gain, jaundice, and hepatitis
b. 6-thioguanine, cytosine arabinoside, busulfan, decarbazine,
carmustine, dactinomycin, and oxaliplatin
E. Immunosuppressant drugs
1. Azathioprine
a. Usually causes a cholestatic or mixed hepatitic-cholestatic liver
injury
b. Histopathology: centrilobular hepatocyte ballooning, canalicular
cholestasis, endothelial cell damage, and nodular regenerative
hyperplasia
2. Cyclosporine
a. Usually presents as bland cholestasis (direct hyperbilirubinemia)
without evidence of hepatocellular damage
3. Methotrexate
a. Histopathology: hepatic fibrosis and macrovesicular steatosis
SECTION 6: Liver
Recommend Reading
Davern TJ. Drug-induced liver disease. Clin Liver Dis. 2012;16:231-245.
Roberts EA. Drug-induced hepatotoxicity in children. In: Kleinman RE, Sanderson IR,
Table of Contents
Goulet O, et al., eds. Walker’s Pediatric Gastrointestinal Disease, 5th ed. Hamilton, Ontario: 6Q
BC Decker; 2008, pp. 893-910.
490
Roberts EA. Drug-induced liver disease. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver
Disease in Children, 4th ed. New York, NY: Cambridge University Press; 2014,
pp. 341-369.
Zhang X, Ouyang J, Thung SN. Histopathologic manifestations of drug-induced

hepatotoxicity. Clin Liver Dis. 2013;17:547-564.

SECTION
6R
Iron Storage Disorders

Table of Contents
6R
Joanne Lai, MD
491
Jaime Chu, MD
Previous edition author: Nitika Arora Gupta, MD
I. Background
A. Iron overload is a result of either:

1. ↑ iron absorption despite normal iron intake (hereditary
hemochromatosis [HH])
2. 2º to causes including hemolysis, transfusion dependency, parenteral
iron overload, chronic liver disease, and aceruloplasminemia
II. Hereditary hemochromatosis
A. Autosomal recessive condition resulting in abnormal regulation of iron

absorption, leading to ↑ body iron stores and organ damage
1. HH most common genetic disorder in Caucasians
2. C282Y substitution (cysteine to tyrosine at position 282) in the HFE
gene most common HH mutation
3. Incidence of C282Y homozygosity in Caucasians is 1 in 250, but full
clinical manifestations seen in 1 in 2,500
4. Pathophysiology: ↑ intestinal iron absorption, ↓ expression of iron-
regulatory hormone hepcidin, and altered function of HFE protein
leads to iron-induced tissue injury and fibrogenesis
5. Non-HFE-related HH includes mutations in hemojuvelin and hepcidin
(juvenile HH) and can present as a severe form of HH, <30 years old,
with cardiac involvement, hypogonadotropic hypogonadism, and liver
fibrosis
1. Symptoms: weakness, fatigue, abdominal pain, arthralgias, diabetes,
amenorrhea, impotence, hypothyroidism, and congestive heart failure
2. Physical findings: hepatomegaly, splenomegaly, arthropathy,
cardiomyopathy, bronze skin pigmentation, and hypogonadism
3. Age of onset is typically 40–60 years; non-HFE HH presents at an earlier
age
C. Diagnosis
1. In a patient with symptoms, physical findings, or family history, obtain
transferrin saturation (TS) and ferritin
2. If TS ≥ 45% or ↑ serum ferritin, then obtain HFE mutation analysis
3. If ↑ aspartate aminotransferase (AST)/alanine transaminase
(ALT) or ferritin >1,000 µg/L in C282Y homozygotes or compound
SECTION 6: Liver
heterozygotes, then liver biopsy recommended to stage fibrosis
a. Perls Prussian blue stain to evaluate the degree of hepatic iron
stores
4. Exclude other disorders of iron overload—alcoholic and nonalcoholic
steatohepatitis, chronic viral hepatitis, and 2º causes of iron overload
Table of Contents
D. Treatment of HFE-related hereditary hemochromatosis 6R

1. If normal serum ferritin , yearly surveillance is recommended
2. If ↑ serum ferritin, treatment with therapeutic phlebotomy to maintain 492
serum ferritin 50–100 µg/L
a. May reverse fibrosis, skin pigmentation, fatigue, and
hypogonadism, but cirrhosis, diabetes, and cardiomyopathy may
not be reversible
3. Dietary iron restriction is unnecessary, although recommend avoidance
of vitamin C supplements (can ↑ iron mobilization and free radical
activity)
4. Iron chelators (e.g., deferasirox) may be helpful if phlebotomy is poorly
tolerated
5. HH patients with cirrhosis should be screened regularly for
hepatocellular carcinoma
E. Evaluation in a patient with a family history
1. Screen adult 1º relatives with TS, ferritin, and HFE mutation analysis
2. Risk of developing HH before 18 years old is negligible
3. If C282Y homozygote or C282Y/H63D heterozygote, then yearly
surveillance with TS, ferritin, and ALT/AST
III. Neonatal hemochromatosis (NH)
A. NH is a syndrome of severe fetal liver disease associated with extrahepatic

siderosis. The vast majority of NH cases are due to gestational alloimmune
liver disease (GALD).
1. GALD is mediated by maternal immunoglobulin G that crosses
the placenta and targets a fetal hepatocyte antigen, leading to
complement-mediated hepatocyte injury
2. Rarely, NH may result from other fetal diseases including trisomy 21,
mitochondrial DNA depletion, and bile acid synthetic defects
3. Because the fetal liver controls the flow of iron from the mother to the
fetus, extrahepatic siderosis seen in pancreas, myocardium, thyroid,
salivary glands, and respiratory system
1. Liver failure soon after birth. NH must be considered in any neonate
presenting in acute liver failure (ALF) or with signs of chronic liver
disease.
2. History of prematurity, intrauterine growth restriction, or
oligohydramnios typically seen. There may be a maternal history of
fetal demise, stillbirth, or early infant death.
3. Clinical: jaundice, ascites, and edema. Renal involvement → oliguria.
Severity may vary.
6R. Iron Storage Disorders

C. Diagnosis
1. Laboratory: direct hyperbilirubinemia, normal or only mildly
↑ ALT/AST, and ↑ α-fetoprotein, hypoglycemia, coagulopathy, and
hypoalbuminemia
2. Iron studies: ↑ serum ferritin (>800 µg/L), ↓ transferrin levels, and ↑ iron
Table of Contents
saturation 6R
3. Differential diagnosis: tyrosinemia, hemophagocytic
lymphohistiocytosis, mitochondrial disease, galactosemia, bile acid 493
synthetic defects, hereditary fructose intolerance, familial intrahepatic
cholestasis, and infection
4. Diagnosis made by demonstrating extrahepatic siderosis
a. Biopsy of salivary gland obtained in a minimally invasive fashion
and can demonstrate iron deposition
b. T2-weighted magnetic resonance imaging can also document
siderosis in extrahepatic tissues, most commonly pancreas, heart,
and adrenal glands
c. Liver biopsy not recommended because hepatic siderosis
also seen in other neonatal liver diseases and absence of liver
siderosis does not exclude NH
1) Histopathology: subacute or chronic injury with loss of
hepatocyte mass, giant cells, pseudoacini, fibrosis, and
collapsed reticulum
2) MAC-mediated hepatocyte injury, demonstrated by
positive staining for the C5b-9 complex, is a unique feature
of congenital alloimmune hepatitis
D. Treatment
1. Double-volume exchange transfusion to remove existing reactive
antibody followed by high-dose, IV immunoglobulin to block antibody-
induced complement activation. This treatment regimen has led to
marked improvement in survival.
2. Normalization of international normalized ratio (INR) may take
4–6 weeks
3. Medical management may fail due to complications of infection,
intracranial hemorrhage, or multiorgan failure
4. Liver transplant considered if medical management fails
5. Recurrence of GALD in the mother’s subsequent pregnancies can be
ameliorated/prevented with IV immunoglobulin administration during
gestation; recommended at 14 weeks, 16 weeks, and then weekly from
18 weeks until the end of gestation
SECTION 6: Liver
Recommended Reading
Bacon BR, Adams PC, Kowdley KV, et al. Diagnosis and management of hemachromatosis:
2011 practice guideline by the American Association for the Study of Liver Diseases.
Hepatology. 2011;54:328-343.
Table of Contents
6R
Lopriore E, Mearin ML, Oepkes D, et al. Neonatal hemochromatosis: management,
outcome, and prevention. Prenat Diagn. 2013;33:1221-1225. 494
Rand EB, Karpen SJ, Kelly S, et al. Treatment of neonatal hemochromatosis with exchange
transfusion and IV immunoglobulin. J Pediatr. 2009;155:566-571.
Whitington PF. Gestational alloimmune liver disease and neonatal hemochromatosis. Semin
Liver Dis. 2012;32:325-332.
Whitington PF, Hibbard JU. High-dose immunoglobulin during pregnancy for recurrent
neonatal hemochromatosis. Lancet. 2004;364:1690-1698.
6R. Iron Storage Disorders

SECTION
6S
Lipid Storage Disease

Table of Contents
6S
Krupa R. Mysore, MD
495
Paula M. Hertel, MD
Previous edition authors: Maria Perez, MD and Carol Potter, MD
I. Epidemiology/definitions
A. Inherited metabolic disorders that result in harmful accumulation of lipids in
the lysosomes of organs including brain, liver, peripheral nerves, spleen, and
bone marrow, causing cellular and tissue damage
B. Incidence is variable, and inheritance is autosomal recessive except Fabry
disease, which is X-linked
II. Lipid metabolism

A. Lipids, as macromolecules, undergo catabolism in lysosomes by acid
hydrolases
B. Glycosphingolipids (GSLs) are carbohydrate moieties attached to a ceramide
backbone
C. GSLs are present in most cellular membranes and involved in cell signaling
D. Loss of entire glucosylceramide biosynthetic pathway is incompatible with
life
E. Other disorders under this category include cholesterol ester storage
disorders
F. The liver is affected to various degrees in most of the lipid storage disorders
III. Common presentations of disorders of lipid metabolism

A. Infants: hepatosplenomegaly, failure to thrive, frequent emesis,
developmental delay, and, occasionally, acute liver failure
B. Older children: massive hepatosplenomegaly, growth problems, lung
disease, neurological issues, and developmental delay
C. ↑ aminotransferases in infancy or early childhood
IV. Niemann-Pick types A (NPD-A) and B (NPD-B): acid

sphingomyelinase deficiency (ASM)
1. Deficiency of ASM enzyme is most commonly due to SMPD1 gene
variation
2. Results in accumulation of lipids, primarily sphingomyelin, in
reticuloendothelial cells, ganglion cells, and other cell types
3. Subtypes
SECTION 6: Liver
a. Infantile-onset neuronopathic NPD-A with death by 3 years of age
b. Later-onset, visceral NPD-B
c. A few intermediate-severity cases have been reported
4. Estimated prevalence is 1:250,000, with ↑ incidence in certain ethnic
groups including Ashkenazi Jews; North African descendants; and
Table of Contents
individuals from Chile, Saudi Arabia, and Turkey 6S

1. Severe early-onset form (NPD-A) 496
a. Presents with hepatosplenomegaly by 3–6 months of age and
↑ serum aminotransferases
b. Clinical: failure to thrive, vomiting, and diarrhea are common
c. Interstitial lung disease with frequent respiratory infections
may develop due to sphingomyelin storage in pulmonary
macrophages
d. “Cherry red spot” (present by 12 months of age) on
ophthalmologic examination due to lipid accumulation in retinal
ganglion cells
e. Progressive hypotonia with loss of reflexes and developmental
delay with severe psychomotor delay, resulting in failure to
progress beyond 10- to 12-month milestones
2. Later-onset form (NPD-B)
a. Hepatosplenomegaly with progressive hypersplenism → 2º
thrombocytopenia
b. Progressive interstitial lung disease with oxygen requirement
c. Retinal cherry red spot in ~1/3 of patients
d. Neurological signs: cerebellar signs, nystagmus, intellectual
disability, and other neurological abnormalities in ~1/3 of patients
e. Short stature, low body weight, and delayed bone age with
↓ serum insulin growth factor-1 concentration
f. Dyslipidemia and early coronary artery disease
C. Diagnosis
1. Molecular genetic testing for pathogenic variants in SMPD1 gene
2. ASM activity in peripheral blood lymphocytes or cultured skin
fibroblasts (<10% in affected patients)
1. Nutrition consultation and consideration of feeding tube placement
2. Occupational, physical, and speech therapy
3. Ophthalmologic examination
4. Neurodevelopmental assessment
5. Laboratory monitoring of liver function tests, complete blood count,
and lipid profile
6. Pulmonary function testing and chest x-rays
7. Bone age assessment
8. Consultation with medical genetics team and counselor
9. Older kids should avoid contact sports to prevent splenic rupture
V. Niemann-Pick type C (NPC)
A. Pathogenesis
1. Defect in cholesterol transport from lysosomes
6S. Lipid Storage Disease

2. Accumulation of sphingolipids and low-density lipoprotein cholesterol
in lysosomes due to impaired efflux of these compounds from the
lysosome
3. >90% of cases due to alterations in NPC1 gene or, rarely, due to NPC2
gene mutations
Table of Contents
4. Prevalence is 1:150,000 in Western Europe 6S

1. Highly variable clinical phenotype 497
a. Classical presentation in early to mid-childhood: ataxia, seizures,
gaze disturbances, and dementia
b. Neonates may present with cholestatic liver disease,
hepatosplenomegaly, ascites, and hypotonia; cirrhosis often
develops
2. Hepatosplenomegaly is less common in childhood and adulthood
3. Dysphagia and dysarthria is progressive
C. Diagnosis
1. Molecular genetic testing for pathogenic variants in NPC1 (~95% of
cases) or NPC2 (~5% of cases) is standard
2. Sphingomyelinase activity in cultured skin fibroblasts is subnormal
3. Bone marrow biopsy reveals foamy Niemann-Pick cells and “sea-
blue” histiocytes with distinctive histochemical and ultrastructural
appearances
a. Findings variable in liver
b. Liver biopsy: features commonly seen in idiopathic neonatal
hepatitis, e.g., giant cell transformation
c. Cholesterol ester crystals may be observed in autophagosomes
on electron microscopic examination (Figure 1)
1. Nutrition consultation and consideration of feeding tube placement
2. Occupational, physical, and speech therapy
3. Regular bowel regimen for older kids and adolescents
FIGURE 1 NPC in an Infant

*
A B A Isonicotinic acid hydrazide (INH)-like appearance
includes giant cell transformation and extramedullary
hematopoiesis. Lipid inclusions are inconspicuous.
Hematoxylin and eosin (H&E).
B Kupffer cells may be conspicuously enlarged due to
accumulation of secondary lysosomes and lipid.
C C Hepatocytes contain large autophagosomes not
unlike those that may be seen in INH. Inset: autophagy
accompanied by cholesterol crystal profiles.
Electron microscopy. Pathology of Pediatric
Gastrointestinal and Liver Disease, The liver in
metabolic disease, 2nd ed., 2014, p. 524, Bove KE,
© Springer with permission of Springer. Photos
courtesy of Milton Finegold, MD.
SECTION 6: Liver
4. Referral to neurologist and pulmonologist
5. Consultation with medical genetics team
VI. Gaucher disease

Table of Contents
1. Caused by a deficiency of acid β-glucosidase (GBA1 gene) 6S

2. Occurs in ~1 in 50,000 live births, but incidence as high as 1 in 855 in
Ashkenazi Jews 498
3. Most common lipid storage disorder
4. Accumulation of glucosylceramide in macrophages in visceral organs,
mostly derived from turnover of cell membranes of leukocytes,
erythrocytes, and platelets
5. Gaucher cells are engorged macrophages containing tubular inclusions
that resemble wrinkled tissue paper on liver and bone marrow biopsies
6. Gaucher cells → inflammation and development of fibrotic changes
1. Type 1 (nonneuronopathic type)—most common; occurs in Ashkenazi
Jews
a. Symptom onset from childhood to adulthood
b. Characterized by massive organomegaly, bone disease
(osteopenia and osteonecrosis), and lung disease
c. Symptoms can be mild or may live well into adulthood
2. Type 2 (acute neuronopathic and infantile type)
a. Onset occurs within 3 months of life
b. Massive organomegaly, abnormal eye movements, and seizures
c. Death usually occurs by 2–4 years of age
3. Type 3 (chronic neuronopathic type)—with milder and more slowly
progressive neurological symptoms and variable age of onset,
organomegaly, and skeletal abnormalities
4. Perinatal-lethal and cardiovascular forms also exist
5. Hepatosplenomegaly almost universal
6. ↑ serum aminotransferases and alkaline phosphatase
7. Portal hypertension and cirrhosis are unusual
8. Severe cytopenias due to splenomegaly and accumulation of Gaucher
cells in bone marrow
9. Cholesterol cholelithiasis
C. Diagnosis
1. Glucocerebrosidase (glucosylceramidase) enzyme activity in peripheral
blood leukocytes, or other nucleated cells, is the gold standard
2. Molecular genetic testing for mutations in GBA gives prognostic
information
3. Liver biopsy shows Kupffer cells and portal macrophages containing
weakly periodic acid-Schiff (PAS)-positive material with distinctive
“crinkled paper” appearance
1. Enzyme replacement therapy is available for type 1 and 3 diseases
2. Twice-monthly IV therapy dramatically ↓ organomegaly and skeletal
abnormalities and prolongs the life of these patients

3. Currently, there is no treatment for the neurological damage caused by
type 2 and 3 Gaucher disease
VII. Lysosomal acid lipase (LAL) deficiency

Table of Contents
A. Pathogenesis 6S
1. LAL deficiency results in accumulation of cholesteryl esters and
triglycerides in organs, → damage to cells and tissues 499
2. Wolman disease and cholesterol ester storage disease (CESD) are both
caused by LAL deficiency
1. Wolman disease is fatal by age 1—severe
2. Infants have massive organomegaly, mental deterioration, distended
abdomen, steatorrhea, jaundice, anemia, and vomiting
3. May have deposits of calcium in adrenal glands
4. CESD results in liver disease with variable rates of progression—slower
progression. May result in cirrhosis.
5. Affected individuals commonly have hypercholesterolemia and at risk
for developing atherosclerosis
C. Diagnosis
1. LAL enzyme activity in peripheral blood cells or liver tissue
2. LIPA gene sequencing
3. Liver biopsy: lipid contained in membrane-bound vesicles (unlike
usual hepatocyte lipid) that is faintly visible on H&E stain and highly
conspicuous on unstained frozen sections examined under polarized
light
D. Treatment/management
1. Treatment of hyperlipidemia with diet and/or medications
(cholestyramine and statins)
2. Management of complications of progressive liver fibrosis or cirrhosis,
including liver transplantation in some cases
FIGURE 2 Cholesterol Ester Storage Disease

*
A B A Hepatocytes are slightly pale and variably
vacuolated. Portal area to left contains plump
macrophages containing granular lacy
amphophilic material. H&E stain.
B Hepatocytes have expanded vacuolated
cytoplasm. Scattered Kupffer cells contain
abundant PAS-positive diastase-resistant
residual bodies. PAS stain after diastase
digestion.
C Frozen section of liver with massive
C D accumulation of cholesterol ester crystals.
Unstained. Polarized light.
D Hepatocyte lipid accumulates in membrane-
bound vesicles (lysosomes), unlike usual
hepatic lipid. Pathology of Pediatric
Gastrointestinal and Liver Disease, The liver in
metabolic disease, 2nd ed., 2014, p. 523, Bove
KE, © Springer with permission of Springer.
SECTION 6: Liver
Recommended Reading
Baris HN, Cohen IJ, Mistry PK. Gaucher disease: the metabolic defect, pathophysiology,
phenotypes and natural history. Pediatr Endocrinol Rev. 2014;12 Suppl 1:72-81.
Table of Contents
Bernstein DL, Hülkova H, Bialer MG, et al. Cholesteryl ester storage disease: review of the 6S
findings in 135 reported patients with an underdiagnosed disease. J Hepatol.
2013;58:1230-1243. 500
Bove KE. The liver in metabolic disease. In: Russo P, Ruchelli ED, Piccoli DA, eds.
Pathology of Pediatric Gastrointestinal and Liver Disease, 2nd ed. Berlin, Heidelberg:
Springer-Verlag; 2014, pp. 503-546.
Grabowski GA. Gaucher disease and other storage disorders. Hematology Am Soc Hematol
Educ Program. 2012;2012:13-18.
Hoffman EP, Barr ML, Giovanni MA, et al. Lysosomal acid lipase deficiency. GeneReviews.
Web site. National Center for Biotechnology Information Web site. http://www.ncbi.nlm.nih.
gov/books/NBK305870/. Published July 20, 2015. Accessed June 6, 2016.
Patterson MC, Hendriksz CJ, Walterfang M, et al. Recommendations for the diagnosis and
management of Niemann-Pick disease type C: an update. Mol Genet Metab.
2012;106:330-344.
Schuchman EH. The pathogenesis and treatment of acid sphingomyelinase-deficient

Niemann-Pick disease. J Inherit Metab Dis. 2007;30:654-663.
Schuchman EH, Wasserstein MP. Types A and B Niemann-Pick disease. Best Pract Res Clin
Endocrinol Metab. 2015;29:237-247.
van Meer G, Wolthoorn J, Degroote S. The fate and function of glycosphingolipid

glucosylceramide. Philos Trans R Soc Lond B Biol Sci. 2003;358:869-873.

SECTION
6T
Systemic Diseases Affecting the Liver

Table of Contents
6T
Alyssa Kriegermeier, MD 501
Elizabeth Rand, MD
Previous edition authors: Sheree Watson, MD and Christine Waasdorp Hurtado, MD
Liver disease may result secondarily from or in association with a wide variety of
extrahepatic processes.
I. Cardiovascular diseases/disturbances
A. Congestive hepatopathy results from passive hepatic congestion from right-

sided heart failure (mitral stenosis, tricuspid regurgitation, pulmonary arterial
hypertension, cardiomyopathy, and constrictive pericarditis) or chronically
↑ central venous pressure as in post-Fontan circulation
1. Patients typically asymptomatic but develop hepatomegaly
2. Laboratory: typically modest (2–3× normal) ↑ aspartate
aminotransferase (AST), alanine transaminase (ALT),
γ-glutamyltransferase (GGT), alkaline phosphatase, and total bilirubin
3. Histology: classic gross finding is “nutmeg liver” due to hemorrhagic
centrilobular area (zone 3) alternating with either areas of steatosis or
normal liver in zones 1 and 2; also notable sinusoidal dilatation without
inflammation on histology. Long standing disease can → fibrosis and
cirrhosis.
4. Treatment: aimed at underlying cardiac disease and use of diuretics if
fluid overloaded
B. Ischemia/hypoperfusion injury occurs as a result of acute hypotension,
severe hypoxemia, or localized interruption of hepatic blood supply (e.g.,
septic shock, respiratory failure, cardiac arrest, hepatic sickle cell crisis, and
hepatic artery thrombosis after transplant)
1. Though usually seen together, hepatic ischemia and hypoperfusion
may exist independently, particularly in complex congenital heart
disease. Clinical and histologic findings overlap considerably.
2. Hepatocellular injury presents with significantly ↑ ALT/AST, which
typically peak 1–3 days after incident and return to normal <5–10 days
3. Significant ↑ in bilirubin and alkaline phosphatase also seen after acute
transaminase elevations and synthetic liver dysfunction seen if injury is
severe/prolonged
4. Histology: centrilobular necrosis of zone 3 hepatocytes in absence of
histological evidence of inflammation
5. Liver biopsy: not recommended if clinical picture is consistent with
ischemic hepatitis
SECTION
SECTION6:6:Liver
Liver
6. Injury usually self-limited if there is correction of underlying
circulatory/respiratory derangements
C. Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)
is an autosomal dominant group of disorders characterized by vascular
malformations of the skin, mucous membranes, and internal organs
Table of Contents
1. Liver involvement noted in up to 75% of patients; however, <10% are 6T

symptomatic. Symptoms depend on type of malformation.
a. Hyperdynamic circulation → high-output cardiac failure from 502
arteriovenous (A-V) or portovenous (hepatic artery or portal vein
to hepatic vein) malformations
b. Clinical: hepatomegaly or hepatic bruit on physical examination
c. Noncirrhotic portal hypertension and complications, e.g.,
hypertensive gastropathy and variceal formation caused by
arterioportal shunting due to ↑ sinusoidal blood flow
d. Biliary ischemia and resultant strictures, cholestasis, and
cholangitis result from diversion of blood flow from the hepatic
artery in A-V or arterioportal malformations (as biliary arterial
supply arises from hepatic artery)
2. Treatment: medical management of complications from hepatic
vascular malformations, and if refractory to medical treatment, then
liver transplantation is the only definitive cure
II. Granulomatous diseases
A. Sarcoidosis is a multisystem disorder of unknown etiology not commonly

seen in children. It is characterized by noncaseating granulomas most
often in lungs and lymph nodes but can also occur within the liver (3rd most
common site; 50%–80% patients)
1. Liver involvement is mostly asymptomatic but → to portal
hypertension, intrahepatic cholestasis, Budd-Chiari syndrome, and
extrahepatic biliary obstruction
a. Portal hypertension is thought to be caused by A-V shunts
around granulomas, leading to ↑ portal blood flow, ↑ resistance
due to intrahepatic granulomas, and granulomatous phlebitis →
ischemia and fibrosis
b. Intrahepatic cholestasis may be confused with primary biliary
cirrhosis (PBC) and primary sclerosing cholangitis (PSC), which
both can occur with sarcoidosis
1) PBC may be differentiated from sarcoidosis, as the
majority of PBC patients have a positive antimitochondrial
antibody (AMA)
2) PBC also more common in females, and typical biopsies
show few granulomas with significant mixed cell
infiltrate/destruction of bile ducts, whereas biopsies from
sarcoid patients typically have limited bile duct damage
but with many granulomas
3) Compared to PSC, sarcoid patients typically lack periductal
6T. Systemic Diseases Affecting the Liver

fibrosis and their bile duct narrowing occurs within a single
area of the biliary system
c. Budd-Chiari syndrome can occur due to narrowing of intrahepatic
veins from compression by granulomas or occlusion by
2o thrombosis
Table of Contents
d. Extrahepatic biliary obstruction has been reported rarely due to 6T

compression of common hepatic duct by granulomas
2. Patients with asymptomatic liver involvement do not require treatment 503
3. Symptomatic patients may respond to steroid therapy, though this
often does not alter progression of disease
4. Azathioprine, methotrexate (MTX), hydrochloroquine, and infliximab
also possible treatments
5. Splenectomy for severe portal hypertension
B. Chronic granulomatous disease is a primary immunodeficiency due
to defects in nicotinamide adenine dinucleotide phosphate oxidase
characterized by recurrent bacterial/fungal infections and tissue granuloma
formation
1. Liver involvement includes granulomas and abscesses most commonly
but also lobular hepatitis, rarely ascites, and noncirrhotic portal
hypertension
III. Connective tissue diseases
A. Systemic lupus erythematosus (SLE) is a chronic immune-mediated

multisystem disease that affects skin, joints, kidneys, lungs, central nervous
system, serous membranes, and other organs
1. Liver involvement occurs in 25%–50% patients at some point but not
required for diagnosis
2. Primary liver involvement typically manifests as ↑ liver enzymes,
though can present as jaundice, ascites, and potentially liver failure
3. Drug-related abnormalities are also common (MTX, nonsteroidal anti-
inflammatory drugs [NSAIDs], and salicylate)
4. Liver vascular disorders (Budd-Chiari and hepatic infarction) also seen
in those who develop antiphospholipid antibodies
5. Histology: small vessel vasculitis, nonspecific portal inflammation,
chronic active hepatitis, hepatic steatosis, nodular regenerative
hyperplasia (NRH), and rarely cirrhosis, though some findings may
be 2º to treatment (i.e., steatosis due to steroids) or viral hepatitis in
setting of immunosuppression
6. Can be confused with autoimmune hepatitis (AIH) clinically and
through laboratory as antinuclear antibodies seen in both AIH and SLE
7. Anti-smooth muscle (anti-F-actin) and antimicrosomal antibodies
(anti-LKM) are more common in AIH, whereas antiribosomal P protein
antibodies more consistent with SLE hepatitis
8. Liver biopsy should be performed to fully evaluate for AIH when
diagnosis is in question
9. SLE hepatitis generally improves with treatment of SLE
SECTION 6: Liver
B. Juvenile idiopathic arthritis (JIA) is a systemic inflammatory disease involving
joints and often extra-articular manifestations
1. Liver involvement not usually significant in JIA, but can present as
↑ alkaline phosphatase (unclear etiology)
2. Histology: often normal but can show NRH, mild portal chronic
Table of Contents
inflammatory, and fatty infiltration 6T

3. Abnormal biopsy findings may be secondary to treatment (NSAIDs,
MTX, and steroids) rather than disease itself 504
C. Sjögren syndrome is an autoimmune disease that primarily affects salivary
and lacrimal ducts
1. Liver involvement is a common, nonexocrine feature of Sjögren
syndrome, which can present with ↑ aminotransferases or ↑ alkaline
phosphatase
2. AIH and PBC also seen with Sjögren syndrome
3. Positive AMAs a sensitive indicator of liver disease in Sjögren
syndrome, as patients with positive AMA often have biopsy findings of
early PBC, even with normal liver enzymes
D. Systemic scleroderma (systemic sclerosis) is an autoimmune disease
leading to tissue fibrosis and vasculopathy of multiple organ systems.
Calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and
telangiectasia (CREST) syndrome is a subset of scleroderma that presents
with subcutaneous CREST
1. PBC is associated with scleroderma (and CREST), so AMAs should be
considered
IV. Endocrinopathies
A. Hyperthyroidism can be due to Grave disease, thyroiditis, or thyroid nodules
1. Liver abnormalities in hyperthyroidism are not uncommon (reports
ranging from 15%–80%) and often exacerbated if cardiac function
compromised by thyrotoxicosis
a. Hepatocellular injury occurs most commonly, but patients can
present with cholestasis
2. Histology in thyrotoxicosis: nonspecific and can show mild centrilobular
cholestasis, lobular inflammation, and fatty infiltration
3. Liver abnormalities typically resolve with treatment
4. Treatment with propylthiouracil can cause ↑ transaminases in up to 1/3
of patients and is typically dose dependent
5. Methimazole can cause liver injury less commonly
6. Patients with Grave disease have ↑ risk of PBC and AIH, which should
be considered if liver abnormalities do not respond to antithyroid
treatment
B. Hypothyroidism can be due to Hashimoto thyroiditis, treatment of
hyperthyroidism, surgery, and pituitary dysfunction
1. Abnormal liver tests common in hypothyroidism and can occur as
↑ aminotransferases but also cholestasis due to ↓ bile excretion
2. Rarely diuretic refractory ascites can occur due to myxedema ascites in
the absence of cirrhosis—ascites fluid has a ↑ protein content with
↓ serum-ascites albumin gradient and predominant lymphocytes

3. Histology: usually normal, but can see centrilobular cholestasis and
rarely fibrosis with long-standing disease and cardiac involvement
4. Hormone replacement typically leads to resolution of abnormalities,
including ascites, but may take months
C. Adrenal insufficiency (Addison disease)
Table of Contents
1. Liver involvement is typically asymptomatic but can often see mild ↑ in 6T

aminotransferases (2–3× normal), which resolve with treatment
D. Adrenal excess (Cushing disease or syndrome) → to nonalcoholic fatty liver 505
disease
E. Autoimmune polyendocrine syndrome type 1 (a.k.a. autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy [APCED]) can be
associated with many autoimmune syndromes, including AIH
V. Ciliopathies
(autosomal recessive polycystic kidney disease [ARPKD], autosomal dominant
polycystic kidney disease, nephronophthisis, Joubert syndrome, Bardet-Biedl
syndrome, Meckel-Gruber syndrome, and Jeune syndrome) are genetic disorders
with defective production of proteins, leading to abnormal/dysfunctional cilia
A. Phenotypes are heterogeneous and often involve retinal degeneration,

renal disease, and cerebral anomalies, and several can be associated with
congenital hepatic fibrosis
B. ARPKD is most common occurring ciliopathy. Up to 70% of patients with
ARPKD have associated congenital hepatic fibrosis (see Section 6Cii.
Cholestasis in Older Children)
VI. Hematologic/oncologic disease

A. Acute/chronic graft-versus-host disease (GVHD) is an immune-mediated
reaction of donor cells against host tissues after allogenic stem cell transplant
and can involve the skin, liver, GI, eye, lungs, and pancreas (liver is 2nd most
common after skin) (see Section 4F. Graft versus Host Disease)
1. Laboratory: ↑ aminotransferases but also frequently early ↑ alkaline
phosphatase, bilirubin, and GGT reflective of bile duct damage
2. Histology in acute GVHD: active inflammatory bile duct damage with
lobular hepatitis and endotheliitis similar to acute cellular rejection in
liver transplant recipients
3. Histology in chronic GVHD: bile duct loss and absence of acute
inflammation (as well as chronic rejection)—however, acute and
chronic histologic definitions may not correlate with the clinical
definitions of acute versus chronic GVHD
B. Hemophagocytic lymphohistiocytosis is a syndrome of excessive immune
activation with activated macrophages and impaired functioning of natural
killer cells and cytotoxic T cells, leading to inflammation
1. Presentation: fevers and multiple organ system involvement (e.g.,
lymphadenopathy, rash, hepatomegaly, and neurologic symptoms)
2. Neonates can present with hydrops fetalis
3. Should be considered in infants and children with acute liver failure
4. Nearly all patients have liver involvement with evidence of hepatitis
SECTION 6: Liver
5. Laboratory: ↑ bilirubin and GGT. With disease progression and
worsening hepatic insufficiency, can see hypertriglyceridemia,
coagulopathy, and disseminated intravascular coagulation.
6. Histology: hemophagocytosis and periportal lymphocytic infiltration
7. Treatment: crucial and includes chemotherapeutic agents and
Table of Contents
treatment of underlying trigger (especially Epstein-Barr virus) if one is 6T

identified, but patients may require stem cell and/or liver transplant
C. Leukemia 506
1. Patients often have hepatomegaly due to leukemic infiltrate (in
advanced disease 95% of acute lymphocytic leukemia, 75% of acute
myeloid leukemia)
2. Biopsy is typically not recommended due to bleeding risk
D. Sickle cell disease (SCD) can result in 1º or 2º liver injury
1. 1º hepatic complications: acute hepatic crisis, hepatic sequestration,
and intrahepatic cholestasis
2. 2º complications: risk for transmitted infections (hepatitis B and C) and
excessive iron stores from chronic transfusions
3. Laboratory: ↑ unconjugated bilirubin due to chronic hemolysis and risk
for cholelithiasis, choledocholithiasis, and cholecystitis
4. Acute hepatic sickle crisis (reflecting biliary or hepatic ischemia) occurs
in up to 10% of patients and presents with RUQ pain, hepatomegaly,
jaundice, and fevers in addition to ↑ transaminases and bilirubin.
Typically resolves with supportive care of crisis (hydration and pain
management).
5. Liver biopsies: discouraged during acute crisis due to significant risk of
hemorrhage
6. Sickle cell intrahepatic cholestasis is a rare but severe complication of
SCD and can be lethal
a. Presentation: RUQ pain, hepatomegaly, fevers, and leukocytosis
but go on to develop striking jaundice, despite mild-moderate
↑ in aminotransferases and direct bilirubin liver enzymes, in
addition to renal impairment, coagulopathy, and may develop
encephalopathy
b. The pathophysiology is likely similar to hepatic crisis, starting with
hepatic sickling, causing vascular stasis and eventually leading to
hepatocyte ballooning and intracanalicular cholestasis
c. Treatment: exchange transfusion and correction of coagulopathy
with products such as fresh frozen plasma
7. Hepatic sequestration crisis, similar to splenic sequestration, where
large numbers of red blood cells are sequestered in the liver
a. Presentation: RUQ pain and progressive hepatomegaly but with
noticeably declining hematocrit and can → hypovolemic shock
b. Treatment: cautious transfusions with attention to
posttransfusion hemoglobin level as patients may autotransfuse
(within hours to days) and develop complications from
hyperviscosity syndrome
8. SCD is increasingly recognized in association with inflammatory bowel
disease and PSC

VII. Kawasaki disease is a vasculitis in children of unknown etiology, presenting
with fever and typically rash, mucus membrane changes, conjunctival injection,
extremity changes, and lymphadenopathy
A. Liver involvement is common, up to 50%, but typically asymptomatic with

Table of Contents
mild to moderate ↑ in liver enzymes 6T

B. Rarely patients can have severe cholestatic hepatitis, gallbladder hydrops,
and acalculous cholecystitis 507
C. Liver manifestations typically improve with treatment of disease
(IV immunoglobulin and high-dose aspirin) but may require percutaneous
biliary drainage or cholecystectomy
Recommended Reading
Fouad YM, Yehia R. Hepato-cardiac disorders. World J Hepatol. 2014;6:41-54.
Maheshwari A, Thuluvath PJ. Endocrine diseases and the liver. Clin Liver Dis.
2011;15:55-67.
Malnick S, Melzer E, Sokolowski N, et al. The involvement of the liver in systemic diseases.
J Clin Gastroenterol. 2008;42:69-80.
Selmi C, De Santis M, Gershwin ME. Liver involvement in subjects with rheumatic disease.
Arthritis Res Ther. 2011;13:226.
Tan CB, Rashid S, Rajan D, et al. Hepatic sarcoidosis presenting as portal hypertension
and liver cirrhosis: case report and review of the literature. Case Rep Gastroenterol.
2012;6:183-189.
Weisberg IS, Jacobson IM. Cardiovascular diseases and the liver. Clin Liver Dis.
2011;15:1-20.
SECTION 6: Liver

Higado 2

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Higado 2

Загружено:

Авторское право:

Доступные форматы

SECTION

Bile Acid Synthetic Defects

A. Bile acids (BAs) are synthesized in hepatocytes from cholesterol through 14

A. BA synthetic defects should be considered in all cholestatic infants

cholestatic infants 6Ni

A. Requires high index of suspicion

A. Give BAs to activate negative feedback mechanism and hinder further

VI. β-hydroxy C-27 steroid oxidoreductase/dehydrogenase

6Ni. Bile Acid Synthetic Defects

VII. Oxysterol 7α hydroxylase deficiency

VIII. Δ4-3 oxosteroid 5β reductase deficiency

A. Δ4-3 oxosteroid 5β reductase catalyzes conversion of the intermediates 7α

IX. Cerebrotendinous xanthomatosis

A. A defect in BA side chain modification

A. Defect results in inhibition of cholesterol side chain oxidation

XI. BA conjugation (amidation) defects

A. Conjugation of cholic and chenodeoxycholic acid into taurine and glycine is

6Ni. Bile Acid Synthetic Defects

FIGURE 1 Galactose Metabolization

III. Hereditary fructose intolerance

6Nii. Disorders of Carbohydrate Metabolism (Glycogen Storage)

F. Aldolase B is expressed in liver, kidney, and small intestine 6Nii

IV. Fructose 1,6-bisphosphatase deficiency

V. Glycogen storage disease (GSD)

Hypoglycemia and metabolic

Ib Glucose Ib—neutropenia and recurrent

Milder than GSD I; tolerate

Classic progressive liver

Most commonly present 1–5

6Nii. Disorders of Carbohydrate Metabolism (Glycogen Storage)

6Nii. Disorders of Carbohydrate Metabolism (Glycogen Storage)

Disorders of Amino Acid Metabolism

II. Hepatorenal tyrosinemia (hereditary tyrosinemia type 1)

coagulopathy, hypoglycemia, and hypoalbuminemia 6Niii

6Niii. Disorders of Amino Acid Metabolism

III. Other forms of tyrosinemia

6Niii. Disorders of Amino Acid Metabolism

Disorders of Lipid Metabolism

I. The β-oxidation cycle is a 4-enzyme-step cyclical process, involving 2 6Niv

6Niv. Disorders of Lipid Metabolism

associated with an acute infection or illness 6Niv

IV. Physical examination

a. Better prognosis than AFLP 6Niv

A. Newborn screening using a tandem mass spectrometric acylcarnitine profile

6Niv. Disorders of Lipid Metabolism

A. Those who present in neonatal period have a poor prognosis

prevent acute episodes 6Niv

6Niv. Disorders of Lipid Metabolism

2. Lacks protective histones 6Nv

6Nv. Mitochondrial Disorders

FADH2 FAD + 2H+ H+

NADH NAD+ + H+ ADP+P ATP

A: The oxidative phosphorylation chain.

highly eosinophilic; progressive portal fibrosis; electron

the few diseases related to alterations in mtDNA and not 6Nv

6Nv. Mitochondrial Disorders

Hematoxylin and Eosin Stain of a Liver Biopsy from a 2-Month-Old Male

Cambridge University Press; 2014.

6Nv. Mitochondrial Disorders

Urea Cycle Defects

Einar Hafberg, MD 465

II. Urea cycle defect

III. Clinical features