Hepatic Inborn Errors Of Metabolism

1
Hepatic Inborn Errors Of Metabolism

• Dr.Mona El Raziky
• M.D. Pediatric Hepatology
• Nasser Institute For Research Treatment

2
When To Suspect Metabolic Liver Disease?

• jaundice,
• hepatomegaly,
• splenomegaly,
• hepatic failure,
• hypoglycemia,
• organic acidemia,
• hyperammonemia,
• hypoprothrombinemia,
• recurrent vomiting,

• failure to thrive or short stature,
• dysmorphic features,
• developmental delay hypotonia,
• neuromuscular deterioration,
• seizures,
• unusual odors,
• rickets,
• or cataracts.

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When To Suspect Metabolic Liver Disease?

• Clinical and laboratory examination can be
  complemented by analysis of tissue obtained by
  liver biopsy.
• This analysis may confirm the suspicion or alert
  the clinician to new possibilities and allow
  enzyme assay and qualitative and quantitative
  assay of stored material. This information will
  have important genetic implications.

4
Differential Diagnosis of Neonatal Cholestasis

• Metabolic
• Disorders of amino acid metabolism
• Tyrosinemia
• Disorders of lipid metabolism
• Wolman's disease
• Nicmann-Pick disease (type C)
• Gaucher's disease
• Disorders of carbohydrate metabolism
• Galactosemia
• Fructosemia
• Glycogenosis IV
• Disorders of bile acid biosynthesis (reductase,
  isomerase)

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Differential Diagnosis of Neonatal Cholestasis

• Other metabolic defects
• Alpha1 -antitrypsin deficiency
• Cystic fibrosis
• Idiopathic hypopituitarism
• Hypothyroidism
• Zellweger (cerebrohepatorenal) syndrome
• Neonatal iron storage disease
• Indian childhood cirrhoris
• infantile copper overload
• Familial erythrophagocytic
• Lymphohistiocytosis
• Arginase deficiency
• Mitochrondrial DNA depletion

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Metabolic Liver Disease

• Most patients with metabolic liver disease
  present in infancy with either
• Cholestasis (alpha1 -antitrypsin deficiency,
  Niemann-Pick disease, cystic fibrosis),
• Acute liver failure (mitochondrial
  disorders,neonatal hemochromatosis,
  galactosemia),
• Multisystem disease (glycogen storage disease).

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Causes of Conjugated Hyperbilirubinemia in Older
Children

• Viral Infections
•    Hepatitis viruses A, B, C, D, E
•    Epstein-Barr virus
•    Cytomegalovirus
•    Herpes simplex
• Metabolic Liver Disease
•    Wilson disease
•    Alpha-1-antitrypsin deficiency
•    Cystic fibrosis
• Biliary Tract Disorders
•    Cholelithiasis
•    Cholecystitis
•    Choledochal cyst
•    Sclerosing cholangitis

• Autoimmune Liver Disease
•    Type 1 (anti-smoooth muscle antibody)
•    Type 2 (anti-liver-kidney-microsomal antibody)
• Hepatotoxins
•    Drugs Acetaminophen
•       Anticonvulsants
•       Anesthetics
•       Antituberculous agents
•       Chemotherapeutic agents
•       Antibiotics
•       Oral contraceptives
•    Other Alcohol, insecticides, organophosphates
• Vascular Causes
•    Budd-Chiari syndrome
•    Veno-occlusive disease

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Tyrosinemia

• Recessive inherited metabolic liver and kidney
  disease
• Deficiency of fumarylacetoacetate hydrolase (FAH)
  .
• Accumulation of the reactive metabolites
  fumarylacetoacetate and maleylacetoacetate and
  their reduced derivatives succinylacetoacetate
  and succinylacetone
• Succinylacetone is a potent inhibitor of
  porphobilinogen synthase.

9
Tyrosine degradation pathway indicating the
level of metabolic block in tyrosinemia type I by
loss of fumarylacetoacetate hydrolase (FAH) and
the site of inhibition induced by
2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cycloheax
anedione (NTBC)
10
Tyrosinemia

• The clinical spectrum of the disorder
• Acute liver failure in infancy.
• Slowly progressive liver cirrhosis complicated by
• a high incidence of childhood hepatocellular
  carcinoma (HCC),
• hypophosphatemic rickets caused by kidney tubular
  dysfunction,
• porphyrialike neurologic crisis.

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Tyrosinemia (Diagnosis)

• neonatal liver disease
• coagulopathy
• severe metabolic disturbances
• Serum amino acid patterns may exhibit high levels
  of tyrosine, phenylalanine, proline, and
  methionine. High levels of alpha-fetoprotein are
  characteristic of tyrosinemia.
• In the untreated patient, urinary succinylacetone
  excretion, the pathognomonic sign of tyrosinemia
  type I, is highly variable ranging from barely
  detectable (i.e., lt 1 mmol/mol creatinine) to
  more than 1000 mmol/mol creatinine.

12
Tyrosinemia (Treatment )

• Was confined to treatment with a
• diet restricted in tyrosine and phenylalanine.
  Although dietary treatment may relieve acute
  symptoms and resolve the kidney disease, the
  prognosis remained poor.
• Liver transplantation became widely accepted as
  the only successful treatment
• At this time, a new principle for treatment of
  tyrosinemia type I based on inhibition of
  tyrosine degradation at the level of
  4-hydroxyphenylpyruvate dioxygenase was reported.

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Tyrosinemia (Treatment )

• Since then, the number of patients treated by the
  inhibitor 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3
  -cyclohexanedione (NTBC) has steadily increased,
  and NTBC treatment has become a first-line
  treatment of tyrosinemia type I.
• The urinary succinylacetone level is a very
  sensitive marker for the efficiency of NTBC
  treatment normalization of plasma level takes 2
  to 3 months after the start of treatment.
• NTBC treatment has greatly improved the survival
  of patients with acute tyrosinemia and has
  reduced the need for liver transplantation during
  early childhood.
•  

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Urea Cycle Disorders

• Deficiency of any of the five enzymes in the urea
  cycle results in the accumulation of ammonia and
  leads to encephalopathy.
• Episodes of encephalopathy and associated
  systems are unpredictable and, if untreated, are
  lethal or produce devastating neurologic sequelae
  in long-term survivors.
• Although these disorders do not produce liver
  disease, the consequences of hyperammonemia
  resemble those seen in patients with hepatic
  failure or in a transient interference with the
  urea cycle, as seen in some forms of organic
  acidemias.
• Investigate for hyperammonemia in any infant or
  child with altered mental status

15
The urea cycle Asterisk N-acetyl glutamate
synthetase 1 carbamyl phosphate synthetase 2
ornithine transcarbamylase 3
argininosuccinate synthetase 4
argininosuccinate lyase 5 arginase
16
 
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Urea Cycle Disorders (Diagnosis)

• Cultured skin fibroblasts may be desirable if
  prenatal diagnosis is considered in future
  pregnancies.
• Carbamyl phosphate synthetase I and ornithine
  transcarbamylase (OTC) are not expressed in
  cultured fibroblasts.
• The enzymatic diagnosis of CPSD and OTCD requires
  liver biopsy.
• Biopsy should be done when establishing the
  diagnosis of the first case in a family.

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Evaluation of hyperammonemia in the neonate
THANtransient hyperammonemia of the newborn PC
pyruvate carboxylase PDH pyruvate
dehydrogenase FAO fatty acid oxidation CPSD
carbamyl phosphate synthetase deficiency OTCD
ornithine transcarbamylase deficiency ASA
argininosuccinic acid.
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Urea Cycle Disorders(Treatment)

• Once hyperammonemia is demonstrated in an infant,
• protein-containing feedings should be
  discontinued immediately,
• appropriate supportive care, (mechanical
  ventilation)
• Maximal calories should be provided in the form
  of intravenous glucose and lipids in an effort to
  reduce catabolism.
• Plans should be immediately made to initiate
  hemodialysis in infants who are encephalopathic
  and have plasma ammonia levels over 10 times the
  upper limit of normal.

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Urea Cycle Disorders(Treatment)

• Maintenance therapy
• dietary protein restrictionsupplementation with
  citrulline or arginine the use of drugs
• The primary drug now used( provides an alternate
  pathway for waste nitrogen excretion) for
  maintenance therapy in patients with urea cycle
  disorders is sodium phenylbutyrate (Buphenyl).
• The drug is typically administered four times a
  day in a dose of 0.4 to 0.6 g/kg/day. It is
  supplied as a powder, which can be mixed with
  food or formula, or as a tablet.

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Urea Cycle Disorders(Treatment)

• Liver transplantation for
• Severe neonatal OTC and CPS deficiency.
• Liver failure and cirrhosis in ASL deficiency.
• Failed medical-pharmacologic treatment.
• Pretransplant care by
• aggressively managing intercurrent
  hyperammonemia,
• vaccinations and prophylaxis are given against
  infectious
• appropriate caloric intake
• Gene replacement

22
Niemann-Pick Disease Type C

• Caused by decreased sphingomyelinase, resulting
  in accumulation of sphingomyelin and cholesterol
  in the reticuloendothelial system of many organs,
  including the liver.
• Sixty-five percent of these children will present
  with prolonged cholestasis and hepatosplenomegaly
  in infancy.
• All of these children will develop neurologic
  complications, with a mean age of onset at 5
  years.
• Most children die in early adolescence from
  respiratory rather than hepatic complications.
• Characterized histologically by lipid-laden foam
  cells and stored sphingomyelin in macrophages.

23
Gaucher's Disease

• Autosomal recessive disorder,
• Deficiency of glucosyl-ceramide beta-glucosidase
  is present throughout the phagocyte-mononuclear
  system.
• Hepatosplenomegaly and respiratory, neurologic,
  and bone disease complicate the clinical course.
• Therapy includes enzyme replacement and bone
  marrow or liver transplantation

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Glycogen Storage Disease

• Hepatomegaly growth failure hypoglycemia,
• the typical presenting signs (type 1 is the
  most prevalent type)
• Type 4 (brancher enzyme deficiency), a rare
  disorder, presents with signs of hepatocellular
  dysfunction and liver failure during the first 2
  years of life.
• The diagnosis of glycogen storage disease is
  based on demonstrating the respective enzyme
  deficiency
• All deficiencies are inherited in an autosomal
  recessive pattern except for phosphorylase kinase
  deficiency (type 9), which follows an X-linked
  pattern.

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Glycogen Storage Disease

• Type 1
• Is the most common.
• Deficiency of hepatic glucose 6-phosphatase
  impairs both conversion of glycogen to glucose
  and the formation of glucose from lactate and
  amino acids (gluconeogenesis).
• Affected persons develop profound hypoglycemia
  after short fasting periods, with associated
  lactic acidemia, hyperuricemia, hypophosphatemia,
  and hyperlipidemia.
• Treatment, aimed at preventing fasting
  hypoglycemia, includes a high-starch diet, often
  with nocturnal cornstarch infusions, and
  continuous nasogastric feedings

27
Hereditary Fructose Intolerance

• An autosomal recessive disorder.
• The disorder results from absence or reduction
  of fructose-1-phosphate aldolase beta in liver,
  kidneys, and small intestine.
• Clinical presentation varies from
• severe vomiting, failure to thrive,
  hepatomegaly, and coagulopathy to acute liver
  failure with jaundice, encephalopathy, and renal
  failure
• Treatment is dietary elimination of fructose.

28
Galactosemia

• Deficiency of the intracellular enzyme galactose
  1-phosphate uridyltransferase usually presents
  within the first few days of life,
• with protracted vomiting shortly after the onset
  of lactose feeding.
• If untreated, accumulation of galactose
  1-phosphate and galactitol occurs in several
  organ systems, and infants will succumb to
  hepatic failure.
• Early treatment consists of removing all sources
  of lactose from the diet and will prevent
  complications.

29
Neonatal Hemochromatosis

• Acute liver failure is uncommon in the newborn
  period neonatal hemochromatosis is the most
  common cause.
• Iron accumulation commences in utero, either as a
  consequence of a primary disorder of
  fetoplacental iron handling or as a secondary
  manifestation of fetal liver disease.
• The diagnosis is established by MR imaging and by
  demonstrating iron accumulation in biopsy tissue
  obtained from the minor salivary gland on the
  lower lip.

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Neonatal Hemochromatosis

• Medical management initially involves supportive
  therapy for acute liver failure.
• Treatment with a combination of antioxidants that
  combines N-acetylcysteine, vitamin E, selenium,
  prostaglandin E1 , and desferrioxamine should be
  started as soon as the diagnosis has been
  established. Liver transplantation is usually
  required, and, if successful, is curative.

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Disorders of Mitochondrial Energy Metabolism

• Primary mitochondrial hepatopathies
• Inherited defects in structure or function of the
  hepatocellular mitochondria.
• Maternally inherited mutations or deletions of
  the mitochondrial genome or
• Putative nuclear gene mutations encoding
  electron transport proteins cause defective
  electron transport, oxidative stress, impaired
  oxidative phosphorylation, and other metabolic
  derangements.

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Disorders of Mitochondrial Energy Metabolism

• Primary mitochondrial hepatopathies
• These defects in turn lead to hepatic failure or
  chronic dysfunction.
• Abnormalities of the electron transport chain
  result in cellular ATP deficiency and the
  generation of toxic free radicals.
• In a patient with liver failure, isolated
  deficiencies of the electron-chain enzymes and
  mitochondrial DNA depletion syndromes must be
  considered

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Disorders of Mitochondrial Energy Metabolism

• Secondary mitochondrial hepatopathies
• The mitochondria are major targets during liver
  injury caused by
• metal overload, drugs, toxins, alcohol,oxidants.
• The current treatment of these disorders is
  empiric, involving agents that may improve the
  oxidation-reduction status of mitochondria,
  promote electron flow, or act as mitochondrial
  antioxidants.
• Liver transplantation can be considered in the
  absence of systemic involvement.

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Inborn Errors of Bile Acid Synthesis

• Defects early in the biosynthetic pathway produce
  
• profound neonatal cholestasis
• severe liver dysfunction
• subacute hepatic failure.
  
• The GGTP values are low
• AP and aminotransferase levels are usually
  elevated.
• Diagnosis is reached by qualitative assessment
  of bile acids in serum and urine.
• Early diagnosis permits therapy with exogenously
  administered bile acids, often with dramatic
  results.
  
  
• Liver transplantation, when required, is
  curative.

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Inborn Errors of Bile Acid Synthesis(Types)

• Primary Defects (Enzymopathies)
• Defective transformation of steroid nucleus
• Delta -3-oxosteroid-5beta reductase deficiency
• 3 beta-hydroxy Delta -C27 steroid
  dehydrogenase/isomerase deficiency
• 24,25-dihydroxy cholanoic cleavage enzyme
  deficiency (25-hydroxylase pathway)
• 7-dehydrocholesterol 7-reductase deficiency (the
  Smith-Lemli-Opitz syndrome)
• Deficiency of 7alpha-hydroxylation
• 2. Defective degradation or transformation of
  cholesterol side chain
• cerebrotendinous xanthomatosis (cholesterol
  27-hydroxylase)
• defective amidation?

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Inborn Errors of Bile Acid Synthesis(Types)

• Secondary Defects (caused by organelle damage)
• Peroxisomal disorders
• Generalized hepatic synthetic dysfunction

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Inborn Errors of Bile Acid Synthesis

• The mechanism of cholestasis is thought to be
  either
• (1) underproduction of normal trophic or
  choleretic primary bile acids that are essential
  for the promotion and secretion of bile,
• (2) overproduction of potentially hepatotoxic
  primitive bile acid metabolites.  
• Patients affected by these disorders have
  previously been considered to have idiopathic
  disease (e.g., idiopathic neonatal hepatitis or
  intrahepatic cholestasis).

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Inborn Errors of Bile Acid Synthesis

• Diagnosis
• Fast atom bombardment-mass spectrometry (FAB-MS)
  and gas chromatography-mass spectrometry (GC-MS),
  have allowed specific delineation of disorders of
  bile acid synthesis and subsegmentation of those
  broader categories.
• The bile acid profiles of urine, serum, and bile
  in these patients are characterized by the
  predominance of atypical bile acids retaining the
  structure of the steroid nucleus characteristic
  of the substrates for the inactive or deficient
  enzyme.
•  

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Inborn Errors of Bile Acid SynthesisZellweger's
Syndrome (cerebrohepatorenal)

•  
• Profound psychomotor retardation,
• hypotonia, characteristic facies,
• cortical cysts of the kidneys,
• and intrahepatic cholestasis.
• Hepatomegaly with jaundice in the first 2 to 3
  weeks of life.
• There is absence of hepatic peroxisomes.
• Biochemical features reflecting absent
  peroxisomal function include excessive urinary
  excretion of all precursors of primary bile
  acids that have not undergone side-chain
  oxidation.
• Increased concentrations of C27 bile acid
  intermediates are present in serum and bile.
• Hepatic histologic features cholestasis, lobular
  disarray, and focal liver cell necrosis, often
  with paucity of intrahepatic ducts.

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Inborn Errors of Bile Acid Synthesis(Treatment)

•  
• Bile acid therapy
• when cholic and chenodeoxycholic acid (100 mg
  each per day) were given orally, a significant
  improvement in biochemical and histological
  aspects occurs.

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DEFECTIVE BILE ACID TRANSPORT IN INHERITED
CHOLESTATIC DISEASES

• Byler's Disease (Progressive Familial
  Intrahepatic Cholestasis)
• Byler's disease is a relatively discrete form of
  PFIC characterized by unrelenting progressive
  intrahepatic cholestasis
• The clinical findings in PFIC-1--pruritus, fat
  malabsorption, and low gamma-GTP The coarsely
  granular bile found in canaliculi on transmission
  electron microscopy in PFIC-1 is also suggestive
  of a defect in bile acid transport at the
  canalicular membrane. levels--resemble those seen
  in 3beta-HSD deficiency.

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METABOLIC DISEASE IN OLDER CHILDREN

• Hepatomegaly
• Glycogen storage disease
• Hereditary fructose intolerance
• Acute liver failure
• Wilson's disease
• Alper's disease
• Valproate toxicity

• Chronic liver disease
• (with or without portal hypertension)
• Alpha1 -antitrypsin deficiency
• Cystic fibrosis
• Tyrosinemia type 1
• Wilson's disease
• Gaucher's disease

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Wilson's Disease

• Autosomal recessive disorder of hepatic copper
  metabolism
• The Wilson's gene has been located on chromosome
  13 and encodes a copper-binding,
  membrane-spanning protein with ATPase that
  regulates metal transport proteins.
• Patients usually present with liver disease
  during adolescence however,
• clinical onset may be detected as early as 3
  years of age.
• Features in childhood include hepatic dysfunction
  (40), psychiatric symptoms (35), and renal,
  hematologic, and endocrinologic symptoms. Chronic
  liver inflammation (often confused with
  autoimmune, chronic-active hepatitis), cirrhosis,
  and fulminant hepatic failure are well-described
  complications. The characteristic Kayser-Fleisher
  rings (present in all patients with
  neuropsychiatric symptoms) are not usually
  detected before age 7 years

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Wilson's Disease (Pathology)

• Acute hepatitis submassive or massive necrosis,
  chronic active hepatitis, and macronodular
  cirrhosis.
• Liver cells are ballooned and fatty change is
  usual.
• In some patients, Mallory's bodies simulating
  acute alcoholic hepatitis are observed. The
  disease may also resemble histologically chronic
  active hepatitis analogous to chronic viral
  hepatitis.
• Cirrhosis usually takes two or three decades to
  occur.
• Copper chelation therapy with penicillamine
  usually retards or reverses liver disease
  progression.

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Wilson's Disease

• Diagnosis
• is established by detecting low levels of serum
  copper (lt 20 mug/dl) and low serum ceruloplasmin,
  an increased level of copper in the urine (gt 100
  mug/24 h), and an elevated hepatic copper level
  (gt 250 mug of copper/1 g of liver (dry weight).
• Treatment
• Pharmacologic treatment includes D-penicillamine,
  triethylene tetramine dihydrochloride (tientene
  generally used in D-penicillamine-intolerant
  patients), and oral zinc.
• Liver transplantation has been successful in
  patients with fulminant hepatitis or advanced
  cirrhosis.

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Alper's Syndrome

• Rare disorder that usually presents with sudden
  onset of
• intractable seizures between the ages of 1 and 3
  years.
• This hepatic disease presents as jaundice,
  hepatomegaly, and coagulopathy, with rapidly
  progressive liver failure.
• The condition is uniformly fatal, and liver
  transplantation is contraindicated because
  neurologic deterioration progresses after
  transplantation

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HEREDITARY HEMOCHROMATOSIS (HHC)

• A common inherited disorder of iron metabolism .
• This disorder described in 1886 as bronze
  diabetes is an
• autosomal recessive
• continuous and inappropriate increase in the
  duodenal absorption of ingested iron.
• The genetic defect is on chromosome 6 and the HHC
  gene has been recently cloned.
• The gene defect now can be tested.
• In HHC there is evidence in the liver of
  increased lipid peroxidation possibly the direct
  effect of the oxidizing potential of ferrous iron
  generating active oxygen species and free
  radicals. The target organs that are damaged in
  iron overload, are the liver, heart, pancreas,
  and endocrine organs.

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In the balanced state, 1 to 2 mg of iron enters
and leaves the body each day. Dietary iron is
absorbed by duodenal enterocytes. It circulates
in plasma bound to transferrin. Most of the iron
in the body is incorporated into hemoglobin in
erythroid precursors and mature red cells.
Approximately 10 to 15 percent is present in
muscle fibers (in myoglobin) and other tissues
(in enzymes and cytochromes). Iron is stored in
parenchymal cells of the liver and
reticuloendothelial macrophages. These
macrophages provide most of the usable iron by
degrading hemoglobin in senescent erythrocytes
and reloading ferric iron onto transferrin for
delivery to cells.
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HEREDITARY HEMOCHROMATOSIS (HHC) Clinical
Manifestations

• Variable age of presentation.
• Most patients present with liver disease after
  the fourth decade of life.
• eight to one male to female ratio explainable
  because of iron loss in females from menstruation
  and childbearing.
• In later years, the heart muscle may be affected
  resulting in cardiomyopathy.
• Other non-hepatic organs affected are the joints
  with chondrocalcinosis typically in the
  interphalangeal joints and metacarpophalangeal
  joints as well as the knees to the back of the
  neck.
• The common endocrine organs which exhibit
  dysfunction are the pituitary gland, and the
  pancreas resulting into testicular atrophy,
  infertility, and diabetes mellitus.
• Most patients show increase pigment in the skin
  mainly due to melanin although in 50 of patients
  increases in iron deposits in the basal cells of
  the epidermis and sweat glands are noted

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HEREDITARY HEMOCHROMATOSIS (HHC) Clinical
Manifestations

• LIVER
• This is organ that is most effected. The liver
  damage as evidenced by cell necrosis and
  increased amino transferase enzymes is not usual.
  
• Rather, the liver has increased hepatocyte and
  later biliary epithelial and Kupffer cell iron
  which after three or four decades is associated
  with fibrosis and later cirrhosis. The risk of
  primary liver cancer increases at this point.
• Thus an early diagnosis of this condition which
  is treatable is mandatory.
• When patients are frankly cirrhotic, many show
  also evidence of diabetes and increased
  pigmentation hence the term, bronze diabetes.

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HEREDITARY HEMOCHROMATOSIS (HHC) Clinical
Manifestations

• LIVER
• Classically, when no other causes of liver injury
  co-exists such as alcohol or hepatitis, when
  liver stores of iron exceed 20 g, cirrhosis may
  ensue.
• Normal hepatic iron concentration is usually less
  than 1000 micrograms per gram/dry weight which
  relates to about 2 g of iron stores.
• Patients with cirrhosis have an excess of 22,000
  micrograms/dry weight equivalent to 20 g of
  liver iron stores.

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HEREDITARY HEMOCHROMATOSIS (HHC)

• Diagnosis
• to measure serum iron, iron binding capacity in
  the ferritin in the blood.
• If these are at the high level of normal,
  patients should be followed up.
• If there is an annual increase of serum
  ferritin approximating 50 micrograms per liter
  per year, the patient should have a liver biopsy.
• Liver biopsy yields important information.
• Prussian blue staining of liver hemosiderin
  correlates with iron stores.
• In the absence of infection or acute disease, if
  the serum iron is less than 60 saturated,
  cirrhosis is very unlikely.
• When hemochromatosis is anticipated, the liver
  should be biopsied and a portion should be sent
  in a metal-free container for an absolute iron
  measurement.

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HEREDITARY HEMOCHROMATOSIS (HHC)

• Management
• Iron should be removed by phlebotomy.
• One unit of blood (500ml) removes to about 250 mg
  of iron.
• In contrast, chelation therapy with deferoxamine
  which is expensive and inconvenient is capable of
  removing 60 mg iron a day.
• Because this is a autosomal recessive disease,
  family screening is recommended. All siblings,
  parents, and children over the age of ten should
  be screened with the serum iron, TIBC and
  ferritin.
• Saturation greater than 50 with an increasing
  serum ferritin is an indication for liver biopsy.
  

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ALPHA-ONE ANTITRYPSIN (AAT) DEFICIENCY

• Is a relatively common autosomal recessive
  disorder,
• It is the most common genetic cause of liver
  disease in children
• The most frequent genetic diagnosis for which
  children undergo liver transplantation.
• AAT synthesized in the endoplasmic reticulum of
  the liver and comprises 80 - 90 of the serum
  alpha-one globulin.
• It is an inhibitor of trypsin and other
  protease.
• Deficiency results in unopposed action of these
  enzymes.
• The lungs are the main target with damage to the
  alveoli resulting in emphysema. The liver
  pathology ranges from acute liver damage, chronic
  active hepatitis, or cirrhosis.

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ALPHA-ONE ANTITRYPSIN (AAT) DEFICIENCY

• The gene for AAT is on chromosome 14 and there
  are about 75 different alleles at this locus.
• M is the most common normal allele,
• Z and S are the most frequent abnormal alleles.
• Pi (protease inhibitor) MM is the normal state
  with normal serum AAT levels.
• Pi ZZ results in a low concentration of serum
  AAT. Pi Null-Null (NN) gives zero levels. Both
  predispose to emphysema. Pi SS and Pi MZ give
  levels about half normal with no lung disease.
• Liver disease tends to occur with mutations where
  AAT accumulates in the hepatocytes, detectable as
  PAS positive granules on special staining of
  liver biopsy tissue.

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ALPHA-ONE ANTITRYPSIN (AAT) DEFICIENCY

• The disease in the liver can present as neonatal
  cholestasis, acute hepatitis, fulminant hepatic
  failure, or chronic active hepatitis and
  cirrhosis.
• The classic subtype for this is Pi ZZ and
  therefore, liver disease is commonly associated
  with lung disease.
• Liver injury is caused by the toxic effect of the
  mutant molecule alpha1 ATZ retained within the
  endoplasmic reticulum (ER) rather than secreted
  into the blood and body fluids.
• Recent basic cell biologic studies have shown
  that the ER quality control system is extremely
  sophisticated It is not surprising, then, that
  there are several different genetic and
  biochemical mechanisms by which the quality
  control system can be altered and an alpha1
  AT-deficient host be rendered susceptible to
  liver injury.

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ALPHA-ONE ANTITRYPSIN (AAT) DEFICIENCY

• Diagnosis
• The diagnosis is suspected by reduced AAT levels
  in the plasma and confirmed as liver biopsy.
• Treatment
• There is no specific treatment for the liver
  lesion
• Hepatic transplantation is required at the end
  stage of liver disease.

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CYSTIC FIBROSIS

• An autosomal recessive pattern of inheritance
  with a prevalence of one in 2,000 and a carrier
  rate of 5.
• Is the most common heritable disorder among white
  populations,
• Is the most common disorder in which the primary
  defect affects cholangiocyte transport systems.
• Is the cause of prolonged cholestasis in
  approximately 1 of newborns with obstructive
  jaundice.
• The gene responsible is on chromosome 7 and has
  been cloned.
• The product is a transmembrane protein regulating
  ion conductance.

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CYSTIC FIBROSIS

• prolonged cholestasis respiratory disease
  
• or meconium ileus
• Approximately 20 of patients develop liver
  disease including fatty change, focal biliary
  fibrosis, multi-lobular biliary cirrhosis due to
  viscous bile resulting in extrahepatic portal
  obstruction and secondary biliary cirrhosis.
• The main target organ of this disorder is of the
  pancreas where pancreatic insufficiency and
  malabsorption, dominate clinically.
• Viscous secretions in the lungs also can
  predispose to chronic lung disease with
  bronchiectasis.

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CYSTIC FIBROSIS

• Diagnosis
• When CF is suspected, a sweat chloride
  measurement greater than 50 mmol/L is diagnostic
  and accurate after 4 weeks of age.
• In younger infants, genetic analysis may be
  useful.
• The most common mutation occurs at position F508
  on chromosome 7. Absence of this abnormality does
  not rule out CF, however, because several other
  genetic mutations have been identified.

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CYSTIC FIBROSIS

• Treatment
• CF-associated cholestasis has evolved
  significantly with the wide availability of UDCA.
  
• Improvement in both the clinical and biochemical
  markers of cholestatic disease has been
  demonstrated following UDCA treatment.
• The long-term response to oral bile acid therapy
  remains to be elucidated, however.
• Liver transplantation may be required.
• If any of the recipient bile duct is left
  behind, liver disease may reoccur.

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HEPATIC PORPHYRIAS

• Heme is a ubiquitous pigment and in tissues it is
  responsible for oxygen transport and metabolism.
• The human porphyrias are a group of disorders
  that reflect bone marrow or hepatic expression of
  the inherited/acquired disorders of heme
  biosynthesis.
• Heme is made from simple precursors, glycine and
  succinic acid, and following seven enzymatic
  steps, protoporphyrin is formed, into which
  enzymatic insertion of iron by ferrochelatase
  results in the biosynthesis of heme

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Biosynthesis Of Heme
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HEPATIC PORPHYRIAS

• There are seven porphyrias, each reflecting a
  defect of enzymatic step in heme biosynthesis.
• The classification of human porphyrias reflects
  the organ of porphyrin overproduction .
• Although uncommon, human porphyria is important
  not only because photocutaneous manifestations
  can be debilitating and disfiguring, but also
  because individuals with mostly inherited hepatic
  porphyrias, are prone to potentially lethal acute
  attacks associated with progressive
  polyneuropathy, acute abdomen, severe psychiatric
  disturbance, and coma.

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HEPATIC PORPHYRIAS

• Clinical Manifestations
• If the metabolic lesion is distal to the
  porphobilinogen (PBG) deaminase step,
  photosensitizing porphyrins may accumulate in the
  plasma and skin resulting
• Photocutaneous lesions in sun exposed areas, i.e.
  the face, the neck, and the extremities -
  particularly the hands (in PCT, HCP, and VP).
• In hepatic porphyrias, other than porphyria
  cutanea tarda (PCT) ingestion of a
  porphyrinogenic drug may result in an acute
  attack in which abdominal pain, polyneuropathy,
  or neurologic disturbances may dominate.
• Bone marrow porphyria may result in
  photomutilation

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Clinical Manifestations of Human Porphyrias
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Algorithm of therapeutic approach to an acute
porphyric attack
71
Classification of Diseases for which OLT Has Been
Performed in Infants and Children

• Obstructive biliary tract disease
• Biliary atresia ( 50 of all transplant
  candidates)
• Sclerosing cholangitis
• Metabolic disease ( 20 of all candidates)
• alpha1 -Antitrypsin deficiency
• Tyrosinemia
• Glycogen storage diseases (GSD) type IV (and,
  rarely, types I, III)
• Wilson's disease
• Neonatal iron storage disease
• Miscellaneous (urea cycle defects)
• Intrahepatic cholestasis ( 5 of all candidates)
• Familial intrahepatic cholestasis (Byler's
  disease)
• Syndromic bile duct paucity (Alagille syndrome)
• Nonsyndromic bile duct paucity
• Idiopathic neonatal hepatitis

• Acute and chronic hepatitis
• Fulminant hepatic failure ( 10 of all
  candidates)
• Acute viral hepatitis (non-alphabet)
• Toxin or drug induced
• Chronic hepatitis/cirrhosis ( 5 of all
  candidates)
• Postviral
• Autoimmune
• Idiopathic
• Tumors ( 1 of all candidates)
• Hepatoblastoma
• Hepatocellular carcinoma
• Sarcoma
• Hemangioendothelioma
• Miscellaneous (1-2 of all candidates)
• Cryptogenic cirrhosis
• Congenital hepatic fibrosis
• Caroli's disease
• Cystic fibrosis
• Cirrhosis resulting from prolonged total
  parenteral nutrition (often combined with small
  bowel transplantation)

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HEPATOCYTE TRANSPLANTATION(HTX)

• Hepatocyte transplantation can correct a
  metabolic defect by serving as the essential
  vehicle for ex vivo gene therapy or
• by providing the vital enzyme that is deficient
  in patients with a liver-based inborn error of
  metabolism.
• Hepatocyte transplantation can also function as a
  life-saving bridge by providing a cellular mass
  temporarily sufficient carry out metabolic
  function for patients with liver failure awaiting
  liver transplantation.

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Potential Applications of Hepatic Gene Therapy

• Genetic diseases of the liver
• Fam.hypercholesterolemia
• Ornithine transcarbamylase deficiency
• Crigler-Najjar type I
• Wilson disease
• Alpha1 -antitrypsin def.
• Progressive familial intrahepatic cholestasis
• Tyrosinemia
• Phenylketonuria
• Maple syrup urine disease
• Mucopolysaccharidoses

• Acquired diseases of the liver
• Cancer (primary and metastatic)
• Chronic viral hepatitis B ,C
• Cirrhosis (of any origin)
• Induction of tolerance to transplanted liver
• Production of nonliver proteins

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THANK YOU