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Hepatic Inborn Errors Of Metabolism

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Title: 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.

3
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)

5
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

6
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).

7
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

8
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.

11
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.

13
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.
  •  

14
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
 
17
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.

18
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.
19
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.

20
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.

21
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

24
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.

25
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26
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.

30
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.

31
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.

32
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

33
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.

34
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.

35
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?

36
Inborn Errors of Bile Acid Synthesis(Types)
  • Secondary Defects (caused by organelle damage)
  • Peroxisomal disorders
  • Generalized hepatic synthetic dysfunction

37
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).

38
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.
  •  

39
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.

40
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.

41
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.

42
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43
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

44
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

45
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.

46
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.

47
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

48
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.

49
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.
50
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

51
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.

52
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.

53
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.

54
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.

55
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.

56
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.

57
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
70
Algorithm of therapeutic approach to an acute
porphyric attack
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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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