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Questions and Answers
What is the primary diagnostic method for Wilson's disease?
What is the primary diagnostic method for Wilson's disease?
Which of the following conditions is associated with impaired copper excretion into the bile?
Which of the following conditions is associated with impaired copper excretion into the bile?
Which of the following best describes the function of ceruloplasmin in copper metabolism?
Which of the following best describes the function of ceruloplasmin in copper metabolism?
Which of the following metabolic diseases involves a mutation in ATP7B that affects copper transport?
Which of the following metabolic diseases involves a mutation in ATP7B that affects copper transport?
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What is the normal range of total body copper in humans?
What is the normal range of total body copper in humans?
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Which of the following clinical manifestations is most likely associated with copper toxicity in Wilson's disease?
Which of the following clinical manifestations is most likely associated with copper toxicity in Wilson's disease?
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The failure to incorporate copper into ceruloplasmin in Wilson's disease is primarily due to a defect in which of the following?
The failure to incorporate copper into ceruloplasmin in Wilson's disease is primarily due to a defect in which of the following?
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What biochemical consequence leads to injury in tissues affected by Wilson's disease?
What biochemical consequence leads to injury in tissues affected by Wilson's disease?
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Which liver condition is associated with a hereditary anomaly including telangiectases and arteriovenous fistulas?
Which liver condition is associated with a hereditary anomaly including telangiectases and arteriovenous fistulas?
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What is a common complication associated with choledocal cysts in adults?
What is a common complication associated with choledocal cysts in adults?
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Which of the following conditions is characterized by segmental dilatation of the large intrahepatic bile ducts?
Which of the following conditions is characterized by segmental dilatation of the large intrahepatic bile ducts?
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Which genetic inheritance pattern is associated with Polycystic Liver-Kidney Disease?
Which genetic inheritance pattern is associated with Polycystic Liver-Kidney Disease?
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What is a common clinical finding in children with choledocal cysts?
What is a common clinical finding in children with choledocal cysts?
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What is the proposed pathogenesis of Caroli’s Disease?
What is the proposed pathogenesis of Caroli’s Disease?
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Which of the following is a complication associated with Caroli’s Disease?
Which of the following is a complication associated with Caroli’s Disease?
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Which condition is known for associated extrahepatic biliary atresia during childhood?
Which condition is known for associated extrahepatic biliary atresia during childhood?
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What is a primary treatment option for patients with a choledocal cyst?
What is a primary treatment option for patients with a choledocal cyst?
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In autosomal dominant Polycystic Liver-Kidney Disease, what chromosomal abnormality is noted?
In autosomal dominant Polycystic Liver-Kidney Disease, what chromosomal abnormality is noted?
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Which liver condition is characterized by a copper accumulation leading to hepatolenticular degeneration?
Which liver condition is characterized by a copper accumulation leading to hepatolenticular degeneration?
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What is the typical age range for onset of symptoms in Wilson's Disease?
What is the typical age range for onset of symptoms in Wilson's Disease?
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Which genetic mutation is associated with Hereditary Hemochromatosis?
Which genetic mutation is associated with Hereditary Hemochromatosis?
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What is the most common phenotype for Alpha-1 Antitrypsin Deficiency?
What is the most common phenotype for Alpha-1 Antitrypsin Deficiency?
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Cystic Fibrosis is primarily caused by a mutation in which type of channel?
Cystic Fibrosis is primarily caused by a mutation in which type of channel?
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Which clinical feature is most often associated with Hereditary Hemochromatosis?
Which clinical feature is most often associated with Hereditary Hemochromatosis?
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What type of necrosis is commonly observed in Wilson's Disease?
What type of necrosis is commonly observed in Wilson's Disease?
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Which of the following is NOT a typical complication of Alpha-1 Antitrypsin Deficiency?
Which of the following is NOT a typical complication of Alpha-1 Antitrypsin Deficiency?
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What key morphological finding is associated with Hereditary Hemochromatosis?
What key morphological finding is associated with Hereditary Hemochromatosis?
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Which condition leads to insufficient protease inhibition primarily affecting the liver and lungs?
Which condition leads to insufficient protease inhibition primarily affecting the liver and lungs?
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Study Notes
Developmental Abnormalities, Metabolic and Vascular Diseases of the Liver
- The presentation covers various liver diseases
- Non-neoplastic liver diseases are a major topic
Nonneoplastic Liver Diseases
- Includes Hepatitis, Biliary Diseases, Alcoholic Liver Diseases, Metabolic Liver Diseases, Drug/toxin-induced Liver Diseases, Vascular Diseases, Infectious Diseases, and Developmental Diseases.
Metabolic Diseases of the Liver
- Several metabolic liver diseases are noted.
- Examples include Wilson's Disease, Hemochromatosis, a1-Antitrypsin Deficiency, Cystic Fibrosis, Glycogen Storage Disease, Thyrosinemia, Mucopolysaccaridosis, Gaucher Disease, Nieman-Pick Disease, and others.
Wilson's Disease
-
Normal Copper Metabolism:
- Ingested copper is absorbed (40-60%) in the duodenum and proximal small intestine
- Absorbed copper enters the liver
- Within hepatocytes, free copper combines with a2-globulin (ceruloplasmin) and excess copper is transported to bile
- Total body copper ranges from 50-150mg
- Ceruloplasmin accounts for 90-95% of plasma copper
-
Pathology in Wilson's Disease:
- ATP7B mutation affects copper transport
- Impaired copper excretion into the bile
- Failure to incorporate copper into ceruloplasmin
- Inhibits ceruloplasmin secretion into the blood
- Nonceruloplasmin bound copper circulates in the body
- Can lead to accumulation in organs (brain, cornea, kidneys, bone, joints)
- Can cause injury through copper-catalyzed formation of reactive oxygen species
- Leading to injury and/or fibrous tissue development
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Diagnosis of Wilson's Disease:
- Age range is 6-40 years
- Accumulation of copper in the liver, brain, and eyes.
- Decreased serum ceruloplasmin levels
- Increased urinary copper excretion
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Pathology of Wilson's Disease:
- Copper accumulation can't usually be detected in hematoxylin/eosin staining
- Fatty changes, acute/chronic hepatitis, massive hepatocyte necrosis, Mallory bodies, and toxic injury to neurons
- Kayser-Fleischer rings seen in the cornea
Hemochromatosis
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Total Body Iron Pool: 2-6 grams (0.5 gr in liver)
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Hereditary Hemochromatosis: Inherited, homozygous recessive, impacting iron absorption regulation
- HFE gene on chromosome 6
- Regulates intestinal iron absorption
- Excess iron absorption
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Secondary Hemochromatosis:
- Iron overload from blood transfusions or iron supplements
- Ineffective erythropoiesis
- Increased oral iron intake
- Congenital atransferrinemia
- Chronic liver disease
-
Manifestations:
- Accumulation of iron in the liver, leading to inflammation and possible damage
- Various symptoms including diabetes mellitus, skin pigmentation, and eventual organ damage in multiple organs.
-
Pathological Features:
- Lipid peroxidation reactions via iron-catalyzed free radicals
- Stimulation of collagen formation
- Interaction with DNA leading to injury/predisposition to hepatocellular carcinoma (HCC)
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Tissue damage due to iron accumulation
a1-Antitrypsin Deficiency
-
a1-Antitrypsin:
- Plasma glycoprotein synthesized by hepatocytes
- Function: inactivates proteases like elastase, cathepsin G, and proteinase 3
- Deficiency location: chromosome 14
- Substitution in the polypeptide gene—not limited to a single protein sequence
- Genetic prevalence ~1/2000 live births ~ 10 - 15% risk of liver disease
-
Pathogenesis:
- Defective protein production and secretion due to mutations in protease inhibitor (Pi) gene (e.g., PiZZ genotype)
- Decreased serum a1-antitrypsin levels
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Clinical manifestations:
- Pulmonary emphysema, bronchiectasis, chronic hepatitis/cirrhosis, neonatal hepatitis/cholestasis, childhood cirrhosis, cutaneous panniculitis, arterial aneurysm, Wegener granulomatosis
Cystic Fibrosis
-
Genetic Mechanism:
- Autosomal recessive trait
- Abnormal chloride channels (CFTR protein)
-
Mechanism:
- Chronic pulmonary disease and pancreatic insufficiency
- Mucus accumulation in organs
-
Associated Condition:
- Secondary biliary cirrhosis due to biliary tract obstruction
Polycystic Kidney Disease (PKD)
-
Autosomal dominant form:
- Mutation on chromosome 16
- Diffusely cystic, small cysts
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Autosomal recessive form:
- Incomplete involution of embryonic bile duct remnants
- May communicate with biliary system, not necessarily pigmented
- Complications: infected liver cysts and cholangiocarcinoma
Neonatal Cholestasis
-
Intrahepatic:
- Neonatal hepatitis (60-70% of cases)
- Metabolic disorders (e.g., α1-antitrypsin deficiency, cystic fibrosis)
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Extrahepatic:
- Extrahepatic biliary atresia
Neonatal Hepatitis
- Non-specific term for intrahepatic cholestasis
- Variety of causes, such as infections, metabolic disorders, and genetic defects
Extrahepatic Biliary Atresia
- Absence or hypoplasia of intrahepatic biliary radicals
- Characterized by bile duct obstruction
- Symptoms develop in early infancy, often with jaundice
Reye's Syndrome
- Cause: Mitochondrial function defect
-
Symptoms:
- Fever, virus-induced illness (influenza, varicella), followed by acute hepatic failure, encephalopathy (brain dysfunction)
-
Clinical findings:
- Microvesicular steatosis, hepatocellular necrosis, inflammation
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