Untitled Quiz

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

• 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

• 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

• Total Body Iron Pool: 2-6 grams (0.5 gr in liver)

• Hereditary Hemochromatosis: Inherited, homozygous recessive, impacting iron absorption regulation

  • HFE gene on chromosome 6
  • Regulates intestinal iron absorption
  • Excess iron absorption

• 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)

• 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

• 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
• 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)
• 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