Chronic Hepatitis Flashcards
Formulate the defining morphological characteristics of chronic hepatitis
Chronic hepatitis = ongoing inflammation of hepatocytes
o Inflammation starts in portal tract, may extend for different distances into hepatic lobule
o Predominantly lymphocytes; different amounts of plasma cells
o Progressive hepatocyte necrosis/regeneration → fibrosis → cirrhosis
Distinguish the main causes of chronic hepatitis.
ABCDDD
o Autoimmune o HBV o HCV o HDV o Drugs: isoniazid, nitrofurantoin o Hepatolenticular Degeneration (Wilson’s disease)
Autoimmune hepatitis
o Female predominance
• Ages 15-25 or middle-aged
Main symptom = fatigue; may be asymptomatic or have polyarthralgia, jaundice
o Increased aminotransferases
• If severe = jaundice (increased serum bilirubin); prolonged INR
o Positive circulating autoantibodies = Polyclonal hypergammaglobinemia
Pathogenesis:
• Genetic predisposition
• Loss of self-tolerance
• Helper T cells infiltrate portal zones = react with hepatocyte antigens
• Plasma cells frequently present in large numbers
• Note: autoantibodies have diagnostic value; no proven pathogenic role
Types:
Type 1: 80% of cases
• ANA: anti-nuclear Ab (ds DNA)
• ASMA: anti-smooth muscle Ab (actin, troponin)
Type II: 4% cases
• Anti-LKM1: anti-liver kidney microsomal (CYP2D6)
• Anti-LC1: anti-liver cytosol (forminminotransferase cyclo demaminase)
• Often young girls; European
Other antibodies:
• Anti-SLA: anti-soluble liver antigen ab (cytokeratin 8, 18)
• Atypical p-ANCA
• Note: in 10% cases = NONE of above Ab’s found
Many immunologic diseases associated with autoimmune hepatitis: Common findings: • Autoimmune thyroiditis • Rheumatoid arthritis • Ulcerative colitis • Graves’ disease
Hereditary Hemochromatosis: characteristics
- Autosomal recessive
- Chromosome 6
- Common among Northern European ancestry (1/300 are homozygotes); rare in Africans, Asians
- Mutation in HFE gene (in 85% cases)
- Result: uncontrolled intestinal iron absorption = accumulated in liver and other tissues (heart, pancreas, pituitary, testes, skin)
Hereditary Hemochromatosis: clinical presentation
- Cirrhosis
- Hepatocellular carcinoma
- Diabetes
- Cardiomyopathy, conduction deficits
- Arthropathy
- Skin “bronzing”
- Gonadal dysfunction (hypogonadism)
Hereditary Hemochromatosis: pathogenesis
Fe absorbed in duodenum: • Enters enterocyte via DMT • Exits enterocyte via ferroportin • Regulated by hepcidin (suppresses Fe absorption by binding to ferroportin) • Transported in blood by transferrin
• In Hemochromatosis = no up-regulation of Hecidin when high transferrin-bound iron → transfer of ion by ferroportin into blood continues to occur
Iron accumulation → cirrhosis and hepatocellular carcinoma
• Lipid peroxidation/oxidative stress
• Stimulation of fibrogenesis
• Direct DNA damage
Hereditary Hemochromatosis: diagnosis
Screening tests:
• Transferrin saturation = increased
• Ferritin = increased
Confirmatory tests:
• HFE gene mutation analysis (most: C282Y homozygotes or C282Y/H63D-compound heterozygotes)
• Liver biopsy: hepatic tissue iron quantification
Wilson’s Disease: characteristics
- Rare autosomal recessive disorder
- Gene ATP7B on chromosome 13
Mutated Cu transporter (P-ATPase) in trans-Golgi network of hepatocytes
• Inability to excrete Cu out of hepatocytes into bile
• Result = accumulation of Cu in liver, brain (basal ganglia), cornea, kidney
Wilson’s Disease: clinical presentation
- Liver: Chronic hepatitis, Cirrhosis, Acute hepatitis, Fulminant liver failure
- Eye: Kayser-Fleischer rings
- Brain: Basal ganglia gliosis “Lenticular degeneration”/Parkinsonian symptoms; Psychosis
- Kidney: Fanconi syndrome = Low uric acid
- RBC: Hemolysis
Wilson’s Disease: pathogenesis
Mutation in ATP7B gene for Cu transporter protein (Wilson ATPase)
• Located in trans-Golgi network of hepatocytes
• Transports Cu for excretion across cannicular membrane → bile
• Also into secretory vesicles = incorporated into Ceruloplasmin = excreted into blood
- With mutation = unable to move Cu out of hepatocytes → accumulation
- Result: necrosis of Cu-loaded hepatocytes → increases blood Cu levels → deposition in cornea, brain (basal ganglia), kidney, and get increased RBC fragility → hemolysis
Wilson’s Disease: diagnosis
Screening tests:
• Ceruloplasmin = low
• 24 hour Urine Copper = high
Confirmatory tests:
• Liver biopsy for tissue copper quantitation = high
Alpha-1 antitrypsin deficiency: characteristics
Characteristics:
• Most abundant serine protease inhibitor = an acute phase reactant product
• Made in RER of hepatocytes
A-1 AT alleles inherited in autosomal co-dominant pattern
• 75 different alleles
• Normal phenotype: PiMM
• Most common deficiency variant: PiZZ
Epidemiology:
• In 1:2000 individuals
• Rare in African-Americans, Asians, Hispanics
• In PiZZ patients >50 years = only 15% have liver disease
Alpha-1 antitrypsin deficiency: clinical presentation
Liver disease:
• Neonatal: hepatitis/cholestatic jaundice
• Adults: increased aminotransferases, cirrhosis, hepatocellular carcinoma
Lung disease: premature emphysema
Alpha-1 antitrypsin deficiency: pathogenesis
Liver disease:
• Accumulation of abnormal protein in ER
• Results in cell death, fibrosis, cirrhosis
Lung disease:
• A-1 AT normally regulates elastase/proteases
• With deficiency: PMN elastase destroys elastic tissue around alveoli
Alpha-1 antitrypsin deficiency: diagnosis
- Determination of A-1 AT level = low
- Pi phenotype (Blood)
- Liver biopsy with PAS stain = accumulation of characteristic globules in hepatocytes
