Chronic Liver Disease
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Transcript of Chronic Liver Disease
Etiologies of Chronic Liver Disease
• Infections, esp. viral• Toxins• Genetic• Drugs• Autoimmune• Vascular• Biliary
Mechanisms of Chronic Liver Injury
• Hepatocyte InjuryInflammation primaryInjury primary – followed by
inflammation
• Biliary Obstruction
• Hepatic venous obstruction
GeneticCystic Fibrosis
Wilson’s DiseaseBiliary Obstruction
FibrosisHepatocellular Necrosis and Inflammation
DrugINH
EstrogensHepatic Venous Outflow Obstruction
PrimaryAgent
Target Cell
Cytokines
Inflammation
Altered Matrix + Matrix Peptides
(Activated Target) Fibrogenesis
Etiologies of Chronic Hepatitis
• Hepatitis C
• Hepatitis B (w/wo Delta)
• Autoimmune Hepatitis
• Drugs
• Wilson’s Disease
Pathogenesis of Liver Injury with Chronic Biliary Obstruction
Obstruction of bile flow
Bile acid, copper accumulation
Alterations in cannicular membrane and tight junctions
Condensation of pericannicular microfilaments
Fibrosis (necrosis and inflammation)
Cirrhosis
Hepatic Resistance Splanchnic blood flow
Decreased NO Increased NO
Potential Mechanisms to Regulate NOS Activity (?)
• Increased caveolin levels
• Decreased phosphorylation
• Increased phosphorylation
• hsp90 signaling
• eNOS gene expression (with sustained flow)
Why Do Varices Bleed?
Erosion Explosion
According to this theory ulceration and acid
reflux are considered important, but this is
not supported by histological
observations
Depends on size and pressure (tension in a
balloon = radius x pressure)
Options for Control of Variceal Bleeding• Medical
Vasopressin (or glypressin) + NTG Somatostatin (or octreotide) Beta blockers
• Procedures SB, Minnesota, or Linton tube Endoscopic sclerotherapy or band ligation TIPS
• Surgical Shunts Variceal interruption Transplant
Elements of Ascites Formation in Cirrhosis
• Portal hypertension• Decreased renal excretion of Na and
water• Decreased serum oncotic pressure
• Lead to an increased formation of hepatic lymph exceeding the capacity of the thoracic duct
Classical Underfilling Theory
Overflow Theory
Sinusoidal Portal Hypertension
SECONDARY SODIUM AND WATER RETENTION
PRIMARY SODIUM AND WATER RETENTION
Plasma Volume Expansion
Ascites Formation
Hepatic Pressure Receptors
Sinusoidal Portal Hypertension
Lymph Formation > Lymph removal
Ascites Formation
Reduction of Plasma VolumeHigh and Low-
Pressure Baroreceptors
Increased Activity of Renin-Angiotensin-Aldosterone and Sympathetic Nervous
Systems and Vasopressin
Hepatorenal Syndrome(Functional Renal Failure)
• Kidney pathologically normal
• Reduced blood flow to renal cortex
• Reduced GFR
• Hypertonic urine, reduced urine Na
• Distinguish from other causes of renal failure
Complicated Ascites in Cirrhosis
• Spontaneous bacterial peritonitis
• Tuberculous peritonitis
• Pancreatic ascites
• Cancer (esp. hepatoma)
• Budd-Chiari syndrome
BACTERAEMIA
BACTERASCITES
Serum complement
RE Function
Ascitic fluid opsonic activity
poor
SBP
GI haemorrhage
Invasive procedures
Ascitic fluid opsonic activity
good
Resolution
First Known Description of Hepatic Encephalopathy
“I’m a great eater of beef but believe it does harm to my wit”
Shakespeare
Twelfth Night
Stages of Hepatic Encephalopathy
Stage 0 - Subclinical; psychomotor test abnormalities
Stage 1 - Lethargy and confusion or excitation, sleep disturbance, decreased attention
Stage 2 - Somnolence, inappropriate behavior
Stage 3 - Stupor but arousable, speech incomprehensible
Stage 4 - Coma
Hypotheses Concerning the Mechanism of Hepatic Encephalopathy
• Ammonia
• Synergistic toxins – ammonia, mercaptans, and free fatty acids
• Increased activity of GABA – benzodiazepine neurotransmission
• False neurotransmitters – aromatic amines
Precipitants of Hepatic Encephalopathy
• Excess nitrogen load• Drugs (sedatives, analgesics, diuretics)• Renal failure• Electrolyte/acid-base abnormalities• Infection• Surgical procedures• Constipation
Management of Hepatic Encephalopathy
• Search for and correction of precipitating factors
• Reduce dietary protein (40 g or less)
• Laxatives, enemas
• Lactulose, antibiotic (neomycin), or combination
• Criteria of response
Lactulose: Mechanism of Altering Colonic Nitrogen Metabolism
• Stimulate bacterial growth and nitrogen incorporation
• Inhibit bacterial catabolism of amino acids, peptides, …
• Cathartic effect
• (Ammonia trapping)