Etiologies of Chronic Liver Disease

Infections, esp. viral

Toxins
Genetic
Drugs
Autoimmune
Vascular
Biliary
Mechanisms of Chronic Liver Injury
Hepatocyte Injury
Inflammation primary
Injury primary followed by
inflammation
Biliary Obstruction
Hepatic venous obstruction

Genetic
Cystic Fibrosis
Wilsons Disease
Biliary
Obstruction
Fibrosis
Hepatocellular
Necrosis and
Inflammation
Drug
INH
Estrogens
Hepatic Venous
Outflow Obstruction
Primary
Agent
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
Wilsons 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 Volume
High 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
Im 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)