Chronic Liver Disease

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Etiologies of Chronic Liver Disease Infections, esp. viral Toxins Genetic Drugs Autoimmune Vascular Biliary

description

Hepatology

Transcript of Chronic Liver Disease

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Etiologies of Chronic Liver Disease

• Infections, esp. viral• Toxins• Genetic• Drugs• Autoimmune• Vascular• Biliary

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Mechanisms of Chronic Liver Injury

• Hepatocyte InjuryInflammation primaryInjury primary – followed by

inflammation

• Biliary Obstruction

• Hepatic venous obstruction

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GeneticCystic Fibrosis

Wilson’s DiseaseBiliary Obstruction

FibrosisHepatocellular Necrosis and Inflammation

DrugINH

EstrogensHepatic Venous Outflow Obstruction

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PrimaryAgent

Target Cell

Cytokines

Inflammation

Altered Matrix + Matrix Peptides

(Activated Target) Fibrogenesis

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Etiologies of Chronic Hepatitis

• Hepatitis C

• Hepatitis B (w/wo Delta)

• Autoimmune Hepatitis

• Drugs

• Wilson’s Disease

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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)

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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)

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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)

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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

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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

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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

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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

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Complicated Ascites in Cirrhosis

• Spontaneous bacterial peritonitis

• Tuberculous peritonitis

• Pancreatic ascites

• Cancer (esp. hepatoma)

• Budd-Chiari syndrome

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BACTERAEMIA

BACTERASCITES

Serum complement

RE Function

Ascitic fluid opsonic activity

poor

SBP

GI haemorrhage

Invasive procedures

Ascitic fluid opsonic activity

good

Resolution

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First Known Description of Hepatic Encephalopathy

“I’m a great eater of beef but believe it does harm to my wit”

Shakespeare

Twelfth Night

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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

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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

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Precipitants of Hepatic Encephalopathy

• Excess nitrogen load• Drugs (sedatives, analgesics, diuretics)• Renal failure• Electrolyte/acid-base abnormalities• Infection• Surgical procedures• Constipation

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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

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Lactulose: Mechanism of Altering Colonic Nitrogen Metabolism

• Stimulate bacterial growth and nitrogen incorporation

• Inhibit bacterial catabolism of amino acids, peptides, …

• Cathartic effect

• (Ammonia trapping)