Portal Hypertension
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Transcript Portal Hypertension
PORTAL HYPERTENSION
Anson W. Lowe
Medicine
October 05, 2015
Understand the role of the liver in protein, carbohydrate,
and drug metabolism.
Understanding the cause and effects of portal
hypertension. Understand the pathophysiology
underlying the therapeutic approaches.
Understand the rationale underlying the use of “liver
function tests”.
Liver; liver function tests; portal hypertension; drug metabolism
Liver Functions
Bilirubin metabolism
Protein Synthesis
◦ Albumin
◦ Coagulation factors (II, V, VII, IX, X)
Bile Salt Metabolism
Lipid Metabolism
Glycogen storage and gluconeogenesis
Drug metabolism/Xenobiotic transformation
Zakim and Boyer, Hepatology, 1996
Albumin
Comprises 50% of the total plasma protein
Provides 80% of the oncotic force
Binds hydrophobic and water-insoluble
compounds such as bilirubin, fatty acids,
sterols, thyroid hormones, and drugs
Sensitive to nutritional status
Half-life = 20 days
Prothrombin Complex
Factors II, V, VII, IX, X are produced only in the
liver
◦ All except for V are vitamin K dependent
Factor VII possesses the shortest half-life, 4-6
hours
The prothrombin time is often used as a
measure of current hepatic synthetic function
Carbohydrate Metabolism
The liver is able to store energy in the form of glycogen
◦ Gluconeogenesis results in the generation of glucose from glycogen
The monosaccharides glucose, fructose, and galactose can be assimilated
into glycogen by the liver
Whether glycogen is synthesized or degraded is regulated by insulin and
glucagon
Lodish et al., Mol Cell Biol (2000)
Carbohydrate Metabolism
Severe liver disease may result in profound
hypoglycemia
Lipoprotein Metabolism
The liver is responsible for the uptake and
secretion of lipoproteins
◦ VLDL represents the major form of triglyceride
secretion to peripheral tissues from the liver
◦ Chylomicron remnants, which are partially depleted
of triglycerides, are taken up by the liver
◦ LDL serves to transfer cholesterol from peripheral
tissues to the liver
Cholesterol Metabolism
Cholesterol is also taken up by the liver as chylomicron remnants or LDL
via the LDL receptor
◦ 50% of all LDL receptors are located in the liver
The liver is the major site for cholesterol synthesis from acetyl CoA
HMG CoA reductase represents the critical enzyme in cholesterol
synthesis
3-hydroxy-3-methylglutaryl-CoA
http://www.indstate.edu/thcme/mwking/cholesterol.html#synthesis
HMG CoA reductase
The critical enzyme in cholesterol synthesis
Activity is regulated
◦ Increases when hepatocyte cholesterol or bile salt
levels are depleted
◦ Inhibited when cholesterol levels are elevated
The target of the class of drugs known as the
“statins”
Drug metabolism
Oxidation of alcohol to aldehyde
RCH2O + NAD+ RCHO + NADH + H+
Oxidation of aldehyde to ketone
RCHO + NAD+ + H2O RCOOH + NADH + H+
Cytochrome P450
Responsible for a variety of oxidative reactions
Inducible
◦ Ethanol, phenobarbitol, warfarin, acetominophen
Ethanol is able to enhance the toxicity of CCl4 and
acetominophen
Liver Disease
Bilirubin metabolism
Protein synthesis
Glucose regulation
Xenobiotic transformation
Portal circulation
◦ Bleeding
◦ Edema from hypoalbuminemia
◦ Portal hypertension
Gray’s Anatomy
Zakim & Boyer, Hepatology, 1996
Normal
Varices
Univ. of Iowa, Peds GI
Portal Hypertension
Gastrointestinal bleeding
◦ Esophageal, gastric, umbilical, hemorrhoidal veins
◦ Portal hypertensive gastropathy
Ascites
Sengstaken-Blakemore tube. Image courtesy of Richard Treger, MD.
www.sages.org/.../june09case.php
Somatostatin
Synthesized as a 116 amino acid preprohormone
2 forms: SS28 and SS14
Source:
◦ Neurons of CNS and PNS
◦ Endocrine cells of the pancreas (D cells) and stomach
Actions in the GI tract
◦ Inhibition of transport
◦ Inhibition of secretion
◦ Splanchnic vasoconstriction
Somatostatin
Clinical Applications
◦ Secretory diarrhea
◦ Pancreatic secretions
◦ Gastrointestinal hemorrhage (variceal bleeding)
induces splanchnic vasoconstriction
Sleisenger & Fordtrans’s Gastrointestinal and Liver Disease, 6th ed. 1998
Zakim & Boyer, Hepatology, 1996
end-side shunt
Zakim & Boyer, Hepatology, 1996
Implantation of a Transjugular Intrahepatic Portosystemic Stent
Rossle, M. et al. N Engl J Med 1994;330:165-171
Hepatic Encephalopathy
0 - normal
1 - inverted sleep pattern, restless, forgetful
2 - lethargic, inappropriate behavior,
disoriented for time
3 - somnolent but arousable; confused
4 - coma/unarousable
Hepatic Encephalopathy
Specific cause is unknown
Elevated ammonia levels correlate with signs
for 90% of patients
Treatment directed at ammonia production
results in clinical improvement
Lactulose
Osmotic laxative
Produces lactic, acetic, and formic acid
Lowers colonic pH
Traps luminal ammonia, imparing its
absorption
Promotes diffusion of ammonia from the
mucosal blood into the gut
Disease Markers in the GI System
Cell specific expression
Cell destruction
◦ Release of cell specific cytoplasmic proteins
Cardiac: troponin (ischemic necrosis)
Liver: Aspartate aminotransferase(AST) and Alanine aminotransferase (ALT) (ischemic necrosis,
viral infections)
Production of new protein
◦ Liver: a-feto-protein (hepatic cancer)
Disease Markers in the GI System
Decline in secretory protein levels in the blood
as a marker of synthetic function
◦ Because of a decline in cell number, plasma proteins
decline
Coagulation factors (short term)
Albumin (long term)
Disease Markers in the GI System
Loss in cellular polarity
◦ Loss of polarity is a manifestation of most
inflammatory and neoplastic processes
Liver (bile duct): alkaline phosphatase, -Glutamyl
transpeptidase