Hepatic Physiology Flashcards
Anesthesia’s goals pertaining to the liver
maintain BP and oxygenation, keep the function that the patient does have
What does the liver do to drugs? (simplified)
makes them water soluble so they can be eliminated by the kidneys
What are the basic structures of a liver lobule?
portal vein, sinusoids, central vein, hepatic artery, bile canaliculi and bile duct, space of disse, lymphatic duct, hepatic cellular plates, kupffer cells, interlobular septa
What makes the structural shape of the liver lobule advantageous?
hexagonal shape that shares blood supply and bile ducts in multiple directions with abutting lobules
What are the two sources of blood supply to the liver?
portal vein
hepatic artery
What is the significance of the space of Disse?
drains into the lymph
What are sinusoids structurally/functionally similar to?
capillaries
What does the liver cell plate do?
collects bile into the bile canaliculi
What organ is a huge source of lymph?
the liver!
Where are the Kupffer cells and what do they do?
inside the sinusoids and are macrophages that remove bacteria
What is the best source of oxygenation to the liver?
the hepatic artery
How much of the livers O2 requirement does the portal vein supply?
50%
Portal vein SvO2
85%
How much of the livers O2 requirement does the hepatic artery supply?
50%
Hepatic artery SaO2
98-100%
The liver has ___ blood flow and ___ vascular resistance
high; low
normal hepatic blood flow
1500mL/minute (25-30% of CO)
How much of the hepatic blood flow comes from the portal vein?
1100 mL/ minute (75% of total)
How much of the hepatic blood flow comes from the hepatic artery?
400 mL/ minute (25% of total)
What is the average portal vein pressure as blood enters the liver?
9 mmHg
Pressure in the hepatic vein leaving the liver to the inferior vena cava is about
0 mmHg
If resistance increases (what can it lead to)
portal hypertension
Hepatic arterial blood flow is dependent on
metabolic demand (autoregulation)
Hepatic portal vein blood flow is dependent on
blood flow to the GI tract and spleen
A decrease in hepatic arterial blood flow produces an ___ portal venous blood flow
increase
If arterial pressure is decreased then
decreased pressure through the hepatic artery and the portal vein
The superior mesenteric artery supplies blood to ___ (which organs)
colon, small intestines, pancreas
The celiac artery supplies blood to ___ (which organs)
stomach, spleen, pancreas
The inferior mesenteric artery supplies blood to ___ (which organs)
the colon
The blood supply from portal vein comes from (which organs)
stomach, spleen, pancreas, small intestines, and colon
Cirrhosis ___ the resistance to blood
greatly increases!
Patho of cirrhosis
destruction of liver parenchymal cells = replacement with fibrous tissue that contracts around the blood vessels = impedes portal vein blood flow
Most common cause of cirrhosis ___
alcoholism
Causes of cirrhosis (besides alcoholism)
viral hepatitis, obstruction of bile ducts, infection in the bile ducts, ingestion of poisons, non-alcoholic fatty liver disease
stages of alcohol induced liver damage (3)
- fatty liver (deposits = liver enlargement) *is recoverable
- liver fibrosis (scar tissue forms) *recovery possible but with scar tissue
- cirrhosis (connective tissue destroys liver cells) *irreversible!!
micronodular cirrhosis
alcohol abuse can lead directly to cirrhosis from repeated exposure of the cells to toxins causing fibrosis and cirrhosis
What medications can cause liver disease?
TPN, amiodarone
What are the 3 most common causes of liver disease?
obesity, T2DM, metabolic syndrome
Metabolic syndrome
HTN, excess glucose and triglycerides, increased fat
NAFLD what does it stand for
non alcoholic fatty liver disease
25% of the US population has ___
NAFLD
NASH
nonalcoholic steatohepatitis (inflammation)
Up to 30% of people with NAFLD will develop
NASH
Up to 20% of people with NASH will develop
cirrhosis
Which receptors does the hepatic artery have?
alpha 1 (vasoconstriction), beta2 (vasodilation), dopa1 (vasodilation)
Which receptors does the portal vein have?
alpha 1, dopa1
sympathetic activation results in hepatic artery and mesenteric vessel ____ and ____ hepatic blood flow
vasoconstriction; decreased
beta 2 adrenergic stimulation ___ the hepatic artery
vasodilates
the liver’s normal blood volume including what is in the veins and sinusoids is
about 450mL
the liver can expand to hold how much blood (in liters)
up to 1 L
when low pressure exists (like in hemorrhage) how much blood can the liver shift into circulation?
as much as 300 mL
How is the bacteria in the blood from the portal vein “cleansed”?
Kupffer cells engulfs the bacteria and goes through phagocytosis
Pores in the sinusoids are ___
very permeable allowing passage of fluid and protein in to the spaces of disse
About how much lymph comes from the liver?
1/2
high hepatic vascular pressure causes ____
fluid transudation into the abdominal cavity
a _____ increase in hepatic venous pressure can increase lymph flow to 20x normal
10-15 mmHg
How does ascites occur?
a high pressure in hepatic venous pressure leads to increase in lymph flow and back up of fluid that leaks through the liver capsule into the abdominal cavity
carbohydrates, fats, and proteins all lead to
the citric acid cycle and ATP production
list some metabolic functions of the liver
carbohydrate, fat, protein, and drug metabolism
carbohydrate metabolism final products
glucose, fructose, and galactose
all cells utilize _____ to produce energy in the form of ATP
glucose
specific liver functions with carbohydrate metabolism
convert galactose and fructose into glucose, storage of glycogen, gluconeogenesis, formation of chemical compounds
What are glucose, fructose, and galactose? What do they have in common?
simple sugars or monosaccharides
have the same chemical formula (C6H12O6) but structural formulas differ
storage of glycogen allows
the liver to remove excess glucose from the blood, store it, and return it to the blood when BG is low (glucose buffer function)
Glucose buffer function
removed excess glucose that is stored in the liver and then returned to the blood when BG gets low
Does glycogen contribute to intracellular osmolality?
no
Structure of glycogen
a branched polymer of glucose (just a bunch hooked together)
when glycogen storage capacity is full, glucose is converted to
fat
insulin ___ glycogen storage
enhances
epinephrine and glucagon ___ glycogen breakdown (aka glycogenolysis)
enhances
hepatic glycogen stores are depleted after a ___
24 hours fast
gluconeogensis kicks in to provide an uninterrupted supply of glucose
gluconeogenesis only occurs when
BG concentration falls below normal
agents that increase gluconeogenesis
glucocorticoids, catecholamines, glucagon, thyroid hormoen
agents that decrease gluconeogenesis
insulin
when carbohydrate storage capacity is saturated the liver converts the excess carbs to
fat
RBCs and renal medulla can only use ___ for energy
glucose
specific liver functions with fat metabolism
oxidation of fatty acids to supply energy, synthesis of large amounts of cholesterol, phospholipids, and lipoproteins, synthesis of fat from carbs and proteins
to derive energy from fat (triglycerides)
they must be split into glycerol and fatty acids
fatty acids are then split by beta oxidation into 2 carbon acetyl radicals that form acetyl CoA which enters the citric acid cycle to create a lot of ATP
the liver cannot use all of the ___ it produces
acetyl CoA
unused Acetyl CoA is
converted to acetoacetic acid which is highly soluble and leaves the hepatocytes enters the blood and absorbed by other tissues which will reconvert into acetyl CoA to be used to produce energy
acetyl CoA can also be used to synthesize
cholesterol and phospholipids
most of the cholesterol synthesized in the liver is converted to
bile salts and secreted into the bile
a small amount of cholesterol is
packaged into lipoproteins and carried to other tissue cells
cholesterol and phospholipids can be used to form
cell membranes, intracellular structures, chemical substances important to cell function
if protein metabolism doesn’t occur
death will occur in a few days
specific liver functions associated with protein metabolism include
deamination of proteins, formation of urea for removal of ammonia, formation of plasma proteins, synthesis of amino acids
Deamination means
removal of nitrogen
essential amino acids have to come from
our diet
Deamination of _____ plays a major role in hepatic gluconeogenesis
alanine
large amount of ammonia are formed by
deamination process
bacteria in gut with subsequent absorption into the blood
essentially all of the plasma proteins with the exception of ____ are formed by ___
immunoglobulins; hepatocytes
the liver can form plasma proteins at the rate of
15-50 g/day
if someone loses 1/2 of their plasma proteins the liver can replace them in about
1-2 weeks
quantitatively the most important plasma proteins are
albumin and alpha1- antitrypsin
albumin is responsible for
maintaining a normal plasma osmotic pressure and is the principal binding and transporting protein
qualitatively the most important plasma proteins are
coagulation factors
transamination
amino radical is transferred from an available amino acid to the keto acid
glycogenesis is
glucose stored as glycogen
glycogenolysis
breakdown glycogen to make glucose
end products of hepatic biotransformation are either
inactivated or are made more water soluble and excreted in urine or bile
phase 1 reactions of hepatic biotransformation
modify substances through cytochrome p450 enzymes and mixed function oxidases
oxidation generates
reactive oxygen species because carboxyl, epoxy, and hydroxyl groups are introduced into the parent compound
the cytochrome p450 system can be induced by
ethanol, barbiturates, ketamine, benzodiazepines
enzyme induction results in an
increase in the production of the enzymes that metabolize these drugs
enzyme induction can lead to ___
tolerance of these drugs
enzyme induction can promote
tolerance to other drugs metabolized by the same enzymes
ranitidine, amiodarone, ciprofloxacin can
prolong the effects of other drugs by inhibiting these enzymes
products of phase 1 reactions may be ___
more active than the parent compound or rendered cytotoxic
drugs with very high rate of hepatic extraction from the circulation
lidocaine, morphine, verapamil, labetalol, propranolol
a decrease in metabolic clearance of drugs that undergo high rate of hepatic extraction is from __
a reduced hepatic blood flow not hepatocyte dysfunction
barbiturates and benzodiazepines are inactivated by
phase 1 reactions
examples of poorly extracted drugs
tylenol, clindamycin, diazepam, digitoxin, warfarin
if someone has liver disease and is given lidocaine what effect will it have on the pharmacokinetics?
the half life is prolonged and the clearance is less so the effect is decreased but stays in the body longer
phase 2 reactions of biotransformation involve
conjugation of a substance with a water soluble metabolite
water soluble metabolites
glucuronide, sulfate, taurine, glycine
conjugated substances can be excreted in
the urine or bile
types of phase 1 reactions
oxidation, reduction, hydrolysis, hydration, dehalogenation
types of phase 2 reactions
sulfation, glucoronidation, glutathione conjugation, acetylation, amino acid conjugation, methylation
the liver is a storage site for
vitamins A, B12, D, E, and K
enough vitamin A can be stored for up to
10 months
enough vitamin B12 can be stored for up to
1 or more years
enough vitamin D can be stored for up to
3-4 months
how does the liver store iron?
as ferritin
hepatic cells produce and excrete ___ which can bind excess iron in body fluids
apoferritin
apoferritin + iron =
ferritin
iron is carried in the blood by
transferrin
vitamin K is a required cofactor for the synthesis of
factor II, VII, IX, X
vitamin k deficiency manifests as
coagulopathy d/t impaired formation of factors 2,7,9,10
which factors are not produced by the liver?
factor VIII and vonwillebrand
the liver is the primary site of degradation for
thyroid hormone, insulin, steroid hormones, glucagon, ADH
hepatocytes continuously secrete ___ into the bile canaliculi
bile salts, cholesterol, phospholipids and conjugated bilirubin
flow of bile from the common bile duct is controlled by
the sphincter of oddi
gallbladder function
reservoir for bile, concentrates biliary fluid by active transport of Na+ and passive H2O reabsorption
Cholecystokinin
is a hormone released from the intestinal mucosa in response to fat and protein that causes contraction of the gallbladder, relaxation of sphincter of oddi and ejection of bile into the small intestine
what is the major end product of Hgb degradation?
bilirubin
bilirubin provides a valuable tool for diagnosing
hemolytic blood diseases and various types of liver disease
after about ___ days RBCs become fragile and their membranes rupture
120
how Hgb is broken down
split into globin and heme, heme ring opened and Fe is released and transported by transferrin, the 4 pyrrole rings of the porphyrin structure are converted to biliverdin which is converted to free bilirubin which combines with plasma albumin
bilirubin bound to plasma albumin is called
free bilirubin, unconjugated / indirect bilirubin
bilirubin is conjugated with
glucuronide* and sulfate
in the intestine 1/2 of the ____ is converted by bacteria to ___ which is reabsorbed back into the blood
conjugated bilirubin; urobilinogen
What does excess bilirubin in the ECF cause?
jaundice
Which kind of bilirubin will cause jaundice?
can be unconjugated or conjugated!
Common causes of jaundice
increased destruction of RBCs (hemolytic jaundice), obstruction of the bile ducts or damage to hepatocytes (obstructive jaundice)
Which kind of bilirubin is toxic?
conjugated
What happens during hemolytic jaundice?
increased production of bilirubin by macrophages and unconjugated bilirubin in the blood
When hepatocytes cannot process all of the bilirubin what happens?
primarily an increase in unconjugated bilirubin but also a secondary increase in conjugated bilirubin
In hemolytic jaundice excretory function of the liver is
not impaired
in hemolytic jaundice the rate of formation of urobilinogen in the intestines ___ and urinary excretion ___
increases; increases
What most often causes obstruction of the common bile duct?
gallstones, malignancy but can also be caused by damage to hepatic cells from hepatitis
in obstructive jaundice most of the bilirubin in the plasma is in the ____ form
conjugated
in hemolytic jaundice majority of the bilirubin in the plasma is in the ____ form
unconjugated
when there is total obstruction of bile flow
no conjugated bilirubin can reach the intestines to be converted so no urobilinogen is reabsorbed into the blood and excreted by the kidney
with total obstruction of bile flow the test for urobilinogen in the urine is
completely negative
serum transaminase measurements reflect
hepatocellular integrity
tests that measure the liver’s synthetic function include
serum albumin, PT/INR, cholesterol, pseudocholinesterase
liver abnormalities are typically divided into
parenchymal disorders (hepatocellular dysfunction) obstructive disorders (biliary excretion)
normal total bilirubin
< 1.5 mg/dL
what does the total bilirubin reflect?
balance between production and biliary excretion
a predominately conjugated hyperbilirubinemia is associated with
an increased urobilinogen and reflect intrahepatic cholestasis, extrahepatic biliary obstruction which may lead to hepatocellular dysfunction
a primarily unconjugated hyperbilirubinemia may be seen with
hemolysis or with congenital or acquired defects in bilirubin conjugation
serum aminotransferases are
enzymes released in the circulation as a result of hepatocellular injury
what are two commonly measured serum aminotransferases?
AST/ALT
which serum aminotransferase is more specific?
ALT (primarily located in the liver)
Alkaline phosphatase is produced by the ____ and excreted into the ___
liver, bone, small bowel, kidneys, and placenta; bile
most of the circulating alk phos comes from ___
bone
in the presence of biliary obstruction alk phos
is synthesized more and released into the circulation
serum albumin has a ___ half life
long half life so its value may initially be normal with acute liver disease
low serum albumin levels are indicative of
chronic liver disease, acute stress, malnutrition
What can cause hypoalbuminemia?
increased loss in urine (nephrotic syndrome) and in the GI tract (enteropathy with protein loss)
increased NH3 in the blood usually reflects disruption of
hepatic urea synthesis
PT measures the activity of
fibrinogen, factor II, V, VII, X
factor VII has a ____ half life
short half life so PT is useful in evaluating hepatic synthetic function of patients with acute or chronic liver disease
if the PT doesn’t correct after IV vitamin K
severe liver disease is likely present
how much time does it take for vitamin K to correct?
24 hours
pre - hepatic classification
bilirubin overload/ increased unconjugated bilirubin
causes of pre-hepatic dysfunction
hemolysis, hematoma reabsorption, bilirubin overload from whole blood (massive transfusion)
intra-hepatic classification
parenchymal/hepatocellular dysfunction
What lab values are affected by intra-hepatic dysfunction?
conjugated bilirubin, aminotransferase enzymes, PT (prolonged), albumin (decreased)
what causes intra-hepatic dysfunction?
viruses, drugs, sepsis, arterial hypoxemia, congestive heart failure, cirrhosis
post-hepatic classification
cholestasis (obstruction)
what lab values are affected by post-hepatic dysfunction?
conjugated bilirubin, alk phos
what causes post-hepatic dysfunction?
stones, cancer, sepsis
how does general and regional anesthesia affect hepatic blood flow?
decreases it due to direct and indirect effects of anesthetic agents themselves, type of ventilation, and surgical procedure
which volatile agent causes the greatest decrease in portal blood flow?
halothane
which volatile agent is the agent of choice for hepatic disease?
isoflurane
hypoxemia produces
increased SNS stimulation and decrease in hepatic blood flow
surgical procedures on or near the liver can
decrease hepatic blood flow by 60% from SNS activation, autoregulation, and direct compression of vessels
drugs that decrease hepatic blood flow
beta adrenergic blockers, alpha 1 agonists, vasopressin
endocrine stress response secondary to fasting and surgical stress results in
increased circulating levels of catecholamines, glucagon, cortisol
the endocrine stress response can be at least partially blunted by
regional anesthesia, deep general anesthesia, pharmacological block of the SNS
all opioids can potentially cause
spasm of the sphincter of Oddi and increases biliary pressure
which opioids cause the most “spasm” of the sphincter of oddi
the phenylpiperdines - fentanyl, sufentanil, alfentanil, remifentanil
IV opioids can induce ___ or result in ____ cholangiograms
biliary colic or result in false positive cholangiograms
persistent abnormalities in liver function test may be indicative of
viral hepatitis, sepsis, idiosyncratic drug reaction, surgical complications
the most common cause of postoperative jaundice is
over production of bilirubin d/t reabsorption of a large hematoma or RBC breakdown following transfusion
hepatitis has been associated with
methoxyflurane, enflurane, isoflurane, halothane
potential mechanisms for halothane hepatitis
formation of hepatotoxic metabolites, immune hypersensitivity
how much of halothane is metabolized?
20%
how much of sevoflurane is metabolized?
1%
halothane hepatitis is a diagnosis of
exclusion
risk factors associated with halothane hepatitis
middle age, obesity, females, repeat exposure (within 28 days)
