Hepatic week 1 Flashcards
What are the functions of the liver?
stores vitamins, minerals, and sugar preventing shortage of nutrients
regulates blood clotting
produces proteins
produces bile needed to digest fat and absorb fat soluble vitamins
helps to fight infection by removing bacteria from the blood
removes toxic byproducts of medications
metabolizes nutrients from food to make energy
The basic functional unit of the liver is
the lobule
How many lobules are in the liver?
50,000-100,000
The largest organ in the body is
the liver
Basic structures of a liver lobule include
portal vein, sinusoids (like capillaries), central vein, hepatic artery, bile canaliculi and bile duct (transport & storage), space of Disse and lymphatic duct, hepatic cellular plates, Kuppfer cells, & interlobular septa
The portal vein and hepatic artery empty into the
central vein
The Space of Disse is where
the lymph fluid flows across and empties into the lymphatic duct
The bile canaculi produces
bile that drains down into the bile duct
The liver receives its blood supply from the
portal vein and hepatic artery
The portal vein supplies _____ of the livers O2 requirement
50%
The portal vein SvO2 is
85%
The hepatic artery supplies ______ of the livers O2 requirement
50%
Describe the blood flow and the resistance in the liver.
The liver has high blood flow and low vascular resistance
Normal hepatic blood flow in the liver is
1500 mL/minute (25-30% of CO)
Describe the blood flow of the portal vein.
1100 mL/min or 75% of total
Describe the blood flow of the hepatic artery.
400 mL/min or 25% of total
Portal vein pressure as blood enters the liver averages
9 mmHg
Pressure in the hepatic vein leaving the liver
enters the vena cava and the pressure is 0 mmHg here
The pressure difference between the portal vein and the hepatic vein demonstrates
resistance to flow in the hepatic sinusoids is very low
Describe the overall blood flow to the liver.
Aorta branches into the celiac artery which shunts blood to the hepatic artery, stomach, spleen, & pancreas before going to the portal vein
The superior mesenteric artery shunts blood to the pancreas, small intestines and colon before going to the portal vein
The inferior mesenteric artery brings blood to the colon then becoming the portal vein
The portal vein and the hepatic artery feed into the liver which then feeds the hepatic veins and ultimately the inferior vena cava
Cirrhosis greatly increases the
resistance to blood flow
The most common cause of cirrhosis is
alcoholism
Other causes (besides alcoholism) of cirrhosis include
viral hepatitis obstruction of bile ducts infection in the bile ducts ingestion of poisons (carbon tetrachloride) non-alcoholic fatty liver disease
Describe how cirrhosis impedes portal vein blood flow.
destruction of liver parenchymal cells results in replacement with fibrous tissue that contracts around the blood vessels (bridging fibrosis)
greatly impedes portal vein blood flow
Stages of alcohol induced liver damage includes
fatty liver
liver fibrosis
cirrhosis
Describe the fatty liver stage.
deposits of fat causes liver enlargement
strict abstinence can lead to a full recovery
Describe the liver fibrosis stage.
scar tissue forms
recovery is possible but scar tissue remains
Describe the cirrhosis stage of alcohol induced liver damage.
growth of connective tissue destroys liver cells
the damage is irreversible!
Repeated exposure of hepatocytes to toxins can lead directly to
fibrosis and cirrhosis, most frequently, micronodular cirrhosis
The most common causes of non-alcoholic fatty liver disease are
obesity, DMII, & metabolic syndrome
-less common but possible are nutrition (patients on TPN) & medication (amiodarone)
Describe the adrenergic receptors located in the hepatic artery.
alpha 1- produces vasoconstriction
beta 2, dopaminergic 1 & cholinergic receptors- produce vasodilation
Describe the adrenergic receptors located in the portal vein.
alpha 1- produces vasoconstriction
dopaminergic 1- produces vasodilation
Sympathetic activation results in
hepatic artery and mesenteric vessel vasoconstriction and decreased hepatic blood flow
-beta 2 adrenergic stimulation vasodilates the hepatic artery
The liver is known as an
expandable organ- large blood reservoir
The livers normal blood volume is
450 mL- includes what is found in the hepatic veins + sinusoids
When high pressure occurs in the right atrium, it produces
back pressure causing the liver to expand
0.5-1 L of blood can be stored in the hepatic veins & sinusoids
When low pressure occurs in the body such as during hemorrhage,
the blood shifts from the hepatic veins and sinusoids into the central circulation (as much as 300 mL)
Hepatic macrophages serve a
blood cleansing function
Blood from the intestinal capillaries that enters the portal vein contains
many bacteria
- blood from the portal vein almost always grows bacilli when cultured but it is extremely rare to grow bacilli from a systemic blood smaple
Kupffer cells that line the hepatic venous sinusoids
cleanse the blood as it passes through the sinuses
-takes 0.01 second for a bacterium to pass into a Kupffer cell after coming into contact with the cell
the bacterium is then digested (phagocytosis)
Additional Kupffer cell roles include
phagocytose cellular debris, viruses, proteins, and particulate matter
release various enzymes, cytokines, and other chemical mediators
Kupffer cells are a part of the
monocyte-macrophage system AKA the reticuloendothelial system
The liver has very high
lymph flow
Pores in the sinusoids are very
permeable and allow easy passage of fluid and protein into the spaces of Disse
this permits large amounts of lymph with a protein concentration similar to plasma to form
About _____ of all lymph in the body comes from the liver
half
High hepatic vascular pressure causes
fluid transudation into the abdominal cavity
When above normal pressures occur in the hepatic vein, this results in
excessive amounts of lymph fluid
-can leak through the outer surface of the liver capsule into the abdominal cavity
A 10 to 15 mmHg increase in hepatic venous pressure can increase lymph flow
to 20x normal
produces ‘sweating’ from the liver surface with large amounts of free fluid entering the abdominal cavity resulting in ascites
Blockage of the portal vein produces high
pressure in the GI tract with transudation of fluid through the gut and into the abdominal cavity resulting in ascites
The liver is a large, chemically reactant pool of cells that:
have a high rate of metabolism
share substrates and energy from one system to another
process and synthesize multiple substances that are transported throughout the body (numerous enzymatic pathways)
The final products of carbohydrate metabolism are
glucose, fructose, and galactose
the liver ends up converting galactose and fructose into glucose for a common final pathway
Glucose is important because
all cells utilize glucose to produce energy in the form of ATP
Describe the 4 steps of carbohydrate metabolism.
Conversion of galactose and fructose to glucose
storage of large amounts of glycogen
gluconeogenesis
Formation of many chemical compounds from intermediate products of carbohydrate metabolism
Glucose, fructose, and galactose are called
simple sugars or monosaccharides
Most of the glucose absorbed following a meal is
normally stored as glycogen
Storage of glycogen allows the liver to
remove excess glucose from the blood, store it, and return it to the blood when BG concentration decrease: glucose buffer function
Glycogen is a readily available source of
glucose that does not contribute to intracellular osmolality
Glucose concentration in the blood after a carbohydrate rich meal can rise
2 to 3 times as much in a person with poor liver function as compared to a person with normal liver function
glycogen is a branched polymer of
glucose
When glycogen storage capacity is exceeded, the excess glucose is
converted to fat
The only organs capable of storing significant amounts of glycogen are
liver and muscle
Insulin enhances
glycogen storage
Epinephrine and glucagon enhance
glycogen breakdown (glycogenolysis)
Hepatic glycogen stores are depleted after
a 24 hour fast;
after this period gluconeogenesis is necessary to provide an uninterrupted supply of glucose
Gluconeogenesis occurs only when
BG concentration falls below normal
vital in maintenance of normal BG concentration
The liver (and kidney) are unique in their ability to
convert amino acids, glycerol, pyruvate, and lactate to glucose
Agents that increase gluconeogenesis:
glucocorticosteroids, catecholamines, glucagon, thyroid hormone
Agents that decrease gluconeogenesis are
insulin
When carbohydrate storage capacity is saturated the liver converts excess carbohydrates to
fat
Excess carbs that are converted to fat are fatty acids that are used for
fuel or stored in the adipose tissue and liver for later use
Most cells can directly use fatty acids as
an energy source
RBCs and the renal medulla can only use glucose
neurons normally use only glucose but can use ketone bodies produced in the liver by the breakdown of FAs following a few days of starvation
Specific liver functions associated with fat metabolism are
oxidation of FAs to supply energy for other body function (known as beta oxidation)
synthesis of large amounts of cholesterol, phospholipids, and lipoproteins
synthesis of fate from carbs & proteins
In order to derive energy from fat (triglycerides)
they must be split into glycerol & FAs
After fatty acids are split into glycerol and FAs, FAs are then split by
beta oxidation into 2- Carbon acetyl radicals that form acetyl coenzyme A (acetyl Co-A)
Acetyl Co-A then enters the
citric acid cycle and is oxidized to liberate tremendous amounts of energy
Beta oxidation can occur in all body cells but occurs especially rapidly in
hepatic cells
The liver CANNOT use all of the acetyl Co-A it produces, it is
converted to acetoacetic acid (combination of 2 acetyl Co-A molecules)
acetoacetic acid is highly soluble and leaves the hepatocytes, enters the blood, and is absorbed by other tissues
tissues reconvert the acetoacetic acid back into acetyl Co-A which enters the citric acid cycle and is oxidized to produce energy
in this way, the liver is responsible for a major part of fat metabolism
Acetyl Co-A is used by the liver to synthesize
cholesterol and phospholipids
About 80% of the cholesterol synthesized in the liver is converted to
bile salts and secreted into the bile
-the remaining cholesterol is packaged in lipoproteins and carried by the blood to all tissue cells in the body
Both cholesterol and phospholipids are used by body cells to form:
cell membranes intracellular structures chemical substances (hormones) important to cell function
____ are also synthesized in the liver and transported predominately in lipoprotiens
phospholipids
Fat metabolism is the
synthesis of fat from proteins & carbs which occurs primarily in the liver
After fat is synthesized, it is transported in
lipoproteins to the adipose tissue to be stored
Protein metabolism is a
critical liver function
-without this function death will occur in a few days
Specific liver functions associated with protein metabolism:
- deamination of proteins
- formation of urea for removal of ammonia from the body fluids
- formation of plasma proteins
- synthesis of amino acids and synthesis of other compounds from amino acids
Essential proteins are those
that cannot be made and must be eaten via the diet
Deamination of the amino acids in proteins is required before
they can be used for energy or before they can be converted to CHO or fats
Deamination is an
enzymatic process which converts AAs into their respective keto acids and results in production of ammonia as a byproduct
The primary site of deamination is
the liver
Deamination of alanine plays a major role in
hepatic gluconeogenesis
minor deamination of glutamine in the kidney
The liver normally deaminates most of the AAs derived from dietary protein consumption, the branched chain AAs are metabolized by
skeletal muscle
Urea forms from
ammonia
urea removes ammonia from the body fluids
Large amounts of ammonia are formed by
deamination process
bacteria in the gut with subsequent absorption into the blood
Urea readily diffuses out of
the liver and is excreted by the kidneys
this is due to its water solubility
If the liver does not perform the function of formation of urea,
ammonia concentration rises rapidly and results in hepatic coma and death
A greatly reduced blood flow through the liver can cause
excessive ammonia in the blood and toxicity
- a porta-caval shunt may be performed in patients with portal vein hypertension but then it can cause an increase in ammonia in the blood sense it bypasses the liver
All of the plasma proteins with the exception of the
immunoglobulins are formed by hepatocytes
The liver can form plasma proteins a the rate of
15 to 50 g/day
After the loss of as much as 1/2 of the plasma proteins, the liver
can replace them in about 1 to 2 weeks
Quantitatively the most important plasma proteins are
albumin which is responsible for maintaining a normal plasma osmotic pressure and the principal binding and transport protein for FAs, hormones, and drugs
alpha 1 antitrypsin
Qualitatively the most important plasma proteins are:
coagulation factors
The synthesis of AAs and other compounds from AAs are among the
most important functions of the liver
The so-called “non-essential” AAs can be synthesized in the
liver by interconversion of one AA to another
A keto acid is formed that has the same chemical composition as the AA to be formed
except at the keto oxygen
An amino radical is transferred from an
available AA to the keto acid to take the place of the keto oxygen
process takes many steps and is called transamination
Many exogenous substances including
drugs undergo hepatic biotransformation
-end products are inactivated or are made more water soluble and can be excreted in the urine or bile
Biotransformation involves
2 types of reactions
Phase 1 reactions modify substances through
CYP450 enzymes and mixed function oxidases
Reduction is
mainly catalyzed by the P450 enzymes
electron added to make it more water solbule
Oxidation is
90% of all reactions
often generates reactive oxygen species because carboxyl, epoxy, and hydroxyl groups are introduced into the parent compound
The CYP450 enzyme system can be induced by
ethanol, barbiturates, ketamine, and 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; this is known as cross-tolerance
CYP450 inhibitors include _______ and can_______
ranitidine, amiodarone, & ciprofloxacin
prolong the effects of other drugs by inhibiting these enzymes
Products of phase 1 reactions may be more
active than the parent compound or may be rendered cytotoxic
-think acetaminophen, isoniazid, halothane
Some drugs have a very high rate of hepatic extraction from the circulation meaning that
a decrease in their metabolic clearance is usually a product of reduced hepatic blood flow now hepatocyte dysfunction
drugs include lidocaine, morphine, verapamil, labetalol, & propranolol
Barbiturates and benzodiazepines are inactived by
phase 1 reactions
Drugs that are poorly extracted include
acetaminophen, diazepam, digitoxin, and warfarin
Compare the half-life volume of distribution and clearance of a normal liver versus liver disease.
liver disease patients have higher half-life & volume of distribution with a lower clearance
Phase II reactions which may or may not follow a phase I reaction involve
conjugation of a substance with a water metabolite
glucuronide (most common), sulfate, taurine, & glycine
Conjugated substances can be excreted
in the urine or bile
Vitamin K is a required cofactor for the synthesis of
Factors II (prothrombin), 7, 9, & 10
Vitamin K deficiency is manifested as a
coagulopathy due to impaired formation of factors 2, 7, 9, and 10
Factor VIII and von willebrand’s factor are
not produced by the liver
the liver is the primary site for degradation for
thyroid hormone, insulin, glucagon, ADH, and steroid hormones (cortisol, aldosterone, and estrogen)
Hepatocytes continuously secrete
bile salts, cholesterol, phospholipids, & conjugated bilirubin into the bile canaliculi
Bile ducts from hepatic lobules eventually form the
left and right hepatic ducts
these ducts combine to form the hepatic duct which with the cystic duct from the gallbladder forms the common bile duct
Flow of bile from the common bile duct is controlled by
Sphincter of Oddi
The Gallbladder serves as
reservoir for bile. through active transport of Na+ and passive H2O reabsorption the gallbladder concentrates biliary fluid
Cholecystokinin is a
hormone released from the intestinal mucosa in response to fat & protein that causes contraction of the gallbladder, relaxation of the Sphincter of Oddi and ejection of bile into the small intestine
Phase I reactions include
oxidation, reduction, hydrolysis, hydration, & dehalogeation
Phase II reactions include
sulfation, glucoronidation, gluthaione conjugation, acetylation, amino acid conjugation, and methylation
The liver is a storage site for vitamins and stores large quantities of
Vitamins A, B12, D, E, and K
enough A can be stored to prevent deficiency for 10 months
enough B12 can be stored for 1 or more years
enough D can be stored for 3 to 4 months
The liver stores iron as
ferritin
Hepatic cells produce and excrete large amounts of a protein called
apoferritin which can bind excess iron in body fluids
Apoferritin + iron equals
ferritin which is then stored in hepatocytes until the iron is needed elsewhere in the body
During low levels of iron in the circulation,
ferritin release iron
Iron is carried in the blood by
transferrin
The apoferritin-ferritin system acts as
an iron storage and buffer system
The major end product of hemoglobin degradation is
bilirubin
Bilirubin is excreted in
the bile and eliminated in the feces
Bilirubin is a valuable tool for diagnosing
hemolytic blood disease and various types of liver disease
After ___ days, RBCs become fragile and their cell membranes rupture
120
The released hemoglobin that is fractured is
phagocytized by tissue macrophages
Describe the process of hemoglobin breakdown.
The hemoglobin is split into globin & heme
the heme ring is opened and the Fe is release and is transported in the blood by Transferrin
The 4 pyrrole rings of the porphyrin structure are converted to biliverdin
biliverdin is rapidly converted to free bilirubin and released from the macrophages
the free bilirubin immediately combines with plasma albumin
The simplistic version of the hemoglobin breakdown is:
hemoglobin–> globin + heme–> Fe + pyrrole rings–> biliverdin–> free bilirubin–> bilirubin + albumin
Bilirubin bound to plasma albumin is called
“free bilirubin”, unconjugated or indirect bilirubin
Free bilirubin is absorbed by
hepatocytes and released from albumin
Bilirubin is then conjugated with
glucoronide
sulfate
Conjugated bilirubin (direct bilirubin) is excreted from the
hepatocytes by an active transport process into the bile canaliculi and then into the intestines
In the intestine about 1/2 of the conjugated bilirubin is converted by
bacteria to urobilinogen which is reabsorbed back into the blood
-some of this is then excreted in the urine
majority of this is re-excreted by the liver back into the intestines and eliminated in the feces
