Download biochem ch 46 [9-4

Liver Anatomy
 Liver receives 75% of blood supply from portal vein (carries blood from small intestine, stomach, pancreas, and
spleen) and 25% from hepatic artery
o Blood from portal vein and hepatic artery mix contents as they enter liver sinusoids
o As blood flows through sinusoids, contents of plasma have relatively free access to hepatocytes (on
other side of endothelial cells)
 Exocrine organ – secretes bile into biliary drainage system
o Hepatocytes secrete bile into canniculus, which flows countercurrent w/sinusoids
o Canniculi empty into bile ducts, which fuse into common bile duct
 Liver surface covered by CT capsule that provides support for blood, bile, and lymphatic vessels; divides liver
lobes into smaller lobules
Liver Cell Types
 Hepatocyte – also called hepatic parenchymal cells; pathways controlled through actions of hormones that bind
to receptors in PM of cells
o Low turnover and long life span; can be stimulated to grow if liver damaged
o Liver mass has relatively constant relationship to total body mass of adult individuals; deviation from
optimal ratio rapidly corrected by proportional increase in hepatocyte replication
 Lining cells of sinusoids
o Endothelial cells – contain fenestrations; no tight BM between them and hepatocytes; small molecules
can get through (not chylomicrons, but chylomicron remnants)
 Capable of endocytosing ligands; secrete cytokines when properly stimulated
 Fenestrations promote free passage of blood components through membrane into parenchyma
o Kupffer cells – tissue macrophages w/endocytotic and phagocytotic capacity; phagocytose denatured
albumin, bacteria, and immune complexes
 Protect liver from gut-derived particulate materials and bacterial products
 When stimulated by immunomodulators, secrete mediators of inflammatory response and
release cytokines that lead to inactivation of foreign substances
 Remove damaged RBCs from circulation
o Hepatic stellate cells – perisinusoidal or Ito cells; lipid-filled cells; primary storage site for vitamin A
 Control turnover of hepatic CT and ECM
 Regulate contractility of sinusoids
 When cirrhosis present, stellate cells stimulated by signals to increase synthesis of ECM, which
diffusely infiltrates liver, interfering w/function of hepatocytes
o Pit cells – liver-associated lymphocytes; NK cells against tumor cells or viruses
Major Functions of the Liver
 Nutrients and wastes from metabolism enter liver through hepatic artery, and nutrients and wastes just
ingested enter liver through portal vein
 Efficient exchange of compounds between sinusoidal blood and hepatocytes comes from fenestrations in
endothelial cells, lack of BM, and low portal BP (resulting in slow blood flow)
 Liver can convert all amino acids into glucose, fatty acids, or ketone bodies
 Secretion of glycoproteins by liver done through gluconeogenic capacity and liver’s access to dietary sugars to
form oligosaccharide chains; also access to dietary amino acids to synthesize proteins
 Specifically designed molecules that target specific hepatic receptors can be used to measure hepatic blood flow
and transport capacity of specific hepatic transporter proteins
 Xenobiotics – compounds that have no nutrient value; potentially toxic
o Many lipophilic, so oxidized, hydroxylated, or hydrolyzed by enzymes in phase I reactions (introduce or
expose hydroxyl groups or other reactive sites that can be used for conjugation (phase II) reactions)
o Conjugation reactions add negatively charged group (glycine or sulfate); secondary metabolite suitable
for excretion
o Major sites of biotransformation – liver, kidney, and intestine
o Contain aromatic rings or heterocyclic ring structures unable to be degraded or recycled into useful
components; hydrophobic, causing molecules to be retained in adipose tissue unless sequestered by
liver, kidney, or intestine for biotransformation
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Sometimes, phase I and phase II reactions turn harmless hydrophobic molecules into toxins or
carcinogens
Conjugation and inactivation pathways also used for inactivation of liver’s own metabolic waste products
o Sulfation used by liver to clear steroid hormones from circulation; sulfate comes from degradation of
cysteine or methionine
Key enzymatic constituents of cytochrome P450-dependent monooxygenase enzymes are NADPH-cytochrome
P450 oxidoreductase and cytochrome P450
o P450 is terminal electron acceptor and substrate-binding site of microsomal mixed-function oxidase
complex; called P450 because when reduced and complexed with CO, absorbance max is 450 nm
o Major role is to oxidize substrates and introduce oxygen to the structure
o P450 enzyme family contains 57 functional genes w/40% sequence homology (overlapping specificity)
 Divided into 9 major families (each subdivided)
 Nomenclature – CYP2E1  CYP denotes cytochrome P450 family, 2 denotes subfamily, E
denotes ethanol, and 1 denotes specific isozyme (CYP2E1 converts EtOH to acetaldehyde)
o CYP3A4 accounts for 30-40% of CYP450 enzymes in liver and 70% of cytochrome enzymes in gut wall
enterocytes
 Metabolizes greatest number of drugs; concomitant ingestion of substrates could induce
competition for binding site, which could alter blood levels
 Many substances impair or inhibit activity (i.e., grapefruit juice)
 HMG-CoA reductase inhibitors require CYP3A4 for degradation; consistently taking it
w/grapefruit juice could increase level in blood to point where it increases muscle and
liver toxicity of statins
o Cytochrome P450 isozymes have features in common
 Contain cytochrome P450, oxidize the substrate, and reduce oxygen
 Have flavin-containing reductase subunit that uses NADPH as substrate
 Found in sER and referred to as microsomal enzymes
 Bound to lipid portion of membrane, probably to phosphatidylcholine
 Inducible by presence of best substrate and somewhat less inducible by substrates for other
P450 isozymes
 Generate reactive free radical compound as intermediate in reaction
o Vinyl chloride – used in synthesis of plastics and can cause angiosarcoma in liver of exposed workers
 Activated in phase I to reactive epoxide by CYP2E1; epoxide can react w/guanine in DNA or can
be converted to chloroacetaldehyde, conjugated w/reduced glutathione, and excreted in series
of phase II reactions
o Aflatoxin B1 – made more toxic by CYP2A1; produced by Aspergillus flavus fungus that grows on peanuts
stored in damp conditions
 Directly involved in hepatocarcinogenesis by introducing G T mutation in p53 gene
 Metabolically activated to 8,9-epoxide by 2 isozymes of cytochrome P450; epoxide modifies
DNA by forming covalent adducts w/guanine residues
 Epoxide can combine w/lysine residues in proteins and be hepatotoxin
o Acetaminophen – metabolized by liver for safe excretion; can be glucuronylated or sulfated for safe
excretion by kidney
 NAPQI is toxic intermediate which can be excreted safely in urine after conjugation
w/glutathione; unstable metabolite
 Can damage cellular proteins and lead to death of hepatocyte
 In high doses, too much NAPQI produced to detoxify properly; results in hepatocyte death
 Individuals who chronically abuse EtOH have increased sensitivity to acetaminophen toxicity
because higher percentage of metabolism directed toward NAPQI
 Effective treatment for acetaminophen poisoning involves use of N-acetyl cysteine, which
cysteine as precursor for increased glutathione production, which enhances phase II reactions,
which reduces NAPQI levels
Insulin and glucagon affect liver glycogenolysis, glycogen synthesis, glycolysis, and gluconeogenesis
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Sustained physiologic increases in GH, cortisol, and catecholamine secretion help sustain normal blood
glucose levels during fasting
o When blood glucose drops, glycolysis and glycogen synthesis inhibited and gluconeogenesis and
glycogenolysis activated; fatty acid oxidation activated
 During overnight fast, blood glucose maintained primarily by glycogenolysis and (if
gluconeogenesis required), energy (6 ATP per glucose molecule) obtained by fatty acid oxidation
o On insulin release, opposing pathways activated such that excess fuels can be stored as either glycogen
or fatty acids; pathways regulated by activation or inhibition of CPK and AMP-activated protein kinase
o Liver can export glucose because it is one of only 2 tissues that express glucose 6-phosphatase
When food supplies plentiful, hormonal activation leads to fatty acid, triacyl-glycerol, and cholesterol synthesis
o High dietary intake and intestinal absorption of cholesterol compensatorily reduces rate of hepatic
cholesterol synthesis; liver acts as recycling depot for sending excess dietary cholesterol to peripheral
tissue when needed as well as accepting cholesterol from tissues when required
Liver is primary organ for synthesizing urea and is central depot for disposition of ammonia in body
o Ammonia travels to liver on glutamine and alanine, and liver converts ammonia nitrogens to urea for
excretion in urine
Liver is only organ that can produce ketone bodies; thus can’t use for energy production (everything else can)
o Ketone bodies produced when rate of glucose synthesis limited (i.e., substrates for gluconeogenesis
limited) and fatty acid oxidation occurring rapidly
o Ketone bodies can cross BBB and become major fuel for nervous system under starvation conditions
Cirrhosis of liver results in portal HTN which, because of increasing back pressure into esophageal veins,
promotes development of dilated thin-walled esophageal veins (varices)
o Synthesis of blood coagulation proteins by liver and required vitamin K-dependent reactions diminished,
resulting in prolonged PT, which in turn increases clotting time
o When esophageal varices rupture, massive bleeding into thoracic or abdominal cavity as well as stomach
may occur
o Much of protein content of blood entering GI tract metabolized by intestinal bacteria, releasing NH4+,
which enters portal vein
o Urea cycle capacity inadequate due to compromised hepatocellular function; NH4+ enters peripheral
circulation, contributing to hepatic encephalopathy
Liver can synthesize and salvage all ribonucleotides and deoxyribonucleotides for other cells to use
o Liver can secrete free bases into circulation for cells to use to convert to nucleotides
Liver is primary site of synthesis of circulating proteins (i.e., albumin and clotting factors)
o Hypoproteinemia may lead to edema because of decrease in protein-mediated osmotic pressure in
blood, causing plasma water to leave circulation and enter interstitial space (edema)
o Because of synthesizing protein, hepatocytes have well-developed ER, Golgi system, and cellular
cytoskeleton
o Albumin important osmotic regulator in maintenance of normal plasma osmotic pressure
o Glycoproteins function in hemostasis, transport, protease inhibition, and ligand binding and as
secretagogues for hormone release
o Acute-phase proteins part of immune response and body’s response to injury synthesized in liver
Liver has high requirement for sugars that go into oligosaccharide portion of glycoproteins (mannose, fructose,
galactose, and amino sugars)
o Liver not dependent on glucose to generate precursor intermediates for pathways because liver can
generate carbs from dietary amino acids (enter gluconeogenesis as pyruvate or intermediate of TCA
cycle), lactate (generated from tissue glycolysis), and glycerol (generated by release of free fatty acids
from adipocyte)
o Most sugars secreted by liver O-linked (carb attached to protein at anomeric C through glycosidic link to
–OH of serine or threonine residue; as opposed to N-linked where N-glycosyl link to amide N of
asparagine residue
o NANA (sialic acid) – sugar synthesized from fructose-6-phosphate and PEP; as circulating proteins age,
NANA residues lost from serum proteins, signaling removal from circulation and eventual degradation
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Asioaloglycoprotein receptor on liver cell surface binds proteins w/less NANA residues, and
receptor-ligand complex endocytosed and transported to lysosomes
 Amino acids from degraded protein recycled within liver
 Major functions of pentose phosphate pathway – generation of NADPH and 5-C sugars
o All cell types, including RBCs carry out this pathway because they need to generate NADPH so activity of
glutathione reductase (enzyme that catalyzes conversion of oxidized glutathione (GSSG) back to reduced
glutathione (GSH) can be maintained
 w/o glutathione reductase, protection against free radical injury lost
o All cells need pathway for generation of ribose
o Liver has much greater demand for NADPH because it uses it for biosynthesis of fatty acids and
cholesterol (used to produce phospholipids) and VLDL and bile salts
 Liver uses NADPH for proline synthesis
 NADPH used by mixed-function oxidases involved in metabolism of xenobiotics
 Liver uses more glutathione and NADPH to maintain glutathione reductase and catalase activity
than any other tissue; concentration of glucose-6-P dehydrogenase (rate-limiting and regulated
enzyme in pentose phosphate pathway) high in liver
Fuels for the Liver
 Principal forms in which energy supplied to liver are high-energy phosphate bonds of ATP, UTP, and GTP,
reduced NADPH, and acyl-CoA thioesters
o Energy for formation of above obtained directly from oxidative metabolism, TCA cycle, or electrontransport chain and oxidative phosphorylation
 After mixed meal, major fuels used by liver are glucose, galactose, and fructose; if EtOH consumed, liver is major
site of EtOH oxidation, yielding acetate and then acetyl-CoA
 During overnight fast, fatty acids become major fuel for liver; oxidized to CO2 or ketone bodies
o Liver can use all amino acids as fuels (use of BCAAs small compared to muscles)
o Urea cycle disposes of ammonia generated from amino acid oxidation
 Liver is major site for use of dietary galactose and fructose; metabolizes them by converting them to glucose and
intermediates of glycolysis
 Entry of glucose into liver dependent on high concentration of glucose in portal vein after high-carb meal
o Km for both glucose transporter (GLUT2) and glucokinase so high, glucose enters liver principally after
concentrations rise in portal blood and not at lower concentration in hepatic artery
o Increase in insulin secretion promotes conversion of glucose to glycogen
 PFK-2 kinase activity active, thus PFK-1 activated by F-2,6-P2, so acetyl-CoA produced for fatty
acid synthesis (acetyl-CoA carboxylase activated by citrate)
o Rate of glucose use by liver determined in part by level of activity of glucokinase, which is regulated by
glucokinase regulatory protein (RP) located in nucleus
 In absence of glucose, glucokinase partially sequestered in nucleus bound to RP in inactive form
 High concentrations of F-6-P promote interaction of glucokinase w/RP; high levels of either
glucose or fructose-1-P block glucokinase from binding to RP and promote dissociation
 RP important for post-transcriptional processing of mRNA for glucokinase; in absence of RP, less
glucokinase produced
o Major regulatory step for liver glycolysis is PFK-1 step
 Even under fasting conditions, ATP concentration in liver high enough to inhibit PFK-1 activity
 Liver glycolysis basically controlled by modulating levels of F-2,6-P2 (product of PFK-2 reaction)
 Increased glucagon activates PKA so PFK-2 phosphorylated and kinase activity inactive
o Glucokinase activators in investigation for type 2 diabetes treatment – enhance glucose metabolism in
pancreas, resulting in increased insulin release
 Fructose-1-phosphate produced from fructose metabolism
o Major dietary source of fructose is sucrose (glucose + fructose)
o Elevation of fructose-1-phosphate indicates elevation of glucose levels as well
 Long-chain fatty acids major fuel for liver during fasting
o Released from adipose tissue triacylglycerols and travel to liver as fatty acids bound to albumin
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In liver, they bind to fatty acid-binding proteins and are activated on outer mitochondrial membrane,
peroxisomal membrane, and sER by fatty acyl-CoA synthetases
o Fatty acyl group transferred from CoA to carnitine for transport through inner mitochondrial membrane,
where it is reconverted back into fatty acyl-CoA and oxidized to acetyl-CoA in β-oxidation spiral
o Enzymes in fatty acid activation and β-oxidation specific for length of fatty acid C chain (long-chain,
medium-chain, and short-chain); major lipids oxidized in liver as fuels are long-chain (palmitic, stearic,
and oleic acids) because they are synthesized in liver (major lipids ingested from meat or dairy sources
and major form of fatty acids present in adipose tissue triacylglycerols)
o Use fatty acids as fuels when concentration of fatty acid-albumin complex increased in blood
Liver and kidney are major sites for oxidation of medium-chain fatty acids; usually enter diet of infants in
maternal milk as medium-chain triacylglycerols (MCTs)
o In intestine, MCTs hydrolyzed by gastric lipase, bile salt-dependent lipases, and pancreatic lipase more
readily than LCTs
o In enterocytes, hydrolyzed MCTs released directly into portal circulation (fatty acids that short are
somewhat water-soluble); in liver, they diffuse through inner mitochondrial membrane and are
activated to acyl-CoA derivatives by medium-chain fatty acid-activating enzyme (MMFAE; present only
in kidney and liver)
o Medium-chain fatty acyl-CoA oxidized by MCAD
Peroxisomes present in greater numbers in liver than any other tissues; contain enzymes for oxidation of very
long-chain fatty acids (C24:0 and phytanic acid), cleavage of cholesterol side chain necessary for synthesis of bile
salts, step in biosynthesis of ether lipids, and several steps in arachidonic acid metabolism
o Peroxisomes contain catalase and are capable of detoxifying H2O2
o Very long-chain fatty acids activated to CoA derivatives by very long-chain acyl-CoA synthetase in
peroxisomal membrane; derivatives oxidized in peroxisomes to 8-C octanoyl-CoA level
o First enzyme in peroxisomal β-oxidation introduces double bond and generates H2O2 instead of FAD(2H);
rest of cycle is same, releasing NADH and acetyl-CoA
o Catalase inactivates H2O2, and acetyl-CoA can be used in biosynthetic pathways (cholesterol & dolichol)
o Octanoyl-CoA leaves peroxisomes and octanoyl group transferred through inner mitochondrial
membrane by medium-chain-length acylcarnitine transferase
 In mitochondria, it reenters β-oxidation via MCAD
o Zellweger (cerebrohepatorenal) syndrome occurs in individuals w/inherited absence of peroxisomes in
all tissues; patients accumulate polyenoic acids in brain tissue because of defective peroxisomal
oxidation of very long-chain fatty acids synthesized in brain for myelin formation
 In liver, bile acid and ether lipid synthesis affected, as is oxidation of very long-chain fatty acids
Peroxisome proliferator-activated receptors (PPARs) play important role in liver metabolism
o Hypolipidemic agents, NSAIDs, and environmental toxins can induce proliferation of peroxisomes in liver
 Receptors that bind above agents (PPARs) stimulate new gene transcription
o Major form of PPAR regulates directly activity of genes involved in fatty acid uptake, β-oxidation, and ωoxidation
o Major PPAR in liver is PPARα; fatty acids are endogenous ligand for PPARα (when level of fatty acids in
circulation increased, there is increased gene transcription for proteins involved in regulating fatty acid
metabolism)
 Problems w/ PPARα cause fatty infiltration of liver during fasting or on high-fat diet
 Inability to increase rate of fatty acid oxidation leads to excessive fatty acid buildup in
hepatocytes and insufficient energy supply with which to make glucose (hypoglycemia)
as well as inability to produce ketone bodies
 Fatty acids eventually stimulate their own oxidation via peroxisome proliferation and
induction of other enzymes needed for oxidation, but PPARα mutations can’t do this
 Fibrates – class of drugs that bind to PPARs to elicit changes in lipid metabolism
 Prescribed for elevated triglyceride levels because they increase rate of triglyceride
oxidation, leading to reduction in serum triacylglycerol levels
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Fibrates, through PPARα stimulation, suppress apoCIII synthesis and stimulate LPL
activity (apoCIII inhibits LPL activity and blocks apoE on IDL, causing IDL particles to
accumulate because they can’t be taken up in liver)
Liver uses pathways of fatty acid metabolism to detoxify hydrophobic and lipid-soluble xenobiotics that either
have carboxylic acid groups or can be metabolized to compounds that contain carboxylic acids
o Benzoate naturally present in plant foods and added to foods such as soda as preservative; structure
similar to that of salicylic acid (derived from degradation of aspirin)
o Salicylic acid and benzoate similar in size to medium-chain-length fatty acids and are activated to acylCoA derivative by MMFAE; acyl group conjugated w/glycine, which targets compound for urinary
excretion
 Salicylurate – glycine derivative of salicylate; major urinary metabolite of aspirin
 Hippurate – glycine derivative of benzoate
o Benzoate has been used to treat hyperammonemia associated w/congenital defects because urinary
hippurate excretion tends to lower free ammonia pool
Reye’s syndrome – vomiting w/signs of progress CNS damage; signs of hepatic injury and hypoglycemia
o Mitochondrial dysfunction w/decreased activity of hepatic mitochondrial enzymes
o Hepatic coma may occur as serum NH3 levels rise
o Associated w/consumption of aspirin by children during viral illness; may occur in absence of exposure
to salicylates
o Liver shows swollen and disrupted mitochondria and extensive accumulation of lipid droplets w/fatty
vacuolization of cells in both liver and renal tubules
Chronic parenchymal liver disease associated w/reduction of LCAT activity
o LCAT synthesized and glycosylated in liver, enters blood where it catalyzes transfer of fatty acid from 2position of lecithin to 3-β-OH group of free cholesterol to produce cholesterol ester and lysolecithin
o In severe parenchymal liver disease, LCAT activity decreased, plasma levels of cholesterol ester reduced
and free cholesterol levels normal or increased
o Plasma triacylglycerols normally cleared by peripheral lipases (LPL and HTGL); activities of both reduced
in hepatocellular disease, so relatively high level of plasma triacylglycerols found in acute and chronic
hepatitis, cirrhosis of liver, and diffuse hepatocellular disorders
o With low LCAT activity and elevated triacylglycerol level, LDL particles have abnormal composition
(triacylglycerol-rich and cholesterol ester-poor)
o HDL metabolism may be abnormal because conversion of HDL3 (less anti-atherosclerotic) to HDL2 (more
anti-atherosclerotic) catalyzed by LCAT
 Reduced activity of LCAT in patients w/cirrhosis leads to decrease in HDL2:HDL3 ratio
 Conversion of HDL2 to HDL3 requires hepatic lipases
 Because HDL2:HDL3 ratio elevated in cirrhosis, lipase deficiency more dominant mechanism
 Results in overall increase in total HDL levels
o Hepatic production of VLDL impaired w/severe parenchymal liver disease; total level of plasma
triacylglycerols relatively normal because LDL is triacylglycerol-rich
o NEFA levels elevated in patients w/cirrhosis because basal hepatic glucose output low
 More NEFA required (via increased lipolysis) to meet fasting energy requirements of peripheral
tissues)
 NEFA levels determined using enzyme-coupled reactions; mixed w/CoA and acyl-CoA
synthetase, which creates acyl-CoA, which is oxidized by acyl-CoA oxidase, producing H2O2,
which is used as source of electrons by peroxidase to reduce chromogenic substrate (color)
Liver is principal site of amino acid metabolism; balances free amino acid pool in blood through metabolism of
amino acids supplied from diet as well as those supplied by skeletal muscles during overnight fast
o Total protein content of body on daily basis approximately constant, so net degradation of amino acids
equal to amount consumed
o Liver contains all pathways for catabolism of all amino acids and can oxidize most carbon skeletons to
CO2; small proportion of carbon skeletons converted to ketone bodies
o Liver contains pathways for converting amino acid carbon skeletons to glucose
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After mixed or high-protein meal, gut uses dietary aspartate, glutamate, and glutamine as fuel (during
fasting, gut uses glutamine from blood as major fuel); ingested acidic amino acids don’t enter general
circulation; N from gut metabolism passed to liver as citrulline or NH4+ via portal vein
o BCAAs (valine, leucine, isoleucine) can be used as fuel by most cell types; after high-protein meal, most
BCAAs not oxidized by liver because of low activity of BCAA transaminase (instead enter peripheral
circulation to be used as fuel by other tissues or for protein synthesis)
 BCAAs are essential amino acids
 Liver takes up whatever amino acids needed to carry out its own protein synthesis
o Most tissues transfer amino acid N to liver to dispose of as urea; produce either alanine (pyruvateglucose-alanine cycle in skeletal muscle, kidney, and intestinal mucosa), glutamine (skeletal muscle,
lungs, neural tissues), or serine (kidney), which are released into blood and taken up by liver
o Liver uses amino acids for synthesis of proteins it requires as well as proteins to be used elsewhere
 Liver uses carbon skeletons for synthesis of heme, purines, and pyrimadines (amino acids
nonessential)
 Alcohol-induced cirrhosis characterized by diffuse fine scarring, fairly uniform loss of hepatic cells, and formation
of small regenerative nodules (micronodular cirrhosis)
o Fibroblasts and activated stellate cells deposit collagen at site of persistent injury, leading to formation
of web-like septa of CT in periportal and pericentral zones, which will eventually connect portal triads
and central veins
o Liver shrinks and becomes nodular and firm as end-stage cirrhosis develops
o Unless weaned of alcohol, person dies of liver failure
 Concentration of amino acids in blood of liver disease patients elevated because of increased rate of protein
turnover (general catabolic effect in severely ill patients) as well as impaired amino acid uptake by diseased liver
o Total protein content of liver small, so muscle is major source of elevated amino acids in catabolic states
o In cirrhotic patients, fasting blood α-amino nitrogen level elevated as result of reduced clearance
 Urea synthesis reduced as well
o Plasma profile of amino acids in cirrhosis – elevated aromatic amino acids (phenylalanine and tyrosine)
and free tryptophan and methionine (caused by impaired hepatic use of amino acids as well as
portosystemic shunting)
 Reduction of BCAAs seen (not known why)
 Most of free amino acid pool in intracellular space, so changes seen in plasma concentrations
don’t necessarily reflect general metabolic fate
 Elevation of aromatics and suppression of BCAAs implicated in pathogenesis of hepatic
encephalopathy
Diseases of the Liver
 Signs and symptoms of liver disease include elevated ALT and AST in plasma (caused by hepatocyte injury or
death), jaundice (accumulation of bilirubin in blood caused by inefficient bilirubin glucuronidation by liver),
increased clotting times, edema (reduced albumin synthesis), and hepatic encephalopathy (reduced urea cycle
leads to excessive ammonia and toxic compounds in CNS)
Hepatic Fibrosis
 Major change when fibrosis initiated is sparse, leaky BM between endothelial cell and hepatocyte replaced
w/high-density membrane containing fibrillary collagen – occurs because increased synthesis of different type of
collagen than normal and reduction in turnover rate of existing ECM components
 Supportive tissues of normal liver contain ECM that includes type IV collagen (doesn’t form fibers),
glycoproteins, and proteoglycans
o After insult to liver, increase in ECM components, some of which contain fibril-producing collagen (types
I and III), glycoproteins, and proteoglycans
o Accumulation of fibril-producing compounds leads to loss of endothelial cell fenestrations; interferes
w/normal transmembrane metabolic exchanges between blood and hepatocytes
 Stellate cell is source of increased and abnormal collagen production; activated by growth factors whose
secretion is induced by injury to hepatocytes or endothelial cells
o Growth factors involved include TGF-β1 (from endothelial cells, Kupffer cells, and platelets) and PDGF
and EGF (from platelets)
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Release of PDGF stimulates stellate cell proliferation and increases their synthesis and release of ECM
materials and remodeling enzymes, including MMPs and tissue inhibitors of MMPs, as well as converting
(activating) enzymes
o Cascade leads to degradation of normal ECM and replacement w/denser, more rigid type of matrix
material; partially result of increase in activity of tissue inhibitors of MMPs for new collagen relative to
original collagen in ECM
Increasing stiffness in liver increases resistance to blood flow through liver; blood flow resistance also increased
by loss of vascular endothelial cell fenestrations, loss of free space between endothelial cells and hepatocytes
(space of Disse), and loss of vascular channels
o Increased vascular resistance leads to elevation of intrasinusoidal fluid pressure
o When portal HTN reaches critical threshold, shunting of portal blood away from liver contributes to
further hepatic dysfunction
o When increasing intraesophageal venous pressure becomes severe enough, walls of veins thins
dramatically and expand to form varices, which may burst suddenly