02.01.12(a): Liver Physiology

Author(s): Rebecca W. Van Dyke, M.D., 2012

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M2 GI Sequence

Liver Physiology

Rebecca W. Van Dyke, MD

Winter 2012

Learning Objectives

• At the end of this presentation students should be able to:• 1. Describe the basic organization of the liver cell plate and its functional • consequences:• a. Blood supply• b. Configuration of hepatocytes• c. Configuration of other liver cells• d. Concentration gradients in sinusoidal blood.• 2. Describe the basic physiological processes the liver utilizes to accomplish

function:• a. transport• b. metabolism• c. biotransformation• d. synthesis• e. secretion• 3. Be able to give examples of the consequences of liver damage on above

processes.• 4. Be able to give examples of possible consequences of liver disease/injury on liver

barrier function and hepatic regeneration.

Industry Relationship DisclosuresIndustry Supported Research and

Outside Relationships

• None

Pancreas

Hepatic artery systemic input

Vena cava systemic outflow

Intestine

Portal venous inflow from gut, spleen and pancreas

Unique Position and Blood Supply of the Liver

Cystic arterysole supply to bile duct

Anatomy of Liver Acinus

portal vein

bile duct

hepatic artery

portal triad

central vein

sinusoids

blood flowbile

Michigan Histology Collection

liver

pancreas

spleenPortal vein: 80%

Hepatic artery: 20%

Dual Blood Supply of Liver

Regents of the University of Michigan

Liver has dual blood supply: 80% portal vein 20% hepatic artery

What are the Functional Consequences of….?

• Increased vena caval pressure/hepatic vein obstruction?

• Decreased hepatic artery blood flow? and/or Decreased portal vein blood flow?

• Effects on the bile duct?

Budd-Chiari Syndrome: Obstruction of the Hepatic Vein(s)

Normal Budd-Chiari

Hemorrhage inpericentral area;hepatic vein obscured

Dilated upstreamsinusoids;atrophic/ischemichepatocytes

Decreased inflow: ischemic infarction

Bile Duct

• Sole blood supply to the bile duct is through the hepatic artery via the cystic artery

• Reduced blood flow through the hepatic artery causes ischemic injury to the extrahepatic bile ducts

• Ischemia or damage to the bile duct often leads to injury, fibrosis, stricture

Liver CellAnatomy:

Considerfunctionalconsequences

Image showing relationship between sinusoid, sinusoid lining cells, and hepatocyte removed.

Scanning Electron micrograph of Liver

Cells in Liver Sinusoid

American Gastroenterological Association

Functional Consequences of Fenestrated Sinusoidal

Endothelium?

Space of Disse

Albumin

Other serumproteins

Kupffer Cell

Tissue macrophage

Filtration devicebacteria, endotoxin

Releases inflammatory mediatorsthat influence hepatocytespositively or negatively

Looking Down a Sinusoid at a Kupffer Cell Poised to Grab Passing Bacteria

Kupffer cells (red)

Ito Cell/Fat-storing Cell

Rare cell, located in sinusoids underendothelium

Stores lipophilic materials such asVitamin A

Stimulated by chronic inflammation/alcoholconverts to myofibroblastproduces collagen and extracellular matrix

Responsible for much of the excess fibroticmaterial in cirrhosis

Ito Cell (Fat-storing Cell) on a Sinusoid (S)

Hepatic Stellate (Ito) Cell(arrows)

Pancreas

Hepatic artery carries circulating nutrients, hormones

Vena cava systemic outflow

Intestine

Portal venous inflow from gut carries products of digestion and pancreatic hormones

Unique Position and Diverse Functions of the Liver: Metabolic Center and Biochemical Factory

Glucose Amino Acids Lipids

Glucose Amino acids Lipids

Liver regulates nutrient flow to systemic circulation during feeding and fasting Liver synthesizes and releases blood proteins Liver takes up and disposes of a wide variety of compounds

The Liver:The Body’s Refinery

Glucose

TCA cycle

Gluconeo- genesis

Glucose

Fed state

Glucose

Fasted state

Amino acids from muscle/cell protein

Glycogen

Other Sugars

Acetyl-CoA

Fatty acid and

Triglyceride synthesis

Liver and Glucose Metabolism

GLUT-2

Defects in Glucose Metabolism in Liver Disease

Acute liver failure: Hypoglycemia (rapid neuronal death)

Chronic liver disease: Insulin resistance and diabetes(unknown mechanism)

Amino AcidsHepatic proteins

Secreted proteins

Albumin Clotting factors

Lipoproteins

TCA cycle

Urea synthesis

Gluconeogenesis

Glucose

Glucose

Ketones

Ketones

Amino Acids

Fed state

Dietary protein

Fasted state

Release from muscle/cell protein

Glycogen

Liver and Amino Acid Metabolism

UREA

Glucose Ketones

Ketones

Fed state

Dietary Triglyceride CM remnants

Fatty acids (adipose tissue)

-oxidationAcetyl-CoA

Prostaglandin synthesis

Phospholipids

Triglycerides

VLDL

VLDL

Fasted state

Apolipo- proteins

Amino acids

FATTY ACIDS

Liver and Lipid Metabolism

hepatocyte

albumin

FABP

free fatty acid pool

excess glucose, amino acidsto

mitochondria for energy

esterification to TAG

Apo B100cholin

e

cholesterol esters

VLDL

Regents of the University of Michigan

Fatty acid metabolism within hepatocytes

LDLCholesterol

Chylomycrons TG

CM remnants TG

BILECholesterolBile acidsPhospholipids

LiverGut

Greater Role of the Liver in Production and

Metabolism of Lipoproteins and Lipids

VLDL-TG

HDL Chol.

Glucose

Fed state (excess)

Dietary triglyceride CM remnants

Fatty acids (adipose tissue)

FATTY ACIDS

-oxidationAcetyl-CoA

Triglycerides

VLDL

VLDL

Fasted state (insulin deficiency)

Apolipo- proteins

+

+ +

-

-

-

Mechanisms Causing Fatty Liver

+

+

Fatty Liver with Inflammation

Hepatic arterycarries arterialblood with blood proteins

Vena cavasystemic outflow

Portal vein carriesvenous blood fromintestine, spleen andpancreas

Liver synthesizes and secretes: Lipoproteins Albumin Clotting factors Anti-proteases (1-anti-trypsin) Fibrinogen Complement factors Ceruloplasmin Transferrin and other binding proteins

Liver as Protein Synthetic Machine

Protein Secretion Defects in Liver Disease

Example Clinical Consequence Albumin Decreased plasma oncotic pressure/

edema Decreased binding of hydrophobic

compounds Clotting factors : Decreased factors II, VII, IX and X Increased bleeding Fibrinogen Decreased fibrin formation in clotting

Defects in Protein Synthesis/release also cause liver disease: Alpha1-Anti-trypsin Deficiency

Image of pathophysiology of alpha-1-anti-trypsin deficiency removed

PAS Stain Showing Retained Globs of MutantAlpha1 Anti-trypsin Protein in Hepatocyte ER

Lipoprotein release: another liver synthetic function

VLDL: a combination of fat andprotein

Pancreas

Hepatic artery systemic input

Vena cava systemic outflow

Intestine

Portal venous inflow from gut, spleen and pancreas

Unique Position and Blood Supply of the Liver The unique position and

blood supply of the liveralso affect liver physiology

Anatomy of Liver Acinus

portal vein

bile duct

hepatic artery

portal triad

central vein

sinusoids

blood flowbile

Michigan Histology Collection

Effect of Efficient Extraction by Hepatocytes in Series

Portal Vein Input

100%

Hepatic Vein

Output

5%

Efficient Extraction of Oxygen by Hepatocytes in Series

Portal vein = 80% of

flow p02 = 44 mm

Hg Hepatic Vein

p02 = 32 mm Hg

Hepatic artery = 20% of

flow p02 = 146

mm Hg

Consequences of Changes inHepatic Blood Flow and/or

Oxygen Delivery?

Peri-central vein (hepatic vein) clotted off with ischemic damage to hepatocytes

HV clot

Peri-centralischemia

Peri-portalnormal tissue

Not all liver cells are alike.

Substances found in higher concentrations in the portal vein•Albumin•CPS•FABP•HMG CoA

Substances found in higher concentrations in the hepatic vein•P450s•ADH•C7H•Cysteine•GR•Gluatamate2G•GS•GLUT-1-KG

Periportal Necrosis from Allyl Formate Toxicity

HV

PV

Pericentral Necrosis from Carbon Tetrachloride Toxicity

HV

PV

Necrosis

Normal cells

Pancreas

Systemic outflow

Intestine

Portal venous inflow from gut

Liver Connects to Intestine through Portal Vein and Bile Ducts

Systemic inflow

Liver excretes fluid (bile) and delivers many organic solutes to the intestine

Bilirubin Bile acids Cholesterol Lipophilic drugs

Bile as a garbage dump

Bile Formation

Functions of Bile

• Transports material to the intestine for excretion– Drugs, toxins, xenobiotics– Cholesterol– Bilirubin– Copper

• Transports bile acids to the intestine to aid in fat absorption

Bile Acids

• Organic acid synthesized in liver from cholesterol

• Conjugated to amino acids

• Secreted in bile - essential for fat digestion/absorption

• Reabsorbed in distal ileum and returned to liver via portal vein

CholesterolBile Acid

OH

Cholesterol: Flat (planar) hydrophobic compound

OH

Metamorphosis to a bile acid

Lose the double bond

OH

Metamorphosis to a bile acid

Shorten the side chain

OH

Metamorphosis to a bile acid

Add a carboxylic acid groupand bend this below the

plane of the rings

COOH

OH

Metamorphosis to a bile acid

Add a hydroxyl groupthat is bent down

COOH

OH

OH

Metamorphosis to a bile acid

Add another hydroxyl group

COOH

OH

OH

OH

Metamorphosis to a bile acid you now have a tri-hydroxy bile acid: cholic acid

COOH

OH

OH

OH

One more change - conjugation of an amino acid to the side chain yields

Taurocholate (taurine conjugated cholic acid)

OH

OH

NHCO COOH

OH- OH-OH-

Hydrophobic side

Hydrophilic side

Conjugated tri-OH Bile Acid

COO-

OH-OH-OH-

Biliary Lipids

Bile acid

Blood

ATP

ADPBile acids

Bile Canaliculus

Hepatocyte

Potential-dependent bile acid transporter

Bile acid

ATP-dependent bile acid transporter

Hepatic Bile Acid Transport

Diffusion

Facilitated diffusion

Bile acid

Na+

Sodium-coupled transport

To intestine for fat digestion

Bile acidsfrom intestine

Enterohepatic Circulation of Bile Acids: recycling is efficient

Liver

ColonSmall bowel

Bile acids cycle between the liver and the small intestine.

Total bile acid pool is about 3 grams.

About 90% of bile acids are reabsorbed in the terminal ileum.

However about 5-10% of bile acids are lost daily into the colon. Effect?

Liver synthesizes about 5-10% of the total bile acid pool each day.

Bile acidsynthesis

Enterohepatic Circulation of Bile Acids: Ilial loss

Liver

Colon 40 cm resectionof terminal ileum

Resection of 40 cm ofthe terminal ileum willresult in what problem?

Bile acid loss into the cecumwill increase. What willthis cause?

Liver upregulates bileacid synthesis and bileacid pool remains normal. Fat absorption remainsthe same.

Bile acidsynthesis

Enterohepatic Circulation of Bile Acids: Loss of most of the ileum

Liver

Colon>100 cm resectionof terminal ileum

Resection of >100 cm ofthe terminal ileum willresult in what problem?

Initially, bile acid loss into the colon will be massive. What will be the initialeffect of this loss of bileacids into the colon?

Bile acidsynthesis

Enterohepatic Circulation of Bile Acids: Lost of Ileum

> 100 cm resectionof terminal ileum

Resection of > 100 cm ofthe terminal ileum willresult in what problemover time?

Liver upregulates bileacid synthesis but cannotkeep up with loss rate. Bile acid pool is reducedFat is malabsorbed.

As the bile acid pool falls,loss into the colon is lessper day and secretory diarrhea due to bile acidsconverts to steatorrhea (+ secretory diarrhea from fatty acids).

Liver

Colon

Bile acidsynthesis

Enterohepatic Circulation of Bile Acid: Cholestyramine

Liver

ColonSmall bowel

Cholestyramine: bile acid binding resin that removes bile acids from the enterohepatic circulation

Liver upregulates bile acid synthesis (using up what compound in the process?)

If liver cannot keep up, what happens?

Less free bile acid in the colon causes what?

Bile acidsynthesis

Bile Canaliculus

Hepatocyte

MRP-2: Multispecific organic anion transporter

ATP

Conjugated bilirubin Glutathione S-conjugates other organic anions

Unconj Bilirubin

SER

Unconj BR

Conj BR

Conj BR

RBC breakdown in RES

Hepatic Bilirubin Transport

Blood

UDP-glucuronide

Unconj BR+

Conj BR

Liver takes up and excretes many other organic compounds:bilirubin is the classic and historic example

Jaundice of the Neonate

• Newborn infants have poorly developed bilirubin conjugation enzymes and jaundice is common.

• Premature infants are even more affected

• Unconjugated bilirubin in the brain causes permanent damage (kernicterus)

• How to prevent brain damage in neonates?

Regents of the University of Michigan

Phototherapy for Unconjugated

Hyperbilirubinemia of the Neonate

Martybugs, Wikimedia Commons.

Bile Canaliculus

Hepatocyte

Multispecific organic anion transporter

ATP

Conjugated bilirubin Glutathione S-conjugates other organic anions

Unconj Bilirubin

SER

Unconj BR

Conj BR

Conj BR

Gilbert's syndrome (mild) Crigler-Najjar syndrome (severe)

Dubin-Johnson syndrome Rotor's syndrome ?estrogen/cyclosporin

Hemolysis

Hepatic Bilirubin Transport and Mechanisms of Hyperbilirubinemia

Blood

Consequences of Liver Disease

for Bilirubin Handling?

Unconj Bilirubin

SER

Unconj BR

Conj BR

Mechanism of Hyperbilirubinemia in Liver Disease

UDP-glucuronide

Unconj BR+

Conj BR

Overall Rate-Limiting Step

Conj BR

Albumin

Bilirubin:Jaundice

The first liver disease test

CDC

Liver Biotransformation/Excretion of Endogenous/Exogenous Compounds

• Bilirubin conjugation is an example

• Many other organic compounds undergo two-step biotransformation

– Example: cholesterol to bile acids

• After biotransformation, metabolites excreted

– Larger, lipophilic molecules excreted in bile

– Smaller (<400 Da) transported to blood and excreted by kidneys

CYP (P450)

ER ER

Phase 1 and Phase 2 Biotransformation in Liver

Glucuronyl transferase

OH OH O Sugar

Phase 1 Phase 2Oxidative reactions (OH-groups added) CYP (P45)-mediated

Conjugation to polar ligands: glucuronide and other sugars amino acids sulfate glutathione

Step-wise Synthesis of Bile Acids from Cholesterol

P450- mediated hydroxylations

Conjugation of side chain to glycine or taurine

Cholesterol

Steps are analogous to Phase I and Phase II steps of drug/xenobiotic metabolism

OH group

amino acid

Pancreas

Intestine mucosal barrier

Liver and Gut Barrier Functions

Insoluble, nonabsorbable compounds Xenobiotics Drugs Bacteria (acid, physical barrier, gut immune system, liver RES)

Liver RES/filter Metabolism Biliary excretion

Liver helps to remove/eliminate:

Xenobiotics: metabolism, excretion Drugs : metabolism, excretion Bacteria : Kupfer cells

Image of liver regeneration process removed

Liver’s Magic Trick: Regeneration

PrometheusBound

P.P.Reubens

An early case ofof hepatic regeneration

P. P. Rubens

Functional Consequences of Losing a Large Amount of Liver

Due to Resection/Necrosis?

• Hypoglycemia

• Poor blood clotting

• Cholestasis and jaundice

• Increased blood ammonia - affects cognitive function

• Decreased drug disposition

• Abnormal lipid metabolism

Summary

• Liver exhibits a wide range of functions• Liver diseases may cause malfunction of

one or more normal function• Functions regulated separately so any one

liver disease can affect each to a different extent

• Liver diseases cause:– Altered liver functions– Altered tests of liver injury

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