Term
| What is the gross anatomical structure of the liver? |
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Definition
Located in right upper quadrant, extending from 5th IC space to right costal margin.
1) Right (65%) and Left (35%) lobes, separated by imaginary line drawn from gallbaldder to IVC
2) Falciform ligament attaches liver to diaphragm and anterior abdominal wall and contains umbilical veins that atrophy and become Ligamentum teres.
3) Glisson’s Capsule: covers entire surface of liver and invaginates at hilum becoming continuous with intra-hepatic connective tissue (Portal Tracts) that contains the branches of the hepatic artery, portal vein, bile duct, peripheral nerves and lymphatic channels |
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Term
| Describe the afferent blood supply of the liver. |
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Definition
Dual afferent system
1) Portal vein (75%) collects blood from splenic, IM and SM veins and delivers Nutrient-rich, Oxygen-poor blood
**hepatopedal (extra-hepatic block) and hepatofugal (intra-hepatic) systems of venous collaterals in case of blockage of portal system**
2) Hepatic artery (25%) delivers systemic, oxygen-rich arterial blood via 3 terminal branches
- Portal plexus (portal tract structures)
- Peribiliary plexus (bile ducts)
- Periportal aterioles- periportal sinusoids (zone 1 of acinus) |
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Term
| What happens to hepatic venous circulation in the case of portal hypertension (cirrhosis or portal vein thrombosis)? |
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Definition
Collateral venous circulation (2 types) allows blood to return to right heart
1) Hepatopedal (deep cystic, epiploic, diaphragmatic, paraumbilical) system becomes active when there is Extra-hepatic blockage of portal system
2) Hepatofugal (Gastroesophageal, rectal, paraumbilical and portorenal) becomes active when there is a INTRA-hepatic blockage. |
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Term
| What is the Hepatic Arterial Buffer Response (HABR)? |
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Definition
Ability of PV flow to reciprocally regulate HA flow via vasodilator ADENOSINE.
1) Decreased PV flow (portal hypertension from cirrhosis or thrombosis) leads to build-up of adenosine in portal tracts
2) Adenosine causes arterial dilation and increased HA flow via binding of adenosine to arterial wall receptors.
**Increased PV flow "washes out" adenosine and limits HA delivery** |
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Term
| What different types of cells make up liver sinusoids? |
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Definition
Liver is ~ 2.5% of body weight, but receives 25% of cardiac
output (High capacitance/compliance system)
Sinusoids have microvilli and contain Kupffer cells, a fenestrated endothelium and are separated from hepatocytes by Space of Disse
1) Peri-portal sinusoids (complex and interconnected)
2) Centri-lobular (larger and straighter with fewer connections) |
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Term
| What is the found in the space of Disse? |
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Definition
Potential space between sinusoid endothelial cell and hepatocyte containing:
1) Stellate (Ito) cells that store Vitamin A and secrete hepatic growth factors and matrix components (collagens)
- Can transform into facultative fibroblasts and myofibroblasts and serve as generators of hepatic fibrosis leading to cirrhosis (regenerative)
2) Pit cells, which are large granular lymphocytes (NK cells) that are active against viruses and tumor cells, and may play a role in regeneration
3) T and B lymphocytes
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Term
| What vasoconstriction/dilation factors regulate Sinusoidal blood flow? |
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Definition
High compliance/capacitance system
1) Constriction
- ET-1, Angiotensin, thromboxane A2, Epi
2) Dilation
- NO, CO, H2S, PGI2 |
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Term
| Describe the efferent blood supply of the liver. |
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Definition
1) Sinusoids drain into terminal hepatic venules (THV), also called "central veins"
2) THVs coalesce into large right, middle and left hepatic veins, which empty into IVC right beneath the right atrium. |
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Term
| How is lymph produced in the liver? |
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Definition
Largest Lymph (high protein and cell content) producer in body (15-20%)!
**T-cell dominant, with innate and adaptive T cells and fewer B cells**
Formed in space of Disse and travels
1) Plexus in portal tracts
2) THVs
3) Glisson's capsule. |
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Term
| Why is the liver not in a chronically "inflamed" state despite being expose constantly to LPS and CpGs from intestinal commensals? |
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Definition
DCs are kept in immature state with increased activation threshold because of IL-6/STAT3 signaling from commensal bacteria.
**Tolerance is overcome with injury** |
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Term
True or False:
THe liver is the primary site of hematopoiesis in adult life. |
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Definition
False: In EMBRYONIC life.
progenitors can be found in adult, but not primary site (bone marrow) |
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Term
| Describe the microanatomical "zonation" of hepatic physiology. |
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Definition
Based on lobule unit and used to demarcate metabolic functions and describe "dynamic zonal metabolism," which is controlled by B-cateninWNT expression and signalling.
1) Zone 1 (periportal)
- Periportal (PP) hepatocytes receive blood first (last to undergo necrosis and first to regenerate)
- Involved in urea formation, gluconeogenesis and OX/Phos energy production
2) Zone 2/3 (perivenous)
- Centrilobular hepatocytes (PC) surrounded by central veins (most susceptible to ischemic insult)
- Glutamine synthesis, glycolysis and drug metabolism |
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Term
| Describe basic biliary tree anatomy. |
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Definition
Biliary epithelial cells (BEC) or "cholangiocytes" line 3-D network of conduits that forms biliary tract and receive blood from hepatic arteries ONLY
BECs alkalinize and dilute bile as it passes from the hepatocytes to the gallbladder
1) Intrahepatic
- Bile canaliculi, canals of Herring, interlobular ducts, intrahepatic ducts and left and right hepatic bile ducts.
2) Extrahepatic
- common hepatic duct, cystic duct, Gallbladder, and common bile duct
**Exits common bile duct and fuses with pancreatic duct to enter duodenum** |
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Term
| What are the 3 major types of Cholangiopathies (directly involve bile ducts)? |
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Definition
Categorized by cause
1) Immune
2) Bacterial, fungal, parasitic and viral infections
3) Vascular/ischemic
4) Drug reactions
5) Genetic
6) Idiopathic
7) Neoplasia |
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Term
| What are the major components that make up bile? |
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Definition
1) Fat absorption
- Water, Inorganic electrolytes, Organic solutes (conjugated bile acids, phospholipids, cholesterol and bile pigment)
2) Excretory functions
- pigments, IgA (enterohepatic circulation) and drug and hormone metabolites. |
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Term
| What is the basic hepatic nerve innervation? |
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Definition
Both sympathetic and parasympathetic
- Sympathetic fibers from T7-T10 synapse in semilunar ganglion of celiac plexus.
- intermingle with right and left vagus and right phrenic nerves to form hepatic arterial plexus |
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Term
| How does normal CHO metabolism occur in the liver? |
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Definition
GLUCOSE homeostasis
1) Glucokinase can drive towards glycolysis
2) Stored as glycogen
3) Fed into 5-pentose phosphate path and nucleotide synthesis. |
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Term
| How does the liver utilize Amino acids and NH3? |
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Definition
Protein comes from diet or tissue turnover (MAJOR) and liver utilizes AA for fuel to a great extent.
1) ALT and AST amino group by transamination (amino given to a keto-glutarate to make glutamate)
2) Glutamate used in Urea cycle (liver has arginase)
- Disposes of ammonia/amino groups that enter liver by: free ammonia in portal blood, glutamate and glutamine |
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Term
| Describe the important steps of the urea cycle. |
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Definition
Urea is toxic to brain!
1) NH4+ combines with CO2 (carbamoyl P synthetase) to form Carbamoyl phosphate
2) L-ornithine combines with Carbamoyl phosphate (OTC) to form L-citrulline
3) L-citrulline combines with Aspartate (Arginosuccinic acid synthetase) to form Arginosouccinate
4) Arginosuccinate is broken into Fumarate and L-arginine by (Arginosuccinase)
5) L-arginine is broken into Urea and L-ornithine by Arginase (unique to liver). |
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Term
| What are the most important serum proteins produced by the liver? |
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Definition
1) Albumin (indicator or nutritional state and severity of liver disease)
- carries, FA, steroids, vitamins, drugs, Ca++ ions, lipophillic substances, bilirubin
- maintains OSMOTIC pressure.
2) Glycoprotein transporters
- Transcortin (corticosteroid), Thyroid-binding, sex-binding, transferrin, lipoproteins
3) Acute phase proteins
- Ceruloplasmin (antioxidant decreased in Wilson's)
- a1-antitrypsin (protease)
- a1-acid glycoprotein (binds drugs)
4) Protective proteins
- a1-antitrypsin
- clotting factors |
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Term
| What are the major roles of the liver in lipid metabolism? |
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Definition
1) Liver regulates metabolism of acetyl CoA
- synthesis of fatty acids
- synthesis of cholesterol
- synthesis of bile salts (acids)
- intrahepatic β-oxidation of fatty acids
2) Packages & secretes triglycerides, cholesterol, etc
3) Fat retention in liver (steatosis or fatty liver):
- liver disease, alcohol, toxins, drugs, (usually reversible) |
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Term
| Describe the pathway of hepatic cholesterol and BA synthesis. |
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Definition
1) 3 molecules of acetyl CoA are united to form HMG CoA
2) HMG CoA reductase is rate limiting step in production of 27-carbon final product cholesterol (makes Mevalonate)
3) Cholesterol is either stored as esters, transported via LP, used to produce steroids elsewhere, or HYDROXYLATED at C7 &/or C12 by 7-a hydroxylase to make Bile Acids
**primary BA are made by LIVER and include cholic acid and chenodeoxycholic acids, while secondary BA are made by the intestine** |
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Term
What are the major components of bile?
What is the difference between primary and secondary BA? |
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Definition
1) Bile is composed of
- bile acids
- phospholipids (Lecithin or "phosphatidylcholine)
- cholesterol
- bile pigments (billirubin)
- "extra cations" that surround COO- groups
**hydrophobic cholesterol and amphipathic BA and phospholipids permit BA formation.**
2a) Primary bile acids (cholic and chenodeoxycholic) synthesized by hepatocytes and transported to canaluicular membrane, where some are secreted (ATP-dependent) into bile.
2b) Secondary bile acids (deoxycholic and lithocholic acids) are formed from primary BA by bacterial action in gut and then returned enterohepatically for re-excretion in bile |
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Term
| How is bilirubin transported in bile? |
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Definition
| Conjugated to one or two glucoronide molecules to enhance solubility. |
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Term
| How does the composition of hepatic bile differ from gallbladder bile? |
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Definition
1) HB has more cholesterol and less BA
2) GB is much more CONCENTRATED (GB mucosa) and ACIDIC |
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Term
| How does the biliary system transport bile out of hepatocytes? |
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Definition
Defects in canalicular transporters cause Cholestasis!
Transporters include:
- Phospholipid: MDR3
- Bile salt: Canalicular bile salt-export pump (BSEP)
- Bilirubin: MDR-associated (MRP2)
- Drugs: various |
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Term
| What are the 2 primary functions of bile and how are BA recycled? |
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Definition
1) EMULSIFICATION of lipids (increase accessibility of substrates to pancreatic enzymes)
2) DISPOSAL of hydrophobic materials like cholesterol, bilirubin, hormones and their metabolites, pigments, drugs, ect.
Enterohepatic circulation handles recycling:
- Terminal illeum takes BA (primary and secondary) to liver via PV
**Basis for treatment of hypercholesterolemia with cholestyramine, which prevents this reabsorption and excretes more in feces**
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Term
| Why give cholestyramine with lovastatin to treat hypercholesterolemia? |
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Definition
1) Cholestyramine binds BA and prevents enterohepatic re-circulation of primary and secondary BA at terminal illeum (increases excretion).
- Liver then makes more BA from cholesterol, lowering cholesterol.
2) Statins inhibit HMG-CoA reductase. |
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Term
| What does age have to due to drug metabolism? |
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Definition
Important at spectrums
1) Children do not have fully developed hepatic enzyme systems
2) Elderly have decreased circulation, lower albumin, and are often on multiple drugs simultaneously |
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Term
In a healthy individual, which of the following is the major factor int he metabolic rate of a given drug?
1. Age
2. Sex
3. Genetics
4. Weight |
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Definition
3
Phase 1 CYPs and Phase 2 enzymes |
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Term
| What are the 4 phases of hepatic drug metabolism? |
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Definition
1) Phase 0
- Sinusoidal uptake into liver cell from blood (depends on structure of drug)
2) Phase 1
- Oxidation, reduction, decarboxylation, ect. (reduces drug activity)
3) Phase 2 (Covalent addition of polar group (inactivation and solubilization)
4) Phase 3 (Efflux pump for excretion via canalicular membrane into bile) |
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Term
| What are 3 carrier proteins for Influx into hepatocytes? |
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Definition
Influx is BASOLATERAL transporter (sinusoid to hepatocyte)
1) NTCP- sodium taurocholate co-transport for Na-dependent uptake of conjugated Bile Salts and drugs.
2) OATP- organic anion transport (un-conjugated bile salts, satins, bilirubin and conjugates)
3) OCTP- organic cation transport (histamines, serotonin, thiamine) |
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Term
| What are 4 carrier proteins for Efflux out of hepatocytes? |
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Definition
Efflux is canalicular (apical)
1) MDR1 (P glycoprotein)- organic anions, xenobiotic and chemotherapy agents
2) MRP2- Bilirubin glucoronides and sulfates
3) MDR3- Phospholipids
4) Canalicular bile salt -export pump (BSEP)
- BIle salts |
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Term
What is the consequence of mutations that change the transporter activity of each of the following?
1) BSEP (ABCB11)
2) MRP2 (ABC2)
3) MRP-3 (ABC3)
4) MDR1 (PGP) |
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Definition
1) Efflux canalicular transporter for bile salts
- Inhibition leads to Cholestasis
2) Efflux transporter for bilirubins and drug metabolites
- Inhibition leads to hyperbilirubinemia
3) Efflux out of hepatocytes into blood- bile salts
- UP REGULATED in cholestasis (since you can't get it to go into bile)
4) Efflux transporter for xenobiotics and chemo drugs
- Inhibition causes cellular accumulation and toxicity |
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Term
| What are the basics of Phase 1 and Phase 2 drug metabolism? |
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Definition
1) Phase 1 (depends on drug structure)
- CYP enzymes found in smooth ER introduce or expose functional groups (oxidation, reduction, decarboxylation)
- CYP3A4>CYP2D6>CYP2C
2) Phase 2 (use energy from activated substrates)
- Covalent additions to phase 1 metabolite to increase solubility and decrease activity (EXCEPT morphine glucoronide)
- Occur in cytosol |
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Term
| What are the important phase 2 drug-metabolizing enzymes and their functions? |
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Definition
Phase 2 involves using energy from activated phase 1 metabolite to covalently modify metabolite in cytosol to a more soluble and less active form.
1) UDP-Glucuronyltransferases (UGTs)
- Glycoproteins in ER of GI that add glucuronic acid from UDP-glucuronic acid to substrate, increasing solubility and decreasing activity.
2) Glutathione S-transferase (GST)- several isoforms
3) Sulfonyltransferases
- Cytosolic enzymes that use PAPS-sulfate as sulfate co-donor cosubstrate. |
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Term
Why should a patient taking Simvastatin be careful not to drink grapefruit juice?
Why is an issue if she is also taking tamoxifen? |
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Definition
grapefruit juice inhibits CYP3A4, which metabolizes statin drugs.
2) Decreased CYP3A4 would cause drug buildup.
3) Statin excreted into bile via MRP2, which is inhibited by Tamoxifen** |
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Term
| What is the role of the liver in hormone metabolism? |
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Definition
Clears hormones from circulation
1) Steroids are metabolized to more water-soluble, less active form via CYP-mediated hydroxylation
2) Peptides like GH, insulin and glucagon are cleared by protein uptake and degradation. |
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Term
| Under what circumstances is acetaminophen a potentially potent hepatotoxin? |
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Definition
Chronic alcohol and Fasting.
KEEP < 4 g/d (8X500 mg)
1) Glucuronidation requires glycogen/glucose
2) Sulfation requires high energy cofactor PAPs
3) Metabolism through CYP2D1 is induced by ETOH and ketones
4) Glutathione resuce prevents in liver disease and fasting
5) Toxic interactions with cellular proteins |
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