Liver Flashcards
1
Q
FUnctions and characteristics for the liver?
A
- 2-2.5% of TBW – largest organ/gland in body
- Adults: 600-1800g average wt (smaller in women)
- 5% neonates (150-170g)
- Adults: 600-1800g average wt (smaller in women)
Multiple life sustaining functions
- Filtration and storage of blood
* Serves as a blood reservoir.
* Kupfer cells within the liver sinusoids avidly remove bacteria and other substances from the portal blood.
- Filtration and storage of blood
- Metabolism of carbohydrates, proteins, fats, hormones, foreign chemicals
* Critical energy metabolism
- Metabolism of carbohydrates, proteins, fats, hormones, foreign chemicals
- Formation of bile
* Critical for emulsification of fats
* Increase surface area for absorption
- Formation of bile
- Storage of vitamins and iron
* Ex: Vit K → formation of coag factors
- Storage of vitamins and iron
- Formation of coagulation factors
* Failure of these fx contributes to intraop/postop hypoperfusion, tissue ischemia and activation of systemic inflammatory response – progression to MODS.
- Formation of coagulation factors
- Alters, excretes and modifies numerous gut derived substances.
- Most vascular organ in the body ~30% CO
2
Q
What is the difference in liver anatomy when looking at it via the surface anatomy vs physiologic anatomy?
A
- Surface anatomy - four distinct topographical lobes: (in picture)
- right
- left
- falciform ligament in between R & L
- caudate
- quadrate
- The surface anatomic description doesn’t correspond to the branches of the liver’s vascular supply and therefore is of limited clinical significance.
- Physiologic anatomy → 8 functionally independent segments (AKA Couinaud system)
- Each segment has its own vascular flow and biliary drainage
- The physiologic segmental division of the liver and is based on divisions of the portal vein, hepatic artery, and biliary ducts.
- This anatomic arrangement facilitates limited segmental resection of the liver w/ relatively bloodless surgical dissection along the planes between the segments and thereby prevents major disruption of hepatobiliary function.
- Couinaud anatomy simplifies efforts to preserve healthy tissue and extirpate diseased regions, and has resulted in improved clinical outcomes for patients undergoing hepatic surgery for neoplasms or trauma-induced injuries
- Each segment has its own vascular flow and biliary drainage
3
Q
Describe hte segmental division of the liver with couinaud’s nomenclature?
A
Liver divided into 8 sections.
- Right and left “hemilivers” divided at the bifurcation of the portal vein along the middle hepatic vein.
Using imaging techniques radiologists can construct precise 3-d models of a pt’s liver – help the surgeon determine operative approach enhancing the resectability of neoplasm or trauma. Significant variability so – CT helpful in determining each pts precise anatomy. Each of the eight segments independent blood supply (arterial and venous) and biliary flow – reduces M and M if done this way.
4
Q
Describe hte microscopic anatomy of the liver using the liver lobule theory?
A
- Basic functional unit
- Hexagonal on cross section
- Six vertically aligned portal canals at corners
- central vein at center of hexagonal cross section
- → drains into hepatic vein → IVC
- Lobule composed of cellular plates that radiate from the central vein like spokes in a wheel (6)
-
Contain → Hepatocytes
- Fx: metabolize drugs, Kreb cycle
- Hepatocytes lined with Kupffer cells
- Kupffer cell Fx: phagocytosis, filtration of blood of toxic material
- each hepatic plate is two cells thick and between the cells lie small bile canaliculi that empty into bile ducts
- space of disse (perisinusoidal space) lie bneeaht large pores (big enough for plasma proteins) of the endothelial lining and connect lymphatic vessels in the interlobular septa (excess fluid removed by lymphatics)
-
Portal Canal contains: (several portal canals, not just 1)
- Connective tissue
- Lymphatics
- Nerves
-
Portal Triad
- Terminal branches Portal Vein
- Hepatic Artery
- Bile Duct
-
Contain → Hepatocytes
5
Q
What is the acinus lobule concept on the microscopic anatomy of the liver?
A
- Acinus
- functional microvascular unit of the liver
- Forms around a vertical axis (the portal canal
- Consists:
- hepatic arteriole
- a portal venule
- a bile ductule
- lymph vessels
- nerves
- Consists:
- Blood flow vertical to the portal triads and directed radially toward the central veins.
- Center of Acinus = terminal vascular supply
- As terminate → form ZONES
- Zone 1: Most O2 rich blood (center)- periportal zone, gets first dibs on O2
- Zone 2: further away
- Zone 3: receives BF after 2 other regions
- New data suggests the “liver architecture more closely resembles the classic lobule more than it does the acinus.”
- Blood enters the center of the acinus and flows centrifugally to the hepatic venules. Bile flows in the opposite direction. The simple liver acinus lies between two or more terminal hepatic venules.
- The difference between lobule and acinus is that the terminal vein is at the center of the lobule and the terminal vein is at the periphery of the acinus.
- The conceptual advantage of the acinus concept is that the blood supply and biliary drainage of a portion of parenchyma reside in the same portal tract, whereas multiple portal vein branches and arteries supply each classic lobule
6
Q
Describe the various zones of the liver in the acinus lobule concept.
A
- Hepatocytes 75-80% liver volume
-
Zone 1 (periportal zone) – HIGHLY METABOLICALLY ACTIVE
- Cells are closest to the portal axis
- receive blood that is rich in O2 and nutrients
- Major site of:
- oxidative metabolism
- aerobic metabolism
- highest Kreb cycle enzymes/highest number mitochondria (gluconeogenesis, b-oxidation fatty acids, amino acid catabolism, bile acid secretion)
- conversion ammonia to urea*
- oxidative metabolism
- Major site of:
- **Most prone to hepatic reperfusion injury*
-
Zone 2 (midzonal region)
- arbitrary intermediary transition zone
- “anatomic reserve”- overlap with zone 1
-
Zone 3 (pericentral) cells at margin of acinus
- receive blood that has exchanged gases and metabolites with cells in zones 1 & 2
- → least resistant to metabolic and anoxic damage (most sensitive)
- Lowest O2 saturation
-
Major site of:
- CYP450
- anaerobic metabolism– high quantity of ER– (glycolysis and lipogenesis)
- general detox and biotransformation drugs, chemicals, toxins) These cells exquisitely susceptible to injury from systemic hypo-perfusion and hypoxemia – zone 3 cell necrosis is characteristic of acetaminophen/halothane toxicity
- **most prone to ischemic damage**
- receive blood that has exchanged gases and metabolites with cells in zones 1 & 2
7
Q
What are hepatic stellate cells?
A
- 8-10% total cell count in liver
- reside in the SD (space of disse) between liver sinusoidal endothelial cells (LSECs) and the hepatocytes
-
Only significant in setting of liver injury
- → differentiate into myofibroblasts which promote fibrotic and inflammatory changes
- Ex: changes seen during cirrhosis→ increase hepatic vascular resistance→ issues (ascites/varices)
- → differentiate into myofibroblasts which promote fibrotic and inflammatory changes
- In normal liver, HSCs are in a quiescent state. In liver injury, these cells become activated in response to cytokines and chemokines generated by hepatocytes, LSECs, as well as leukocytes and Kupffer cells. The stellate cells proliferate and differentiate into myofibroblasts participating in hepatic inflammation and fibrosis.
8
Q
What are myeloid cells in the liver?
A
-
Kupffer cells - 20-30% cell count in liver aka resident tissue macrophages (20-30% of of nonparenchymal cells)
- Represent 80-90% of macrophages in body (so not less impt vs hepatocytes & LSEC)
- Present in portal and lobular liver sinusoids
- Fx: Phagocytosis of toxic and pro-inflammatory substances (& noninfectious particles)
- Once phagocytosed, these particles are unable to induce proinflammatory responses in the liver. Thus by prevalence and location, these cells serve critical roles in innate and adaptive immunity by detoxification where they down-regulate potentially proinflammatory triggers that could disrupt hepatic homeostasis.
- Represent 80-90% of macrophages in body (so not less impt vs hepatocytes & LSEC)
-
Dendritic and myeloid derived suppressor cells
- the least abundant of myeloid cells
- Immunosuppressant functions may be helpful in acute hepatitis
- but harmful in chronic viral infections and cancer
- Hepatic dendritic cells are present in normal liver and reside in the portal area and promote tolerance to phagocytosed particles
- Hepatic myeloid-derived supressor cells suppress immune response in the liver. In acute hepatitis they reduce inflammation and limit tissue injury. Their immune suppressive function has been a/w adverse effects in certain pathologic conditions. In chronic viral hepatitis, they may promote viral persistence. They have also been a/w suppression of immune response to hepatic tumors.
9
Q
Role of lymphocytes in the liver?
A
- Innate (natural killer cells etc.)
- Adaptive immune response (B and T cells)
- Cells of lymphatic origin that can be detected in the liver include natural killer (NK) cells, NK T cells (NKT), mucosal-associated invariant T cells, and γδ T cells in addition to major histocompatibility restricted CD4+ T cells, CD8+T cells, and B cells.
- These cells are distributed throughout the liver parenchyma and serve critical roles in the innate (NK, NKT, mucosal-associated invariant T cells, and γδ T cells) and adaptive (major histocompatibility restricted CD4+ T cells, CD8+T cells, and B cells) immune responses. These cells work primarily to maintain hepatic homeostasis by promoting tolerance to foreign substances. However, when necessary, these MHC-restricted cells can promote the clearance of foreign substances by expanding in response to them while recruiting additional cells from extrahepatic sources such as the lymph nodes and the spleen.
10
Q
What is the innervation of the liver?
A
- Stimulation of SNS fibers post-ganglionic T3-T11
-
increases hepatic vascular resistance (decreased blood volume) → release blood into central circulation (referred to earlier as liver storing blood)
- autotransfuion of up to 80% hepatic blood (400-500 mL) if needed in SNS stimulation
- increases glycogenolysis and gluconeogenesis (increased BG)
- (catabolic/mobilization of energy mode)
-
increases hepatic vascular resistance (decreased blood volume) → release blood into central circulation (referred to earlier as liver storing blood)
- Stimulation of PSNS (vagus nerve)
- increases glucose uptake and glycogen synthesis
- (anabolic storage mode)
- increases glucose uptake and glycogen synthesis
- Branches of the splanchnic nerves (postganglionic sympathetic fibers from T6-11), vagus nerve, and phrenic nerve enter the liver w/ the major blood vessels and bile ducts. These nerve fibers form an intercommunicating plexus, w/ synapses on the terminal arterioles and venules.
- Sympathetic innervation of the hepatic and splanchnic vasculature plays a major role in regulating the volume of whole blood stored in, and expelled from, the hepatic reservoir. Studies in canine model = sympathoadrenal stimulation (e.g., hypercarbia, pain, hypoxia) can abruptly decrease hepatic blood flow and splanchnic vascular capacitance. Within seconds, splanchnic nerve stimulation can autotransfuse up to 80% of the hepatic blood (400–500 mL) into the central circulation. Other studies = vagal stimulation alters the tone of presinusoidal sphincters and influences blood flow distribution within the liver rather than total hepatic blood flow.
11
Q
What are some characteristics of the hepatic vascular system?
A
- 25-30% of CO = 1350ml/min
- Portal Vein = 1050 ml/min
- BF: 70-75%
- Oxygenation: 50%
- Blood drained from GI tract into here
- formed by confluence of splenic and superior mesenteric veins and receives blood from GI tract, spleen, pancreas and gallbladder
- portal vein has numerous tributaries of little importance until portal HTN present, and then these connections form large portosystemic shunts which allow venous blood flow to bypass liver and produce pathologies (ie esophageal varices)
- Blood drained from GI tract into here
- Hepatic Artery= 300 ml/min
- BF: 25%
- Hepatic artery arises from the celiac trunk in 80% of the population, the rest the superior mesenteric artery
- Oxygenation: 50%
- Branch off celiac artery (Also supplies rest of GI tract)
- 100% oxygenation going through even though less BF
- BF: 25%
- Portal vein pressure = 9mmHg
- Hepatic vein leading to vena cava = 0mmHg
- Normal Physiology:
- HIGH flow
- LOW resistance/pressure
- Normal Physiology:
12
Q
What regulates hepatic blood flow?
A
- Hepatic arterioles have a myogenic response to stretching keeps local blood flow constant, despite changes in BP
- Increase in transmural pressure (BP) → vasoconstriction (preventing elevations of local BF)
- Decrease in transmural pressure (Bp)→ vasodilation (preserving perfusion during systemic hypotension)
- don’t see this same regulation in portal vein!!
-
Considerations:
- Auto regulation of hepatic artery is present in metabolically active liver (postprandial hyperosmolarity)
- usually absent in fasted state → most OR patients are NPO
- VA dose-dependently decrease response
- Pressure-flow auto regulation does not exist in the portal circulation
-
Drop in BP → directly influence hepatic BF
- Liver sensitive to hypoTN episodes
- Auto regulation of hepatic artery is present in metabolically active liver (postprandial hyperosmolarity)
- Although the liver receives 25% of CO, regional blood flow within the organ is such that certain areas are highly prone to ischemia. Intrinsic (regional microvascular) and extrinsic (neural and hormonal). Also decreases in ph or O2 and inc in CO2 of the portal blood promote increases in hepatic artery flow
13
Q
What is the hepatic arterial buffer response?
A
- Changes in portal venous flow induce reciprocal changes in hepatic arterial flow
- As portal venous flow decreases → adenosine builds up in the periportal region
-
Adenosine → direct effect on hepatic arterial wall→ DILATE → arteriolar resistance falls → increase hepatic arterial BF
- (artery compensates) This response is limited to a 50% reduction of portal venous flow and a corresponding twofold increase in hepatic artery flow
-
Adenosine → direct effect on hepatic arterial wall→ DILATE → arteriolar resistance falls → increase hepatic arterial BF
- As portal venous flow decreases → adenosine builds up in the periportal region
- Increases in portal venous flow → washes out adenosine from the periportal region → raising arteriolar resistance and lowering hepatic arterial flow
- Although the buffer response can substantially increase hepatic arterial flow, it cannot preserve total hepatic blood flow when portal venous flow falls precipitously. Furthermore, pathophysiologic states, such as endotoxemia and splanchnic hypoperfusion, may decrease or even abolish the buffer response. Neural, myogenic, or metabolic influences (e.g., portal venous oxygen content or pH) may alter the buffer response
- Fortunately because the hepatic artery carries a higher oxygen content, this is an effective mechanism for hepatic protection.
14
Q
What are some extrinsic influences on portal circulation?
A
-
Tone of pre-portal splanchnic organ arterioles regulate portal vein flow
- Determines how much blood goes through the portal system
- Decreases in pH or PaO2 (portal blood)- Acidosis
- → increases hepatic arterial flow (compensates)
-
Postprandial hyperosmolarity
-
increases both hepatic arterial and portal venous flow
- Lots of nutrients needing to be picked up
-
increases both hepatic arterial and portal venous flow
Portal venous pressure (usually 7-10mmHg) reflects both splanchnic arteriolar tone and intrahepatic resistance to flow. postsinusoidal sphincters control venous resistance in the liver.
15
Q
What are the humoral influences on portal circulation in the hepatic arteries vs portal veins?
A
-
Hepatic arterial bed
- α1 -, α2 -, and β2 -adrenergic receptors
-
Portal vein
- only α-receptors
16
Q
How does epinephrine affect liver blood flow?
A
-
Epinephrine (all equal efficacy in receptors)
-
Arterial side: initial vasoconstriction (α-receptor), followed by vasodilation (β-receptor)
- More balanced effect of epi on arterial beds vs vein because vein only has alpha receptor (missing Beta-2 dilation)
- Portal Vein: only vasoconstriction (α-receptor)
- Drop in portal vein flow
-
Arterial side: initial vasoconstriction (α-receptor), followed by vasodilation (β-receptor)
17
Q
Dopamien effect on portal circulation?
A
vasoactive effects weak compared w/ epi and norepi
18
Q
Glucagon effects on portal circulation?
A
- dose-dependent relaxation of hepatic arterial smooth muscle
-
antagonizes vasoconstrictor responses of the hepatic artery to various physiologic stimuli-including increases in SNS tone (vasodilation)
- ex: liver dx → liver not metabolizing glucagon → excessive levels of glucagon → wide spread dilation)–> causes hyperdynamic circulation seen in liver failure
19
Q
Angiotensin II effect on portal circulation?
A
- severely constrict_s hepatic arterial &_ _portal venou_s beds, & markedly ↓ both mesenteric & portal venous flow
- blood flow to liver may plummet
20
Q
Vasopressin effect on portal circulation?
A
- intensely constricts splanchnic arterial bed- distributes BF out and into central system
- Ex: tx varices → dec BF going to liver and therefore decreasing the blood flow bypassing liver and going to varices
- Lowers portal venous resistance
- effective treatment for portal hypertension/esophageal varices*
21
Q
What is the relationship between liver and the lymph system?
A
- Large quantities of lymph form in the liver
- 50% of lymph in the body
- Liver sinusoidal epithelium → Extreme permeability
- allows passage of fluid and proteins into spaces of Disse
- Protein content of liver lymph
- 6g/dl (close to plasma- 80-90% protein content of normal plasma)
- Normal IVC pressures ~ 9
- Increase IVC pressures ~ 10-15 mmHg → resistance through liver gone up → increases blood flow
- hepatic lymph flow ↑ as much as 20X normal
- sweating from liver surface can cause lg. amt. of free fluid in the abd cavity → ascites
Rich plexus of lymphatic channels formed converge to form 12-15 channels that exit via porta hepatis to eventually drain into the thoraic duct. When pressure in hepatic veins rises 3-7mmHg, excessive amounts of fluid begin to transude into the lymph and leak through the outer surface of the liver capsule directly into the abd cavity. Blockage of portal flow through the liver also causes high capillary pressures in the entire portal vascular system of the GIT, resulting in edema of the gut wall and transudation of fluid through the serosa of the gut wall into the abdominal cavity= ascites.
22
Q
What are some alterations seen in the liver with cirrhosis?
Causes of cirrhosis?
A
- Destroyed liver parenchymal cells replaced with fibrous tissue that contracts around blood vessels
- → impedance to portal blood flow through liver
- Higher resistance vessel
- Consequences:
- Increase formation of lymph
- Sweating from liver/Ascites
- Increase BF through azygos/hemiazygos veins → bleeding (not meant to handle high flow)
- Consequences:
- Secondary to
- Alcoholism
- poison ingestion (carbon tetrachloride)
- viral disease (hepatitis)
- bile duct obstruction
- infection
Also the portal system can be blocked w/ a large clot – return of blood from intestines and spleen through liver portal blood flow system is impeded and portal HTN results w/ inc capillary pressure in the intestinal wall to 15-20mmHg. Pt. often dies d/t excessive loss of fluid from the capillaries into the lumens and walls of the intestine.
23
Q
How does the liver regenerate?
A
- Remarkable ability to restore itself after partial hepatectomy or acute liver injury
- as long as uncomplicated by viral infection of inflammation
- 70% of total liver mass can be regenerated in animal models (5-7 days)
- as long as uncomplicated by viral infection of inflammation
- Liver growth closely regulated to maintain optimal liver to body weight ratio
- Normal liver function possible when 80% of liver resected
- Issue: Chronic Liver disease (ex: fibrosis, inflammation, viral infection) → regenerative process severely impaired – function deteriorates
Partial hepatectomy (up to 70% removed) causes the remaining lobes to enlarge and restores the liver to its original size (in rats only takes 5-7 days). During regeneration, hepatocytes replicate once or twice and then when original size and volume of liver are achieved hepatocytes revert to usual quiescent state. Control of this still poorly understood – hepatocyte growth factor important factor causing liver cell division and growth. Also epidermal growth factor, cytokines (TNF and interleurkin-6). Transforming growth factor –B a cytokine is a potent inhibitor of liver cell proliferation helps terminate the process.
24
Q
Describe how the liver is considered a blood reservoir?
A
- Expandable organ
- Hepatic arteries, veins and capillaries contain 450 ml blood = 10-15% TBV
- a large, expandable venous organ capable of acting as a valuable blood reservoir in times of excess blood volume and capable of supplying extra blood in times of diminished blood volume.
- ~20% of blood is in arteries, 10% is in capillaries, and 70% is in veins
- Hepatic arteries, veins and capillaries contain 450 ml blood = 10-15% TBV
- Translocation of blood:
- With increased right heart failure/ increased right atrial pressure liver
- → accommodate an extra liter of blood (pushes blood back to liver)
- Intense SNS stimulation (pain, hypoxia, hypercarbia) can abruptly decrease hepatic blood flow and volume
-
80% of flow (400-500ml) can be expelled in a matter of seconds (ex: for hemorrhage)
- Autonomic innervation of the liver coupled w/ the neurohumoral input from the systemic circulation allows for rapid precise control of the reservoir volume.
-
80% of flow (400-500ml) can be expelled in a matter of seconds (ex: for hemorrhage)
- Anesthetics & liver disease impair this response and severe liver dx pts have impaired vasoconstriction as well incapacitating the splanchnic reservoir – prevent redirection of blood flow to heart and brain
- The normal liver moderates the hypotensive response to acute blood loss and hypovolemia
- With increased right heart failure/ increased right atrial pressure liver
25
Q
Why is the liver considered an endocrine ordgan?
A
- Insulin growth factor – 1- somatomedin
- mediates actions of hormones from other endocrine glands (bone growth in children)
- . Insulin-like growth factor promotes systemic growth, especially bone growth in children.
- Angiotensinogen - precursor of angiotensin II/ all angiotensin proteins, fluid and electrolyte balance
- regulates SBP (systemic tone)
- Regulates water and Na
- Thrombopoietin –
- regulates plt production by stimulating bone marrow precursor cells to differentiate into plt-generating megakaryocytes.
- Hepcidin
- responsible for iron homeostasis and regulates intestinal iron absorption, plasma iron concentrations, and tissue iron distribution by inducing degradation of the hepcidin receptor, ferroportin
- Conversion thyroxine (T4) to tri-iodothyronine (T3)
- T4 (inactive) to T3 (active)
- Inactivation of corticosteroids, ADH, aldosterone, estrogen, androgens, insulin,
- The interaction of altered hormone levels and diminished hepatic synthesis of hormone binding globulins w/ altered metabolism and receptor regulation leads to significant endocrine abnormalities in pts w/ liver disease.
- Nearly half the insulin produced by the pancreas never reaches the systemic circulation bc it’s degraded during a single passage through the liver.
- In addition to hormone synthesis, the liver participates in endocrine function by inactivating many hormones, including thyroxine, aldosterone, antidiuretic hormone, estrogens, androgens, and insulin.
26
Q
How do kupfer cells work in the liver?
A
(10% hepatic mass)
- line hepatic venous sinuses
- clean blood of toxins, bacteria etc.
- process antigens
- When a bacterium comes into momentary contact with a Kupffer cell, < 0.01 second the bacterium passes inward through the wall of the Kupffer cell
- Can produce and recruit inflammatory mediators/neutrophils
- Impairment in advanced disease contributes to sepsis/MODS (w/ GI pathology or splanchnic ischemia)
- because blood flow is bypassing the kuppfer cells and going into systemic circulation before being “caught”
- In sepsis, Kupffer cells are responsible for scavenging bacteria, inactivating bacterial products, and clearing inflammatory mediators.Kupffer cell activation (e.g., by inflammatory stimuli) produces or triggers the release of proinflammatory substances (reduced oxygen species, nitro-radicals, leukotrienes, proteases), including cytokines and chemokines, which recruit neutrophils to the liver and heighten the inflammatory response. Although Kupffer cells are essential for defending the body against foreign intrusions, their activation can also harm the liver when they induce, or exacerbate, hepatocellular injury in diseases involving the liver
27
Q
Role of liver in carbohydrate metabolism?
A
- Maintenance of normal BG [] .
- In a person with poor liver function, blood glucose concentration after a meal rich in carbs may rise 2-3X as much as a healthy person.
- During fasting, hypoglycemia is initially prevented by glucagon mediated glycogenolysis – glycogen stores are rapidly mobilized and converted to glucose which is released into the circulation. With prolonged fasting – gluconeogenesis. In patients with advanced liver disease hyperglycemia often occurs portosystemic shunting allows blood to bypass the liver – glucose rich. Hypoglycemia may also develop with very advanced disease B1078-9 postprandial glucose levels are often much higher in patients with hepatic dysfunction.
- Large Storage of glycogen
- via glycogenesis in fed state (75 grams or 24 hours worth) = “glucose buffer function”
- Lipogenesis storage (fat) after 75 grams reached
- Storage of glycogen allows the liver to remove excess glucose from the blood, store it, and then return it to the blood when the blood glucose concentration falls to low.
- Conversion of galactose & fructose to glucose
- Gluconeogenesis (from AA and triglycerides)
- Gluconeogenesis occurs when the glucose concentration falls below normal. Large amounts of amino acids and glycerol from triglycerides are converted into glucose
- Formation of many chemical compounds from intermediate products of carbohydrate metabolism
28
Q
What is the liver’s role in lipid metabolism?
A
- Beta-oxidation of fatty acids to supply energy for body
- (ketone body formation in the fasting patient)
- Cholesterol, phospholipids and lipoprotein synthesis
- Critical components of cell membranes
- Cholesterol: component of biliary salts (ability to absorb nutrients and vit K from GI tract)
- cholesterol is precursor of steroid hormones, vitamins, and bile acids
- Synthesis of fat from proteins and carbohydrates
- With its glycogen stores full, the liver will efficiently convert glucose to fatty acids and triglycerides. Dietary fatty acids absorbed from the intestines reach the liver by the lymph and blood, mostly in the form of chylomicrons. The nutritional and hormonal status determines whether the liver oxidizes, stores, or releases free fatty acids.
29
Q
What is the liver’s role in protein metabolism?
A
- Deamination of amino acids
- (use for fuel)
- The body will die without the liver’s contribution to protein metabolism for more than a few days. Deamination of amino acids is required before they can be used for energy or converted into carbs or fats (small amt can occur in other tissues like the kidney).
- Formation of urea
- (removes ammonia from bodily fluids)
- Large amounts of ammonia are formed by the deamination process, and additional amounts are formed in the gut by bacteria and then absorbed into the blood.
- Without urea from the liver, ammonia levels will rise = hepatic coma and death.
- Whenever there is greatly decreased blood flow to the liver such as a portal vein – vena cava shunt – excessive ammonia in the blood will occur – toxic
- Thus, with a failing liver (and normal renal function), the blood urea nitrogen (BUN) concentration typically remains low, whereas nitrogenous wastes (e.g., ammonia) collect in blood and other tissues and may contribute to hepatic encephalopathy.
- Plasma protein formation
- (hormones, albumin, coagulant factors, cytokines, chemokines)
- Essentially all of the plasma proteins with exception of part of the gamma globulins (antibodies formed mainly by plasma cells in the lymph tissue of the body) are formed by hepatic cells.
- 90% of plasma proteins via liver – why ascites and edema with cirrhosis.
- The liver can form plasma proteins at a maximum rate of 15-50g/day (50% loss of plasma proteins can be replenished in 1-2 weeks). Plasma protein depletion causes rapid mitosis of the hepatic cells and growth of the liver to a larger size with rapid output plasma proteins until normal levels achieved.
- Amino acid synthesis and interconversions
- All non-essential amino acids can be formed by the liver
- Hepatocytes convert amino acids to keto acids, glutamine, and ammonia via transamination and oxidative deamination reactions
- Produce 12-50 mg protein per day
30
Q
What are some of hte vitamins and iron the liver stores?
A
- vitamin A (10 months worth)
- vitamin D (3-4 months worth)
- vitamin B12 (>1 year worth)
- iron as ferritin = “blood iron buffer”
- Liver secondary to Hgb for storage of iron
- The hepatic cells contain large amounts of a protein called apoferritin combines reversibly with iron to form ferritin stored when excess is available to be used for later shortages. G862
- Liver secondary to Hgb for storage of iron
31
Q
What are the coagulation factors formed in the liver?
A
- All coagulation factors formed in liver
- Except:
- vWF
- VIII
- VIII is made in both the liver and endothelial cells – often patients have enough even in severe liver disease
- III (tissue thromboplastin)
- IV (calcium)
- Except:
- Vitamin K dependent: need bile salts to get vit K!
- Prothrombin/Factor II
- Factor VII
- Factor IX
- Factor X
- Proteins C and S (anticoagulants)
- Thrombopoietin → plts
- Stimulate plt production!
- Synthesizes Anticoagulant factors
- antithrombin III, plasminogen activator inhibitor, Proteins C, S, Z, and fibrinolytic factors
- liver dx: see coagulation issues
- antithrombin III, plasminogen activator inhibitor, Proteins C, S, Z, and fibrinolytic factors
- Clearance of activated coagulation factors including fibrinolysins, TPAs (clearance essential for control of fibrinolytic states)
32
Q
What is liver’s role in the formation of erythrocytes and bilirubin?
A
- Liver responsible ~ 20% of heme production
- Used to produce cytochrome P450 enzymes
-
Deficiency in porphobilinogen deaminase (an enzyme in the biosynthetic heme pathway and CYP450 enzymes) → acute intermittent porphyria
- Consequences: NO BARBITUATES
- The liver is the primary erythropoietic organ of the fetus between the 9th and 24th week of gestation. It continues to be a major site of hematopoiesis until an infant is about 2 months of age. In healthy adults, the liver is responsible for about 20% of heme production; bone marrow makes the rest
- Metabolism of hgb produces bilirubin
- Hepatocytes responsible for conjugating bilirubin and releasing it into the bile to be eliminated via alimentary tract
33
Q
What is the liver’s role in excreting drugs, hormones and other substances?
A
- Detoxify or excrete into bile
- Ex: sulfonamides, penicillin, ampicillin, calcium, & erythromycin
- Termination of anesthetic effects via transformation by liver
- Predictable termination of the pharmacologic effects of many anesthetic agents depends on the liver for metabolic biotransformation into inactive products that can be eliminated
- Metabolize Endocrine gland hormones
- chemically alter and excreted by liver
- ex: thyroxine, (steroid hormones) estrogen, cortisol & aldosterone
- chemically alter and excreted by liver
34
Q
Role of liver in secreion of bile?
A
- Secretes 500 ml/day from common bile duct to duodenum
- Contains conjugated bile salts, cholesterol, phospholipids, conjugated bilirubins, electrolytes
- Bile acids
- help alkalinize & emulsify large fat particles
- → increase surface area for digestion/aiding absorption
- excretion of several waste products from blood
- ex: xenobiotics, bilirubin, calcium, & cholesterol
- Compounds >300-500 Daltons = too large for the kidney
- help alkalinize & emulsify large fat particles
- Considerations:
- Opioids interfere w/ biliary flow
- → increasing pressure in common bile duct or inducing spasm in sphincter of Oddi
- Mimics angina in awake pt
- Tx: Antagonize action w/ → (dilate bile duct)
- VA’s
- naloxone, nitroglycerin, atropine
- glucagon *
- → increasing pressure in common bile duct or inducing spasm in sphincter of Oddi
- Opioids interfere w/ biliary flow
35
Q
Impact of advanced liver disease on drug pharmacokinetics? (from ppt notes)
A
- Significant liver disease – portosystemic shunts allow orally administered drugs to bypass the first pass clearance + decreased liver blood flow= prolonged terminal half-life and increased systemic effects of high extraction drugs.
-
Hypoalbuminia increased free fraction – increased systemic effects, also increases elimination of those with low hepatic extraction ratios.
- If ascites is present may have an increased Vd.
- Doses should be decreased 50%
- It is often difficult in liver disease to predict the pharmacokinetics and pharmacodynamics of drugs.
- Often, cirrhotic patients with co-existing disease are better served receiving a hepatically cleared agent at reduced doses (careful titration) if it provides superior efficacy and side effects than less hepatically cleared agents.
36
Q
Whatis liver’s role in the cyp450 system?
A
- Liver has more than 20 different CYP enzymes
- Lots of genetic differences in people
- Up to four fold variation
- Lots of genetic differences in people
- Many of these isozymes contribute to:
- oxidation of drugs
- environmental toxins
- steroid hormones
- lipids
- bile acids
- Hepatocytes of zone 3 have the highest content of CYP proteins
- Zone 3: most sensitive to ischemic damage
- Also site of biotransformation → if toxic metabolites produced → impacts zone 3 cells
- Ex: acetaminophen → produce toxic metabolites (zone 3 most vulnerable)
- Also site of biotransformation → if toxic metabolites produced → impacts zone 3 cells
- Zone 3: most sensitive to ischemic damage
- Advanced cirrhosis lowers both total CYP and hepatic perfusion and results in significantly reduced clearances of many substances.
37
Q
Refresh on cyp inducers (in notes)
A
- Phenobarbital, phenytoin-> induce several different cyp proteins
- Smoke from cigarettes, cannabis–> induces CYP 1A2
- Alcohol–> induces CYP2EI, CYP3A4
- Induces of CYP not only affect own metabolism, but affect drug metabolism and biologic action of many other substances
- CYP induces activate nuclear orphan receptor transcriptional regulators and can participate in hepatic adaptation to chronic drug admin
- Genetic and environmental influneces are most important variable affecting drug metabolism
38
Q
What is intrinsic clearance of the liver?
A
- Reflects fraction of delivered drug load that is metabolized or extracted during a single pass through liver
-
High clearance – hepatic clearance approaches rates at which they transverse the liver
- Hepatic metabolism/clearance DEPENDS on hepatic BF
- Ex: decrease hepatic BF → highest impact on drugs listed below
- Ex: (see Box 22-1 Miller 8
- Lidocaine
- Diphenhydramine
- metoprolol
- Hepatic metabolism/clearance DEPENDS on hepatic BF
-
High clearance – hepatic clearance approaches rates at which they transverse the liver
-
Low clearance - hepatic clearances are relatively independent of hepatic blood flow
-
Aka: capacity dependent elimination
- Ex: anything changing free fraction of drug effects rate of clearing drug (low albumin [] )
-
Ex:
- Diazepam
- Acetaminophen
- warfarin
-
Aka: capacity dependent elimination
39
Q
What are some lab tests that show hepatocellular damage?
A
-
ALT (Serum alanine aminotransfersase)- SELECTIVE
- Only present in the liver (more selective for LIVER damage)
- Found primarily in zone 1 hepatocytes (area of oxidative metabolism)
- Only present in the liver (more selective for LIVER damage)
-
AST (Serum aspartate aminotransfersase)
- Present in a wide variety of tissues (liver, heart, skeletal muscle, brain, heart)
- Found primarily in zone 1 hepatocytes
- No prognosis can be done with levels of AST/ALT
- Found primarily in zone 1 hepatocytes
- Present in a wide variety of tissues (liver, heart, skeletal muscle, brain, heart)
-
LDH (lactate dehydrogenase)
- Nonspecific
-
GST
- Isoenzyme B found exclusively in liver
-
Specifically ZONE 3
- Worry about ischemic damage/toxic metabolite damage
-
Specifically ZONE 3
- *Highly sensitive
- Half-life (60-90 min)- short
- Track injury evolution
- Found in all acinar hepatocyte zones
- Isoenzyme B found exclusively in liver
40
Q
What lab tests assess bile flow status?
A
-
Alkaline phosphatase (AP) isoenzymes
- 2-4X increase → suggests cholestatic disease
- Levels vary w/:
- gender, age, blood type
- increased in CHF, pregnancy, smokers, growth spurts, sepsis, hepatitis, etc.
- general screen
-
5’-nucleotidase (5’NT)
- Helps differentiate between intrahepatic vs extrahepatic issue
-
Gamma glutamyl transferase (GGT)
- Nonspecific
-
Serum bilirubin
- HELPFUL → Reflects hepatic excretion capability
- Conjugated levels
- High levels: →
- Mechanical outflow obstruction (→ jaundice)
- High levels: →
- Unconjugated levels:
- High levels → indicates difficulty w/ liver conjugating (2)
- High Hgb metabolism (Ex: hematoma or several blood tx → lots of bilirubin to conjugate)
- High levels → indicates difficulty w/ liver conjugating (2)
- Conjugated levels
- HELPFUL → Reflects hepatic excretion capability
63
Q
Pathophys for cirrhosis-induced portal HTN?
A
. Cirrhosis and portal HTN induce circulatory changes that decrease the effective blood volume.
→ activates volume receptors and stimulates neurohumoral and intrarenal reflexes to decrease renal blood flow and to increase renal retention of sodium
- vicious cycle, all leads to retaining more and more fluid, ascites getting worse, and risk of variceal bleeding increasing
Schematic of pathways for cirrhosis-induced portal hypertension:
- the forward and backward theories.
- Cirrhosis and portal hypertension induce circulatory changes that decrease the effective blood volume.
- This activates volume receptors and stimulates neurohumoral and intrarenal reflexes to decrease renal blood flow and
- increase renal retention of sodium.
PVBF, portal venous blood flow; HABF, hepatic arterial blood flow; THBF, total hepatic blood flow; A-V, arteriovenous; PG’s, prostaglandins; ADH, antidiuretic hormone; ANF, atrial natriuretic factor; PAF, platelet activating factor.
91
Q
What are TIPS procedures?
A
Transjugular Intrahepatic Portal-Systemic Shunt Procedure
- percutaneously created intrahepatic connection of portal and systemic circulations
- Uses: ESLD to decrease portal pressure and attenuate complications related to portal hypertension
- Hook up PV to HV
- (Uses ex: variceal bleeding or refractory ascites)
- Improve QOL (not long term)–> minimizes need for paracentesis frequently
- Hook up PV to HV
- Diversion of PBF into the hepatic vein is achieved by placement of an expandable intraparenchymal tract
- Uses: ESLD to decrease portal pressure and attenuate complications related to portal hypertension
Pic:
Miller Figure 73-7 (TIPS) procedure.
A stent (or stents) passed through the IJ vein over a wire into the hepatic vein (A); dilated esophageal varices (EV) are apparent. The wire and stent or stents are then advanced into the portal vein (B), after which blood can pass through the portal vein into the hepatic vein and bypass and decompress dilated esophageal veins (C).
