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Human Body_TP > Liver Physiology > Flashcards

Liver Physiology Flashcards

1
Q

liver

A

-2nd largest organ after the skin
-weighs 1200-1500 grams
-located under the right diaphragm

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2
Q

what are some functions of the liver?

A

biotransformation, detoxification, protein synthesis, metabolism, storage, and immunity

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3
Q

major blood vessels to and from the liver

A

-gets a lot of the blood flow from the intestines
-almost all other organs have blood flow to it that is arterial like the skin which has arteries that bring oxygenated blood to skin cells and @ capillary level there is transfer of nutrients and oxygen
-liver gets a lot of blood flow from the portal vein (75%) and only 25% from the hepatic artery

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4
Q

portal system

A

-a lot of blood flow from the portal veins draining intestines (proteins, amino acids, sugars)
-veins absorb these nutrients and need to go to liver first —> portal system drains blood from the esophagus to rectum plus spleen, pancreas, and gallbladder

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5
Q

liver circulation

A

portal vein, hepatic artery, and bile duct enter into the liver anatomically and branch together (portal triad) —> tripling of vessels that enter into portal tracts
-ultra structure of liver is defined by numerous portal tracts
-as blood from hepatic artery and portal vein enter into sheets of hepatocytes, blood flows between them and coalesce into central lobular vein that then drains into the hepatic veins that lead to inferior vena cava —> right heart

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6
Q

liver as a filter

A

doesn’t have capillaries, instead it is has sinusoids with large gaping holes with no basement membranes —> allows for macromolecules to pass through (free transport) to be sampled by the liver

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7
Q

fibrosis of the liver + compromised blood flow —> what are consequences of this compromised blood flow?

A

-decrease in normal metabolism
-portal hypertension

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8
Q

portal hypertension

A

-ohm’s law: V=IR or delta P=flow*resistance —> when resistance goes up, the pressure must also go up to maintain the same amount of flow
-capillarization of the liver —> fibrosis acts as pseudo basement membrane, which prevents a lot of blood flow

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9
Q

3 patterns blood will take to go back to heart in portal hypertension

A
  1. engorge vessels in esophagus where there are anastomoses from veins that drain directly to the portal system
  2. engorge veins near rectum in proximity to the other veins that are not part of the portal system
  3. leak fluid off the liver into the abdominal cavity
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10
Q

portal hypertension: ascites

A

-leakage into peritoneal sapce (vacusealed) and where there is fluid that makes the abdomen bulge out —> massive ascites @ end stage liver disease- sometimes have to drain fluid to relieve pressure on diaphragm

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11
Q

portal hypertension: varices

A

-engorged vessels and when they bleed there is a fountain of blood
-esophageal bleed can be fatal

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12
Q

what are some other causes of portal hypertension?

A

-blood clot above the liver or before vessels of the liver (portal vein thrombosis) can lead to hepatocellular damage with clot superior to liver
-budd-chiari syndrome
-constrictive pericarditis- backflow of pressures to liver with fibrosis from the heart
-schistomaisis- fluke infection in sub-saharan Africa- eggs of trematode are deposited before entry to hepatocytes —> swelling but liver is intact

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13
Q

hepatic parenchymal cells

A

-hepatocytes- 80% of the liver (800 million)- highly transcriptionally active
-second largest cells in the body after the neuron
-aid in metabolic functions like digestion, phase I vs phase II, and detoxification

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14
Q

biotransformation

A

-elements absorbed from the intestinal tract have to be transformed to be used by the rest of the body
-small, water soluble molecules can be directly filtered at the kidney and excreted in the urine
-a lot of substances in the blood are big, bound to plasma protein, and cannot be excreted to urine directly —> biotransformed by the liver into water-soluble molecules that can be excreted in the bile or urine
-uptake from blood across the basolateral/sinusoidal membrane
-chemical modification and degradation
-export into the bile across the apical membrane
-export into the blood across the basolateral membrane

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15
Q

phase I modifications

A

-basic redox rxns involved in both detoxifying elements and making them useful for cells
-P-450 cytochromes

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16
Q

P-450 cytochromes

A

-transform drugs into useful compounds or used in accelerating metabolism of drugs to try and find a way to circumvent the body’s functions (many drugs utilize the same P450 enzyme to be transformed)
-oxidation
-hydroxylation
-dealkylation- dealkynate before natural substances
-dehalogenation
-reduction
-diverse, more than 150 isoforms
-found on ER
-expression can be induced or suppressed (alcohol can induce P450 2E1)

17
Q

phase II modifications

A

-conjugation for water solubility (enzymes conjugate to glucuronate, sulfate, and glutathione)
-critical for substances to circulate the body and detoxify substances

18
Q

tylenol’s effect on the liver + alcohol

A

-normally metabolized by phase II enzymes
-small part transformed by cytochrome P450 2E1 and while end product is safe, very reactive intermediate that can cause hepatocellular damage or cytotoxicity
-b/c more than abundant glutathione storage, NAPQI is glutathiated and rapidly excreted
-normally don’t have to worry about tylenol in small amounts but don’t mix with alcohol —> alcohol revs up synthesis of 2E1 and produces more reactive intermediate NAPQI and the alcohol is also reducing the glutathione storages by reducing the ability for NAPQI to be metabolized
-patients who have acetaminophen hepatotoxicity are treated with glutathione

19
Q

bilirubin metabolism (internal substance)

A

-bilirubin is a potentially toxic catabolic product of heme metabolism
-it is what is produced when hemoglobin is metabolized
-hemoglobin is toxic to us since it is inorganic —> coupled for pseudostability where the heme ring stabilizes the iron in its core and it’s clever with cooperative behavior
-bilirubin is detoxified and metabolized in the liver

20
Q

bilirubin metabolism pt. 2

A

-heme ring itself is very toxic and @ the end of RBC lifespan, the hemoglobin is recycled —> macrophages of the spleen chew up membranes and in the spleen is where you have destruction of the ring
-heme oxygenase disassociates iron from heme ring and produces biliverdin and biliverdin reductase converts biliverdin to bilirubin that’s not water soluble —> transported with proteins to the liver —> unconjugated bilirubin is taken out by transporters and biotransformed by urinogluconiride transferase into mono and digluconiride bilirubin (water soluble) (conjugated)

21
Q

bilirubin metabolism pt. 3

A

-passaged through the bile duct cells to the gallbladder where it’s stored
-once bilirubin enters into the lumen, it’s deconjugated and converted by bacterial enzymes into urobilinogen, which is then converted by bacterial enzymes to sterobilien and secreted in feces
-some urobilinogen is absorbed by intestines —> sent to bloodstream —> filtered @ kidney as urine (urobilin)

22
Q

jaundice

A

-caused by hepatocellular damage
-sickle cell anemia- overwhelm ability to conjugate from increased RBC turnover- liver can function fine to metabolism bilirubin but it’s too much
-you can biochemically distinguish pathway people are having an issue by measuring conjugated fraction (direct bilirubin) by the unconjugated fraction (indirect bilirubin)
-if the total minus the conjugated is high, you have low direct bilirubin and upstream of liver
-if the total minus the conjugated is low, you have high conjugated bilirubin and that is in liver failure
-obstruction- gallbladder can form gallstones with disfunction and stones can get stuck in biliary ducts leading to jaundice
-the way the tubing is hooked up with the common bile duct and pancreatic duct coalescing into one duct leading to duodenum —> pancreatic cancer can obstruct flow of bile, which is painless jaundice

23
Q

hepatocytes zonation

A

-hepatocytes are mulitiplicitious and revealed by location in liver —> zonation of hepatocytes
-portal tracts have high O2 tension blood and hepatocytes near them are bathed in this (zone 1)
-hepatocytes next to the centrolobular vein won’t have much access to O2 rich blood but other nutrients (zone 3)

24
Q

port-central axes of damage

A

-microorgan physiology in liver —> porto-central axis and liver damage can be found in this gradient according to blood flow
-gradients in O2 tension, cell hormones, and nutrients
-cytochrome p450 enzymes and damage from alcohol
-metabolism
-microbial translocation

25
Q

what is the key metabolic pathway governing zonation?

A

beta-catenin pathway, which is true for P450 enzymes

26
Q

CYP2E1 pathway

A

centrolobular predominance of expression —> people who drink alcohol seem to have damage to hepatocytes surrounding the centrolobular vein

27
Q

hepatic non-parenchymal cells

A

-biliary endothelium (cholangiocytes)
-liver sinusoidal endothelium
-hepatic stellate cells
-kupffer cells
-dendritic cells
-lymphocytes (T cells, B cells, NK cells)
-NK cells

28
Q

biliary system

A

-bile duct cells form bilecaniculi and they coalesce into larger bile ductuals, which coalesce into large bile ducts
-right and left hepatic ducts combine into the common hepatic duct
-instead of bile flowing downwards, it accumulates in the gallbladder and @ regular intervals the gallbladder contracts to push bile into common bile duct to combine with pancreatic duct to one spot in duodenum
-bile and pancreatic fluid enter duodenum and small sphincter of oddi

29
Q

bile formation

A

-hepatocytes secrete bile
-cholangiocytes contribute to the bile
-gallbladder concentrates bile
-mix of bilirubin, bile salts, and cholesterol
-make bile salts to emulcify fats
-cholesterol is a progenitor of bile salts

30
Q

bile function

A

-bile acids are excreted into intestines and emulcify fats injested (excretory route for many molecules)
-bile salts are absorbed along with fats @ terminal illeum (lipid digestion and absorption)

31
Q

bile composition

A

-most bile acids, fatty acids, bilirubin, phospholipids, and cholesterols are in the gallbladder bile rather than the hepatic bile
-more of the proteins may be in the hepatic bile

32
Q

bile acid formation

A

-cholesterol goes through several reactions —> becomes chenodeoxycholic acid —> one hydroxylation is added and it becomes cholic acid
-ATP + coASH form AMP + PPI —> cholic acid becomes cholyl-CoA which then becomes taurocholic acid and glycocholic acid

33
Q

enterohepatic circulation of bile acids

A

-bile acids are produced daily —> secreted into the duodenum —> emulcify fats from duodenum to terminal illeum, where a lot of absorption occurs
-bacterial enzymes are required to form secondary bile acids that are responsible emulcifiers
-primary bile acids are cholic and chenodeoxycholic acid then the secondary bile acids are deoxycholic acid and lithocholic acid

34
Q

liver as an immune organ

A

-topologically inside of small intestine is the outside world that we absorb from
-tons of bacteria in the intestines
-every time you absorb you’re picking up pieces of bacterial cell walls that trigger sensors
-venous blood includes CRP, complement components, acute-phase proteins, clotting factors, proteins, sugars
-arterial blood brings in modified plasma proteins
-intestinal blood has nutrients, LPS, environmental toxins, pathogens, food antigens, and immune cells

35
Q

bacterial toxins (LPS)

A

-set of compounds produced by class of bacteria that can be toxic
-endotoxins like LPS are made in cell walls of gram negative bacteria
-LPS is important since it contributes to septic shock
-LPS is a PAMP to TLR4 whose downstream effect is TNFalpha, which is the constituent that makes us feel in shock

36
Q

kupffer cells

A

-liver macrophages
-phagocytosis
-antigen processing and presentation
-produce cytokines, prostanoids, nitric oxide, and reactive oxygen intermediates
-detoxifies LPS
-AOAH cleaves 2 of the 6 hydroxyl groups from LPS
-hexylated LPS is what binds to TLR4 —> cleave off groups you are left with tetrahexylated LPS and doesn’t signal
-critical for innate immunity where the liver manages everything from the outside world like the lungs
-large # of liver cells are involved in adaptive immunity

37
Q

lymphocytes

A

-25% of non-parenchymal cells are lymphocytes
-majority are alpha-beta cells in peripheral blood but in liver you see NK/NKT cells
-more Tregs to help reduce signalling when we eat a meal (immuno tolerant)

38
Q

hepatic stellate cells

A

-storage of vitamin A
-transdifferentiate into myofibroblasts under activating conditions
-cells responsible for extracellular proteins that lead to fibrosis

39
Q

hepatic lymphocytes

A

-T cell CD4:CD8 ratio is reversed —> typically in blood you have 2:1 ratio but in liver it is 1:2
-T cell tolerance allows for liver transplants
-NK/NKT cells make up 50% of hepatic lymphocytes
-plasmacytoid dendritic cells (pDCs) produce type I interferon in response to bacteria

Human Body_TP (25 decks)

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