Digestive System: The Liver Part B

Front 1

Cytochrome P450 Enzymes / Phase I Enzymes

Back 1

-deactivate the drug (makes less highly active - don't want it to go on forever)
-break down drugs to metobolites
-metabolites need to be more water soluble:
1. rid in urine
2. rid in bile
* if not made soluble: precipitation occurs: makes stones
-most prominent in liver
-but can be also found in intestines, lungs, etc.
-CYP450, each enzyme is termed an isoform since each derives from a diff gene
-classified in sets = CYP then followed by #s & letters

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Conjuctive Enzymes / Phase II Enzymes

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-breakdown to metabolites
-stick compound on to make hydrophillic (water soluble)
-ex: glucuronic acid (glucuronidation), sulfuric acid, acetic acid, or an aa added

*most drugs broken down by P450/Phase I
-difficult drugs go thru phase I & II or can just go thru Phase II

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3 Fxns that Hepatic Metabolism Depends On

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1. Liver Fxn: assessed by "liver enzymes" transaminase enzymes AST, ALT (NOT p450 enzymes) commonly measured as blood tests
-liver cells die = spill contents into blood, if high know cells are dying @ too fast of rate (transaminase levels should be low)
2. Nutritional State: vitamins, minerals imp for liver's drug metabolizing enzymes to work properly
3. CP450 inhibition & CP450 induction: drug prescription impact, presence/absence of other drugs that can affect liver's enzymes particulary the P450 enzymes

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Cytochrome P450 Enzyme Inhibition

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-pat has to be on more than 1 medication (risk of drug-drug interaction)
-decreased metabolic activity of P450 enzymes leading to decreased metabolism of drugs
-can selectively inhibit 1 subgroup of P450 isoenzymes or can non-selectively inhibit activity of all isoenzymes
-ex: if take b-blockers then diagnosed w/ depression put on prozac -> which inhibits b-blocker enzymes = b-blockers not broken down therefore build up in bloodstream (highly active)

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Cytochrome P450 Enzyme Induction

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-not as common as inhibitors
-increased synth of P450 enzymes lead to increased metabolism of drugs
-inducer can selectively increase one subgroup of P450 isoenzme or can non-selectively increase activity of all isoenzymes
-breaks down drug too quickly = no effect of drug left to even work

Front 6

Vitamin D Activation

Back 6

2 ways to get vitamin D:
1a: ingest VitD
1b: sunlight
2. skin has enzyme that activates 7-dehydrocholesterol (pro-VitD) --> Cholecalciferol (VitD3)
3. send to liver (add OH group) 25-Hydroxycholecalciferol
4. send to kidney (add OH group) 1, 25-dyhydroxycholecalciferol *ACTIVE VITD*

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Major Types of Plasma Proteins

Other proteins found in blood:

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Liver produce vast majority:
Albumin
Globulin
Fibrinogen
-all albumin & fibrinogen & 50-80% of globulin are formed in liver

insulin, GH, ADH, PTH, etc...

Front 8

Plasma Protein Fxns:
1. Albumin

2. Globulin

3. Fibrinogen

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1. Albumin
a. exert oncotic pressure across capillary walls (prevents plasma loss) maintain higher conc in blood creating a diff conc in capillaries (allow passage of materials)
b. supply ~15% of buffering capacity of blood
c. transport of thyroid, adrenocorical, gonadal & other hormones
d. carrier for metals, ions, FA, aa, bilirubin, enzymes & drugs

2. Globulin - same as albumin's c & d
a. participate in immune response (gamma-globulin: only plasma protein liver doesn't produce)

3. participate in blood clotting

Front 9

Synthesis of Blood Clotting Factors

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-majority produced in the liver
-all essential for proper blood clotting cascade

Front 10

Recipe for Bile

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-most imp liver fxn in relation to digestion
-made by hepatocytes
-organic constituents of bile are:
>bile salts (~50%) critical for digest.
>phospholipids (~40%): critical for digest.
>cholesterol (~4%): waste
>bile pigments such as bilirubin (~2%): waste
>bile also contains: electrolytes & water (secreted by cells lining the bile duct)
-less water therefore eliminates less soluble products

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Types of Bile Acids

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-in intestines, 4 diff types:
1. primary: cholic acid
2. primary: chenodeoxycholic acid
-sent to SI & LI
-in LI bacteria convert to secondary
3. secondary: deoxycholic acid
4. secondary: lithocholic acid
-bile acids can be reabsorbed-->go into bloostream conjugate w/ aa & be put back thru GI tract

Front 12

Bile Acids vs. Bile Salts

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-bile acids eventually become bile salts
-liver conjugates the bile acids w/ aa glycine or taurine to form salts
-this makes them amphipathic (both hydro-phobic & -philic) at duodenal pH

Front 13

Phospholipids

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-variety found in bile
-most common = lecithin
-critical for digestion
-phospholipids = amphipathic
-form micelles, arrange to trap inside nonsoluble particles
-hydryophillic head, hydorphobic tail

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Cholesterol

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-used to make steroids & cell mem
-also makes bile acids
-hepatic synth of bile acids = majority of cholesterol breakdown in body
~500mg of cholesterol are converted to bile acids & eliminated in bile everyday
-can only put so much cholesterol into bile = finite ability
-too much causes probelms

Front 15

Bilirubin

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-waste product of hemoglobin degradation
-too much = jaundice
-RBC degradation: liver & spleen filter out old cells
-hemoglobin broken down into:
>globin: protein aa pool
>heme: broken to iron (recycled) & rest = waste (biliverdin -> bilirubin -> sterocobilin (stool brown))

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Types of Bilirubin

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1. Free bilirubin / unconjugated / indirect
-spleen
-transported in blood attached to albumin
2. conjugated bilirubin / direct bilirubin
-liver
-as free bilirubin passes thru liver, released from albumin & moved into hepatocytes to perform:
1. uptake of bilirubin from blood
2. conjugate bilirubin to protein
-involves attach of glucuronic acid to bilirubin
-cataclyzed by: glucuronyl transferase
-most water soluble
3. excrete bilirubin into bile

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Other Bile Constituents

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Ions: Na, K, Ca, Cl, HCO3 & water are secreted into bile by epithelial cells lining bile ducts

other waste products --> lipophilic drugs & metabolites, Ag-Ab complexes, etc.

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Bile Synthesis

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formation of bile occurs in 3 steps:
1. hepatocytes actively secrete bile into the bile canals (canaliculi)
2. intrahepatic & extrahepatic ducts not only transports bile but cells that line ducts = cholangiocytes secrete watery, HCO3 rich fluid
-steps 1 & 2 produce ~900ml/day of "hepatic bile"
3. b/w meals ~1/2 the hepatic bile is diverted to gallbladder, stores the bile & removes salts & water
-concentrates key remaining solutes - bile salts, bilirubin, cholesterol, & lecithin by 10-20 fold
-during meals = bile reaching duodenum is mix of "dilute" hepatic bile & "concetrated" gallbladder bile

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Bile Fxns

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1. bile provides sole excretory route for many solutes that are not excreted by the kidneys

2. secreted bile salts & lecithin required for normal lipid digest & absorp in the SI

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Liver Disorders

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most hepatic derangements cause similar signs & symptoms:
1. jaundice: excess bilirubin, liver not eliminate properly
2. uncontrollable bleeding: liver not make all clotting factors
3. impaired toxin metabolism:can't metabolize alcohol & drugs properly
4. edema: not make plasma proteins (no oncon. pressure)
5. osteomalacia: no activ. of VitD= no absorp of Ca in bones
6. hyper- or hypoglycemia: cells die, stored glucose released

-hepatocytes generate well; is a problem when continous damage occurs ex: hepatitus: when virus never leaves, continous infect = scarring

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Assessment of Liver Malfxn:

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-increased bilirubin levels in plasma
-increased liver enzymes in plasma (ex: alkaline phosphatase, ALT/SGPT, AST/SGOT, & others)
-decreased plasma protein levels (ex: albumin)
-increased prothrombin time (PT): prothrombin contents of blood will be low w/ liver disease, cause blood to take a longer than norm time to clot

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Liver Panel

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-also known as liver (hepatic) fxn test (LFT) used to detect & monitor disease/damage
-consists of 7 tests run at same time:
1. ALT (alanine aminotransferase): enzyme found in liver; best test for detect hepatocytes
2. ALP (alkaline phosphatase): enzyme related to bile ducts; often increased when they are blocked/inflamed; when this occurs, the ALP can overflow like backed up sewer & seep out o fliver & into blood
3. AST (aspartate aminotransferase): enzyme found in liver & heart & muscles in body
4. bilirubin: 2 diff test often used together:
-total measures all in blood
-direct measure conjugated
5. albumin: measure main protein made by liver & whether or not liver is making an adequate amount of this protein
6. total protein: measures albumin & all other proteins in blood, include Ab

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Cirrhosis

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-diffuse liver scarring & fibrosis
-hardening of liver
-scar tissue: hepatocytes die & collagen laid down= scarring
-response to repeat cell injury & result inflamm. rxn
-causes: hepatitis & alcohol
-only tx = liver transplant

Front 24

Jaundice

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-bilirubin accumulates in blood (hyperbilirubinemia)
-skin, sclera of eyes & mucous mem turns yellow (jaundice, icterus)
-detectable when total plasma bilirubin is >2.0mg/dL (normal=0.1-1.2mg/dL)
-accum = no damage & no pain
-toxic to brain: adults cannot pass BBB but newborns BBB not yet developed can damage

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3 Types of Jaundice

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1. Pre-hepatic (hemolytic) jaundice: before liver, sickle cell anemia, body breaking down RBC @ high rate therefore generate lots of hemoglobin (RBC live ~7-8days)
2. Intahepatic Jaundice: the liver (due to cirrhosis, hep), both unconjugated & conjugated are elevated
3. Post-hepatic (obstructive) jaudice: obstruct of bile ducts (gallstone) unconjugated bilirubin usually still enters liver cells & becomes conjugated; conjugated returns to blood & elevates
-bili collects in canaliculi->ruptures into blood (liver stops making bile)

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Jaundice in Neonates

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-usually harmless condition, lasting no longer than 2 weeks after delivery
-hepatic machinery for conjugating & excreting bilirubin doesn't fully mature until ~2 weeks of age
-hence common for newborns to develop transient & mild unconjugated hyperbilirubinemia
-breastfed have higher incidence of hyperbilirubinemia than do bottle-fed babies
-breastmilk contain b-glucuronidase: unconjugates bilirubin in SI, absorped from SI & into blood, thereby raise plasma levels of bilirubin

Front 27

Bilirubin Lights

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-light waves of 450nm wavelengths convert unconjugated bilirubin into highly-water soluble form that is excreted from body via the kidneys
-lower bilirubin in blood
-adults cannot use this method: skin too thick & more fat layers