fall chem week 1

dual blood supply

25% hepatic artery (branch or aorta, oxygen rich), 75% portal vein (drains digestive tract, nutrient rich), 1500mL per min

portal vein sources

stomach (drugs, alc, metabolism/detox), spleen (bilirubin comjugated, excretion), pancreas (insulin, glucagen, reg glu metabolism), small intest and colon

portal vein source small intestine and colon

monosacch, AAs, FAs- metabolism, prot synth, storage

ammonia- conversion to urea

drugs, toxins- metabolism/detox

microbial products- removed

lobule

functional unit of liver, hexagonal, portal triad at each corner, blood flows into sinusoid channels surrounded by hepatocutes, central vein leads to heparuc vein

potral triad

bile duct, branch of portal vein, branch of hepatic artery

lobule blood flow

portal vein branch and hepatic artery branch> sinusoid space> central vein> inferior vena cava

kupffer cells in the sinusoids

macrophages, phagocytize bacteria, toxins, and damaged/aged rbc

hepatocytes in the sinusoids

abt 80% of liver vol, radiate in plates from central vein, responsible for major liver func, regenerates

lobule bile flow

bile canliculi> intrahepatic ducts> right and left hepatic dict> common hepatic duct> common bile duct> duodenum

liver carb metabolism glycogenesis fed state

small intestines deliver glu and other monosaccharaides from food to liver for glycogen storage through the portal vein

liver carb metabolism glycogenolysis fasted state

glycogen> G6P> glucose> circulation

glucagon, portal vein, liver, hepatic vein, heart

liver carb metabolism glyconeogenesis fasted state

lactate, glycerol, glucogenic AAa > G6P> glucose> circulation

lipid metabolism uptake and synthesis fed state

excess glu> FA> trig> VDLD> circulation (portal vein, liver, hepatic vein, heart)

chylomicron remnants> FA, chol, apoprotein > chol esters, bile acids, into membranes > VLDL track ,bile ducts

lipid metabolism breakdown/energy production fasted state

adipose trig> lipolysis> glycerol and FA> gluconeogensis and B-oxidation> NADH and FADH2 and acetyl-coA> TCA cycle> ETC> ATP

lipid metabolism breakdown/energy production prolonged fasted low insulin

acetyl-coA> ketogenesis> acetoacetate and BOHB and acetone> tissues and exhalation/urine

protein metabolism

regulates bodys AA pool (small continually changing supply) and nitrogen disposal, dietary proteins, body protein breakdown (normal cell turnover, skeletal muscle proteolysis during fast), synthesis of nonessential AAs

liver synthesizes nonessential AAs

alanine, aspartate, glutamate

liver synthesizes nearly all plasma proteins except- Ig, adult hgb

albumin, coag factors I, II, V, VII, IX-XIII, acute phase reactants (crp, hapt, ceruloplasmin, complement)

liver synthesizes enzymes

ALT, AST, ALP, GGT

amino acid catabolism

no dedicated storage form, AAs not used for synthesis are catabolized, transamination, deamination

transamination

transfer amino group to another carbon skeleton

deamination

remove amino group, free NH3, carbom skeleton

gatekeeper- first pass metabolism

metabolism of oral drugs before they reach systemic circulation, which may reduce bioavailability compared with other routes

metabolism by liver includes

inactivate a drug, activate a prodrug, produce active or toxic metabolite, make substance easier to excrete

first metabolism rxns

oxidation/reduction, hydroplysis, hydroxylation, demethylation, conjugation (attach polar group)

liver is a reservoir for

glycogen, vitamins (fat soluble= A D E K, water= B12), iron, copper, trig (limited storage, excess accumulation> hepatic steatosis fatty liver)

biliary function secretion

bile acids for fat digestion/adsorption

biliary function excretion

conjugated bilirubin, excess chol, drug and toxin metabolites

bilirubin metabolism

rbc breakdown, transport bound to alb, conjugation, transport in bile, bacterial action and oxidation, fate of urobilinogen

rbc breakdown

heme and globin, heme = iron and biliverdin= unconjugated bili, macrophaged to liver spleen bm

transport bound to alb

unconjugated bili binds in circulation

conjugation

unconjugated bili-alb becomes alb and conjugated bili-GlcA (bilirubin diglucuronide), hepatocyte

bacterial action and action

urobilinogen, stercobilin, stool

fate of urobilinogen

urine or stool

bilirubin general

most eliminated in stool as stercobilin, unconjugated in blood

unconjugated bilirubin

indirect, water insoluble nonpolar, binds to alb for transportation, not in urine, calculated total - direct, ref= 0.2-0.8

conjugated bilirubin

direct, water soluble polar, free in plasma, in urine when elevated in plasma, ref= 0-0.2

total bilirubin ref range

adults 0.2-1

premature infants 24hrs 1-6, 48hrs 6-8, 3-5 days 10-12

full term infants same excpt 3-5 days 4-6

urine= neg

jaundice

yellow skin, sclera, mucous membranes, hyperbilirubinemia, iceterus (dark yellow), kernicterus (nuero damage from severe unconjugated hyperbilirubinemia during infancy)

prehepatic

hemolytic jaundice, increased bilirubin load, high unconjugated bili, no bilirubinuria

hepatic

hepatocellular jaundice, intrinsic liver problems causing high unconj and no bilirubinuria in conjugation, high conj and bilirubinura in transport, and mixed conj/unconj

posthepatic

obstructive jaundice, biliary obstruction (inflammation, scar tissue, gallstones, tumors), chalky pale stool, high conj bili, bilirubinuria

gilberts syndrome

most common cause of jaundice due to intermittent unconj hyperbilirubinemia, benign, autosomal recessive, 5% of the US (UGT1A1 mutation chromosome 2), conj at 30%, total bilirubin 1.5-3

crigler-najjar syndrome

UGT1A1 gene, type 1= complete absence of the enzyme, type 2= severe enzyme def, rare, death

neonatal jaundice- physiologic

transient, increased rbc turnover causing increased bilirubin production, immature UGT1A1 at birth, common in preterm infants

neonatal jaundice- rapidly rising bili

unbound bilirubin enters brain causing kernicterus, critical result called asap, results interpreted based on age in hours and gestational age

neonatal jaundice- phototherapy

converts unconj bilirubin into water soluble photoisomers, excreted without UGT1A1 conjugation

neonatal jaundice- exchange transfusion

bilirubin at exchange threshhold or sogns of acute biliniogen encephalopathy

dubin-johnson syndrome

rare, autosomal recessive, MRP2 def, canalicular transporter protein, defective excretion into bile, conj hyperbilirubinemia + bilirubinuria, total 2-5, >50% conj, benign, black liver with dark pigmented granules

rotor syndrome

mutations affecting OATP1B1 and OATP1B3, transport conj bili from blood into hepatocytes, impaired reuptake causing conj bili remains in circulation, mild conj hyperbilirubinemia + bilirubinuria, benign

total bilirubin lab results

high in pre, hepatic, and post

indirect bili aka unconj

very high in pre, high in hepatic, normal or slightly high post

direct bili conj

pre normal, high hepatic, very high post

urine bilirubin

neg pre, variable hepatic, pos post

urine urobilinogen

high pre, variable hepatic, neg post

steatosis

fat accumulation in hepatocytes

hepatitis

liver inflammation and hepatocyte injury

steatohepatitis

steatosis with inflammation and injury

regenerative nodules

clusters of regenerating hepatocytes surrounded by scar tissue

cirrhosis

advanced fibrosis (excess scar tissue) and regenerative nodules (clusters of hepatocytes regrowing within scar tissue) that distort liver structure and blood flow causing portal hypertension or increased pressure in the portal venous system

cholestasis

reduced or blocked bile flow

cirrhosis symptoms

early compensated disease may be asymptomatic, fatigue weight loss jaundice itching, reduced protein synthesis edema and bleeding, ascites, variceal bleeding, encephelopathy, confusion from high ammonia

ascites

portal hypertension back pressure

variceal bleeding

portal hypertension back pressure

cirrhosis labs

normal to mild elevated liver enzymes, elevated- bili ammonia PT/INR & GGT, decreased albumin, low plt due to decrease TPO synthesis of liver and splenomegaly indicating portal hypertension

causes of cirrhosis

alc associated liver disease ALD (most common in US) and metabolic dysfunction associated steatohepatitis MASH (fatty liver disease, MASLD non alc fatty disease)

cirrhosis flow

fat overload> steatosis> hepatocyte injury> inflammation> fibrosis> cirrhosis

ethanol metabolism- acetaldehyde accumulation

toxic, hepatocyte injury and inflam cause elevated hepatocyte ALT release, damage to hepatocyte mitochondria causing elevated mitochondrial AST release

ethanol metabolism- excess NADH

alters liver metabolism, low fatty acid oxidation and high trig syn cause fatty liver, high lactate= lactic acidosis, low gluconeogenesis= hypoglycemia, high ketone production, malnutrition

ethanol metabolism- chronic heavy alc use

induces CYP2E1 (liver enzyme, alternate etoh causing acetaldehyde and reactive O2), oxidative stress causes need for antioxidant glutathione recycle increasing GGT, increased toxin drug metabolites

MASLD

insuline resistance, metabolic dysfunction, elevated ALT and slightly AST, weight loss, metabolic control

ALD

heavy alc use, very high AST, high ALT and GGT, EtOH abstinence

hepatitis (B C D) causes of cirrhosis flow

hepatocyte infection> immune attack> hepatocyte injury> inflam> fibrose> cirrhosis

autoimmune causes of cirrhosis flow

bile duct injury narrowing/obstruction> cholestasis (reduced bile flow)> bile acid retention in liver> hepatocyte injury> inflam> fibrosis> cirrhosis

inherited disorders/ autoimmune hep/ drugs causes of cirrhosis flow

gene defect> toxic accumulation> hepatocyte injury> inflam> fibrosis> cirrhosis

inherited disorders

hemochromatosis (iron), wilson disease (copper), a1-antitrypsin def (misfolded)

liver tumors primary

begin in hepatic or biliary cells, hepatocellular carcinoma HCC (most common, with cirrhosis or chronic hep B/C, AFP may increase)

liver tumors metastatic

90-95% (more common than primary), common in colorectal, pancreatic, breast, lung

Reye syndrome

rare acute encephelopathy and fatty liver injury in children, following viral illness due to aspirin/other salicylate use, high ammonia and AST/ALT

drug induced liver injury DILI

intrinsic- predictable and dose related (acetominophen), idiosyncratic- unpredictable and patient specific, pattern- hepatocellular (AST/ALT), cholestatic (ALP/D bili), or mixed

transcutaneous bilirubin TcB

noninvasive est from light reflected by skin, screens newborns for hyperbilirubinemia, high requires total bilirubin, treatment guided by blood test, less reliable during phototherapy

bili specimen handeling

protect from light (30-50% loss/hr), separate from cells and analyze asap, hemolysis- false decrease if diazo, lipemia interferes (prefer fasting)

diazo rxn

bilirubin + diazotized sulfanilic acid= colored azobilirubin, direct bili reacts without accelerator, total bilirubin requires accelerator for uncoj bilirubin

malloy-evelyn diazo method

using methanol as accelerator, red-purple product 560 nm, affected by pH and protein levels

jendrassik-grof diazo ref method

uses caffeine-benzoate as accelerator and ascorbic acid to stop rxn, alkaline taryrate shifts to blue 600 nm, more sensitive and less affected by acidity or protein

urine bili diazo rxn

bilirubin + diazonium salt= colored azobilirubin, color intensity increases with bilirubin concentration, semiquantitative neg-3+, ref neg, historical-ictitest= confimatory

urine urobiliogen

ehrlich reagent= red color, fresh 2 hr specimen, exposed to light/unrefirg= oxidated to urobilin, ref less than 1

aminotransferases

enzymes released with hepatocyte injury

ALT and AST

increase= acute viral toxic or ischemic injury, does not measure remaining liver func

ALP

increase with cholestasis due to reduced bile flow, localized to bile canaliculi microvilli, very high post hepatic obstruction, produced by bone, increase during preg and growth, high GGT hepatic source

GGT

liver and bile duct membranes, inctease with cholestasis and hepatobiliary injury, sensitive nonspecif, id source not cause

ammonia

toxin nitrogen waste converts to urea by liver, increases with severe live dysfunction and portosystemic shunting (portal blood bypasses the liver), associates but poor correlation with hepatic encephalopathy, hemolysis = increase

synthetic function tests

livers ability to make proteins, albumin changes slowly reflecting chronic dysfunc, low albumin not specific for liver disease, PT/INR change quickly as clotting factor syn falls