Lecture 11: Liver Phsyiology | Quizlet

Substances received from portal to and systemic circulation

stimuli for liver to process absorbed nutrients and other substances from the GI tract and secrete bile

Porta hepatis

central area of the liver where the portal vein, common duct, and hepatic artery enter

Hepatic Arteries

vessels of the liver that are oxygen rich and from systemic circulation

Portal Vein

-nutrient rich

-from venous drainage of abdominal GI system and spleen

-Branches of portal vein

-Hepatic aa.

-Intrahepatic bile ducts

-Lymphatics

-Nerves

contents of the portal triad

sinusoids

portal vein and hepatic aa. empty into the ____________________

Lobule

-consists of stacks of anastomosing plates of hepatocytes one cell thick

• Arranged in cords and are surrounded by sinusoids (basolateral surface) which bathe the hepatocytes with mixed portal and arterial blood

• And bile canaliculi (apical surface)

• High-flow

• High-compliance

• Low-resistance

describe fluid flow in liver under normal conditions

Zone 1

What zone of the liver:

closest to portal tract and richest in O2

Zone 2

What zone of the liver:

intermediate layer

Zone 3

What zone of the liver:

-closes to central vein and lowest in O2

-exposed to modification made by hepatocytes in earlier zones

Zone 1

What zone of the liver:

Examples of reactions: Amino acid catabolism, gluconeogenesis, glycogenolysis, ureagenesis, oxidative energy metabolism

Zone 3

What zone of the liver:

Examples of Reactions: Glycolysis, glycogen synthesis, liponeogenesis, bile acid synthesis, biotransformation of drugs

Sinusoids

-walls formed formed from leaky endothelial cells

-large fenestrations and large gaps between adjacent cells

Space of Disse

-gap between the basolateral membranes of the hepatocytes and the sinusoidal wall

-microvilli project into here

Space of Disse

-contains stellate cells (Ito cells)

• Store fat or fat soluble vitamins (like vitamin A)

• Inflammation can result in Ito cells transforming to myofibroblasts

• Results in collagen production, fibrosis, and cirrhosis

Kupffer Cells

-hepatic macrophages

Reside in the sinusoidal lumen

• Part of the reticuloendothelial system

• Can break down red blood cells and hemoglobin

• Remove unwanted particles

Kupffer Cell

_________________ activation is responsible for early ethanol-induced liver injury

Kupffer Cell

• Activation increases tumor necrosis factor-alpha and reactive oxygen species

• TNFα enters the stellate cell leading to collagen synthesis and fibrosis

Vitamin A

-liver stores 10 mo worth

• Stored in hepatic stellate cells (Ito Cells)

• Since it is a fat-soluble vitamin, there is a risk of excess

Vitamin D and B9

the liver stores 3-4 months worth of what vitamins?

Vitamin B12

the liver stores 3-4 s worth years of what vitamins?

Hemochromatosis

disorder associated with deposits of excess iron that causes multiple organ dysfunction.

Basolateral Membrane

‒ Na/K ATPase

‒ H+/Ca ATPase

‒ GLUT2

‒ Na/AA cotransporters

‒ Bile acid transporters (Na+depdendent)

• Bilirubin transporter (OATP)

• Lipid transport

‒ K+ and Cl- channels

‒ Na/H+ exchanger

‒ Na/HCO3 cotransport

Apical Membrane

-bile secretion

• Bile acids (BSEP)

• Bilirubin

• Cholesterol

• Phosphatidylcholine (MDR3)

• Drug metabolite transporters

• Cl-/HCO3 exchanger

• Cl- channels

• Na can enter bile canaliculi via paracellular route

Transferrin

transports free iron in the blood

Biliverdin

-the first substance formed in bilirubin metabolism

-rapidly reduced to free bilirubin

Free Bilirubin

-unconjugated form

-immediately combines strongly with plasma albumin

-transported with albumin in blood and interstitial fluids

Glucuronyl Transferase

-conjugates bilirubin mostly with glucronic acid to form bilirubin glucuronide

Bilirubin (Conjugated)

-direct bilirubin

-water soluble

-excreted from hepatocytes by an active transport process into bile canaliculi and then into the intestines

Urobilinogen

-formed from half of the conjugated bilirubin by bacterial action

-water soluble

-some is reabsorbed thru intestinal mucosa back in the blood

Urobilinogen

-excreted in urine

-gives urine its yellow color

Stercobilin

most of urobilinogen is converted to _________________ and excreted in feces, giving it a brown color

Prehepatic Jaundice

-increased bilirubin produduction

• Causes: hemolysis (hemolytic anemia)

• conjugation mechanism is overwhelmed, and an abnormally large amount of unconjugated bilirubin is found in the blood.

Intrahepatic Jaundice

-impairment in liver function

-• Causes: defect in: bilirubin uptake, bilirubin conjugation, or bilirubin secretion into the bile canaliculi

• Unconjugated OR conjugated bilirubin may be increased in the plasma

Crigler-Najjar syndrome

UDP glucurosyl transferase defiency that may cause intrahepatic jaundice

Dubin-Johnson syndrome

MRP2 transorter defect that may cause intrahepatic jaundice

Posthepatic Jaundice

-extrahepatic outflow of bilirubin is decreased

• Causes: blockage of extrahepatic bile ducts by gallstones, tumors or pancreatitis

• Conjugated bilirubin in plasma increased

Jaundice

-occurs when the equilibrium between bilirubin production and clearance is disrupted

-A yellowish tint to skin and deep tissues results from large quantities of bilirubin in the extracellular fluid

• Glucose buffering

• Formation of compounds from intermediaries

• Conversion to fat

what does liver do with carbohydrates

• Deamination of aa and formation of urea

• Protein synthesis

• Conversion to fat

What does liver do with proteins?

• Fatty acid oxidation

• Storage and transport of lipid

• Cholesterol homeostasis

What does liver do with lipids?

• Synthesis and degradation of macronutrients

• Provide energy for export (glucose and ketone bodies)

major metabolic functions of the liver

GLUT2

monosaccharides enter the liver via ____________

increases; decreases

after a meal, insulin _______________ and glucagon ___________________

-broken down for energy (glycolysis)

-stored as glycogen

fate of glucose in the liver

Galactose and Fructose

what two things can be combined to form glucose in the liver

fat

excess carbohydrates in the liver are converted to __________

Glucose-6-Phosphate

-key enzyme, only in the liver, that allows glucose to exit the hepatocytes

Utilized or broken down immediately

fate of amino acids in the liver

Keto-acids and Ammonia

deamination of amino acids in the liver leads to _________________ and ______________

Chylomicron Remnants

-contain less triglycerides and higher ration of fatty acids and cholesterol

-take up by the liver using the LDL related receptor

Acetyl CoA

beta-oxidation of fatty acids yields __________________-

• Can enter the Krebs cycle and be a source of ATP

• Or can form ketone bodies

what happens with Acetyl CoA in the liver

Triglyerides

-formed from re-esterfied fatty acids

-stored or exported as VLDLs

Cholesterol

-vital to membrane integrity and a substrate for several compounds

-needs to be kept at a steady state

• Synthetic reactions (bile acids, steroid hormones)

• Excretion in bile

• Excretion in feces as free cholesterol or in sloughed cells

fate of cholesterol in the liver

HMG-CoA reductase

key enzyme in the rate limiting step of cholesterol synthesis

Detoxification

• Conversion of toxic chemicals to non-toxic metabolites

• Conversion of active drugs to inactive drugs

• Some hormones are degraded in the liver

Bioactivation/Toxification

• Vitamin D activation

• Prodrugs to active drugs or more active metabolites

• Non-toxic chemicals can become toxic after

Phase I

What phase of biotransformation in the liver:

oxidation and reduction catalyzed by cytochrome P-450 enzymes

Phase II

What phase of biotransformation in the liver:

-conjugation of phase I products with sulfate, glucuronate and glutathione

-critical for detoxification

-makes molecules more hydrophilic and able to excreted

Ammonia

-toxic and produced in the body

-liver eliminates 95% of it by converting it to urea

-highly membrane permeant

-neurotoxic

Stellate Cells

-activation of hepatic ___________________ can lead to deposition of collagen and result in severe fibrosis, compromising liver function.

Portal Hypertension

• Liver loses its ability to accommodate increases in blood flow

• Resistance to blood flow through the liver ↑ portal venous pressure

Hypoalbuminemia

-decreases plasma colloid oncotic pressure

-Fluid shifts from the plasma to the interstitial space - Ascites

Cirrhosis

irreversible fibrosis

Liver Failure

Common causes

• Alcohol abuse

• Viral hepatitis

• Acetaminophen overuse/dose (and other drugs)

• Mushroom poisoning (Amanita phalloides)

Liver Failure

Clinical features

• Portal hypertension ---> esophageal varices

• Hypoalbuminemia ---> Ascites, edema

• Cholestasis / gallstones

• Coagulopathy

• Decreased clotting factor production

• Decreased Vitamin K absorption (why?)

• Encephalopathy from increased NH3

• Glucose metabolism abnormalities

• Gynecomastia in males

Prothrombin Time (PT)

-measurement of blood clotting

-prolonged in certain clotting disorders

-can be prolonged in liver disease because clotting factors synthesized in the liver

Ammonia

elevated levels means there is a problem with the ura cycle or liver failure

Total Protein

measure of circulating serum proteins

Unconjugated Bilirubin

Elevated in pre-hepatic jaundice and certain liver

conditions (where liver can't conjugated)

Conjugated Bilirubin

Elevated in post-hepatic jaundice and certain liver conditions (where liver may be able to conjugated by bilirubin can be excreted)

Alkaline Phsophatase (ALK)

-Enzyme found in bone and the biliary system.

-Elevation could mean problem in the biliary system (intrahepatic or extrahepatic)

Aspartate Aminotransferase (AST)

-Enzyme found in hepatocytes (and other cells).

-Elevation could mean active hepatocyte injury.

Alanine Aminostransferase (ALT)

-Enzyme found in hepatocytes (and other cells).

-Elevation could mean active hepatocyte injury.

6-8 g/dL

normal levels of total protein

3.5-4.8 g/dL

normal levels of albumin

0.3-1.2 Mg/dL

normal levels of total bilirubin

30-115 IU/L

normal levels of alkaline phosphatase

10-48 IU/L

normal levels of AST

10-40 IU/L

normal levels of ALT