Fisiología Hepática - FARMACIA UNR

Overview of Liver Function and Circulation

Unique Blood Circulation of the Liver

• The liver has a unique double blood supply: it receives arterial blood from the hepatic artery (a branch of the aorta) and venous blood from the digestive tract via the portal vein.

• Both blood supplies converge in capillaries within the liver, leading to central veins that drain into the inferior vena cava.

First-Pass Metabolism

• The liver acts as a "first-pass" organ, processing nutrients and xenobiotics absorbed from the digestive tract before they enter systemic circulation. This is crucial for initial metabolism.

Storage and Metabolic Functions

• The liver stores various substances including iron, copper, glucose (as glycogen), and fat-soluble vitamins. It plays a significant role in carbohydrate metabolism through processes like glycogenesis and gluconeogenesis.

• It also participates in lipid metabolism, synthesizing most plasma proteins (except immunoglobulins) and cholesterol, along with bile salts. Additionally, it detoxifies drugs and dietary toxins entering through digestion.

Detoxification Processes in the Liver

Excretion Mechanisms

• Bile secretion is essential for eliminating metabolic waste products and detoxified compounds from the body. This process highlights the liver's excretory function.

Phases of Drug Detoxification

• Drugs undergo two main detoxification phases in the liver:

• Phase 1 involves mixed-function oxidase enzymes (mainly cytochrome P450 family), which introduce oxygen into drug molecules to create more polar metabolites suitable for excretion or potentially toxic active forms.

• Phase 2 consists of conjugation reactions that further modify these metabolites or original compounds to enhance water solubility for easier excretion via bile; common conjugates include glucuronic acid, sulfate, or glutathione derivatives.

Hepatic Morphology and Bile Formation

Structure of Hepatic Lobules

• A hepatic lobule contains branches of both hepatic arteries and portal veins that deliver blood to sinusoids lined by hepatocytes—the primary cells involved in bile formation through their apical membranes forming bile canaliculi.

Blood Flow Dynamics

• Blood flows from portal areas into central veins after passing through sinusoids where hepatocytes interact closely with blood components; this structure facilitates efficient nutrient processing and bile production.

Functional Zones within Hepatocytes

Zonal Metabolic Differences

• Hepatocytes are categorized into three zones based on their proximity to portal spaces or central veins:

• Zone 1: Closest to portal areas; specialized for high oxygen levels and nutrient uptake.

• Zone 2: Intermediate zone with varying metabolic functions.

Hepatic Functions and Bile Secretion

Key Hepatic Functions

• The liver performs essential tasks such as the genesis of bile, beta-oxidation of fatty acids, cholesterol synthesis, urea synthesis, and bile formation. These processes are particularly dependent on bile salts received from the intestine via the portal vein.

• Hepatocytes in zone 1 are highly active in cell division and hepatic regeneration due to their high oxygen content. In contrast, hepatocytes in zone 3 specialize in functions like colitis, glycogenesis, bile acid synthesis from cholesterol, glutamine synthesis, and detoxification.

Bile Secretion Process

• Bile secretion begins with the formation of canalicular bile by hepatocytes through their apical membranes. This process involves active secretion of compounds into the canaliculus that induces osmotic movement of water.

• Bile salts synthesized from cholesterol play a crucial role in determining biliary flow. The rate-limiting step is catalyzed by cholesterol 7 alpha-hydroxylase.

Transport Mechanisms

• Bile salts are transported into the canaliculus via an export pump for bile salts. Hepatocytes also uptake these salts through sodium-mediated transport systems.

• Glutathione is another solute contributing to biliary flow independent of bile salts; it is transported into the canaliculus by multi-drug resistance-associated proteins (MDR).

Role of ATP-Binding Cassette Transporters

• Proteins like MDR2 and MRP2 belong to the ABC transporter superfamily and utilize ATP hydrolysis to actively concentrate solutes within the canalicular space.

• Bicarbonate is also a key component transported into the canaliculus via chloride exchange mechanisms which help generate osmotic forces driving water passage through aquaporins.

Impact on Cellular Integrity

• Due to their amphipathic nature, bile salts can potentially damage cellular membranes if concentrated excessively; thus protective transporters exist for phospholipids and cholesterol.

• The interaction between phospholipids (like phosphatidylcholine), cholesterol, and bile salts forms mixed micelles that mitigate membrane damage caused by free bile acids.

Modulation During Digestion

• The initial modification of bile occurs as it passes through larger intrahepatic ducts lined with cholangiocytes capable of both secretory and absorptive functions depending on physiological conditions.

• Postprandial states elevate secretin levels which stimulate cholangiocyte activity leading to increased bicarbonate-rich fluid secretion into biliary ducts.

Absorption Mechanisms

• In absence of secretin stimulation during fasting states, cholangiocytes primarily absorb solutes including glucose back into circulation rather than secreting them into bile.

Mechanisms of Bile Acid Transport and Function

Apical Membrane Transport Mechanisms

• The apical membrane utilizes sodium-dependent transporters for amino acids and bile salts to enter cells, indicating a complex interaction with sodium co-transport systems similar to those in hepatocytes.

Bile Flow and Storage

• Bile is initially formed in hepatocytes, then transported through bile ducts where it may undergo modifications before reaching the common hepatic duct and cystic duct leading to the gallbladder.

Concentration of Bile Salts

• During storage in the gallbladder, water and electrolytes are reabsorbed, concentrating bile salts. This process is triggered by stimuli such as acetylcholine and cholecystokinin, leading to gallbladder contraction.

Gallbladder Epithelium Characteristics

• The gallbladder epithelium is impermeable to bile salts while allowing isotonic fluid absorption via a counter-transport system that exchanges protons for sodium ions, facilitating water movement due to osmotic pressure.

Synthesis of Bile Acids

• Hepatocytes synthesize primary bile acids from cholesterol through enzymatic reactions initiated by cholesterol 7 alpha-hydroxylase, which serves as a rate-limiting step in their production.

Metabolism of Bile Acids

• Primary bile acids can be metabolized by intestinal bacteria into secondary bile acids upon reaching the intestine. These secondary acids can be reabsorbed back into circulation or taken up by hepatocytes.

Conjugation Process

• Both primary and secondary bile acids are conjugated with small molecules like glycine or taurine in the liver, significantly lowering their pKa values and ensuring they exist as bile salts at physiological pH.

Therapeutic Uses of Synthetic Bile Acids

• The synthetic bile acid ursodeoxycholic acid has therapeutic properties for treating conditions like primary biliary cholangitis due to its ability to dissolve gallstones and improve liver function.

Recirculation of Bile Acids

• After synthesis in hepatocytes, bile acids flow through larger ducts under secretin stimulation. In absence of this stimulus, there can still be reabsorption of water and electrolytes before storage in the gallbladder.

Digestive Function of Bile Acids

• Upon release into the duodenum via the common bile duct, conjugated bile acids aid lipid digestion by increasing surface area for pancreatic enzyme action necessary for nutrient absorption.

Reabsorption Mechanism

• Conjugated bile acids are reabsorbed in the ileum through sodium-mediated transport systems (ASBT), entering portal circulation before returning to hepatocytes for another cycle known as enterohepatic recirculation.

Calculating Biliary Flow Rates

Biliary Flow Dynamics and Metabolism

Biliary Flow and Excretion of Bile Salts

• The relationship between bile salt excretion velocity and total biliary flow is characterized by a line with an increasing slope, indicating that as bile salt excretion increases, so does the total biliary flow.

• When extrapolating to zero bile salt excretion velocity, a constant value of biliary flow independent of bile salts can be identified. This represents the baseline biliary flow.

• The equation governing this relationship states that total biliary flow equals the efficiency of bile salts multiplied by their excretion rate plus a constant representing the independent biliary flow at zero excretion.

Discrimination Between Hepatic and Ductal Biliary Flow

• To differentiate between fractions originating from hepatocytes (canalicular) and those from bile ducts, a small inert carbohydrate (e.g., 122) is used as a tracer that follows water movement without alteration in the ducts.

• A similar extrapolation method applied to canalicular flow will yield values for both independent and dependent flows concerning bile salts, allowing for precise calculations of each component's contribution to total biliary flow.

Secretin's Role in Biliary Flow

• The positive difference between total independent biliary flow and canalicular independent flow indicates stimulation likely due to secretin, which enhances certain fractions of biliary secretion.

• Total independent biliary flow can be calculated by combining canalicular independent flows with additional components derived from other sources when extrapolated correctly.

Bilirubin Metabolism Overview

• Bilirubin synthesis occurs predominantly from hemoglobin breakdown in senescent erythrocytes (85%) and other proteins (15%), primarily within reticuloendothelial cells like macrophages in the spleen. Initial steps involve conversion into biliverdin before being reduced to bilirubin through enzymatic reactions.

• Due to its high lipophilicity, bilirubin binds to albumin for transport in blood until it reaches the liver where it undergoes further processing for eventual excretion. This binding facilitates its solubility during circulation.

Hepatic Processing of Bilirubin

• Once inside hepatocytes, bilirubin interacts with specific transport proteins facilitating its conjugation with glucuronic acid via UGT enzymes within the endoplasmic reticulum, forming more soluble conjugated forms suitable for elimination through bile or urine.

Hepatic Processing of Bilirubin and Related Compounds

Metabolism of Bilirubin

• Bilirubin is processed in the intestines, where it can be converted into free bilirubin by intestinal bacteria. This process also leads to the formation of a compound called orovino-gen.

• Approximately 25% of this compound can be reabsorbed back into circulation through the liver, contributing to its recycling via hepatic excretion.

Excretion Pathways

• Conjugated bilirubin may face excretion challenges, leading to systemic reflux and filtration through kidneys as urinary pigments, accounting for about 1% of circulating bilirubin.

• The handling of bromosulfophthalein (BSF), a cholagogue dye, is discussed as a tool for evaluating hepatic uptake and excretion systems due to its high affinity for liver processing.

Experimental Use of BSF

• BSF is non-toxic and measurable spectrophotometrically; it undergoes conjugation with glutathione in hepatocytes after parenteral administration.

• Following BSF administration, plasma concentration decay follows an exponential kinetic pattern observable on a semi-logarithmic scale.

Kinetic Phases in Hepatic Processing

• Two distinct phases are identified: a rapid phase (alpha) indicating quick uptake by hepatocytes and a slower phase (beta) reflecting conjugation processes and excretion via MRT2 transporters.

• The values obtained from these phases help estimate hepatic uptake efficiency (alpha) and conjugation/excretion processes (beta).

Implications for Liver Function Assessment

• Bromosulfophthalein's transport mechanisms share pathways with other detoxifying compounds like bilirubin, making it useful for detecting potential hepatic dysfunction.