Either a decrease in the volume of bile formed or an impaired secretion of specific solutes into bile, which results in elevated serum levels of bile salts and bilirubin
Liver
The main organ where exogenous chemicals are metabolized and eventually excreted
Liver
It facilitates the performance of its enormous task of maintaining the metabolic homeostasis of the body
It is the first organ to encounter ingested nutrients, vitamins, metals, drugs, and environmental toxicants as well as waste products of bacteria that enter portal blood
Efficient scavenging or uptake processes extract these absorbed materials from the blood for catabolism, storage, and/or excretion into bile
Lobule
Classically, the liver is divided into hexagonal lobules oriented around terminal hepatic venules (also known as central veins)
Portal triad
At the corners of the lobule, containing a branch of the portal vein, a hepatic arteriole, and a bile duct
Acinus
The preferred concept of a functional hepatic unit, divided into three zones: Zone 1 (closest to the entry of blood), Zone 2 (intermediate), and Zone 3 (abuts the terminal hepatic vein)
Blood entering the acinus consists of oxygen depleted blood from the portal vein (60% to 70% of hepatic blood flow) plus oxygenated blood from the hepatic artery (30% to 40%)
Hepatocytes in zone 3 are exposed to substantially lower concentrations of oxygen than hepatocytes in zone 1, and zone 3 is hypoxic compared to other tissues
Heterogeneities in protein levels of hepatocytes along the acinus generate gradients of metabolic functions
Hepatocytes in the mitochondria rich zone 1 are predominant in fatty acid oxidation, gluconeogenesis, and ammonia detoxification to urea
There are higher levels of glutathione in zone 1 and greater amounts of cytochrome P450 proteins, particularly CYP2E1, in zone 3
Sinusoids
The channels between cords of hepatocytes where blood percolates on its way to the terminal hepatic vein
Sinusoidal cells
Endothelial cells (lined with fenestrae), Kupffer cells (resident macrophages), and stellate (Ito) cells (synthesize collagen and store vitamin A)
Bile
Contains bile acids, cholesterol, glutathione, bilirubin, phospholipids, and other organic anions, proteins, metals, ions, and xenobiotics
Canalicular lumen
The space formed by specialized regions of the plasma membrane between adjacent hepatocytes
Canaliculi
Channels between hepatocytes that connect to a series of larger and larger channels or ducts within the liver
Bile salts and other osmolytes
The major driving force of bile formation, actively transported into the canalicular lumen
Influx transporters in hepatocytes and cholangiocytes
Apical sodium-dependent bile salt transporter (ASBT)
Efflux transporters in hepatocytes and cholangiocytes
Bile salt export pump (BSEP)
Heterodimeric ATP binding cassette transporter G5/G8 (ABCG5/G8)
Multidrug resistance protein (MRP)
Breast cancer resistance protein (BCRP)
Multidrug resistance associated protein (MRP)
Heterodimeric organic solute transporter alpha and beta
Canalicular multiple organic anion transporter (MOAT) system and multiple drug resistant (MDR) P-glycoproteins
Exporters of particular relevance to canalicular secretion of toxic chemicals and their metabolites
Biliary excretion is important in the homeostasis of metals, notably copper, manganese, cadmium, selenium, gold, silver, and arsenic
Inability to export Cu into bile is a central problem in Wilson's disease, a rare genetic disorder characterized by accumulation of Cu in the liver and then in other tissues
Bile ducts modify bile by absorption and secretion of solutes, and biliary epithelial cells express phase I and phase II enzymes that may contribute to the biotransformation of toxicants present in bile
Toxicant related impairments of bile formation are more likely to have detrimental consequences in populations with other conditions where biliary secretion is marginal, such as neonates
Types of hepatobiliary injury
Hepatocyte/cell death
Canalicular cholestasis
Bile duct damage
Sinusoidal disorders
Disruption of the cytoskeleton
Immune-mediated response
Immune-mediated response
Diclofenac
Ethanol
Halothane
Neonates
Infants in the first 28 days after birth
Neonates are more prone to develop jaundice
When treated with drugs that compete with bilirubin for biliary clearance
Types of Hepatobiliary Injury
Hepatocyte/Cell Death
Canalicular cholestasis
Bile duct damage
Sinusoidal disorders
Immune-mediated response
Fatty Liver
Fibrosis and cirrhosis
Tumors
Hepatocyte/Cell Death
Most common type of response when exposed to toxicant
Toxins causing Hepatocyte/Cell Death
Acetaminophen (most common)
Allyl alcohol
Copper
Dimethylformamide
Ethanol (most common)
Canalicular cholestasis
Decrease in the volume of bile formed or an impaired secretion of specific solutes into bile
Toxins causing Bile duct damage
Alpha-naphthylisothiocyanate
Amoxicillin
Methylene dianiline
Sporidesmin
Toxins causing Immune-mediated response
Diclofenac
Ethanol
Halothane
Tienillic acid
Toxins causing Fatty Liver
Amiodarone (drug for HTN)
CCl4
Ethanol
Fialuridine
Tamoxifen
Valproic acid
Toxins causing Fibrosis and cirrhosis
CCI4
Ethanol
Thioacetamide
Vitamin A
Vinyl chloride
Necrosis
Cell swelling, Leakage, Nuclear disintegration (karyolysis), Influx of inflammatory cells
Apoptosis
Cell shrinkage, Formation of apoptotic bodies, Nuclear fragmentation, Lack of inflammation
Hepatocyte death can occur in a focal, zonal, or panacinar (widespread) pattern