14- Liver Biochemistry Flashcards
This is the largest solid organ in the body, and is approx. 3% of body weight (weights 1500 g).
Liver
The liver consists of 2 lobes, each of which is subdivided into multiple lobes and sinusoids. It is also covered by a capsule of…
Connective Tissue
What is the blood supply to the liver?
75% supplied by portal vein
25% supplied by hepatic artery
The liver has a biliary component made of what?
Bile Ducts
Gallbladder
The two ways blood flows into the liver are 1) oxygen-rich blood flowing into the liver through the ______ ______ and 2) nutrient-rich blood coming from the bowel flowing into the liver through the _______ _______.
Hepatic A. (25%)
Portal V. (75%)
Blood flows out of the liver through 3 hepatic veins into a big vein called the…
Inferior Vena Cava
Bile flows out of the liver through the…
Bile Duct
These are 80% of liver cells that carry out most of the metabolic functions of the liver, capable of regeneration.
Hepatocytes
These liver cells allow exchange of material from liver to blood and vice versa via pores and fenestrations in the plasma membrane.
Endothelial Cells
These liver cells are present in the lining of the sinusoids. They are macrophages that protect the liver from gut derived microbes, remove damaged/dead RBCs, orchestrate immune response, and secrete cytokines.
Kupffer Cells
Kupffer Cells have well-developed endocytic and phagocytic functions, and lots of _________ are present in these cells.
Lysosomes
These liver cells serve as a storage site for Vitamin A and other lipids.
Hepatic Stellate Cells
This are natural kill cells that protect the liver against viruses and tumor cells.
Pit Cells (Lymphocytes)
These cells line bile ducts and control the bile flow rate and bile pH.
Cholangiocytes
The liver is the primary receiving, distribution, and recycling center of the body. It’s also responsible for _________ metabolism.
Carbohydrate
The liver plays a central role in glucose metabolism, specifically in maintaining optimal levels of circulating glucose. Maintaining glucose levels under fed, fasting, and starvation states is called…
Glucostasis
The liver also synthesizes and stores glucose in the form of…
Glycogen
The liver will release glucose when its blood glucose levels are low, this called…
Glycogenolysis
Liver has ________ ________ which permits the release of free glucose to the blood (unlike muscle which keeps the ________ ________ for its own use).
Glucose 6 Phosphate
Glucose 6 Phosphate
The liver can synthesize glucose from non-carbohydrate sources, principally through the breakdown of body’s proteins. This is called…
Gluconeogenesis
Under conditions of starvation, the liver makes _______ _______ for use as energy source.
Ketone Bodies
A major function of the liver is ________ ________. This involves inactivation, detoxification, and biotransformation of metabolites and xenobiotics.
Waste Management
The liver receives blood from enteric circulation via the _______ _______ and from the periphery via the _______ _______. There is low portal blood pressure.
Portal V.
Hepatic A.
In the liver, there is a lack of basement membrane and absence of tight junctions between hepatocytes and endothelial cells. There are gaps between endothelial cells and fenestrations (pores) in the endothelial cell membrane. These features allow what?
Greater access and increased contact between liver and blood
Bile is made of _______ _______, which are amphipathic with polar and nonpolar regions. These help to form micelles which increase surface area of lipids, thus exposing them to lipases.
Strong Detergents
Bile acids and bile salts are synthesized from…
Hepatic Cholesterol
Bile is made in hepatocytes, released into bile canaliculi, then stored and concentrated in the _________.
Gallbladder
Bile is released into the _________ in response to food.
Duodenum
Bile (SALT/ACID) is the protonated form, while bile (SALT/ACID) is the de-protonated form.
Acid
Salt
Describe the steps of emulsification by bile salts.
1) Cholic Acid (a typical bile acid) ionizes to give its cognate bile salt.
2) Hydrophobic surface of this bile salt associates with triacylglycerol, and several such complexes aggregate to form a micelle.
3) The hydrophilic surfaces of the bile salts face outward, allowing the micelle to associate with pancreatic lipase/colipase.
4) Hydrolytic action of lipase/colipase frees FAs to associate in a much smaller micelle that is absorbed through intestinal mucosa.
In the synthesis of bile acids, they start as Cholesterol and are converted to 7a-Hydroxycholesterol via __________. This is the rate-limiting step.
7a-Hydroxylase
In the synthesis of bile acids, 7a-Hydroxycholesterol is present in the ER of hepatocytes. It is then converted to what two acids?
Chenodeoxycholic Acid
Cholic Acid
Bile acids are _________ before secretion.
Conjugated
What are the primary bile acids?
Cholic Acid
Chenodeoxycholic Acid
What are the primary conjugated bile acids?
Cholic Acid = Glycocholic Acid and Taurocholic Acid
Chenodeoxycholic Acid = Glycochenodeoxycholic Acid and Taurochenodeoxycholic Acid
After the primary conjugated bile acids make their way into the gallbladder, the result are primary ______ ______ that secrete into the duodenum emulsify dietary lipids to aid in their digestion and absorption.
Bile Salts
When primary bile salts leave the gallbladder, they can also be deconjugated and dehydroxylated by bacteria. This turns them back into primary and secondary bile acids, which are absorbed by the ileum and are then excreted in feces or recycled to the liver via the enterohepatic circulation. What are the secondary bile acids?
Deoxycholic Acid (derived from Cholic Acid) Lithocholic Acid (derived Chenodeoxycholic Acid)
Non-absorbable bile-acid binding resins such as __________ cause a large increase in excretion of bile acids. The rate of bile acid synthesis is increased by induction of 7a-Hydroxylase, which leads to a depletion of the liver cholesterol pool. This results in an increase in hepatic uptake of LDL cholesterol by receptor-mediated and receptor-independent mechanism. This lowers plasma cholesterol levels.
Cholestyramine
These are crystals made up of bile supersaturated with cholesterol.
Gallstones
This is insufficient secretion of bile salts or phospholipids into the gallbladder, or excess cholesterol secretion into bile. Results in the formation of gallstones.
Cholelithiasis
Chronic disturbance in ______ ______ metabolism leads to malabsorption syndromes (steatorrhea), and deficiency in fat-soluble vitamins.
Bile Salt
Liver is the primary site for conversion and or degradation of ________ (compounds made in the body) and ________ (compounds ingested from outside, no nutrition value and potentially toxic).
Metabolites
Xenobiotics
Briefly describe the phases of inactivation and detoxification of Xenobiotics.
Phase I = Polarity is increased
Phase II = Functional groups are conjugated for safe excretion
Phase I of Xenobiotic detoxification is catalyzed by what enzyme?
Cytochrome P450 (CYP)
In Xenobiotic detoxification, each phase has 4 reactions that occur. What are they?
Phase I = Reduction, Oxidation, Hydroxylation, Hydrolysis
Phase II = Conjugation, Sulfation, Methylation, Glucuronidation
Most drugs are metabolized in the liver. Hepatic metabolism increases the _________ and hence their ability to be excreted. Generally, drug metabolites are less pharmacologically active than parent drug.
Hydrophilicity
Some drugs are inactive when administered but converted to active form after metabolism in the liver, these are called ________.
Prodrugs
These are a superfamily of proteins (18 families) and are heme-containing. Present in ER, and play a key role in the metabolism of multiple hydrophobic compounds.
Cytochrome P450 (CYP)
CYPs co-localize with NADPH to form _________. The ratio of these is 4:1, making _______ rate limiting.
CYPR (Cytochrome P450 Reductase)
CYPR (Cytochrome P450 Reductase)
Of the 18 family CYP, 3 are responsible for most of the phase I drug metabolism. These are…
CYP1
CYP2
CYP3
CYPs detoxify pharmacological agents, and CYPs are inducible by their substrate. Certain drugs that form a stable complex with a particular CYP (INHIBIT/STIMULATE) metabolism of other drugs that are normally substrates for that CYP.
Inhibit
Agents that inhibit CYP will cause (INCREASE/DECREASE) in drug levels in plasma.
Increase
Agents that stimulate CYP will cause (INCREASE/DECREASE) in drug levels in plasma.
Decrease
The lower the pKa is of a bile acid, the more ionized the molecule is. This means they are a better detergent. What are the pKa of Cholic Acid, Glycocholic Acid, and Taurocholic Acid?
Cholic Acid = 6 (least efficient)
Glycocholic Acid = 4
Taurocholic Acid = 2 (most efficient)
Examples of CYP inhibitors include ______ ______ and ______ ______. For example, if a patient takes statins with one of these then there will be an INCREASE in statin levels in plasma.
Citrus Juices
Grapefruit Juice
An example of a CYP inducer is ______ ______ ______. For example, if a patient takes statins and this together, there will be a DECREASE in statin levels in the plasma.
St. John’s Wort
For example, CYP1A2 metabolizes caffeine and theophylline. It is inhibited by antibiotic ciprofloxacin. What happens if these are taken together?
Metabolism of caffeine and theophylline will be slower and their plasma levels will be INCREASED.
***Remember, CYP inhibitors will increase plasma levels and CYP stimulators will decrease plasma levels!
Allelic variation and polymorphisms of CYPs exist in individuals. This can influence the catalytic activity of CYPs and influences drug metabolism. ________ CYPs to identify gene-relevant polymorphisms may become more common in order to personalize an individual’s response to a particular drug.
Genotyping
A drug may be toxic in excess. Sometimes it is toxic in certain individuals and not in others, which may be due to genetic or immunologic causes (i.e., Tylenol or Acetaminophen). Elimination of Tylenol occurs via conjugation with _______ ______ or _______ which are then excreted via kidney.
Glucuronic Acid
Sulfate
In Acetaminophen overdose, the capacity for normal conjugation is overwhelmed. It is oxidized by the liver CYP3A4 to _________. This causes free radical-mediated peroxidation of membrane lipids and damages hepatocytes. Serious enough to lead to hepatic failure and death.
NABQ1
NABQ1 is detoxified by _________, but in Acetaminophen overdose these stores become depleted so they can’t detoxify it. A sulphydryl compound called _______ ______ is given as an antidote to Acetaminophen poisoning.
Glutathione
N-acetyl Cysteine
In diseases of the liver, the major change that usually occurs is that the normally leaky basement membrane between endothelial cells and hepatocytes are replaced by high density membrane containing…
Fibrillar Collagen
In diseases of the liver, spaces between endothelial cells and fenestrations in plasma membrane are lost. There is increased stiffness of hepatic vascular channels that offers resistance to free flow of blood through the liver. This causes elevated intra-sinusoidal pressure and portal _________.
Hypertension
In diseases of the liver, there is impairment of what?
Free exchange of material between hepatocytes and blood!
What is assessed in a liver function/metabolic panel?
- Albumin
- Transaminases (ALT and AST)
- Alkaline Phosphatase
- Prothrombin Time (PT)
- Bilirubin (Unconjugated and Conjugated)
- Urea (BUN)
- Glucose
- Triacylglycerol
- Cholesterol (Total and VLDL, LDL, HDL)
These are involved in the interconversion of amino acids and keto acids and are required for protein and carbohydrate metabolism. Both are located in the mitochondria.
ALT (also found in cytoplasm)
AST
***These are transaminases – alanine amino transferase (ALT) and aspartate amino transferase (AST)
Serum activity of ALT and AST (INCREASES/DECREASES) in liver disease, as the enzymes released from damaged hepatocytes. ALT is more sensitive since it is also cytosolic.
Increases
