Table of Contents
- Roles of the Liver
- Shape and Structure of the Liver
- Fine Structure of the Liver
- Cell Types of the Liver
- The Detoxication of Organic Exogenous Substances: Biotransformation
- The Decomposition of Ethanol
- Alcohol Dehydrogenase
- The Consequences of Alcohol Consumption
- Popular Exam Questions on the Detoxication Function of the Liver
Roles of the Liver
In the adult body, the liver is the central organ of metabolism. Its tasks include producing blood proteins (albumin, coagulation factors), bile and antigens, storing vitamins, synthesising starting products for hormone production, storing glycogen from glucose as an energy reserve, and detoxifying the body from endogenous (ammonia) and exogenous (e.g. medications) substances.
All nutrients resorbed from the intestine and accepted into the blood pass through the portal vein vena hepatis portae (portal circulation) to the liver, where they are either removed or returned to the blood if necessary.
By-products that form in the liver can be expelled in two ways:
- Expulsion via the kidney: Water-soluble products (medications, alcohol) are delivered by the liver cells to the liver sinusoids, from which they pass into the bloodstream to the kidney, and are then expelled with urine.
- Expulsion via the gall bladder: As the largest exocrine gland, the liver produces about 600-800 ml per day. Non-water-soluble substances pass through the bile capillaries in the intestine and are expelled with stool.
Shape and Structure of the Liver
The dark red liver is located in the right upper abdomen, weight approx. 1.5-2 kg and is soft.
Symptoms: Because of its consistency, in an accident the liver is prone to rupture, which may be accompanied by intra-abdominal bleeding (blunt abdominal trauma).
Neighbouring organs leave characteristic impressions on its surface.
There are two different surfaces, one of which is a facies diaphragmatica which faces and is coalesced with the diaphragm, and a facies visceralis facing the abdominal organs. Ventrally the facies diaphragmatica passes into the facies visceralis along the margo inferior. Due to its coalescence with the diaphragm, the liver moves during respiration, caudally during inspiration. The non-coalesced surface is covered by the peritoneum viscerale and its position is thus intraperitoneal.
A shell of conjunctive tissue, the tunica fibrosa or Glisson’s triad, surrounds the entire organ. It is connected to the peritoneum by a tela subserosa. Septa protruding inward from the shell divide the liver into its four morphologically distinct lobes: lobus dexter (largest lobe), lobus sinister, lobus quadratus (ventral) and lobus caudatus (dorsal).
Furthermore, the division into 8 macroscopically identical segments is of clinical relevance. It stems from the arrangement of blood vessels and biliary ducts and allows for a clear demarcation to other segments for the resection of individual segments.
The following structures always run together (triad), from the beginning of the macroscopically dominant liver portal (porta hepatis) down to the smallest units of the liver:
- Arterial vessels (oxygen-rich, arteria hepatica propria and branches)
- Portal venous vessels (nutrient-rich, vena portae hepatis and branches)
- Biliary ducts (ductus hepatici dexter and sinister and branches, merge into the ductus hepaticus communis)
The efferent vv. hepaticae run independently from the triad!
Fine Structure of the Liver
The smallest, most sparse conjunctive tissue divides the liver parenchyma into lobes (lobuli hepatis). These are polyhedral and are arranged around a central vein (vena centralis). Multiple adjacent lobes form periportal areas at their point of contact, or conjunctive tissue gussets, into which flow the aforementioned incoming vessels and outgoing biliary ducts.
Depending on the consideration of the function of the parenchyma in question, there are three different entities: A central vein lobule, a portal vein lobule (also periportal/portal lpbule) and a liver acinus.
Central vein lobule
In the centre of this organ is the vena centralis, around which radiate trabeculae are arranged by hepatocytes and liver sinusoids. Liver sinusoids are extended spaces between the liver cell trabeculae with a fenestrated endothelium, into which blood flows from the portal vein and the a. hepatica propria toward the v. centralis. The entire exchange of blood and hepatocytes occurs on a stretch of 0.5 mm. The fenestrated endothelium is separated from the adjacent liver parenchyma by a plasma-filled space, the spatium perisinusoideum, or the space of Disse.
Portal vein lobule
As the name itself implies, the focus here is the periportal area. Central veins form the corners, and the bile passes in the central outlet. Three or more central vein lobules form one portal vein lobule.
The division into the liver acinus stems from different metabolic zones. The shape of an acinus is rhombic, and two periportal areas and two vv. centrales form each corner of the rhombus.
Cell Types of the Liver
Liver cells (hepatocytes)
Arranged around the central vein in a star shape, these large cells have many cellular organelles and often have multiple nuclei due to their metabolic activity. Their tasks include the production of bile, the breakdown of hormones and the regulation of the acid-base balance. They form a one- to multi-layered epithelium. The basolateral surface facing the space of Disse shows a trimming of microvilli. Opposite this is the apical or biliary cellular pole. Two opposing apical membranes of the hepatocytes border the canaliculi biliferi (bile capillaries).
These phagocytising scavenger cells are part of the mononuclear phagocyte system of the immune system, and are antigen-presenting macrophages. They may gather, store and break down cell debris, foreign substances, obsolete erythrocytes and bacteria from the portal vein blood. They also lie atop the sinus endothelium and bulge their cell bodies into the sinusoidal lumen.
These fat-storing stellate cells are located in the space of Disse and store vitamin A. After increased vitamin A intake the cells proliferate. Ito cells play an important role in the pathogenesis of liver cirrhosis, and are believed to be responsible for the increased collagen production.
The natural killer cells = NK cells are liver-specific lymphocytes and stick to endothelial cells.
The Detoxication of Organic Exogenous Substances: Biotransformation
Substances taken in from the environment, and which cannot find immediate use as nutrients, are expelled or metabolised by the organism if possible. The metabolism of such substances is referred to as biotransformation.
Most biotransformation reactions occur in the liver and include enzymatically catalysed reactions that aim to make endogenous or exogenous substances water-soluble and to expel them. Generally an inactivation of active or toxic substrates occurs, with the objective of rendering them harmless.
On the other hand, there are also substances that are only converted into toxic substances by this reaction, and which can then harm the body. The most well-known example of this is benzopyrene, which is contained in the tobacco smoke of cigarettes, though it also forms when grilling. The biotransformation reaction with the cytochrome P450 enzyme results in the ultimately cancerogenic diol epoxide, which reacts with the base guanine in the DNA, thereby resulting in permanent damage to the organism.
Biotransformation encompasses two successive reaction types: A phase I reaction (conversion reaction) and a phase II reaction (formation of conjugates).
Phase I reaction
This reaction is also called a conversion or functionalisation reaction. The name itself allows for an idea of the process: Oxidation, reduction and hydrolysis reactions are attached to the starting compound of functional groups, or exposed. The monooxygenases involved in the oxidation reactions bind oxygen and transfer one of the two O-atoms to the respective starting substrate.
The second atom is released upon the formation of water. Due to the parallel reaction behaviour of this enzyme group, or the reaction with both the oxygen as well as the substrate, monooxygenases are also referred to as mixed-function oxygenases. Most monooxygenases are cytochrome P450 enzymes (CYP) that vary from one another in their substrate specificity.
Other enzymes of the phase I reaction are:
|Catalysis of oxidations||Catalysis of reductions||Catalysis of hydrolyses|
|Mono-aminooxidases and monooxygenases containing FAD||Cytochrome P450 enzymes||Esterases|
|Xanthin oxidase||Epoxide hydrolases, sometimes associated with cytochrome P450|
|ALDH (aldehyde dehydrogenase)|
|ADH (alcohol dehydrogenase)|
Phase II reaction
With this biotransformation, also known as a conjugation reaction, substrates are bound to additional chemical groups. Substrates are both endogenous (steroid hormones, bilirubin, bile pigments) and exogenous substances (medication, alkaloids, preservatives, environmental toxins). Phase II reactions are distinctive in that the transferred groups were previously activated by binding to a coenzyme. They thus exhibit high group transfer potential. A lot of energy is released during the split of the bonding phase, which is utilised during energy coupling for the transfer in the biotransformation reaction. Transferases are involved in all phase II reactions.
Conjugation with glucuronic acids:
The transfer of the glucuronic acids occurs through the UDP glucuronic acid to the OH, COOH, NH2 and SH groups of endogenous or exogenous substances. The resulting glucuronides are expelled through the gall bladder.
Conjugation with glutathione:
Glutathione is a natural form of protection for cells against oxygen radicals. It is made from the tripeptide glu-cys-gly. The transfer to the substrate catalyses the enzyme glutathione S-transferase (GST). In more precise terms, the conjugation is facilitated by the SH group of the central cysteine. After the split of the glutamine and glycine, the remaining amino group of the cysteine is acetylated, and mercapturic acid forms, which is in turn expelled through the kidneys.
Conjugation with acetyl groups:
This transfer occurs with amino groups and is catalysed by N-acetyltransferase. An inactivation of sulfonamides occurs in this manner, and the important tuberculostatic isoniazid (INH) is of significance.
Conjugation with methyl groups:
S-adenosylmethionine is involved. The transfer takes place from methyl groups to N-, O- and S-atoms.
Conjugation with Sulfate Groups:
The sulfate group is separated from 3′-phosphoadenosine-5′-phosphosulphate (PAPS) and transferred to amino and OH groups.
The Decomposition of Ethanol
In many industrialised countries, a large percentage of all diseases is attributed to alcohol abuse. Thousands of people die from the “drug” alcohol annually. The role played by ethanol in the energy metabolism of the populace is significant: Each citizen consumes approximately the amount of ethanol per month that equates to a share of 5 % of all consumed energy sources.
Ethanol in the form of alcohol is broken down in the liver to acetyl-CoA. This process occurs in three steps: First the ethanol in the cytosol is oxidised to acetaldehyde by alcohol dehydrogenase. In turn the acetaldehyde is oxidised to acetate by aldehyde hydrogenase.
Alcohol/aldehyde dehydrogenase require NAD+ as an oxidant. The oxidation of the ethanol takes place parallel both in the peroxisomes and the peroxidases. These catalyse the oxidation with hydrogen peroxide (H2O2), which is reduced to H2O. Acetate forms from this ethanol.
Upon frequent or chronic consumption of alcohol, as is the case with alcoholics, an inducible microsomal ethanol oxidase (MEOS) is also found in the endoplasmatic reticulum. This system drives one method of ethanol metabolism in the liver independent from alcohol dehydrogenase.
It was discovered by Lieber and DeCarli in 1968. The microsomal ethanol oxidase is a member of the cytochrome P450 family and the monooxigenases. This enzyme takes on an oxygen atom and transfers one of the atoms to the substrate, and the other O2 atom is converted to water by accepting two protons. The formation of acetic acid is catalysed in this manner.
The conversion of other substrates can be decreased or deferred to toxic metabolites through the activity of the MEOS and the induced cytochromes. One example is the detrimental effect of some medications in alcoholics, in whom the side effects of a medication can be amplified.
Furthermore, it was determined that MEOS exhibits a sort of retention or memory function. This is because after activation upon the first small sip of alcohol after withdrawal therapy, MEOS is regenerated and metabolises ethanol very quickly. The pressure to drink more is thus increases and commonly results in relapse.
The name aldose reductase is used synonymously for alcohol dehydrogenase (ADH). The enzyme is part of the class of oxidoreductases and appears in the human body in both the liver and the stomach. ADH catalyses both the reaction of ethanol to an aldehyde, as is the case in breaking down alcohol, as well as the reverse reaction of acetaldehyde into ethanol, as occurs in the last step of alcoholic fermentation by yeast.
As with all enzymatically catalysed reactions, the enzyme remains unchanged by the reaction. Depending on how much ADH is present in the body, one can conclude the amount of alcohol the individual can tolerate. This varies from person to person. Usually, people from East Asian countries as well as indigenous peoples are more sensitive to ethanol than Europeans, for instance, due to their less effective form of ADH.
It is assumed that, regardless of country of origin, at least six slightly different types of ADH coexist in the body. They all share the same structure: They consist of a dimer of two polypeptide chains, whereby each sub-unit contains two zinc ions essential for the enzyme’s function. The zinc ion is localised in the active centre and its function is to stabilise the hydroxyl groups of the ethanol. The cofactor NAD is involved in the oxidation of the ethanol to acetaldehyde: C2H5OH+NAD→NADH+H+
Alcohol dehydrogenase is also responsible for other alcohols not being truly toxic initially. For instance, it oxidises methanol into the significantly more toxic methanal (formaldehyde), and ethylene glycol to glycolic or oxalic acid. This type of poisoning is treated by administering ethanol. For as long as the ethanol is broken down in the liver, methanol is expelled through the kidneys and no poisoning will occur.
The presence of ADH has also been verified in insects, such as the fruit fly. However, this enzyme is not bound to a metal ion and is not related to human ADH whatsoever.
The Consequences of Alcohol Consumption
Regular consumption of alcohol is rumoured to have preventative effects. As much as one half-litre of beer or wine per day is said to decrease the risk of arteriosclerosis. Excessive consumption of alcohol, however, is dangerous. The breakdown of ethanol in the liver results in overproduction of NADH and acetyl-CoA.
NADH inhibits the citric cycle and the acetyl-CoA increases the synthesis of triacylglycerine (TAG) and fatty acids. This results in the formation of a fatty liver. Eventually this will inflame and develop into fatty liver hepatitis. To protect itself the liver produces more and more conjunctive tissue. It progressed into an advanced state of cirrhosis of the liver.
The growth of conjunctive tissue in the liver makes continuous, uninterrupted blood flow impossible. A clot appears in the portal vein. The blood seeks other ways to the heart, including along the stomach. This causes severe widening of the vessels, which morphologically look like varicose veins and bear the name varices. However, these vessels are not designed for the additional blood and are exposed to a high risk of collapsing (variceal haemorrhage). Bilirubin, a by-product of haemoglobin, is now increasingly transported in the blood, causing the skin and the underlying vessels to appear yellow (jaundice = icterus).
Popular Exam Questions on the Detoxication Function of the Liver
The solutions are found beneath the references.
1. Which of these tasks is not performed by the liver?
- Production of blood proteins (albumin, coagulation factors)
- Storage of vitamins
- Synthesis of starting products for hormone production
- Production of aldosterone
2. Which of the following statements is true?
- NK cells are lymphocytes that appear in more places than just the liver.
- The vitamin A-storing Ito cells are localised in the space of Disse.
- Hepatocytes are part of the mononuclear phagocyte system.
- Liver cells produce alcohol dehydrogenase.
3. Which of the following statements on biotransformation is incorrect?
- Enzymes are involved in most reactions.
- The liver is the main site of biotransformation reactions.
- Ethanol oxidase is a member of the family of cytochrome P450 enzymes.
- Alcohol dehydrogenase is a dimer made from polypeptide chains with a central magnesium ion.