General Health - Liver - A student's guide
Located just under the ribs on the right-hand side of the body, the liver is our largest gland and is estimated to have over 500 functions. These include:
Processing digested food from the gut
Controlling levels of fats, amino acids and glucose in the blood
Converting excess glucose into glycogen
Converting liver glycogen back into glucose to top up blood sugar levels
Converting stored fats into forms that can be used by the tissues to make energy
Removing the nitrogen group from amino acids to form urea
Converting essential amino acids into their non-essential counterparts
Breaking down nucleotides into uric acid ready for excretion
Synthesising plasma proteins
Breaking down old, worn-out red blood cells
Clearing the blood of particles and microbes
Manufacturing, regulating and detoxifying numerous hormones, including the sex hormones
Neutralising and destroying alcohol, drugs and toxins
Synthesising vitamin A from beta-carotene
Activating vitamin D
Storing some vitamins and minerals, including:
the fat-soluble vitamins A, D E and K
the minerals iron and copper
some B vitamins
Liver structure and blood supply
In order to carry out all these functions, the liver filters a staggering 1.4 litres of blood per minute. This enters from two separate pathways, with fresh, oxygenated blood arriving from the heart through the hepatic artery, while nutrient- (and possibly toxin-) enriched blood from the digestive system is ferried to the liver via the portal vein. These two blood supplies are mixed in the liver and are processed together.
The liver itself is made up of four lobes, with each lobe comprising hundreds of smaller processing units called lobules. Each lobule is hexagonal in shape and made up of columns of liver cells radiating from a central vein, while blood vessels called sinusoids run between each pair of columns of cells. The blood is delivered to the periphery of each lobule by tiny branches of the hepatic artery and portal vein. The mixed blood then passes through the sinusoids, where the liver cells clean it before it’s collected in the central vein, which eventually links up with the main hepatic veins leaving the liver.
The two main types of cell in the liver are the hepatocytes and the Kupffer cells.
Hepatocytes are the major functional cells in the liver, responsible for carrying out the bulk of the liver’s biochemical functions. They make up about 80% of the liver’s volume and are the cells that are arranged in columns either side of the sinusoids in each lobule
A Kupffer cell is a special type of phagocytic cell that readily ingests foreign substances, removing them from the blood stream. They line the sinusoids in the liver ready to pounce on any potential pathogens
As well as cleaning the blood, the liver is also the site of bile manufacture. To facilitate this, tiny little collecting ducts, called bile canaliculi, are nestled between the columns of hepatocytes. This means each column of hepatocytes has a sinusoid on one side and a bile canaliculus on the other. The bile canaliculi are all interconnected; eventually joining up to form the hepatic duct, which drains bile from the liver to the gallbladder. Overall, the structure of the liver allows substances to be taken from the blood stream by the liver cells, processed and then either stored, returned to circulation for removal via the kidneys or deposited in the bile for excretion via the digestive system.
One of the liver’s most important functions is detoxification. It is responsible for turning fat-soluble toxins into water-soluble compounds that can be eliminated via the urine or bile. This process of turning toxins into non-toxic metabolites is carried out by the hepatocytes and occurs in two steps; phase I and phase II. This can be likened to the processes of chopping up and mopping up!
Most toxins that arrive at the liver have to undergo phase I detoxification. These first steps of biotransformation are required to expose or add reactive chemical groups onto a toxin to prepare it for mopping up in phase II.
The chemical reactions that occur in phase I include oxidation, reduction, hydrolysis, hydration and dehalogenation.
The reactions are carried out by groups of enzymes, with each enzyme having a different toxin specificity.
The cytochrome P450 family
By far the most common family of enzymes in the phase I system are those belonging to the cytochrome P450 superfamily. These enzymes use oxygen and NADH (an activated form of vitamin B3) to add a reactive hydroxyl radical to different types of toxin. The downside of this process is that often the modified toxin is more reactive that the original structure. If these new ‘chopped-up’ toxins are not quickly ‘mopped up’ by phase II processes they can start to damage the liver and other cells by either binding to cell components such as proteins, lipids and nucleic acids or creating oxidative stress.
Phase II is all about reducing a toxin’s reactivity and preparing it for excretion. This is done via one of six different conjugation reactions, each of which involves sticking a water-soluble chemical group onto the toxin to create a compound that the body can safely and speedily excrete. In most cases, the new chemical group reacts with the part of the toxin that was activated in the phase I reaction.
Compromised liver function
For healthy detoxification, it’s important that the phase I and II liver pathways function in balance. If toxins are chopped up faster than they can be mopped up, reactivate phase I metabolites can build up in the liver, causing oxidative damage. What’s more, imbalanced liver function leads to changes in metabolism that can affect the body’s ability to handle toxins, as well as influencing the levels of various steroids, fatty acids and other signalling molecules in the body. Since the liver carries out so many vital functions, compromised liver function can result in a wide range of symptoms, including:
Poor appetite or nausea, especially in the morning
Difficulty digesting fatty foods
Pale, fatty stools that float
Intolerance to alcohol
Itching on the arms, legs, palms of the hands and soles of the feet
Tiredness and fatigue
Problems sleeping, typically waking between 1am and 3am
Slight yellowing of the whites of eyes
Dark circles under the eyes
High cholesterol levels
A weakened immune system
Weight gain, especially around the abdomen
Offensive body odour
A feeling of overheating
Mood changes, such as anger and irritability
Multiple allergies and sensitivities
Compromised liver function is different to serious liver pathologies, such as cirrhosis, hepatitis and liver cancers, because the liver has not yet been permanently damaged. Patients typically present with normal blood test results, but their liver is not working as efficiently as it should be, causing the body to become overloaded and toxic.
Factors affecting liver function
Many different factors can influence liver detoxification. Some of these are permanent effects, such as those caused by genetic differences, while others are a result of environmental influences inducing (speeding up) or inhibiting (slowing down) certain liver pathways.
Genetics – the presence of different versions of the genes that encode for the enzyme systems in the liver can strongly influence how well a person’s liver is able to handle a particular substance. Genetic differences have been demonstrated in the enzymes of the cytochrome P450 family, as well as in the enzymes responsible for phase II metabolism(1) and those specific to metabolising alcohol. These can result in differences in how slowly or quickly someone can metabolise a drug or may affect someone’s ability to handle toxins(2,3).
Age – liver function is generally less efficient at the extremes of age. In newborn babies, the phase I and II liver metabolism enzymes are present but their activity is much slower than in adults(4), while in the elderly, gradual decrease in the efficiency of liver detoxification is thought to contribute to the health effects seen with ageing(5).
Gender – the circulating level of specific sex hormones can influence certain liver enzymes. One such example is the CYP3A family of detoxification enzymes, which are affected by the level of progesterone. In premenopausal women, these enzymes are generally 30-40% more efficient than in men or postmenopausal women. The activity of these enzymes is also increased in pregnancy when progesterone levels are elevated. This explains why pregnant women may need to change their dose of certain medications(6).
Disease – diseases that impair liver function, such as alcoholic liver disease, fatty liver, biliary cirrhosis and liver cancer, can all lead to lower detoxification activity in general. In addition, some other health conditions can actually cause changes in the activity of particular liver enzymes. One such example is the increase in activity of CYP2E1 (a phase I enzyme that is involved in alcohol metabolism and gluconeogenesis) in people who are diabetic or obese. The reason CYP2E1 is induced in these conditions is not fully understood, but may be to do with the role CYP2E1 plays in energy metabolism(7).
Medications – certain drugs and natural agents can inhibit phase I liver metabolism. These agents often interact with other medications because they slow their liver metabolism.
Smoking – the polycyclic hydrocarbons in cigarette smoke increase phase I activity without inducing phase II. This raises the level of oxidative stress in the liver and increases the chance of DNA damage.
Alcohol – ethanol can increase the activity of certain phase I enzymes, resulting in a significant increase in reactive oxygen species and oxidative damage(8).
Chargrilled meat – the aryl amines that form when meat is chargrilled or barbequed have similar effects on liver detoxification to the chemicals in cigarette smoke.
Improving liver function
To improve liver function, it’s important to work with clients to reduce their dietary and environmental exposure to potential toxins as well as ensuring optimum levels of liver-supporting nutrients and foods.
To function at its best, the liver requires a good supply of phase I and II cofactor nutrients, as well as an abundance of natural substances that help protect the liver from free radicals and fat accumulation. A good liver support supplement plan should include:
B vitamins – these are vital cofactors for the action of the cytochrome P450 enzyme system and other phase I enzyme families. A good supply of B vitamins helps to protect the liver from the damaging effects of alcohol(9,10,11,12), while vitamins B3 and B5 also help the liver to process cholesterol effectively(13). Some B vitamins are also required for phase II. For example, B5 is important for the acetylation pathway, while B6 and B12 are needed as cofactors for glutathione manufacture(14).
N-acetyl-cysteine – used medically to treat paracetamol overdose and other causes of liver failure, this sulphur-based amino acid replenishes glutathione stores(15). This supports the phase II glutathione conjugation pathway and ensures adequate glutathione to help neutralise free radicals before they can damage the liver.
Glutamine – this is also a precursor to glutathione. It too can support the liver’s antioxidant defences and glutathione conjugation pathways, as well as supporting the amino acid conjugation pathway. Glutamine is also important for the metabolism of protein in the liver, helping to protect liver cells from the ammonia produced during the urea cycle(16).
Methionine – this is the most important human lipotrophic agent (a substance that prevents accumulation of fat in the liver). It is an important cofactor for the phase II methylation pathway and can also be converted to cysteine and used to make glutathione(17). Human studies indicate methionine can lower acetaldehyde levels after alcohol ingestion. Because acetaldehyde is toxic, methionine may be effective in reducing the damaging effects of alcohol(18).
Choline – like methionine, choline also assists in the phase II methylation pathway in the liver and is protective against fatty liver disease and cirrhosis(19).
Taurine – as a sulphur-containing amino acid, taurine supports the phase II sulphation and amino acid conjugation pathways. It’s needed for proper metabolism of a whole variety of environmental toxins and drugs and is often low in people with chemical sensitivities. Taurine is helpful for fatty liver, high blood cholesterol and gallbladder problems as it aids bile production and excretion(20).
Antioxidants – a good supply of antioxidants is vital to neutralise the free radicals formed in phase I detoxification(21). This includes the antioxidant vitamins A, C and E, as well as the minerals zinc, copper, selenium and manganese, which act as cofactors for important antioxidant enzymes in the liver. Additional antioxidant nutrients of use include CoQ10, alpha-lipoic acid, reduced glutathione and flavonoids.
Milk thistle – this herb has been used for hundreds of years as a liver tonic. It has strong antioxidant properties and has been shown to help protect the liver from the damaging effects of phase I metabolites(22,23).
Foods for a fabulous liver
As well as supporting overall liver detoxification, foods can be used to help protect the liver and keep phase I and II metabolism balanced. Some of the top ingredients include:
Brassica vegetables – these contain a compound called indole-3-carbinol which can reduce phase I activity(24) while inducing the phase II glutathione conjugation pathway(25), helping to clear toxins more effectively. Broccoli and sprouts are particularly beneficial as these also contain the powerful antioxidant sulphoraphane.
Asparagus – this spring vegetable has been shown to increase the activity of two key enzymes that metabolise alcohol in the liver; alcohol dehydrogenase and aldehyde dehydrogenase(26).
Beetroot – red beetroot has been shown to support the activity of the liver enzymes glutathione peroxidase, glutathione reductase and superoxide dismutase, helping to reduce oxidative stress and DNA damage(27).
Apples – a recent animal study has shown that apples can protect the level of antioxidant enzymes in the liver and reduce DNA damage after toxin exposure(28).
Tomatoes – these red fruits are rich in the pigment lycopene, which has been shown to protect against the development of fatty liver as well as helping to preserve liver glutathione levels(29).
Red grapes – ellagic acid, found in red grape skins, is a flavonoid that can speed up phase II while slowing down phase I.
Dark berries – rich in antioxidant anthocyanidins, dark coloured berries have been shown to help protect the liver from the effects of oxidative damage(30).
Soy foods – these have been shown to help induce phase II liver detoxification(31).
Lemons – rich in the phytochemical D-limonene, which can help protect against glutathione depletion(32).
Garlic and onions – these pungent foods naturally contain chemicals called sulphides, which can induce phase II liver enzymes(33).
Turmeric – the yellow pigment curcumin from turmeric is a powerful antioxidant and anti-inflammatory. It has been shown to induce glutathione production, aid the phase II glutathione conjugation reactions and reduce phase I activity(34).
Ginger – animal studies suggest ginger can help protect the liver by increasing the activity of liver-protecting enzymes, such as superoxide dismutase, glutathione peroxidase and catalase(35).
Rosemary – contains the flavonoids carnosol, carnosic acid, rosmanol and ursolic acid, which are potent, free radical scavengers. Carnosol and carnosic acid can also induce certain phase II detoxification enzymes(36).
Oregano – animal studies suggest that dietary oregano can help improve the impaired antioxidant status in states of liver toxicity(37).
Green tea – a recent review found a significant protective role of green tea against various liver diseases(38).
To maximise the benefits of these foods, the ideal situation is to get clients to include four or more of these foods on a daily basis. However, for clients whose initial nutritional status is very poor, a food-based antioxidant complex or superfood smoothie powder can be an excellent tool for boosting therapeutic nutrient intake.
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