The liver: detoxification, deamination and the making of urea

Excretion, and the two things it is mostly about

Excretion is the removal from the body of the waste products of metabolism: substances made by the body's own reactions that would do harm if they accumulated. The definition excludes most of the material that leaves in the faeces, which is undigested food, bacteria and shed gut lining; passing it out is egestion. Faeces are therefore not an excretory product in that sense.

Two waste products dominate, and both come out of reactions you have already studied. Carbon dioxide is made continuously by respiring cells, is carried to the lungs mostly as hydrogencarbonate ions, and is excreted at the alveoli. Left in the blood it forms carbonic acid and the pH falls, which changes the charge on the R groups of every protein in the body, so a rise in carbon dioxide is dangerous long before it is a shortage of anything.

Nitrogenous waste is the second. A meal containing more protein than the body needs cannot simply be stored: there is no store for amino acids in the way there is glycogen for glucose and fat for lipid. The surplus is broken up instead, the nitrogen-containing part is stripped off in the liver, and it leaves the body as urea in the urine. Urea is made in the liver and excreted by the kidney.

A third excretory pathway also runs through the liver. Old red blood cells are broken down and the haem group is converted into bile pigments, which leave in the bile, pass into the gut and colour the faeces. Faeces therefore contain some body-derived material, including bile pigments and shed cells, as well as undigested food.

Excretion

The removal from the body of the waste products of metabolism, such as carbon dioxide and urea.

Egestion

The removal of undigested food and other material that has never taken part in the body's metabolism.

Deamination

The removal of the amino group from an amino acid, producing ammonia and a keto acid.

Detoxification

The conversion by the liver of a toxic substance into one that is less toxic and can be excreted.

An organ with two blood supplies

Everything the liver does depends on what arrives in its blood, and it is one of very few organs fed by two vessels rather than one. Between them they deliver roughly a quarter of everything the heart pumps while you are resting.

The hepatic artery branches from the aorta and brings oxygenated blood, which the liver needs as much as any tissue: its cells respire hard and it is one of the warmest organs in the body. The hepatic portal vein is the unusual one. It carries blood that has already passed through the capillaries of the stomach, small intestine and large intestine, so it is deoxygenated but loaded with everything that has just been absorbed: glucose, amino acids, mineral ions, and any drug, alcohol or toxin that came in with the meal. About three quarters of the liver's blood arrives this way.

One consequence follows directly. Every molecule absorbed from the gut reaches the liver before it reaches anywhere else, so the liver sets the concentration the rest of the body sees. That is why blood glucose is regulated there, and why a drug swallowed rather than injected may be largely broken down before it has been anywhere near the tissue it was meant for.

The hepatic vein takes blood away, back to the inferior vena cava and so to the heart. And one further vessel leaves the liver carrying something that is not blood: the bile duct, which takes bile to the gall bladder and from there to the duodenum.

The lobule, and the cells inside it

Cut the liver and it looks uniform, but under a microscope it is built from a repeated unit a millimetre or so across called a lobule. Drawn in section a lobule is roughly hexagonal, with a vein running down its axis and blood vessels at its corners.

At each corner of the hexagon sit branches of the hepatic artery and of the hepatic portal vein, together with a bile ductule. Blood from both vessels runs from the corners towards the middle along wide, leaky capillaries called sinusoids, mixing as it goes, so oxygen and absorbed food reach the same cells at the same time. What is left drains into the central vein running down the middle of the lobule, and the central veins join to form the hepatic vein.

The cells packed either side of every sinusoid are the hepatocytes, and they do nearly all of the work. They are cubical with a large nucleus, and their specialisation lies in their contents rather than their shape: a great deal of smooth endoplasmic reticulum, where detoxification happens, abundant rough endoplasmic reticulum and Golgi for the plasma proteins they secrete, dense mitochondria for the ATP all of it consumes, and granules of stored glycogen. Their surface facing the sinusoid carries microvilli, so exchange with the blood is rapid.

Scattered along the sinusoids are Kupffer cells, which are macrophages fixed in place. They engulf bacteria arriving from the gut and break down worn-out red blood cells, and it is their handling of haem that produces the bile pigments. Bile itself is secreted by the hepatocytes into fine channels called bile canaliculi that run between them, out to the bile ductules at the corners of the lobule. The two flows run in opposite directions: blood inwards to the central vein, bile outwards to the corners.

Lobule

The repeating structural unit of the liver: a roughly hexagonal block of hepatocytes with a central vein at its axis.

Sinusoid

A wide, leaky capillary running from the edge of a lobule to its central vein, carrying mixed blood from the hepatic artery and hepatic portal vein.

Hepatocyte

A liver cell, carrying out detoxification, deamination, storage and the secretion of bile.

Kupffer cell

A macrophage fixed in a sinusoid, which engulfs bacteria and breaks down old red blood cells.

Detoxification, and what alcohol does to a liver

A toxin is a molecule the body cannot use and cannot afford to leave circulating. The liver's answer is nearly always the same: change it chemically, usually by oxidising it, until it is less harmful and soluble enough for the kidney to excrete. Enzymes in the smooth endoplasmic reticulum of hepatocytes, the cytochrome P450 group among them, handle most drugs and many hormones this way; the liver breaks down insulin, oestrogen and testosterone once they have done their work, which is part of why hormonal signals fade. Catalase in the same cells decomposes the hydrogen peroxide that metabolism keeps producing, and hepatocytes carry more of it than almost any other cell.

Alcohol is the standard worked example, and is a two-step oxidation. Ethanol is oxidised by ethanol dehydrogenase to ethanal, and ethanal is oxidised in turn by ethanal dehydrogenase to ethanoate, which is converted into acetyl coenzyme A and fed into respiration. Both steps hand hydrogen to NAD, so both produce reduced NAD.

The accumulation of reduced NAD is what causes the damage. A liver dealing with a great deal of alcohol accumulates reduced NAD, and a cell with plenty of reduced NAD has no need to oxidise fatty acids: it synthesises them instead. Fat therefore builds up in the hepatocytes, which is fatty liver, and it is reversible if the drinking stops. Sustained over years, the cells are damaged and die, fibrous scar tissue replaces them, and the organ becomes hard and shrunken with far fewer working cells. That is cirrhosis, and it is not reversible, because although the liver regenerates lost tissue remarkably well, it cannot replace tissue that has been turned into scar.

Deamination and the ornithine cycle

Amino acids surplus to requirements are broken down in the hepatocytes, and the first step is deamination: the amino group is removed and leaves as ammonia, while the rest of the molecule becomes a keto acid. The keto acid is useful and goes nowhere unpleasant: it is respired for ATP, or converted into glucose or into fat for storage. It is the ammonia that is the problem.

Ammonia is small, extremely soluble and very toxic. It raises the pH of solutions it enters and interferes with the reactions of respiration in the brain, and a concentration high enough to be dangerous is a very low one. An animal living in fresh water can simply let it diffuse out across the gills, because there is unlimited water outside to dilute it. A land animal cannot excrete ammonia this way.

The ornithine cycle, also called the urea cycle, runs in the hepatocytes. State where each step takes place as well as what joins and leaves.

In the first step, inside a mitochondrion, ammonia combines with bicarbonate, derived from carbon dioxide, and the product joins ornithine to give citrulline and water. In the second, in the cytoplasm, citrulline acquires the second nitrogen from aspartate and becomes arginine. In the third, also in the cytoplasm, the arginine is hydrolysed to urea and ornithine. The ornithine returns to the start of the sequence and is used again, which is what makes it a cycle, and the urea diffuses into the blood.

Overall, one nitrogen enters as ammonia, the second comes from aspartate, and the carbon comes from bicarbonate, giving one molecule of urea per turn at a cost in ATP. Several specifications simplify this to two molecules of ammonia and one of carbon dioxide; use the form your specification states, and keep the source of each atom consistent within an answer.

The remaining question is why the ATP is spent at all, when ammonia could be excreted directly.

Because ammonia would have to be excreted in enormous volumes of water. To keep the concentration in the blood below the level that damages the nervous system, a mammal would need to produce urine at a rate no land animal could drink to replace. Urea is far less toxic and still soluble, so it can be carried in the blood at concentrations tens of times higher and concentrated further in the urine. The ATP is spent in order to conserve water. Freshwater fish excrete ammonia directly across the gills at no metabolic cost; birds, reptiles and insects convert nitrogen instead to uric acid, which is almost insoluble and can be excreted as a paste, which is what makes a shelled egg possible in the first place, since a developing embryo sealed in a shell cannot afford either water loss or a soluble poison.