bile

views updated May 29 2018

bile is a greenish-yellow fluid produced by the liver, and passing from there into the duodenum; it has a number of functions, which will be described shortly. But bile also has a remarkable history, for in early medicine bile made up two of the four humours, which were blood, phlegm, yellow bile, and black bile. For about 2000 years an excess of black bile was thought to make patients melancholic, and an excess of yellow bile to make them choleric.But let your friends in verse suppose
What ne'er shall be allowed in prose,
Anatomists can make it clear
The liver minds its own affair;
And parts and strains the vital juices,
Still layes some useful bile aside,
To tinge the chyles insipid tide;
Else we should want both bile and satire
And all be burst with pure good nature.
Matthew Prior , 1664–1721

The belief that bile had such a profound effect on human nature disappeared in the early nineteenth century, when humoral medicine was overtaken by the new scientific rationalism.

Bile is a complex biochemical mixture, made continuously by the liver — 500–1000 ml/day passing down into the duodenum via the bile duct. There is a diversion in this journey: a small 50 ml sac — the gall bladder — fills with bile from the liver, and, by absorbing water across its walls, concentrates bile 5–6-fold. Shortly after a meal the gall bladder contracts and empties, and the concentrated bile is added to the partially digested food (‘chyles insipid tide’ in Prior's poem above). Bile has two broad functions: it plays a digestive role in the breakdown and absorption of fat, and it excretes substances from blood which cannot be excreted by the kidneys. These substances are usually fat soluble; they may be produced by the body, or come from outside, like drugs. In composition, bile is 97% water; its other major components are bile salts, cholesterol, phospholipids, bile pigments, and electrolytes (minerals).

Bile acids and bile salts

The function of these remarkable molecules is inextricably involved with cholesterol. The two main bile acids, cholic acid and chenodeoxycholic acid, are both made from cholesterol in the liver and pass into the bile in combination with amino acids, as bile salts. Cholesterol is virtually insoluble in water, and in the words of the 1989 Nobel prizewinners, Brown and Goldstein, ‘Cholesterol is a Janus-faced molecule. The very property that makes it useful in the cell membrane, namely its insolubility in water, also makes it lethal.’ (The authors were referring to the crucial part played by cholesterol in the pathological process of atherosclerosis.) So the body has resorted to some remarkable strategies to excrete this difficult substance, and it seems that cholesterol excreted by the liver is partly extracted from the circulation and partly made by the liver itself. The body's main strategy is to use bile salts as detergents: the molecules have a water-soluble (hydrophilic) side and a fat-soluble (hydrophobic) side. This enables bile salts to make small parcels (‘micelles’) including several different molecules, with cholesterol as contents and bile salts as the wrapping. The hydrophobic aspect of the bile salt faces inwards, and the hydrophilic aspect faces outwards into the aqueous component of bile.

The bile micelles pass into the duodenum, where the detergent action of the bile salts emulsifies fats, which are then broken down by the enzyme lipase from the pancreas. Bile salts also assist the final absorption of the products of fat digestion. Both bile and lipase are necessary for the proper absorption of fats by the small intestine. Without one or other of these two, there is deficiency of the vital fat-soluble vitamins, A, D, E and K, and malabsorption causes fat to appear in the faeces (steatorrhoea).

Bile salts pass down the entire length of the small intestine, but instead of their being degraded or excreted in faeces, a remarkable phenomenon occurs. The bile salts are absorbed as whole molecules at the far end of the small intestine (the terminal ileum) and pass up the portal vein to the liver, whence they are re-secreted into bile. This circuit, known as the entero-hepatic circulation, represents extraordinary parsimony, for at any one time only 3–5 g of bile acids are present in the body; this 3–5 g is known as the bile acid pool, and it circulates 6–10 times a day. About 0.5 g of bile acids is lost in the faeces per day, which means that an average bile acid molecule survives in the entero-hepatic circulation for about 3 days, making 18–30 cycles. During this time, it will escort many hydrophobic molecules (such as cholesterol) into the small intestine, and help with the emulsification and absorption of a significant quantity of fat. We have no idea why the body should indulge in this metabolic penny-pinching. If the terminal ileum is diseased, or has to be surgically removed, the bile acids pass into the colon, where they produce watery diarrhoea.

It is of interest that vitamin B₁₂ is also absorbed from the terminal ileum, and passes up the portal vein; the liver metabolizes some of it and the products pass into the watery phase of the bile; reabsorption provides an entero-hepatic circulation. Vitamins B₁₂ cannot be synthesized in the body, so this is an appropriate device for conservation of a precious molecule. Damage to, or surgical removal of, the terminal ileum produces the syndrome of pernicious anaemia, a consequence of vitamin B₁₂ deficiency.

Cholesterol gallstones

The commonest disorder of bile formation is the presence of gallstones, and the commonest type of gallstone consists of cholesterol, which comes out of solution in the gall bladder. Gallstones cause symptoms by passing out of the gall bladder and obstructing the bile duct; the time-honoured treatment consists of surgically removing the gall bladder. More recently, stones have been treated medically, by increasing the bile acid/cholesterol ratio of bile. This is achieved simply by taking synthetic bile acids by mouth. Unfortunately it may take many months to dissolve existing gallstones, and even if it does have the desired effect, the patient will need to take bile acids indefinitely to prevent the recurrence of stones. Stones can also be disintegrated inside the gall bladder by the ingenious use of high frequency waves (‘lithotrypsy’).

Some races (Finns, Swedes and North American Indian women) have high cholesterol/bile acid ratios in their bile, and are very prone to gallstones. These races have a high animal fat diet, rich in cholesterol. In races whose diets contain little animal fat (Japanese and Masai for example) the bile contains little cholesterol, and gallstones are rare — but the formation of cholesterol stones is not just a question of diet. It has been found that the cholesterol concentration of bile varies with the time of day, for example, which makes the phenomenon of cholesterol crystallization much more difficult to analyse.

Bile pigments

The life of red blood cells is about 120 days, and their death is associated with the release of haemoglobin, which makes up the greater part of the red cells. Macrophages are chiefly responsible for their destruction; the globin protein is reused, while the haem is detached from the iron, which is also reused. Haem is a ring (tetrapyrrole) structure and cannot be reused. Within the macrophage the ring is broken, and the four constitutent pyrrole groups are arranged in a straight chain — biliverdin (green) — and finally bilirubin (yellow). The changes in skin seen after bruising represent this conversion, for blood produced by the bruise is taken up by the local macrophages, and the blood in the macrophage undergoes the red to green to yellow conversion.

Under normal circumstances, bilirubin is released by the macrophage into blood. Bilirubin is insoluble in water, and is transported in blood by being attached to very large molecules, plasma albumin. When this bound bilirubin reaches the liver it separates from the plasma protein, and enters the liver cell, but, because of its insolubility, some device needs to be employed by the liver to incorporate it into bile. The way that the liver achieves this is not to include it in the centre of a micelle, but to attach, or conjugate, it to glucuronic acid, which makes the bilirubin water-soluble. (The yellow-green colour of bile is derived from bilirubin.)

Conjugated bilirubin (or bilirubin glucuronide) passes down the bile duct in the bile; unlike bile salts, it has no role in digestion. It passes into the intestine, where bacterial action converts it to urobilinogen, which is very water-soluble. Some urobilinogen is absorbed across the gut wall and passes into the blood whence it may be either resecreted into bile (as an entero-hepatic circulation), or excreted by the kidneys. It is urobilinogen that gives urine its yellow colour. The urobilinogen that is not absorbed from the gut passes down the small intestine to the colon, and its final product, stercobilin, gives rise to the brown colour of faeces. Bilirubin is thus a ubiquitous colouring agent.