CHOLELITHIASIS

Chairman : Professor Oliver FitzGerald

Epidemiology and Pathogenesis of Gallstones : J. S. Doyle (Dublin)

The Goose that laid the Golden Bile: Gallstone Dissolution in Man with

Chenodeoxycholic Acid: R. H. Dowling (London)

Panel Discussion : Chairman, speakers and Dr. J. Fielding (Dublin)

CHAIRMAN Ladies and gentlemen, we are now coming to the last of the programmes

for this morning. It is one of considerable interest to physicians, and of some interest to surgeons. I don't think there are enough of them here to feel that they are over worried, but I do think it is an important subject in- deed, not only in relation to just the biliary tract but also to other areas in the body. I think it would be much simpler if we started by asking Dr. Doyle to talk about the epidemiology and pathogenesis of gallstone formation.

EPIDEMIOLOGY AND PATHOGENESIS OF GALLSTONES

J. Stephen Doyle

Department of Gastroenterology, St. Laurence's Hospital, Dublin.

Historical Note

G ALLSTONES have been known to man for many years. The first written report, in this case occurring in the liver of the ox, was by Trallianus about 400 A.D. (Thudichum et al.). Gentile de Foligno of Padua, obiit

1348, is credited with the first observation of gallstones in man. (Rolleston and McNee, 1929). Calculi have been found in Egyptian mummies dating back to 1000 BC. (Womack et ah, 1963).

With the onset of safe anaesthesia in the mid-Victorian era, gallstones became the province of the surgeon. Only in very recent years with in- creasing knowledge of the pathogenesis of cholelithiasis has the physician once more turned his attention to this sphere of interest.

Gallstone Composition Our knowledge concerning the composition of gallstones has been

greatly enhanced by the application of new analytical techniques, i.e. micro- analytical analysis, histochemical staining, crystallography, infra-red spec- troscopy and x-ray diffraction.

Sutor and Woolley (1971), by x-ray diffraction methods, have demon- strated the dominant part played by cholesterol in their analysis of stones

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CHOLELITHIASIS 111

from eight countries but have also confirmed the wide variation in the am- ounts of cholesterol in stones from various parts of the world. From their work the 'average' stone would appear to contain 71 per cent cholesterol, 15 per cent calcium carbonate, 6 per cent calcium palmitate and 8 per cent of other trace substancas including calcium phosphate, bile pigments, alpha palmitic acid and glycoprotein.

However, the modern stone can in a very arbitrary manner be divided into two major types, i.e. the Western stone with up to 89 per cent choles- terol and the non-Western stone with up to 41 per cent cholesterol. Many other factors of interest are known. English gallstones and possibly Irish stones also have a high content of calcium carbonate. Other regional dif- ferences are known.

Why these basic differences occur is unknown but may have a significant part to play in medical treatment. Unalterable metabolic pathways may be responsible but hopefully the causes may be dietary or environmental : both of which may be manipulated.

Methods of predicting gallstone composition in vivo are required as at the present stage of our knowledge stones with a high calcium content would appear to be less responsive to the modern methods of dissolution. However, beyond routine x-ray examination, which is far too coarse, no suitable method for predicting gallstone composition is available. As a result of this, the best source of possible information, in any particular patient, may be a detailed analysis of the bile itself.

Epidemiology of Gallstones Our knowledge of the epidemiology of gallstones at this time is fragmen-

tary. In recent years it has become apparent that gallstone incidence is constantly changing. The old adage of fair, fat, fertile and forty gets little support from modern studies. Adequate epidemiological surveys still may hold the key to aetiology and thus in turn lead to prevention in the future.

Method of Assessing Gallstone Prevalence Four main methods are available to assess gallstone prevalence in any

particular community.

1. Perform a cholecystographic survey of a large number of randomly sel- ected people.

2. Review of continuous autopsy reports in large general hospitals. 3. Assessment of hospital clinical records. 4. Review operation records on a national scale.

Sampliner et al. (1970) have used the first method in Pima Indians with some success. Clinical records have not proven fruitful.

We have attempted to use methods (2) and (4) to review the situation in Ireland.

In Ireland the Medico-Social Research Board records approximately 60 per cent of the total acute general hospital admissions. In 1972, 1,962 cases of choielithiasis, cholecystitis and cholangiitis were reported. These occur-

112 IRISH JOURNAL OF MEDICAL SCIENCE--SUPPLEMENT, JULY 1974

red in a total of 146,264 hospital admissions (Dean, 1973). The expected sex differential and age distribution is maintained.

Thus in Ireland, allowing for a total population of 3.0 million, we can produce figures of incidence of 10.1 discharges for bilary tract disease per 10,000 members of the population. This compared with a figure of 10.2 in in Ireland may be lower than in England and Wales.

Of the original 1,965 cases reported in Ireland in 1972, 1,384 cases came to cholecystectomy. By extrapolation again this would represent 98.9 oper- ations per 100,000 of the population in the year under survey. In the Bristol area in 1970 the equivalent figure was 78.0 operations per 100,000 of the population. This would suggest a difference though not statistically sig- nificant.

In 800 consecutive autopsies at St. Laurence's Hospital for the years 1970-73, 39 cases of gallstones were found, i.e. 4.9 per cent (Holland and Warner, 1974). Only two cases were found in females for the 41 to 50 year age group. By world standards this figure is low.

The prevalence of gallstones in different countries have been estimated over the years by different methods and techniques. Unfortunately most of the studies are not directly comparable.

1968 in England and Wales based on figures from the Annual Report on the Hospital In-patient Enquiry. Allowing for the 4 year difference the incidence

Heaton in an excellent review of the world literature in 1973 has gathered much material which is of considerable interest (Bouchier, 1973a). Gall- stones are exceptionally common, i.e. over 50 per cent, in Indians in the United States and also in Sweden. They are common, i.e. over 5 per cent of population, in U.S.A., Israel, United Kingdom, Germany, South African Whites, Australia and Singapore. They are rare, i.e. under 5 per cent in South African Bantus, Egypt, Thailand, India, Japan and Ireland. The prev- alance is very rare, i.e. less than 1 per cent in Sub-Saharal Africa, Green- land and Canadian Eskimos.

The composition of gallstones vary and generally in Westernised com- munities there is a high cholesterol content and in under developed coun- tries a low cholesterol content and a high pile pigment content.

In Japan, where detailed studies have been done, the urban communities demonstrate examples of the Western type of stone and rural areas show the Oriental pattern.

In Sub-Saharal Africa some of the best documented examples of low incidence in the world have been reported. In Ghana, in 4,395 consecutive autopsies performed from 1923 to 1955, no gallstones were found. In the first five years at Ibadan University Hospital in Nigeria only 27 patients were admitted to the surgical wards on account of gallstone disease.

It is widely held that gallstones are increasing in frequency and that this keeps step with the Westernisation of native communities. It is difficult to prove this definitely but certainly the incidence of cholecystectomy has trebled or quadrupled between 1940 and 1970. This changing pattern has been supported by data from Japan, United States and Canada. It is of interest to note that the Eskimos of Canada, where originally gallstones

CHOLELITHIASIS 113

were unknown, have had an epidemic of this disease in certain Westernised communities during the past ten years (Bouchier, 1973).

The Pathogenesis of Gallstone Formation

Cholesterol is a major component in most gallstones. This insoluble substance is held in solution in bile by its interaction with bile salts and phospholipids with the formation of mixed micelles which are molecular aggregates of these substances that exist in true solution. Hepatic bile is normally almost or fully saturated with cholesterol. A hypersaturated solu- tion of bile with cholesterol is known as lithogenic bile.

With the knowledge that the pool size of primary bile acids can be altered in man with resultant changes in the solubilisation of cholesterol (Vlahcenic et al., 1971) leading in some cases to the dissolution of gall- stones : an exciting new chapter in the gallstone story is unfolding.

Bouchier (1973b) has reviewed the biochemistry of gallstone formation and his treatise exemplifies our present state of knowledge.

Cholesterol Insoluble biliary cholesterol is in the free unesterified form and amounts

to 8 per cent of the lipids in normal hepatic bile. Intestinal cholesterol ab- sorption and synthesis are related to the amount of bile acids available and the bile acids, therefore, have an important role in mediating hepatic chol- esterol synthesis, it is important to realize that the cholesterol concentra- tion in bile is unrelated to serum values.

Phosphollplds The major phospholipid in bile is lecithin which accounts for 96 per cent

and lysolecithin producing 3 per cent. Phospholipid estimation, therefore, is usually restricted to the estimation of lecithin. Phospholipids are virtually insoluble in water but they can form molecules with a bi-molecular structure which produces a form of liquid crystal which forms with bile salts an ex- panded mixed micelle which in turn is better able to dissolve cholesterol than a solution of bile salts alone.

Blle Aclds The primary bile acids are produced in the liver. Eighty per cent of the

bile acids are cholic acid and chenodeoxycholic acid.

The secondary bile acids are formed in the colon by the action of bac- teria which catalyse dehydroxylation of the primary bile acids. The most important secondarybi le acid is deoxycholic acid formed from cholic acid. Lithocholic acid is nc)t absorbed from the colon and, beyond a postulated carcinogenic role due to stasis (Burkitt, 1971) is of little practical impor- tance. Bile acids are conjugated with the amino-acids glycine and taurine.

Much is known about the bile salt pool in man. The enterohepatic cir- culation of the primary bile salts vary. Chenodeoxycholic acid is absorbed at double the rate of cholic acid (Vlahcenic et al., 1971). This may have therapeutic implications as by increasing the bowel transit time by the

114 IRISH JOURNAL OF MEDICAL SCIENCE--SUPPLEMENT, JULY 1974

addition of bran to the diet, the proportions of cholic acid to chenodeoxy- cholic acid can be changed in the total bile salt pool and thus changing a lithogenic bile to a non-lithogenic bile (Pomare and Heaton, 1973).

Cholesterol SolubiUty Cholesterol solubility in bile is determined by the ratio of cholesterol to

bile acids and phospholipids. A popular and elegant method of showing these three components is to plot them in triangular co-ordinates (Admirand and Small, 1968), using this method any single bile sample can be plotted as an individual point on the graph. Using a diagram of this nature the relative quantities of cholesterol, phospholipids and bile salts in milli-moles per litre are expressed as a percentage of the total amount of the three components. Using this method there is a small area in the bottom left hand corner of the triangle known as the micellar zone and points under this curved line are under-satured with cholesterol and those above the line are super-saturated representing lithogenic bile. A true solubility line crossing the micellar zone has been described. It is by manipulating the quality of bile as traced in these triangular diagrams that enables dissolution of gall- stones tO occur.

There are well defined biochemical abnormalities in the bile of patients with cholesterol stones. The liver secretes bile that is saturated with chol- esterol and contains relatively less bile salts and phospholipids. Patients of this type seem to have a complete derangement of lipid metabolism in the liver along with a reduction in size of the bile salt pool and an increased secretion of biliary cholesterol. Patients with pigment stones do not have any abnormality of biliary lipids.

Many patients with lithogenic bile do not form gallstones. Thus many of our older concepts such as gall-bladder stasis, gall bladder infection, the presence of excessive glycoproteins in the gall bladder and other factors must still be implicated in the aetiology of gallstones.

Heaton, influenced by the concepts of Cleave et al. (1969), in a hypoth- esis for the aetiology of gallstones has claimed that the formation of chol- esterol rich gallstones is primarily a metabolic disease in which the liver fails to provide sufficient bile salts to keep cholesterol in solution in the bile and that this is due to the overconsumption in our Western civilisation of refined carbohydratese with a consequent low roughage intake promoting colonic stasis and also with the production of obesity.

This hypothesis is one of great interest and one supported by the known facts at this time. It has a very practical lesson for us all, as if it is correct, the addition of three tablespoonfuls of bran daily to our diet, as advocated by Burkitt, should prevent the formation of gallstones and if already present may even cause their dissolution.

References

Admirand, W. H. and Small, D. M. 1968. The physiochemical basis of cholesterol gallstone formation in man. J. Clin. Invest. 47, 1043.

Bouchier, I. A. D. 1973a. Clinics in Gastroenterology, Ch. 4. The Epidemiolocly of Gallstones and Suggested Aetiology. W. B. Saunders, London. p. 67.

Bouchier, I. A. D. 1973Jb. Clinics in Gastroenterology, Ch. 3. The Biochemistry of Gallstone Formation. W. B. 51aunders, London. p. 49.

CHOLELITHIASIS 115

Burkitt, D. P. 1971. Epidemiology of cancer of the colon and rectum. Cancer 28, 3. Cleare, T. L., Campbell, G. D. and Painter, N. S. 1969. Diabetes, Coronary Thrombosis and

the Saccharine Disease, 2nd Edn. Bristol: Wright. Dean, G. 1972. Annual Report of Medico-Social Research Board. Holland, P. J. D., Warner, S. 1974. Gallstones in analysis of 800 consecutive autopsies.

In press. Pomare, E. W. and Heaton, K. W. 1973. Alteration of bile salt metabolism by dietary fibre

(bran) abstract. British Society of Gastroenterology Meeting, London. Sept. p. 27. Polleston, H. and McNee, J. W. 1929. Diseases of the Liver, Gall Bladder and Bile Ducts.

3rd Edition, London. Macmillan & Co. Sampliner, R. E., Bennett, P. H., Comess, L. J., Rose, F. A. and Burch, T. A. 1970. Gall

bladder disease in Pima Indians. New Eng. J. Med. 283, 1358. Sutor, D. J. and Wooley, S. E. 1971. A statistical survey of the composition of gallstones in

eight countries. Gut 12, 55. Thudichum, J. L. W. 1863. Treatise on Gallstones; their Chemistry, Pathology and Treatment.

London, Churchill. Vlahcenic, Z. R., Millen, J. R., Farrar, J. T. and Swell, L. 1971. Kinetics and pool size of

primary bile acids in man. Gastroenterology, 61, 85. Womack, N. A., Zeppa, R. and Irvine, G. L. 1963. Anatomy of gallstones. Ann Surg. 157,

670.

CHAIRMAN Now Dr. Hermon Dowl ing is going to tel l us about gal ls tone dissolut ion.

THE GOOSE THAT LAID THE GOLDEN BILE: GALLSTONE DISSOLUTION IN MAN WITH CHENODEOXYCHOLIC ACID *

R. Hermon Dowling t

Department of Medicine, Royal Postgraduate Medical School, London, W.12.

Introduction

E LECTIVE cholecystectomy is a safe operat ion and in the vast major i ty of pat ients, once the ga l lb ladder has been removed, p rob lems due to gal l- stones, such as cholecyst i t is , b i l ia ry col ic, obst ruc t ive jaund ice and

assoc iated pancreat i t is , are over. However, as with any abdomina l opera- t ion, removal of the ga l lb ladder does car ry a s l ight r isk and the overal l mor ta l i ty f rom this operat ion is p robab ly st i l l around 0.5 per cent. The reported preva lence of ga l ls tones var ies cons iderab ly and in a recent rev iew of nine di f ferent papers from western ised countr ies, the inc idence of gal l- stones found at autopsy var ied f rom 6.3 to 44 per cent with a mean of 19.4 per cent (Zahor et al., 1974). At a conservat ive est imate, therefore, if one assumes a preva lence f igure of 10 per cent, at any one t ime there must be approx imate ly 400,000 people in I reland with gal ls tones. Many of these

1" Present address : Gastroenterology Unit, Department of Medicine, Guy's Hospital Medical School, London, SEI 9RT.

* Different aspects of this subject have also been reviewed recently elsewhere (Dowling, R. H., 1973, "The dissolution of gallstones" in the 9th Symposium on Advanced Medicine, Ed. G. Walker, Pitman Medical).