SURGICAL JAUNDICEASPECTS OF PATHOGENESIS AND DIAGNOSIS

H. D. RITCHIE Ch.M., F.R.C.S., F.R.C.S.Ed.Professor of Surgery, The London Hospital

A DISPASSIONATE REVIEW of our attempts during the past hundred yearsto understand the problems of obstructive jaundice might well reachsome rather embarrassing conclusions. This is particularly so with re-gard to the pathogenesis and diagnosis of the condition, to which I shallconfine my remarks here.Try as they did, many contributors in these fields seem to have

been unable to avoid retarding progress. Perhaps the first major detourarose from the work of Ehrlich and van den Bergh. In 18831 the formershowed that bilirubin could be divided into 'indirect' and 'direct' typeson the basis of the diazo reaction. In 19002 the azo-bilirubin compoundwas first isolated and studied chemically and spectroscopically byProscher, and from these in 1918 van den Bergh3 was able to elaboratehis famous test, which was totally to supersede its less sensitive Gmelinand Salkowski equivalents.

This led to Barron and Bumstead's classical experiments in 19284which showed that during the first few hours of biliary obstructionthe van den Bergh test on the blood gave an 'indirect' reaction. Thiswas followed by the famous 'biphasic response' and some hours laterthe reading became 'direct'. To find an explanation for this rapidlychanging picture challenged the ingenuity of some of the most eminentauthorities. For my part I can well remember as an undergraduatebefore my final examinations in Edinburgh struggling but failing tomaster the explanations available.The main problem arose from what we might call the van den Bergh

hypothesis, although he did not himself elaborate it as such, that onlybilirubin which has passed through the liver cell and been secretedinto the bile gives the 'direct' reaction. Much confusion stemmed fromthis in the clinical situation, and when significant amounts of the pig-ment present in the blood during what seemed to be a medical jaundicewere found to be direct-reacting, the diagnosis was sometimesjeopardized.

It was not until the work of Cole, Lathe, and Billing in 19545 thatany clear idea of the reason for this began to emerge. They showedThe 25th Simpson Smith Lecture, West London Hospital

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that it was possible by chromatography to separate direct-reacting bili-rubin into two distinct moieties, which they designated pigment I andpigment II. In 1955 Billing6' 7 found that both pigments accumulatedin the serum in obstructive jaundice and in 1956 Billing and Lathe8showed that pigment II constituted most of the bilirubin in freshhuman bile.

It then only remained for Bollman and Hoffman in 1957 to demon-strate that after hepatectomy direct-reacting pigment I accumulated inthe serum, and the mystery was cleared up. Obviously a direct-reacting

HoursFig. 1. Bilirubin concentrations in blood and lymph before and after ob-

struction of the common bile duct following cholecystectomy.

pigment could be made in the body which had not traversed the liverand been excreted in the bile. Thus at last the 'van den Bergh hypo-thesis' was laid to rest and we could move on.

In the meantime, however, a further obstacle was encountered. It wasin 1930 that Rich9 had published his celebrated paper on 'The Patho-genesis of the Forms of Jaundice'. In this he reviewed the availableevidence and attempted a classification of jaundice on the basis ofwhether or not the pigment responsible for the icterus had been ex-creted into the biliary tree. Of the van den Bergh test he wrote, 'I shallnot enter into a description of this now well-known test other than tomention that when it is applied to bilirubin which has not yet passed

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through the liver cells there occurs a delayed, or so-called indirectreaction; whereas, in contrast, bilirubin taken from the bile ducts orfrom the gall bladder or that regurgitated into the blood from thebile canaliculi, gives a prompt or direct reaction'. This seems tohave been the first use of the word 'regurgitation', in this sense, inthe literature. He took the view that when the van den Bergh test onthe plasma gave the direct reaction this indicated that whole bile con-taining bile acids and cholesterol, as well as bilirubin, had beenregurgitated from the biliary tree into liver lymph and the blood stream.

This explanation seemed admirably to fit the observed facts and wasto hold sway for more than 30 years. It contains two major premises.First that during the course of bile duct obstruction secretion of formed

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Fig. 2. Secretion of bromsulphalein into the bile during obstruction of thecommon bile duct.

bile into the biliary tree continues unchecked. Secondly that it is thenregurgitated or 'vomited back' into the lymph or blood. He went on toelaborate his subdivision of jaundice into two main types, calling thatvariety which results from a primary failure of the liver cells to secretebilirubin into the ducts 'retention' jaundice and that which he believedto be due to passage of formed bile from the biliary tree back into the

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lymph and blood 'regurgitation' jaundice. He did not himself offer anyexperimental evidence for these views.

Thirty years later, however, studies during bile duct obstructionshowed a different situation10. It can be seen from Figure 1 that after24 hours of obstruction all evidence of 'regurgitation', into the fymph atleast, has disappeared. But what of secretion into the biliary tree duringthis latter period? Serial analysis of pent-up bile where biliary obstruc-tion had been present for several days gave the required information.When bromsulphalein, which is handled by the liver in much the sameway as bilirubin, is used as a tracer none of it can be found in bilefrom the biliary tree once obstruction has been present for a day ortwo (Fig. 2).And so we now know that during biliary obstruction a short phase

of 'regurgitation' lasting 24 hours ensues, but only in the absence of afunctioning gallbladder. Thereafter and throughout the period of ob-struction secretion of bile into the biliary tree does not apparentlyoccur. Thus in its turn the 'regurgitation' hypothesis of Rich was foundto be suspect and we had to return to the drawing board as it were,to re-think how we should now subdivide jaundice.

Classifications of jaundice abound in the literature. Some have serveda useful purpose, others have not. Table I shows four of the best knownof these. The pathological classification of McNee in the top left-handcorner is still widely used and serves to remind particularly theundergraduate of the main causes. It is, however, in difficulty when, forexample, the cholestatic variety of viral hepatitis is being considered.

TABLE ITYPES OF JAUNDICE

McNee RichHaemolytic "Retention"Toxic or infective "Regurgitation"Obstructive

N. AmericanPrehepatic MedicalHepatic SurgicalPosthepatic

Most surgeons now tend to approach the problem by asking whetherthese people need an operation or not. The simplicity of the NorthAmerican classification speaks for itself and, for the surgeon, it is per-haps to be preferred to its predecessors because of the emphasis it putson therapy. Here again, however, we have met with waming signs.Alarming reports of the dangers of mistakenly operating on patientswhose jaundice is due to viral hepatitis appeared in the literature. Shal-don and Sherlock in 195711, Datta et al. in 196312 and Turner andSherlock in 196413 painted a grim picture of the outcome. The latter re-

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ported a personal experience of 12 patients of whom 5 died within 4weeks of operation, while 4 of the remainder had a protracted illnesswith ascites. They gave no further details. As a substitute for surgeryin cases where the diagnosis was in doubt they have advised a sort of'medical laparotomy' employing the steroid diagnostic test, liver biopsy,or percutaneous cholangiography on the grounds that these proceduresare safer.

These strictures prompted an analysis of the results of surgery injaundiced cases at The London Hospital. We tried to ascertain howmany 'mistaken laparotomies' our surgeons had been making for jaun-dice and how many patients were in fact having operations during anattack of viral hepatitis. Of 152 laparotomies for jaundice performedduring the 5-year period studied, 3 (2%) were 'mistaken'. The jaundicewas due to viral hepatitis in 2 of these cases and to a drug in one. All3 patients survived (Table II).

Similarly, in a much larger series published in 1963 by Harville andSummerskill14 from the Mayo Clinic the jaundice was found to bemedical in origin in 1.7% of cases. The mortality in this series fromoperating in the presence of hepatocellular disease can be calculated

TABLE IICOMPARATIVE MORTALITY FROM "MISTAKEN" LAPAROTOMY AND PERCUTANEOUS

LIVER BIOPSYMortality from "mistaken" laparotomy Mortality from percutaneous liver

for jaundice biopsy (Zamcheck &London Hospital Mayo Clinic14 Klausenstock15).

(1961-1965) (1950-1961)NIL 0.14% 0.17%

to have been 0.14% of 2,800 laparotomies in jaundiced patients (TableII). This may be compared with a mortality of 0.17% in 20,000 liverbiopsies on anicteric patients reported by Zamchek and Klausenstock'5in 1953, this being one of the procedures advocated to avoid the risksof surgical laparotomy. These authors noted that the risk of liver biopsywas higher in jaundiced patients and this has been our experience.

Thus it became clear that in cases where the diagnosis continued tobe in doubt timely laparotomy was to be preferred to most of theinvestigative extravaganzas which had been developed to avoid it. Inour experience the risks of procrastination may be as great as those ofundue urgency. If after 5-6 weeks of jaundice the diagnosis has notbecome clear we believe that laparotomy is indicated.

But how are we to diagnose a surgical jaundice earlier than this?Our experience with percutaneous cholangiography had not suggestedthat it was free from risk. The method consists in introducing a longneedle through the skin into the liver in an attempt to puncture a dilated

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duct. If this is done bile is aspirated and radio-opaque dye injected.The only lesion which can be identified with certainty by this techniqueis an extrahepatic obstruction'6. It cannot finally exclude this,14' 17, 18since if the needle fails to enter a duct nothing is seen on subsequentradiology. Biliary peritonitis and haemoperitoneum may follow theprocedure"9, 20. That most people using the technique have a surgeonstanding by to perform laparotomy may be regarded as testimony tothe general awareness of these hazards.Our search for a less risky method has led us to use a combination

of tests performed by passing a tube through the mouth into the duo-denum. This enables us to test pancreatic function, look in the duodenaljuice for neoplastic cells, and finally to have a duodenogram carried outby the radiologist. As in all investigative work of this type we find thatexperienced nursing personnel achieve the best cooperation from thepatients and the most reliable results from the tests. I should like hereto recognize the work done by two London Hospital Sisters, Sister MissKeenan and Sister Mrs. Barrah, who do these tests in our Gastro-intestinal Investigation Unit.We have performed some 300 of these tests and find them a useful

adjunct to the early diagnosis of lesions in the pancreas or duodenumor at the ampulla. They will not, however, demonstrate stones in thecommon bile duct or a high bile duct carcinoma, although occasionallycell cytology may reveal this. In jaundiced patients they seem to be par-ticularly helpful. During a 3-year period recently we have had theopportunity to study 75 patients21. The diagnosis in these cases wasconfirmed at operation or from the subsequent clinical course, whichnow extends from 1 to 3 years. If the surgeon had accepted the find-ings of these tests, laparotomy would have been indicated in 40 ofthese patients. This would have been correct in 39. In the 40th patientintrahepatic secondaries from a previously excised colonic carcinomawere present. In the remaining 35 patients no evidence of a lesion in thepancreas or duodenum or at the ampulla was demonstrated. Here againwith one exception the combined findings of the three tests were cor-rect. A carcinoma near the neck of the pancreas obstructing the commonbile duct was missed. In fact, in this series of 75 patients all but oneof the carcinomas of the pancreas and all the ampullary tumours werediagnosed by the tests (Table III).

TABLE IIITRIPLE TEST FINDINGS IN 75 JAUNDICED PATIENTS

1. All but one of the carcinomas of the pancreas (29) and all ampullarytumours were diagnosed by the tests.

2. No case of 'medical' jaundice gave a positive result.3. Tests do not demonstrate:

stones in the common bile duct.high bile duct neoplasms.

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We must bear in mind, however, that while these tests may helpus to avoid laparotomy in medical jaundice they do not solve all ourproblems in the diagnosis of obstructive jaundice. They will not demon-strate stones in the common bile duct or high bile duct neoplasms, buthere the need for early operation is perhaps less.

This then would appear to be a safe method of expediting the diag-nosis of certain types of jaundice. But many problems remain. So oftenin jaundice due to panpreatic carcinoma, for example, the surgeon findsthe lesion too far advanced to be able to do more than a palliativeoperation.

In reviewing the whole field, however, we may be reassured by theknowledge that once more we are moving forward, and in the wordsof Horace: 'Quad optanti divom promittere nemo auderet volvendadies en attulit ultro'-'What no one of the Gods would dare to promisein answer to our prayers-lo, time itself as it rolls its course, has ac-complished for us' !

REFERENCES1. EHRLICH, P. (1883) Quoted by van den Bergh (ref. 3).2. PROSCHER, -. (1900) Quoted by van den Bergh (ref. 3).3. VAN DEN BERGH, H. A. (1918). Die Gallenfarbstoffim Blute. Leiden, van Doesburgh.4. BARRON, E. S. G., and BUMSTEAD, J. H. (1928) J. exp. Med., 47,999.5. COLE, P. G., LATHE, G. H., and BILLING, B. H. (1954) Biochem. J., 57, 514.6. BILLING, B. H. (1955) J. clin. Path. 8, 126.7. BILLING, B. H. (1955) J. clin. Path.. 8, 130.8. BILLING, B. H., and LATHE, G. H. (1956) Biochem. J., 63, vi.9. RICH, A. R. (1930) Johns Hopk. Hosp. Bull., 47, 338.

10. RITCHIE, H. D. (1959). Ch.M. Thesis University of Edinburgh.11. SHALDON, S., and SHERLOCK, S. (1957) Brit. med. J., 2, 734.12. DATTA, D. V., SHERLOCK, S., and SCHEUER, P. J. (1963) Gut, 4, 223.13. TURNER, M. D., and SHERLOCK, S. (1964). In Surgery of the Gall Bladder and Bile Ducts, ed. R. Smith

and S. Sherlock. London, Butterworths.14. HARVILLE, D. D., and SUMMERSKILL, W. H. J. (1963) J. Amer. med. Ass., 194,257.15. ZAMCHEK, M., and KLAUSENSTOCK, 0. (1953). New Engl. J. Med., 249, 1062.16. GEORGE, P., YOUNG, W. B., WALKER J. G., and SHERLOCK, S. (1965) Brit. J. Surg., 52, 779.17. GEORGE, P. (1966). In Postgraduate Gastroenterology, ed. T. J. Thompson and I. E. Gillespie. London,

Bailli6re.18. THORBJARNARSON, B. (1967) Surgery, 61, 347.19. GLENN, F., EVANS, J. A., MUJAHED, Z., and THORBJARNARSON, B. (1962) Ann. Surg., 156, 451.20. THORBJARNARSON, B., MUJAHED, Z., and GLENN, F. (1967) Ann. Surg., 165, 33.21. BOURKE, J. B., SWANN, J. C., BROWN, C. L., and RITCHIE, H. D. (1972) Lancet, 1, 605.

HAMILTON BAILEY PRIZEAPPLICATIONS ARE NOW invited by the British Section of the International Col-lege of Surgeons for the third Hamilton Bailey Prize. This is a travellingscholarship worth 750, and consultants or senior registrars in surgery, radiology,or anaesthetics may apply. Applications should be sent to the Secretary of theBritish Section, Royal Northern Hospital, Holloway Road, London, N.7, notlater than 31st May 1973.

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