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The Prophylactic Portacaval Shunt
999
THE LANCET The
Prophylactic Portacaval Shunt
BLEEDING from
oesophageal
varices is the most
horrific of emergencies facing the patient with
portal hypertension. Its onset can never be predicted, and it can happen out of the blue, at the most inopportune moment. The haemorrhage is almost always large, necessitating emergency admission to hospital and transfusion of an average of 1 11 units (pints) of blood, and even up to 52 pints. Moreover, if the bleeding cannot be controlled, emergency operation carries a very high mortality. It is not surprising, therefore, that much thought has been given to preventing this catastrophe. This might be achieved by the operation of portacaval anastomosis, in which the high-pressure portal venous system is joined to the low-pressure inferior vena caval one, usually end-to-side, but sometimes side-to-side. The portal hypertension is thus relieved. The operation is technically difficult, and even in experienced hands, and when performed electively, it carries a mortality of about 10-15%. In a series of elective portacaval anastomoses done at the Royal Free Hospital, London, after a bleed from oesophageal varices, the early postoperative death-rate was 12-5% and the five-year survival 65%. Those who survived with a patent shunt did not bleed subsequently from oesophageal varices. The mortality depends on the state of the patient - the good-risk patient has an operative mortality of 6-9%, and the poor-risk one has a mortality of 50%.2,3It is clear, therefore, that, particularly in the good-risk patient, the operation offers a reasonable chance of success with an acceptable risk. Why should it not be recommended as a prophylactic procedure, before the patient has had the terrifying experience of the first haemorrhage ? Hitherto the answer has not been clear. The chances of a patient with oesophageal varices ever having a bleed are uncertain. One group suggests that
an
initial hsemor-
rhage from varices may be anticipated in a fifth of patients with cirrhosis and portal hypertension who have not bled previously and are followed up for average of 42 months.5 A quarter of such patients will die from the variceal haemorrhage. What are the most serious long-term major complications of the operation ? The answer to this question is all too clear. 38% of patients who had elective operations at the Royal Free Hospital suban
1. 2.
Sherlock, S., Alpert, L. Proc. R. Soc. Med. 1965, 58, 257. Hourigan, K., Sherlock, S., George, P., Mindel, S. Br. med. J. 1971, iv, 473. 3. Brown, G. J. A., Walker, R. M. Lancet, 1967, ii, 854. 4. McDermott, W. V., Jr., Palazzi, H., Nardi, G. L., Mondet, A. New Engl. J. Med. 1961, 264, 419. 5. Jackson, F. C., Perrin, E. B., Smith, A. G., Dagradi, A. E., Nadal, H. M. Am. J. Surg. 1968, 115, 22.
sequently developed a chronic severe portal systemic encephalopathy.2 This agrees with results of previous series from the United Kingdom,6 but it is more than the 20% reported from the United The United States patients, however, States.7 mostly had liver disease of the alcoholic, and such patients are less likely to develop postoperative hepatic encephalopathy, provided that they abstain 2 from alcohol. There have now been reports of four prospective controlled trials of prophylactic portacaval shunting for relief of portal hypertension in patients with cirrhosis.5,8-1o In 1968, JACKSON and co-workers5 published the results of a cooperative investigation conducted at twelve Veterans Administration hospitals in the United States. The 112 patients were male and mostly had cirrhosis of the alcoholic. All had proven oesophageal varices. They were randomised into 58 who were medically treated and 54 who received a portacaval anastomosis. In 1969, RESNICK and the Boston Inter-Hospital Liver Group8 reported 93 patients of similar type to those described by JACKSON et al.: 48 had a surgical portacaval anastomosis and 45 were treated medically. Finally, CONN and his co-workers from Yale, in two papers, cover the results in 170 patients studied over thirteen
years.9,10o JACKSON
and his group concluded that the operation did not prolong survival.5 This was also the view of RESNICK and his co-workers.8 The group from Yale,9,10 on the basis of an extremely comprehensive investigation, found that, in fact, the overall cumulative mortality-rate was slightly greater in the patients who had a prophylactic portacaval anastomosis than in those who did not. All, however, agreed that the mortality from variceal haemorrhage in the patients operated on became almost nonexistent. This was confirmed by objective evidence such as disappearance of oesophageal varices postoperatively, as viewed by endoscopy or by radiology. The deaths in the Yale patients were largely due to hepatic failure. The patients died some 3-5 years after the shunt, whether they had the end-to-side or side-to-side variety. Other effects were seen in the shunted compared with the control group. Haemosiderosis is generally believed to follow portacaval anastomosis, and this was confirmed in the Yale trial. A careful investigation based on comparison of iron stores in liver-biopsy specimens taken before and at the conclusion of the trial showed that haemo6. Read, A. E., Laidlaw, J., Sherlock, S. Lancet, 1961, i, 961. 7. Grace, N. D., Muench, H., Chalmers, T. C. Gastroenterology, 1966, 50, 684. 8. Resnick, R. H., Chalmers, T. C., Ishihara, A. M., Garceau, A. J., Callow, A. D., Schimmel, E. M., O’Hara, E. T., and the Boston Inter-Hospital Liver Group. Ann. intern. Med. 1969, 70, 675. 9. Conn, H. O., Lindenmuth, W. W. New Engl. J. Med. 1968, 279, 725. 10. Conn, H. O., Lindenmuth, W. W., May, C. J., Ramsby, G. R. Medicine, Baltimore, 1972, 51, 27. 11. Williams, R., Williams, H. S., Scheuer, P. J., Pitcher, C. S., Loiseau, E., Sherlock, S. Q. Jl Med. 1967, 36, 151.
1000
siderosis was more common in the shunted patients.12 The full-blown clinical picture of hsemochromatosis was not seen. More of the shunted patients became diabetic, but the difference between them and the controls was not statistically significant.10 Ascites in a patient with cirrhosis depends partly on increases in portal venous pressure, and therefore would be expected to resolve after a successful portacaval shunt. This was suggested by the Boston trial,88 although differences were not statistically significant. As
expected, hepatic encephalopathy was a major complication after shunting.10 29% of the unshunted had episodic hepatic coma compared with 45% of those with portacaval anastomosis. These episodes accounted to a great extent for the increased number of hospital admissions in the shunted group. 10 The more serious chronic recurrent spontaneous portal-systemic encephalopathy was much more frequent in the shunted, occurring in 19%. The quality of life, particularly the intellectual aspects, in these patients was greatly reduced. The results of these carefully conducted controlled trials of portacaval shunting as a prophylactic procedure are extremely disappointing, as the authors of these four important papers recognise. How may the results be improved ? Better selection of patients will probably prove only partly effective. The trials so far reported largely concern urban, alcoholic, Americans of low socioeconomic status. The incidence of encephalopathy, however, is as high-if not higher-in a United Kingdom series of largely non-alcoholic patients of higher socioeconomic status, having elective shunts after a proven serious variceal haemorrhage.6 Accurate prediction of which patient with oesophageal varices will bleed, and how soon, might make the operation more justifiable. Such soothsaying has proved impossible, although ascites (or a history of it) has been regarded as -a good indication that haemorrhage is imminent.l0 Deaths after portacaval shunt are mostly due to hepatocellular failure. After the operation hepatic blood-flow is reduced,13 and this must be a major factor in the’ultimate liver failure. Operations must be devised which will lower portal blood-pressure but maintain perfusion of the liver with blood. Operations have been devised, such as anastomosis of the portal vein with an artery,14 but none has achieved practical application as a clinical procedure. In the meantime-faute de mieux-clinicians recommend end-to-side portacaval anastomosis for the elective management of portal hypertension in a youngish patient with established well-compensated cirrhosis who has previously bled from oesophageal varices, even though the results as a whole are dis12. Conn, H. O. Gastroenterology, 1972, 62, 61. 13. Redeker, A. G., Geller, H. M., Reynolds, T. B. J. clin. Invest. 1958, 37, 606. 14. Maillard, J. N., Benhamou, J.-P., Rueff, B. Surgery, St. Louis, 1970, 67, 883.
appointing.2 On the basis of the controlled trials done so far, portacaval anastomosis is not useful as a prophylactic procedure. Hormone and Vitamin D BETWEEN administration of vitamin D to deficient animals and an increase in intestinal absorption of calcium there is a 12-24-hour delay." At first this lag was attributed to the gut rather than to the time
Parathyroid
required for conversion of vitamin D to an active form. But DELucA’s group in Wisconsin 16 found that at least part of the explanation is that vitamin D is converted in the liver to a more polar metabolite, 25-hydroxycholecalciferol (25-H.c.c.), which is now thought to be the main circulating form of the vitamin. For some time it was also regarded as the final active form on bone and gut as well. But this is incorrect. Several metabolites 17,18 of 25-H.c.c. were soon recognised, and one, 1,25-dihydroxycholecalciferol (1,25-D.H.C.C.)19,20 is much more potent and acts more rapidly than the others.21,22 Further, KODICEK and his team 23 at Cambridge had made an important and unexpected discovery: they found that the kidney is the sole site of hydroxylation of 25-H.c.c. to 1,25-D.H.c.c. Thus the kidney can be regarded as an endocrine organ which secretes a highly active hormone which regulates calcium transfer by the gut and the bone. This view is strengthened by further work from the Wisconsin team,24 in which they examined the effects of high and low calcium diets on the metabolism of 25-H.c.c. in D-deficient rats. On the low-calcium diet, 1,25D.H.C.C. was maximally produced, but rats on the high-calcium diet converted the 25-H.c.c. to 21,25D.H.C.C., a metabolite much less active on bone and gut. If such a mechanism operated in man it would provide a means of adaptation to different calcium intakes. BOYLE and his co-workers 24 believed that the changes in serum-calcium on the different diets in their experiment were the probable determining factors. But close inspection of their data shows that this conclusion is much less well substantiated, although it remains a plausible suggestion. MAcINTYRE and his colleagues at the Royal Postgraduate Medical School have now added a further 15. Schachter, D., Kimberg, D. V., Shenker, H. Am. J. Physiol. 1961,
200, 1263. Blunt, J. W., DeLuca, H. F., Schnoes, H. K. Biochemistry, 1968, 7, 3317. 17. Lawson, D. E. M., Wilson, P. W., Kodicek, E. Biochem. J. 1969, 115, 269. 18. Cousins, R. J., DeLuca, H. F., Gray, R. W. Biochemistry, 1970, 9, 16.
3649. 19. Lawson, D. E. M., Fraser, D. R., Kodicek, E., Morris, H. R., Williams, D. H. Nature, 1971, 230, 228 20. Holick, M. F., Schnoes, H. K., DeLuca, H. F. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 803. 21. Myrtle, J. F., Norman, A. W. Science, 1971, 171, 79. 22. Haussler, M. R., Boyce, D. W., Littledike, E. T., Rasmussen, H. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 177. 23. Fraser, D. R., Kodicek, E. Nature, 1970, 228, 764. 24. Boyle, I. T., Gray, R. W., DeLuca, H. F. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 2131.
THE LANCET The
Prophylactic Portacaval Shunt
BLEEDING from
oesophageal
varices is the most
horrific of emergencies facing the patient with
portal hypertension. Its onset can never be predicted, and it can happen out of the blue, at the most inopportune moment. The haemorrhage is almost always large, necessitating emergency admission to hospital and transfusion of an average of 1 11 units (pints) of blood, and even up to 52 pints. Moreover, if the bleeding cannot be controlled, emergency operation carries a very high mortality. It is not surprising, therefore, that much thought has been given to preventing this catastrophe. This might be achieved by the operation of portacaval anastomosis, in which the high-pressure portal venous system is joined to the low-pressure inferior vena caval one, usually end-to-side, but sometimes side-to-side. The portal hypertension is thus relieved. The operation is technically difficult, and even in experienced hands, and when performed electively, it carries a mortality of about 10-15%. In a series of elective portacaval anastomoses done at the Royal Free Hospital, London, after a bleed from oesophageal varices, the early postoperative death-rate was 12-5% and the five-year survival 65%. Those who survived with a patent shunt did not bleed subsequently from oesophageal varices. The mortality depends on the state of the patient - the good-risk patient has an operative mortality of 6-9%, and the poor-risk one has a mortality of 50%.2,3It is clear, therefore, that, particularly in the good-risk patient, the operation offers a reasonable chance of success with an acceptable risk. Why should it not be recommended as a prophylactic procedure, before the patient has had the terrifying experience of the first haemorrhage ? Hitherto the answer has not been clear. The chances of a patient with oesophageal varices ever having a bleed are uncertain. One group suggests that
an
initial hsemor-
rhage from varices may be anticipated in a fifth of patients with cirrhosis and portal hypertension who have not bled previously and are followed up for average of 42 months.5 A quarter of such patients will die from the variceal haemorrhage. What are the most serious long-term major complications of the operation ? The answer to this question is all too clear. 38% of patients who had elective operations at the Royal Free Hospital suban
1. 2.
Sherlock, S., Alpert, L. Proc. R. Soc. Med. 1965, 58, 257. Hourigan, K., Sherlock, S., George, P., Mindel, S. Br. med. J. 1971, iv, 473. 3. Brown, G. J. A., Walker, R. M. Lancet, 1967, ii, 854. 4. McDermott, W. V., Jr., Palazzi, H., Nardi, G. L., Mondet, A. New Engl. J. Med. 1961, 264, 419. 5. Jackson, F. C., Perrin, E. B., Smith, A. G., Dagradi, A. E., Nadal, H. M. Am. J. Surg. 1968, 115, 22.
sequently developed a chronic severe portal systemic encephalopathy.2 This agrees with results of previous series from the United Kingdom,6 but it is more than the 20% reported from the United The United States patients, however, States.7 mostly had liver disease of the alcoholic, and such patients are less likely to develop postoperative hepatic encephalopathy, provided that they abstain 2 from alcohol. There have now been reports of four prospective controlled trials of prophylactic portacaval shunting for relief of portal hypertension in patients with cirrhosis.5,8-1o In 1968, JACKSON and co-workers5 published the results of a cooperative investigation conducted at twelve Veterans Administration hospitals in the United States. The 112 patients were male and mostly had cirrhosis of the alcoholic. All had proven oesophageal varices. They were randomised into 58 who were medically treated and 54 who received a portacaval anastomosis. In 1969, RESNICK and the Boston Inter-Hospital Liver Group8 reported 93 patients of similar type to those described by JACKSON et al.: 48 had a surgical portacaval anastomosis and 45 were treated medically. Finally, CONN and his co-workers from Yale, in two papers, cover the results in 170 patients studied over thirteen
years.9,10o JACKSON
and his group concluded that the operation did not prolong survival.5 This was also the view of RESNICK and his co-workers.8 The group from Yale,9,10 on the basis of an extremely comprehensive investigation, found that, in fact, the overall cumulative mortality-rate was slightly greater in the patients who had a prophylactic portacaval anastomosis than in those who did not. All, however, agreed that the mortality from variceal haemorrhage in the patients operated on became almost nonexistent. This was confirmed by objective evidence such as disappearance of oesophageal varices postoperatively, as viewed by endoscopy or by radiology. The deaths in the Yale patients were largely due to hepatic failure. The patients died some 3-5 years after the shunt, whether they had the end-to-side or side-to-side variety. Other effects were seen in the shunted compared with the control group. Haemosiderosis is generally believed to follow portacaval anastomosis, and this was confirmed in the Yale trial. A careful investigation based on comparison of iron stores in liver-biopsy specimens taken before and at the conclusion of the trial showed that haemo6. Read, A. E., Laidlaw, J., Sherlock, S. Lancet, 1961, i, 961. 7. Grace, N. D., Muench, H., Chalmers, T. C. Gastroenterology, 1966, 50, 684. 8. Resnick, R. H., Chalmers, T. C., Ishihara, A. M., Garceau, A. J., Callow, A. D., Schimmel, E. M., O’Hara, E. T., and the Boston Inter-Hospital Liver Group. Ann. intern. Med. 1969, 70, 675. 9. Conn, H. O., Lindenmuth, W. W. New Engl. J. Med. 1968, 279, 725. 10. Conn, H. O., Lindenmuth, W. W., May, C. J., Ramsby, G. R. Medicine, Baltimore, 1972, 51, 27. 11. Williams, R., Williams, H. S., Scheuer, P. J., Pitcher, C. S., Loiseau, E., Sherlock, S. Q. Jl Med. 1967, 36, 151.
1000
siderosis was more common in the shunted patients.12 The full-blown clinical picture of hsemochromatosis was not seen. More of the shunted patients became diabetic, but the difference between them and the controls was not statistically significant.10 Ascites in a patient with cirrhosis depends partly on increases in portal venous pressure, and therefore would be expected to resolve after a successful portacaval shunt. This was suggested by the Boston trial,88 although differences were not statistically significant. As
expected, hepatic encephalopathy was a major complication after shunting.10 29% of the unshunted had episodic hepatic coma compared with 45% of those with portacaval anastomosis. These episodes accounted to a great extent for the increased number of hospital admissions in the shunted group. 10 The more serious chronic recurrent spontaneous portal-systemic encephalopathy was much more frequent in the shunted, occurring in 19%. The quality of life, particularly the intellectual aspects, in these patients was greatly reduced. The results of these carefully conducted controlled trials of portacaval shunting as a prophylactic procedure are extremely disappointing, as the authors of these four important papers recognise. How may the results be improved ? Better selection of patients will probably prove only partly effective. The trials so far reported largely concern urban, alcoholic, Americans of low socioeconomic status. The incidence of encephalopathy, however, is as high-if not higher-in a United Kingdom series of largely non-alcoholic patients of higher socioeconomic status, having elective shunts after a proven serious variceal haemorrhage.6 Accurate prediction of which patient with oesophageal varices will bleed, and how soon, might make the operation more justifiable. Such soothsaying has proved impossible, although ascites (or a history of it) has been regarded as -a good indication that haemorrhage is imminent.l0 Deaths after portacaval shunt are mostly due to hepatocellular failure. After the operation hepatic blood-flow is reduced,13 and this must be a major factor in the’ultimate liver failure. Operations must be devised which will lower portal blood-pressure but maintain perfusion of the liver with blood. Operations have been devised, such as anastomosis of the portal vein with an artery,14 but none has achieved practical application as a clinical procedure. In the meantime-faute de mieux-clinicians recommend end-to-side portacaval anastomosis for the elective management of portal hypertension in a youngish patient with established well-compensated cirrhosis who has previously bled from oesophageal varices, even though the results as a whole are dis12. Conn, H. O. Gastroenterology, 1972, 62, 61. 13. Redeker, A. G., Geller, H. M., Reynolds, T. B. J. clin. Invest. 1958, 37, 606. 14. Maillard, J. N., Benhamou, J.-P., Rueff, B. Surgery, St. Louis, 1970, 67, 883.
appointing.2 On the basis of the controlled trials done so far, portacaval anastomosis is not useful as a prophylactic procedure. Hormone and Vitamin D BETWEEN administration of vitamin D to deficient animals and an increase in intestinal absorption of calcium there is a 12-24-hour delay." At first this lag was attributed to the gut rather than to the time
Parathyroid
required for conversion of vitamin D to an active form. But DELucA’s group in Wisconsin 16 found that at least part of the explanation is that vitamin D is converted in the liver to a more polar metabolite, 25-hydroxycholecalciferol (25-H.c.c.), which is now thought to be the main circulating form of the vitamin. For some time it was also regarded as the final active form on bone and gut as well. But this is incorrect. Several metabolites 17,18 of 25-H.c.c. were soon recognised, and one, 1,25-dihydroxycholecalciferol (1,25-D.H.C.C.)19,20 is much more potent and acts more rapidly than the others.21,22 Further, KODICEK and his team 23 at Cambridge had made an important and unexpected discovery: they found that the kidney is the sole site of hydroxylation of 25-H.c.c. to 1,25-D.H.c.c. Thus the kidney can be regarded as an endocrine organ which secretes a highly active hormone which regulates calcium transfer by the gut and the bone. This view is strengthened by further work from the Wisconsin team,24 in which they examined the effects of high and low calcium diets on the metabolism of 25-H.c.c. in D-deficient rats. On the low-calcium diet, 1,25D.H.C.C. was maximally produced, but rats on the high-calcium diet converted the 25-H.c.c. to 21,25D.H.C.C., a metabolite much less active on bone and gut. If such a mechanism operated in man it would provide a means of adaptation to different calcium intakes. BOYLE and his co-workers 24 believed that the changes in serum-calcium on the different diets in their experiment were the probable determining factors. But close inspection of their data shows that this conclusion is much less well substantiated, although it remains a plausible suggestion. MAcINTYRE and his colleagues at the Royal Postgraduate Medical School have now added a further 15. Schachter, D., Kimberg, D. V., Shenker, H. Am. J. Physiol. 1961,
200, 1263. Blunt, J. W., DeLuca, H. F., Schnoes, H. K. Biochemistry, 1968, 7, 3317. 17. Lawson, D. E. M., Wilson, P. W., Kodicek, E. Biochem. J. 1969, 115, 269. 18. Cousins, R. J., DeLuca, H. F., Gray, R. W. Biochemistry, 1970, 9, 16.
3649. 19. Lawson, D. E. M., Fraser, D. R., Kodicek, E., Morris, H. R., Williams, D. H. Nature, 1971, 230, 228 20. Holick, M. F., Schnoes, H. K., DeLuca, H. F. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 803. 21. Myrtle, J. F., Norman, A. W. Science, 1971, 171, 79. 22. Haussler, M. R., Boyce, D. W., Littledike, E. T., Rasmussen, H. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 177. 23. Fraser, D. R., Kodicek, E. Nature, 1970, 228, 764. 24. Boyle, I. T., Gray, R. W., DeLuca, H. F. Proc. natn. Acad. Sci. U.S.A. 1971, 68, 2131.