Putnam, CW

Starzl, TE

English

PubMed

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'I. a. .'r. n· ·9. Commentary JAMA THE JOURNAL of the American Medical Association September 1,1975 VOl 233, No9 Portal Diversion ry IS, :-Ie e· ns, Treatment for Glycogen Storage Disease and Hyperlipemia g) n a ·8 i n· d· T 'p ·3 ; PORTAL vein diversion has been used for many years to stop or prevent hemorrhage from esophageal varices or, less commonly, to treat intractable ascites. Since both the bleeding and ascites formation are due, at least in part, to blockage of the splanchnic venous return at or near the liver, the objective has been purely hemodynamic: relieve the obstruction, and the resulting portal venous hyperten-sion will also be relieved. Within the last few years, a new dimension has been added to the old operation of portacaval shunt by employ-ing this procedure to favorably alter the course of patients with two inborn errors of metabolism, glycogen storage disease, and type II hyperlipoproteinemia. We will discuss the potential postoperative risks borne by patients sub-mitted to portal diversion for these new Indications and the probable mechanisms that explain the benefits of por-tacaval shunt-these have been clarified by some recent advances in hepatic physiology. Glycogen Storage Disease The first portal diversion I for hepatic glycogen storage j" disease was performed more than 11 years ago in a girl who is still alive. By short-circuiting splanchnic venous . blood around the liver, it was hoped to make glucose more ~t: readily available to peripheral tissues, and thus to relieve hypoglycemia and coincidentally to deglycogenate the liver and palliate other metabolic derangements such as acidosis. In order to avoid the potential complication of he-patic encephalopathy, which commonly follows portacaval shunt in dogs, the operation of portacaval transposition" was selected, whereby the bypassed portal flow is replaced with venous blood from the suprarenal inferior vena cava. Transposition was also performed by Riddell et al" of Bristol,England, in a boy who is still alive 91h years later. In that patient, the caval-to-portal venous anastomosis clotted' so that the liver was not provided with replace-ment flow as was intended. After a second patient of ours died from complications of the transposition,' the simpler and technically safer operation of end-ta-side portacaval shunt was used in all seven subsequent cases at our cen-From the Department of Surgery. the Veterans Administration Hospital, and the University 01 Colorado Medical Center. Denver. Reprint requests to Department of Surgery. University of Colorado Medi-cal Center. 4200 E Ninth Ave. Denver. CO 80220 (Or. Starzl) .. JAMA. Sept 1. 1975-Vol 233. No 9 ter' and in all cases described elsewhere. Our seven surviv-ors with end-ta-side portacaval shunt have been followed up for periods of from one to three years. The specific enzyme deficiencies in the Colorado cases' were of glucose-6-phosphatase (type I disease) in five pa-tients, amyla-I-6-glucosidase (type III B) in three pa-tients, and phosphorylase (type VI) in one patient. Preop- . eratively, all the children had retardation of growth, and all but the one with type VI disease had episodic hypogly-' cemia and acidosis. After portal diversion, the survivors had accelerated growth, and in all but one the height increase was in a spurt. The preexisting hypoglycemia was not relieved in some children but was variably improved in others. Liver size was either diminished or remained unchanged. In the latter event, the relative degree of hepatomegaly was steadily reduced as body growth occurred, When present, other metabolic abnormalities including secondary hyper-lipemia, hyperuricemia, and platelet dysfunction were usually ameliorated. All other authors who have recorded their experience with portal diversion for glycogen stor-age disease have also emphasized a high degree of pallia-tion in their patients."'" Hyperlipemia In glycogen storage disease the liver is usually pat-ently abnormal mainly because of the accumulation of glycogen, but also because of ·fibrosis, which occurs in a surprisingly high percentage of cases.' By contrast, the liver in homozygous type II hyperlipoproteinemia, the other metabolic disease for which portacaval shunt has been performed, is morphologically normal. The explana-tion for the elevated serum cholesterol and low-density lipoprotein levels in this autosomal, dominant-inherited disorder is by no means understood. 'Goldstein and Browne have suggested that there may be an absence of or defect in the cell surface receptor sites that normally bind and transport low-density lipoprotein cholesterol into the cell. Because cholesterol does not enter the cell, they suggest that there is an absence of the normal feedback suppres-sion of cholesterol synthesis. Whatever its cause, the homozygous form of type II hy-perlipoproteinemia has a shockingly poor prognosis if there is no good response to medical therapy. Lipid-rich deposits are laid down in widely separated, superficial and deep Portal Diversion-Starzl & Putnam 955 \ t , t . Coronary arteriogram 16 months after portacaval shunt. Diffuse narrowing of coronary arteries seen in preoperative study had resolved except for three discrete areas of occlusive disease; note one (arrow). parts of the body, including blood vessels, in which prema-ture atherosclerosis is the consequence. Cardiac valves are similarly affected, and aortic stenosis is particularly com-mon. The patients usually die of cardiovascular complica-tions before 20 years of age. In an effort to reduce the serum cholesterol and lipo-protein levels, and with the informed consent of the child and her mother, we performed an end-to-side portacaval shunt on March 1, 1973, in an ll-year-old girl with homozygous. type II hyperlipoproteinemia that was re-fractory to medical treatment.'" The patient had suffered a myocardial infarction about two months previously. Af-ter surgery, the serum cholesterol values fell from about 800 mg/loo ml to levels that were consistently below 400 mg/loo ml. Unsightly xanthomas began to resorb from visible subcutaneous and tendinous locations. At the same time, attacks of the preexisting angina pectoris became less frequent and finally stopped."'·" The child had cardiac catheterization three months before, which was 16 months after the end-to-side porta-caval shunt was performed." On the second occasion, there was good evidence that reversal of aortic stenosis had occurred, with a diminution of the aortic valve gradient from 56 to 10 mm Hg. The coronary arteries were also thought to be less diseased than before, al-though three stenoses were still present (Figure). On Sept 23, 1974, tlie girl died suddenly while coming home from school. At autopsy, 18% months after portacaval shunt, the most important findings were present in the cardio-vascular system.'" The heart weighed 510 gm (normal, 200 gm). There was a large left ventricular aneurysm, which was the result of the old myocardial infarction. The three coronary artery stenoses identified by angiography three months earlier were still present, but there were no throm-boses or areas of fresh infarction. The aortic valve easily admitted the tip of a finger. Many arteries, as well as the aorta, had residual xanthomatous deposits. The right and left lungs weighed 415 and 340 gm, respectively; histologic findings consistent with the chronic right-sided heart fail-956 JAMA, Sept 1, 1975-Vol.233. No 9 ure, from which she had suffered since the original myocar-dial infarction, were prescnt. The conclusion was that death was caused by an acute cardiac arrhythmia related to the residual coronary artery disease or to the earlier myocardial infarction. The portaca\'al shunt was widely patent. The liver. which weighed 618 gm, was grossly normal, and microscop-ically it was unchanged from the biopsy specimen that was obtained six months postoperatively.'· On light and electron microscopy, the most prominent findings were shrinkage of the hepatocyte size, depletion of rough endo-plasmic reticulum, and the accumulation of intracytoplas-mic lipid deposits. Hepatic function had not been changed by portacaval shunt, as judged by standard liver function tests. We have performed a portacaval shunt on a second pa-tient with the same diagnosis. This 7-year-old girl had preoperative serum cholesterol values that, while she was on a very low cholesterol diet, averaged 997 ± 47 (SD) mg/loo ml. Six months after the shunt, the cholesterol level measured in the same laboratory was 600 mg/lOO ml (a 40% reduction), despite a relaxation of the diet. As in the first case, this child had aortic stenosis and angina pectoris; it is too early to say if these findings will . be ameliorated. Central Registry A plea has been made by Ahrens" that all patients with homozygous type II hyperlipemia who are treated by porta-caval shunt be carefully studied and faithfully reported to it central registry~ In this way ,tlle-Iipid-Iowering qualities of portal diversion will be promptly confirmed or denied, and in addition, clinical investigations that will shed light on the reasons for the antilipemic effect of the operation should be possible. So far, we have heard of seven more similar cases treated with portacaval shunt within the last few months, but without enough details to warrant comment. At the present time, we believe that portacaval shunt for hyperlipemia should be restricted to the highly lethal homozygous type II variety and then only if medical man-agement fails. The certain establishment of the diagnosis and the appropriate investigation of each case require that such patients be seen in institutions that have a so-phisticated interest in lipid metabolism. It is hoped that the proper study of these cases will lead to information that can be applied to other forms of hyperlipemia and the resulting premature atherosclerosis. Mechanisms for Metabolic Change Publications from our laboratory for the past ten years that have been summarized recently"·" have shown that venous blood returning from the splanchnic organs has special liver-supporting qualities that are not provided by equal volumes of other kinds of venous or arterial blood and that can affect hepatic hypertrophy, hyperplasia, and basic function. These qualities have been ascribed mainly to the endogenous hormones, especially insulin, that are released by the splanchnic viscera and thus arrive at the liver in high physiologic concentrations. The importance Portal Diversion-Starzl & Putnam . of such hormone effects on the liver probably assumes in-creased pertinence in hepatic homeostasis because the richness in nutrients of the same portal blood presum-ably contributes to important hormone-substrate inter-relationships. With end-to-side portacaval shunt, both nutritional and hormonal substances are diverted extrahepatically and may have contributed to the desired postoperative effects, both in glycogen storage disease and in hyperlipemia. Re-cent animal studies have demonstrated that hepatic cho-lesterol synthesis is greatly and permanently depressed after portal diversion, thus probably explaining most of the lipid-lowering influence of this procedure.'s Other observations"" have suggested that an increased peripheral insulinemia after portacaval shunt may explain the accelerated growth of children with glycogen storage disease. Ahrens13 has speculated on further possibili-ties and has suggested studies by which these hypotheses could be validated or repudiated. Potential Hazards Collectively, the special hormonal and nutritional ingre-dients described in portal venous blood have been termed hepatQtrophic substances. Their diversion from the liver, as with a portacaval shunt, produces derangements in ei-ther morphologic features or function of the liver; in ani-mals this may become severe and life-threatening. The most serious complication, and one that remains a poten-tial specter, is hepatic encephalopathy. In dogs, seizures, coma, and death occur regularly withi ll a few weeks after portacaval shunt, at the same time as the rough endoplas-mic reticulum of the hepatocytes is' decreased in amount, undergoes noticeable dilatation, and is depleted of ribo-somes. '" Other changes in the liver cells include deglyco-genation and the widespread accumulation of lipid vacu-oles in the cytoplasm. Fortunately, the human appears resistant to the toxic effects of portal diversion. This species difference has made it possible to consider portal diversion for its meta-bolic effects in patients. Detectable clinical morbidity in-volving the liver-brain axis has not been seen in our pa-tients who have been followed up for as long as 11 years. . Nevertheless, the clinical applications accept a "trade-off" of distinctly suboptimal conditions of liver perfusion in return for metabolic improvements that are derived from these suboptimal conditions. Realization of this fact will encourage a conservative and discriminating attitude JAMA, Sept 1. 1975-Vol 233, No 9 about the recommendation of portacaval shunt for meta-bolic purposes. THOMAS E. STARZL, MD, PHD CHARLES W. PUTNAM, MD University of Colorado Medical Center Denver This work was supported by research grants from the Veterans Admini. tration, grants AI·AM-08898 and AM-07772 from the National Institutes of Health, and grants RR-00051 and RR·00069 from the General Clinical Re-search Centers Program of the Division of Research Resources, National Institutes of Health. References 1. Stanl TE, Marchioro TL, Sexton AW, et al: The effect of portacaval transposition on carbohydrate metabolism: Experimental and clinical ob-servations. Surgery 57:687-697, 1965. 2. Child CG, Barr D, Holswade GR, et al: Liver regeneration following portacaval transposition in dogs. Ann SUTg 138:600-608, 1953. 3. Riddell AG, Davies RP, Clark AD: Portacaval transposition in the treatment of glycogen-storage disease. Lancet 2:1146-1148, 1966. 4. Starzl TE, Putnam CW, Porter KA, et al: Portal diversion for the treatment of glycogen storage disease. Ann SUTg 178:525-539, 1973. 5. Starzl TE, Brown BI. Blanchard H, et al: Portal diversion in glycogen storage disease. Surgery 65:504-506, 1969. 6. Boley SJ, Cohen MI. Gliedmao ML: Surgical therapy of glycogen stor-age disease. Pediatrics 46:929-933. 1970. 7. Folkman J, Philippart A, Tze W-J, et al: Portacaval shunt for glycogen storage disease: Value of prolonged intravenous hyperalimentation before surgery. Surgery 72:306-314, 1972. 8. Hermann RE, Mercer RD: Portacaval shunt in the treatment of glyco-gen stol'3ge disease: Report of a case. Surgery 65:499-503. 1969. 9. Goldstein JL, Brown MS: Familial hypercholesterolemia: Identi-fication- of a defect in the regulation of 3-hydroxy-3-methyl-glutaryl_ coenzyme A reductase activity associated with overproduction of choleS- -tero\. Proc Natl Acad Sci USA 70:28W-2808. 1973. 10. Starzl TE, Chase HP, Putnam CW, et al: Portacaval shunt in hyper-lipoproteinemia. Lancet 2:940-944, 1973. 11. Starzl TE, Chase HP, Putnam CW, et al: Follow·up of patient with portacaval shunt for the treatment of hyperlipidaemia. Lancet 2:714-715, 1974. 12. Stan! TE, Chase HP, Putnam CW, et al: Portacaval shunt in hyper-lipidemia. Lancet 2:1263, 1974-13. Ahrens EH Jr: Homozygous hypercholesteraemia and the porta-caval shunt: The need for a concerted attack by surgeons and clinical researchers. La neet 2:449-451, 1974. 14. Stanl TE: Portal hepatotrophic factors: A century of controversy, Judd Lecture, in Najarian JS, Delaney JP (eds): Surgery of tM LiveT, Bili-ary Tract and Pancreas. New York, Intercontinental Medical Book Corp, 1975, pp 495-524. 15. Starzl TE, Francavilla A, Halgrimson CG, et al: The origin, hormonal nature. and action of hepatotrophic substances in portal venous blood. Surg Gyneool Obstet 137:179-199, 1973. 16. Stan! TE, Lee 1-Y. Porter KA. et al: The influence of portal blood upon lipid metabolism in normal and diabetic dogs and baboons. Surg Gynecol Obstet 140:381-396, 1975. 17. Putnam CWo GotHn RW, Stan! TE: Increased venollS insulin after portacaval shunt for glycogen storage disease, to be published. 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Portal Diversion: Treatment for Glycogen Storage Disease and Hyperlipemia

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Portal Diversion: Treatment for Glycogen Storage Disease and Hyperlipemia

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