December
EDITORIALS
1992
chronic ethanol administration and immunization with acetaldehyde adduct (abstr). Hepatology 1991;14:132A. 34. Koskinas J, Kenna JG, Bird GL, Alexander
GJM, Williams R. Immunoglobulin A antibody to a 200-Kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. Gastroenterology 1992;103:1860-1867. 35. Swerdlow MD, Chowdhury LN. IgA deposition in liver in alcoholic liver disease. Arch Path01 Lab Med 1984;108:416-419. 36. Van de Wiel A, van Hattum J, Schurman
H-J, Kater L. Immunoglobin A in the diagnosis of alcoholic liver disease. Gastroenterology 1988;94:457-462.
37. Tuma DJ, Newman
MR, Donohue TM, Sorrel1 MF. Covalent binding of acetaldehyde to proteins: participation of lysine residues. Alcoholism Clin Exp Res 1987;11:579-584.
38. Thiele GM, Sorrel1 MF, Tuma DJ, McDonald TL, Klassen LW.
Characterization
of a monoclonal
antibody
specific for pro-
1973
teins modified with acetaldehyde under reducing conditions (abstr). Alcoholism Clin Exp Res 1992;16:408. 39. Klassen LW, Sorrel1 MF, Tuma DJ, Thiele GM. Antigenic specificity of RT1.l: a monoclonal antibody specific for reduced acetaldehyde protein adducts (abstr). Alcoholism Clin Exp Res 1992;16:632. 40. Klassen LW, Tuma DJ, Thiele GM. Acetaldehyde-protein adducts prepared under non-reducing conditions elicit an antibody response specific for reduced protein adducts (abstr). Alcoholism Clin Exp Res 1992;16:408.
Address requests for reprints to: Dean J. Tuma, Ph.D., Liver Study Unit, Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska 68105. This is a U.S. government work. There are no restrictions on its use.
Somatostatin and Portal Hypertensive Bleeding: A Safe Therapeutic Alternative? Somatostatin (SMS) is the product of a gene located on the long arm of chromosome 3, which codes for the cellular production of a 116-amino acid protein (preprosomatostatin). This protein undergoes tissue specific posttranslational processing to produce, initially, the 92-amino acid prosomatostatin and, ultimately, the two principal biologically active peptides, SMS,, and SMS,,, which contain 14 and 28 amino acids, respectively.’ The relative proportions of these peptides vary considerably in different tissues and SMS,, is the predominant form found in the brain, pancreas, upper gut, and enteric neurons.’ Cells producing SMS are found in many parts of the body and are typically either neurons or endocrinelike cells (D cells).3 The SMS produced by these cells can act locally, as neurotransmitters, neuromodulators, and paracrine regulators, and systemically, as true hormones. SMS binds to high-affinity receptors that appear to be coupled to guanosine triphosphate (GTP)-binding (G) proteins.4 It has been suggested that when SMS binds with its receptor it activates guanine nucleotide-regulatory subunits that inhibit membranebound adenylate cyclase and also enhance K+ conductance across the membrane. The resultant decrease in intracellular cyclic adenosine monophosphate (AMP) levels is responsible for the cyclic AMP-dependent actions of SMS. The increase in Kf conductance results in hyperpolarisation of the cell, which decreases Ca2+ influx through voltage-sensitive channels, leading to a decrease in intracellular
Ca2+ concentration, which is responsible for the cyclic AMP-independent actions of SMS.4 Although the physiological role of the SMSs in many tissues is poorly defined, the wide distribution of cells capable of producing SMS3 suggests that it has an important regulatory role in the control of many biological processes. The plasma half-life of SMS is extremely short, approximately 2 minutes, probably because of the rapid metabolism by plasma and tissue peptidases5B6 This restricts its therapeutic potential to parenteral administration as a continuous intravenous infusion with or without a bolus loading dose. The cyclic structure of SMS is essential for its biological activity, and amino acids 7-11 in SMS,, are of particular importancee7 A synthetic analogue (SMS201-995; octreotide) is also available for clinical use. It is also a cyclic peptide and shares four amino acids in common with the 7-11 amino acids of SMS,,. The longer half-life (1-2 hours) and greater potency of this synthetic peptide’ makes it suitable for intermittent subcutaneous administration as well as continuous infusion. Both SMS and octreotide have been shown to affect splanchnic hemodynamics.g-” They both increase splanchnic arteriolar resistance and thus reduce inflow into the portal venous system and result in decreased portal and portasystemic collateral blood flow. All studies have indicated that the administration of SMS is accompanied by a decrease in azygos blood flow, an index of blood flow through
1974 EDITORIALS
superior portasystemic collaterals and presumably esophagogastric varices; however, the reported effects on measures of portal venous and intravariceal pressure have been variable.” Despite the apparent minimal and variable effect of these peptides on splanchnic venous pressures, most studies on their use in the treatment of acute variceal bleeding indicate that they are at least equivalent to vasopressin, vasopressin and glyceryl trinitrate, balloon tamponade, and emergency sclerotherapy in the control of bleeding.” Although the available studies are encouraging with regard to the use of SMS or octreotide in the treatment of variceal bleeding, the occasional discordant result12 indicates that further studies are necessary before their exact role in the treatment of this clinical problem can be accurately defined. The potential therapeutic value of SMS and octreotide has been considerably enhanced by their apparent excellent safety profile. Neither randomized controlled study comparing SMS with placebo identified any side effects that could be specifically related to SMS,‘2*13and the therapy-related side effects appear less than those observed with the other therapeutic strategies used to control portal hypertensive bleeding. In this issue of GASTROENTEROLOGY, the report from Gin& et a1.14indicates that caution should still be exercised in the use of SMS and presumably its synthetic analogues in the treatment of acute variteal bleeding. The authors clearly show that SMS administered as a constant intravenous infusion at a dose recommended for the treatment of variceal bleeding was associated with significant adverse effects on the renal circulation and the renal tubular handling of sodium and water. These changes were greater in the patients with decompensated liver disease (ascites) and were unrelated to changes in systemic hemodynamics or the neurohumoral pressor systems recognized as important in the control of renal vascular tone and tubular function. The effect of SMS on the renal circulation in this group of cirrhotic patients indicated that renal vascular resistance had increased, and, as glomerular filtration rate decreased, this change in resistance must have been caused by a preferential increase in afferent arteriolar tone. The ability of SMS to increase vascular tone has also been observed in other regional vascular beds in both animal models of portal hypertension and patients with cirrhosis.g-‘1,‘5 Both SMS and octreotide increase splanchnic arteriolar resistance. Additionally, octreotide has been shown to increase systemic vascular resistance in the portal vein-ligated model of portal hypertension.15 Finally forearm vascular resistance and mean arterial pressure have been shown to increase significantly in cir-
GASTROENTEROLOGYVol.103,No.6
rhotic patients with ascites after a single subcutaneous dose of octreotide, 250 pg.16 The mechanism by which SMS and its analogues affect vascular tone remains the subject of speculation. The effects on renal and other regional vascular beds are probably not the result of a direct action of SMS on the local regulatory mechanisms that control vascular tone, because changes in the renal circulation are not evident during the intrarenal infusion of SMS in dogs.17 SMS receptors have yet to be found in endothelial or vascular smooth muscle cells, and renal effects of SMS were not evident in a study in which insulin, glucagon, and growth hormone were simultaneously infused at a rate sufficient to maintain the basal plasma levels of these hormones.‘* By exclusion, these studies imply that the increased vascular tone found in various regional vascular beds is more likely to be the result of the SMS-induced inhibition of the secretion of a number of vasodilatory peptides. This conclusion is consistent with the hypothesis that in patients with liver disease the development of portal hypertension and portosystemic collaterals is associated with increased circulating levels of endogenous vasodilatory peptides arising in the splanchnic vascular system and exerting variable effects on the different regional vascular beds, depending on the local receptor type and density.‘g-21 It is also consistent with the finding in the study reported by Gin& et alI4 that the renal circulation of the patients with ascites, and presumably those with more advanced liver disease, portal hypertension, and portosystemic shunts, were more sensitive to the vasoconstricting effects of SMS. Endogenous vasodilatory peptides are capable of modulating renal vascular tone, as supported by the knowledge that glucagon can increase both glomerular filtration rate (GFR) and renal plasma flow (RPF)22 and by the fact that the renal circulatory changes that follow a protein meal or amino acid infusion, presumably because of the release of vasoactive gastrointestinal tract peptides, can be prevented by the simultaneous administration of SMS.“’ The presence of a low renal vascular resistance and glomerular hyperfiltration in some patients with well-compensated cirrhosis that appears to be at least partially dependent on the presence of portosystemic shunts would also support this interpretation.23 The fact that renal circulatory changes did not correlate with changes in circulating glucagon in the study reported by Gin& et a1.14does not exclude the possibility that changes in vasodilatory peptides were responsible for the SMS-induced changes in the renal circulation. Glucagon is considered to be only partially responsible for the splanchnic hyperemia associated with portal hypertension in the experi-
December
1992
mental animal,” and this may have weakened any possible relationship. Additionally, the change in glucagon levels may have also been affected by the glucose challenge and may not have paralleled the changes that occurred in other vasodilatory peptides. Finally, as Gin& et al. state, plasma glucagon levels were only determined at the end of the study period, and these measurements may not have been representative of the glucagon concentrations throughout the study period. Gin&s et a1.14also report that the infusion of SMS was associated with a decrease in the urinary excretion of prostaglandin E, (PGE,). The significance of this finding in relation to the SMS-induced changes in renal function remains uncertain. It could purely reflect the dependence of urinary prostaglandin excretion on urine flow and tubular reabsorption.24 However, it raises the intriguing possibility that the renal effects of any circulating endogenous vasodilators may be partly dependent on the stimulation of renal PG synthesis and release. The effects of SMS on renal function are similar to the vasoconstricting, antinatriuretic, and antidiuretic effects of indomethacin (a prostaglandin synthetase inhibitor), and, as with indomethacin, the effects were much more evident in the patients with ascites.25s26 Although there was no correlation between the SMS-induced changes in renal function and the change in urinary PGE, concentration, this is not surprising because urinary prostaglandins are recognized as a poor reflection of intrarenal prostaglandin synthesis, particularly at a cortical leveLz7 and the majority of studies have not shown a consistent relationship between the changes in the urinary excretion of prostaglandins and the changes in renal hemodynamics or tubular handling of salt and water that follow the administration of prostaglandin synthetase inhibitors.28*2g Although the changes in urine flow rate and Naf excretion correlated significantly with the changes in renal plasma flow and may have been entirely due to the effects of SMS on the renal circulation, it is possible that at least the antidiuretic effects of SMS identified in the study by Gin& et a1.l4 were also directly induced by SMS acting on the renal tubule. SMS receptors have been identified in the collecting duct of the nephron,30 and SMS is recognized to have an independent direct antidiuretic effect similar to that of antidiuretic hormone.3* Before accepting the obvious therapeutic implications of the report by Gin&s et alal4 it is necessary to emphasize the fact that the study was performed under conditions of a volume load (5% glucose, 20 mL/kg over 45 minutes, plus replacement of urine volume) to maintain urine flow and ensure accuracy of the half-hourly clearance measurements. Studies
EDITORIALS
1975
reporting a similar effect on the renal circulation and tubular handling of Na+ and water in healthy and diabetic subjects have also been performed under conditions of a volume-induced diuresis.32-34 Whether similar findings would be evident in patients who are actively bleeding from varices remains impossible to determine. This question is even more pertinent in view of the conflicting results reported by Mountokalakis et al. in the only other study of the effects of SMS on renal function in cirrhotics. They reported that Octreotide infused at a rate of 40 ug/h produced a significant increase in urine volume and creatinine clearance and a decrease in urinary osmolality. In this study, the patients all had ascites and probably had a decreased effective arterial blood volume (EABV) [average basal urine output, 0.42 mL/min; creatinine clearance, 67.7 mL/h (range, 35-115 mL/h)], although neurohumoral markers of EABV were not measured. They also received only 240 mL of 5% glucose over 2 hours during the 6-hour study period. In contrast, the study by Gin& et al. was performed during a volume load, conditions that would have at least partly corrected any decrease in EABV. The differences evident between these two studies may be due to differences that existed between the EABV of the groups of patients studied. SMS decreases plasma renin activity (PRA) in patients with essential hypertension and a high renin concentration36 and limits the increase in PRA that follows the administration of furosemide, (3-adrenergic stimulation, or head-up tilting.37-3g Additionally, SMS receptors have been identified in adrenal glomerulosa cells4’ and angiotensin II-induced aldosterone synthesis is inhibited by SMS.41 Based on these findings, one could envisage a situation in which the effects of SMS on the renin/angiotensin/aldosterone system could be of greater significance than its effects on endogenous vasodilators. The overall effect of SMS on renal function would then depend on the resultant balance between these competing vasoactive systems. Certainly studies assessing the effect of SMS on renal function in cirrhotics in the absence of a volume load are necessary to clarify this issue. Finally, SMS has profound effects on gastrointestinal function, and this may have important implications for its use in patients with liver disease, particularly at a time of portal hypertensive bleeding. SMS affects gastrointestinal motility, delaying intestinal transit, and alters both the digestion and absorption of food. Although SMS has been shown not to decrease the systemic bioavailability of the byproducts of protein digestion following a mea1,42 its use, compared with that of vasopressin, which decreases intestinal transit time, could theoretically favor the development of complicating encephalopathy.
GASTROENTEROLOGY Vol. 103, No. 6
1976 EDITORIALS
In summary, although experience with the use of SMS has indicated that it is relatively safe in the treatment of portal hypertensive bleeding, the report by Gin& et a1.14indicates that its clinical use should still be carefully monitored, particularly for evidence of adverse effects on renal function. Further studies are necessary to clarify the mechanisms by which SMS alters renal function in patients with cirrhosis and also to determine if the clinical setting in which it is administered is indeed important in determining the outcome. FRANCIS J. DUDLEY, M.D. Gastroenterology Department Alfred Hospital Prahran, Australia
15.
16.
17. 18.
19.
20.
References LP, Pictet RL, Rutter WJ. Proc Nat1 Acad Sci USA 1982;79:4575-4579. 2. Pate1 YC, Zingg HH, Srikant CB. Somatostatin-14 like immunoreactive forms in the rat: characterization, distribution and biosynthesis. In: Pate1 YC, Tannenbaum GS, eds. Somatostatin. New York: Plenum, 1985:71-87. 3. Reichlin S. Somatostatin. New Engl J Med 1983;309:14951. Shen
1501. 4. Schonbrunn
5.
6.
7. 8.
9.
A, Koch BD. Mechanisms by which Somatostatin inhibits pituitary hormone release. In: Reichlin S, ed. Somatostatin: basic and clinical status. New York: Plenum, 1987;121135. Sheppard M, Shapiro B, Pimstone B, Kronheim MB, Gregory M. The metabolic clearance and plasma half disappearance time of exogenous somatostatin in man. J Clin Endocrinol Metab 1979;48:50-53. Griffiths EC, Jeffcoate SL, Holland DT. Inactivation of somatostatin by peptidases in different areas of the rat brain. Acta Endocrinol 1977;85:1-4. Reichlin S. Somatostatin. N Engl J Med 1983;309:1556-1563. Pless J, Bauer W, Briner U, Doepfner W, Marbach P, Maurer R, Petcher TJ, Reubi JC, Vanderscher J. Chemistry and pharmacology of SMS 201-995, a long acting octapeptide analogue of somatostatin. Stand J Gastroenterol 1986;21(Suppl 119):5464. Bosch J, Kravetz D, Rodes J. Effects of somatostatin on hepatic and systemic hemodynamics in patients with cirrhosis of the liver. Comparison with vasopressin. Gastroenterology 1981;
21.
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23.
24.
25.
26.
27. Zipser
28.
80:518-525. 10. Bosch J, Kravetz
29.
11.
30.
12.
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14.
D, Mastai R, Navasa M, Silva G, Chesta J, Rodes J. Effects of somatostatin in patients with portal hypertension. Hormone Res 1988;29:99-102. Burroughs AK. Somatostatin and octreotide for variceal bleeding. J Hepatology 1991;13:1-4. Valenzuela JE, Schubert T, Fogel MR, Strong RM, Levine J, Mills PR, Fabry TL, Taylor LW, Conn HO, Posillico JT and a Multicenter Study Group. A multicenter, randomized, double-blind trial of Somatostatin in the management of acute hemorrhage from esophageal varices. Hepatology 1989;lO: 958-961. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D’Heygere F, McIntyre N. Randomized, double blind, placebo-controlled trial of Somatostatin for variceal bleeding: Emergency control and prevention of early variceal rebleeding. Gastroenterology 1990;99:1388-1395. Gin&s A, Salmeron JM, Gines P, Jimenez W, Salo J, Piera C,
Claria J, Rivera F, Arroyo V, Rodes J. Effects of somatostatin on renal function in cirrhosis. Gastroenterology 1992;103: 1868-1874. Albillos A, Colombato LA, Lee FY, Groszmann RJ. Chronic octreotide treatment ameliorates peripheral vasodilatation and prevents sodium retention in portal hypertensive rats (abstr). Hepatology 1991;14:122A. Rodriguez-Perez F, Groszmann RJ. Peripheral hemodynamics in cirrhotic patients with and without ascites: effect of octreotide (abstr). Gastroenterology 1992;102:A875. Reid IA, Rose JC. An intrarenal effect of somatostatin on water excretion. Endocrinology 1977;100:782-785. Castellino P, Coda B, DeFronzo R. Effect of amino acid infusion on renal hemodynamics in humans. Am J Physiol 1986;251:F132-F140. Sikuler E, Kravetz D, Groszmann RJ. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model Am J Physiol 1985;248:G618-G625. Benoit JN, Barrowman JA, Harper SL, Kvietys PR, Granger DN. Role of humoral factors in the intestinal hyperemia associated with chronic portal hypertension. Am J Physiol 1984;247:G486-G493. Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983;244:G52-G57. Johannesen J, Lie M, Kiil F. Effect of glycine and glucagon on glomerular filtration and renal metabolic rates. Am J Physiol 1977;233:F61-F66. Wong F, Massie D, Hsu P, Dudley F. Glomerular hyperfiltration in well compensated alcoholic cirrhosis (abstr). Hepatology 1991;14:87A. Kaye Z, Zipser R, Hahn J, Zia P, Horton R. Is urinary flow rate a major regulator of prostaglandin E excretion in man? Prostaglandins Med 1980;4:303-309. Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin Al on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979;77:215-222. Wong F, Massie D, Hsu P. Dudley F. Effect of an oral prostaglandin El analogue on indomethacin induced renal dysfunction in alcoholic cirrhosis (abstr). Hepatology 1990;12:870A.
31.
32.
33.
RD, Lifschitz MD. Prostaglandins and related compounds, In: Epstein M, ed. The kidney in liver disease. 3rd ed. Baltimore: Williams & Wilkins, 1988:393-416. Zipser RD, Little T, Ziperovich H, Duke R. The role of arachidonic acid metabolites in the functional renal impairment associated with liver disease. In: Dunn MJ, Patron0 C, Cinotti GA, eds. Prostaglandins and the kidney. New York: Plenum, 1983:263-274. Laffi G, LaVilla G, Pinzani M, Ciabattoni G, Patrignani P, Mannelli M, Cominelli F, Gentilini P. Altered renal and platelet arachidonic acid metabolism in cirrhosis. Gastroenterology 1986;90:274-282. Yamada Y, Post SR, Wang K, Tager HS, Bell GI, Seino S. Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney. Proc Nat1 Acad Sci USA 1992;89:251255. Berthold H, de1 Pozo E. Antidiuretic effect of Sandostatin (SMS 201-995) in healthy volunteers. Acta Endocrinol 1989;120:708-714. Pedersen MM, Christensen SE, Christiansen JS, Pedersen EB, Mogensen CE, Orskov H. Acute effects of a somatostatin analogue on kidney function in type 1 diabetic patients. Diabet Med 1990;7:304-309. Vora J, Owens DR, Luzio S, Atiea J, Ryder R, Hayes TM. Renal response to intravenous Somatostatin in insulin-dependent
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34.
35.
36. 37.
1992
diabetic patients and normal subjects. J Clin Endocrinol Metab 1987;64:975-979. Tulassay Z, Tulassay T, Szucs L, Nagy I. Effects of long acting Somatostatin analogue on renal functions. Horm Metab Res 1990;22:555-556. Mountokalakis T, Kallivretakis N, Mayopoulou-Symvoulidou D, Karvountzis G, Tolis G. Enhancement of renal function by a long-acting Somatostatin analogue in patients with decompensated cirrhosis. Nephrol Dial Transplant 1988;3:604-607. Izumi Y, Honda M, Hartano M. Effect of somatostatin on plasma renin activity. Endocrinol Jpn 1979;26:389-394. Rosenthal J, Escobar-Jimenez F, Raptis S, Pfeiffer EF. Inhibition of furosemide induced hyperreninaemia by growth hormone release inhibiting hormone in man. Lancet 1976;1:772-
EDITORIALS
1977
Effect of a new Somatostatin analogue SMS 201-995 (sandostatin) on the renin-aldosterone axis. Clin Endocrinol 1988; 28:25-32. 40. Aguilera G, Parker DS, Catt KJ. Characterization of somatostatin receptors in rat adrenal glomerulosa zone. Endocrinology 1982;111:1376-1382. 41. Aguilera G, Harwood JP, Catt KJ. Somatostatin modulates effects of Angiotensin II in adrenal glomerulosa zone. Nature 1982;292:262-263, 42. Trevisani F, Bernardi M, de Palma R, Servadei D, Piazzi S, Capelli M, Gasbarrini G. Effects of somatostatin on plasma ammonia and amino acid profile during fasting and after protein feeding in cirrhotic patients. Hepatogastroenterology 1986;33:56-60.
774. 38. Rosenthal
J, Escobar-Jimenez F, Raptis S. Prevention of somatostatin rise in blood pressure and plasma renin activity mediated by beta-receptor stimulation. Clin Endocrinol 1977;6:455-462. 39. Sieber C, Gnadinger M, de1 Pozo E, Shaw S, Weidmann P.
Address requests for reprints to: Francis J. Dudley, M.D., Gastroenterology Department, Alfred Hospital, Commercial Road, Prahran, Australia 3181. 0 1992 by the American Gastroenterological Association
EDITORIALS
1992
chronic ethanol administration and immunization with acetaldehyde adduct (abstr). Hepatology 1991;14:132A. 34. Koskinas J, Kenna JG, Bird GL, Alexander
GJM, Williams R. Immunoglobulin A antibody to a 200-Kilodalton cytosolic acetaldehyde adduct in alcoholic hepatitis. Gastroenterology 1992;103:1860-1867. 35. Swerdlow MD, Chowdhury LN. IgA deposition in liver in alcoholic liver disease. Arch Path01 Lab Med 1984;108:416-419. 36. Van de Wiel A, van Hattum J, Schurman
H-J, Kater L. Immunoglobin A in the diagnosis of alcoholic liver disease. Gastroenterology 1988;94:457-462.
37. Tuma DJ, Newman
MR, Donohue TM, Sorrel1 MF. Covalent binding of acetaldehyde to proteins: participation of lysine residues. Alcoholism Clin Exp Res 1987;11:579-584.
38. Thiele GM, Sorrel1 MF, Tuma DJ, McDonald TL, Klassen LW.
Characterization
of a monoclonal
antibody
specific for pro-
1973
teins modified with acetaldehyde under reducing conditions (abstr). Alcoholism Clin Exp Res 1992;16:408. 39. Klassen LW, Sorrel1 MF, Tuma DJ, Thiele GM. Antigenic specificity of RT1.l: a monoclonal antibody specific for reduced acetaldehyde protein adducts (abstr). Alcoholism Clin Exp Res 1992;16:632. 40. Klassen LW, Tuma DJ, Thiele GM. Acetaldehyde-protein adducts prepared under non-reducing conditions elicit an antibody response specific for reduced protein adducts (abstr). Alcoholism Clin Exp Res 1992;16:408.
Address requests for reprints to: Dean J. Tuma, Ph.D., Liver Study Unit, Veterans Affairs Medical Center, 4101 Woolworth Avenue, Omaha, Nebraska 68105. This is a U.S. government work. There are no restrictions on its use.
Somatostatin and Portal Hypertensive Bleeding: A Safe Therapeutic Alternative? Somatostatin (SMS) is the product of a gene located on the long arm of chromosome 3, which codes for the cellular production of a 116-amino acid protein (preprosomatostatin). This protein undergoes tissue specific posttranslational processing to produce, initially, the 92-amino acid prosomatostatin and, ultimately, the two principal biologically active peptides, SMS,, and SMS,,, which contain 14 and 28 amino acids, respectively.’ The relative proportions of these peptides vary considerably in different tissues and SMS,, is the predominant form found in the brain, pancreas, upper gut, and enteric neurons.’ Cells producing SMS are found in many parts of the body and are typically either neurons or endocrinelike cells (D cells).3 The SMS produced by these cells can act locally, as neurotransmitters, neuromodulators, and paracrine regulators, and systemically, as true hormones. SMS binds to high-affinity receptors that appear to be coupled to guanosine triphosphate (GTP)-binding (G) proteins.4 It has been suggested that when SMS binds with its receptor it activates guanine nucleotide-regulatory subunits that inhibit membranebound adenylate cyclase and also enhance K+ conductance across the membrane. The resultant decrease in intracellular cyclic adenosine monophosphate (AMP) levels is responsible for the cyclic AMP-dependent actions of SMS. The increase in Kf conductance results in hyperpolarisation of the cell, which decreases Ca2+ influx through voltage-sensitive channels, leading to a decrease in intracellular
Ca2+ concentration, which is responsible for the cyclic AMP-independent actions of SMS.4 Although the physiological role of the SMSs in many tissues is poorly defined, the wide distribution of cells capable of producing SMS3 suggests that it has an important regulatory role in the control of many biological processes. The plasma half-life of SMS is extremely short, approximately 2 minutes, probably because of the rapid metabolism by plasma and tissue peptidases5B6 This restricts its therapeutic potential to parenteral administration as a continuous intravenous infusion with or without a bolus loading dose. The cyclic structure of SMS is essential for its biological activity, and amino acids 7-11 in SMS,, are of particular importancee7 A synthetic analogue (SMS201-995; octreotide) is also available for clinical use. It is also a cyclic peptide and shares four amino acids in common with the 7-11 amino acids of SMS,,. The longer half-life (1-2 hours) and greater potency of this synthetic peptide’ makes it suitable for intermittent subcutaneous administration as well as continuous infusion. Both SMS and octreotide have been shown to affect splanchnic hemodynamics.g-” They both increase splanchnic arteriolar resistance and thus reduce inflow into the portal venous system and result in decreased portal and portasystemic collateral blood flow. All studies have indicated that the administration of SMS is accompanied by a decrease in azygos blood flow, an index of blood flow through
1974 EDITORIALS
superior portasystemic collaterals and presumably esophagogastric varices; however, the reported effects on measures of portal venous and intravariceal pressure have been variable.” Despite the apparent minimal and variable effect of these peptides on splanchnic venous pressures, most studies on their use in the treatment of acute variceal bleeding indicate that they are at least equivalent to vasopressin, vasopressin and glyceryl trinitrate, balloon tamponade, and emergency sclerotherapy in the control of bleeding.” Although the available studies are encouraging with regard to the use of SMS or octreotide in the treatment of variceal bleeding, the occasional discordant result12 indicates that further studies are necessary before their exact role in the treatment of this clinical problem can be accurately defined. The potential therapeutic value of SMS and octreotide has been considerably enhanced by their apparent excellent safety profile. Neither randomized controlled study comparing SMS with placebo identified any side effects that could be specifically related to SMS,‘2*13and the therapy-related side effects appear less than those observed with the other therapeutic strategies used to control portal hypertensive bleeding. In this issue of GASTROENTEROLOGY, the report from Gin& et a1.14indicates that caution should still be exercised in the use of SMS and presumably its synthetic analogues in the treatment of acute variteal bleeding. The authors clearly show that SMS administered as a constant intravenous infusion at a dose recommended for the treatment of variceal bleeding was associated with significant adverse effects on the renal circulation and the renal tubular handling of sodium and water. These changes were greater in the patients with decompensated liver disease (ascites) and were unrelated to changes in systemic hemodynamics or the neurohumoral pressor systems recognized as important in the control of renal vascular tone and tubular function. The effect of SMS on the renal circulation in this group of cirrhotic patients indicated that renal vascular resistance had increased, and, as glomerular filtration rate decreased, this change in resistance must have been caused by a preferential increase in afferent arteriolar tone. The ability of SMS to increase vascular tone has also been observed in other regional vascular beds in both animal models of portal hypertension and patients with cirrhosis.g-‘1,‘5 Both SMS and octreotide increase splanchnic arteriolar resistance. Additionally, octreotide has been shown to increase systemic vascular resistance in the portal vein-ligated model of portal hypertension.15 Finally forearm vascular resistance and mean arterial pressure have been shown to increase significantly in cir-
GASTROENTEROLOGYVol.103,No.6
rhotic patients with ascites after a single subcutaneous dose of octreotide, 250 pg.16 The mechanism by which SMS and its analogues affect vascular tone remains the subject of speculation. The effects on renal and other regional vascular beds are probably not the result of a direct action of SMS on the local regulatory mechanisms that control vascular tone, because changes in the renal circulation are not evident during the intrarenal infusion of SMS in dogs.17 SMS receptors have yet to be found in endothelial or vascular smooth muscle cells, and renal effects of SMS were not evident in a study in which insulin, glucagon, and growth hormone were simultaneously infused at a rate sufficient to maintain the basal plasma levels of these hormones.‘* By exclusion, these studies imply that the increased vascular tone found in various regional vascular beds is more likely to be the result of the SMS-induced inhibition of the secretion of a number of vasodilatory peptides. This conclusion is consistent with the hypothesis that in patients with liver disease the development of portal hypertension and portosystemic collaterals is associated with increased circulating levels of endogenous vasodilatory peptides arising in the splanchnic vascular system and exerting variable effects on the different regional vascular beds, depending on the local receptor type and density.‘g-21 It is also consistent with the finding in the study reported by Gin& et alI4 that the renal circulation of the patients with ascites, and presumably those with more advanced liver disease, portal hypertension, and portosystemic shunts, were more sensitive to the vasoconstricting effects of SMS. Endogenous vasodilatory peptides are capable of modulating renal vascular tone, as supported by the knowledge that glucagon can increase both glomerular filtration rate (GFR) and renal plasma flow (RPF)22 and by the fact that the renal circulatory changes that follow a protein meal or amino acid infusion, presumably because of the release of vasoactive gastrointestinal tract peptides, can be prevented by the simultaneous administration of SMS.“’ The presence of a low renal vascular resistance and glomerular hyperfiltration in some patients with well-compensated cirrhosis that appears to be at least partially dependent on the presence of portosystemic shunts would also support this interpretation.23 The fact that renal circulatory changes did not correlate with changes in circulating glucagon in the study reported by Gin& et a1.14does not exclude the possibility that changes in vasodilatory peptides were responsible for the SMS-induced changes in the renal circulation. Glucagon is considered to be only partially responsible for the splanchnic hyperemia associated with portal hypertension in the experi-
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mental animal,” and this may have weakened any possible relationship. Additionally, the change in glucagon levels may have also been affected by the glucose challenge and may not have paralleled the changes that occurred in other vasodilatory peptides. Finally, as Gin& et al. state, plasma glucagon levels were only determined at the end of the study period, and these measurements may not have been representative of the glucagon concentrations throughout the study period. Gin&s et a1.14also report that the infusion of SMS was associated with a decrease in the urinary excretion of prostaglandin E, (PGE,). The significance of this finding in relation to the SMS-induced changes in renal function remains uncertain. It could purely reflect the dependence of urinary prostaglandin excretion on urine flow and tubular reabsorption.24 However, it raises the intriguing possibility that the renal effects of any circulating endogenous vasodilators may be partly dependent on the stimulation of renal PG synthesis and release. The effects of SMS on renal function are similar to the vasoconstricting, antinatriuretic, and antidiuretic effects of indomethacin (a prostaglandin synthetase inhibitor), and, as with indomethacin, the effects were much more evident in the patients with ascites.25s26 Although there was no correlation between the SMS-induced changes in renal function and the change in urinary PGE, concentration, this is not surprising because urinary prostaglandins are recognized as a poor reflection of intrarenal prostaglandin synthesis, particularly at a cortical leveLz7 and the majority of studies have not shown a consistent relationship between the changes in the urinary excretion of prostaglandins and the changes in renal hemodynamics or tubular handling of salt and water that follow the administration of prostaglandin synthetase inhibitors.28*2g Although the changes in urine flow rate and Naf excretion correlated significantly with the changes in renal plasma flow and may have been entirely due to the effects of SMS on the renal circulation, it is possible that at least the antidiuretic effects of SMS identified in the study by Gin& et a1.l4 were also directly induced by SMS acting on the renal tubule. SMS receptors have been identified in the collecting duct of the nephron,30 and SMS is recognized to have an independent direct antidiuretic effect similar to that of antidiuretic hormone.3* Before accepting the obvious therapeutic implications of the report by Gin&s et alal4 it is necessary to emphasize the fact that the study was performed under conditions of a volume load (5% glucose, 20 mL/kg over 45 minutes, plus replacement of urine volume) to maintain urine flow and ensure accuracy of the half-hourly clearance measurements. Studies
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reporting a similar effect on the renal circulation and tubular handling of Na+ and water in healthy and diabetic subjects have also been performed under conditions of a volume-induced diuresis.32-34 Whether similar findings would be evident in patients who are actively bleeding from varices remains impossible to determine. This question is even more pertinent in view of the conflicting results reported by Mountokalakis et al. in the only other study of the effects of SMS on renal function in cirrhotics. They reported that Octreotide infused at a rate of 40 ug/h produced a significant increase in urine volume and creatinine clearance and a decrease in urinary osmolality. In this study, the patients all had ascites and probably had a decreased effective arterial blood volume (EABV) [average basal urine output, 0.42 mL/min; creatinine clearance, 67.7 mL/h (range, 35-115 mL/h)], although neurohumoral markers of EABV were not measured. They also received only 240 mL of 5% glucose over 2 hours during the 6-hour study period. In contrast, the study by Gin& et al. was performed during a volume load, conditions that would have at least partly corrected any decrease in EABV. The differences evident between these two studies may be due to differences that existed between the EABV of the groups of patients studied. SMS decreases plasma renin activity (PRA) in patients with essential hypertension and a high renin concentration36 and limits the increase in PRA that follows the administration of furosemide, (3-adrenergic stimulation, or head-up tilting.37-3g Additionally, SMS receptors have been identified in adrenal glomerulosa cells4’ and angiotensin II-induced aldosterone synthesis is inhibited by SMS.41 Based on these findings, one could envisage a situation in which the effects of SMS on the renin/angiotensin/aldosterone system could be of greater significance than its effects on endogenous vasodilators. The overall effect of SMS on renal function would then depend on the resultant balance between these competing vasoactive systems. Certainly studies assessing the effect of SMS on renal function in cirrhotics in the absence of a volume load are necessary to clarify this issue. Finally, SMS has profound effects on gastrointestinal function, and this may have important implications for its use in patients with liver disease, particularly at a time of portal hypertensive bleeding. SMS affects gastrointestinal motility, delaying intestinal transit, and alters both the digestion and absorption of food. Although SMS has been shown not to decrease the systemic bioavailability of the byproducts of protein digestion following a mea1,42 its use, compared with that of vasopressin, which decreases intestinal transit time, could theoretically favor the development of complicating encephalopathy.
GASTROENTEROLOGY Vol. 103, No. 6
1976 EDITORIALS
In summary, although experience with the use of SMS has indicated that it is relatively safe in the treatment of portal hypertensive bleeding, the report by Gin& et a1.14indicates that its clinical use should still be carefully monitored, particularly for evidence of adverse effects on renal function. Further studies are necessary to clarify the mechanisms by which SMS alters renal function in patients with cirrhosis and also to determine if the clinical setting in which it is administered is indeed important in determining the outcome. FRANCIS J. DUDLEY, M.D. Gastroenterology Department Alfred Hospital Prahran, Australia
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Claria J, Rivera F, Arroyo V, Rodes J. Effects of somatostatin on renal function in cirrhosis. Gastroenterology 1992;103: 1868-1874. Albillos A, Colombato LA, Lee FY, Groszmann RJ. Chronic octreotide treatment ameliorates peripheral vasodilatation and prevents sodium retention in portal hypertensive rats (abstr). Hepatology 1991;14:122A. Rodriguez-Perez F, Groszmann RJ. Peripheral hemodynamics in cirrhotic patients with and without ascites: effect of octreotide (abstr). Gastroenterology 1992;102:A875. Reid IA, Rose JC. An intrarenal effect of somatostatin on water excretion. Endocrinology 1977;100:782-785. Castellino P, Coda B, DeFronzo R. Effect of amino acid infusion on renal hemodynamics in humans. Am J Physiol 1986;251:F132-F140. Sikuler E, Kravetz D, Groszmann RJ. Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model Am J Physiol 1985;248:G618-G625. Benoit JN, Barrowman JA, Harper SL, Kvietys PR, Granger DN. Role of humoral factors in the intestinal hyperemia associated with chronic portal hypertension. Am J Physiol 1984;247:G486-G493. Vorobioff J, Bredfeldt JE, Groszmann RJ. Hyperdynamic circulation in portal hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am J Physiol 1983;244:G52-G57. Johannesen J, Lie M, Kiil F. Effect of glycine and glucagon on glomerular filtration and renal metabolic rates. Am J Physiol 1977;233:F61-F66. Wong F, Massie D, Hsu P, Dudley F. Glomerular hyperfiltration in well compensated alcoholic cirrhosis (abstr). Hepatology 1991;14:87A. Kaye Z, Zipser R, Hahn J, Zia P, Horton R. Is urinary flow rate a major regulator of prostaglandin E excretion in man? Prostaglandins Med 1980;4:303-309. Boyer TD, Zia P, Reynolds TB. Effect of indomethacin and prostaglandin Al on renal function and plasma renin activity in alcoholic liver disease. Gastroenterology 1979;77:215-222. Wong F, Massie D, Hsu P. Dudley F. Effect of an oral prostaglandin El analogue on indomethacin induced renal dysfunction in alcoholic cirrhosis (abstr). Hepatology 1990;12:870A.
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diabetic patients and normal subjects. J Clin Endocrinol Metab 1987;64:975-979. Tulassay Z, Tulassay T, Szucs L, Nagy I. Effects of long acting Somatostatin analogue on renal functions. Horm Metab Res 1990;22:555-556. Mountokalakis T, Kallivretakis N, Mayopoulou-Symvoulidou D, Karvountzis G, Tolis G. Enhancement of renal function by a long-acting Somatostatin analogue in patients with decompensated cirrhosis. Nephrol Dial Transplant 1988;3:604-607. Izumi Y, Honda M, Hartano M. Effect of somatostatin on plasma renin activity. Endocrinol Jpn 1979;26:389-394. Rosenthal J, Escobar-Jimenez F, Raptis S, Pfeiffer EF. Inhibition of furosemide induced hyperreninaemia by growth hormone release inhibiting hormone in man. Lancet 1976;1:772-
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Effect of a new Somatostatin analogue SMS 201-995 (sandostatin) on the renin-aldosterone axis. Clin Endocrinol 1988; 28:25-32. 40. Aguilera G, Parker DS, Catt KJ. Characterization of somatostatin receptors in rat adrenal glomerulosa zone. Endocrinology 1982;111:1376-1382. 41. Aguilera G, Harwood JP, Catt KJ. Somatostatin modulates effects of Angiotensin II in adrenal glomerulosa zone. Nature 1982;292:262-263, 42. Trevisani F, Bernardi M, de Palma R, Servadei D, Piazzi S, Capelli M, Gasbarrini G. Effects of somatostatin on plasma ammonia and amino acid profile during fasting and after protein feeding in cirrhotic patients. Hepatogastroenterology 1986;33:56-60.
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Address requests for reprints to: Francis J. Dudley, M.D., Gastroenterology Department, Alfred Hospital, Commercial Road, Prahran, Australia 3181. 0 1992 by the American Gastroenterological Association
