Alterations in gastric secretion after portacaval shunting

Alterations in Gastric Secretion after Portacaval Shunting JAMES C. THOMPSON, M.D., Torrance,

All substances that are absorbed or elaborated by the gut normally pass through the liver, and the establishment of a portacaval shunt provides a systemic access for these materials, some of which are normally altered or destroyed by the liver. In 1933 Lebedinskaja [I] reported that construction of an Eck fistula [2] greatly increased acid output in dogs with Pavlov pouches. She believed that the hypersecretion was probably caused by interference with the detoxifying action of the liver and suggested that normal hepatic function is necessary for normal function of the gastric glands. Gerez and Weiss [3] confirmed this postshunt hypersecretion and suggested that under normal circumstances gastric secretagogues are partially detoxified on passage through the liver. The demonstration of acid hypersecretion after portacaval shunting and the reported relation between liver disease, portacaval shunting and peptic ulcer have evoked great interest and have been the subject of several reviews [h-11,inter &a]. In the following report I will briefly summarize information from animal experiments on the relation of portaeaval shunting to gastric secretion, and will relate these studies, if possible, to clinical experiences with cirrhotic and shunted patients. Experimental Studies The overwhelming majority of experiments on gastric hypersecretion after portacaval shunting have been performed in dogs and have had two aims: determining the spectrum of effect of shunting on gastric secretion and

From the Departments of Surgery. Harbor General Hospital, 1000 West Carson Street. Torrance, California 90509, and the UCLA School of Medicine, Los Angeles, California. This work was supported by U.S.P.H.S. Grants AM-07961 and AM-07962, and by a grant from the John A. Hartford Foundation, Inc.

854

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identifying the agent responsible for hypersecretion. Studies on the Effect of Portacaval Shunting on Gastric Secretion. Postshunt hypersecretion was first observed in dogs that had been stimulated by a meat meal [1,3], an observation that has been widely confirmed [12-19,inter alia]. Gregory [20,21]observed an increased gastric secretory response to food after gradual occlusion of the portal vein. This was confirmed by Dubuque, Mulligan, and Neville [15] who further observed that acid hypersecretion persisted when the previously occluded portal vein was shunted into the vena cava. Clarke and co-workers [1.2,14] showed that food-stimulated gastric secretion from denervated Heidenhain pouches showed a more than threefold increase after portacaval shunting. Silen and Eiseman [19]observed that hypersecretion after food ingestion was greatly diminished if the dog had been fasted before the meal and suggested that the responsible secretagogue must in some way arise from or be stimulated by meat. Early evidence indicated that stimuli from the gastric antrum might be augmented after ligation of the portal vein [21], and subsequent studies showed that the secretory response to antral stimuli was increased after establishment of a portacaval shunt [6,22]. Since hypersecretion has been demonstrated in antrectomized dogs after portal vein ligation [21] and portacaval transposition [14,23,24], the augmented acid output is clearly not dependent on the antrum. Responses to vagal stimuli were reported to be augmented by portal vein occlusion 1211 and portacaval shunting [25]. Olbe [25] studied three Pavlov pouch dogs and reported that the insulin-stimulated gastric secretion increased threefold after portacaval transposition. In our studies with gastric fistula [17] and Pavlov pouch dogs (unpublished data), we found no The

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significant postshunt alteration in gastric secretion stimulated by the vagal stimulant, 2_ deoxy-D-glucose. Dragstedt and his group [26] obtained a fivefold increase in gastric secretion from completely denervated pouches of the entire stomach after portacaval transposition. Hubens and Deloyers [27] found that portacaval transposition increased the secretory response to gastrin II and to a cholinergic stimulus. Persistence of hypersecretion after portacaval shunting in dogs in which the cephalic and antral phases were inoperative [24,26] suggested that shunting augments the intestinal phase of gastric secretion [ll]. Castaneda and colleagues 1281 found that postshunt hypersecretion persisted in dogs in which either the proximal or distal half of the small bowel had been resected and suggested that the secretagogue originated from the entire small intestine. This was confirmed in a series of ingenious venous shunting experiments by Clarke and co-workers [29,30]. We have shown that food-stimulated gastric secretion from antrectomized dogs with denervated fundic pouches is increased eight- to twenty-twofold after portacaval transposition [i7], and acid secretion from a Heidenhain pouch stimulated by perfusion of an intestinal loop with homogenized liver has been reported to be greatly increased by portacaval transposition [27]. Studies of the effects of various types of food on postshunt hypersecretion have shown that meals of some pure protein will stimulate secretion nearly as well as will a regular mixed meat meal [31]. Although secretion after carbohydrate and fat ingestion is much less than that after protein ingestion [311, it undergoes a percentage augmentation after portacaval shunting similar to that seen with protein [13,19]. Southwell and colleagues [32] were unable to show a postshunt increase in gastric secretion, collected for one hour only, after the intrajejunal instillation of dextrose solution, olive oil, or amino acid solution. Occlusion of the portal vein results in an increase in basal or fasting gastric secretion [21]. This augmentation of basal secretion has generally been confirmed in studies on dogs with portacaval shunts [13,18,19,25,27] although it is not a uniform finding [13,32]. Some of the more interesting discrepancies in results are seen in studies on the effect of Vol.

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portacaval shunting on histamine-stimulated gastric secretion. The majority of reports indicate an augmentation of secretion stimulated by histamine after portacaval shunting [13,18, 27,33,34]. In two of three studies in which dogs with experimental hepatic cirrhosis underwent shunting, a postshunt increase was found in the secretory response to histamine [33,34] ; in one no increase occurred [35]. Hayashi and colleagues [l61 failed to detect any change in response to histamine in nine dogs subjected to portosystemic shunts using four different shunting procedures. In our laboratory [l7] six dogs with denervated Heidenhain pouches and innervated gastric fistulas were studied after gastric secretion had been stimulated by the intravenous infusion of histamine at 24 pg./ kg./hr. for eight hours. (This dose of histamine, expressed as the base, is approximately half the maximal dose for the denervated pouch 1361.) We found that portacaval transposition resulted in a 20 per cent decrease in the acid output from the denervated pouch and a 48 per cent decrease in the acid output from the innervated pouch. In the studies previously discussed, the histamine had been administered subcutaneously or intramuscularly, and there is some possibility that the differences in our results might be due to the route of administration, although they agree with reports that showed no postshunt increase in histaminestimulated secretion [16,35]. Although most experimental studies with portacaval shunting have been performed in dogs, acid hypersecretion after shunting has also been demonstrated in rats [37-391. Day and colleagues [373 found that the average twenty-four hour secretion of 2.83 ml. was increased to 7.55 ml. after portacaval shunting. Fischer and Snyder [39] observed that preshunt acid secretion in rats averaged 26.8 PEq. of hydrochloric acid per thirty minutes and that this was increased to 115.1 pEq. of hydrochloric acid per thirty minutes after shunting. In addition to studies on gastric secretion, an increase in gastric blood flow after shunting has been reported [40]. This was shown to be associated with an increase in cardiac output and with a relative and absolute increase in blood flow to the stomach, especially to the antrum, which received more than double the control level of blood flow after shunting [4ll. The increased gastric secretion after portacaval 855

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shunting may be due partially to diminished portal pressure with consequent improvement of circulation to the gastric mucosa [4%]. Portacaval shunting has been shown to result in spontaneous duodenal ulceration [16] and to increase greatly the mortality from experimental ulcers caused by histamine injection [15]. Hayashi and colleagues [16] studied the gastric secretory effects of mesocaval, splenocaval, and portacaval shunts. All three procedures resulted in acid secretion that more than doubled the control values, but mesocaval anastomoses resulted in the highest and splenocaval shunts in the lowest degree of hypersecretion. Gradual occlusion of the portal vein has been shown to result in acid hypersecretion [15,20, 211. Obstruction of the portal or splenic vein caused an increased weight of the stomach and predisposed to histamine-induced ulceration [43]. Studies on the Mechanism of Postshunt Hypersecretion. As soon as hypersecretion was reliably demonstrated to follow the construction of a portacaval shunt, investigators began to speculate on the nature of the agent responsible for the increased acid output. Gerez and Weiss [3] suggested that portal venous blood normally contains stimulants to gastric secretion that are partially absorbed or destroyed on passage through the liver, and that shunting allows these substances access to the systemic circulation. There is abundant evidence that the agent is humoral [40,44,451. It has been suggested that cholinergic mechanisms may trigger its release [27] and that the agent itself may be a peptide similar to gastrin [SS]. A secretagogue has been reported in the blood after prolonged portal occlusion [46]. Role of liver damage: Since portacaval shunts are performed in patients with moderate to severe liver damage, and since Eck fistulas in dogs are attended by progressive hepatic dysfunction, it is important to differentiate between the specific effects of liver damage and those of shunting on gastric secretion. Silen and co-workers [33,47,48] produced liver injury in dogs by the chronic administration of carbon tetrachloride. These dogs became cirrhotic and were found to have an increased acid output. It was suggested that the damaged liver either failed to inactivate portal secretagogues or released a humoral stimulant of acid secre856

tion. Guth [35] also reported increased gastric secretion in dogs rendered cirrhotic with carbon tetrachloride, but this secretion was not increased on subsequent portacaval shunting, contrary to the experience of Silen’s group [33]. Silen and co-workers [49] reported that biliary obstruction resulted in increased gastric secretion; in a further study, the increased gastric secretion was found to persist after removal of the obstruction if irreversible liver damage had occurred, but secretion returned to normal if hepatic function was reversible [50]. They suggested that the cirrhotic liver released a secretagogue. Streicher [51] reported in 1941 that progressive liver damage was followed by diminished acidity of gastric juice. These findings have been confirmed by Orloff and his colleagues [34,52,53] who reported a strong correlation between diminished acid output and deteriorated liver function. Clarke and colleagues [14] elected to use the portacaval transposition technic of Child and associates [54] in their classic study on the effect of portacaval shunting on gastric secretion because they wished to obviate significant alterations in liver function. Hepatic regeneration did not occur in the Eck fistula dog but proceeded at a good rate in dogs in which the vena cava and portal vein had been transposed [54]. Dogs with portacaval transposition were easily maintained in good health and showed normal liver function tests as well as normal hepatic histology, in dramatic contrast to dogs with Eck fistulas [55]. Nicoloff and co-workers [56] studied the effect of improving the oxygenation of the shunted liver by arterial anastomosis to the hepatic end of the divided portal vein. They observed that there was a great increase in acid output despite an excellent hepatic blood supply and normal results of liver function tests, and concluded that decreased liver function does not play a role in postshunt hypersecretion. There is no explanation now available for the different results reported in studies on the effect of liver injury on gastric secretion. It would seem that hepatic damage itself does not cause an increase in acid output and that postshunt hypersecretion is clearly independent of hepatic injury. Role of histamine: The role of histamine in all of gastric physiology [573 is as controversial

Gastric

as the suggestion that histamine may be the agent responsible for postshunt hypersecretion. Irvine and Code [58] reported increased acid output from the stomach and increased excretion of histamine after a meat meal. They suggested that histamine liberated into the portal vein may be partially inactivated by the liver. Irvine and colleagues [59] later reported that alternate portal and caval injections of histamine showed that hepatic transit greatly diminished the gastric secretory response and the urinary excretion of histamine, suggesting that histamine is inactivated or destroyed by the liver. Silen and Eiseman [19] confirmed this finding and suggested that portacaval shunting might provide systemic access for histamine absorbed from the gut. Normally inactivated by passing through the liver, this histamine might be the agent responsible for postshunt hypersecretion. They [60] later observed that the histamine content of postprandial blood taken from the portal vein was much greater than that of arterial blood. An increase in the histamine concentration in arterial plasma after a meat meal in both normal dogs and those with shunts was also reported, but the difference between the control and shunted dogs was not significant. They suggested that histamine, arising from exogenous protein, is liberated into the portal vein and that it may be the agent responsible for the increased gastric secretion after portacaval shunting. We have studied the histamine content (determined by a fluorometric technic [61]) of portal and systemic venous blood three hours post cibum. These data, shown in Table I, indicate that there was no difference in the histamine content of portal versus peripheral venous blood. Also against the suggestion that absorbed histamine is responsible for the increased gastric secretion after shunting are the elevated levels of fasting gastric secretion found after shunting [13,18.19,25,27]. Hubens and Deloyers [27] have objected to the proposed etiologic role of absorbed histamine; they found that the increased gastric secretory response to intestinal stimuli observed after shunting was blocked by agents that do not affect histamine-stimulated gastric secretion (atropine and local and vagal anesthetics). Studies on acid secretion and blood histamine concentration in control, cirrhotic, and shunted dogs have shown no increase in blood histamine Vol. 117. June

1969

TABLE

I

Secretion

after

Blood Histamine (nanograms/ml.)*

Portacaval

Shunting

Levels

Dog No.

Portal Vein

Peripheral Vein

T 1608 T 1631 T 1691

23.6 10.6 51.2

T 1700 T 1807 Average

12.3 26.5 24.8

20.6 4.5 43.0 12.7 36.1 23.4

*Histamine concentration in whole blood from antrectomized dogs. Samples taken three hours after a meat meal. There is no significant difference between the portal and peripheral blood histamine levels.

after a meal, and there was no correlation be_ tween the level of blood histamine and the amount of acid secreted [62,63]. An increased level of histamine in the blood was found after the induction of cirrhosis and after portacaval shunting [63], but Rex, Code, and ReMine [18] found no change in the urinary excretion of histamine in fasting dogs after portacaval shunting. The other suggestion involving histamine and portacaval shunting is that shunting may bring about an increased synthesis or diminished destruction of histamine with consequently greater gastric secretion. Day and coworkers [37] studied gastric hypersecretion in shunted rats and found an increased concentration of histamine in the liver, duodenum, and gastric mucosa after portacaval shunt. Fischer and Snyder [38,39,61] observed a fourfold increase in gastric secretion in shunted rats and an increase in the gastric mucosal concentration of histamine and histidine decarboxylase. The postshunt hypersecretion was suppressed by administration of histidine decarboxylase inhibitor, NSD-1055. The authors suggested that the postshunt hypersecretion is due to the liberation of greatly augmented stores of histamine in gastric mucosa, incident to a greater rate of synthesis after shunting. Reichle and co-workers [65] found an increased histamine excretion in the urine of shunted rats. We [17] have repeated some of these studies in clogs and have found no significant increase in the mucosal histamine concentration after shunting. There was no significant amount of histidine decarboxylase in the mucosa of the dog before or after portacaval transposition, and we found that the administration of NSD-1055 did not alter the postshunt hypersecretion. In evaluat857

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ing any finding regarding the role of histamine in gastric secretion in the rat, one must remember that the rat shows many unusual reactions and is the “maverick of histamine metabolism” [57]. The recent report of a very high level of blood histamine in a patient with a postshunt peptic ulcer [66] indicates the need for a comparison in the metabolism of histamine between normal and shunted patients. Role of gastrin: Although there were early suggestions that gastrin might be the etiologic agent responsible for postshunt hypersecretion [6,22], it is clear from subsequent studies that if gastrin has any role at all, it is a secondary one. Prior antrectomy does not prevent the development of hypersecretion after shunting [17,24,25] or subsequent ligation of the portal vein [21]; similarly, the hypersecretion after shunting is not abolished by subsequent antrectomy [14,25]. Although antrectomy subsequent to shunting did not abolish hypersecretion, it did result in a 43 per cent diminution in postshunt hypersecretion [28]. Systemic shunting of venous blood draining only that segment of the gut distal to the ligament of Treitz will cause acid hypersecretion [25,29], but caval shunting of the splenic vein alone has been observed to cause a doubling of acid output [16]. It is interesting to note that some agents are active on both portal and systemic administration whereas other compounds have diminished activity when given into the portal vein [67]. Histamine given intraportally is less than half as potent a gastric secretagogue as it is on systemic administration [19,59,68,69]. Bendett, Fritz and Donaldson [70] showed that the intragastric administration of histamine caused no stimulation of gastric secretion in control patients but evoked a vigorous acid output in patients after portacaval shunting. Secretin [71] and pentagastrin [16,69,72] have also been shown to be largely inactivated on passage through the liver. Gillespie and Grossman [68] showed that crude hog gastrin evoked similar strong gastric secretory responses on systemic and portal injection into dogs. This has been confirmed in dogs [73] and in rats [74]. Pancreozymin-cholecystokinin, which contains the same terminal 5 amino acids as does gastrin, has been reported to produce the same response on portal and on systemic injection [75]. We [69] have recently found that the portal injection of pure 058

synthetic human gastrin into the portal vein of dogs causes a stimulation of secretion from the denervated fundic pouch of the dog that is significantly less than that seen with systemic injection, and measurement of gastrin in the hepatic vein by radioimmunoassay would suggest that some gastrin is deactivated or destroyed on hepatic transit. Role of intestinal phase: Gerez and Weiss [3] first suggested that postshunt hypersecretion might be caused by a secretagogue absorbed from the intestine. Kohatsu and colleagues [26] observed that shunting resulted in gastric hypersecretion in dogs in which the cephalic and antral phases were inoperative [ 14,17,24,25] and concluded that secretion was due to a gastric secretory hormone or secretagogue elaborated by the intestine. A humoral agent has been demonstrated in studies with postcibal portal venous blood which stimulated gastric secretion on autotransfusion around the liver [44] and on cross transfusion [45]. Systemic shunting of blood draining the intestine distal to the ligament of Treitz brings about an increase in gastric secretion [16,25, 29,80]. Clarke, McKissock, and Cruze [29] found that the transposition of a previously created mesocaval shunt, which resulted in blood from the splenic vein going into the systemic circulation and blood from the gut distal to the ligament of Treitz going into the liver, resulted in loss of postshunt hypersecretion. Further studies with staged alterations in the venous drainage of the gut suggested that the secretory agent also originates, in part, from the colon [ 301. Resection of the proximal or distal half of the small bowel did not abolish the increased gastric secretion after shunting [28], and agents which are known to suppress the intestinal phase of gastric secretion (secretion, phenergan, and atropine) have been shown to suppress gastric hypersecretion after portacaval shunting [27,76]. Role of increased reactivity of gastric mucosa: Gillespie and Grossman [68] suggested

that the increased reactivity to antral stimuli noted after portacaval shunting was not caused by an increase in the amount of gastrin reaching the systemic circulation, but was due rather to an increase in the response to all forms of stimulation of parietal cells after portacaval anastomosis. Other investigators have also made this suggestion 118,271 and Hubens and The

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Deloyers [27] have further proposed that there may be an increase of the parietal cell mass after shunting. Since postshunt hypersecretion is easily detectable within three to four days after shunting, it would not appear to be due to an increase in the mass of parietal cells. Similarly, our findings that the same group of dogs showed substantial increase in the responsiveness to food and no increased responsiveness to 2-deoxy-Dglucose or to histamine give strong evidence that there is no general increase in reactivity [17]. There is general agreement that postshunt hypersecretion is caused, in part at least, by an unmasking of the intestinal phase. It would appear that the responsible agent is not an absorbed foodstuff since an augmentation of fasting secretion is a characteristic of the phenomenon. Moreover, an increased reactivity to pentagastrin [I71 and to gastrin II [27] has been shown, and many have been able to show an increased reactivity to histamine. There may well be more than one phenomenon involved. The aforementioned finding [I71 and that of Hayashi [16] showing increased secretion after splenocaval shunt would suggest that gastrin may be involved to some extent. There is also evidence that gastrin is partially deactivated on hepatic transit [69]. There may be a slight increase in the total amount of circulating histamine as suggested by Clarke, Miller, and McKissock [30] and as suggested in unpublished findings from our laboratory of an increased concentration of blood histamine in dogs shunted for more than six months. The nature of the humoral agent elaborated by the intestine on contact with food is unknown, but it may well be an intestinal form of gastrin whose active tetrapeptide fragment is in an exposed position and therefore easily deactivated on passage through the liver.

Shunting

made more difficult by the disparity between the incidence of peptic ulcer in clinical and in autopsy series and by the uncertainty as to whether an appropriate control series would consist of chronically ill debilitated patients or patients who are entirely well. The painstaking study of Watkinson [77] clearly shows that, in addition, the main determinant of the incidence of peptic ulceration in an autopsy series is the diligence with which the pathologist looks for mucosal scars. Watkinson [77] reported two separate series, in one of which 1’7 to 23 per cent of men over thirty-five years of age were found to have peptic ulcer, whereas in the other, the incidence was only half as great. Thus, the incidence of peptic ulcer in men over thirty-five years of age in these two carefully controlled series varies from 8.5 to 23 per cent. Reports on the effect of liver disease and of portacaval shunting on human gastric secretion have also conflicted greatly. Patients

with Cirrhosis

Clinical Studies

Incidence of Peptic Ulcer. Several reports have suggested that patients with cirrhosis have an increased incidence of peptic ulceration [6-8,78-801; others have questioned the existence of any such relationship [ 9,10,81]. The accumulation of the reports of Clarke [4], Liebowitz [8], Koide, Texter, and Borden [7], MacDonald and Mallory [9], Schriefers and colleagues [82], and Tabaqchali and Dawson [79] yields 4,256 patients with cirrhosis, 315 of whom had peptic ulceration, an average incidence of 7.4 per cent. Since no age- and sexadjusted control group is available, it is impossible to know if this represents any increase in the incidence of peptic ulcer from that of the general population. This incidence is within the range of reported control series [9,77,83], however, and it would appear that the burden of proof would rest upon those who wish to demonstrate a clear statistical relation between cirrhosis and peptic ulcer.

Evaluation of any relationship between peptic ulcer and liver disease with or without a portacaval shunt is an extremely complicated problem. Many patients with hepatic cirrhosis have peptic ulcers, and bleeding from gastric or duodenal ulcers is one of the most common serious complications after an operation for portacaval shunting. Demonstrating true statistical correlation between any two disease processes is difficult, however, and for these two it is

Contrary to studies on the incidence of peptic ulcer, most reports on gastric secretion in cirrhotic patients are in agreement that acid output is diminished in these patients [42,70,81, 841. Ostrow, Timmerman, and Gray [421 found the basal and histamine-stimulated acid secretion to be less than that of control patients in both compensated and decompensated cirrhotic patients. Patients who had cirrhosis and peptic

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Gastric

Secretion

in

Cirrhotic

Patients.

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TABLE

Peptic

II

Ulcer after Portacaval Number of Patients Shunted

Authors Bendett, Fritz, and Donaldson [70] Child [97] Clarke and co-workers I141 Dubuque, Mulligan, and Neville [ 151 Liebowitz [8] Linton, Ellis, and Geary

I921 Ludington [93] McDermott and coworkers [86] Mikkelsen, Turrill, and Pattison [94] Rousselot and coworkers [OS] Schriefers, Schreiber, and Esser [82] Tabaqchali and Dawson I791 Wantz and Payne [89] Wilkinson and Riddell (961 Total * Duodenal ulcer/gastric

Shunt

Peptic Ulcer Num-

Per

ber

cent

UU/ GU*

O/l

11

1

9.1

100

5

5.0

62

5

8.0

312

60 50

9 8

15.0 16.0

6/2

137 a

22 3

16.0 38.0

172

237

35

15.0

230

16

7.0

104

6

5.7

125

2

1.6

35 101

5 9

14.0 9.0

4/l 6/3

65 1325

5 131

7.7 9.9

312

13/3

ulcer.

ulcer had acid secretory outputs in the upper range of normal. Scobie and Summerskill [81] found the basal and the maximal histamine acid secretion to be significantly below normal in cirrhotic patients. Clarke, Costarella, and Ward [84] found no significant difference in the basal or food-stimulated acid secretory potential of control and cirrhotic patients. Although it is questionable that cirrhotic patients have an increased incidence of ulcer, they do indeed fall prey to pept.ic ulceration. In the presence of a low normal acid secretory output, the explanation for the development of peptic ulceration in cirrhotic patients may rest on diminished mucosal resistance in patients with chronic liver disease. Patients with Portacaval

Shunts

Incidence of Peptic Ulcer. The first evidence of a clear association between peptic ulcer and portacaval shunts was the report of Dubuque, Mulligan, and Neville [15] who observed a 15 per cent incidence of upper gastrointestinal ul860

ceration in sixty patients followed up for as long as eight years after construction of a portacaval shunt. Many reports have accepted or suggested an increased incidence of peptic ulcer in patients with portacaval shunts [14,15,66,85873; others have questioned or denied this relationship [8,10,79,88,89]. The virulent behavior of postshunt peptic ulcers has been commented upon, however, even by some who may not accept an increased incidence of ulceration [8,88-901. The combined data from fourteen reports are shown in Table II. The occurrence of 131 peptic ulcers in 1,325 patients is an incidence of about 10 per cent, which may or may not be significantly different from the 7.4 per cent incidence of peptic ulceration in cirrhotic patients previously reported herein. Of the fiftytwo cases in which the information is available, the ulcer was located in the duodenum in thirty-six instances (69 per cent) and in the stomach in sixteen cases (31 per cent). At least two explanations have been advanced for the putative relationship between peptic ulcer and portacaval shunting. Anton and Woodward [66] reported a postshunt ulcer patient with a high level of blood histamine and suggested that histamine may play an etiologic roleintheproposedincreased incidenceof peptic ulcer after portacaval shunt surgery. Ashikari and Dreiling [85] reported a diminished output of alkaline pancreatic juice after portacaval shunting and suggested that the loss of the neutralizing capacity of pancreatic juice may be a factor in the genesis of postshunt ulcer. Gastric Secretory Studies in Shunted tients. Although there are several gastric

Pa-

secretory studies available on shunted patients [42,70,79,81,82,84,96,97], the reports are notin general agreement, and it is not possible clearly to document hypersecretion in postshunt patients. In reports of gastric secretory studies performed before and after shunting in fiftynine patients [42,70,79,82,96,97], there was great variability in the responses of gastric acid secretion to shunting. Bendett, Fritz, and Donaldson [ 701 reported no change in the basal or maximal histamine-stimulated secretion in eleven patients before and after portacaval shunting. Ferrarese and Ronzini [97] studied ten patients subjected to various forms of portosystemic shunts. They found that the maximal histamine-stimulated secretion was greatly The American

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Gastric

increased in two patients, slightly to moderately increased in five patients, unchanged in two patients, and diminished in one patient. This great variability in results is characteristic of all reported studies. Ostrow, Timmerman, and Gray [421 studied two patients before and after shunting, one of whom showed an increase in both basal and histamine-stimulated secretion, whereas the other showed no change. Schriefers, Schreiber, and Esser [82] studied caffeine-stimulated gastric secretion in seventeen patients before and after shunting and found an increase in acid output in seven postshunt patients and no change or diminished acid secretion in ten patients. Tabaqchali and Dawson [79] studied two patients before and after portacaval shunting, one of whom had a remarkable increase and one a slight increase in basal acid output. In both, the histaminestimulated secretion was diminished postoperatively. Wilkinson and Riddell [96] studied seventeen patients before and after shunting, of whom only three showed an increase of the basal acid output and two an increase in the histamine-stimulated acid output after shunting. It is of interest that postshunt hypersecretion has been reported more commonly in studies in which secretory determinations were made only on postshunt patients (without preoperative control studies) than in studies performed pre- and postoperatively on the same patient. Ostrow, Timmerman, and Gray E4.21 studied eleven postshunt patients and found that both basal and histamine-stimulated secretion were higher than in a group of cirrhotic control patients, a finding that has been reported by others [79,82]. Clarke, Costarella, and Ward [84], however, found no difference in the basal or food-stimulated secretion in a series of control, cirrhotic, and postshunt patients. Scobie and Summerskill [81] studied four patients after shunting and found levels of basal secretion and of maximal histamine secretion that were not significantly different from those of control cirrhotic patients. It is of interest to note that in two postshunt patients in whom hypochlorhydria had been induced to treat the peptic ulcer syndrome, severe ammonia intoxication intervened [98]. It was suggested that the diminished acid output and the resultant overgrowth of the small bowel flora might enhance the production of ammonia. Vol. 117, June 1969

TABLE

III

Secretion

after

Portacaval

Shunting

Maximal Gastric Secretory Rates before and after Portacaval Shunting Before After shunting shunting

Stimulus

Per cent

Patient F.S. L.W. F.S.

0.42 1.77 46.5

0.77 3.77 32.7

+ a3 +113 - 20

L.W.

7.3

14.4

+

Insulin (15 u. intravenously)

F.S. L.W.

36.7 5.2

42.4 3.0

+ 15.5 - 42

Pentagastrin (6 pg./kg. subcutaneously)

F.S. L.W.

32.3 11.6

28.2 6.3

-

12.5 46

intestinal phase (500 ml. 1 M glytine into distal duodenum)

F.S. L.W.

3.3 4.5

1.8 2.1

-

45 53

Basal Histalog (100 mg. subcutaneously)

97

Since the intestinal phase of gastric secretion is uniformly augmented by experimental shunting procedures and since the effect of shunting on other gastric secretory stimuli tends to be variable even in experimental animals, it would seem important to test the effect of portacaval shunting on the intestinal phase of gastric secretion in man [IO]. We have studied pre- and postoperative secretory responses to insulin, betazole, pentagastrin, and to the intestinal instillation of 1 M glycine solution. The results on two patients indicated that basal secretion was augmented after shunting (Table III) whereas the other studies showed decreased or variable responses. Coda The mechanism for postshunt hypersecretion has not yet been completely unraveled. It results in an increase in gastric secretion that augments the response to food in particular, and in some studies does not affect the response to vagal or to histamine stimulation. Postshunt hypersecretion does not appear to be caused by liver injury; indeed, some forms of experimental hepatic damage and human hepatic cirrhosis seem both to result in diminished acid output. Histamine absorbed from the gut, or any other secretagogue arising from meat, does not seem to be responsible for postshunt hypersecretion since it would not account for the increased fasting secretion seen in shunted ani861

Thompson mals or in the increased response to pentagastrin or to gastrin II in fasting shunted dogs. In addition, there does not seem to be any difference in the histamine level in portal and peripheral blood, and in our studies 1171 there was no increased response to exogenous histamine in shunted dogs. The possibility that there may be an increased level of circulating histamine in shunted animals is more difficult to deal with. The increased concentration of histamine and histidine decarboxylase in the mucosa of shunted rats, and the diminution in postshunt hypersecretion in rats after the administration of a histidine decarboxylase inhibitor have not been substantiated in studies with dogs [17]. There may be, as suggested by Clarke, Miller, and McKissock [30], a liminal increase in the total amount of circulating histamine which might cause some augmentation of gastric secretion. Although there is abundant evidence that postshunt hypersecretion is not dependent on gastrin, there are suggestions that when present the gastrin mechanism may contribute to an increase in acid output after shunting: splenocaval shunting doubled acid secretion [16], antrectomy after shunting caused a diminution in acid secretion [23], and portal injection of human gastrin I in the dog caused a lesser secretory response than did systemic injection [ 691. The augmented intestinal phase response to food is clearly the single most impressive finding in shunted animals. Although the intestinal phase is responsible for a large part of postshunt hyperseeretion, it is not the only mechanism involved. Basal secretion in fasted animals is augmented after shunting, and the early response (within one hour) to food is clearly increased after shunting (for example, Figure 4 in reference 17), and there is no postshunt increase in early intestinal phase secretion (within one hour) in shunted dogs [32]. Postshunt hypersecretion would appear to depend on some agent released from the intestine on contact with food. This may well be an intestinal form of gastrin, and there is evidence that antral gastrin and perhaps minimal increases in circulating histamine may also have additive effects. The results of clinical studies are inconclusive. The incidence of peptic ulcer in cirrhotic patients is not clearly increased. Gastric secre862

tion is diminished, and ulcerogenesis in cirrhotic patients is not dependent on increased acid secretion but may be caused by a diminished mucosal resistance in patients with chronic liver disease. There is a 10 per cent incidence of ulcer in patients with portacaval shunt and this may represent a significant increase over the incidence in the control population. Hypersecretion of acid in shunted patients has not been documented. To answer this question, a large number of intestinal phase secretory studies on patients before and after shunting will be required. References 1.

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