General review

Portal Hypertension and Bleeding Esophageal Varices Kaj Johansen, MD, PhD, W. Scott Helton, MD, Seattle, Washington

Portal hypertension and bleeding esophageal varices (BEV) are a major cause worldwide of human morbidity and mortality. This review considers important contemporary data related to portal hypertension and BEV, derived when possible from prospective randomized human trials. Excellent recent comprehensive reviews [1-5] provide more details.

EPIDEMIOLOGY Portal hypertension has numerous pre-, intra-, and posthepatic causes (Table I). In Western countries BEV most commonly result from various forms of hepatic cirrhosis, in 90% of circumstances due to chronic alcoholism [6]. Portal hypertension in Asian and developing countries arises primarily as the consequence of postnecrotic cirrhosis or schistosomiasis [7]. BEV are a major reason why hepatic cirrhosis ranks ninth among all causes of death in the United States [8]. Management of BEV is extraordinarily costly: in 1980 charges per hospitalization to treat variceal bleeding ranged from $35,000 to $53,000 [9].

ANATOMY AND PATHOPHYSIOLOGY Normal portal venous flow is about 1200 ml/min; due to minimal resistance to flow through the nondiseased liver, normal portal venous pressure is 5-7 mmHg, and the corrected portal pressure (portal vein pressure minus inferior vena cava pressure) rarely exceeds 5 mmHg [2]. In cirrhosis progressive fibrosis occludes the hepatic sinusoids; portal vein flow falls while portal From the Department of Surgery, University of Washington School of Medicine, Seattle, Washington. Reprint requests: Kaj Johansen, MD, PhD, Department of Surgery, RF-25, University of Washington School of Medicine, Seattle, Washington 98195. 553

collateral flow rises, primarily via the coronary and short gastric venous complexes. These connect via the esophagogastric variceal plexus with the azygos and hemiazygos tributaries of the superior vena cava. Other portal-systemic collaterals, generally of less clinical relevance, arise between the recanalized umbilical vein and veins of the abdominal wall, the inferior mesenteric and hemorrhoidal veins, and various retroperitoneal collaterals, especially in the left perirenal region. Large "iatrogenic" portal-systemic collaterals may form in postabdominal surgical adhesions [10] and in abdominal wall stomata [ 11]. Portal pressure in cirrhosis is approximately 20 mmHg [2], and may exceed 40 mmHg in variceal bleeders. Varices do not bleed unless corrected portal pressure exceeds 12 mmHg [12]. Risk of bleeding from varices relates roughly to their size, confluence, and endoscopic signs of incipient or recent bleeding [13,14]. Absolute portal pressure, medications, types of food, or concurrent esophagitis are not predictive of variceal bleeding; BEV may be associated with upper respiratory infection in children [15]. In a minority of cases portal hypertension arises from occlusion of the extrahepatic portal [16] or splenic [17] vein. Neonatal sepsis is the most common cause of extrahepatic portal vein occlusion in children [ 16,18]; in adults hepatocellular carcinoma [19] or various hypercoagulable states [20] may be implicated. "Sinistral" or "left-upper-quadrant" portal hypertension arises from thrombosis or extrinsic compression of the splenic vein, usually secondary to pancreatitis or cancer, and results in gastric varices [17,21].

PRESENTATION AND DIAGNOSIS In patients with BEV, symptoms and signs of advanced hepatic dysfunction are common--as-

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TABLE l.--Causes of portal hypertension Pre-sinusoidat Extrahepatic Portal vein thrombosis Splenic vein occlusion Increased splenic blood flow (e.g. myelofibrosis) Intrahepatic Schistosomiasis Congenital hepatic fibrosis Portal zone infiltrations (reticulosis, sarcoidosis) Other causes not defined by pre-, intra-, or post-sinusoidal obstruction Hematologic diseases (lymphomas, leukemia, myeloproliferative disorders) Idiopathic (portal phlebosclerosis, Banti's syndrome) Nodular abnormalities (partial nodular transformation, regenerative hyperplasia) Sinusoidal Cirrhosis Sinusoidal occlusion (vitamin A toxicity, Gaucher's disease, myeloid metaplasia) Alcoholic hepatitis Post-sinusoidal Hepatic vein occlusion (vascular occlusion due to malignancy, Budd-Chiari syndrome) Veno-occlusive disease Alcoholic central hyaline necrosis

cites, mild to marked jaundice, muscle wasting, and encephalopathy (either spontaneous or as a consequence of gastrointestinal blood). Splenomegaly is the earliest physical sign of portal hypertension [2]. Cutaneous and soft tissue changes may include spider angiomata, palmar erythema, male gynecomastia and testicular atrophy, feminization of hair distribution, and abdominal wall venous collaterals. A tender palpable liver suggests acute alcoholic hepatitis or malignancy. Patients with BEV usually present with painless hematemesis; melena is a less common initial symptom. Laboratory data may be normal, although elevations in serum bilirubin, hepatocellular enzymes, and prothrombin time are common. Serum albumin level and platelet, polymorphonuclear leukocyte, and red-cell counts may be depressed. Blood alcohol levels may be elevated. Ultrasound or duplex scanning have become initial imaging techniques of choice in portal hypertension [22]. Fiberoptic esophagogastroduodenoscopy (EGD) is the mainstay of the diagnosis (and initial management) of BEV. The number, size, length, confluence, and distribution of varices can be determined by EGD; active bleeding sites may be visualized. Non-variceal causes of upper gastrointestinal hemorrhage, present in up to 20% of patients with esophageal varices [23], can be identified. In 90% of cases, bleeding arises from esophageal varices near the gastroesophageal junction [2,3]. Occasionally gastric varices are the site of bleeding [17,21,24], and even more rarely bleeding may result from duodenal [25], stomal [11], or rectal [26] varices or from portal hypertensive gastropathy [27].

INITIAL M A N A G E M E N T The diagnosis of BEV is generally made by EGD, at which time active bleeding from varices, or signs of recent variceal hemorrhage are noted. Endoscopic injection sclerotherapy (EIS) can be accomplished simultaneously and is highly effective: bleeding halts in more than 90% of cases [28-30]. Fiberoptic endoscopes are more effective than rigid ones [31]. Sclerosant materials, volumes injected, frequency of repeat EGD and sclerotherapy, and technique (intra- versus para-variceal [32]) are unresolved issues [33,34]. Endoscopic banding of esophageal varices may be an effective alternative [35]. Vasopressin, a splanchnic vasoconstrictor which diminishes portal tributary flow, is commonly administered intravenously (IV) to lower portal pressure and, hopefully, reduce early recurrent hemorrhage. Addition of nitroglycerin may reverse the cardiac and mesenteric ischemic effects of vasopressin [36,37]; a potent venodilator, nitroglycerin may itself further lower portal pressure [38]. Somatostatin has a similar therapeutic effect as vaso. . . . . . . [39-41]; it has fewer toxic side-effects but is much more expensive [2]. Although recurrent bleeding is reduced significantly with vasopressin or somatostatin administration, controlled trials have not demonstrated a survival benefit of such therapy [39,41]. Trials of sympatholytic [42,43] or serotininactive [44] agents have been conducted. Blood and blood products must be administered to the variceal bleeder as needed; all patients with BEV should be hospitalized, for early rebleeding occurs in at least 50%, and definitive therapy should be planned at the first hospitalization. Mortality risk approaches 50% per hospital admission [3,45].

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TABLE II.mAcute management of bleeding esophageal varices

Treatment Medical resuscitation Vasoconstrictor therapy Somatostatin Tamponade Tamponade and vasoconstrictor Sclerotherapy* Esophageal transection Portocaval shunt

Immediate Control (%)

Early Rebieeding (%)

Hospital Mortality (%)

0-83 29-71 53-70 42-86 86-100

8-80 33-45 20-47 24-58 21-57

25-80 30-58 20 13-56 12-24

74-95 71-100 81-100

13-50 0-26 0-19

9-56 24-75 17-56

References 3,45,124,126 36,38,39,41,123-125 39-41 29,30,49,50,72,78,122,126

29,49,53,72,78,122 73-76,127 56-56,128,129 53,54,57,91

*Alone or fot~wing tamponade therapy

Whether BEV patients can be effectively managed in the community setting or should be stabilized and transferred to a specialized center is unclear. In 5-10% of BEV patients, bleeding is relentless despite sclerotherapy and intravenous vasoconstrictor therapy. Such bleeding can be controlled in most cases by gastroesophageal balloon tamponade [46-49]. Care must be taken with tube insertion and balloon inflation to avoid esophageal or gastric rupture [50]. Since aspiration pneumonitis is commonplace in this setting, endotracheal intubation and mechanical ventilation are prudent. Coronary vein obliteration by transhepatic arteriographic techniques has been proposed [51]. While early control of hemorrhage can be obtained, complications (including early rebleeding and portal vein thrombosis) are substantial [52] and this technique is now rarely used. Because of the relatively high incidence of early rebleeding following EIS, balloon tamponade, transhepatic arteriographic variceal obliteration, and other palliative treatments, some have argued for emergency definitive therapy--portal decompression, devascularization, or transplantation. Orloff reports a remarkably low operative mortalit y - a s low as 17% in recent reportswin unselected cirrhotics with BEV receiving emergency portacaval shunt within eight hours of hospital admission; survival is 79% at two years in his series [53]. A prospective randomized trial comparing emergency shunt versus maximal medical therapy (except EIS) showed significant advantages for shunted patients in terms of control of bleeding (100% versus 45%), blood requirements (5.8 versus 15.5 units), and early survival (8 I% versus 45%) [54]. A randomized trial of emergency portacaval shunt versus EIS is underway in San Diego. Emergency esophageal transection, utilized originally in the 1960s [55], has been resurrected as an early "definitive" treatment [56]. Several series reveal relatively low operative mortality and rebleeding in the acute setting; however, risk of later hemorrhage from gastric or recurrent esophageal varices may be substantial [56-58]. Results of var-

ious types of acute intervention are indicated in Table II.

DEFINITIVE T R E A T M E N T Orthotopic liver transplantation (OLT) is the only curative therapy for portal hypertension and its underlying hepatic cirrhosis. OLT to treat BEV can be performed with a one-year survival rate approaching 80% in variceal bleeders [59]; thus, Rikkers' proposal [60] that the initial management question should be: "Is this patient a candidate for OLT?" seems sensible. Potential OLT candidates with BEV should be treated by EIS or, if portal decompression is required, distal splenorenal, mesocaval, or other shunts which did not involve the hilum of the liver. Novel arteriographic portacaval communications (v.i.) may be advantageous in this setting. While a prior shunt can no longer be considered an absolute contraindication to OLT [61], scarring and adhesions associated especially with portacaval shunts clearly make subsequent OLT more technically challenging [62,63]. Some have argued that OLT is no less warranted or successful in alcoholic cirrhotics than in patients with nonalcoholic causes of end-stage liver disease [64]; others disagree [65]. Whatever the answer, advanced age, medical comorbidity, unavailability of donor livers, or patient noncompliance eliminate most cirrhotics with variceal bleeding as candidates for OLT. Some other form of definitive therapy must be planned in such patients because of their dismal prognosis (without treatment, recurrent variceal bleeding occurs in 28% of Child Class A, 48% of Child Class B, and 68% of Child Class C cirrhotics within one year [3,66], with more than 90% dead within five years [2,3,45]). Available "definitive" treatment includes pharmacologic therapy with beta blockers, chronic injection sclerotherapy, esophagogastric devascularization, or various forms of portal decompression. Chronic beta blockade to prevent recurrent variceal hemorrhage has been evaluated in several

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TABLE III.--Pugh-Child classification [55,81] Clinical and biochemical measurements Encephalopathy (grade) Ascites Bilirubin (mg%) Albumin (g/L) Prothrombin time (seconds prolonged) Overall severity: Grade A = 5-6 points Grade B = 7-9 points Grade C = 10-15 points

Points scored for increasing severity of liver disease 1

2

3

None Absent 1 to 2 > 3.5 1 to 4

1 and 2 Slight 2 to 3 2.8 to 3.5 4 to 6

3 and 4 Moderate > 3 < 2.8 > 6

prospective randomized trials in Europe and the United States, with conflicting results. All studies show a significant drop in corrected portal pressure in treated patients. Several European trials [67--69] have demonstrated a significant reduction in recurrent BEV. However, a majority of controlled studies [68-71] have demonstrated no reduction in mortality in this setting. The reason for these differences is unclear but may relate to patient selection (alcoholic patients appear to benefit less) and study design. The efficacy of variceal sclerotherapy in the acute setting is well established (v.s.), and this technique has also been widely used as chronic therapy against recurrent BEV [72-77]. Numerous controlled trials have demonstrated that varices can be eradicated by this technique; however, only two studies [29,75] demonstrated a survival advantage for patients with BEV treated with chronic injection sclerotherapy. Up to 60% of patients treated with chronic EIS will have recurrent bleeding [72-76]. Many patients will either be noncompliant or will refuse chronic EIS, and the complications associated with EIS [78-80] are cumulative with time. Therefore, alternative therapy for recurrent or intractable variceal hemorrhage in patients undergoing EIS must be available. Portal decompressive surgery is highly effective at halting further variceal bleeding, with long-term success rates in most series exceeding 90%. A significant risk of encephalopathy and accelerated liver failure accompanies shunt surgery, especially in decompensated cirrhosis. The Child [81] or Pugh [55] scoring systems are used to predict outcome following portal decompression or esophageal transection (Table III). Total shunts (portacaval, central splenorenal, or mesocaval) are technically easiest to perform. Sideto-side shunts are most effective at relieving ascites. Interposition shunts using prosthetic grafts historically have had a high rate of graft thrombosis and recurrent variceal hemorrhage [82]; the use of smaller-caliber, externally-supported prosthetic grafts [83] may improve patency rates. Portacaval

shunts cause encephalopathy to some degree in at least 50% of patients [84]; this may be mitigated by partial portal decompression via small-orifice shunts [83-85], the beneficial effects of which are felt by some [83] to result from maintenance of portal perfusion of the liver, and by others [84,85] to prevention of neurotoxin absorption from the intestinal lumen. Controlled trials comparing total shunts and optimal medical therapy demonstrated, at best, nonsignificant trends toward increased survival in surgical patients. Reduced mortality from recurrent variceal hemorrhage in shunted patients was virtually neutralized by an increased mortality from liver failure [86-89] (Table IV). Prospective comparison of emergency total shunt and endoscopic sclerotherapy in Child C cirrhotics initially demonstrated a marked advantage for sclerotherapy (90); however, at four years follow-up, recurrent bleeding, units of blood transferred and numbers of hospital days were significantly higher among sclerotherapy patients, with no difference in survival between the two groups [91 ]. Selective portal decompressive procedures, most specifically the distal splenorenal shunt of Warren [92], theoretically provide simultaneous variceal decompression and preservation of antegrade portal flow [84,92,93]. The distal splenorenal shunt can be performed with relatively minimal risk of mortality-generally less than 10% [92-103]. Variceal rebleeding may recur in up to 10% of patients who have undergone distal splenorenal shunt [102]. Because antegrade portal flow is lost in at least 50% of operated patients within one year [93,104], encephalopathy risks rise substantially, particularly in alcoholic cirrhotics [ 105,106]. The addition of splenopancreatic disconnection [107], designed to preserve prograde portal flow, makes the selective shunt procedure even more technically taxing. Controlled trials of the distal splenorenal shunt compared to maximal medical therapy (including EIS) demonstrated a convincing initial survival advantage to patients randomized to sclerotherapy [74,95, I01]. However, more than one-third of such

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TABLE IV--Survival and rebleeding in trials of sclerotherapy versus shunt surgery

Study location [ref] Barcelona ~ [101] Nebraska D [95] San Francisco c [91] Atlanta a'd [108] Milan a [130] Barcelona" [131]

Year reported 1987 1987 1987 1990 1990 1991

% of patients rebleeding Shunt Sclerotherapy 14 38 19 57 0 75 3 41 5 35 3 40

Encephaiopathy (%) Shunt Sclerotherapy 24 8 16 7 25 28 nr nr 5 11 40 12

Long-term modality Sclerotherapy Shunt 50 (5 years) 55 35 (2 years) 35 72 (18 months) 88 57 35 (4 years) 10 (2 years) 5 21 (2 years) 27

100% of patients had (a) distal splenorenal shunt, DSRS, or (8) end-side portocaval shunt b82% of shunted patients had DSRS, 18% had side-side portocaval shunt c100% of patients were Childs C and actively bleeding; 40% of sclerotherapy patients crossed over to portocaval shunt for rebleeding d35% of patients in sclerotherapy crossed over to DSRS for rebleeding nr = not reported; all reported incidences of encephalopathy

patients have significant recurrent bleeding. Surgical shunt "salvage" of such sclerotherapy failures results in a highly significant (p = 0.01) survival advantage in patients treated with such "combination" therapy [74,108]. Such an approach is much less effective if patients are non-compliant or live a great distance from the medical center [95]. Comparisons of total and selective shunts [94,96100,109] have, in the main, failed to demonstrate a definitive survival difference [103] (Table V). Total shunts are technically easier and may be particularly appropriate in the emergency setting. Selective shunts may result in less incapacitating postshunt encephalopathy, especially in nonalcoholic cirrhotics [105,106], making them the procedure of choice in elective settings. Various devascularization procedures, combining esophageal transection, splenectomy, and extensive ligation of gastroesophageal venous collaterals, have been proposed as a non-shunt alternative to provide protection against recurrent variceal hemorrhage [110,111]. While risk of rebleeding and encephalopathy is acceptably low following performance of these procedures, they are technically taxing, and operative mortality and morbidity are substantial. Angiographic portal-systemic decompression techniques have been attempted for more than 20 years [112]. Initial clinical trials in the 1980s showed early technical success without reliable long-term patency [113]. The recent development of expandable metal stents has enabled development of the transhepatic intraparenchymal portal-systemic shunt (TIPS) [114,115]. Among 25 patients in a San Francisco series, the procedure demonstrated ini-

tial technical success in 100%, a primary patency of 88% (3/25 TIPS occluded but were reopened arteriographically) and a 30-day mortality of 20% (none from recurrent bleeding) [I 15]. TIPS may be especially useful in patients with BEV as a "bridge" to transplantation. No randomized trials comparing TIPS and conventional treatment have been conducted; a prospective comparison of TIPS versus EIS is in progress at the University of California, San Francisco, while a comparison of TIPS and operative portal decompression in Child A and B cirrhotics with BEV is underway at the University of Washington in Seattle.

PROPHYLAXIS While seeming to be a logical approach, prophylaxis against BEV, i.e. therapy administered prior to the first variceal hemorrhage, does not appear to be warranted. This may not be surprising in view of the fact that only a third of cirrhotics develop varices, and of these only a third suffer a variceal hemorrhage. Prophylactic sclerotherapy has not definitively improved survival; in fact, two series show an increased morbidity and mortality in patients randomized to sclerotherapy, and a higher incidence of subsequent BEV, than control patients [116,117]. Four controlled trials in the 1950s and 1960s demonstrated no survival advantage associated with prophylactic portocaval shunt [118]. Finally, prospective randomized trials of propranolol administered prophylactically to cirrhotics whose varices have never bled show a substantial reduc-

TABLE V--Selective versus nonselective portosystemic shunting for long-term control of bleeding esophageal varices [94,96-99,132] Shunt

Variceal bleeding (%)

Hospital mortality (%)

Portocaval shunt Selective shunt

4-12 9-27

0-13 2-13

Encephalopathy (%) Mild Severe

17-45 8-51

9-33 0-12

5 year survival (%)

19-53 24-60

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tion in risk of BEV [11%121], but no resultant difference in survival.

SUMMARY Bleeding from esophageal varices exacts a high mortality and extraordinary societal costs. Prophylaxis-medication, sclerotherapy, or shunt surgery to prevent an initial bleeding episode is ineffective. In patients who have bled from varices, endoscopic injection sclerotherapy can control acute bleeding in more than 90% of patients. Because recurrent bleeding frequently occurs and survival without definitive therapy is dismal, selection of a permanently effective treatment is mandatory once variceal bleeding has been controlled. Long-term injection sclerotherapy can be performed in compliant patients; it is relatively safe but is associated with a 30-50% rebleeding rate. Betablockers significantly reduce portal pressure and recurrent bleeding but have not been shown to diminish mortality from BEV. Portal decompressive surgery permanently halts bleeding in more than 90% of patients; the risk of operative mortality is high in decompensated cirrhotics, and long-term complications of encephalopathy and accelerated liver failure may limit indications for shunt surgery to good-risk cirrhotics who are not liver transplant candidates. Devascularization procedures have a low operative mortality and encephalopathy rate but unacceptably high rates of recurrent bleeding. Liver transplantation is curative therapy for bleeding esophageal varices and the associated underlying hepatic dysfunction; cost and availability of donor organs generally limit its use in this setting to variceal bleeders with end-stage liver disease not associated with active alcoholism.

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Portal hypertension and bleeding esophageal varices.

Bleeding from esophageal varices exacts a high mortality and extraordinary societal costs. Prophylaxis--medication, sclerotherapy, or shunt surgery to...
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