Portal hypertension

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Portal hypertension

Geoffrey H. Haydon, John Isaac, John A.C. Buckels and Simon P. Olliff

Introduction

The management of portal hypertension has evolved from a surgical discipline into one with the majority of patients successfully treated by medical and radiological therapies. Surgery still has a distinct role for a limited number of patients, chiefly those with extrahepatic portal hypertension and those suitable for liver transplantation (which can cure both the complications and the underlying liver disease). As patients with gastrointestinal (GI) bleeding will often be referred for a surgical opinion, it is important that the surgeon has a good understanding of the pathophysiology of variceal bleeding as well as the treatment options.

Portal hypertension itself does not require treatment, but intervention is indicated when the risk of bleeding from varices is present or when complications such as actual variceal haemorrhage or the formation of ascites occur. The management of many patients commences with a herald variceal bleed, which requires effective therapy before a plan can be made for longer-term treatment. A significant choice of options is now available, many of which are evidence based. These include: pharmacotherapy to both prevent and treat variceal bleeding; endoscopic options of injection therapy or variceal ligation; radiologically placed transjugular intrahepatic portosystemic shunts (TIPS); and surgical options (surgical shunts and liver replacement). The selection of these options needs to be tailored to the individual patient, taking into account their general fitness, including severity of any underlying liver disease and the local medical facilities and expertise available.

This chapter will briefly outline the causes, pathophysiology and natural history of portal hypertension, but will concentrate on the evaluation and management of both asymptomatic patients and patients who present with an acute bleed, together with longer-term strategies. In addition, specific recommendations will be made for the management of ascites and for patients with hepatic venous outflow obstruction due to Budd–Chiari syndrome.

Aetiology and pathophysiology of portal hypertension

Traditionally, portal hypertension has been classified as prehepatic, intrahepatic or posthepatic, with the intrahepatic causes subdivided into presinusoidal, sinusoidal and postsinusoidal (Table 8.1). Prehepatic causes are usually due to portal vein thrombosis, which is discussed later in this chapter. The main cause of portal hypertension in the West is cirrhosis. This is a sinusoidal obstruction to portal flow with varying causes. Viral hepatitis and alcoholic liver disease are the most common causes, but others include primary biliary cirrhosis, primary sclerosing cholangitis and haemochromatosis. Presinusoidal obstruction due to hepatic fibrosis occurs in schistosomiasis. Worldwide, this is one of the commonest causes of portal hypertension and, as it is usually associated with normal liver function, has a better prognosis. The main causes of postsinusoidal portal hypertension are hepatic venous thrombosis (Budd–Chiari syndrome) and veno-occlusive disease.

Table 8.1

Causes of portal hypertension

Presinusoidal	Sinusoidal	Postsinusoidal
Extrahepatic	Cirrhotic	Budd–Chiari syndrome
Portal vein thrombosis	Postviral (B, C)	Veno-occlusive disease
Splenic vein thrombosis	Alcoholic	Caval web
Increased splenic flow (tropical splenomegaly, myelofibrosis)	Cryptogenic Primary biliary cirrhosis Primary sclerosing cholangitis	Constrictive pericarditis
Intrahepatic	Chronic active hepatitis
Schistosomiasis	Haemochromotosis
Congenital hepatic fibrosis	Wilson’s disease
Sarcoidosis	Non-cirrhotic
	Acute alcoholic hepatitis
	Cytotoxic drugs

Experimental studies have demonstrated that the initial factor in the pathophysiology of portal hypertension is the increase in vascular resistance to portal blood flow. In cirrhosis, this increase in resistance occurs in the hepatic microcirculation (sinusoidal portal hypertension), and is a consequence of both a ‘passive’ and an ‘active’ component. The ‘passive’ component is the mechanical consequence of the hepatic architectural disorder resulting from histological cirrhosis, and the ‘active’ component is the active contraction of portal/septal myofibroblasts, activated stellate cells and portal venules. The increase in intrahepatic tone is probably a consequence of an imbalance between an increase in the endogenous vasoconstrictor substances, such as endothelin, noradrenaline, leukotrienes and angiotensin II, and a relative decrease in the endogenous vasodilator nitric oxide.¹ Vasodilatory drugs (for example, calcium channel blockers) may restore the equilibrium in intrahepatic tone, although they are not used for this indication in clinical practice.

The other major pathophysiological factor contributing to portal hypertension is an increase in portal venous blood flow through the portal circulation resulting from splanchnic arteriolar vasodilatation caused by an excessive release of endogenous arteriolar vasodilators (endothelial, neural and humoral). This can be corrected by means of splanchnic vasoconstrictors such as terlipressin and non-selective beta-blockers. Many drugs that lower portal pressure both reduce intrahepatic vascular resistance and decrease portal venous inflow.

An important but rare form, segmental or left upper quadrant portal hypertension, occurs in patients with splenic vein thrombosis. This should be suspected in patients with bleeding gastric varices but normal liver function, particularly if there is a history of either acute or chronic pancreatitis.

The natural history of portal hypertension

The prevalence of oesophageal varices in patients with cirrhosis and portal hypertension is high. When cirrhosis is diagnosed, varices are present in 40% of compensated and 60% of decompensated cirrhotics.² After the initial diagnosis of cirrhosis, varices develop with an incidence of 5% per year; subsequently, they may progress from small to large at an incidence of 10–15% per year.³ Rapid progression of hepatic decompensation is associated with a rapid increase in size, whilst improvement in liver function, particularly when associated with removal of the injurious agent (e.g. abstinence from alcohol), may result in a decrease in size or disappearance of the varices.⁴^,⁵

The overall incidence of variceal bleeding following diagnosis is of the order of 25% in unselected patients. The most important predictive factors of variceal bleeding are severity of liver dysfunction, size of varices and intravariceal wall pressure (which although difficult to measure may correlate at endoscopy with the presence of red spots or red weals).⁶ Traditionally, liver dysfunction has been classified using the Child–Pugh score⁷ (Table 8.2), but a more recent scoring system, the MELD (Model for End-stage Liver Disease), may be a better prognostic indicator (Box 8.1).⁸ Variceal size may be the best single predictor of variceal bleeding and generally it is used to decide whether a patient should be given prophylactic therapy or not. Whether a patient dies from a variceal bleed depends on the severity of the accompanying liver failure; those with a high Child–Pugh or MELD score have been reported to have as high a risk of mortality as 30–50% within 6 weeks of the index bleed.⁹ However, a more realistic figure would be 20% at 6 weeks with an immediate mortality from uncontrolled bleeding as low as 5–8%. Indeed, in 40–50% of patients who bleed and develop hypotension, variceal bleeding stops spontaneously, probably as a result of reflex splanchnic vasoconstriction with associated reduction in portal pressure and blood flow; this beneficial response is nullified by over-transfusing the patient.

Box 8.1 Model for End-stage Liver Disease (MELD)

MELD is calculated for patients over the age of 12 based on the following variables:

• Serum creatinine (mg/dL)

• Total bilirubin (mg/dL)

• INR (international normalised ratio).

The formula incorporates these variables as:

The following rules must be observed when using this formula:

• 1 is the minimum acceptable value for any of the three variables.

• The maximum acceptable value for serum creatinine is 4.

• The maximum value for the MELD score is 40. All values higher than 40 are given a score of 40.

• If the patient has been dialysed twice within the last 7 days, then the value for serum creatinine used should be 4.0.

In being considered for liver transplantation, patients with a diagnosis of liver cancer are assigned a MELD score based on how advanced the cancer is, using the TNM staging system.

Table 8.2

Child–Pugh classification

Grade A 5–6 points; Grade B 7–9 points; Grade C 10–15 points.

^*In primary biliary cirrhosis, the point scoring for bilirubin level is adjusted as follows: 1, < 68; 2, 68–170; 3, > 170.

The incidence of re-bleeding ranges between 30% and 40% within the first 6 weeks; this risk peaks in the first 5 days following the index bleed. Bleeding gastric varices, active bleeding at emergency endoscopy, low serum albumin levels, renal failure and a hepatic venous pressure gradient > 20 mmHg have all been reported as significant indicators of an early risk of re-bleeding.10–12 Patients surviving a first episode of variceal bleeding have a very high risk of re-bleeding (63%) and death (33%), and this is the basis for treating all patients to prevent further bleeding.⁹

Presentation

Portal hypertension may present acutely with variceal bleeding or be discovered during the investigation of a patient with liver disease. Varices are usually easily diagnosed at endoscopy and patients will then be investigated systematically. A classification of the grading of varices is given in Table 8.3. Presentation of patients with liver disease is variable and ranges from non-specific tiredness to advanced encephalopthy with decompensation. External features of advanced liver disease such as spider naevi, palmar erythema and ascites are easy to detect, although these signs will be lacking in many patients. Splenomegaly is probably the most useful physical sign, although some patients will have the classic sign of dilated umbilical vein collaterals (caput medusae).

Table 8.3

Classification of oesophageal and gastric varices

Imaging

Doppler ultrasonography is a useful and easily obtained initial imaging modality for patients with suspected portal hypertension. Spleen size and the state of the liver parenchyma can be assessed together with portal and hepatic vein patency and flow velocity, and the presence or absence of varices can often be inferred. Computed tomography (CT) and magnetic resonance imaging (MRI) now give detailed roadmaps of vascular anatomy prior to any surgical intervention with no need for invasive angiography in most cases.

Management of varices

The management of oesophageal varices will be considered in three sections: the prevention of bleeding in patients with varices who have never bled (primary prophylaxis); the longer-term management of patients who have bled to prevent future bleeding episodes (secondary prophylaxis); and the emergency resuscitation and initial control of the acute bleeding episode. Though the emergency management of many patients will be in a district general hospital, patients may require referral to specialised centres with expertise in liver diseases and where recourse to specialised radiological intervention is available. As pharmacological therapy is employed in the majority of cases, the treatment aims of this will be discussed first.

Therapeutic aims for pharmacological therapy in portal hypertension

The hepatic venous pressure gradient (HVPG) reflects accurately portal pressure in sinusoidal portal hypertension and is readily measured by hepatic vein catheterisation.

Varices do not develop until the HVPG increases to 10–12 mmHg and the HVPG must be greater than 12 mmHg for the appearance of complications such as variceal bleeding and ascites.¹³ Longitudinal studies of patients with complications of portal hypertension have demonstrated that when an HVPG decreases to less than 12 mmHg with pharmacological therapy, TIPS or an improvement in liver function, variceal bleeding is prevented and varices may decrease in size or disappear altogether.¹⁴ When this target is not reached, a substantial reduction in portal pressure by more than 20% still offers protection against variceal bleeding¹⁵ and thus these two parameters are regarded as the end-points to therapeutic strategies to lower portal pressure.

Recent evidence suggests that these therapeutic end-points may also reduce the risk of other complications of portal hypertension, including ascites, spontaneous bacterial peritonitis and hepatorenal syndrome.¹⁶^,¹⁷

Oesophageal varices

Primary prophylaxis for the prevention of variceal haemorrhage

All patients with cirrhosis should be screened for varices at the time of first diagnosis of their cirrhosis. In patients with grade I varices at index endoscopy, a follow-up endoscopy should be performed after 12 months to detect the progression from grade II to III varices. Patients without varices should be re-evaluated 2–3 years after their index endoscopy.

The mainstay of primary prophylactic therapy in the prevention of variceal haemorrhage is the non-selective β-adrenergic receptor blocker (beta-blocker). Twelve trials using beta-blockers in this context have been reported.

A meta-analysis has indicated that indefinite treatment with propanolol or nadolol significantly reduces the bleeding risk from 25% with non-active treatment or placebo to 15% with beta-blockers over a median follow-up period of 24 months; there was no significant reduction in mortality.³ The benefit of therapy was only proven in those patients with grade II (or larger) varices; there was no evidence to support the use of primary prophylactic therapy in patients with grade I varices.

Withdrawal of therapy was associated with a return to the same bleeding risk (25%) as the untreated subpopulation; indeed, there may also be an increased risk of mortality over untreated patients in those individuals who stop therapy.¹⁸^,¹⁹

Assessment of the success of primary prophylactic therapy is ideally undertaken by measurement of the HVPG before and after initiating therapy, with the aim being to reduce the HVPG to < 12 mmHg or to reduce it by > 20% from its baseline value.¹⁴ In practice, however, measurement of HVPG does require specific training and is probably not cost-effective for assessing primary prophylactic therapy. Thus, the clinician faces the question of how to adjust the dose of beta-blocker to maximise its beneficial effects. Traditional practice has recommended a stepwise increase in dose until the heart rate decreases by 25%, is < 55 beats per minute, or there is arterial hypotension or clinical intolerance. This means that the dose of the beta-blocker is titrated against its β₁ effects (cardiac) and clinical tolerance; however, a fall in portal pressure results from blockade of both β₁ and β₂ receptors, and the fall in portal pressure does not readily correlate with the fall in heart rate or blood pressure. Therefore, titration solely against clinical tolerance may be the most useful surrogate marker of the maximal dose of beta-blocker in the absence of HVPG measurement.

There appears to be no advantage of one non-selective beta-blocker over another. However, the newest approach to increase response to beta-blockers has been the use of carvedilol, a drug that combines a non-selective beta-blocker action with an α₁-adrenoceptor blocker action. This causes a marked decrease in portal pressure, but has the side-effect of systemic hypotension.

When compared with propanolol, carvedilol significantly increased the number of patients achieving a target reduction of HVPG (< 12 mmHg or > 20% reduction from baseline HVPG).¹⁹ There is considerable controversy about how to give the carvedilol because of its hypotensive side-effects; however, the above study demonstrated that lower doses (12.5 mg/day) result in good tolerance. In practice, the usual starting dose is 6.25 mg/day and the usual maintenance dose 12.5 mg/day.

In patients who are unable to tolerate beta-blockers (15–20%) because of side-effects or relative/absolute contraindications (for example, asthma), treatment with nitrates is ineffective, despite its portal pressure-lowering properties.²⁰ Therefore, variceal band ligation (VBL) therapy is the only option for patients with high-risk varices (grade II or above) and contraindications to beta-blockers. More controversially, a meta-analysis has suggested that VBL is a more effective mode of treatment than beta-blockers for primary prophylaxis.²¹ However, this analysis included four trials, only two of which have been published in full; therefore, it seems reasonable to recommend that, for the time being, beta-blockers remain the primary prophylactic therapy of choice in terms of cost and convenience. Of course, VBL does not reduce portal pressure (and therefore measurement of HVPG following endoscopic monotherapy is of no value) and this may leave the patient at risk of developing other complications of portal hypertension. An algorithm for the primary prevention of variceal bleeding is given in Fig. 8.1.

Figure 8.1 Algorithm for primary prevention of variceal bleeding.

Prevention of re-bleeding from oesophageal varices (secondary prophylaxis)

Following a variceal bleed, patients with cirrhosis should be managed in two ways: firstly, they should receive urgent and active treatment for the prevention of re-bleeding; secondly, they should be examined for signs of physiological stress following their bleed, which might indicate a need for an elective liver transplant assessment (Fig. 8.2). Management of non-cirrhotic patients is discussed later in this chapter.

Figure 8.2 Algorithm for secondary prevention of variceal bleeding.

Endoscopic variceal band ligation therapy or beta-blocker therapy are the treatments of choice for the prevention of re-bleeding from oesophageal varices.

Meta-analyses of studies using beta-blocker therapy to prevent re-bleeding have demonstrated both a significantly decreased mortality (27% in controls to 20% in beta-blocker-treated individuals) and a decreased incidence of re-bleeding (63% to 42%).³

VBL also both improves survival and significantly decreases re-bleeding rates; it is superior to endoscopic sclerotherapy since it is associated with significantly fewer complications.²²^,²³ Currently, it is unclear whether pharmacological therapy is better than VBL or vice versa; studies have demonstrated a variety of outcomes with reference to re-bleeding rates, but none have indicated any clear difference in survival.¹⁵^,²⁴^,²⁵ A combination of pharmacological therapy and endoscopic therapy is commonly used, but evidence suggesting a better outcome with this combination compared with monotherapy is hard to find. Likewise, combination therapy of nitrates and beta-blockers has not been consistently shown to be more effective than beta-blockers alone or VBL.¹⁵^,²⁶

Re-bleeding is still common with pharmacological or endoscopic therapy (30–50% at 2 years) and in these cases second-line therapies should be offered. This will depend on the underlying aetiology and fitness and age of the patient, and may be TIPS, shunt surgery or liver transplantation; these are considered later in this chapter.

Treatment for bleeding oesophageal varices

Variceal bleeding is a medical emergency and the first priority is to achieve adequate resuscitation of the patient in a safe environment, preferably a high-dependency or intensive care unit. On presentation, airway protection is essential, especially for intoxicated patients or those withdrawing from alcohol. Subsequent therapy is aimed at correcting hypovolaemic shock. Over-transfusion should be avoided because of the risk of a rebound increase in portal pressure with continued bleeding or re-bleeding.

Antibiotics should be instituted from admission, since these increase the survival of bleeding patients; norfloxacin 400 mg/12 hours or ciprofloxacin 250 mg/12 hours are the antibiotics of choice.²⁷^,²⁸

Finally, early therapy should also involve starting a vasoactive drug from admission (usually terlipressin or octreotide); a number of randomised controlled trials demonstrate that early administration of vasoactive drugs facilitates endoscopy, improves control of bleeding and reduces the 5 day re-bleeding rate.²⁹^,³⁰ Initiation of these measures in association with endoscopic therapy at the time of diagnostic endoscopy will control bleeding in approximately 75% of patients. However, as in most trials, in acute variceal bleeding this combined approach failed to improve overall mortality compared with drug or endoscopic therapy alone. The optimal duration of vasoactive drug therapy is not well established and requires evaluation; current recommendations are to continue the drug for 5 days, since this covers the period of maximum risk of re-bleeding.

Endoscopic therapy should be performed at the time of diagnostic endoscopy, within 12 hours of admission in a resuscitated patient. However, if the patient is stable, endoscopic therapy can probably be postponed until within normal working hours. There are multiple randomised controlled trials examining modes of endoscopic therapy in acute variceal bleeding. These have compared: endoscopic therapy with no therapy; endoscopic therapy with vasoactive drug therapy; endoscopic sclerotherapy with variceal band ligation therapy; combined endoscopic therapy with variceal band ligation therapy; and endoscopic therapy with TIPS. Endoscopic therapy is certainly superior to no therapy;³¹ of the two endoscopic therapies, variceal band ligation therapy should be considered the treatment of choice since it is associated with significantly fewer complications (oesophageal stricturing or oesophageal ulcer formation) and significantly fewer sessions of therapy to eradicate the varices. However, there is probably no difference in re-bleeding or mortality rates between the two therapies. Likewise, there is little evidence to support combined endoscopic therapy for the treatment of bleeding varices.³² In practice, however, it is sometimes beneficial for the endoscopist to use a small volume of sclerosant initially to improve vision in order to place some variceal bands to achieve eventual haemostasis. If endoscopic therapy fails to control bleeding, balloon tamponade should be used as a ‘bridge’ until definitive therapy can be offered. In practice, this usually means a further attempt at endoscopic band ligation therapy followed by second-line therapies. An algorithm for the management of variceal bleeding in cirrhotics is given in Fig. 8.3.

Figure 8.3 Algorithm for the management of variceal bleeding.

Gastric varices

Gastric varices are most commonly caused by cirrhosis complicated by portal hypertension and are the source of 5–10% of all upper GI bleeding episodes. Patients with pancreatic disease, especially inflammatory pancreatic disease, can also develop splenic vein thromboses with subsequent formation of isolated gastric varices. There have been sporadic reports of gastric varices developing after endoscopic therapy for bleeding oesophageal varices, particularly after endoscopic sclerotherapy. The risk of bleeding from gastric varices is no greater than from oesophageal varices and it is probable that pharmacological therapy is equally as effective as primary prophylactic therapy in oesophageal varices, so patients with gastric varices should also receive non-selective beta-blockers as first-line therapy. There are no reports of primary attempts at prophylactic therapy using endoscopic-based therapy.

Treatment of acute gastric variceal bleeding is very challenging. Medical management is similar to the treatment of oesophageal varices. Terlipressin and octreotide are useful for control of acute bleeding, while beta-blockers may also be as effective as secondary prophylactic therapy. The Sengstaken–Blakemore tube may have some utility for controlling bleeding from junctional (GOV1 or GOV2) varices but has little effect on controlling bleeding varices in the fundus or further down the stomach. Some endoscopic therapies are promising, but quality data are scarce; sclerotherapy, glue injection, thrombin and variceal band ligation therapy have all been reported. Control of bleeding using sclerotherapy with cyanoacrylate has been reported as efficacious in 62–100% of cases, with successful obliteration of varices in 0–94%.³³^,³⁴

A randomised controlled trial from Taiwan has confirmed that endoscopic sclerotherapy with cyanoacrylate was more effective and also safer than band ligation in the management of bleeding gastric varices.³⁵

The major rescue therapy (indeed, some may consider it the primary therapy) for bleeding gastric varices used in the UK is TIPS, which has a success rate for initial haemostasis of greater than 90% and re-bleeding rates of 20–30%.

Recently, the first prospective, randomised controlled trial comparing TIPS with cyanoacrylate injection in the prevention of gastric re-bleeding was published. This concluded that TIPS was more effective than glue injection in preventing re-bleeding from gastric varices, although the two modalities shared a similar mortality rate and frequency of complications.³⁶

It is imperative that all patients treated with any of the above-mentioned interventions (for bleeding oesophageal and gastric varices), except medical management, also receive treatment with a proton-pump inhibitor (PPI) to suppress acid secretion and to prevent complications related to acid interaction with bands, injection sites and treatment-related ulcers.

Portal hypertensive gastropathy

The presence of portal hypertensive gastropathy (PHG) is strongly correlated with the severity of cirrhosis, its overall prevalence in cirrhosis being about 80%.³⁷ However, the incidence of acute bleeding is low, occurring in about 2.5% of patients over an 18-month follow-up period, with an associated mortality of 12.5%; the incidence of chronic bleeding is significantly higher at 12%. Propanolol, octreotide and terlipressin have all been proposed for the treatment of acute bleeding from PHG based on their ability to decrease portal blood flow. In a randomised controlled trial, propanolol was found to reduce recurrent bleeding from PHG.³⁸ Once again, TIPS is considered as the rescue therapy of choice in patients who have repeated bleeding from PHG despite propanolol therapy.

Second-line therapies

Second-line therapies include the less invasive radiological techniques of TIPS or open surgery, which can range from direct oversewing of bleeding veins to surgical shunts and ultimately liver replacement.

TIPS (transjugular intrahepatic portosystemic shunt)

TIPS is a non-surgical method of creating a portocaval shunt. Its principal use is in treating active variceal bleeding not controlled by medical and endoscopic means or preventing re-bleeding. It therefore has a role in both elective and emergency situations. TIPS is appropriate in selected cases of refractory ascites, hepatic hydrothorax, portal hypertensive gastropathy, Budd–Chiari syndrome and hepatorenal syndrome. TIPS may facilitate surgery in patients with portal hypertension requiring hepatic or other abdominal surgery, although it is not generally used prior to liver transplant without other specific indications.

TIPS is created by needle puncture from a hepatic vein to a major intrahepatic portal vein branch. The track is maintained by a stent.

The degree of shunting can be tailored to some extent by adjusting the diameter of the balloon-dilated shunt against the resulting pressure gradient, directly measured through the catheter.³⁹

Occasionally there are severe and life-threatening complications but in the majority of cases few and only minor complications occur. Simpler radiological interventions can restore and maintain most narrowed or occluded TIPS, providing satisfactory secondary patency. Patients require regular follow-up by Doppler ultrasound, and elective venography may be performed to treat stenoses before significant bleeding recurs. As with any shunt there is a risk of encephalopathy. This is greater in older patients, wider diameter shunts and in those with prior encephalopathy or more advanced liver disease. Patients with precarious liver function may deteriorate into liver failure as a result of reduced portal perfusion.

An early disadvantage of TIPS was the poor primary patency rate, but this can be significantly improved by the use of covered stents, as demonstrated in a recent randomised trial.⁴⁰

TIPS has been compared unfavourably with surgery (see later section on surgical shunts) because of the high rate of reintervention, yet overall survival has been similar in randomised trials of both H-graft portocaval shunts and distal splenorenal shunts versus TIPS.⁴¹^,⁴² However, TIPS is usually preferred in patients with more advanced liver disease and in those likely to need future transplantation. Patients with more severe liver disease may be candidates for liver transplantation, but TIPS can stabilise some to enable survival long enough to receive a successful transplant. Moreover, the MELD score can be used to predict likely survival following TIPS.⁴³

TIPS for variceal bleeding

Uncontrolled bleeding from oesophagogastric or ectopic varices in the presence of a patent portal vein can usually be controlled by TIPS. The procedure can be performed on patients considered too sick for surgery. The mortality of these patients is due more to their general condition rather than the TIPS procedure. The 30-day mortality after TIPS in the UK National Confidential Enquiry into Perioperative Death study was 17%.⁴⁴ In this study, 80% of patients dying after TIPS had the procedure performed urgently or as an emergency for bleeding varices.

TIPS can be combined with embolisation of varices as there is direct access to the portal system. This is done particularly in acute bleeding to further reduce the risk of haemorrhage. Reduction of extrahepatic portosystemic shunting may also improve portal venous flow towards the liver and the TIPS. In some cases this may counter encephalopathy as well as helping to maintain flow in the TIPS.

Meta-analyses of several trials compare TIPS with endoscopic sclerotherapy and/or banding for prevention of recurrent variceal bleeding.⁴⁵^,⁴⁶ Additional medical therapy was included in some. TIPS was more successful at preventing re-bleeding but with no overall improvement in mortality. Encephalopathy was overall more frequent in the TIPS patients, but not in every trial. In some studies patients in the endoscopic groups were rescued by TIPS because of significant recurrent bleeding. General consensus is that endoscopic and medical therapy should be the primary treatment and TIPS reserved for those cases where control is not achieved. TIPS may be combined effectively with medical treatment or endoscopic variceal eradication after bleeding has been controlled. Long-term TIPS surveillance and reintervention may then be less necessary.⁴⁷^,⁴⁸

Other procedures have been used to control bleeding from varices when venous anatomy permits catheter access. Retrograde balloon occlusion of gastric varices has been mainly used in Asia as an alternative to TIPS when there is a patent gastrorenal venous connection.⁴⁹^,⁵⁰

Surgical options

Until endoscopic sclerotherapy was introduced in the early 1970s, the only practical options were surgical. These ranged from oesophageal transection and devascularisation procedures, to portosystemic shunt procedures and, more recently, liver transplantation, which is the treatment of choice for patients with variceal bleeding who meet the acceptance criteria.

Devascularisation procedures have been popular in Japan but were rarely used in the West and have been largely superseded by TIPS.

Portal systemic shunts

The variety of surgical shunts described for portal hypertension is perhaps a testament to the ingenuity of surgeons (Fig. 8.4). With the passing of the ‘shunt era’ most surgical trainees will not have seen a shunt, which now has a limited application for a selected group of patients. These are mainly those with non-cirrhotic portal hypertension and patients living in areas where newer therapies are not available. However, in some units where an active interest in shunt surgery has been maintained, a combination of very experienced surgeons and an excellent organisation has allowed for good results with emergency shunt surgery.⁵¹

Figure 8.4 Non-selective (a–d) and selective (e–g) portosystemic shunts. (a) End-to-side portocaval. (b) Side-to-side portocaval. (c) Mesocaval (jugular vein graft or prosthesis). (d) Proximal splenorenal. (e) Small-diameter PTFE H-graft portocaval. (f) Distal splenorenal (Warren). (g) Left gastric-to-IVC (Inokuchi).

A controlled crossover trial comparing distal splenorenal (Warren) shunt (DSRS) with endoscopic sclerotherapy showed that shunting produced better control of bleeding but did not produce any survival advantage.⁵²

Shunt operations can be classified into selective or non-selective shunts. The former carry lower rates of hepatic encephalopathy but are less successful in controlling acute bleeding. The two main procedures that have achieved popularity are the DSRS and the interposition portocaval or mesocaval shunt utilising a small-diameter prosthetic H-graft (see Fig. 8.4e,f). Direct primary portocaval anastomosis produces the most effective lowering of portal pressure but with the highest encephalopathy rates, and the advantage of the small-diameter portocaval H-graft is that it is selective and maintains some portal flow. This shunt has been compared to TIPS in a single-centre randomised trial in which the entry criterion was variceal bleeding in patients who had failed or ‘were not amenable to’ sclerotherapy or banding; recruitment was rapid, which suggests a low threshold to proceed with second-line therapies.⁵³ There was a higher 30-day mortality in shunt patients but a better long-term control of bleeding than that seen in the TIPS patients. It should be recognised that the expertise needed for TIPS insertion and the protocols for subsequent surveillance will vary between centres, such that results should be interpreted with caution as they may reflect local interest and expertise. It had previously been established that shunt surgery for cirrhotics carries significant postoperative mortality rates, being as high as 26.1% for Child C patients even in specialised centres.⁵⁴ Furthermore 5-year survival rates in patients with advanced liver disease are poor and shunt surgery carries an additional burden due to the risks of hepatic encephalopathy.

A recently reported multicentre randomised trial of TIPS versus DSRS showed no overall difference in survival and a tendency for TIPS to be more cost-effective in terms of lives saved.⁴²^,⁵⁵

On current evidence there is no role for routine shunting in cirrhotic patients. Shunts should be avoided in patients in whom transplantation is an option as they significantly increase the risk of surgery. If endoscopic and radiological approaches fail, surgery away from the liver hilum is recommended either as a splenorenal or interposition mesocaval shunt.⁵⁶

Liver transplantation

With the improved results and wider application of liver transplantation, this has become the definitive treatment for many patients with variceal bleeding. However, results are inferior for patients transplanted around the time of an acute bleed. Furthermore, there are reports of oesophageal complications, including perforation in grafted patients who have undergone recent endoscopic therapy. Thus, the indications for liver replacement are more to do with the stage of the underlying liver disease, although the priority for grafting will be influenced by a history of recent bleeding or a high risk for re-bleeding.

In 1997, minimal selection criteria, based on studies of the natural history of compensated chronic liver diseases, were developed to aid such a process.⁵⁷ The minimal listing criteria were: an estimated 1-year survival ≤ 90%; Child–Pugh score ≥ 7 (Class B or C); or portal hypertensive bleeding; or an episode of spontaneous bacterial peritonitis regardless of the Child–Pugh score. The basis of these criteria is that the expected outcome of the untreated patient would be significantly worse than that of the outcomes from liver transplantation. This recognises the significantly worse prognosis of decompensated cirrhosis, which in those with hepatitis C, for example, dramatically reduces from a 91% 5-year survival to 50%.⁵⁸ Spontaneous bacterial peritonitis carries an adverse outcome in these patients, with 1-year survival falling from 66% to 38% in one report,⁵⁹ and despite the many therapeutic modalities available for treatment, the only definitive therapy for recurrent variceal bleeding is liver transplantation.⁶⁰

Broadly, liver transplantation should be considered in any patient who is able to cooperate with the treatment and in whom an anticipated survival rate of at least 50% at 5 years postgrafting is likely to be achieved. The decisions to proceed to liver replacement should be made by a multidisciplinary team including an experienced hepatologist. Today, MELD scoring is widely used to list patients for liver transplant. Transplanting a patient with a MELD of < 15 is associated with a poorer outcome than would be expected on the waiting list and transplanting these patients may not be the best use of the limited organ pool (see Box 8.1).

Selection of second-line therapy

Non-cirrhotic

The easiest groups to consider are those without cirrhosis. If such patients fail with pharmacological or endoscopic therapy then a surgical shunt is the treatment of choice. For those with portal vein thrombosis, a distal splenorenal shunt is recommended and has the advantage of preserving the spleen. For non-cirrhotics with a patent portal vein, the choice rests between a portocaval or distal splenorenal depending on local expertise.

Cirrhotic

It is clear that if the patient is a potential transplant candidate they should be assessed for this once the initial bleeding has been controlled. If the bleeding cannot be controlled they should be considered for urgent TIPS insertion and then for liver replacement. Patients who are unsuitable for transplantation may be candidates for TIPS provided they do not have significant encephalopathy as this may worsen following the procedure. Once the transplant candidates, patients who are high risk because of comorbidity, and uncooperative patients who are actively drinking are identified as unsuitable for shunting, there are relatively few potential candidates for a TIPS procedure. Clearly, in areas where transplantation is not available as an option, patients should be considered for shunting provided they are Child A or B.

Management of ascites

Ascites is a common feature of portal hypertension, although the exact mechanisms remain under debate.⁶¹ Ascites in chronic liver disease can be effectively treated by a number of medical, surgical or radiological techniques. The new development of ascites should be investigated for bacterial peritonitis, portal vein thrombosis or hepatic malignancy. Initial treatment involves dietary sodium restriction and diuretic therapy. Unresponsive patients may benefit from regular large-volume paracentesis with concurrent intravenous administration of 20% human albumin.⁶² Though peritoneovenous shunting is effective in controlling ascites, potential risks include disseminated intravascular coagulation, sepsis and cardiac failure. It has few advantages over large-volume paracentesis and is not recommended for patients who are transplant candidates.⁶³ Refractory ascites is an indication for transplant assessment.

TIPS can also be very effective in controlling ascites refractory to medical treatment, but many such patients have very advanced liver disease with poor prognosis. The immediate risk is worsening liver failure and hepatic encephalopathy, and advice from an experienced hepatologist should be sought before TIPS. Older patients and those with renal dysfunction fare worse, and if patients with severe ascites are liver transplant candidates this may be a better option than TIPS. Patients with better liver function and disproportionate ascites, especially those with liver disease that can improve, e.g. by withdrawal from alcohol, respond well to TIPS. Some trials have shown TIPS to be more effective than medical treatment plus paracentesis, but patient selection is most important. Some studies have shown an improved survival and quality of life in patients having TIPS for ascites, whereas others have not.64–66 Surgical shunts are no longer recommended for resistant ascites due to high perioperative mortality and encephalopathy rates.

Budd–Chiari syndrome

Budd–Chiari syndrome is a rare condition resulting from occlusion of the hepatic veins. Presenting features include acute abdominal pain, ascites, acute fulminant liver failure or chronic liver failure, and can mimic many other conditions. Ultrasonography (US) will show absent or abnormal hepatic venous drainage. CT will often reveal abnormal liver perfusion that can be difficult to interpret and cases may be initially misdiagnosed as advanced hepatic malignancy. One common feature is the compensatory hypertrophy of the caudate lobe of the liver. This occurs as it has venous drainage separate from the three main hepatic veins. This regenerated liver is clearly life preserving, although pressure from the caudate may compound a tendency to caval thrombosis, which is seen in a proportion of patients. The majority of patients will have or will develop evidence of a thrombophilic state and should all be assessed by an expert haematologist. Given the lifetime risks of further thromboses, all patients require long-term anticoagulation. Referral to a specialised centre with suitable hepatology, radiology and surgical expertise is advised.

Acute Budd–Chiari syndrome

In the acute presentation there will usually be abdominal pain and swelling. If there is a short stenosis or occlusion of the hepatic vein(s) and/or inferior vena cava (IVC), balloon dilatation or stenting is very effective. Transjugular, transfemoral or transhepatic access may be required. Occlusion or stenosis of the IVC (sometimes a web) may similarly respond to balloon dilatation. If the dilated or recanalised segment of hepatic vein is not satisfactorily maintained after balloon inflation, a metal stent can be inserted to maintain the patent lumen.⁶⁷ These approaches have the benefit of restoring physiological hepatic vein outflow in at least one of the main hepatic veins. Adjunctive pharmacological or mechanical thrombolysis may assist these procedures in selected cases, especially when acute thrombosis complicates an otherwise successful vein recanalisation. There are individual case reports of systemic thrombolysis producing improvement but these are rare.⁶⁸

TIPS can be used in both acute and chronic Budd–Chiari, and would now be regarded as the treatment of choice for those not responding to medical therapy and/or hepatic vein recanalisation.⁶⁹^,⁷⁰

A recent study has shown that TIPS was the most frequent treatment modality applied in a 2-year multicentre European study of new Budd–Chiari presentations.⁷¹ The advantage of TIPS is decompression of the portal vein above the compressed part of the IVC within the caudate lobe and avoidance of laparotomy. With their tendency to thrombosis, Budd–Chiari patients have a greater need for reintervention than other TIPS patients but covered stents have shown improved patency.⁷²

Extended TIPS can be a successful treatment for patients with Budd–Chiari syndrome complicated by portal and mesenteric vein thrombosis. A few cases have been described in which TIPS was a stabilising factor before liver transplantation, but most patients improve sufficiently after TIPS to avoid the need for transplantation. If TIPS cannot be achieved then surgical shunt can be performed or liver transplant when there is significant liver failure. In summary, there is a progressive hierarchy of radiological procedures that can manage the majority of Budd–Chiari patients according to their individual venous anatomy. These procedures are effective in combination with appropriate medical therapy.⁷³

If the radiological approach fails, the type of surgical shunt will depend on the patency of the vena cava. If the cava is patent a mesocaval shunt using a length of autologous internal jugular vein between the superior mesenteric vein and the infrarenal vena cava is recommended. For cases with caval occlusion, a meso-atrial shunt using a graft of reinforced polytetrafluoroethylene (PTFE) between the superior mesenteric vein and the right atrium can be performed. Selection of patients for shunting is not easy and our experience suggests that patients with jaundice as an early symptom are at risk of decompensation and should be considered for liver grafting. If the patient develops fulminant hepatic failure, then emergency liver transplantation is the only potential option. High success rates are reported but recurrence can occur and all patients will require long-term anticoagulation.

Chronic Budd–Chiari syndrome

Many patients present with significant ascites and marked changes on liver biopsy, which include significant fibrosis or even cirrhosis. It is likely that for some patients the hepatic venous obstruction is sequential and that the condition is asymptomatic until a second or final (third) hepatic vein is occluded. Either hepatic vein dilatation or TIPS should be performed based on the presence of identifiable hepatic veins within the liver.⁷⁰^,⁷³ Shunt procedures should be reserved for radiological approach failures. Our local experience is that significant jaundice is an adverse prognostic sign and in these cases liver transplantation may be required.

Non-cirrhotic portal hypertension

Portal hypertension is uncommon in the absence of cirrhosis. The causes are mainly portal vein thrombosis, periportal fibrosis and segmental, usually left upper quadrant, portal hypertension associated with splenic vein thrombosis.

Portal vein thrombosis

Portal vein thrombosis is rare in the West but is seen more frequently in Third World countries and is thought to be the result of umbilical sepsis in the neonatal period. Presentation can be in early childhood but is usually delayed to the early teenage years. The symptoms are usually that of a sudden variceal bleed, although some patients may be picked up by the presence of significant splenomegaly with or without haematological features of hypersplenism. The management of the acute bleed is similar to patients with cirrhosis. Re-bleeding or the presence of large gastric varices should be considered as a clear indication for a surgical shunt. Given the risks of splenectomy in the young, a spleen-preserving procedure is recommended. In a small child, splenorenal shunts are less practical because of the small size of the vessels and interposition mesocaval shunts using autologous jugular vein have high success rates with good long-term patency.⁷⁴ In larger children, the distal splenorenal (Warren) shunt is usually favoured, although side-to-side splenorenal shunts have been reported in significant numbers from centres with a high prevalence of portal vein thrombosis.⁷⁵ The natural history of these patients is interesting in that as they grow the varices become less symptomatic, and certainly shunting is not indicated unless bleeding episodes occur.

Extensive mesenteric venous thrombosis is a potentially lethal complication seen in a few patients with portal vein thrombosis. Many patients will present with gut infarction but those presenting late pose major management problems. Careful angiography may reveal particularly dilated mesenteric collaterals, which might allow ad hoc shunts to the cava, but currently only medical therapies to lower portal pressure can be recommended.

Segmental portal hypertension

Segmental portal hypertension should always be considered as the potential cause of bleeding in patients with pancreatic pathology as they may have splenic vein thrombosis. Those with advanced pancreatic malignancy can usually be controlled with medical therapy or sclerotherapy. Patients with chronic pancreatitis who develop variceal bleeding secondary to splenic vein thrombosis should be considered for splenectomy, which will usually be curative.

TIPS and portal vein thrombosis

Interventions have extended into the portal venous system by percutaneous transhepatic, transjugular and even the trans-splenic routes in selected cases.⁷⁶ Limited acute portal vein thrombus is relatively easily treated by TIPS combined with thrombolysis, including clot disruption by balloon or other devices.⁷⁷ Patients with normal liver may only require transhepatic portal vein procedures for success, but those with hepatic portal hypertension benefit from TIPS improved outflow as well. Chronic portal vein thrombosis is often associated with extensive portal collaterals forming a portal vein cavernoma. If there is an appropriate clinical indication, then these can be traversed and the main portal vein flow can be restored by balloon dilatation and/or stent insertion.⁷⁸ More extensive occlusion involving the splenic and superior mesenteric veins may respond but with more difficulty, and those with underlying liver disease fare worse.

Key points

• Patients with grade II varices or worse who have not bled should be treated with beta-blockers unless there are medical contraindications.

• Endoscopic band ligation is the initial treatment of choice for acute variceal bleeding.

• After bleeding, patients should enter a programme of variceal ligation or beta-blockade to prevent recurrent bleeding.

• TIPS should be considered in patients in whom endoscopic therapy is unsuccessful.

• Liver transplantation should be considered in appropriate cases once variceal bleeding is problematic.

• Shunt surgery should be considered for non-cirrhotic patients with recurrent variceal bleeding and for Child–Pugh stage A and B patients who live in areas where TIPS or transplantation is unavailable.