MANAGEMENT PROBLEMS IN LIVER DISEASE Management of portal hypertension, BuddeChiari syndrome and portal vein thrombosis What’s new? C Andrew K Burroughs C Abstract The risk of variceal bleeding can be estimated by the size of varices, the presence of endoscopic red signs and the degree of liver dysfunction. All patients with large varices, and those with cirrhosis and severe liver disease, irrespective of the size of varices, should be given primary prophylaxis with non-selective b-blockers. Banding ligation is equivalent and is used if there are contraindications or intolerance to these drugs. Acute variceal bleeding should be managed in a gastrointestinal bleeding unit. Prophylactic third-generation cephalosporins and vasoactive drugs should always be given. Ligation or sclerotherapy should take place at diagnostic endoscopy. Secondary prophylaxis of variceal bleeding is mandatory with combined b-blockers and ligation. Hepatic outflow obstruction syndromes have a wide spectrum of presentation. Underlying thrombophilic conditions should be sought. A fulminant presentation requires liver transplantation. Decompression with transjugular intrahepatic stent shunt is effective in many cases and can also be used in cases of portal vein thrombosis. Hepatic and other venous webs can be treated with interventional radiological techniques. Anticoagulation is first-line therapy and should be continued lifelong; it should also be used in non-cirrhotic portal vein thrombosis, and considered in cirrhotic portal vein thrombosis. C C C It is likely, but not proven, that these risk factors also apply to non-cirrhotic portal hypertension. The risk factors for gastric variceal bleeding are unknown. Varices bleed from the lower 5 cm of the oesophagus, just above the oesophagogastric junction. The mechanism of bleeding is explosive, caused by high pressure, rather than erosive as a result of reflux of gastric acid. If varices have bled, the risk of rebleeding is at least 70%; there is only a modest association between the risk of rebleeding and the degree of liver dysfunction. At admission up to 50% of patients have culture-positive sepsis. Keywords antibiotics; anticoagulation; BuddeChiari syndrome; hepatic venous outflow syndromes; ligation of varices; portal hypertension; portal vein thrombosis; propranolol; terlipressin Management of acute bleeding episodes Admission to hospital: any patient with melaena or haematemesis should be admitted to hospital, particularly if chronic liver disease is suspected, and managed by a joint medicalesurgical team (preferably part of a gastrointestinal bleeding unit), with intensive nursing care. Initial assessment e clinical and laboratory evidence of the severity of bleeding and the degree of liver dysfunction and infection must be sought on admission, because all have prognostic significance. The following should be evaluated: haemoglobin/haematocrit, white blood cell count, platelet count serum urea and electrolytes, and creatinine prothrombin and partial thromboplastin times baseline liver function tests blood and urine cultures ascitic tap chest radiograph ECG blood gases (in patients with decompensated cirrhosis or suspected chest disease). In severe chronic liver disease, the principal problems are: the degree of hepatocellular failure the complications of portal hypertension. Portal hypertension and gastrointestinal bleeding Risk of variceal bleeding1 In cirrhotics with oesophageal varices that have not bled, the risk of bleeding is related to the: size of the varices (tension on the vessel wall is greater, for the same pressure, in a larger vessel than in a smaller vessel) presence of red signs at endoscopy (red weal marks) degree of liver dysfunction. Andrew K Burroughs MBChB Hons FEBG FRCP FMedSci is a Consultant Physician and Hepatologist and Professor of Hepatology at the Royal Free Hospital and University College London, London, UK. Competing interests: none declared. MEDICINE 39:10 In acute variceal bleeding, antibiotics should always be used as they reduce early rebleeding and mortality e intravenous thirdgeneration cephalosporins are effective. Transjugular intrahepatic stent shunt (TIPSS) improves survival when used as first-line therapy in patients unlikely to respond to endoscopic methods. Removable oesophageal covered stents stop bleeding, and are also an option in this group of patients. Injection of adhesive glues are particularly effective for acutely bleeding gastric varices For primary prophylaxis of variceal bleeding, non-selective b-blockers are the first-line treatment option In secondary prophylaxis against variceal rebleeding, combined banding ligation and non-selective b-blockers is the most effective treatment TIPSS with covered stents have greatly improved patency rates and are part of the treatment algorithms for gastric variceal bleeding, BuddeChiari syndrome (BCS) and portal vein thrombosis (PVT) Anticoagulation is first-line therapy in BCS and non-cirrhotic PVT, followed by radiological intervention. The risk of further thrombosis outweighs the risk of bleeding. The evidence in favour of anticoagulation in PVT with cirrhosis is less robust 607 Ó 2011 Elsevier Ltd. All rights reserved. MANAGEMENT PROBLEMS IN LIVER DISEASE The presence of any of the following indicates a poor prognosis: jaundice ascites encephalopathy low serum albumin prolonged prothrombin time raised serum creatinine shock or low haemoglobin on admission infection and other concomitant disease. vasoconstrictor activity and a longer duration of effect than vasopressin because it is cleaved in the circulation. Terlipressin is contraindicated in ischaemic heart disease. The ECG must be monitored during therapy. Somatostatin and octreotide have almost no adverse effects. Neither has more than a modest effect on portal pressure, but they alter blood flow through varices. Somatostatin 250 mg by IV bolus followed by 250 mg/hour by infusion is superior to placebo and has an efficacy similar to that of tamponade, terlipressin and sclerotherapy. Octreotide (long-acting somatostatin) 50 mg/hour acts similarly but there is far less evidence for its efficacy. Vasopressin plus nitroglycerin, terlipressin and somatostatin are less effective in decompensated cirrhosis. Only terlipressin has been shown to increase survival compared with placebo. The role of vasoactive drugs is therefore confined to adjuvant therapy or as a ‘holding measure’ until more definitive therapy can be given. Initial therapy: is aimed at correcting hypovolaemia, stopping the bleeding, and preventing the complications of gastrointestinal bleeding and deterioration of liver function.1 Hepatic encephalopathy and fluid retention should be treated and prevented by standard methods. Potassium canrenoate can be given intravenously as a substitute for oral spironolactone. To prevent sodium overload, sodium chloride infusions should not be used and strict attention must be given to electrolyte balance. Prophylactic antibiotics (oral quinolones) are mandatory. If sepsis is either suspected or obviously present, the most suitable ‘blind’ treatment is a third-generation cephalosporin (e.g. cefotaxime), depending on nosocomial bacterial resistance profiles; nephrotoxic antibiotics must be avoided. The use of antibiotics from admission reduces early rebleeding and improves survival.1e3 Alcohol withdrawal problems must be anticipated. Intravenous benzodiazepines are suitable sedatives, but should be monitored carefully and titrated for their sedative effect. In patients with symptoms of alcohol withdrawal, adequate treatment is required before endoscopy. All alcoholics should be given intravenous thiamine preparations on admission. Enteral and, occasionally, parenteral nutrition should be administered to patients with poor nutrition, when bleeding has been controlled. Vitamin K1, 10 mg intravenously (IV) should be given routinely. There is no evidence that gastric acid suppression is beneficial, but intravenous or oral ranitidine should be given when the bleeding is caused by a gastric mucosal lesion. The target haemoglobin concentration for transfusion should be 8 g/dl as this reduces the chances of early rebleeding.1 Balloon tamponade: controls bleeding in more than 90% of patients. Most tubes have four lumens to inflate the gastric balloon, inflate the oesophageal balloon, aspirate the stomach, and aspirate above the oesophageal balloon. The patient should, preferably, be intubated before insertion. Balloon tamponade should be used to prevent exsanguination when transfusion cannot match the blood volume lost, and to enable safe transport of the patient to a referral centre. Balloons should, ideally, remain in place for no more than 12 hours (and certainly no more than 24 hours) to reduce the risk of local mucosal ischaemic damage. A further endoscopic procedure (sclerotherapy, banding or glue injection) must be performed immediately after the balloon has been removed, because the risk of rebleeding is high. Another form of tamponade, which allows the patient to eat and drink, is an expandable, covered and removable mesh metal stent, which can be placed endoscopically or radiologically. Visualization of the portal anatomy and liver: should be undertaken early, particularly when hepatocellular carcinoma is suspected or the patient is a candidate for surgery or a transjugular intrahepatic stent shunt (TIPSS). Ultrasonography and echo Doppler ultrasonography should exclude an obvious spaceoccupying lesion and establish the patency of the portal and hepatic veins. It may be difficult to obtain good views; retrograde CO2 portography (Figure 1) or splanchnic arteriography with views of the venous phase may be necessary to visualize the portal vein. Emergency endoscopic techniques: sclerotherapy, banding ligation, and injection of glue are the only methods that stop active bleeding effectively in 85% of patients with variceal bleeding.1,4,5 All require expertise. In sclerotherapy, sclerosant (5% ethanolamine in the UK) is injected into and/or next to the variceal columns, 2e3 cm above the oesophagogastric junction. A single injection session controls bleeding in 70% of patients; in 85%, bleeding is controlled after two sessions. The success of the procedure is related partly to the severity of liver disease. Injection of 1% human thrombin or cyanoacrylate glues is also effective. No benefit is gained by using more than two injection sessions e TIPSS should be preferred. Minor complications (e.g. retrosternal pain, fever, oesophageal ulceration, sympathetic pleural effusion) are common, but major complications (e.g. oesophageal perforation, mediastinitis, venous embolization of sclerosant, infection) are rare. Banding ligation places pre-stretched rubber bands on variceal columns using a delivery device mounted at the end of an endoscope. It is slightly more effective than sclerotherapy and has fewer complications, but requires double intubation so as to load the banding device. Vasoactive drugs: are given on the suspicion of portal hypertensive bleeding and before endoscopy as follows:4 Terlipressin, 2 mg IV 6-hourly, is a synthetic analogue of vasopressin (triglycyl lysine vasopressin) with intrinsic TIPSS: is placed radiologically. A transjugular approach is most commonly used to enter the hepatic vein (Figure 2). It is particularly useful for continued bleeding after endoscopic therapy, and for gastric variceal bleeding.6 It may have a role as Endoscopy: should be performed only when resuscitation has been achieved. Nasal oxygen should be given and pulse oximetry measured. If sedation is required, endoscopy should be performed under a brief general anaesthetic.1 MEDICINE 39:10 608 Ó 2011 Elsevier Ltd. All rights reserved. MANAGEMENT PROBLEMS IN LIVER DISEASE Figure 1 (a) Typical spider-web appearance on hepatic venography. (Note retrograde portal filling.) (b) Typical compression of intrahepatic inferior vena cava. (Pressures e 19 mmHg right atrium, 56 mmHg intrahepatic inferior vena cava, 38 mmHg intrahepatic inferior vena cava.) (c) CO2 portogram (50 ml injection) showing a fully patent portal vein in a cirrhotic patient just before insertion of a transjugular intraheptic portosystemic stent shunt. No radiological dye is needed. first-line therapy in selected patients at high risk of failing with endoscopic methods. Portal vein thrombosis is not a contraindication and often can be resolved by TIPSS placement.1,4 It is available only in specialized centres. Patients should be referred before the onset of severe infective or renal complications. fatal complications are rare. In randomized studies, banding ligation is more effective and safer than repeated sclerotherapy and has replaced it. Endoscopic follow-up should be undertaken every 3 months, once the varices have been eradicated. If they reappear, they should be treated again, as above. If varices have not reappeared after 1 year, 6-monthly checks can be instituted; if no varices are seen after 2 years, annual checks are sufficient. Surgery: TIPSS has replaced emergency surgery; oesophageal staple-gun transection is rarely needed. Emergency shunts are seldom used, as are devascularization procedures (if portal and mesenteric thrombosis is present). Isolated splenic vein thrombosis is treated by splenectomy. Pharmacological therapy: non-selective b-blockers (e.g. propranolol) lower pressure in the varices by reducing cardiac output (b1-blockade), by allowing unopposed b-vasoconstriction in the splanchnic bed (b2-blockade) and by a specific effect on the collateral circulation. However, not all cirrhotic patients respond and some do not tolerate b-blockade. When the hepatic venous pressure gradient (HVPG) is reduced to 12 mmHg or less, or it falls by at least 20% from baseline, the risk of rebleeding is very low and other complications of cirrhosis are reduced. Non-selective b-blockers are usually given in increasing daily doses to achieve a resting pulse rate of 60 beats/minute or a maximal tolerance in terms of hypotension or other collateral effects. Repeated portal Prevention of rebleeding The recommended therapy is combined banding ligation and non-selective b-blockers.1 Banding ligation: ligation of each varix is performed at 1e2week intervals. The aim is to obliterate the varices in the lower oesophagus, resulting in a fibrosed oesophageal wall and/or small thrombosed varices. Complications are less severe following elective banding than after emergency banding, and MEDICINE 39:10 609 Ó 2011 Elsevier Ltd. All rights reserved. MANAGEMENT PROBLEMS IN LIVER DISEASE contraindications or intolerance to b-blockers; survival is similar and bleeding less but iatrogenic bleeding is reported. Prevention of varices is not possible with non-selective b-blockers alone.9 Intrahepatic stent shunt Hepatic vein Right main portal vein branch BuddeChiari syndrome Aetiology and presentation BuddeChiari syndrome is an obstruction of the major hepatic veins.10 The principal cause is thrombosis, caused by a thrombophilic disorder in 75% of patients. Primary myeloproliferative disorders are most common, but all genetically based prothrombotic tendencies (e.g. protein S or protein C deficiencies, factor V Leiden, JAK2 mutations) can be a cause, particularly in association with the oral contraceptive pill and puerperium. Paroxysmal nocturnal haemoglobinuria and lupus anticoagulant must also be considered. The classical syndrome of ascites, hepatomegaly and abdominal pain occurs with obstruction at any level of the hepatic venous outflow tract, from the hepatic venule to the right atrium. ‘Hepatic venous outflow block’ is the best term for these conditions. Constrictive pericarditis should always be considered because it mimics this presentation. An asymptomatic form is also recognized. The rapidity and extent of thrombosis determines the severity of congestion and necrosis spreading out from the central veins, and thus the clinical presentation. A fulminant presentation caused by massive ischaemic necrosis is indistinguishable from fulminant liver failure. In chronic cases, the thrombosis is asynchronous, accounting for atrophy and congestion of adjacent parts of the liver; fibrosis and, eventually, cirrhosis supervene with chronic portal hypertension. Classically, there is hypertrophy of the caudate lobe, which drains directly into the inferior vena cava and often compresses it.10 Left gastric vein Portal vein Metal expandable stent covered with polyethylene Inferior vena cava Intrahepatic stent shunt links the hepatic vein with the intrahepatic portal vein. The hepatic vein is usually cannulated via the transjugular route, through the heart. Figure 2 pressure measurements are invasive, but act as a ‘splanchnic sphygmomanometer’7; their clinical applicability is debated.8 Shunt surgery: with the advent of endoscopic therapy, surgery is now a salvage procedure, particularly in patients who are not candidates for transplantation. Major complications are operative mortality, portosystemic encephalopathy and deterioration of liver function caused by diversion of portal blood, which deprives the liver of hepatotrophic factors and prevents ‘detoxification’ of the portal blood. Use of small-bore 8-mm interposition H-graft portacaval shunts reduces the incidence of encephalopathy. Selective shunts (e.g. distal splenorenal shunt) also cause less encephalopathy but this advantage is lost after 2 years.4 Diagnosis The clinical background and an ascitic tap with a high protein content should raise the possibility of BuddeChiari syndrome. Doppler ultrasonography is usually sufficient to confirm the diagnosis. The portal vein is also thrombosed in 10% of patients and the inferior vena cava in 20%; thus, a detailed radiological and haemodynamic assessment (including caval pressure measurements above and below the liver) is needed. A typical ‘spider-web’ appearance on hepatic venography is diagnostic, and retrograde CO2 portography often outlines the portal vein (Figure 1). Minimal use or avoidance of radiological contrast should be routine, to minimize renal dysfunction.10 Liver biopsy should be performed; it often shows diagnostic features of centrilobular necrosis and sinusoidal congestion (transjugular biopsy is often necessary but not always feasible). It is useful to assess the degree of necrosis and fibrosis, but these have minor prognostic value. Bone marrow examination and chromosomal analysis are essential to assess the prognosis in myeloproliferative disorders.10 Screening for thrombophilic disorders (including screening of relatives) must always be undertaken.10 Devascularization surgery: should be reserved for patients in whom non-operative treatments have failed and who cannot undergo shunt surgery or TIPSS. Transplant surgery is complicated more by devascularization than by shunts as a result of the formation of numerous adhesions, which contain portal hypertensive collaterals that bleed extensively. TIPSS: TIPSS using polyethylene-covered stents, maintain greater patency and need far less re-intervention than the older ‘bare’ stents. Rebleeding rates are less than with endoscopic therapy, but there is an increased risk of hepatic encephalopathy.1 Primary prophylaxis for bleeding from varices A non-selective b-blocker is the first choice, as these drugs produce a statistically significant reduction in bleeding and a trend towards reduced mortality. In cirrhosis, varices should be evaluated endoscopically.1 If there are no contraindications, those with varices at risk of bleeding, including patients with small varices and poor liver function, should be given bblockers.1 Band ligation has been used in those with MEDICINE 39:10 Management The initial therapy is anticoagulation. If there is no improvement further measures must be considered.10 Shunts: management of BuddeChiari syndrome should, ideally, be undertaken in a transplant centre because shunting can 610 Ó 2011 Elsevier Ltd. All rights reserved. MANAGEMENT PROBLEMS IN LIVER DISEASE bleeding. The evidence for benefit of anticoagulation in cirrhotic PVT is less clear-cut; the risk and adverse consequences of variceal bleeding are far greater than in those without cirrhosis.12 Increasingly, anticoagulation is used for patients awaiting liver transplantation as thrombotic extension into the superior mesenteric vein may make the surgery impossible.13 Bleeding gastro-oesophageal varices are treated as described previously. PVT is not a contraindication to TIPSS, which is successful in 65% of cases.13 It can be used if bleeding is not controlled by endoscopic methods, or when anticoagulation is contraindicated, particularly before transplantation, although it is preferable to anticoagulate after TIPSS to increase patency rates. Thrombolytic therapy is rarely effective but has been used in cases of very recent acute mesenteric infarction, or when surgery for this complication is not possible.12,13 A precipitate hepatic failure and transplantation is then an emergency rescue procedure.10 Early referral is essential. Options for decompression with shunts are limited in patients with thrombosis or severe compression of the inferior vena cava; only a suprahepatic shunt (from splanchnic veins to the heart e meso-atrial shunt) or TIPSS (which can be performed even in those with obstructed hepatic veins) is suitable. Otherwise, TIPSS or a sideto-side portacaval shunt is the procedure of choice. A surgical shunt should not be used in patients who present acutely. A 95% 5-year survival can be achieved in chronic cases. All forms of shunting reduce hepatic parenchymal perfusion, so liver reserve and reversible liver injury must be assessed to ensure adequate residual function. Liver transplantation: is the preferred option when shunting is impossible or fails; 5-year survival is 70% or more and it may be the treatment of choice in fulminant cases.11 Balloon dilatation: when isolated webs are found in the hepatic veins and inferior vena cava (more common in the Far East), balloon dilatation of these often relieves the obstruction.10 REFERENCES 1 de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of the Baveno V Consensus Workshop on methodology of diagnosis and therapy in portal hypertension. J Hepatol 2010; 53: 762e88. 2 Hou MC, Lin HC, Liu TT, Kuo BI, Lee SD. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal haemorrhage: a randomized trial. Hepatology 2004; 39: 746e53. 3 Thalheimer U, Triantos CK, Samonakis DN, Patch D, Burroughs AK. Infection, coagulation and variceal bleeding in cirrhosis. Gut 2005; 54: 556e63. 4 de Franchis R, ed. Proceedings of the Fifth Baveno International Consensus Workshop on methodology of diagnosis and treatment of portal hypertension. Oxford: Blackwell Publishing, 2011. 5 Triantos CK, Goulis J, Patch D, et al. An evaluation of emergency sclerotherapy of varices in randomised trials: looking the needle in the eye. Endoscopy 2006; 38: 797e807. 6 Chau T, Patch D, Chan Y, Nagral A, Dick R, Burroughs AK. Salvage transjugular portosystemic shunts e gastric fundal compared with esophageal variceal bleeding. Gastroenterology 1998; 114: 981e7. 7 Abraldes J, Tarantino I, Turnes J, Garcia-Pagan J, Rodes J, Bosch J. Haemodynamic response to pharmacological treatment of portal hypertension and long term prognosis of cirrhosis. Hepatology 2003; 37: 902e8. 8 Villaneuva C, Aracil C, Colomo JM, et al. Clinical trial: a randomized controlled study on prevention of variceal rebleeding comparing nadalol and ligation vs hepatic venous pressure gradient guided pharmacological therapy. Aliment Pharmacol Ther 2009; 29: 397e408. 9 Groszmann RJ, Garcı́a-Tsao G, Bosch J, et al. Beta-blockers to prevent gastro-oesophageal varices in patients with cirrhosis. N Engl J Med 2005; 353: 2254e61. 10 Senzolo M, Cholongitas E, Patch D, Burroughs AK. Update on the classification, assessment of prognosis and therapy of BuddeChiari syndrome. Nat Clin Pract Gastroenterol Hepatol 2005; 2: 182e90. 11 Mentha G, Giostra E, Majno PE, et al. Liver transplantation for BuddeChiari syndrome: a European study of 248 patients from 51 centres. J Hepatol 2006; 44: 520e8. 12 Tsochatzis EA, Senzolo M, Germani G, Gatt A, Burroughs AK, et al. Systematic review: portal vein thrombosis in cirrhosis. Aliment Pharmacol Ther 2010; 31: 366e74. 13 Webster GJM, Burroughs AK, Riordan SM. Review article: portal vein thrombosis e new insights into aetiology and management. Aliment Pharmacol Ther 2005; 21: 1e9. Anticoagulation: should be used long term, particularly after shunting and after liver transplantation, regardless of whether a cause is found. Multiple thrombophilic risk factors may coexist, including as yet unidentified ones. Thrombolytic therapy is not usually effective.10 Portal vein thrombosis (PVT) Aetiology and presentation The causes are umbilical sepsis and any intra-abdominal sepsis causing secondary thrombosis, and also carcinoma of the pancreas and other malignancies.12,13 Thrombophilic syndromes are the principal primary cause, coagulation defects being more common than myeloproliferative disorders. PVT can occur as a complication of cirrhosis in 0.6e16% e the most frequent causes are invasion by hepatocellular carcinoma (HCC), as well as a pro-coagulant tendency in patients with advanced cirrhosis and a decreased hepatopetal flow. PVT is an adverse prognostic factor in cirrhosis, whether or not associated with HCC.12,13 Patients may be asymptomatic, with splenomegaly that is either palpable or diagnosed incidentally by imaging, or may present with bleeding from varices at the gastro-oesophageal junction or further down the gastrointestinal tract, or rarely with an acute abdomen due to mesenteric infarction. Diagnosis Ultrasound Doppler is the imaging modality of choice, followed by cross-sectional CT or MRI with contrast, to diagnose associated malignancies and to define the extent of thrombosis. A thrombophilia screen should be performed, as for BuddeChiari syndrome, and relatives screened if this is positive.12 Management In the absence of malignancy in non-cirrhotic PVT, lifelong anticoagulation should always be evaluated as first-line therapy, as the risk of further thrombosis is substantially greater than that of bleeding.12 Many centres eradicate varices by ligation before starting anticoagulation, whether or not there has been previous MEDICINE 39:10 611 Ó 2011 Elsevier Ltd. All rights reserved.