Portal hypertension and ascites

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1 Portal hypertension and ascites Muhammad S Mirza Guruprasad P Aithal Abstract Portal pressure is the product of portal blood flow and resistance; an increase in either leads to increased portal pressure. Cirrhosis is the underlying cause in most cases, but portal hypertension can develop due to pre-, intra- and post-hepatic obstruction to the flow, secondary to variety of causes. Diagnosis can be established by a combination of non-invasive imaging of portal vasculature and clinical or serological markers for the cause underlying cirrhosis. Development of gastro-oesophageal varices and ascites are the most important clinical manifestation of portal hypertension. Non-selective beta-blockers and endoscopic band ligation are effective in primary and secondary prevention of variceal bleeding. Active variceal haemorrhage is managed using a combination of vasoactive drugs (e.g. terlipressin) and endoscopic band ligation. If these measures fail, transjugular intrahepatic portosystemic stent (TIPS) insertion achieves haemostasis. Diuretic therapy with spironolactone and furosemide are the mainstays of management of ascites. If ascites becomes refractory, repeat large-volume paracentesis and TIPS in selected cases help to control symptoms. Development of ascites is an important landmark in the natural history of cirrhosis and liver transplantation should be considered definitive treatment. Keywords cirrhosis; ascites; TIPS; varices Definition Portal pressure is the product of portal blood flow and intrahepatic resistance. Conditions that cause an increase in flow or resistance increase portal pressure. Portal hypertension is a portal venous pressure of >5 mmhg. Transjugular hepatic venous catheterization is used to measure free and wedged hepatic venous pressures. The clinical consequences of portal hypertension occur if hepatic vein pressure gradient is 10 mmhg. Aetiology and pathogenesis Portal hypertension is classified according to the site of the obstruction to blood flow into pre-hepatic, intrahepatic and post-hepatic causes (Table 1). Cirrhosis is the commonest cause Muhammad S Mirza FRCS(Ed) is a Research Fellow in General Surgery at Derby City General Hospital, Derby, UK. Conflicts of interest: none declared. Guruprasad P Aithal FRCP is a Consultant Hepatologist and Special Lecturer at University Hospital, Nottingham, UK. Conflicts of interest: none declared. Causes of portal hypertension Prehepatic portal hypertension Thrombosis of the portal vein Intra-abdominal sepsis Chronic pancreatitis Pancreatic neoplasia Prothrombotic state Thrombosis of the splenic vein Chronic pancreatitis Pancreatic neoplasia Splanchnic arteriovenous fistula Intrahepatic portal hypertension Predominantly pre-sinusoidal involvement Cirrhosis (alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, haemochromatosis) Schistosomiasis Nodular regenerative hyperplasia Polycystic disease Myeloploriferative diseases Hepatic metastases Granulomatous (sarcoidosis, tuberculosis) Predominantly post-sinusoidal involvement Budd Chiari syndrome Veno-occlusive disease Post-hepatic portal hypertension Constrictive pericarditis Obstruction of the inferior vena cava Right heart failure Tricuspid regurgitation Table 1 of portal hypertension. In cirrhosis, increased sinusoidal pressure due to fibrosis and regenerative nodules is amplified by reduced concentrations of vasodilators (e.g. nitric oxide). Concentrations of nitric oxide are increased in the splanchnic and systemic circulation probably due to gut-derived endotoxaemia. These haemodynamic changes eventually lead to the clinical manifestations of portal hypertension (Figure 1). Clinical features History-taking should be directed towards determining the cause and complications of portal hypertension (Table 2). The physical signs of chronic disease of the liver (e.g. spider naevi, red palms, gynaecomastia) suggest cirrhosis as a cause of portal hypertension. Ascites in portal hypertension rarely develops in the absence of cirrhosis and is detected in only 10% of patients with thrombosis of the portal vein. Weight gain may be the early sign of fluid accumulation before ascites becomes clinically detectable. Ascites indicates decompensated liver disease and is a marker of poor prognosis. Investigations Evaluation should be individualized depending on the presentation. Investigations should aim to confirm liver disease and to SURGERY 25: Elsevier Ltd. All rights reserved.

2 Pathogenesis of portal hypertension Altered architecture; reduced concentration of nitric oxide within the liver Intrahepatic resistance Cirrhosis Increased concentration of nitric oxide in the splanchnic and peripheral systems Splanchnic and systemic vascular resistance Sinusoidal pressure Portosystemic gradient Portal inflow Effective arterial blood volume Ascites Collaterals Activated neurohumoral systems Retention of salt and water Figure 1 Clinical features of portal hypertension History Risk factors for cirrhosis Intravenous drug abuse Infusion of blood products Metabolic syndrome (diabetes, obesity, hypertension, dyslipidaemia) Alcohol abuse Risk factors for non-cirrhotic portal hypertension Chronic pancreatitis, pancreatic cancer Procoagulative disorders Symptoms of gastrointestinal bleeding Haemetemesis Malena Haematochezia Hypovolaemic shock Physical signs Signs of portal hypertension Dilated veins in the anterior abdominal wall with flow away from the umbilicus Ascites Splenomegaly Caput medusae Signs of liver disease Jaundice Spider naevi Palmer erythema Asterixis Gynaecomastia Table 2 identify the underlying cause (Table 3). Sequestration of white blood cells associated with splenomegaly usually leads to pancytopenia and cirrhosis is associated with an abnormal clotting profile. Chronic viral hepatitis can be diagnosed using hepatitis- B and -C serology. Autoantibody and immunoglobulin profiles point towards the diagnosis of autoimmune liver diseases. Diagnosis of haemochromatosis can be established with raised iron indices and HFE genotyping. Metabolic syndrome predisposes to non-alcoholic fatty liver disease and is a cause of cirrhosis. Imaging: abdominal ultrasound can establish ascites and splenomegaly. Duplex Doppler ultrasound allows imaging of the portal vein and its major tributaries, as well as the hepatic veins. Imaging and flow patterns in the hepatic veins are particularly important to exclude thrombosis of the hepatic vein. Portal circulation can be evaluated using CT and MRI if Doppler studies Specific investigations in portal hypertension To identify the causes of cirrhosis Liver function tests Viral hepatitis-b and -C serology Antinuclear, antimitochondrial, anti-smooth muscle antibody Iron indices (ferritin, transferrin saturation) α1-antitrypsin Caeruloplasmin (in those aged <40 years) Liver biopsy Portal vascular imaging Duplex Doppler ultrasonography CT or MRI angiography/portography Transjugular hepatic venous pressure gradient Consequences of portal hypertension Endoscopy of the upper gastrointestinal tract Table 3 SURGERY 25: Elsevier Ltd. All rights reserved.

3 are inconclusive. MRI angiography can detect portosystemic collaterals and obstruction of portal vascular structure. Selective angiography of the superior mesenteric artery or splenic artery may be indicated in certain instances if other tests are inconclusive. Hepatic venous pressure gradient is the gold standard for defining and assessing the severity of portal hypertension, but has limited applications in routine clinical practice in the UK. Portosystemic collaterals in portal hypertension (schematic) Oesophageal varices Liver Gastro-oesophageal varices One of the main consequences of portal hypertension is the development of extensive portal systemic collaterals (Figure 2). The collateral circulatory bed develops through a dynamic interplay of distinct physiological processes, including: raised sinusoidal pressure (in cirrhosis) vasodilation vascular remodelling angiogenesis. Nitric oxide and vascular endothelial growth factor have important roles in each of the steps of formation of collateral vessels. Collaterals form predominantly due to dilation of pre-existent embryonic channels. The left gastric vein is the main vessel responsible for the development of oesophageal varices; short gastric veins lead to the dilation of fundal and gastro-oesophageal varices (Figures 2 and 3). Significant portosystemic collaterals can also develop in the rectum, periumbilical, retroperitoneal and peristomal regions (ectopic varices). In cirrhosis, the prevalence of varices at diagnosis ranges from 0 10% of patients with compensated disease to 70 80% of those with decompensated cirrhosis. The tension in the variceal wall increases with increasing wedged hepatic venous portal gradient and the size of the varix. This is manifested by cherry red spots and red wale markings. Advanced cirrhosis (as indicated Portosystemic collaterals and oesophageal varices (schematic) Para-oesophageal vein Perforating vein Posterior branch Left gastric vein Figure 2 Oesophageal varices Cardiac venous plexus Anterior branch Portal vein Left gastric vein Splenic vein Gastric varices Short gastric vein Figure 3 Spleen by Child Pugh class; see Malignant tumours of the liver, page 34) is likely to be associated with significant thrombocytopenia. Combination of these clinical parameters increases the probability of variceal bleeding. Variceal rupture accounts for about 15% of haemorrhages of the upper gastrointestinal tract (see Peterson, CROSS REFERENCES). Management of gastro-oesophageal varices Primary prevention: annual endoscopy of the upper gastrointestinal tract can detect newly formed varices. Non-selective β-blockers (e.g. propranolol) reduce portal flow and pressure by decreasing cardiac output (β1 receptors) and splanchnic arterial flow (β2 receptors). This halves the risk of first variceal bleeding. Endoscopic band ligation should be considered: if β-blockers are contraindicated (asthma, peripheral vascular disease, heart failure) for those intolerant to the medication. The benefits of banding outweigh the risks in high-risk groups (moderate/large varices, advanced cirrhosis). Treatment of acute variceal haemorrhage: the goals of management are to resuscitate adequately, achieve haemostasis and prevent rebleeding. Resuscitation follows the rules of airway, breathing and circulation. Restitution of blood volume should be done cautiously and conservatively using plasma expanders to maintain haemodynamic stability and packed red blood cells to maintain haemoglobin concentration at 8 10 g/dl (depending on the haemodynamic status, ongoing bleeding and comorbidities; see SURGERY 25: Elsevier Ltd. All rights reserved.

4 Mackenzie, CROSS REFERENCES). Patients with hepatic encephalopathy with large haemetemesis are at risk of aspiration and may need airway protection, particularly during endoscopy of the upper gastrointestinal tract. Pharmacological therapy vasoactive drugs should be started as soon as possible (even before diagnostic endoscopy) if the suspicion of variceal bleeding is high. Terlipressin and octreotide reduce splanchnic blood flow and facilitate cessation of bleeding. Treatment is maintained for 3 5 days from the onset. Endoscopy of the upper gastrointestinal tract should be done with adequate airway protection using endotracheal intubation if the risk of aspiration is high. Endoscopy helps to establish the cause of upper gastrointestinal bleeding; non-variceal sources (e.g. ulcers, Mallory Weiss tear, portal hypertensive gastropathy) account for the bleeding in 15 25% of patients with cirrhosis. Variceal ligation (banding) is the preferred treatment if oesophageal varices are the cause of bleeding. Injection sclerotherapy may be used in the acute setting if ligation is technically difficult. Variceal sclerotherapy and ligation have not been shown to be effective in the treatment of gastric varices. Injection with tissue adhesive (e.g. N-butyl-cyanoacrylate) is superior (Figure 4), but should be done only by an experienced endoscopist. Balloon tamponade (Sengstaken Blakemore tube) should be used as a temporary measure in cases of massive bleeding. The tube can be inserted via the nose or mouth and the gastric balloon inflated with about 250 ml of air. Gentle traction is applied to the tube (using a 250 ml fluid bag) so that the balloon tamponade assists haemostasis. The Sengstaken Blakemore tube achieves control of bleeding in 90% of cases, but is associated with a high risk of aspiration, so adequate airway protection (preferably with endotracheal intubation) is crucial. The gastric balloon should not be kept inflated continuously for >24 hours. Inflation of the oesophageal balloon is necessary only in exceptional circumstances. The pressure should be maintained at mmhg when the oesophageal balloon is inflated; the balloon should be deflated for 2 4 minutes every hour to avoid pressure necrosis of the oesophagus. Transjugular intrahepatic portosystemic shunt (TIPS) acts as a side-to-side portocaval shunt. It controls acute variceal bleeding that is refractory to a combination of medical and endoscopic management. This combination controls bleeding in 80 90% of bleeding episodes; TIPS is used as salvage therapy if endoscopic therapy fails to control bleeding. A needle is inserted under fluoroscopic guidance from the right hepatic vein to the right portal vein. The track is dilated to 8 12 mm and a metal stent is deployed to support the shunt wall. TIPS is effective in controlling bleeding due to portal gastropathy. Antibiotic prophylaxis up to 20% of cirrhotic patients hospitalized due to gastrointestinal bleeding have bacterial infections; an additional 50% develop an infection while hospitalized. Besides a higher mortality, bacterial infections are also associated with a higher rate of variceal bleeding. Antibiotics prevent bacterial infections and spontaneous bacterial peritonitis. Prevention of hepatic encephalopathy lactulose by mouth or via nasogastric tube may reduce the risk of encephalopathy by decreasing the nitrogenous load from the gut. Nutrition malnutrition contributes to morbidity and mortality in these patients (see Kaushal, CROSS REFERENCES), so feeding should be resumed as soon as possible. A nasogastric tube can be inserted about 24 hours after bleeding stops. Surgical management surgery has a limited role in the management of acute variceal bleeding; TIPS is a less invasive method of decompressing the varices. Emergency portocaval shunts, oesophageal transection and devascularization are rarely done. Patient selection is crucial in determining the success of surgical portosystemic shunts and can be done using the Child Pugh classification. Shunt surgery in patients with Child Pugh type-c cirrhosis carries a significant mortality, while liver transplantation offers improved survival in this group of Injection of histoacryl glue into gastric varices. a Shows the injection needle being inserted into gastric varix. b Shows a column of blood extruding from the injection site. c Shows solidification of the blood in the process (i.e. haemostasis). Figure 4 SURGERY 25: Elsevier Ltd. All rights reserved.

5 patients. Benefits and risks of liver transplantation should be compared with those for shunt surgery In Child Pugh type- C and type-b patients. Side-to-side lienorenal shunt is a good option if other therapies have failed. Shunt surgery could be considered in selected patients with non-cirrhotic portal hypertension if endoscopic intervention has been unsuccessful and TIPS is not feasible. Secondary prevention: overall, about 70% of patients who have had one episode of variceal bleeding rebleed. Non-selective β-blockers are the first-line treatment for the prevention of rebleeding. Endoscopic ligation to eradicate the varices is required if: the patient is non-compliant the patient is intolerant to β-blockers β-blockers are contraindicated the patient is high risk (Child Pugh type-c, large varices). Ascites Ascites is an abnormal amount of intraperitoneal fluid; it is a major complication of cirrhosis, occurring in 50% of patients during ten years of follow-up. Ascites is an important landmark in the natural history of cirrhosis because it is associated with a 50% mortality over two years and signifies the need to consider liver transplantation as a therapeutic option. Seventy-five percent of patients who present with ascites have underlying cirrhosis; others are due to: malignancy (10%) heart failure (3%) tuberculosis (2%) pancreatitis (1%) and other rare causes. The mechanism by which ascites develops is summarized in Figure 1. Portal hypertension associated with cirrhosis is a critical factor in the pathogenesis, and is associated with circulatory changes characterized by arterial vasodilation, effective circulatory hypovolaemia, and the retention of sodium and water in the kidney. The rapid and high inflow of arterial blood into the splanchnic microcirculation is an additional factor increasing hydrostatic pressure in the portal circulation. Concentrations of albumin in plasma have little influence on the rate of ascites formation. Investigations The underlying cause of ascites is usually obvious from history-taking and physical examination, but other causes of ascites must be excluded. The essential investigations on admission include diagnostic paracentesis (see below) and abdominal ultrasound. Blood tests (urea and electrolytes, liver function tests, prothrombin time, full blood count) should be done. Diagnostic paracentesis entails removal of ascitic fluid from the peritoneal cavity using a needle. This is done 15 cm lateral to the umbilicus, usually in the left lower quadrant of the abdomen. Twenty millilitres are withdrawn for inoculation into blood culture bottles and the tests outlined below carried out. Diagnostic paracentesis can be done without fresh frozen plasma or platelet infusions despite the coagulopathy and thrombocytopenia seen in most cirrhotic patients. The serum-ascites albumin gradient is calculated by subtracting the ascitic fluid albumin concentration from the serum albumin; it is far superior in classifying ascites (97% accuracy) than the classification based on ascitic fluid protein concentration. A value of 11 g/l suggests that ascites is due to cirrhosis with portal hypertension or other causes of transudates (e.g. cardiac failure, nephritic syndrome). A value of <11 g/l is a feature of exudates secondary to tuberculosis, malignancy and pancreatitis. High concentrations of ascitic amylase are diagnostic of pancreatic ascites. Ascitic fluid neutrophil count and culture an ascitic neutrophil count of >250 cells/mm 3 is diagnostic of spontaneous bacterial peritonitis in the absence of a known perforated viscus or inflammation of intra-abdominal organs. Injecting ascites fluid into blood culture bottles at the bedside doubles the chance of identifying the organism in cases of spontaneous bacterial peritonitis. Other tests requests for ascitic fluid cytology and culture for mycobacteria should be done only if clinical suspicion of malignancy or tuberculosis is high. Management Restriction of dietary salt: a no added salt diet of 90 mmol/day (5.2 g salt/day) is adequate. A low salt diet eliminates ascites in 10 20% of patients. Fluid restriction: there is no role for water restriction in patients with uncomplicated ascites. Impaired free water clearance is seen in 25 60% of patients with ascites due to cirrhosis, and many develop spontaneous hyponatraemia. Fluid restriction to 1.5 l/day is common practice in patients with hyponatraemia <125 mmol/l, but this may exacerbate the effective central hypovolaemia that drives the non-osmotic secretion of antidiuretic hormone. This may further increase circulating antidiuretic hormone and lead to worsening of renal function. Correction of effective hypovolaemia with 200 ml of 20% albumin to inhibit the stimulation of antidiuretic hormone release should be considered. Emerging data support specific vasopressin-2 receptor antagonists in the treatment of dilutional hyponatraemia. Diuretics: the first-line treatment of ascites should be spironolactone alone, increasing from 100 mg/day to 400 mg/day. A stepped-care approach is used, starting with modest restriction of dietary salt together with an increasing dose of spironolactone. If this fails, frusemide (up to 160 mg/day) is added with careful biochemical and clinical monitoring. Spironolactone and frusemide act synergistically. Therapeutic paracentesis is the first-line treatment for largevolume or refractory ascites. Large-volume paracentesis with colloid replacement is rapid, safe and effective. Paracentesis of <5 l of ascites should be followed by plasma expansion with a synthetic plasma expander; volume expansion with albumin is not required. Large-volume paracentesis (>5 l) should be done in a single session with volume expansion using 8 g albumin/l (100 ml of 20% albumin per 2.5 l of ascites drained). Failure to give volume expansion can lead to post-paracentesis circulatory SURGERY 25: Elsevier Ltd. All rights reserved.

6 dysfunction, resulting in renal impairment and electrolyte disturbances. After paracentesis, ascites recurs in about 93% of patients if diuretic therapy is not instituted. TIPS can be used for the treatment of refractory ascites requiring frequent paracentesis or hepatic hydrothorax. TIPS: reduces portal pressure decreases the activation of the renin angiotensin aldosterone system (see Lote, CROSS REFERENCES) increases sodium excretion. Control of ascites is achieved in 90% of cases and complete resolution in 75% of cases. TIPS has been shown to resolve hepatic hydrothorax in 60 70% of patients. Recently, with polytetrafluoroethylene-covered stents, the long-term outcome from TIPS has improved with lowered frequency of hepatic encephalopathy (25% with standard stents). TIPS is associated with a less favourable outcome in advanced Child Pugh class- C patients. Surgical shunts Peritoneovenous shunts have been used effectively in the management of refractory ascites, particularly if therapeutic paracentesis and TIPS are unfeasible. Complications include: shunt infection occlusion cocoon formation (making future transplantation difficult) significant mortality. Portocaval shunts (particularly side-to-side) have high surgical mortality, but may have to be considered if other treatments are inappropriate. Liver transplantation should be considered in patients with cirrhotic ascites (particularly if resistant or refractory). The development of ascites is associated with a mortality of 50% within two years of diagnosis; prognosis is worse if complications (Table 4) develop. Fifty percent of patients die within six months if ascites becomes refractory to medical therapy. Therapeutic paracentesis and TIPS do not improve long-term survival without transplantation for most patients. Patients with ascites due to cirrhosis Complications of ascites Spontaneous bacterial peritonitis Hepatorenal syndrome Umbilical hernia Pleural effusion Respiratory difficulties Table 4 have an overall one-year survival after liver transplantation of 85%. Cross references Kaushal MV, Farrer K, Anderson ID. Nutritional support. Surgery 2004; 22(8): Lote C. The renin angiotensin system and regulation of fluid volume. Surgery 2006; 24(5): Mackenzie I. Fluid and electrolyte balance, anaemia and blood transfusion. Surgery 2005; 23(12): Peterson M, Thomas WEG. Gastrointestinal haemorrhage. Surgery 2005; 23(6): Further reading Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005; 41: Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal haemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 2001; 120: Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006; 55(suppl 6): 1 2. Orug T, Soonawalla ZF, Tekin K, Olliff SP, Buckels JA, Mayer AD. Role of surgical portosytemic shunts in the era of interventional radiology and liver transplantation. Br J Surg 2004; 91: SURGERY 25: Elsevier Ltd. All rights reserved.