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Portal hypertension and ascites
HEPATOBILIARY SURGERY
Portal hypertension and ascites
circulation. These haemodynamic changes eventually lead to the clinical manifestations of portal hypertension (Figure 1).
Clinical features
Naaventhan Palaniyappan
History taking should be directed towards determining the cause and complications of portal hypertension (Box 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.
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 prehepatic, intrahepatic and posthepatic obstruction to the flow, secondary to variety of causes. Diagnosis can be established by a combination of non-invasive imaging or portal vasculature and clinical or serological markers for the cause underlying cirrhosis. Development of gastrooesophageal 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 drug (e.g. terlipressin) and endoscopic band ligation. If these measures fail, transjugular intrahepatic portosystemic shunt (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.
Investigations Evaluation should be individualized depending on the presentation. Investigations should aim to confirm liver disease and to
Causes of portal hypertension Prehepatic portal hypertension C Thrombosis of the portal vein Intra-abdominal sepsis Chronic pancreatitis Pancreatic neoplasia Prothrombotic state
Keywords Ascites; cirrhosis; TIPS; varices
C
Chronic pancreatitis Pancreatic neoplasia
Definition C
Portal pressure is the product of the portal 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.
Splanchnic arteriovenous fistula
Intrahepatic portal hypertension C Predominantly pre-sinusoidal involvement Cirrhosis (alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, haemachromatosis) Schistosomiasis Nodular regenerative hyperplasia Polycystic liver disease Myeloproliferative disease Hepatic metastasis Granulomatous (sarcoidosis, tuberculosis)
Aetiology and pathogenesis Portal hypertension is classified according to the site of the obstruction to blood flow into prehepatic, intrahepatic and posthepatic causes (Box 1). Cirrhosis is the most common cause 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). In contrast, vascular sheer stress and gut-derived endotoxemia increase concentrations of nitric oxide in splanchnic and systemic
C
Predominantly post-sinusoidal involvement Budd-Chiari syndrome Veno-occlusive disease
Naaventhan Palaniyappan MRCP BMBS is a Clinical Research Fellow in Hepatology at NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. Conflicts of interest: none declared.
Posthepatic portal hypertension C Constrictive pericarditis C Obstruction of inferior vena cava C Right heart failure C Tricuspid regurgitation
Guruprasad P Aithal FRCP PhD is Professor of Hepatology at NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. Conflicts of interest: none declared.
SURGERY 32:12
Thrombosis of the splenic vein
Box 1
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Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
I
S
S
P
P
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E
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Figure 1
identify the underlying cause (Box 3). Sequestration 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 haemachromatosis 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.
severity of portal hypertension. Transjugular hepatic venous catheterization is used to measure the free (with balloon deflated) and wedged (with balloon inflated) hepatic venous pressures. In cirrhosis, HVPG gives an accurate estimate of the portal pressure. HVPG of greater than 10 mmHg predicts the development of complications of portal hypertension and signifies clinically significant portal hypertension (CSPH). HVPG also predicts the clinical outcomes in patients undergoing resection for hepatocellular carcinoma.
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 are inconclusive. MRI angiography can detect portosystemic collaterals and obstruction and portal vascular structure. Selective angiography of the superior mesenteric artery or splenic artery may be indicated in certain instances if other tests are inconclusive.
Non-invasive assessment of portal hypertension: as HVPG is a fairly invasive procedure, several non-invasive techniques have been proposed to measure portal hypertension. This is either based on evaluating the elements relating to the pathogenesis of portal hypertension or evaluating the clinical consequences of portal hypertension. Serum markers and transient elastography (measurement of liver stiffness) assess the degree of hepatic fibrosis and the increased hepatic vascular resistance, thus reflecting the degree of portal hypertension. Magnetic resonance elastography (MRE) has a theoretical advantage over ultrasoundbased transient elastography as stiffness of the whole liver is assessed. Spleen stiffness, in isolation or in combination with other clinical parameters, has been studied as a potential marker of the development of CSPH but further clinical studies are needed before being adopted into clinical practice.
Hepatic venous pressure gradient (HVPG): which is the difference between the wedged and free hepatic venous pressure (HVP), is the gold standard for defining and assessing the
SURGERY 32:12
662
Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
Clinical features of portal hypertension
Specific investigations in portal hypertension
History C Risk factors for cirrhosis
To identify the causes of cirrhosis C Liver function tests C Viral hepatitis B and C serology C Antinuclear, antimichondrial, antismooth muscle antibody C Iron indices (ferritin, tranferin saturation, HFE genotyping) C a1-antitrypsin C Ceruloplasmin (in those aged <40 years)
Intravenous drug use Infusion of blood products Metabolic syndrome (diabetes, dyslipidaemia) Alcohol abuse C
C
obesity,
hypertension,
Risk factors for non-cirrhotic portal hypertension Chronic pancreatitis, pancreatic cancer Procoagulative disorders
Liver biopsy Portal vascular imaging C Duplex Doppler ultrasonography C CT or MRI angiography/portography C Transjugular hepatic venous pressure measurements
Symptoms of gastrointestinal bleeding
Haemetemesis Malaena Haematochezia Hypovolaemic shock
gradient
(HVPG)
Consequences of portal hypertension C Upper gastrointestinal tract endoscopy
Physical signs C Signs of portal hypertension Dilated veins in the anterior abdominal wall with flow away from the umbilicus Ascites Splenomegaly Caput medisae
Box 3
Gastro-oesophageal varices
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 preexistent 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 gastrooesophageal varices (Figure 2). Portal hypertensive gastropathy refers to the endoscopic appearances of gastric mucosa with characteristic mosaic-like pattern, mainly in the body and fundus of the stomach. 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 0e10% of patients with compensated disease to 70e80% of those with decompensated cirrhosis. HVPG of more than 10 mmHg predicts the development of varices. The tension in the variceal wall increases with the increasing wedged hepatic venous pressure and the size of the varix. This is manifested by ‘cherry red’ spots and red wale markings. Advanced cirrhosis (as indicated by Child-Pugh score; see ‘Malignant tumours of the liver’) 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 and is associated with 10e20% mortality rate.
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.
Management of gastro-oesophageal varices Primary prevention: annual endoscopy of the upper gastrointestinal tract can detect newly formed varices. Non-selective bblockers (e.g. propranolol, timolol) reduce the cardiac output (b1 receptors) and splanchnic arterial flow (b2 receptors); thus reducing portal pressure. Although b-blockers do not prevent formation of new gastro-oesophageal varices they may prevent enlargement of varices in patients with portal hypertension.
C
Signs of liver disease
Jaundice Spider naevi Palmar erythema Asterixis Gynaecomastia
Box 2
Non-cirrhotic portal hypertension (NCPH) NCPH is a group of liver disorders with portal hypertension without any evidence significant liver parenchymal dysfunction. The underlying disease processes are primarily vascular in nature and a prothrombotic state is thought to play a major role in the pathogenesis. The prevalence of NCPH varies across the globe; it is relatively uncommon in the west but forms up to 30% of the total portal hypertensive patients in the Far East. In contrast to cirrhotic portal hypertension, HVPG in NCPH is normal or only mildly elevated. Patients with NCPH commonly present with variceal bleeding, and splenomegaly.
SURGERY 32:12
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Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
a
b
Figure 2
However, proportion of subjects (about 15%) are intolerant to bblockers or have contraindications to such therapy. Carvedilol (non-selective b-blocker with a1-blockade vasodilating properties) has recently been shown to be as effective and better tolerated. Endoscopic band ligation can be used for primary prophylaxis when b-blockers can’t be used for this purpose. The benefits of banding outweigh its risks when used selectively in high risk groups (moderate/large varices, decompensated cirrhosis).
adhesive (e.g. N-butyl-cyanoacrylate) is superior (Figure 3), but should only be done only by experienced endoscopists. Balloon tamponade (SengstakeneBlakemore tube) e 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 SengstakeneBlakemore 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 more than 24 hours. Inflation of the oesophageal balloon is necessary only in exceptional circumstances. The pressure should be maintained at 20e40 mmHg when the oesophageal balloon is inflated; the balloon should be deflated for 2e4 minutes every hour to avoid pressure necrosis of the oesophagus. Transjugular intrahepatic portosystemic shunt (TIPS) e 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 80e90% 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 8e12 mm and a metal stent is deployed to support the shunt wall (Figure 4). TIPS is effective in controlling bleeding due to portal gastropathy. Antibiotic prophylaxis e up to 20% of cirrhotic patients hospitalized due to gastrointestinal bleeding have bacterial infections; an additional 50% develop an infection while being 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 (SBP). Prevention of hepatic encephalopathy e lactulose by mouth or via nasogastric tube may reduce the risk of encephalopathy by decreasing the nitrogenous load from the gut.
Treatment of acute variceal haemorrhage: the goals of management are to adequately resuscitate, achieve haemostasis and prevent bleeding. Resuscitation e 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 8e10 g/dL (depending on haemodynamic status, ongoing bleeding and comorbidities; see Mackenzie).3 Pharmacological therapy e 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 3e5 days from the onset. Endoscopy of the upper gastrointestinal tract e should be done with adequate airway protection using endotracheal intubation. Patients with hepatic encephalopathy with large haemetemesis are at risk of aspiration. Endoscopy helps to establish the cause of upper gastrointestinal bleeding; non-variceal sources (e.g. ulcers, MalloryeWeiss tear and portal hypertensive gastropathy) account for the bleeding in the 15e25% 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
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HEPATOBILIARY SURGERY
Figure 3 Injection of glue into gastric varices: a shows a column of blood solidify as it exudes out of a varix; b shows ‘stalactite sign’ of glue exuding out of a hole in the varix.
Nutrition e malnutrition contributes to morbidity and mortality in these patients (see Kaushal),1 so feeding should be resumed as soon as possible. A nasogastric tube can be inserted about 24 hours after bleeding stops. Surgical management e surgery has limited role in the management of acute variceal bleeding; TIPS is a less invasive method of decompressing the varices. Emergency portocaval shunts, oesophageal transaction and devascularization are rarely done. Patient selection is crucial in determining the success of surgical portosystemic shunts and can be done using Child-Pugh classification. Shunt surgery in patients with Child-Pugh C cirrhosis carried a significant mortality, while liver transplantation offers improved survival in this group of patients. Benefits and risks of liver transplantation should be compared against those for shunt surgery in Child-Pugh B and C 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.
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 b-blockers b-blockers are contraindicated the patient is high risk (Child-Pugh 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 10 years of follow-up. Ascites is an important landmark in the natural history of cirrhosis because it is associated with 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; the remainder 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
Secondary prevention: overall, about 70% of patients who have had one variceal bleeding rebleed. Non-selective b-blockers are
Figure 4 Transjugular intrahepatic portosystemic shunt (steps involved in each of the above pictures).
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Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
circulating antidiuretic hormone. Plasma expansion with albumin (complemented by terlipressin) may be useful in correcting the effective hypovolaemia. Vasopressin-2 receptor antagonists increase solute-free water excretion and thus provide a new pharmacological dimension in the treatment of dilutional hyponatraemia. The initial trials with V2-receptor antagonists (vaptans) have shown promising results in correcting the sodium levels but safety concerns need to be addressed and longer-term outcomes need to be studied.
critical factor in the pathogenesis, and is associated with circulatory changes characterized by arterial vasodilation, effective hypovolaemia, and the retention of sodium and water in the kidney. Although total body sodium increases, there is a disproportionately high renal retention of solute-free water resulting in dilutional hyponatraemia. Patients with hyponatraemia have a higher rate of hepatic encephalopathy, SBP and hepatorenal syndrome. The rapid and high in flow 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.
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. Furosemide (up to 160 mg/day) is added especially when peripheral oedema is present. Careful biochemical and clinical monitoring is important to avoid overdiuresis leading to hypokalaemia and intravascular hypovolaemia.
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 and full blood count) should be done.
Therapeutic paracentesis: is the first-line treatment for large or refractory ascites. Large volume paracentesis with colloid replacement is rapid, safe and effective. 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 dysfunction, resulting in renal impairment and electrolyte disturbances. After paracentesis, ascites recurs in about 93% of patients if diuretic therapy is not instituted.
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 is 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 e 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 suggests that ascites is due to cirrhosis with portal hypertension or other causes of transudates (e.g. cardiac failure, nephrotic syndrome). A value of <11 g 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 e ascitic neutrophil count of >250 cells/mm3 is diagnostic of SBP 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 SBP. Other tests e requests for ascitic fluid cytology and culture for mycobacteria should be done only if clinical suspicion of malignancy or tuberculosis is high.
TIPS: (Figure 4) 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-angiotensinaldosterone system (see Lote)2 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 60e70% of patients. TIPS has significant advantages over large volume paracentesis in controlling ascites. TIPS significantly increases the risk of hepatic encephalopathy and higher cost of TIPS makes it a second line therapy in the management of refractory ascites.
Surgical shunts Peritoneovenous shunts e 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 e (particularly side-to-side) have high surgical mortality, but may have to be considered in exceptional circumstances.
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 10e20% of patients. Fluid restriction: there is minimal role for water restriction in patient with hyponatraemia in ascites as this may exacerbate the effective central hypovolaemia and further increases the
SURGERY 32:12
Liver transplantation: should be considered in patients with cirrhotic ascites (particularly if resistant or refractory). The
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HEPATOBILIARY SURGERY
REFERENCES 1 Kaushal MV, Farrer K, Anderson ID. Nutritional support. Surgery 2004; 22: 196e200. 2 Lote C. The renin-angiotensin system and regulation of fluid volume. Surgery 2006; 24: 154e9. 3 Mackenzie I. Fluid and electrolyte balance, anaemia and blood transfusion. Surgery 2005; 23: 453e60.
Complications of ascites C C C C C
Spontaneous bacterial peritonitis Hepatorenal syndrome Umbilical hernia Pleural effusion Respiratory difficulties
FURTHER READING Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005; 41: 386e400. Gines P, Cardenas A. The management of ascites and hyponatraemia in cirrhosis. Semin Liver Dis 2008; 1: 43e58. Moores KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006; 55(suppl 6): 1e2. Orug T, Soonawalla ZF, Tekin K, Olliff SP, Buckels JA, Mayer AD. Role of surgical portosystemic shunts in the era of interventional radiology and liver transplantation. Br J Surg 2004; 91: 769e73. Wong CL, Holroyd-Leduc J, Thorpe KE, Straus SE. Does this patient have bacterial peritonitis or portal hypertension? How do I perform a paracentesis and analyze the results? JAMA 2008; 299: 1166e78.
Box 4
development of ascites is associated with a mortality of 50% within two years of diagnosis; prognosis is worse if complications (Box 4) develop. Fifty percent of patients die within six months if ascites becomes refractory to medical therapy. Therapeutic paracentesis and TIPS do no improve long-term survival without transplantation for most patients. Patients with ascites due to cirrhosis have an overall one year survival after liver transplantation of 85%. A
SURGERY 32:12
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Ó 2014 Elsevier Ltd. All rights reserved.
Portal hypertension and ascites
circulation. These haemodynamic changes eventually lead to the clinical manifestations of portal hypertension (Figure 1).
Clinical features
Naaventhan Palaniyappan
History taking should be directed towards determining the cause and complications of portal hypertension (Box 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.
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 prehepatic, intrahepatic and posthepatic obstruction to the flow, secondary to variety of causes. Diagnosis can be established by a combination of non-invasive imaging or portal vasculature and clinical or serological markers for the cause underlying cirrhosis. Development of gastrooesophageal 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 drug (e.g. terlipressin) and endoscopic band ligation. If these measures fail, transjugular intrahepatic portosystemic shunt (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.
Investigations Evaluation should be individualized depending on the presentation. Investigations should aim to confirm liver disease and to
Causes of portal hypertension Prehepatic portal hypertension C Thrombosis of the portal vein Intra-abdominal sepsis Chronic pancreatitis Pancreatic neoplasia Prothrombotic state
Keywords Ascites; cirrhosis; TIPS; varices
C
Chronic pancreatitis Pancreatic neoplasia
Definition C
Portal pressure is the product of the portal 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.
Splanchnic arteriovenous fistula
Intrahepatic portal hypertension C Predominantly pre-sinusoidal involvement Cirrhosis (alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, haemachromatosis) Schistosomiasis Nodular regenerative hyperplasia Polycystic liver disease Myeloproliferative disease Hepatic metastasis Granulomatous (sarcoidosis, tuberculosis)
Aetiology and pathogenesis Portal hypertension is classified according to the site of the obstruction to blood flow into prehepatic, intrahepatic and posthepatic causes (Box 1). Cirrhosis is the most common cause 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). In contrast, vascular sheer stress and gut-derived endotoxemia increase concentrations of nitric oxide in splanchnic and systemic
C
Predominantly post-sinusoidal involvement Budd-Chiari syndrome Veno-occlusive disease
Naaventhan Palaniyappan MRCP BMBS is a Clinical Research Fellow in Hepatology at NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. Conflicts of interest: none declared.
Posthepatic portal hypertension C Constrictive pericarditis C Obstruction of inferior vena cava C Right heart failure C Tricuspid regurgitation
Guruprasad P Aithal FRCP PhD is Professor of Hepatology at NIHR Biomedical Research Unit in Gastrointestinal and Liver Diseases at Nottingham University Hospitals NHS Trust and the University of Nottingham, UK. Conflicts of interest: none declared.
SURGERY 32:12
Thrombosis of the splenic vein
Box 1
661
Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
I
S
S
P
P
–
E
–
Figure 1
identify the underlying cause (Box 3). Sequestration 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 haemachromatosis 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.
severity of portal hypertension. Transjugular hepatic venous catheterization is used to measure the free (with balloon deflated) and wedged (with balloon inflated) hepatic venous pressures. In cirrhosis, HVPG gives an accurate estimate of the portal pressure. HVPG of greater than 10 mmHg predicts the development of complications of portal hypertension and signifies clinically significant portal hypertension (CSPH). HVPG also predicts the clinical outcomes in patients undergoing resection for hepatocellular carcinoma.
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 are inconclusive. MRI angiography can detect portosystemic collaterals and obstruction and portal vascular structure. Selective angiography of the superior mesenteric artery or splenic artery may be indicated in certain instances if other tests are inconclusive.
Non-invasive assessment of portal hypertension: as HVPG is a fairly invasive procedure, several non-invasive techniques have been proposed to measure portal hypertension. This is either based on evaluating the elements relating to the pathogenesis of portal hypertension or evaluating the clinical consequences of portal hypertension. Serum markers and transient elastography (measurement of liver stiffness) assess the degree of hepatic fibrosis and the increased hepatic vascular resistance, thus reflecting the degree of portal hypertension. Magnetic resonance elastography (MRE) has a theoretical advantage over ultrasoundbased transient elastography as stiffness of the whole liver is assessed. Spleen stiffness, in isolation or in combination with other clinical parameters, has been studied as a potential marker of the development of CSPH but further clinical studies are needed before being adopted into clinical practice.
Hepatic venous pressure gradient (HVPG): which is the difference between the wedged and free hepatic venous pressure (HVP), is the gold standard for defining and assessing the
SURGERY 32:12
662
Ó 2014 Elsevier Ltd. All rights reserved.
HEPATOBILIARY SURGERY
Clinical features of portal hypertension
Specific investigations in portal hypertension
History C Risk factors for cirrhosis
To identify the causes of cirrhosis C Liver function tests C Viral hepatitis B and C serology C Antinuclear, antimichondrial, antismooth muscle antibody C Iron indices (ferritin, tranferin saturation, HFE genotyping) C a1-antitrypsin C Ceruloplasmin (in those aged <40 years)
Intravenous drug use Infusion of blood products Metabolic syndrome (diabetes, dyslipidaemia) Alcohol abuse C
C
obesity,
hypertension,
Risk factors for non-cirrhotic portal hypertension Chronic pancreatitis, pancreatic cancer Procoagulative disorders
Liver biopsy Portal vascular imaging C Duplex Doppler ultrasonography C CT or MRI angiography/portography C Transjugular hepatic venous pressure measurements
Symptoms of gastrointestinal bleeding
Haemetemesis Malaena Haematochezia Hypovolaemic shock
gradient
(HVPG)
Consequences of portal hypertension C Upper gastrointestinal tract endoscopy
Physical signs C Signs of portal hypertension Dilated veins in the anterior abdominal wall with flow away from the umbilicus Ascites Splenomegaly Caput medisae
Box 3
Gastro-oesophageal varices
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 preexistent 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 gastrooesophageal varices (Figure 2). Portal hypertensive gastropathy refers to the endoscopic appearances of gastric mucosa with characteristic mosaic-like pattern, mainly in the body and fundus of the stomach. 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 0e10% of patients with compensated disease to 70e80% of those with decompensated cirrhosis. HVPG of more than 10 mmHg predicts the development of varices. The tension in the variceal wall increases with the increasing wedged hepatic venous pressure and the size of the varix. This is manifested by ‘cherry red’ spots and red wale markings. Advanced cirrhosis (as indicated by Child-Pugh score; see ‘Malignant tumours of the liver’) 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 and is associated with 10e20% mortality rate.
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.
Management of gastro-oesophageal varices Primary prevention: annual endoscopy of the upper gastrointestinal tract can detect newly formed varices. Non-selective bblockers (e.g. propranolol, timolol) reduce the cardiac output (b1 receptors) and splanchnic arterial flow (b2 receptors); thus reducing portal pressure. Although b-blockers do not prevent formation of new gastro-oesophageal varices they may prevent enlargement of varices in patients with portal hypertension.
C
Signs of liver disease
Jaundice Spider naevi Palmar erythema Asterixis Gynaecomastia
Box 2
Non-cirrhotic portal hypertension (NCPH) NCPH is a group of liver disorders with portal hypertension without any evidence significant liver parenchymal dysfunction. The underlying disease processes are primarily vascular in nature and a prothrombotic state is thought to play a major role in the pathogenesis. The prevalence of NCPH varies across the globe; it is relatively uncommon in the west but forms up to 30% of the total portal hypertensive patients in the Far East. In contrast to cirrhotic portal hypertension, HVPG in NCPH is normal or only mildly elevated. Patients with NCPH commonly present with variceal bleeding, and splenomegaly.
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a
b
Figure 2
However, proportion of subjects (about 15%) are intolerant to bblockers or have contraindications to such therapy. Carvedilol (non-selective b-blocker with a1-blockade vasodilating properties) has recently been shown to be as effective and better tolerated. Endoscopic band ligation can be used for primary prophylaxis when b-blockers can’t be used for this purpose. The benefits of banding outweigh its risks when used selectively in high risk groups (moderate/large varices, decompensated cirrhosis).
adhesive (e.g. N-butyl-cyanoacrylate) is superior (Figure 3), but should only be done only by experienced endoscopists. Balloon tamponade (SengstakeneBlakemore tube) e 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 SengstakeneBlakemore 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 more than 24 hours. Inflation of the oesophageal balloon is necessary only in exceptional circumstances. The pressure should be maintained at 20e40 mmHg when the oesophageal balloon is inflated; the balloon should be deflated for 2e4 minutes every hour to avoid pressure necrosis of the oesophagus. Transjugular intrahepatic portosystemic shunt (TIPS) e 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 80e90% 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 8e12 mm and a metal stent is deployed to support the shunt wall (Figure 4). TIPS is effective in controlling bleeding due to portal gastropathy. Antibiotic prophylaxis e up to 20% of cirrhotic patients hospitalized due to gastrointestinal bleeding have bacterial infections; an additional 50% develop an infection while being 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 (SBP). Prevention of hepatic encephalopathy e lactulose by mouth or via nasogastric tube may reduce the risk of encephalopathy by decreasing the nitrogenous load from the gut.
Treatment of acute variceal haemorrhage: the goals of management are to adequately resuscitate, achieve haemostasis and prevent bleeding. Resuscitation e 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 8e10 g/dL (depending on haemodynamic status, ongoing bleeding and comorbidities; see Mackenzie).3 Pharmacological therapy e 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 3e5 days from the onset. Endoscopy of the upper gastrointestinal tract e should be done with adequate airway protection using endotracheal intubation. Patients with hepatic encephalopathy with large haemetemesis are at risk of aspiration. Endoscopy helps to establish the cause of upper gastrointestinal bleeding; non-variceal sources (e.g. ulcers, MalloryeWeiss tear and portal hypertensive gastropathy) account for the bleeding in the 15e25% 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
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Figure 3 Injection of glue into gastric varices: a shows a column of blood solidify as it exudes out of a varix; b shows ‘stalactite sign’ of glue exuding out of a hole in the varix.
Nutrition e malnutrition contributes to morbidity and mortality in these patients (see Kaushal),1 so feeding should be resumed as soon as possible. A nasogastric tube can be inserted about 24 hours after bleeding stops. Surgical management e surgery has limited role in the management of acute variceal bleeding; TIPS is a less invasive method of decompressing the varices. Emergency portocaval shunts, oesophageal transaction and devascularization are rarely done. Patient selection is crucial in determining the success of surgical portosystemic shunts and can be done using Child-Pugh classification. Shunt surgery in patients with Child-Pugh C cirrhosis carried a significant mortality, while liver transplantation offers improved survival in this group of patients. Benefits and risks of liver transplantation should be compared against those for shunt surgery in Child-Pugh B and C 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.
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 b-blockers b-blockers are contraindicated the patient is high risk (Child-Pugh 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 10 years of follow-up. Ascites is an important landmark in the natural history of cirrhosis because it is associated with 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; the remainder 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
Secondary prevention: overall, about 70% of patients who have had one variceal bleeding rebleed. Non-selective b-blockers are
Figure 4 Transjugular intrahepatic portosystemic shunt (steps involved in each of the above pictures).
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circulating antidiuretic hormone. Plasma expansion with albumin (complemented by terlipressin) may be useful in correcting the effective hypovolaemia. Vasopressin-2 receptor antagonists increase solute-free water excretion and thus provide a new pharmacological dimension in the treatment of dilutional hyponatraemia. The initial trials with V2-receptor antagonists (vaptans) have shown promising results in correcting the sodium levels but safety concerns need to be addressed and longer-term outcomes need to be studied.
critical factor in the pathogenesis, and is associated with circulatory changes characterized by arterial vasodilation, effective hypovolaemia, and the retention of sodium and water in the kidney. Although total body sodium increases, there is a disproportionately high renal retention of solute-free water resulting in dilutional hyponatraemia. Patients with hyponatraemia have a higher rate of hepatic encephalopathy, SBP and hepatorenal syndrome. The rapid and high in flow 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.
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. Furosemide (up to 160 mg/day) is added especially when peripheral oedema is present. Careful biochemical and clinical monitoring is important to avoid overdiuresis leading to hypokalaemia and intravascular hypovolaemia.
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 and full blood count) should be done.
Therapeutic paracentesis: is the first-line treatment for large or refractory ascites. Large volume paracentesis with colloid replacement is rapid, safe and effective. 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 dysfunction, resulting in renal impairment and electrolyte disturbances. After paracentesis, ascites recurs in about 93% of patients if diuretic therapy is not instituted.
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 is 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 e 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 suggests that ascites is due to cirrhosis with portal hypertension or other causes of transudates (e.g. cardiac failure, nephrotic syndrome). A value of <11 g 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 e ascitic neutrophil count of >250 cells/mm3 is diagnostic of SBP 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 SBP. Other tests e requests for ascitic fluid cytology and culture for mycobacteria should be done only if clinical suspicion of malignancy or tuberculosis is high.
TIPS: (Figure 4) 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-angiotensinaldosterone system (see Lote)2 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 60e70% of patients. TIPS has significant advantages over large volume paracentesis in controlling ascites. TIPS significantly increases the risk of hepatic encephalopathy and higher cost of TIPS makes it a second line therapy in the management of refractory ascites.
Surgical shunts Peritoneovenous shunts e 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 e (particularly side-to-side) have high surgical mortality, but may have to be considered in exceptional circumstances.
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 10e20% of patients. Fluid restriction: there is minimal role for water restriction in patient with hyponatraemia in ascites as this may exacerbate the effective central hypovolaemia and further increases the
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Liver transplantation: should be considered in patients with cirrhotic ascites (particularly if resistant or refractory). The
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REFERENCES 1 Kaushal MV, Farrer K, Anderson ID. Nutritional support. Surgery 2004; 22: 196e200. 2 Lote C. The renin-angiotensin system and regulation of fluid volume. Surgery 2006; 24: 154e9. 3 Mackenzie I. Fluid and electrolyte balance, anaemia and blood transfusion. Surgery 2005; 23: 453e60.
Complications of ascites C C C C C
Spontaneous bacterial peritonitis Hepatorenal syndrome Umbilical hernia Pleural effusion Respiratory difficulties
FURTHER READING Boyer TD, Haskal ZJ. The role of transjugular intrahepatic portosystemic shunt in the management of portal hypertension. Hepatology 2005; 41: 386e400. Gines P, Cardenas A. The management of ascites and hyponatraemia in cirrhosis. Semin Liver Dis 2008; 1: 43e58. Moores KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006; 55(suppl 6): 1e2. Orug T, Soonawalla ZF, Tekin K, Olliff SP, Buckels JA, Mayer AD. Role of surgical portosystemic shunts in the era of interventional radiology and liver transplantation. Br J Surg 2004; 91: 769e73. Wong CL, Holroyd-Leduc J, Thorpe KE, Straus SE. Does this patient have bacterial peritonitis or portal hypertension? How do I perform a paracentesis and analyze the results? JAMA 2008; 299: 1166e78.
Box 4
development of ascites is associated with a mortality of 50% within two years of diagnosis; prognosis is worse if complications (Box 4) develop. Fifty percent of patients die within six months if ascites becomes refractory to medical therapy. Therapeutic paracentesis and TIPS do no improve long-term survival without transplantation for most patients. Patients with ascites due to cirrhosis have an overall one year survival after liver transplantation of 85%. A
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