Assessing portal hypertension in liver diseases

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1 Expert of Gastroenterology & Hepatology ISSN: (Print) (Online) Journal homepage: Annalisa Berzigotti, Susana Seijo, Enric Reverter & Jaime Bosch To cite this article: Annalisa Berzigotti, Susana Seijo, Enric Reverter & Jaime Bosch (2013), Expert of Gastroenterology & Hepatology, 7:2, , DOI: /egh To link to this article: Published online: 10 Jan Submit your article to this journal Article views: 3965 Citing articles: 84 View citing articles Full Terms & Conditions of access and use can be found at

2 For reprint orders, please contact Assessing portal hypertension in liver diseases Expert Rev. Gastroenterol. Hepatol. 7(2), (2013) Annalisa Berzigotti 1,2, Susana Seijo 1,2, Enric Reverter 1,2 and Jaime Bosch* 1,2 1 Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain 2 Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Hospital Clínic, c/villarroel 170, Barcelona, Spain *Author for correspondence: Tel.: jbosch@clinic.ub.es Portal hypertension is a common complication of chronic liver diseases and is responsible for most clinical consequences of cirrhosis, which represent the more frequent causes of death and liver transplantation in these patients. This review is aimed at clarifying the state-of-the art assessment of portal hypertension and at discussing recent developments in this field. Particular attention is paid to new noninvasive techniques that will be soon available for potential routine use. Keywords: hepatic hemodynamics hepatic venous pressure gradient liver stiffness noninvasive methods ultrasound Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert s Ltd. Medscape, LLC is accredited by the AC to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at (4) view/print certificate. Release date: 28 January 2013; Expiration date: 28 January 2014 Learning objectives Upon completion of this activity, participants will be able to: Analyze the initial evaluation of a patient with suspected portal hypertension Assess testing for gastroesophageal varices among patients with portal hypertension Evaluate patterns of portal hypertension on measurement of the hepatic venous pressure gradient Distinguish clinically significant elevations in the hepatic venous pressure gradient /EGH Expert s Ltd ISSN

3 Berzigotti, Seijo, Reverter & Bosch Financial & competing interests disclosure Editor Elisa Manzotti Publisher, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. Author Charles Vega Health Sciences Clinical Professor; Residency Director, Department of Family Medicine, University of California, Irvine, CA, USA Disclosure: Charles P Vega, MD, has disclosed no relevant financial relationships. Authors and Credentials Annalisa Berzigotti, MD, PhD Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain Disclosure: Annalisa Berzigotti, MD, PhD, has disclosed no relevant financial relationships. Susana Seijo, MD Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain Disclosure: Susana Seijo, MD, has disclosed no relevant financial relationships. Enric Reverter, MD Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain Disclosure: Enric Reverter, MD, has disclosed no relevant financial relationships. Jaime Bosch, MD, PhD, Professor of Medicine; Chief, Hepatology Section Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic-Institut d Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Spain Disclosure: Jaime Bosch, MD, PhD, has disclosed no relevant financial relationships. Definition Portal hypertension is a frequent syndrome most often caused by chronic liver diseases which is characterized by an increased portal pressure gradient (PPG; the difference in pressure between the portal vein and the inferior vena cava [IVC], which represents the perfusion pressure of the liver with portal blood). The increased portal pressure leads to other consequences, such as splenomegaly, growth of an extensive network of portal-systemic collaterals that shunt portal blood flow to the systemic circulation bypassing the liver and development of a hyperkinetic circulatory state [1]. In normal conditions the PPG ranges between 1 and 5 mmhg. Portal hypertension becomes clinically significant (associated with risk of clinical complications) when the PPG increases to 10 mmhg or above. Values between 5 and 9 mmhg represent subclinical portal hypertension [1 3]. Natural history The relevance of portal hypertension derives from the frequency and severity of its complications, which represent the first cause of hospital admission, death and liver transplantation in patients with cirrhosis. These include formation of esophageal or gastric varices, variceal bleeding, ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, portopulmonary hypertension, hepatopulmonary syndrome, hepatic encephalopathy, portal hypertensive gastro pathy (PHG), enteropathy and colopathy and disturbances in the metabolism of endo- and xeno-biotics normally metabolized by the liver. Portal hypertension is an almost unavoidable consequence of cirrhosis [1]. Between 80 and 90% of totally asymptomatic patients already have an elevated PPG (measured clinically as an increase in the hepatic venous pressure gradient [HVPG]) and endo scopy discloses that 40% already have esophageal varices. Among those without varices, this will appear at a rate of 6% per year (over 10% in those with a HVPG >10 mmhg). If untreated, bleeding occurs within 2 years in 10 30% of patients with varices, depending on the size of varices, presence of red color signs, degree of liver failure and of HVPG elevation. Variceal bleeding is associated with a 6-week mortality of 12 20% and if no effective therapy is provided will recur in two-thirds of the patients within 2 years. Current medical treatment decreases the risk of first and/or recurrent variceal bleeding by approximately 50%, indicating that better treatments are required. Pathophysiology Portal hypertension is initiated by an increased resistance to portal blood flow and aggravated by an increased portal-collateral blood flow [4]. Such increased resistance to portal blood flow is most commonly due to chronic liver disease (cirrhosis of the liver), which is the most common cause of portal hypertension worldwide, followed by hepatic schistosomiasis. Other causes of portal hypertension account for less than 10% of cases; among these relatively uncommon causes the more frequent are extrahepatic portal vein occlusion and idiopathic noncirrhotic portal hypertension. 142 Expert Rev. Gastroenterol. Hepatol. 7(2), (2013)

4 Hepatic vascular resistance in cirrhosis increases by a dual mechanism; first there is a structural component, related to distortion of liver microcirculation by fibrosis, nodule formation, angiogenesis and vascular occlusion. In addition, there is an increased hepatic vascular tone (dynamic component), owing to the contraction of activated hepatic stellate cells and myofibroblasts around the hepatic sinusoids and in fibrous septa and of vascular smooth muscle cells in the hepatic vasculature. This dynamic component accounts for approximately 30% of the increased hepatic resistance in cirrhosis and represents a liver vascular dysfunction, with increased local production of vasoconstrictors (endothelins, angio tensin-ii, norepinephrine and thromboxane A2) and reduced release of endothelial vasodilators (mainly nitric oxide, but also carbon monoxide) [4]. In advanced stages increased splanchnic (portal-collateral) blood flow plays a major role maintaining and aggravating portal hypertension. It is caused by a marked splanchnic arteriolar vasodilation and neoangiogenesis in response to an increased release of VEGF, nitric oxide and other splanchnic vasodilators. Splanchnic vasodilatation is so marked as to determine systemic hypotension, vascular underfilling, stimulation of endogenous vasoactive systems, plasma volume expansion and increased cardiac index (hyperkinetic syndrome), which plays a key role in the pathogenesis of ascites and renal dysfunction in cirrhosis. Formation of portal systemic collaterals and varices is not only due to increased portal pressure causing opening of pre-existent vessels at sites of communication between the portal and systemic circulation, but is also dependent on angiogenesis [5]. These disturbances provide a rational basis for the treatment of portal hypertension and are being used as therapeutic targets [4]. The abovementioned considerations highlight the importance of an early recognition and precise diagnosis of portal hypertension for a correct management of patients with chronic liver diseases. This requires the use of a number of techniques that have found increased applicability as recent studies have shown that they provide relevant prognostic information. These are reviewed in this paper. Etiology & classification of portal hypertension Any disease that may interfere with portal blood flow (at any level between the spleen Posthepatic PH Increased FHVP; HVPG normal or slightly increased Intrahepatic PH Sinusoidal Increased HVPG due to increased WHVP Presinusoidal Normal or slightly increased HVPG Prehepatic PH Normal HVPG Normal WHVP and FHVP and the right atrium) may cause portal hypertension. Therefore, causes of portal hypertension can be classified according to their anatomical location in: prehepatic (involving the spleno portal mesenteric venous axis), intrahepatic and posthepatic, as summarized in Figure 1 [1,6]. Cirrhosis is the most common cause of portal hypertension in western countries. All other causes included in so-called noncirrhotic portal hypertension, account for less than 10% of the cases. In other geographical areas schistosomiasis (Africa) and portal vein thrombosis (India) are leading causes of portal hypertension. Expert Rev. Gastroenterol. Hepatol. Future Science Group (2013) Constrictive pericarditis Tricuspid valve diseases Budd Chiari syndrome Congenital malformations and thrombosis of the IVC Liver cirrhosis Severe acute hepatitis (viral and alcoholic), chronic active hepatitis, mastocytosis, Gaucher s disease, vascular maligancies, amyloidosis, acute fatty liver of pregnancy, hypervitamin A; SOS (previously VOD) Schistosomiasis Nodular regenerative hyperplasia, partial nodular transformation, congenital hepatic fibrosis Idiopathic portal hypertension Peliosis hepatis, polycystic liver disease, arsenic, copper sulfate and vinyl chloride monomer poisoning, sarcoidosis, tuberculosis, primary biliary cirrhosis, amyloidosis Portal vein thrombosis Splenic and mesenteric vein thrombosis Arteriovenous fistulae Congenital stenosis of PV Extrinsic compression of the portosplenic venous axis Figure 1. Classification of portal hypertension based on the site of increased resistance and on the hemodynamic findings. FHVP: Free hepatic venous pressure; HVPG: Hepatic venous pressure; IVC: Inferior vena cava; PH: Portal hypertension; PV: Portal vein; SOS: Sinusoidal obstruction syndrome; WHVP: Wedge hepatic venous pressure

5 Berzigotti, Seijo, Reverter & Bosch Portal vein thrombosis is the main cause of prehepatic portal hypertension. In adults, prothrombotic diseases that are either congenital (such as antithrombin, protein C or S deficiency) or acquired (such as myeloproliferative neoplasm) and/or local factors such as sepsis, abdominal trauma, pancreatitis or surgery are responsible for 70% of cases, whereas the remaining 30% are idiopathic. In children, portal vein thrombosis is often related to omphalitis or umbilical vein catheterization. Portal vein thrombosis may present as two distinct clinical scenarios; acute or chronic (portal cavernoma); its diagnosis is based on imaging techniques [7]. Intrahepatic portal hypertension can be further classified considering the site of increased resistance and the results of hepatic vein catheterization (see below). Presinusoidal portal hypertension is characterized by normal or slightly increased HVPG values, with normal or slightly increased wedged hepatic venous pressure (WHVP) and normal free hepatic venous pressure (FHVP). Idiopathic portal hypertension, nodular regenerative hyperplasia, schistosomiasis, sarcoidosis, tuberculosis and early stages of primary biliary cirrhosis are the main causes of presinusoidal intrahepatic portal hypertension. Sinusoidal portal hypertension is found in most chronic liver diseases (including secondary biliary cirrhosis) and is characterized by an increase in WHVP with normal FHVP, resulting in high HVPG; cirrhosis is the most common cause. In postsinusoidal portal hypertension, HVPG is normal and both WHVP and FHVP are increased, such as in the Budd Chiari syndrome. In some diseases hepatic vein catheterization can show the evolution of the pathology. For example, schistosomiasis in the initial phase induces the formation of portal granulomas and fibrosis obliterating portal venules (presinusoidal portal hypertension); HVPG is normal in this phase. Later on, fibrosis may extend out of the portal tract and cause sinusoidal portal hypertension, with high HVPG and a hemodynamic and clinical pattern resembling cirrhosis. Budd Chiari syndrome is the most frequent cause of posthepatic portal hypertension. The obstruction of hepatic venous outflow can be present from the small hepatic venules (and be truly intrahepatic) up to the entrance of the IVC into the right atrium. Budd Chiari syndrome is usually caused by underlying prothrombotic disorders (mainly myeloproliferative disorders) and its diagnosis is usually made by imaging techniques. Gold-standard technique to assess portal hypertension: measurement of HVPG The pressure gradient between the portal vein and the IVC (PPG) represents the liver portal perfusion pressure; its normal value is up to 5 mmhg. Direct measurements of portal pressure can be performed through transhepatic or transvenous catheterization of the portal vein. This technique further requires catheterizing the IVC to determine the PPG. Because of this and of the risk of intraperitoneal bleeding, direct measurements of portal pressure are rarely used and are limited to selected cases of presinusoidal portal hypertension, such as in the case of patients with esophageal varices, patent portal vein and normal WHVP. The measurement of HVPG is a safe and reproducible technique that is the preferred way of measuring the PPG in cirrhosis (sinusoidal portal hypertension). HVPG is defined as the difference between WHVP and FHVP. It is based on the concept that when the blood flow in a hepatic vein is blocked by a wedged catheter, the static column of blood transmits the pressure from the preceding communicated vascular territory, in this case, the hepatic sinusoids. Thus, WHVP is a measurement of the hepatic sinusoidal pressure and not of portal pressure itself. As in cirrhosis the intersinusoidal communications are lost due to fibrosis, septa and nodule formation, the sinusoidal pressure equilibrates with portal pressure. It is well demonstrated that WHVP adequately reflects portal pressure in alcoholic liver disease [8], hepatitis C- [8] and hepatitis B-related cirrhosis [9], which are the most frequent etiologies of chronic liver disease. The use of balloon-tipped catheters is recommended to measure HVPG [1], since the volume of the liver circulation that is sensed is much larger than that obtained by wedging the catheter, which enhances the reliability and accuracy of the measurement [10]. Technical aspects HVPG measurement is carried out at the hepatic hemodynamics laboratory under light conscious sedation (midazolam 0.02 mg/kg intravenously) [11] and with noninvasive vital sign monitoring (by electrocardiography, arterial blood pressure and pulse oxymetry); under local anesthesia, with ultrasound assistance [12], the right jugular vein (or the femoral or antecubital vein) is catheterized, a venous introducer is placed and a balloontipped catheter is guided under fluoroscopic control through the right atrium and IVC into the main right hepatic vein. FHVP is measured by maintaining the tip of the catheter free in the hepatic vein, at 2 4 cm from its opening into the IVC (Figure 2A). If the difference between FHVP and IVC pressure is greater than 2 mmhg, it is likely that the catheter was inadequately placed, and the report should contain this information. It should be noted that right atrial pressure cannot substitute FHVP for the measurement of HVPG [13]. The WHVP is measured by occluding the hepatic vein by inflating the balloon at the tip of the catheter (Figure 2B). Adequate occlusion of the hepatic vein is confirmed by slowly injecting 5 ml of contrast dye into the vein with the balloon inflated. This procedure should reveal a typical wedged pattern, without reflux of the contrast dye or washout through communications with other hepatic veins. The existence of veno venous communications (Figure 2C) is very rare in cirrhosis, while it is commonly observed in idiopathic portal hypertension [14,15] and in other noncirrhotic portal hypertensive diseases. Therefore their presence should be documented and reported. The WHVP should be measured until the value remains stable (usually more than 60 s). All measurements should be taken in triplicate and permanent tracings (Figure 2D) should be obtained using a multichannel recorder and adequately calibrated transducers. Some practical tips to achieve adequate measurements according to published recommendations [1,16] are outlined in Box Expert Rev. Gastroenterol. Hepatol. 7(2), (2013)

6 There are no absolute contraindications to HVPG measurement; the limitations of the technique and the procedures that can be performed during hepatic vein catheterization (beside HVPG) are summarized in Table 1. Hepatic vein catheterization usually carries only a modest discomfort. Complications are infrequent (<1% of cases); most of them are related to local injury at the venous access site. This risk is markedly reduced with the use of ultrasound guidance for performing the venous puncture. Passage of the catheter through the right atrium rarely causes arrhythmias, which are usually transient. In the authors experience no fatalities have occurred in over 12,000 procedures in 30 years. Applications Measurement of HVPG is a useful clinical tool in hepatology and is currently considered the best surrogate of clinical events in liver diseases [17]. Its main clinical applications are listed below. HVPG in the classification of portal hypertension In patients with portal hypertension of unknown causes the finding of an increased HVPG owing to an increase in WHVP indicates an increase in sinusoidal pressure, which is most frequently due to cirrhosis. A normal HVPG with normal WHVP and FHVP is typical of presinusoidal portal Figure 2. Measurement of hepatic venous pressure. (A) FHVP is measured by maintaining the tip of the catheter free in the hepatic vein at 2 4 cm from its opening into the inferior vena cava. (B) WHVP is measured by occluding the hepatic vein by inflating the angiographic balloon (arrow) at the tip of the catheter. Adequate occlusion of the hepatic vein is confirmed by slowly injecting 5 ml of contrast dye into the vein with the balloon inflated. Please note the typical wedged pattern distal to the balloon. (C) A washout of contrast dye through communications with other hepatic veins (arrow) prevents a correct measurement of the hepatic venous pressure. (D) Typical tracing of pressures measured in the hepatic vein obtained using a multichannel recorder and adequately calibrated transducers. FHVP: Free hepatic venous pressure; WHVP: Wedged hepatic venous pressure. Box 1. An abecedary of tips for obtaining adequate measurements of the HVPG. hypertension, while posthepatic portal hypertension features increased FHVP and WHVP (Figure 1). Amplitude of the scale in the recording system: use an appropriate scale for venous pressure measurements (full range 40 mmhg). Set recorders at 1 mmhg = 1 mm paper. Amplitudes used for arterial pressure measurements are not adequate. Balloon catheter: use balloon-tipped catheters. These allow occlusion of a medium size or large hepatic vein, minimize variability and facilitate repeat measurements. Check for adequate occlusion of the hepatic vein and for absence of communications between hepatic veins by injecting by hand 5 ml of iodinated contrast. Calibrate: the transducer should be calibrated against known external pressures before starting measurements (e.g., 13.6 cm H 2 O should read 10 mmhg, 27.2 cm H 2 O should read 20 mmhg and 40.8 cm H 2 O should read 30 mmhg). Transducers that do not calibrate exactly should be discarded. Place the transducer at the level of the right atrium (mid-axillary line). With transducer open to air (zero pressure) adjust the recorder to read zero. Duplicate measurements: do all measurements at least by duplicate (by triplicate if differences between measurements are >1 mmhg). Variability often reflects mistakes. Events: any event that may cause an artifact, such as coughing, moving or talking should be noted. Free pressure: FHVP should be measured with the catheter tip less than 4 cm in the hepatic vein. FHVP should not exceed IVC pressure by more than 2 mmhg. IVC pressure should be measured at the level of the hepatic vein ostium. Get permanent tracings: all measurements should be recorded on a permanent data recording system (paper printouts and/or digital memory), to allow subsequent review of the pressure tracings. Readings from a monitor screen are not adequate. Hold-on: venous pressures should be allowed to stabilize over a period of at least 1 min for WHVP and 20 s for FHVP (some patients may require longer). A slow speed (<5 mm/s) should be used in the recorder. Rinse the catheter with 5% dextrose before any measurement. FHVP: Free hepatic venous pressure; IVC: Inferior vena cava; WHVP: Wedged hepatic venous pressure

7 Berzigotti, Seijo, Reverter & Bosch Table 1. Hepatic venous pressure gradient measurement: relative contraindications, limitations and associated procedures. Relative contraindications Limitations Associated procedures Allergy to iodine contrast medium: iodine contrast can be avoided and CO 2 can be used instead HVPG does not reflect the PPG when increased resistance is predominantly located at presinusoidal sites (portal vein thrombosis; schistosomiasis, initial stages of primary biliary cirrhosis; idiopathic portal hypertension) Transjugular liver biopsy Previous episodes of cardiac arrhythmia: caution when moving the catheter in the right cardiac atrium Platelet <20,000 or PT <30%: platelet and frozen plasma replacement can be used if needed Prognostic stratification in patients with cirrhosis & acute alcoholic hepatitis The HVPG is a strong independent prognostic indicator in compensated and decompensated cirrhosis. Table 2 summarizes prognostic value of different HVPG thresholds in patients with cirrhosis (not undergoing therapy with β-blockers). Cross-sectional and prospective clinical hemodynamic studies have shown that in compensated patients the complications of portal hypertension, such as ascites, variceal formation and hepatorenal syndrome do not occur until the HVPG is at least 10 mmhg [3,18]. Therefore, portal hypertension is subclinical when the HVPG is 6 9 mmhg and becomes clinically significant when HVPG increases above 10 mmhg. While patients with a HVPG below 10 mmhg are at negligible risk of experiencing portal hypertension-related complications, patients with a HVPG over 10 mmhg are at an increased risk of decompensation and of hepatocellular carcinoma [19]. Variceal bleeding may appear when HVPG is over 12 mmhg. An increased mortality risk is observed when HVPG is above 16 mmhg [20,21] and during acute variceal bleeding a HVPG >20 mmhg (measured Table 2. Prognostic significance of hepatic venous pressure gradient thresholds according to the compensated or decompensated stage of cirrhosis. Clinical setting Compensated cirrhosis Decompensated cirrhosis HVPG (mmhg) Increased risk of threshold Check for the absence of communications between hepatic veins that may preclude an adequate measurement of WHVP Presence [18] and development of gastroesophageal varices [2] First clinical decompensation in patients without varices [76] Development of HCC [19] Decompensation after surgery for HCC [24,25] Variceal bleeding [18,20,77 79] First clinical decompensation in patients with varices [80]; mortality [81] Variceal rebleeding and mortality [21] Failure to control variceal bleeding in patients actively bleeding from varices [22,50]; mortality Mortality in patients with alcoholic cirrhosis and AAH [82] Spontaneous bacterial peritonitis [83] AAH: Acute alcoholic hepatitis; HCC: Hepatocellular carcinoma; HVPG: Hepatic venous pressure gradient. Measurement of hepatic blood flow and liver clearance by ICG infusion Wedged hepatic retrograde portography using CO 2 as contrast medium HVPG: Hepatic venous pressure gradient; ICG: Indocyanine green; PPG: Portal pressure gradient; PT: Prothrombin time; WHVP: Wedged hepatic venous pressure. within 48 h of admission) predicts failure to control bleeding and low 1-year survival [22]. In patients with decompensated cirrhosis listed for liver transplantation HVPG holds prognostic value independent from that of model for end-stage liver disease (MELD) score [23]. Liver resection for hepatocellular carcinoma is contraindicated in patients with HVPG >10 mmhg [24,25] due to a high risk of irreversible hepatic decompensation within 3 months. Portal pressure may increase during episodes of acute alcoholic hepatitis and HVPG >22 mmhg is associated with a poor survival. This emphasizes the relevance of measuring HVPG at the time of transjugular liver biopsy in these patients. Steatosis may also concur to increase the HVPG in nonalcoholic fatty liver disease but the prognostic significance of this finding is unknown [21]. Assessment of the hemodynamic response to pharmacological therapy for portal hypertension A good hemodynamic response is defined as a reduction of HVPG below 12 mmhg or at least by 20% of the baseline value, either by means of pharmacological treatment or due to an improvement in liver disease [26]. When this target reduction is accomplished, the risk of variceal bleeding, rebleeding and other complications of portal hypertension such as ascites, spontaneous bacterial peritonitis and hepatorenal syndrome markedly decreases and survival improves [26]. Failure to achieve these targets ( reduction below 12 mmhg or more than 20% from baseline) constitutes the strongest independent predictor of variceal bleeding or rebleeding [26]. Given these observations, it has been suggested that the treatment of portal hypertension should be individualized by measuring the portal pressure response to therapy in order to maximize clinical effectiveness. The need of repeated measurements of HVPG 146 Expert Rev. Gastroenterol. Hepatol. 7(2), (2013)

8 may be reduced by testing the acute hemodynamic response to intravenous β-blockers [27,28]. Evaluation of progression & regression of chronic liver disease Chronic viral hepatitis HVPG has been shown to correlate with the histological severity of liver fibrosis in patients with HBV- and HCV-related chronic hepatitis [8]. Moreover, HVPG changes parallels changes in histology after effective antiviral therapy. Rincon et al. [29] showed a significant HVPG reduction after effective antiviral therapy in patients with advanced chronic HCV hepatitis. This was confirmed in patients with HCV-related cirrhosis achieving sustained virological response [30]. Thus, serial HVPG measurements allow evaluating progression/regression in chronic hepatitis C and evaluating the response to antiviral treatment [31]. HCV recurrence after liver transplantation HVPG is an excellent marker to identify patients at highest risk of severe HCV recurrence and hepatic decompensation after liver transplantation. Portal hypertension, as indicated by HVPG >6 mmhg, accurately selected patients at risk of cirrhosis recurrence and worsening of liver function [1], in fact this was better than liver biopsy. HVPG changes mirrored the changes in liver histology induced by antiviral therapy in liver transplant recipients with recurrent HCV infection [32]. Evaluation of PPG after TIPS placement The measurement of PPGt (the gradient between portal pressure and IVC pressure) during and after transjugular intrahepatic porto systemic shunt (TIPS) placement is the gold-standard technique to assess its correct hemodynamic functioning. The TIPS target is to decrease the PPG below 12 mmhg [3]. In the follow-up TIPS is considered to work properly if PPG remains below 12 mmhg. Above this threshold TIPS dysfunction is diagnosed, which should be corrected by balloon angioplasty or restenting to prevent recurrence of complications of portal hypertension [3]. Gold-standard technique to assess the presence of gastroesophageal varices: endoscopy Upper GI tract endoscopy is the gold-standard technique for identifying esophageal and gastric varices and is essential for the endoscopic management of variceal hemorrhage [33]. Deep sedation with propofol (±fentanil or remifentanil) much improves the acceptability of endoscopy and patients comfort. Diagnostic endoscopy findings related to portal hypertension are esophageal varices (EV), gastric varices and PHG. Rarely, ectopic duodenal varices can be found. The risk of bleeding from EV is tightly related to their size and presence of so-called highrisk signs [34]. Size of EV is semi quantitatively graded as small, medium or large [34]. Small varices are minimally elevated veins that collapse but do not disappear with insufflation, medium varices are tortuous veins occupying less than a third of the esophageal lumen and large varices are those involving more than a third of the lumen. Since treatment recommendations include both medium and large varices, grading can be simplified to small ( 5 mm) and large varices [33]. The presence of red wales (longitudinal dilated venules resembling whip marks on the variceal surface) or red spots should be assessed and reported, as they are associated to increased bleeding risk and prompt primary prophylaxis even in patients with small varices [34]. A similar increase in bleeding risk occurs with more advanced liver failure (Child Pugh classes B C). Gastric varices are less prevalent than EV and are the source 5 10% of upper digestive bleeding episodes in cirrhosis. They are commonly classified based on their relationship with esophageal varices as well as their location [35]. Gastroesophageal varices are an extension of esophageal varices and are subclassified into two types: GOV1, the most common, extend along the lesser curvature. GOV2 extend from EV along the fundus. Isolated gastric varices (IGV) in absence of EV may be located in the fundus (IGV1; splenic vein thrombosis must be ruled out), while IGV2 are located in the body, antrum or along the pylorus. As for EV, the presence of red spots, gastric variceal size and Child Pugh class (C>B>A) are risk factors for hemorrhage. GOV1 and IGV may bleed at relatively low HVPG (10 12 mmhg); this might be due to the fact that these varices are usually very large and therefore their wall tension (which is determined as the product of transmural pressure and vessel radius) may reach high values at a lower pressure than EV. PHG is a very common finding in cirrhosis (prevalence between 11 and 80%). It is graded as mild (mosaic-like pattern), and severe (red-point lesions/cherry-red spots/black-brown spots) [33], and is more often observed in the fundus and corpus of the stomach. Gastric antral vascular ectasia (GAVE), also known as watermelon stomach, is endoscopically characterized by red patches and spots in a diffuse or linear distribution in the gastric antrum. Other typical features include gastric ectasia and dilation and biopsy can identify thrombi, spindle cell proliferation and fibrohyalinosis. Only 30% of GAVE cases occur in patients with portal hypertension and GAVE should not be considered a portal hypertension-specific feature. In particular, GAVE should be distinguished from severe PHG [36] owing to their different response to the treatment of portal hypertension. While β-blockers and TIPS can be used in severe PHG causing significant blood losses, GAVE is unresponsive to these treatments [37]. Use of endoscopy in clinical practice: screening & follow-up of EV EV is present in approximately 30 40% of compensated cirrhosis at first observation and up to 60% of decompensated cirrhosis. There is consensus that it is mandatory to screen for EV by endoscopy when the diagnosis of cirrhosis is established. In patients without varices, incidence of EV is 5 10%/year; endoscopy must therefore be repeated every 2 3 years in this population [33]. Patients with an HVPG >10 mmhg or with liver function deterioration are at higher risk for developing varices, so the interval could be shortened. In patients with small varices, increase in size is observed with a 10 15% annual incidence; hence, in this population endoscopy should be repeated every 1 2 years [33]. In 147

9 Berzigotti, Seijo, Reverter & Bosch patients undergoing primary pharmacological prophylaxis there is no need of performing follow-up endoscopies [33]. Other endoscopic techniques used in the field of portal hypertension Endoscopic videocapsule This has been recently introduced as it may improve patients tolerance and adherence for the screening and surveillance of EV. First studies and a meta-analysis reported a correct identification of EV and red wale marks in about 80% of cases, but subsequent studies disclosed a lower diagnostic value [38]. Videocapsule weaknesses are a poor diagnostic value for gastric varices and PHG, a poor cost effectiveness ratio, difficulties in assessing variceal size and non applicability in 6% of patients who can not swallow the pill-cam. Portal enteropathy has been recently characterized by videocapsule and enteroscopy, describing several types of mucosal abnormalities such as edema, erythema, reticular mucosal pattern and small bowel varices. Videocapsule is a useful tool in diagnosing obscure sources of bleeding (small bowel varices and vascular ectasias) [39]. Endoscopic ultrasound Endoscopic ultrasound provided with color- or power-doppler can be useful in diagnosing IGV that may mimic thickened gastric folds and it has shown to improve the efficacy of cyanocrilate injection for the treatment of gastric varices [40]. Measurement of variceal pressure Variceal pressure can be measured at endoscopy either by direct variceal puncture (which is hampered by the risk of precipitating variceal bleeding) or using a noninvasive endoscopic pressure sensitive gauge [41]. The latter technique has been shown to be accurate for assessing variceal pressure and its changes after either acute or chronic pharmacological therapy [42] and provides prognostic information. However, measurements are difficult in small varices and require specific training. Currently, its use is limited to research studies. Liver biopsy as a technique to improve knowledge concerning portal hypertension Liver biopsy has been used for several indications: diagnosing and grading liver diseases, and to guide therapeutic decisions [43]. It can be performed either by percutaneous or transvenous (transjugular) routes. The latter is performed during hepatic vein catheterization, is safer and preferable in high-risk patients (due to thrombopenia or ascites) and has the advantage of adding histological and hemodynamic information in the same procedure. An adequate liver specimen should be of at least 15 mm length and contain 6 complete portal tracts; ideally, specimens should be mm and have 11 portal tracts [44]. Limitations of liver biopsy include its invasiveness and sampling errors due to underrepresentation of liver pathology as biopsy specimens account for only 1 out of 50,000 of the liver parenchyma. Liver biopsy has a key role in the differential of intrahepatic causes of portal hypertension, but is marginal in prehepatic or posthepatic portal hypertension: in patients with portal vein thrombosis liver biopsy should be performed only when concomitant cirrhosis or nodular regenerative hyperplasia is suspected. In Budd Chiari syndrome, liver biopsy should be considered when imaging fails demonstrating large hepatic veins or IVC obstruction but the odds for a Budd Chiari syndrome diagnosis remains high [7]. Liver biopsy is the gold standard for the diagnosis of cirrhosis. Limitations of the technique include falsenegative results or underestimation of the disease severity due to a sampling error and inter- and intra-observer variability, in particular in macronodular cirrhosis. Liver biopsy can provide information on the severity of portal hypertension in patients with cirrhosis: small nodule size and increased septal thickness were associated with higher HVPG [45] and clinical decompensation. Recently, quantitative computer-assisted digital-image analysis (DIA) of histological liver sections has been validated for assessing liver fibrosis (as fibrosis area). Limitations of DIA include the use of additional resources, and require evaluating inter- and intra-observer variability. Studies showed that DIA is a better histological index that traditional stage scores (e.g., Ishak score) and should be used in future studies validating liver stiffness (LS) and other noninvasive markers of fibrosis. Calvaruso et al. showed that the degree of fibrosis of liver biopsies, measured using DIA, correlated well with HVPG in 115 patients with post-transplant HCV infection, including all stages of fibrosis [46]. These results were further validated by another study showing that the fibrosis area measured by DIA correlated with HVPG in patients with cirrhosis [47]. Noninvasive techniques to assess portal hypertension HVPG and endoscopy are current gold-standard techniques to assess portal hypertension and esophageal varices. However its use is limited by their invasiveness. Patients would undoubtedly benefit from noninvasive tests that are able to provide similar information. As any diagnostic test, noninvasive techniques should be safe, easy to perform, inexpensive, accurate and reproducible. Ideally, such tests should be predictive of long-term clinical outcomes. Clinical data & physical examination In the absence of anamnestic data, the cheapest and most immediate information on presence of portal hypertension is that provided by physical examination; splenomegaly, spider nevi, presence of abdominal wall collateral circulation and ascites (±edema) are highly specific of the syndrome [48], but the sensitivity of physical signs is low in patients with compensated cirrhosis. In a recent study in patients with well-compensated cirrhosis, spider nevi were independent predictors of esophageal varices [49]. Laboratory tests A further step is represented by laboratory tests, having the advantage of being inexpensive and independent of expertise. Albumin, bilirubin, international normalized ratio (INR) or their combination in the Child Pugh score correlate with HVPG [21,50] and with the prevalence and grade of esophageal varices in cirrhotic 148 Expert Rev. Gastroenterol. Hepatol. 7(2), (2013)

10 Table 3. Prediction of clinically significant portal hypertension by transient elastography. Study (year) Patients (n) Etiology Design Patients with CSPH (%) patients. In a study from our group in patients with compensated cirrhosis, a model combining albumin, ALT and INR had an area under the curve (AUC) of in predicting clinically significant portal hypertension (CSPH; HVPG >10 mmhg) [49]. Thrombocytopenia is the single laboratory test most frequently associated with the presence of varices and of large esophageal varices [51]. Most serum fibrosis markers have not been specifically studied in predicting portal hypertension but some data suggest that they might be useful. Fibrotest showed a good accuracy in one study [52], but as 92% of the studied population had CSPH its specificity is questionable. YKL-40 and collagen propeptide PIIINP were predictive of short-term survival and increased relative-risk of death in patients with alcoholic liver disease [53]; hyaluronic acid had a predictive value equivalent to Child Pugh score in a cohort of patients with HCV-related cirrhosis followed-up for a median of 38 months [54]. Measurement of LS by transient elastography Transient elastography (TE; Fibroscan, Echosens, Paris, France) is a well-validated technique for the noninvasive assessment of liver fibrosis [55]. Measurements are performed with an ultrasound transducer built on the axis of a vibrator; a vibration of mild amplitude and low frequency is transmitted, inducing a wave that propagates through the liver tissue, and pulse-echo acquisitions are performed to measure the velocity of propagation of the wave, which is directly related to tissue stiffness. Since fibrosis is the main determinant of tissue stiffness and of hepatic resistance to portal blood flow (the major determinant of portal pressure in early stages of portal hypertension), TE has been tested in recent years as a novel way of obtaining numerical, objective and operator-independent noninvasive surrogate data of HVPG [55]. In a study performed in patients with hepatitis C recurrence after liver transplantation, LS showed a good linear correlation with fibrosis and HVPG [56]; specifically, a LS 8.74 kpa had a sensitivity and specificity of 90 and 81%, respectively, for the diagnosis of HVPG >6 mmhg in this population. Five subsequent studies provided evidence of a good accuracy (AUC range: Correlation of LS and HVPG (R) Prediction of CSPH (HVPG 10 mmhg) Cutoff AUC Vizzutti et al. (2007) 61 HCV Prospective [60] Lemoine et al. (2008) 48 Alcohol HCV Retrospective Bureau et al. (2008) 150 Several Prospective [85] Sanchez-Condé et al. (2011) 38 HIV-HCV Prospective [86] Llop et al. (2012) 79 Several + potentially resectable HCC Prospective [59] AUC: Area under the curve; CSPH: Clinically significant portal hypertension; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HVPG: Hepatic venous pressure gradient; LS: Liver stiffness Ref ) of TE for diagnosing and ruling-out CSPH (HVPG >10 mmhg) in patients with cirrhosis (Table 3) [57], LS showing a significant linear correlation with HVPG (R range: ). The cutoff for predicting CSPH varies across studies, mainly due to differences in the choice of sensitivity or specificity. This limitation is largely overcome by applying a pragmatic rule, choosing a very sensitive cutoff to rule-out CSPH and a very specific cutoff to rule it in. In doing so, a LS <13.6 kpa confidently rules-out CSPH, while LS 21.1 kpa accurately diagnoses it. Interestingly, a recent study [58] showed that both HVPG 10 mmhg and LS 21.1 kpa were good predictors of clinical decompensation, with substantially equal discriminative ability (AUC: vs 0.837; not significant). On the other hand, patients with intermediate values (LS between 13.6 and 21.1 kpa) cannot be easily classified as having or not having CSPH. This was also shown recently in patients with potentially resectable hepatocellular carcinoma, indicating that TE might be used to rule-out or confirm CSPH, and thus for indicating or contraindicating surgery [59] whenever HVPG is not available. On the other hand, it should be underlined that above the threshold value of 13.6 kpa the correlation of LS and HVPG is less accurate [60], probably reflecting that at HVPG >10 mmhg development of portals systemic collaterals and increased portal collateral blood flow means that fibrosis is no longer the main mechanism responsible for portal hypertension [60]. This also partially explains why TE is not accurate enough to predict the presence and size of esophageal varices (accuracy does not exceed 65 75% in the published studies with adequate sample size). In summary, TE can be very useful to rule out or rule in CSPH, but there is a considerable gray zone (between 13.6 and 21.1 kpa) and the technique is not accurate enough to substitute HVPG to quantify the exact severity of portal hypertension. Major technical limitations of TE include the lack of visualization of the parenchyma in the region of interest and failure to obtain any measurement or unreliable results in 3 16% of cases [61] mostly because of obesity or presence of ascites. Moreover, the influence of the etiology of cirrhosis (e.g., alcoholic vs viral cirrhosis) on the cutoffs of TE for CSPH have not been specifically studied, and should be addressed by future studies. [84] 149

11 Berzigotti, Seijo, Reverter & Bosch Newer methods for estimating LS include magnetic resonance imaging elastography (MRE) [62] and ultrasound-based (sonoelastography) methods (strain ratios, acoustic radiation force impulse imaging [ARFI] and shear-wave velocity estimation). While MRE is accurate but too costly to be routinely used, sonoelastography is increasingly used, as it can be implemented on ultrasound equipment and overcome technical limitations of TE. Among sonoelastography methods ARFI (Virtual Touch Tissue Quantification; Siemens Healthcare, Erlangen, Germany) is the best validated so far. ARFI uses mechanical excitation of the tissue using short-duration (262 µ) that propagate shear waves and generate localized, µ-scale displacements in tissue. The shear-wave velocity (expressed in m/s) is measured in a 10-mm long and 6-mm wide region that can be chosen by the operator on real-time imaging. ARFI has already shown to hold a similar accuracy as TE in predicting significant fibrosis and cirrhosis [63] and preliminary data in assessing the consequences of portal hypertension suggest similar results. An important limitation that is probably inherent to all elastography techniques is that LS can increase independent of fibrosis due to food ingestion, inflammation, cholestasis and liver congestion. Spleen stiffness Since splenomegaly in cirrhosis is a direct consequence of portal hypertension, spleen stiffness has been recently proposed as a new noninvasive parameter with better accuracy than LS for predicting CSPH and esophageal varices. Data obtained by MRE [64], TE [65], real-time elastography [66] and ARFI appear promising, and future studies assessing the performance of noninvasive predictors of portal hypertension should include this parameter. Imaging techniques: ultrasound & color Doppler ultrasound Ultrasonography (US) is the first-line imaging technique recommended for the diagnosis and follow-up of patients with portal hypertension [67], since it is noninvasive, cheap and can be performed at bedside. US is highly specific for the diagnosis of cirrhosis and portal hypertension, but its sensitivity is relatively low in compensated patients. Diagnosis of cirrhosis on conventional US is based on changes in liver morphology and signs of portal hypertension [67]. The most accurate single US sign for the diagnosis of cirrhosis is nodularity of liver surface. This should be specifically investigated using high-frequency transducers, with better diagnostic performance than conventional abdominal US probes. The combination of nodular liver surface and portal flow mean velocity <12 cm/s has 80% accuracy discriminating patients with chronic hepatitis with severe fibrosis from those with cirrhosis and its combination with TE allows an optimal accuracy in difficult patients [68]. In patients with known cirrhosis, US-Doppler has >80% specificity diagnosing CSPH, but sensitivity does not exceed 40 70%, particularly in compensated patients [67]. While the presence of one or more signs allows establishment of a robust diagnosis, their absence cannot exclude CSPH. The presence of portal systemic collaterals (patent paraumbilical vein, spleno renal collaterals, dilated leftand short-gastric veins), and inversion of flow within the portal system are 100% specific of CSPH. Some collaterals, such as leftgastric vein >3 mm and short-gastric veins, strongly suggest the presence of esophageal varices, and their development/increase in number have been associated with a greater proportion of variceal formation and growth [67,69]. On the other hand, it should be underlined that US and Doppler-US are very accurate for detecting portal vein and hepatic veins thrombosis [70]. As portal vein thrombosis often takes place in patients with cirrhosis and hepatocellular carcinoma, which can be detected by US, and can aggravate a previously stable condition, US should be routinely performed to rule-out these complications in patients with cirrhosis presenting a new clinical event [67]. Splenomegaly is the most common and sensitive sign of portal hypertension. It is an independent predictor of esophageal varices, and is a marker of CSPH in compensated cirrhotic patients. Progressive spleen enlargement has been shown to predict variceal formation and growth, and is associated with a higher probability of clinical decompensation [67,69]. Other US and Doppler-US signs of CSPH include dilatation of portal vein (diameter >13 mm); lack or reduced respiratory variations of splenic and superior mesenteric vein diameter; reduced portal vein velocity; increased congestion index of portal vein; altered hepatic vein Doppler pattern; increased intraparenchymal hepatic and splenic artery resistance and pulsa tility index; increased intraparenchymal renal artery resistance and pulsatility index and reduced mesenteric artery resistance and pulsatility index [67,69]. While US signs can reliably indicate CSPH, the correlation of HVPG with these parameters is unsatisfactory; thus US signs can not be used as surrogates of HVPG. US are highly sensitive in diagnosing ascites, which is the most common clinical decompensation of cirrhosis and holds a severe prognostic significance. Also, increased intrarenal arteriolar resistance index correlates with renal vasoconstriction in patients with cirrhosis; it is observed in about 40% of patients with ascites and is accurate in detecting hepatorenal syndrome. Small liver size, splenomegaly >14.5 cm, mean portal vein velocity below 10 cm/s and loss of pulsatility of hepatic veins have been all associated with higher mortality on follow-up in patients with compensated cirrhosis [67,69]. US-Doppler is useful in the noninvasive follow-up of TIPS [71]. However, US-Doppler is insufficiently accurate to be used as a surrogate of changes of HVPG during medical therapy of portal hypertension [67,69]. CT scan & MRI CT and MRI allow a very accurate visualization of the portal venous system. Single detector and multidetector CT scanning are reliable in detecting large esophageal varices (specificity: %; sensitivity: %), with moderate interobserver variability; however, the sensitivity in detecting small varices is lower. CT screening of varices was more cost-effective than endoscopy screening and than CT followed by endoscopy in patients 150 Expert Rev. Gastroenterol. Hepatol. 7(2), (2013)

12 with small varices on CT. However, CT scan implies substantial irradiation, which should be carefully considered in risk benefit assessment. Dynamic contrast-enhanced single-section CT scans and compartmental analysis of time/intensity curves of liver MRIs after injection of a gadolinium chelate allow a quantitative measurement of portal and azygos blood flow [72]. Portal fraction of liver perfusion and mean transit time on MRI show a moderate correlation with HVPG [73]. CT and/or MRI should be used in clinical situations requiring a detailed assessment of the portal venous system, such as to assess the extent of thrombosis; to detect portal cholangiopathy in patients with a portal cavernoma; to map collateral circulation in patients with ectopic variceal bleeding, and before TIPS placement, especially in difficult patients, such as those with Budd Chiari syndrome. Combination of different noninvasive methods The combination of different methods provides theoretical advantages over the use of a single method, since falsely positive and/or negative results of one method may be overcome by the use of another, and complementary information may lead to more robust predictions. There are scarce data on the prediction of CSPH (as assessed by HVPG) by a combination of tests. A study performed before TE showed that the combination of simple laboratory tests (INR, albumin and ALT) allowed predicting CSPH in patients with compensated viral cirrhosis [49], but external validation showed less accuracy than that observed in the original series. As for the prediction of varices, platelet count and spleen diameter are almost invariably found among the combinations tested in cirrhosis. Platelet count to spleen diameter ratio improves the predictive ability of the two tests as assessed separately and values >909 had 100% negative-predictive value for the presence of esophageal varices in the original study [74], suggesting that endoscopy could be avoided in these patients. However, subsequent independent series showed a quite lower predictive value. Other models for predicting varices of any size or large varices included portal vein diameter and prothrombin time [38]. Again, while initial prospective studies in compensated cirrhosis suggested good discriminating ability, validation series failed to confirm adequate predictive accuracy. A recent study in patients with compensated hepatitis B cirrhosis suggested that the combination of LS, spleen size and platelet count in the so-called LSPS (LS spleen size/platelet count) is very accurate in predicting the presence of varices, high-risk varices and variceal bleeding [75]. This promising noninvasive approach should be validated by further studies, including other etiologies of cirrhosis, before its use can be recommended in clinical practice. Expert commentary & five-year view We have very good methods for the evaluation of portal hypertension in chronic liver diseases. Unfortunately, for the more relevant aspects (detection of portal hypertension, its severity, degree, changes during therapy and detection and characterization of esophageal and gastric varices) we currently have to rely on invasive techniques (even if these are moderately invasive), such as hepatic vein catheterization for the measurement of HVPG, endoscopy to evaluate the presence, size and aspect of the varices, and liver biopsy to confirm cirrhosis and to perform an histological diagnosis in doubtful cases. These methods have the advantage of being very robust and well validated and do not require complicated technology (thus being available in most settings of healthcare delivery). However, invasiveness imposes limitations in terms of cost and patients discomfort, thus restricting the use of these techniques. Clearly, if these were truly noninvasive their use would be much more extensive. Is that going to change in years to come? As commented upon in this review, we are already there for some aspects as the detection of CSPH (equivalent to an HVPG 10 mmhg), since techniques as TE [55], precise measurements of spleen size by ultrasound, liver surface nodularity analysis and combined indices/algorithms based on these already allow sufficient sensitivity and specificity (above 80 90%) to permit a fair clinical judgment. Still, it remains to be proved if these noninvasive tools allow equally accurate estimates in different etiologies of cirrhosis and in situations such as after removal of the cause of cirrhosis by successful etiological therapy. We are a little bit more distant from noninvasive diagnosis with regards to detection of varices, as the techniques that can be used as an alternative for endoscopy are either too expensive and of uncertain sensitivity (such as the pill-cam) or carry other inconveniences (such as radiation exposure and risk from CT scans). In this field the authors personal bet regards the use of new developments in 3D contrast ultrasound using new transducer technology, which has a strong potential for substituting CT/MR scans at a much lower cost and at the bedside. As for noninvasive measurements of HVPG, the authors do not foresee any clinically applicable substitute with enough accuracy at short time, this is an unfulfilled need that deserves more research given the many applications of this technique. This is particularly so for the applications requiring an exact measurement, such as assessing the effects of therapy, for which noninvasive methods are unlikely to be accurate enough. On the other hand, this situation is a typical case of where one would like to be able to check periodically if the treatment applied is reaching the desired targets, similar to what is done in the treatment of arterial hypertension with sphygmomano meters, which are a proven valid noninvasive method to measure arterial blood pressure in clinical practice. Even considering that our armamentarium to decrease portal pressure has been expanding, it is difficult to conceive that a given drug, or drug combination, will provide adequate coverage for most patients as to allow obviating to check the degree of portal pressure reduction actually achieved by the treatment. Personalized medicine would undoubtedly benefit markedly from such a portal sphygmomanometer, especially in high-risk situations, such as primary prophylaxis in decompensated patients with large varices or in the prevention of rebleeding

13 Berzigotti, Seijo, Reverter & Bosch Key issues Hepatic venous pressure gradient (HVPG) measurement is the gold-standard technique for the assessment of portal hypertension in cirrhosis. Endoscopy is the gold-standard technique for diagnosing gastroesophageal varices. The use of HVPG in portal hypertension ranges from diagnostic purposes to prognostic stratification and guidance of therapy. HVPG is currently the best surrogate marker of clinical events in cirrhosis. Noninvasive evaluation is a rapidly evolving field. Currently used techniques include laboratory parameters, imaging and elastography. Noninvasive techniques cannot replace HVPG and diagnostic endoscopy. Transient elastography, alone or combined with other parameters, allows discrimination with good accuracy for patients with and without clinically significant portal hypertension, thereby reducing the need for invasive diagnostic procedures. 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16 To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education () credit, please go to journal/expertgastrohep. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited For technical assistance, American Medical Association s Physician s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in activities. For further information on this award, please refer to org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this activity are eligible for AMA PRA Category 1 Credits. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA credit certificate and present it to your national medical association for review. Activity Evaluation Where 1 is strongly disagree and 5 is strongly agree 1. The activity supported the learning objectives. 2. The material was organized clearly for learning to occur. 3. The content learned from this activity will impact my practice. 4. The activity was presented objectively and free of commercial bias You are seeing a 55-year-old man with a history of chronic hepatitis C virus infection as well as heavy alcohol use. He has not had regular follow-up with a physician, and you are concerned regarding his risk for portal hypertension and cirrhosis. What should you consider regarding the initial evaluation for this patient? A The sensitivity of physical signs for portal hypertension is superior to their specificity B A reduced serum albumin level is the most accurate laboratory assessment to identify varices C Ultrasound is highly specific for the diagnosis of cirrhosis and portal hypertension D The most accurate ultrasound sign of cirrhosis is reduced liver size 2. The patient s initial evaluation suggests that he has cirrhosis. What should you consider regarding the assessment of gastroesophageal varices in this case? A Varices are considered large only if they occlude more than half of the esophageal lumen B Gastric varices result in as many cases of gastrointestinal bleeding as esophageal varices C Gastric antral vascular ectasia (GAVE) is only present in cases of portal hypertension D Surveillance endoscopy should be repeated every 2 to 3 years among patients with cirrhosis 3. The patient eventually undergoes measurement of hepatic venous pressure gradient (HVPG) with a venous catheter. Given his history of cirrhosis due to chronic hepatitis C virus infection and excessive alcohol use, what are the expected findings on this testing? A Normal HVPG and slightly increased wedged hepatic venous pressure (WHVP) B Slightly increased HVPG and reduced WHVP C Normal HVPG, elevated free hepatic venous pressure (FHVP), and elevated WHVP D Normal FHVP, elevated HVPG, and elevated WHVP 4. Which of the following values for HVPG is considered the threshold for clinically significant portal hypertension? A 10 mm Hg B 16 mm Hg C 20 mm Hg D 33 mm Hg 155