Accepted Article
Portal Hypertension - Pathophysiology, Diagnosis and Management Paper Title: Portal Hypertension - Pathophysiology, Diagnosis and Management1 Short Title: Portal Hypertension Current Concepts Main Text Word Count: 3513 Abstract Word Count: 104
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/imj.12590
This article is protected by copyright. All rights reserved.
Accepted Article
Authors Dr. Stephen Bloom1 Hepatology Research Fellow Eastern Health Author involvement - Concept design - Literature review - Drafting and revision Dr. John Lubel1 (Formal Correspondence Author) Acting Director of Gastroenterology Directory of Hepatology Eastern Health Author involvement - Concept design - Drafting and revising - Final approval of final version
1
Gastroenterology and Hepatology, Eastern Health, Melbourne, Victoria, Australia 2
Gastroenterology and Hepatology, Alfred Health, Melbourne, Victoria, Australia
Correspondence to: Level 2, 5 Arnold Street Box Hill 3128 Victoria, Australia [email protected] PH: 9094 9555 FAX: 9899 9137
This article is protected by copyright. All rights reserved.
Dr. William Kemp2 Consultant Gastroenterologist and Hepatologist Alfred Health Author involvement - Concept design - Drafting and revising - Final approval of final version
Accepted Article
3
Abstract Portal hypertension is an important complication of liver disease, although other conditions may also be implicated. As a result of elevated pressures within the portal vein a number of complications can arise including the development of oesophageal and gastric varices, ascites, hepatic encephalopathy as well as complications secondary to circulatory dysfunction such as hepatorenal syndrome, portopulmonary syndrome and hepatopulmonary syndrome. This review outlines the pathogenesis and diagnosis of portal hypertension and outlines the management of these various important clinical sequelae. The management of oesophageal and gastric varices is particularly important and both the emergency management together with prophylactic management of this condition are described.
Key Words: Portal hypertension, cirrhosis, varices, ascites, encephalopathy, hepatorenal syndrome, portal hypertensive gastropathy
Disclosures John Lubel has received honorariums/speakers fees/educational grants and departmental support from BMS, Janssen, MSD, Roche, Bayer and Ferring.
Many of the clinically significant complications of cirrhosis arise as a consequence of increased portal hypertension (PHT). This is defined as hepatic venous pressure gradient (HVPG) greater than 5mmHg, with complications arising once this exceeds 10mmHg. Portal hypertensive complications are associated with high morbidity and mortality and include; variceal bleeding, portal hypertensive gastropathy, ascites, and hepatic
encephalopathy. These conditions present a challenge to the Australian health system with the economic costs associated with treating liver disease estimated to be higher than that of type 2 diabetes and chronic kidney disease combined.1
This article is protected by copyright. All rights reserved.
Over the last decade our
Accepted Article
4
understanding of portal hypertension has increased dramatically allowing for optimization of management and new therapeutic approaches.
Portal Hypertension Pathophysiology The portal vein acts as the major outflow tract for the splanchnic circulation. The portal system is a low pressure, low resistance system. In the healthy state, considerable postprandial increases in portal venous blood flow do not significantly alter portal pressure due to the highly compliant nature of this system. The normal portal vein pressure is 5mmHg or less and is a product of blood flow (Q) and resistance (R) according to Ohm’s law: Portal Pressure = Q (blood flow) x R (portal resistance)
The aetiology of increased portal resistance is commonly categorized according to anatomical location into pre-hepatic, intra-hepatic and post-hepatic causes (Table 1). In the western world sinusoidal PHT secondary to cirrhosis is the most common cause of PHT. In cirrhosis the architectural changes associated with fibrosis and nodule formation result in a fixed alteration to sinusoidal blood flow. In contrast to this fixed hepatic resistance, there is a dynamic component which arises from contraction of myelofibroblasts within the space of Disse.2 These myelofibroblasts originate from hepatic stellate cells, which in the healthy state are the predominant storage site for vitamin A. In the presence of inflammation, cytokines released from injured hepatocytes stimulate the recruitment and transdifferentiation of hepatic stellate cells into contractile myofibroblasts with the capacity to deposit collagen. An excess of locally produced vasoconstrictor peptides together with a relative depletion in hepatic nitric oxide (NO) contribute to this dynamic component of
This article is protected by copyright. All rights reserved.
Accepted Article
5
hepatic resistance. These reversible components may represent up to 30% of the total resistance to portal blood flow.3 The increased pressure within the portal venous system induces shear stresses in the splanchnic vessels, and together with translocation of bacterial lipopolysaccharides results in excessive systemic NO production.4 The subsequent systemic vasodilatation activates a number of homeostatic regulatory systems such as the renin-angiotensin-aldosterone system (RAAS) and antidiuretic hormone (ADH) causing sodium and water retention. These events result in an increase in splanchnic vasodilation and blood flow with resultant increase in flow into the portal venous system further exacerbating PHT.2 Detection of Portal Hypertension The presence of portal hypertension may be clinically silent, however findings such as splenomegaly, ascites and abdominal wall collaterals (caput medusae) strongly suggest its presence. . Radiological imaging such as doppler ultrasound and computerised tomography (CT) may demonstrate the presence of collateral vessels, alterations in portal venous flow, splenomegaly and ascites, thereby supporting the diagnosis of portal hypertension. Despite this, the first presentation of portal hypertension may be with variceal haemorrhage, and this needs to be urgently excluded in any patient with suspected liver disease who has significant gastrointestinal haemorrhage. Direct measurement of portal venous pressures is invasive and requires significant procedural experience. This technique involves the introduction of a balloon catheter via
This article is protected by copyright. All rights reserved.
Accepted Article
6
the jugular or femoral vein into the hepatic vein. The HVPG is derived from subtracting free hepatic vein pressure (FHVP) from wedge hepatic vein pressure (WHVP): HVPG = WHVP - FHVP
PHT is defined by a hepatic venous pressure gradient (HVPG) > 5mmHg. Clinically significant PHT is defined as an HVPG ≥ 10mmHg. This threshold is required for the development of complication of PHT such as porto-systemic collaterals, varices, ascites and circulatory dysfunction. Variceal haemorrhage is associated with HVPG greater than 12mmHg and when HVPG is greater than 20mmHg following variceal haemorrhage, the risk of death increases five-fold.5 Likewise the risk for development of hepatocellular carcinoma increases to 6-fold when the HVPG is >10mmHg.6 The routine use of HVPG in clinical practice is generally limited to specialist centres. The role that less invasive methods of predicting PHT, such as liver stiffness measurement (LSM) using transient elastography, is yet to be established. The ideal LSM to determine
significant PHT requires further validation however a LSM of >20kpa appears to have a high specificity (92.3%) while a LSM >13kpa has a high sensitivity for PHT (94%).7, 8The use of a ratio of spleen size and platelet count in combination with LSM may overcome these limitations with recent literature demonstrating a combined sensitivity and specificity greater than 80% for detection of significant PHT.9
This article is protected by copyright. All rights reserved.
Accepted Article
7
Complications of Portal Hypertension Gastrointestinal Haemorrhage Oesophageal Varices Oesophageal varices are present in 40% of patients with an initial diagnosis of Child Pugh A cirrhosis and in 60% of patients with signs of decompensation.17 Those without varices at initial assessment develop them at an incidence of 7% per year.18 Seven percent of small varices (1.37 Diuretics should be ceased in the setting of
This article is protected by copyright. All rights reserved.
Accepted Article
15
severe renal impairment or severe hyponatremia (
Portal Hypertension - Pathophysiology, Diagnosis and Management Paper Title: Portal Hypertension - Pathophysiology, Diagnosis and Management1 Short Title: Portal Hypertension Current Concepts Main Text Word Count: 3513 Abstract Word Count: 104
This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/imj.12590
This article is protected by copyright. All rights reserved.
Accepted Article
Authors Dr. Stephen Bloom1 Hepatology Research Fellow Eastern Health Author involvement - Concept design - Literature review - Drafting and revision Dr. John Lubel1 (Formal Correspondence Author) Acting Director of Gastroenterology Directory of Hepatology Eastern Health Author involvement - Concept design - Drafting and revising - Final approval of final version
1
Gastroenterology and Hepatology, Eastern Health, Melbourne, Victoria, Australia 2
Gastroenterology and Hepatology, Alfred Health, Melbourne, Victoria, Australia
Correspondence to: Level 2, 5 Arnold Street Box Hill 3128 Victoria, Australia [email protected] PH: 9094 9555 FAX: 9899 9137
This article is protected by copyright. All rights reserved.
Dr. William Kemp2 Consultant Gastroenterologist and Hepatologist Alfred Health Author involvement - Concept design - Drafting and revising - Final approval of final version
Accepted Article
3
Abstract Portal hypertension is an important complication of liver disease, although other conditions may also be implicated. As a result of elevated pressures within the portal vein a number of complications can arise including the development of oesophageal and gastric varices, ascites, hepatic encephalopathy as well as complications secondary to circulatory dysfunction such as hepatorenal syndrome, portopulmonary syndrome and hepatopulmonary syndrome. This review outlines the pathogenesis and diagnosis of portal hypertension and outlines the management of these various important clinical sequelae. The management of oesophageal and gastric varices is particularly important and both the emergency management together with prophylactic management of this condition are described.
Key Words: Portal hypertension, cirrhosis, varices, ascites, encephalopathy, hepatorenal syndrome, portal hypertensive gastropathy
Disclosures John Lubel has received honorariums/speakers fees/educational grants and departmental support from BMS, Janssen, MSD, Roche, Bayer and Ferring.
Many of the clinically significant complications of cirrhosis arise as a consequence of increased portal hypertension (PHT). This is defined as hepatic venous pressure gradient (HVPG) greater than 5mmHg, with complications arising once this exceeds 10mmHg. Portal hypertensive complications are associated with high morbidity and mortality and include; variceal bleeding, portal hypertensive gastropathy, ascites, and hepatic
encephalopathy. These conditions present a challenge to the Australian health system with the economic costs associated with treating liver disease estimated to be higher than that of type 2 diabetes and chronic kidney disease combined.1
This article is protected by copyright. All rights reserved.
Over the last decade our
Accepted Article
4
understanding of portal hypertension has increased dramatically allowing for optimization of management and new therapeutic approaches.
Portal Hypertension Pathophysiology The portal vein acts as the major outflow tract for the splanchnic circulation. The portal system is a low pressure, low resistance system. In the healthy state, considerable postprandial increases in portal venous blood flow do not significantly alter portal pressure due to the highly compliant nature of this system. The normal portal vein pressure is 5mmHg or less and is a product of blood flow (Q) and resistance (R) according to Ohm’s law: Portal Pressure = Q (blood flow) x R (portal resistance)
The aetiology of increased portal resistance is commonly categorized according to anatomical location into pre-hepatic, intra-hepatic and post-hepatic causes (Table 1). In the western world sinusoidal PHT secondary to cirrhosis is the most common cause of PHT. In cirrhosis the architectural changes associated with fibrosis and nodule formation result in a fixed alteration to sinusoidal blood flow. In contrast to this fixed hepatic resistance, there is a dynamic component which arises from contraction of myelofibroblasts within the space of Disse.2 These myelofibroblasts originate from hepatic stellate cells, which in the healthy state are the predominant storage site for vitamin A. In the presence of inflammation, cytokines released from injured hepatocytes stimulate the recruitment and transdifferentiation of hepatic stellate cells into contractile myofibroblasts with the capacity to deposit collagen. An excess of locally produced vasoconstrictor peptides together with a relative depletion in hepatic nitric oxide (NO) contribute to this dynamic component of
This article is protected by copyright. All rights reserved.
Accepted Article
5
hepatic resistance. These reversible components may represent up to 30% of the total resistance to portal blood flow.3 The increased pressure within the portal venous system induces shear stresses in the splanchnic vessels, and together with translocation of bacterial lipopolysaccharides results in excessive systemic NO production.4 The subsequent systemic vasodilatation activates a number of homeostatic regulatory systems such as the renin-angiotensin-aldosterone system (RAAS) and antidiuretic hormone (ADH) causing sodium and water retention. These events result in an increase in splanchnic vasodilation and blood flow with resultant increase in flow into the portal venous system further exacerbating PHT.2 Detection of Portal Hypertension The presence of portal hypertension may be clinically silent, however findings such as splenomegaly, ascites and abdominal wall collaterals (caput medusae) strongly suggest its presence. . Radiological imaging such as doppler ultrasound and computerised tomography (CT) may demonstrate the presence of collateral vessels, alterations in portal venous flow, splenomegaly and ascites, thereby supporting the diagnosis of portal hypertension. Despite this, the first presentation of portal hypertension may be with variceal haemorrhage, and this needs to be urgently excluded in any patient with suspected liver disease who has significant gastrointestinal haemorrhage. Direct measurement of portal venous pressures is invasive and requires significant procedural experience. This technique involves the introduction of a balloon catheter via
This article is protected by copyright. All rights reserved.
Accepted Article
6
the jugular or femoral vein into the hepatic vein. The HVPG is derived from subtracting free hepatic vein pressure (FHVP) from wedge hepatic vein pressure (WHVP): HVPG = WHVP - FHVP
PHT is defined by a hepatic venous pressure gradient (HVPG) > 5mmHg. Clinically significant PHT is defined as an HVPG ≥ 10mmHg. This threshold is required for the development of complication of PHT such as porto-systemic collaterals, varices, ascites and circulatory dysfunction. Variceal haemorrhage is associated with HVPG greater than 12mmHg and when HVPG is greater than 20mmHg following variceal haemorrhage, the risk of death increases five-fold.5 Likewise the risk for development of hepatocellular carcinoma increases to 6-fold when the HVPG is >10mmHg.6 The routine use of HVPG in clinical practice is generally limited to specialist centres. The role that less invasive methods of predicting PHT, such as liver stiffness measurement (LSM) using transient elastography, is yet to be established. The ideal LSM to determine
significant PHT requires further validation however a LSM of >20kpa appears to have a high specificity (92.3%) while a LSM >13kpa has a high sensitivity for PHT (94%).7, 8The use of a ratio of spleen size and platelet count in combination with LSM may overcome these limitations with recent literature demonstrating a combined sensitivity and specificity greater than 80% for detection of significant PHT.9
This article is protected by copyright. All rights reserved.
Accepted Article
7
Complications of Portal Hypertension Gastrointestinal Haemorrhage Oesophageal Varices Oesophageal varices are present in 40% of patients with an initial diagnosis of Child Pugh A cirrhosis and in 60% of patients with signs of decompensation.17 Those without varices at initial assessment develop them at an incidence of 7% per year.18 Seven percent of small varices (1.37 Diuretics should be ceased in the setting of
This article is protected by copyright. All rights reserved.
Accepted Article
15
severe renal impairment or severe hyponatremia (
