Clinical Practice Guidelines

Clinical Practice Guidelines

Clinical Practice Guidelines Vascular diseases of the liver About these slides These slides give a comprehensive overview of the EASL clinical practice guidelines on vascular diseases of the liver The guidelines were published in full in the June 2016 issue of the Journal of Hepatology The full publication can be downloaded from the Clinical Practice Guidelines section of the EASL website Please cite the published article as: European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Vascular diseases of the liver. J Hepatol 2016;64:179202 Please feel free to use, adapt, and share these slides for your own personal use; however, please acknowledge EASL as the source About these slides Definitions of all abbreviations shown in these slides are provided within the slide notes

When you see a home symbol like this one: , you can click on this to return to the outline or topics pages, depending on which section you are in These slides are intended for use as an educational resource and should not be used in isolation to make patient management decisions. All information included should be verified before treating patients or using any therapies described in these materials Please send any feedback to: [email protected] Guideline panel Chair: Juan Carlos Garcia-Pagn Panel members: Elisabetta Buscarini, Harry LA Janssen, Frank WG Leebeek, Aurelie Plessier, Laura Rubbia-Brandt, Marco Senzolo, Jeoffrey NL Schouten, Armando Tripodi, Dominique C Valla (EASL Governing Board Representative)

EASL CPG VDL. J Hepatol 2016;64:179202 Outline Methods Background Guidelines The future for VDL EASL CPG VDL. J Hepatol 2016;64:179202 Grading evidence and recommendations Vascular diseases of the liver Key recommendations Unresolved issues in treatment and monitoring Methods Grading evidence and recommendations Grading evidence and recommendations Grading is adapted from the GRADE system1 Grade of evidence A: High quality Further research is very unlikely to change our confidence in the estimate of effect

B: Moderate quality Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate effect C: Low/very low quality Further research is very likely to have an important impact on our confidence in the estimate of effect and may change the estimate effect. Any estimate of effect is uncertain Grade of recommendation 1: Strong Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost 2: Weaker Variability in preferences and values, or more uncertainty: more likely a weak recommendation is warranted. Recommendation is made with less certainty; higher cost or resource consumption 1. Guyatt GH, et al. BMJ 2008:336:9246; EASL CPG VDL. J Hepatol 2016;64:179202 Background Vascular diseases of the liver Vascular diseases of the liver

Collection of rare conditions, each affecting <5/10,000 patients Represent an important worldwide health problem Non-cirrhotic portal hypertension is a common characteristic of many VDL Results in high morbidity and mortality Patients are usually young Otherwise normal life expectancy Adequate management is mandatory to avoid reduced life expectancy These guidelines do not cover all VDL, but are focused on specific conditions More frequent, despite being rare More data available EASL CPG VDL. J Hepatol 2016;64:179202 Guidelines Key recommendations Topics 1. 2. 3.

4. 5. 6. 7. 8. 9. Splanchnic vein thrombosis in patients without underlying liver disease BuddChiari syndrome Acute portal vein thrombosis (non-cirrhotic, non-malignant) Extrahepatic portal vein obstruction (non-cirrhotic, non-malignant) Idiopathic non-cirrhotic portal hypertension Hepatic vascular malformations in hereditary haemorrhagic telangiectasia Sinusoidal obstruction syndrome Cirrhosis as a prothrombotic condition: portal vein obstruction Management of anticoagulation in patients with liver disease Click on a topic to skip to that section Aetiology of SVT in patients without liver disease Splanchnic vein thrombosis includes BuddChiari syndrome (thrombosis of the hepatic venous system) Portal vein thrombosis Both conditions are caused by uncommon pro-thrombotic disorders Myeloproliferative neoplasms are the leading cause Thrombophilia Other local and systemic factors

Aetiology of BCS and PVT is often multifactorial EN-Vie study: 2 factors in 46% and 10% of patients, respectively In >60% of patients with SVT with inherited thrombophilia, an additional risk factor was found EASL CPG VDL. J Hepatol 2016;64:179202 Risk factors in BCS and PVT Risk factor BCS frequency (%) PVT frequency (%) Thrombophilia Inherited Acquired 21 44 35 19 Myeloproliferative neoplasm JAK2V617F positive 49 29

21 16 Hormonal factors Oral contraceptives Pregnancy 38 33 6 44 44 0 PNH 19 0 Other systemic factors 23 ND Local factors 0 21

EASL CPG VDL. J Hepatol 2016;64:179202 Investigations for splanchnic vein thrombosis In patients with SVT without an underlying liver disease, diagnosis of the underlying aetiological factors is important Recommendations Grade of evidence Grade of recommendation Investigate patients with BCS and PVT for underlying local and systemic prothrombotic factors. Identification of one risk factor should not deter from looking for additional risk factors A 1 Work-up consists of diagnosis for inherited and acquired thrombophilia factors, myeloproliferative neoplasms, paroxysmal nocturnal haemoglobinuria and autoimmune disorders A 1 Investigate patients with both BCS and PVT for local risk factors, including intra-abdominal inflammatory conditions and abdominal malignancies

A 1 Thrombophilia screening should include protein S, protein C and antithrombin levels, FVL mutation, prothrombin G20210A gene variant and antiphospholipid antibodies (APAs). In case of APA positivity, this should be repeated after 12 weeks A 1 EASL CPG VDL. J Hepatol 2016;64:179202 Investigations for splanchnic vein thrombosis MPNs are a common underlying cause of abdominal vein thrombosis JAK2V617F mutation is of major importance in the diagnostic strategy for MPN Recommendations Grade of evidence Grade of recommendation Test for MPNs by testing for JAK2V617F mutation in SVT patients, and in individuals with normal peripheral blood cell counts A

1 In JAK2V617F mutation-negative patients, calreticulin mutation screening should be performed and if both are negative, bone marrow histology should be considered. Patients have to be referred to a haematologist B 2 Treat the underlying condition appropriately B 1 In case of an underlying MPN, anticoagulant treatment should be given indefinitely for SVT patients B 1 EASL CPG VDL. J Hepatol 2016;64:179202 BuddChiari syndrome: Definition and diagnosis BCS is defined by the obstruction of hepatic venous outflow Primary BCS: caused by thrombosis Western countries: pure hepatic vein thrombosis is the most common Asia: pure IVC or combined IVC/hepatic vein block predominates

Secondary BCS: other causes, such as malignant invasion Pathophysiological consequences of obstruction include: Sinusoidal congestion Liver ischaemia Hepatocellular necrosis Diagnosis requires unequivocal radiological confirmation of hepatic venous flow obstruction EASL CPG VDL. J Hepatol 2016;64:179202 BuddChiari syndrome: Definition and diagnosis BCS is defined by the obstruction of hepatic venous outflow Primary BCS: caused by thrombosis Western countries: pure hepatic vein thrombosis is the most common Asia: pure IVC or combined IVC/hepatic vein block predominates Secondary BCS: other causes, such as malignant invasion Covered by this guideline Recommendations Grade of evidence Grade of recommendation

Consider diagnosis of BCS in any symptomatic or asymptomatic patient with acute or chronic liver disease A 1 Doppler ultrasound is the first line of investigation for BCS. MRI and CT have to be used for diagnostic confirmation A 1 Re-evaluate the patient with an expert radiologist in patients with negative imaging studies but a high suspicion of BCS A 1 Refer patients with BCS to expert centres A 1 EASL CPG VDL. J Hepatol 2016;64:179202 Stepwise therapeutic algorithm for BCS Based on retrospective cohorts and prospective series of patients

No RCTs Medical treatment Angioplasty/stenting/thrombolysis TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 Stepwise therapeutic algorithm for BCS Based on retrospective cohorts and prospective series of patients No RCTs Patients should receive anticoagulation as soon as possible for an indefinite period Medical treatment Angioplasty/stenting/thrombolysis TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 Consider potential for bleeding complications

Stepwise therapeutic algorithm for BCS Based on retrospective cohorts and prospective series of patients No RCTs Patients should receive anticoagulation as soon as possible for an indefinite period Medical treatment Angioplasty/stenting/thrombolysis TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 Consider potential for bleeding complications Treatment of underlying cause (e.g. MPNs) should be logically initiated concomitantly BuddChiari syndrome: Medical treatment Prompt anticoagulant therapy is important

Reduce risk of clot extension Reduce risk of new thrombotic episodes Recommendations Grade of evidence Grade of recommendation Initiate therapy for complications of portal hypertension as recommended in patients with cirrhosis C 2 Treat all BCS patients with anticoagulation, in the absence of major contraindications A 1 Portal hypertension complications, when adequately treated, are not a contraindication for anticoagulation B 1 Consider brief interruption of anticoagulation therapy whenever an invasive procedure is performed, including paracentesis B

1 EASL CPG VDL. J Hepatol 2016;64:179202 Stepwise therapeutic algorithm for BCS Based on retrospective cohorts and prospective series of patients No RCTs Medical treatment Angioplasty/stenting/thrombolysis Angioplasty/stenting is the definitive treatment for less than 10% of Western BCS patients TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 Experience of correcting hepatic venous outflow obstruction with thrombolysis is limited Stepwise therapeutic algorithm for BCS

Based on retrospective cohorts and prospective series of patients No RCTs Surgical shunts have not demonstrated a survival advantage in patients with BCS Medical treatment Angioplasty/stenting/thrombolysis TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 However, TIPS has a lower morbidity and mortality rate than surgery and is feasible in most patients with IVC obstruction and in those with severe IVC stenosis BuddChiari syndrome: Angioplasty and stenting Patients non-responsive to medical treatment should progress to the next therapeutic steps

Angioplasty/stenting and portal shunts Recommendations Grade of evidence Grade of recommendation Consider angioplasty/stenting as the first-line decompressive procedure in patients with short hepatic vein stenosis or IVC stenosis A 1 Closely monitor these patients for early detection of liver deterioration. Treat patients who do not respond to initial therapy, or do not respond to angioplasty/stenting with portal shunt techniques A 1 TIPS, using PTFE-covered stents, is the shunt treatment of choice A 1 Discuss surgical shunting when TIPS is not feasible or fails B

1 EASL CPG VDL. J Hepatol 2016;64:179202 Stepwise therapeutic algorithm for BCS Based on retrospective cohorts and prospective series of patients No RCTs LTx is associated with survival similar to that in patients initially treated with TIPS Medical treatment Angioplasty/stenting/thrombolysis TIPS Liver transplant EASL CPG VDL. J Hepatol 2016;64:179202 Some patients with severe BCS may benefit from LTx without prior TIPS No reliable way to identify such patients BuddChiari syndrome: LTx

Liver transplantation is the last therapeutic step BCS may recur after LTx Incidence of recurrent BCS after LTx is markedly reduced by early anticoagulation treatment and lifelong maintenance Recommendations Grade of evidence Grade of recommendation Propose liver transplantation as a salvage treatment for patients in whom shunt techniques have failed A 1 Anticoagulation needs to be continued in most BCS patients after liver transplantation B 1 Screen patients with BCS for HCC. Distinction between benign and malignant liver nodules is very difficult and may need referral to specialized centres A 1

EASL CPG VDL. J Hepatol 2016;64:179202 BuddChiari syndrome and pregnancy Excellent maternal outcome provided disease is well controlled Fetal outcome is less favourable Pregnancies reaching Week 20 of gestation have acceptable prognosis Vitamin K antagonists associated with high risk of miscarriage and congenital malformation Perform pregnancy test as soon as possible If positive, switch to LMWH Periodic monitoring of anti-Xa activity EASL CPG VDL. J Hepatol 2016;64:179202 Acute portal vein thrombosis: Definition and diagnosis Recent thrombus formation within the portal vein and/or right or left branches Thrombus may extend into the mesenteric or splenic veins Guidelines refer to acute PVT occurring in the absence of malignancy or cirrhosis Recommendations

Grade of evidence Grade of recommendation Consider diagnosis of acute portal vein obstruction in any patient with abdominal pain A 1 Use Doppler ultrasound as the first-line investigation for acute PVT. Use CT for diagnostic confirmation and the assessment of extension A 1 Establish or rule out underlying cirrhosis or obliterative portal venopathy C 1 Consider intestinal infarction in patients with persisting severe abdominal pain, rectal bleeding, moderate or massive ascites, or multiorgan dysfunction. Closely monitor for signs of deterioration B

1 EASL CPG VDL. J Hepatol 2016;64:179202 Acute portal vein thrombosis: Aims of therapy Prevent extension of thrombosis to mesenteric veins Leading to mesenteric venous infarction Achieve portal vein recanalization Abdominal pain and systemic inflammation and/or thrombophilic factor Inform radiologist of PVT suspicion Screen for general and local cause Start LMWH Add antibiotics if septic thrombophlebitis Treat cause when accurate Persisting abdominal pain despite

adequate anticoagulation? Organ failure? Rectal bleeding? YES Discuss urgent laparotomy with expert surgeon EASL CPG VDL. J Hepatol 2016;64:179202 Confirm acute PVT on unenhanced and contrast CT scan NO 1. Close monitoring 2. 6 months anticoagulation with coumarin Acute portal vein thrombosis: Anticoagulation Thrombus extension is prevented with early initiation of anticoagulation therapy Recommendations Grade of evidence Grade of recommendation Initiate immediate anticoagulation with LMWH in the absence of major contraindications to anticoagulation A

1 Screen for HIT in patients with a sudden unexplained platelet count fall 50% or to a value less than 150 x 10 9/L* A 1 Initial treatment should be with LMWH. Monitor anti-Xa activity in overweight patients, pregnancy, and poor kidney function, targeting a level between 0.5 and 0.8 IU/mL A 1 Use oral VKAs for long-term anticoagulant treatment, targeting an INR between 2 and 3 B 1 Anticoagulation therapy should be given for at least 6 months A 1 *Especially in those in whom unfractionated heparin was initiated EASL CPG VDL. J Hepatol 2016;64:179202

Acute portal vein thrombosis: Prognosis Recanalization of the portal vein can occur up to 6 months following treatment Recanalization of mesenteric and splenic veins increases steadily up to 12 months Over half (55%) of the patients not achieving recanalization will develop gastroesophageal varices 2-year probability of variceal bleeding: 12% 2-year probability of ascites: 16% Recommendations Grade of evidence Grade of recommendation Perform a CT scan to assess recanalization of the portal venous system after 612 months B 1 Screen for gastroesophageal varices in unrecanalized patients A 1 Perform MRI cholangiography in patients with persisting cholestasis

or biliary tract abnormalities suggestive of portal biliopathy B 2 EASL CPG VDL. J Hepatol 2016;64:179202 Extrahepatic portal vein obstruction EHPVO occurs due to: Malignant invasion Portal vein narrowing due to a malignant tumour Thrombosis EASL CPG VDL. J Hepatol 2016;64:179202 Extrahepatic portal vein obstruction EHPVO occurs due to: Malignant invasion Portal vein narrowing due to a malignant tumour Thrombosis Covered by this guideline EASL CPG VDL. J Hepatol 2016;64:179202 Extrahepatic portal vein obstruction EHPVO occurs due to:

Malignant invasion Portal vein narrowing due to a malignant tumour Thrombosis Following acute thrombosis in the absence of recanalization Portal venous lumen obliterates Porto-portal collaterals develop EASL CPG VDL. J Hepatol 2016;64:179202 Extrahepatic portal vein obstruction EHPVO occurs due to: Malignant invasion Portal vein narrowing due to a malignant tumour Thrombosis Following acute thrombosis in the absence of recanalization Portal venous lumen obliterates Porto-portal collaterals develop 2 months Portal cavernoma 1. Francoz C, et al. J Hepatol 2012;57:20312; EASL CPG VDL. J Hepatol 2016;64:179202 Helical CT showing organized PVT with cavernoma (white arrow)1

Extrahepatic portal vein obstruction: Diagnosis EHPVO should be considered in patients with features of portal hypertension or hypersplenism Essential features are: Absence of visible lumen corresponding to the portal vein Presence of numerous serpiginous vascular channels in porta hepatis Recommendations Grade of evidence Grade of recommendation Consider EHPVO in any patient with features of portal hypertension, hypersplenism or abdominal pain, or biliary tract disease A 1 Consider screening for EHPVO in patients with myeloproliferative disease and antiphospholipid syndrome B 2 Use Doppler ultrasound as first-line investigation to diagnose EHPVO. Use CT for diagnostic confirmation and further assessment

A 1 Rule out underlying cirrhosis or obliterative portal venopathy whenever liver tests are abnormal, a cause for CLD is present, or the liver is dysmorphic, or results of liver elastometry are abnormal C 1 EASL CPG VDL. J Hepatol 2016;64:179202 Extrahepatic portal vein obstruction: Outcome Most frequent complication is GI bleeding related to portal hypertension Followed by recurrent thrombosis and, more rarely, biliary complications Recommendations Grade of evidence Grade of recommendation Perform MRI cholangiography in patients with persisting cholestasis or biliary tract abnormalities suggestive of portal biliopathy B 2

Manage portal hypertension according to the guidelines for cirrhosis B 1 After prophylaxis for GI bleeding: Treat underlying prothrombotic conditions according to corresponding guidelines B 1 Consider permanent anticoagulation in patients with a strong prothrombotic condition, or past history suggesting intestinal ischaemia or recurrent thrombosis on follow-up B 2 Instigate long-term anticoagulation in case of underlying MPN B 2

EASL CPG VDL. J Hepatol 2016;64:179202 Chronic EHPVO: Determining need for permanent anticoagulation Underlying prothrombotic disorders and local factors may require specific therapy Chronic EHPVO Implement prophylaxis for portal hypertension-related bleeding YES Consider long-term anticoagulation Permanent, strong prothrombotic condition?* YES Consider long-term anticoagulation *Assessment based on personal and familial history of unprovoked deep vein thrombosis, and on findings of isolated or combined prothrombotic conditions EASL CPG VDL. J Hepatol 2016;64:179202 NO Past history of intestinal ischaemia

NO Monitor, propose RCT INCPH: Diagnosis Many disorders are associated with non-cirrhotic intrahepatic portal hypertension Infiltrative diseases, vascular malignancies, schistosomiasis, congenital hepatic fibrosis, sarcoidosis Idiopathic non-cirrhotic portal hypertension (INCPH)* can be diagnosed if all these disorders have been excluded No gold standard diagnostic test for INCPH INCPH should be considered in any patient with portal hypertension Particularly when there is no other cause of liver disease Recommendations Grade of evidence Grade of recommendation INCPH diagnosis requires the exclusion of cirrhosis and other causes of non-cirrhotic portal hypertension B 1

Perform liver biopsy for the diagnosis of INCPH A 1 *INCPH has previously been referred to as: hepatoportal sclerosis, non-cirrhotic portal fibrosis, idiopathic portal hypertension, incomplete septal cirrhosis and nodular regenerative hyperplasia EASL CPG VDL. J Hepatol 2016;64:179202 Diagnostic criteria of INCPH All 5 criteria must be fulfilled Splenomegaly*/hypersplenism Oesophageal varices Ascites (non-malignant) Minimally increased HVPG Portovenous collaterals 3. Exclusion of CLD causing cirrhosis or non-cirrhotic portal hypertension

Chronic HCV or HBV NASH/ASH Autoimmune hepatitis Hereditary haemochromatosis Wilson disease Primary biliary cirrhosis 4. Exclusion of conditions causing non-cirrhotic portal hypertension Congenital liver fibrosis Sarcoidosis Schistosomiasis 1. 1 clinical sign of portal hypertension 2. Exclusion of cirrhosis on liver biopsy 5. Patent portal and hepatic veins *Splenomegaly must be accompanied by additional signs of portal hypertension in order to fulfil this criterion; Chronic liver disease must be excluded since severe fibrosis might be understaged on liver biopsy EASL CPG VDL. J Hepatol 2016;64:179202 INCPH: Treatment

Treatment and prophylaxis of variceal GI bleeding Endoscopic therapy controls acute variceal bleeding in 95% of patients and reduces risk of rebleeds Despite lack of data, endoscopic band ligation is preferable TIPS should be considered in case of uncontrolled bleeding Anticoagulation cannot be generally recommended Can be considered in patients with clear underlying prothrombotic conditions or in those who develop PVT Recommendations Grade of evidence Grade of recommendation Manage portal hypertension according to the guidelines for cirrhosis B 1 Screen, at least every 6 months, for the occurrence of PVT B 1 Consider liver transplantation in INCPH patients who develop liver

failure or unmanageable portal hypertension-related complications B 1 EASL CPG VDL. J Hepatol 2016;64:179202 Hepatic vascular malformations in HHT: Definition HHT* is an autosomal dominant genetic disorder Characterized by widespread cutaneous mucosal and visceral telangiectasias Affects 12/10,000 people Clinical presentation of HHT varies widely Number, type and location of telangiectasias or larger VMs Diffuse liver VMs are unique to HHT Presence should always lead to the search of HHT diagnostic criteria *Also known as RenduOslerWeber disease EASL CPG VDL. J Hepatol 2016;64:179202 Curaao clinical criteria and grading of liver VMsao clinical criteria and grading of liver VMs HHT - Curaao Description clinical criteria

Epistaxis Spontaneous and recurrent Telangiectases Multiple, at characteristic sites: lips, oral cavity, fingers, nose Visceral lesions GI telangiectasia, pulmonary, hepatic, cerebral or spinal A-V malformations Family history A first-degree relative with HHT according to these criteria Liver VMs in HHT Doppler ultrasound grading 0+ Hepatic artery diameter >5 and <6 mm, and/or Peak flow velocity >80 cm/sec, and/or Resistivity index <0.55, and/or Peripheral hepatic hypervascularization 1 Hepatic arterial dilatation, only extrahepatic >6 mm, and PFV >80 cm/sec, and/or Resistivity index <0.55 2 Hepatic arterial dilatation, extra- and intrahepatic, PFV >80 cm/sec Possibly associated with moderate flow abnormality of hepatic and/or portal veins 3 Complex changes in hepatic artery and its branches, with marked flow abnormalities Abnormality of hepatic and/or portal vein flow 4 Decompensation of arteriovenous shunt with: Dilatation of hepatic and/or portal vein Marked flow abnormalities in both arteries and veins EASL CPG VDL. J Hepatol 2016;64:179202 Curaao clinical criteria and grading of liver VMsao clinical criteria and grading of liver VMs HHT - Curaao

Description clinical criteria Epistaxis Spontaneous and recurrent Telangiectases Multiple, at characteristic sites: lips, oral cavity, fingers, nose Visceral lesions GI telangiectasia, pulmonary, hepatic, cerebral or spinal A-V malformations Family history A first-degree relative with HHT according to these criteria Liver VMs in HHT Doppler ultrasound grading 0+ Hepatic artery diameter >5 and <6 mm, and/or Peak flow velocity >80 cm/sec, and/or Resistivity index <0.55, and/or Peripheral hepatic hypervascularization Diagnosis is confirmed with 3 Curaao clinical criteria and grading of liver VMs ao criteria 1 Hepatic arterial dilatation, only extrahepatic >6 mm, and PFV >80 cm/sec, and/or 2: HHT is likely Resistivity index <0.55 1: unlikely 2

Hepatic arterial dilatation, extraandHHT intrahepatic, PFV >80 cm/sec Possibly associated with moderate flow abnormality of hepatic and/or portal veins 3 Complex changes in hepatic artery and its branches, with marked flow abnormalities Abnormality of hepatic and/or portal vein flow 4 Decompensation of arteriovenous shunt with: Dilatation of hepatic and/or portal vein Marked flow abnormalities in both arteries and veins EASL CPG VDL. J Hepatol 2016;64:179202 Hepatic vascular malformations in HHT: Diagnosis Consider HHT in subjects presenting with diffuse liver VMs* Recommendations Grade of evidence Grade of recommendation Complete investigation for liver VMs in: HHT patients with symptoms/signs suggestive of complicated liver VMs A 1

All subjects at risk of HHT; liver VM diagnosis and staging offer the advantages of proper patient management and follow-up A 2 A 1 Doppler ultrasound is the ideal first-line imaging for the diagnosis and staging of liver VMs. Where expertise is lacking, multiphase CT is a suitable alternative to investigate symptomatic liver VMs *Grade of evidence A, Grade of recommendation 2 High-output cardiac failure, ascites, gastrointestinal bleeding, cholangitis, encephalopathy, and mesenteric angina EASL CPG VDL. J Hepatol 2016;64:179202 Hepatic vascular malformations in HHT: Diagnosis Echocardiographic evaluation of cardiac function and morphology gives a non-invasive estimate of haemodynamic impact of liver VMs Recommendations Grade of evidence Grade of recommendation

Propose echocardiographic evaluation to patients with liver VMs* at baseline and during follow-up, to monitor impact of liver VMs B 2 Liver biopsy: a. Is not necessary in the diagnosis of hepatic VMs related to HHT A 1 b. If needed for other reasons, in a patient with known or suspected HHT, consider the risk of increased bleeding with percutaneous transcapsular route A 1 B 1 Discuss FNH first in a HHT patient with liver mass(es), and use non-invasive, contrast-enhanced imaging for diagnostic

confirmation *Particularly if severe (grade 3-4) EASL CPG VDL. J Hepatol 2016;64:179202 Hepatic vascular malformations in HHT: Treatment No treatment is recommended for asymptomatic liver VMs 8% of patients with liver VMs are symptomatic and require intensive medical treatment HOCF: salt restriction, diuretics, beta blockers, digoxin, ACE inhibitors, antiarrhythmic agents, cardioversion and radiofrequency catheter ablation Complications of PH and encephalopathy: as for cirrhotic patients Cholangitis: antibiotics Response rates are high 63% show a complete response 21% show a partial response EASL CPG VDL. J Hepatol 2016;64:179202 An intensive approach to symptomatic liver VMs is warranted A cautious approach to major remedies is required Hepatic vascular malformations in HHT: Major remedies

Invasive therapies for liver involvement should only be considered in HHT patients not responding to intensive medical therapy* Recommendations Grade of evidence Grade of recommendation Take advice from a team with expertise in HHT before making any decision regarding treatment of liver VMs and, notably, OLTx A 1 Obtain assessment and treatment by a cardiologist for HOCF prior to considering invasive therapy B 1 Regard transarterial embolization of liver VMs as a palliative and risky procedure to be discussed in patients with HOCF or mesenteric angina who are not candidates for OLTx. Consider cholangiopathy as a contraindication to transarterial embolization B 2

Regard OLTx as the only curative treatment for liver VMs, if intractable HOCF or portal hypertension, and urgently, for ischaemic bile duct necrosis B 1 HOCF is the predominant complication of HHT HOCF and complicated PH each account for ~50% hepatic VM-associated deaths *Grade of evidence B, Grade of recommendation 1 EASL CPG VDL. J Hepatol 2016;64:179202 Sinusoidal obstruction syndrome* Characterized morphologically by loss of sinusoidal wall integrity Well-established complication of myeloablative regimens in HSCT Associated with a large number of drugs and toxins

Actinomycin D Azathioprine Busulfan Carmustine Cytosine arabinoside Cyclophosphamide Dacarbazine Gemtuzumab ozogamicin Melphalan Mercaptopurine Mitomycin Oxaliplatin Pyrrolizidine alkaloids Urethane Terbinafine

Traditional herbal remedies 6-mercaptopurine 6-thioguanine Post-bone marrow transplant Total-body irradiation Hepatic irradiation (high doses) Platelet transfusion containing ABO-incompatible plasma Signs and symptoms include Weight gain, tender hepatomegaly and jaundice *Previously known as veno-occlusive disease of the liver EASL CPG VDL. J Hepatol 2016;64:179202 Sinusoidal obstruction syndrome: Diagnosis Lack of specific clinical signs or serological diagnostic tools makes recognition of SOS challenging Diagnosis is based on a high index of clinical suspicion After exclusion of potential mimicking causes Acute liver graft versus host disease (GvHD)

Liver infections (virus, fungi) Sepsis associated with cholestasis Other drug-induced liver diseases Cardiac diseases Other causes of ascites Parenteral nutrition Haemolysis Renal failure EASL CPG VDL. J Hepatol 2016;64:179202 Sinusoidal obstruction syndrome: Diagnosis Lack of specific clinical signs or serological diagnostic tools makes recognition of SOS challenging Diagnosis is based on a high index of clinical suspicion After exclusion of potential mimicking causes Recommendations Grade of evidence Grade of recommendation Consider a diagnosis of SOS whenever liver disease occurs in patients with HSCT, cancer chemotherapy, immunosuppression in solid organ transplantation or IBD B 1 Consider SOS in patients with weight gain, associated with or

without ascites, tender hepatomegaly and jaundice. Exclude other common causes of these symptoms* C 1 In patients who do not meet clinical criteria of SOS or when other diagnoses have to be excluded, use transjugular liver biopsy, and haemodynamic evaluation C 1 *Including sepsis, other types of drug toxicity and graft versus host disease EASL CPG VDL. J Hepatol 2016;64:179202 SOS: Prophylaxis and treatment Recognition of risk factors is helpful to prevent SOS Pre-existing liver disease Previous SOS Type of regimen Abnormal pre-operative GGT, age, female sex, indocyanin green retention rate at 15 minutes, cycles of chemotherapy, and a short interval between the end of chemotherapy and surgical liver resection*

Recommendations Grade of evidence Routinely control risk factors for SOS Use defibrotide to prevent SOS in patients undergoing HSCT Other means of prophylaxis need further investigation Use supportive measures for the treatment of complications of established SOS *In the context of solid cancer treatment (in particular colorectal liver metastasis) EASL CPG VDL. J Hepatol 2016;64:179202 Grade of recommendation B 1 B 2 B 1 Cirrhosis as a prothrombotic condition: Portal vein obstruction Venous thromboembolism, once considered unlikely in cirrhosis, has

recently been reported1,2 PVT is the most common thrombotic event occurring in cirrhotic patients3 Recommendations Grade of evidence Grade of recommendation Evaluate portal vein patency in all patients with cirrhosis listed or potential candidates for liver transplantation B 2 Always evaluate the extension of PVT with CT scan or MRI A 1 In patients with underlying HCC, rule out neoplastic PVT by contrast enhanced ultrasound/CT scan/MRI or biopsy of the thrombus A 1 Consider screening for underlying genetic thrombophilic conditions in patients with PVT and cirrhosis B

2 1. Northup PG, et al. Am J Gastroenterol 2006;101:15248; 2. Sogaard KK, et al. Am J Gastroenterol 2009;104:96101; 3. Rodriguez-Castro KI, et al. Transplantation 2012;94:114553; EASL CPG VDL. J Hepatol 2016;64:179202 Anticoagulation in liver disease A procoagulant imbalance is apparent in cirrhotic patients 1 Anticoagulants were contraindicated Now a possibility in patients with cirrhosis who present with thrombosis Recommendations Grade of evidence Grade of recommendation Anticoagulation must always be started after adequate prophylaxis for gastrointestinal bleeding A 1 Consider anticoagulation at therapeutic dose for at least 6 months B 1

In patients with superior mesenteric vein thrombosis, with a past history suggestive of intestinal ischaemia or liver transplant candidates, consider lifelong anticoagulation C 2 Once PVT has been repermeated, consider prolonging anticoagulation for some months and until transplant in liver transplant candidates B 2 In liver transplant candidates who have progressive PVT not responding to anticoagulation, consider referral for TIPS B 2 1. Tripodi A, Mannucci PM. N Engl J Med 2011;365:14756 EASL CPG VDL. J Hepatol 2016;64:179202 Anticoagulation in liver disease Upon binding to antithrombin, unfractionated heparin neutralizes both FXa and thrombin A major concern on the use of heparins in cirrhosis is the reduction of antithrombin that is a typical feature of patients with advanced disease

Recommendations Grade of evidence Unfractionated heparin should be used with laboratory monitoring with the APTT as the test for dose adjustment and a therapeutic interval aimed at 1.52.5 prolongation over the normal value, keeping in mind that the above therapeutic interval may vary between centres depending on the reagent being used for testing. An additional problem is that the baseline APTT in cirrhosis is often prolonged beyond normal and therefore unfractionated heparin will probably be under-dosed. For the above reasons unfractionated heparin is probably not indicated in cirrhosis EASL CPG VDL. J Hepatol 2016;64:179202 Grade of recommendation C 2 Anticoagulation in liver disease Whether fixed or weight-adjusted LMWH is as effective/safe in patients with liver cirrhosis as in other patients is unclear Only randomized trial so far showed that a fixed prophylactic dose of LMWH, without laboratory monitoring, was effective and safe in preventing PVT in cirrhotic patients1 Recommendations Grade of evidence

Grade of recommendation Low molecular weight heparin should be used at fixed or weight-adjusted dose for prophylaxis or treatment without laboratory monitoring. From the limited experience thus far, the anti-Xa assay in cirrhosis is not representative of the real anticoagulation. Patients who are obese, with renal insufficiency or pregnant should be strictly monitored by regular clinical visits and should be advised to report immediately any sign that may be suggestive of an adverse event 1. Villa E, et al. Gastroenterology 2012;143:125360 EASL CPG VDL. J Hepatol 2016;64:179202 C 2 Anticoagulation in liver disease Owing to their relatively narrow therapeutic window, VKAs need strict laboratory monitoring to maintain patients at a suitable dose Recommendation on vitamin K antagonists Grade of evidence Vitamin K antagonists should be used with regular laboratory monitoring with an INR aimed at a therapeutic interval of 2.03.0. This limitation, inherent in the use of this scale in cirrhosis, should be kept in mind: the INR value might not be representative of the

real anticoagulation and the results may vary between centres Warning on anticoagulation Grade of evidence Before anticoagulation, consider carefully the risk/benefit ratio for individual patients. Risk factors for bleeding are oesophageal varices if not treated prior to anticoagulation and severe thrombocytopenia EASL CPG VDL. J Hepatol 2016;64:179202 Grade of recommendation C 2 Grade of recommendation C 2 The future for VDL Unresolved issues in treatment and monitoring Unresolved issues in treatment and monitoring Randomized trials are urgently needed To assess the efficacy/safety of:

LMWH VKAs DOACs in cirrhosis Alternative laboratory monitoring should be developed and validated In cirrhotic patients treated with LMWH or VKAs EASL CPG VDL. J Hepatol 2016;64:179202

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    Comparing Vegetation in a Riparian Zone to an Upland Area in a Colorado Montane Forest. By: Abby Branson. Vegetation Ecology, Summer 2013. Mountain Research Station, University of Colorado, Boulder
  • Cell Cycle, Mitosis, and Meiosis

    Cell Cycle, Mitosis, and Meiosis

    Cell Cycle, Mitosis, and Meiosis Why do cells divide? Most cells go through a series of changes in order to maintain homeostasis. Cells need to reproduce (divide) when their surface area can no longer supply the much larger volume with...
  • Sports Diplomacy

    Sports Diplomacy

    Sports Diplomacy A Timeline Objectives (1) In this presentation, we aim to highlight past and present sports diplomacy events. Sports diplomacy can be defined in many ways, but three main perspectives will be used here: Firstly, the use of sport...
  • Chapter 13 Subcultures - Texas Tech University

    Chapter 13 Subcultures - Texas Tech University

    Subcultures, Microcultures, and Consumer Identity. Consumers' lifestyles are affected by group membership within the society-at-large. Subcultures of age, race/ethnicity, place of residence. Microcultures share a strong identification with an activity or art form. Have own unique set of norms, vocabulary,...
  • Investigation into Significant Anesthesia Adverse Events during the

    Investigation into Significant Anesthesia Adverse Events during the

    Despite the challenges in the POISE trial from 2008, there have been two subsequent studies in 2013 that endorse the assertion that metoprolol has a higher incidence of stroke as compared to Atenolol, Esmolol, Labetalol, and Bisoprolol. In animal models:...
  • Colorado AgriScience Plant Science

    Colorado AgriScience Plant Science

    Colorado AgriScience Plant Science ... Stem Cuttings Vegetative Parts of a Plant Stem Tip Cuttings Normally include the terminal bud Stem 2-4" is used Cut made just below the node Remove lower leaves Apply rooting hormone Insert in media deep...
  • Lecture - McGill CIM

    Lecture - McGill CIM

    COMP 558Lecture 3RGBThurs. Sept. 6, 2018. Cameras. Digital SLR (annual sales ~ 10 million units per year) Smart phone (annual sales: over 1 billion units per year) Image size. 1 megapixel (one million pixels) e.g. "720p" is 1 MP (1280...