Transjugular intrahepatic portosystemic shunt in...

ACTAUNIVERSITATIS

UPSALIENSISUPPSALA

2017

Digital Comprehensive Summaries of Uppsala Dissertationsfrom the Faculty of Medicine 1338

Transjugular intrahepaticportosystemic shunt in thetreatment of symptomatic portalhypertension

KERSTIN ROSENQVIST

ISSN 1651-6206ISBN 978-91-554-9940-2urn:nbn:se:uu:diva-321538

Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, ingång50, Akademsika sjukhuset, Uppsala, Friday, 1 September 2017 at 09:15 for the degree ofDoctor of Philosophy (Faculty of Medicine). The examination will be conducted in English.Faculty examiner: Professor Lars Lönn (Copenhagen University Hospital, Rigshospitalet).

AbstractRosenqvist, K. 2017. Transjugular intrahepatic portosystemic shunt in the treatmentof symptomatic portal hypertension. Digital Comprehensive Summaries of UppsalaDissertations from the Faculty of Medicine 1338. 63 pp. Uppsala: Acta UniversitatisUpsaliensis. ISBN 978-91-554-9940-2.

Portal hypertension (PHT) is a condition with serious complications, such as variceal bleeding,refractory ascites and bowel ischemia. The cause of PHT may be pre-, intra- or post-hepatic.Initial treatment is pressure-reducing drugs and the treatment of acute symptoms.

Ten patients presented with severe abdominal pain and acute portomesenteric venousthrombosis. Their response to systemic anticoagulation was insufficient. Treatment withprimary continuous thrombolysis by a transhepatic or transjugular approach in four patientsresulted in major complications, incomplete recanalization and a 75% survival rate. Treatmentwith repeated transjugular thrombectomy (TT) combined with the creation of a transjugularintrahepatic portosystemic shunt (TIPS) achieved near complete recanalization, promptsymptom relief and 100% survival in five patients treated with this method as the primaryintervention. In one patient, treated with TT and TIPS secondary to surgical thrombectomy andbowel resection, the outcome was fatal.

Nineteen patients with portal vein thrombosis presented with acute or threatening varicealbleeding or refractory ascites. TIPS was feasible in 16 of the 18 patients in whom it wasattempted and symptom relief was achieved in the majority of them.

In 14 patients with Budd-Chiari syndrome, 13 patients were treated with TIPS, four of themafter previous liver vein angioplasty. The 5-year transplantation-free survival rate was 100% inpatients treated with primary TIPS.

In 131 patients with variceal bleeding treated with TIPS, the survival at 12 months in patientswith and without cirrhosis was 70% and 100% respectively and in accordance with previousstudies. A high Child-Pugh score prior to TIPS and severe HE within 12 months after TIPSwas related to an increased mortality. The occurrence of HE after TIPS did not correlate withthe PSG after TIPS. Re-bleeding within 12 months after TIPS occurred in 10 patients and wasassociated with TIPS dysfunction.

In conclusion, endovascular intervention, mainly TIPS, seems to be safe and effective fortreating patients with complications of PHT, regardless of the underlying cause of disease andsite of venous blood flow obstruction. HE may occur more frequently after TIPS than medicaland endoscopic treatment, but is often mild and easily treated. In selected patients with PHT,TIPS may improve survival.

Keywords: Portal hypertension, TIPS, transjugular, portal venous thrombosis, mesentericvenous thrombosis, liver cirrhosis, interventional radiology

Kerstin Rosenqvist, Department of Surgical Sciences, Radiology, Akademiska sjukhuset,Uppsala University, SE-75185 Uppsala, Sweden.

© Kerstin Rosenqvist 2017

ISSN 1651-6206ISBN 978-91-554-9940-2urn:nbn:se:uu:diva-321538 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-321538)

To Anton and Oskar Rosenqvist

Illustrations: Cover: Fredrik Rorsman, Department of Gastroenterology and Hepatology, Uppsala University Hospital, Sweden Page 11: Printed with the kind permission of the Vascular Liver Disease Group www.valdig.eu

List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I Rosenqvist K, Eriksson LG, Rorsman F, Sangfelt P, Nyman R.

Endovascular treatment of acute and chronic portal vein thrombosis in patients with cirrhotic and non-cirrhotic liver. Acta Radiol. 2016 May;57(5):572-9.

II Rosenqvist K, Sheikhi R, Eriksson L-G, Rajani R, Rorsman F, San-felt P, Nyman R. Endovascular treatment of symptomatic Budd-Chiari syndrome – in favour of early TIPS. Eur J Gastroenterol Hepatol. 2016 Jun;28(6):656-60.

III Rosenqvist K, Ebeling Barbier C, Rorsman F, Sangfelt P, Nyman R. Repeated thrombectomy through a transjugular intrahepatic portsystemic shunt. An effective and safe way to treat acute portomes-enteric venous thrombosis. Submitted

IV Rosenqvist K, Sheikhi R, Nyman R, Rorsman F, Sangfelt P, Ebeling Barbier C. Transjugular intrahepatic portosystemic shunt treatment of variceal bleeding in an unselected patient population. Submitted.

Reprints were made with permission from the relevant publisher.

Contents

Contents ....................................................................................................... vii

Introduction ................................................................................................... 11

Background ................................................................................................... 12 Portal hypertension ................................................................................... 12 Liver cirrhosis .......................................................................................... 13 Variceal bleeding ...................................................................................... 14 Portal and mesenteric vein thrombosis ..................................................... 14 Budd-Chiari syndrome ............................................................................. 15 Endovascular interventional radiology ..................................................... 16 TIPS .......................................................................................................... 17 Registry of interventional radiology in portal hypertension ..................... 18

Aims .............................................................................................................. 22 Paper I .................................................................................................. 22 Paper II ................................................................................................ 22 Paper III ............................................................................................... 22 Paper IV ............................................................................................... 22

Materials and methods .................................................................................. 23 Patients and study designs ........................................................................ 23

Paper I .................................................................................................. 23 Paper II ................................................................................................ 24 Paper III ............................................................................................... 24 Paper IV ............................................................................................... 25

Methods of interventional radiology ........................................................ 26 Portal venography ................................................................................ 26 Portal and mesenteric vein angioplasty (paper I) ................................. 26 TIPS ..................................................................................................... 26 Liver vein dilatation and stent for BCS (paper II) ............................... 26 Transhepatic thrombolysis in PVT (paper I) ....................................... 27 Transjugular thrombectomy in PMVT (paper III) ............................... 27 Embolization of the cutaneous transhepatic canal ............................... 27

Ethics ........................................................................................................ 28

Results ........................................................................................................... 29 Paper I ...................................................................................................... 29 Paper II ..................................................................................................... 34 Paper III .................................................................................................... 36 Paper IV ................................................................................................... 39

Discussion ..................................................................................................... 42 Interventional radiology in portal vein thrombosis (PVT) ....................... 42 Chronic portal vein thrombosis ................................................................ 42 Acute portomesenteric venous thrombosis (PVMT) ................................ 43 Budd-Chiari Syndrome ............................................................................ 45 TIPS in variceal bleeding ......................................................................... 46 TIPS dysfunction ...................................................................................... 47 Hepatic encephalopathy ........................................................................... 48 Importance and limitations of the portal pressure gradient ...................... 49 Limitations ............................................................................................... 49 Future work .............................................................................................. 50

Conclusions ................................................................................................... 51 Paper I .................................................................................................. 51 Paper II ................................................................................................ 51 Paper III ............................................................................................... 51 Paper IV ............................................................................................... 51

Acknowledgements ....................................................................................... 53

References ..................................................................................................... 55

Abbreviations

BCS Budd-Chiari syndrome BCS-PI Budd-Chiari syndrome prognostic index CP Child-Pugh CT Computer tomography GAVE Gastric antral vascular ectasia HCC Hepatocellular carcinoma HE Hepatic encephalopathy HVPG Hepatic venous pressure gradient INR International normalized ratio IVC Inferior vena cava MELD Model for end-stage liver disease NAFLD Non-alcoholic fatty liver disease TT Transjugular thrombectomy OLT Orthopic liver transplant PHT Portal hypertension PPG Portal pressure gradient PSC Primary sclerosing cholangitis PSG Portosystemic gradient PTFE Polytetrafluoroethylene PV Portal vein PVT Portal vein thrombosis SMV Superior mesenteric vein TIPS Transjugular intrahepatic portosystemic shunt PMVT Portomesenteric venous thrombosis WHVP Wedged hepatic venous pressure

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Introduction

Portal hypertension (PHT) is a serious condition with complications such as variceal bleeding, refractory ascites and hepatorenal syndrome (1). Recently, treatment strategies for severe PHT have shifted from mainly pharmacologi-cal, with surgery as rescue, to pharmacological combined with endoscopic and methods of interventional radiology (2–5). The presented papers evaluate the outcome of interventional radiology, mainly with the creation of a transjugular intrahepatic portosystemic shunt (TIPS), in patients with symptomatic portal hypertension at Uppsala University Hospital. Papers I and III discuss patients with portal vein thrombosis (PVT) and Paper II discusses patients with Budd-Chiari syndrome (BCS). Paper IV presents the results in patients with variceal bleeding.

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Background

Portal hypertension PHT is defined as an increased difference in the pressure gradient between the portal vein and the hepatic veins. The most common cause of PHT, liver cir-rhosis, impairs the intrahepatic portal blood flow and can be induced by many different entities including abundant alcohol intake, viral infections and auto-immune disease (6). Pre-hepatic obstruction of the portal vein, caused by por-tal vein thrombosis, tumour vein invasion or mechanical obstruction, is less common. Post-hepatic obstruction of hepatic venous outflow (BCS) is a rare cause of PHT.

When the hepatic venous pressure gradient (HVPG) reaches 10 mmHg or more, PHT is considered to be clinical significant (7). In cirrhotic patients gastro–oesophageal varices develop at a gradient of 10–12 mmHg, and at a gradient of >12 mmHg there is a high risk of variceal bleeding (8), associated with a 6-week mortality rate of 10–20% (9). Other consequences of PHT are ascites, hepatic encephalopathy (HE) and jaundice (6). The HVPG represents the pressure difference between the portal vein (PV) and the inferior vena cava (IVC) (10). To avoid the transhepatic puncture re-quired to reach the PV, the preferred method of obtaining the HVPG is to compare the indirect wedged hepatic venous pressure (WHVP) with the pres-sure in the IVC. The WHVP is obtained, via a transjugular access, by cathe-terising a small hepatic vein as far as possible, to occlude the vein before measuring the pressure, which then represents the pressure in the hepatic si-nusoids (10). The WHVP has been shown to accurately reflect the portal pres-sure in alcoholic and hepatitis C virus cirrhosis (11) but may underestimate the pressure in the PV in pre-hepatic induced PHT (12).

In the papers presented in the thesis, the true PV pressure has been measured and the gradient obtained by comparison with the pressure in the right atrium, namely the portosystemic gradient (PSG). While this is a frequently used method, the pressure in the right atrium may differ slightly from the pressure in the IVC, and the PSG and the HVPG cannot be considered completely equal (10). Recently, it has been reported that general anaesthesia can affect the gra-dient between the PV and the IVC, the portal pressure gradient (PPG), and

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that a repeated PPG in the same patients when awake is slightly higher (13). Hence, several factors affect the measurement and the different techniques used make it difficult to compare results related to the pressure gradient from different studies.

Liver cirrhosis Liver cirrhosis is the irreversible final stage of chronic liver disease. Even though liver cirrhosis is both common and associated with high mortality the pathophysiology is not fully understood (14). The major causes are abundant alcohol intake, chronic hepatitis B and C and non-alcoholic fatty liver disease (NAFLD) (1). A daily intake of 30-80 gram of alcohol (2-5 glasses of wine) is associated with a risk of developing liver cirrhosis (15). In patients with alcohol-induced liver cirrhosis the prognosis is poor if abundant alcohol intake is continued, with a five year survival rate of around 35% (15). In liver cirrho-sis due to hepatitis C infection the five-year survival is 85-91% and if the cir-rhosis is decompensated it is 51% (16). The prevalence of NAFLD has in-creased in recent years and NAFLD is now the most common cause of chronic liver disease in the US (17). The prevalence of NAFLD worldwide is around 20% and it is considered the hepatic manifestation of metabolic syndrome (18). When liver disease progresses, blood flow in the intrahepatic portal veins is impaired, due to both structural (fibrosis and regenerative nodules) and dy-namic (increased hepatic vascular tone) changes (19). With the increased por-tal pressure, compensated (asymptomatic) liver cirrhosis turns into decompen-sated cirrhosis (with symptoms of portal hypertension) (6). Patients with de-compensated liver cirrhosis have an expected survival of about two years (6).

To predict mortality, several prognostic models have been suggested; the most widely used are the Child-Pugh (CP) classification (20) and the model for end-stage liver disease (MELD) score (21). In the CP classification, the level of bilirubin, albumin, international normalized ratio (INR), ascites and HE are converted into points and the sum of the five components form the total score. A higher score correlates to more severe liver disease. A score of 5-6 points is considered CP class A, 7-9 points CP class B and 10-15 points CP class C. The prognosis for patients in CP class C is poor with a one year mortality of around 50% (22). Even though different prognostic models have proved better in selected patients, the CP score is still a robust and dependable method for predicting mortality in patients with liver cirrhosis (23). The MELD score is based on the three variables of bilirubin, creatinine and INR and was initially developed to estimate survival prognosis after the creation of a transjugular intrahepatic portosystemic shunt (TIPS) (21). Since then, it has proven to be a

14

dependable prognostic tool for estimating survival in end stage liver disease (24). The primary treatment in cirrhosis is of the underlying disease, which is alco-hol abstinence, anti-viral treatment and metabolic control. Complications of decompensated liver cirrhosis are treated accordingly. In patients with refrac-tory ascites, diuretics are the first line treatment and non-selective beta block-ers may be used with careful monitoring, with TIPS recommended as second-ary prophylaxis (7). The treatment of variceal bleeding is discussed in detail below. Occurrence of hepatocellular carcinoma (HCC) is strongly associated with liver cirrhosis, mainly with cirrhosis due to chronic hepatitis C and B (25). HCC is the most common malignant primary liver tumour and the third leading cause of all cancer-related deaths worldwide (25).

Variceal bleeding As the pressure in the portal vein system increases in advanced PHT, pre-ex-isting portosystemic collaterals dilate into variceal veins (26). In cirrhosis, the most common sites are oesophageal and gastric, but variceal veins can develop at any site along the gastrointestinal tract (27). Bleeding occurs in about one fourth of patients with cirrhosis and variceal veins, and the risk of bleeding is associated with the size of the varices, degree of liver dysfunction, and pres-ence of red wale marks (red spots on the varices, visible at endoscopy) (28). The mortality rate six weeks after variceal bleeding has been estimated at around 10-20% (7). First line treatment for an acute episode of variceal bleeding is medical (vas-oactive drugs and antibiotics) in combination with the endoscopic band liga-tion of varices (7). In patients where the initial treatment fails, a TIPS should be considered (7). Early TIPS, i.e. performed within 72 hours of the onset of the primary bleeding episode, has recently shown to improve survival in pa-tients at high risk of treatment failure (29,30) and this has been incorporated into the current guidelines (7,31). More than 130 patients with variceal bleed-ing have been treated with TIPS at Uppsala University Hospital since 2002.

Portal and mesenteric vein thrombosis The PV originates at the confluence of the superior mesenteric vein (SMV) and the splenic vein, and accounts for the main blood supply to the liver. Ob-struction of the PV leads to PHT and the formation of portosystemic collat-erals in gastric, oesophageal, duodenal and jejune veins. Chronic obstruction

15

leads to fibrotic transformation of the PV with multiple small surrounding ve-nous collateral veins, a portal cavernoma (32). The national prevalence of PVT is reported to be 1% (33) but can, in patients with cirrhosis, be as high as 25% (34). The aetiology for PVT is often local, as liver cirrhosis, hepatobiliary malignancies, infections and inflammatory conditions; it is less commonly systemic, as congenital and acquired myeloproliferative disorders (33).

Patients with PVT may be asymptomatic if the thrombus is partial and the onset gradual, but acute PVT with the involvement of mesenteric veins is rarely asymptomatic (35–38). How the disease develops depend on the exten-sion of PVT, whether it is occlusive or partial and the degree of recanalization (36,39–43). Spontaneous recanalization is rare (44,45) and systemic anticoag-ulation is the first line of treatment (7). Further treatment is based on the symp-toms and the calculated risk of complications, but symptomatic patients with insufficient response to medical treatment, or who are unsuitable for antico-agulation, often need invasive intervention (45,46). PVT has, until recently, been considered a contraindication for TIPS. However, an increasing number of studies show that TIPS is a valuable and safe intervention in both cirrhotic and non-cirrhotic patients with PVT (41,47–52).

Acute extensive portomesenteric venous thrombosis (PMVT) can be a life-threatening condition due to the risk of developing bowel ischemia in the acute setting (38,42,53). The risk of developing complications is higher if PMVT recanalization is not achieved (36) and the mortality rate is 20-50% (54,55). PMVT is a rare condition (56) which makes it difficult to collect larger series for study. With systemic anticoagulation as the primary treatment, recanaliza-tion is achieved in less than half of the patients (45,46). Reports of invasive treatment are often in very limited study populations (57–61). Thrombolysis by direct (transhepatic and transplenic) or indirect (via the superior mesenteric artery) routes may be associated with fatal complications (35,59,62). Transjugular thrombectomy (TT) in combination with the creation of a TIPS seems very effective for recanalization and symptom relief (57,58,61,63), but there are only a few reported cases and the method needs to be further inves-tigated.

Budd-Chiari syndrome BCS is defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the junction of the IVC and the right atrium, regardless of the cause (64). It is a rare disease with local variation in aetiology. In the western hemisphere, hepatic vein obstruction is the predominant cause while obstruction of the IVC is more common in the eastern hemisphere (47). In

16

Sweden, the incidence is 0.8 per million per year and the most common aeti-ology is myeloproliferative disorder (65). Clinical presentation may vary from asymptomatic to liver failure. Common symptoms are abdominal pain, hepa-tomegaly and ascites (66). Untreated, the prognosis for symptomatic BCS is poor with an estimated 3-year survival of only 10% (67).

For many years, the treatment of BCS has been mainly medical, with antico-agulation, and orthopic liver transplantation (OLT) as a rescue treatment. The current treatment recommendations are to follow a step-wise approach includ-ing anticoagulation, angioplasty/thrombolysis, TIPS and OLT. TIPS should be attempted in patients with insufficient response to anticoagulation where angioplasty of liver veins is not feasible, but not in patients with a high risk of TIPS failure according to the Budd-Chiari syndrome prognostic index (BCS-PI) (7). However, in a multi-centre study of BCS the intervention-free 5-year survival was only 29% (68) and in a previous national study in which patients were mainly treated medically the 1- and 5-year transplantation-free survival rates were 47% and 28%, respectively (65). The survival rates are higher in studies of patients with BCS treated with interventional radiology methods, 78-87% (69–71). It has been suggested that earlier intervention with the crea-tion of a TIPS may lead to improved results and possibly prevent further is-chemic liver damage (72).

Endovascular interventional radiology Angiography, the visualization of blood vessels, is now a standard procedure in most radiological departments. With magnetic resonance imaging (MRI) or computer tomography (CT), blood vessels can be detected even without con-trast media. For intervention, however, the blood vessel must still be reached by surgery or from the inside by endovascular techniques. It is almost 90 years since the development of clinical arteriography in the late 1920s. The initial technique required a large needle for the transcutaneous puncture to allow a catheter to be threaded through the needle into the vessel. A contrast medium was then injected through the catheter and vessels visual-ized with plain radiography. The use of large needles limited the method to large vessels and led to a high risk of bleeding (73). In 1953, the Swedish radiologist Sven-Ivan Seldinger introduced a new technique in which a thin metal wire was inserted through the needle, the needle removed and a catheter threaded onto the wire and inserted into the artery (74). This method, which allowed smaller needles and could be used in almost any vessel, is known as the Seldinger Technique and is used worldwide.

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The use of the Seldinger Technique and the development of flexible catheters, guide wires, stents, stent grafts and embolization material, means that a major part of vascular surgery is now performed using the endovascular approach. Small catheters also allow the injection of oncologic agents into selected tu-mour-feeding vessels. There is currently rapid development of endovascular treatment in the field of oncology.

TIPS The aim of the creation of a TIPS is to establish an efficient outflow from the portal vein and thus reduce PHT. An example is provided in Fig.1. The first report of human TIPS procedures was presented in 1983 (75) and the use of stents to keep the shunt patent was introduced in 1988 (76). In the early years, the frequency of procedure-related complications and shunt dysfunction was high, but as reports showed lower morbidity and mortality after TIPS than with the previous surgical shunts the method started to spread in the early 1990s (77). The first TIPS procedure was performed in Uppsala in 1993, but it would take nine years until the procedure was repeated.

Fig.1. Venography moments after a transjugular intrahepatic portosystemic shunt (TIPS) has been inserted. The blood from the main portal vein passes through the TIPS stent (black arrow) into the hepatic veins.

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As knowledge and technical skills have improved, TIPS has proven to be a very safe method with low procedure-related mortality (78). The rate of shunt patency improved dramatically with the introduction of stents covered with polytetrafluoroethylene (PTFE) (79,80) and the number of TIPS procedures increased rapidly. In the last ten years, about 260 TIPS procedures have been performed in Uppsala alone. The outcome after TIPS depends mainly on the aetiology of PHT (78). TIPS may improve survival and symptom-relief in se-lected patients with liver cirrhosis and variceal bleeding (30) and refractory ascites (81,82), but the effects in hepatorenal and the hepatopulmonary syn-dromes are less well defined (78). In patients with PVT and BCS, TIPS is not only feasible, it may improve long-term survival (35,79,83).

HE is a frequent complication in liver cirrhosis and a significant predictor of death (6). The incidence of HE is correlated to the severity of liver deficiency. However, the incidence of HE after TIPS is higher than in patients with liver cirrhosis in general (84) and can be as high as 51% (82). As HE is associated with the cause, as well as the treatment, of PHT in patients with liver cirrhosis it is hard to identify risk factors, but a high MELD score, a low PSG after TIPS, a big reduction in PSG, shunt stenosis and a previous history of HE have all been suggested as being associated with a higher risk of HE after TIPS (85–87).

Registry of interventional radiology in portal hypertension Following ethical approval in 2012, patients with PHT treated with interven-tional radiology at Uppsala University Hospital were registered in a database specifically created for this purpose. The aim was to gather information about the clinical status prior to, and after, intervention, as well as the type of inter-vention, complications and number of re-interventions. The registry was set up on the hospital’s internal server and secured with individual passwords ac-quired only by physicians in the hepatology department and the radiologists who performed the procedures. Patients were informed of the database and possible inclusion in studies, retrospectively if they had already been treated.

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Fig. 2 Number of interventional radiography procedures in the treatment of portal hypertension performed per year at Uppsala University Hospital.

To date, the database includes about 325 patients, aged 16-78, more than two-thirds males. The number of patients treated each year is presented in Fig. 2. The methods included in the database are transjugular liver biopsy, PSG meas-urement, recanalization and angioplasty of veins (liver veins, PV and SMV), TIPS, dilatation of shunt stenosis, reduction of shunt diameter and emboliza-tion of collateral veins. Indications for interventions are presented in Fig. 3 and aetiologies of PHT are presented in Fig. 4.

0

10

20

30

40

50

60

2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

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Fig. 3. Indications for intervention in patients in the registry of portal hypertension. Other includes portal vein thrombosis, Budd-Chiari syndrome and pre-surgical in-vestigations.

Ascites34%

Hydrothorax2%

Oesofageal variceal bleeding

37%

Gastric variceal bleeding

10%

Stomal variceal bleeding

2%

Gastrointestinal ischemia

2%

Other13%

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Fig. 4. Aetiology of portal hypertension (PHT) in patients in the registry of portal hypertension. Other includes primarily inflammatory bowel disease. NAFLD=non-alcoholic fatty liver disease.

Alcohol cirrhosis

37%

Viral cirrhosis14%

NAFLD10%

Cirrhosis of other cause

11%

Portal vein thrombosis

9%

Budd-Chiari syndrome

6%

Other13%

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Aims

The general aim was to evaluate the procedure-related safety of interventional radiology in patients with symptomatic PHT by: reporting the frequency of technical success and re-interventions; to evaluate the long-term effects in terms of disease progression, survival rate, post-procedure complications, and the recurrence of symptoms; to roughly compare results in Uppsala with in-ternational results; and to find areas for improvement in the techniques used.

Paper I To report the results of endovascular treatment of portal venous thrombosis at Uppsala University Hospital.

Paper II To assess the safety and efficiency of endovascular treatment of symptomatic patients with BCS and to compare mortality with symptomatic BCS patients in the same region treated with only sporadic endovascular techniques.

Paper III To retrospectively evaluate the efficacy and safety of repeated TT through a TIPS, created in the same session, in patients with acute PMVT.

Paper IV To evaluate the safety and efficacy of TIPS in patients with portal hyperten-sion and variceal bleeding in a clinical setting. End-points were re-bleeding, survival, TIPS-dysfunction and adverse events.

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Materials and methods

Patients and study designs Paper I A retrospective review of the log of radiology interventions from January 2002 to February 2013 identified a total of 21 patients (15 men, 6 women; mean age 53 years; range 20–75 years) with PVT treated with endovascular procedures. Clinical data were collected from the medical records. In patients with cirrhosis, liver function was assessed using the CP score (20). Diagnostic CT scans were reviewed to estimate the extent and onset of thrombosis. Acute PVT was defined by the absence of collaterals and the rapid onset of ab-dominal pain, intestinal ischemia, and/or infarction within 14 days of the di-agnosis. Chronic PVT was defined as a decrease in intra-luminal density in the portal vein, a replacement of the original main portal vein (MPV) with a fibrotic cord, or a portal cavernoma. Threatening variceal bleeding was de-fined as very large varicose veins combined with previous episodes of gastro-intestinal bleeding, thrombocytopenia, and/or need of surgery. Patients with variceal bleeding were treated with current standard methods, such as band ligation, vasoactive drugs, and antibiotics prior to intervention. The patients were selected for intervention because of an insufficient response to conservative treatment. The aim of intervention was to reduce portal hyper-tension by the creation of a TIPS and/or recanalization of the portal vein. In-formed consent was obtained from the patients included in the study.

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Paper II A retrospective review of the intervention log January 2003 to May 2015 iden-tified a total of 14 patients with BCS, six men and eight women, who were treated with interventional radiology. Clinical data, including aetiology, time from onset, presenting symptoms, method of intervention, PSG, complica-tions, recurrence of symptoms, re-interventions, occurrence of OLT, clinical status at latest follow-up and survival, were collected from medical records. The degree of liver function was assessed and followed using the CP score (20). Prognostic indices before TIPS were calculated: the Rotterdam score (1.27 × encephalopathy + 1.04 × ascites- + 0.72 × INR + 0.004 × bilirubin) (88) and the BCS-TIPS PI score [age (years)] × 0.08 + bilirubin (mg/dl) × 0.16 + INR × 0.63 (69). Dysfunction of TIPS was defined as the need for revision. The aim of the intervention was to reduce the PHT by recanalizing an ob-structed liver vein or by creating a shunt between the PV and the IVC.

Paper III Between September 2014 and May 2016, six consecutive patients (all men, aged 39 to 51) with acute extensive PMVT were treated with repeated TT through a TIPS created in the same session. Data was collected retrospectively from medical records and from the radiology information system. CT scans and venograms were reviewed. Clinical baseline information is presented in Table 1. All 6 patients had acute onset of severe abdominal pain (≤ 2 weeks). The CT scans demonstrated extensive PMVT and mesenteric stranding and/or bowel wall oedema. The venograms verified extensive thrombosis of the SMV including several branches and partial or complete thrombosis of the portal vein. The splenic vein was complete or partially occluded in three patients. All patients received systemic anticoagulation therapy (heparin or low molec-ular weight heparin) immediately at diagnosis, but without symptom relief.

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Table 1. Clinical data prior to transjugular thrombectomy in combination with crea-tion of a transjugular intrahepatic portosystemic shunt.

Pt

No

Age (in

years)

/sex

Aetiology Indication for intervention Time from

symptoms

to diagnosis

Time from

diagnosis to

transjugular

throm-

bectomy

1 50/M Unknown Worsening abdominal pain

despite anticoagulation

7 days 1 day

2 51/M Heterozygote

mutation Fac-

tor V

Persistent abdominal pain


4 3 days

3 49/M ITP, liver cir-

rhosis



14 days 1 day

4 48/M Unknown Persistent abdominal pain


11 days 2 days

5

58/M Cirrhosis, pre-

vious liver-

transplantation


despite anticoagulation +

kidney failure

4 days 2 days

6 39/M AT III defi-

ciency

Worsening abdominal pain

despite surgical throm-

bectomy and resection of

necrotic bowel

14 days 4 days

Pt no= patient number, M=male, ITP=Idiopathic thrombocytopenic purpura, AT III deficiency=Antithrombin III deficiency,

Paper IV All patients with variceal bleeding treated with TIPS January 2002-May 2016 were reviewed retrospectively using the local PHT database. One patient was lost in follow-up, the remaining 131 patients were included. 116 patients had liver cirrhosis. In patients with cirrhosis, the degree of liver disease was as-sessed according to CP score (20) and MELD score (89). End-points were re-bleeding, survival, TIPS dysfunction and adverse events. Re-bleeding was de-fined as hematemesis or melena together with transfusion of two or more units of blood. TIPS dysfunction was defined as stenosis or occlusion of the TIPS. HE was considered mild when it subdued with treatment of the percipient fac-tor and/or with laxatives, and severe when recurrent or permanent (84). Stat-View 5.0.1 (SAS Institute, Cary, North Carolina) was used for statistical anal-yses. The significance level was set at 0.05 in all analyses.

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Methods of interventional radiology Portal venography Access to a right sided portal venous branch was achieved by transcutaneous and transhepatic puncture with a 0.9 mm needle, guided by ultrasound. A GOLD® introducer set (Cook Medical, Bloomington, IN, USA) with a 0.46 mm (0.018 inch) guide wire and a 1.67 mm (5 French) catheter was placed in the PV or the SMV. Venography was performed with iodinated contrast media (240 mgI/ml).

Portal and mesenteric vein angioplasty (paper I) A 0.89 mm (0.035 inch) guide wire was used to pass through PV and SMV thrombosis and concurrent stenosis. The affected parts of the PV and SMV were dilated with 8–10 mm balloons and, when needed, self-expanding bare metal stents (LUMINEXX® Bard Peripheral Vascular, Inc, TempeAZ, USA) were used to keep the lumen patent.

TIPS A 0.46 mm guide wire was left in an intrahepatic portal venous branch to vis-ualize the portal vein during the TIPS procedure. A TIPS set (Cook Medical, Bloomington, IN, USA) was used for the rest of the procedure. The 3.3 mm (10 French) sheath was inserted through the right jugular vein and positioned in the right atrium for pressure measurements, as the PSG was obtained by comparing the pressures of the right atrium and the portal vein. When possible, a liver vein was catheterized (possible in all patients except four with BCS) and the shunt was created by aiming the TIPS needle towards the guide wire in a portal branch. When no liver vein could be re-canalized, the shunt was created between the IVC and an intrahepatic portal branch. The parenchymal canal was dilated and PTFE-covered stents (GORE® VIATORR® Tips En-doprothesis Gore Medical, W. L. Gore & Associates, Inc, Flagstaff AZ, USA) were inserted to keep the shunt open. Stent diameter was 10 mm and stents were dilated to 8-10 mm. Blood flow through the shunt was confirmed using portal venography. The TIPS procedures were performed under general an-aesthesia.

Liver vein dilatation and stent for BCS (paper II) Liver vein venography was performed using a transjugular approach. When possible, a liver vein was re-canalized and dilated with balloons. If needed, stents were used to keep the lumen patent. Haemostasis of the jugular puncture site was obtained by manual compression.

27

Transhepatic thrombolysis in PVT (paper I) In extensive acute PVT, an infusion catheter (Uni-fuse™, AngioDynamics, Latham NY, USA) was positioned through the thrombus, with the distal end in open lumen in the MPV or SMV. A bolus dose of 2-8 mg of Alteplase (Actilyse® Boehringer Ingelheim, Ingelheim am Rhein, Germany), was in-jected and followed by infusion with 1-2 mg per hour until the next venogra-phy. In addition to medical thrombolysis, over-the-wire mechanical throm-bectomy catheters were used in two patients, Rotarex (Straub Medical, Wangs, Switzerland) in one and Aspirex (Straub Medical, Wangs, Switzer-land) in one. Thrombolysis was discontinued when no further recanalization was achieved or if major complications with haemorrhaging occurred.

Transjugular thrombectomy in PMVT (paper III) After creation of a TIPS, TT was performed. A pharmacomechanical throm-bectomy system (AngioJetTM Boston Scientific Corporation, Quinzy, MA, USA) with active aspiration and pulse delivery of 5-22 mg Alteplase (Acti-lyse®) was used in four of the patients. Residual thrombotic material was re-moved with a rotational thrombectomy device system (Cleaner 15, Argon medical device, Plano, USA) in all patients. TT, with or without pulse deliv-ered Alteplase, was performed until recanalization was achieved in the main venous branches. The MPV and SMV were dilated with 8-10 mm balloons to compress remaining thrombi and in one case a 10 mm bare metal stent (Protege™ EverFlex+™ Self-Expanding stent, Medtronics, Minneapolis, MN) was positioned in the SMV to maintain an open lumen. Interventional procedures were repeated under local anaesthesia 0-2 times within 24-72 hours, to maximize the clearance of thrombotic material and blood flow through the MPV, SMV and TIPS. Between the procedures there was a continuous infusion of heparin in four patients. To facilitate the control venograms, a central venous catheter was left in the jugular vein in four pa-tients.

Embolization of the cutaneous transhepatic canal Embolization with NESTER® embolization coils (Cook Medical, Blooming-ton, IN, USA) ended the procedures. A single dose of antibiotic (cefotaxim) was administered intravenously before interventions.

28

Ethics Informed consent was collected and the retrospective study of logs and charts was approved by the ethical committee on 7 November 2012 (Dnr2012/134) and 27 July 2016 (Dnr2016/288).

29

Results

Paper I Eleven patients had liver cirrhosis; one of them also had a thrombogenic dis-order. In the 10 non-cirrhotic patients, the underlying cause of the PVT was thrombogenic (n=7), post-inflammatory (n=1), post-surgical (n=1) or un-known (n=1). The use of systemic anticoagulation after diagnosis varied due to different symptoms, thrombophilic states and the referring hospital. Four non-cirrhotic patients with extensive PVT and SMV involvement and symptoms of bowel ischemia were treated with continuous local thrombolysis, three transhepatic and one transjugular through a TIPS created in the same session. Interventions and outcome in these patients is presented in table 2. Partial recanalization was achieved but thrombolysis had to be discontinued prematurely in three patients due to severe haemorrhages that required blood transfusion; re-occlusion occurred early in all patients. Despite renewed thrombolysis combined with TIPS in two patients, the recanalization and TIPS remained patent in only one of the four patients. Apart from haemorrhages, complications were septicaemia in two patients and stenosis of the jejunum that required surgery in one patient. Three of the patients recovered and one patient died six weeks after intervention due to progressive liver failure.

30

Table 2. Venous involvement, interventions and outcome in the four non-cirrhotic patients with acute PMVT treated with continuous local thrombolysis.

No=patient number, PV=portal vein, SMV=superior mesenteric vein, IMV= inferior mesenteric vein, TIPS=transjugular intrahepatic portosystemic shunt, IHPV=intrahe-patic portal vein, SV=splenic vein

No

Ve-nous in-volve-ment

Interven-tion

Re-canali-zation

Com-plica-tions

Re-inter-vention

TIPS and recanali-zation pa-tency

Clinical status at endpoint

1 PV, SMV, IMV

TIPS and continuous local thrombo-lysis for 42 hours

Partial in MPV, SMV and IMV, none in IHPV

Hema-toma, sepsis

None Occlusion Dead (6 weeks after interven-tion)

2 PV, SMV, SV

Transhepatic continuous local thrombo-lysis for 48 hours

Partial in MPV and SMV, com-plete in SV

Infec-tion

TIPS and continu-ous thrombo-lysis for 72 hours, TIPS dila-tation

Patent No recurrent symptoms

3 PV, SMV, SV


Partial in PV, SMV and SV

Hemo-thorax

None Occlusion No recurrent symptoms

4 PV, SMV, SV


Partial in PV and SMV, none in SV

Hema-toma x 2

Coiling of hepatic artery x 2, TIPS and con-tinuous thrombo-lysis for 72 hours

Occlusion No recurrent symptoms

31

Fig. 5. Non-cirrhotic patient with Waldenström’s macroglobulinemia, chronic portal vein thrombosis and recurrent variceal bleeding. CT (a) showed cavernous transfor-mation of the main portal vein (MPV) (white arrow) and classic signs of portal hy-pertension with large collateral veins (black arrow), ascites (white arrowheads), dif-fuse mesenteric stranding and splenomegaly (*). A portal venogram (b) confirmed the finding of a cavernous MPV (white arrow). Venogram (c) after partial recanali-zation and an established connection between liver vein and the portal vein showed reversed blood flow into large collaterals (black arrow). Venogram (d) after stent in-sertion showed good flow through the transjugular intrahepatic portosystemic shunt (blank arrow) and reduced flow into collateral veins (black arrow).

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Six non-cirrhotic patients presented with acute/threatening variceal bleeding and chronic PVT (table 3). In three of them, the recanalization of the MPV and TIPS was successful and PSG was normalized after intervention. An ex-ample is demonstrated in Fig 5. The TIPS stayed patent in these three patients, although one of them had variceal re-bleeding and transient episodes of HE. In one of the six patients, complete recanalization of the MPV was achieved with PTA and a stent, but the PV re-occluded and blood flow could not be restored. Recanalization failed in the last two patients. All these six patients were free of symptoms at follow-up. Table 3. Indication and outcome in six non-cirrhotic patients with chronic portal vein thrombosis

No

Indication Inter- vention

Compli-cations

Reinter vention

TIPS and re-canalization patency

Re-bleed ing

5 Large varices.

previous bleed-ing

TIPS HE TIPS dila-tation

Patent Yes

6 Acute variceal bleeding

Portal venog-raphy

No Not appli-cable

Not applicable No

7 Large varices pre surgery

TIPS No Patent No

8 Large varices and previous bleeding

Portal venog-raphy

No Not appli-cable

Not applicable No

9 Large varices, thrombocyto-penia

Recanaliza-tion, portal PTA and stent

No Recanali-zation

Occlusion No

10 Previous vari-ceal bleeding

Recanaliza-tion, TIPS

No No Patent No

No=patient number, TIPS=transjugular intrahepatic portosystemic shunt

The eleven cirrhotic patients presented with acute/threatening variceal bleed-ing (n=10) or refractory ascites (n=1). The clinical presentation, PVT exten-sion, interventions and outcome are presented in table 4. Recanalization of the MPV and primarily successful TIPS were achieved in all. PSG was nor-malized post-intervention in the seven patients in whom the gradient was ob-tained. Three patients had variceal re-bleeding: one due to TIPS occlusion; one patient due to progressive liver failure; and one patient due to gastric an-tral vascular ectasia (GAVE). Five patients had re-interventions. In eight of the 11 patients, the TIPS was patent at the 12-month follow-up or until death. Two patients (with patent shunts) had a liver transplant. Three of the patients with a patent shunt died. The survival rate in patients with liver cirrhosis was 73% at 12 months and all five deaths during follow-up were due to progressive liver failure.

33

Table 4. Clinical presentation, interventions, and outcome in the 11 patients with liver cirrhosis. No = patient number, A = acute, C = chronic, SMV = Superior mes-enteric vein, PV=portal vein, TIPS=transjugular intrahepatic portosystemic shunt, HE=hepatic encephalopathy, GAVE= gastric antral vascular ectasia.

No

Onset

Indica-tion

SMV in-volvement

Interven-tion in addition to re-canaliza-tion of the MPV

Compli-cations

Re-inter-vention

TIPS pa-tency

Re-bleed-ing/death

11 A Large varices, thrombo-cytopenia

No TIPS Mild HE No Yes No/No

12 A Acute variceal bleeding

No TIPS No No Yes No/No

13 C Acute variceal bleeding

No TIPS Occult hema-toma

No Yes No/Yes


Yes Portal PTA

No TIPS No No/No

15 C Refrac-tory asci-tes

Yes TIPS Sepsis, mild HE

No No No/Yes


No TIPS, por-tal stent

Cutane-ous in-fection, mild HE

Thrombo-lysis and TIPS dila-tation

No No/Yes



Mild HE No Yes Yes/yes


No TIPS

Liver capsule hema-toma

Emboliza-tion of col-laterals

Yes No/Yes

19 C Acute variceal bleeding GAVE

Yes TIPS Portal stent

Pulmo-nary em-bolism

Recanaliza-tion, TIPS dilatation, emboliza-tion of col-laterals

Yes Yes/No


No Trans-plenic TIPS

No Recanaliza-tion

Yes Yes /No

21 C Large varices, previous liver transplant


No No Yes No/No

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Paper II The time from symptom to diagnosis of BCS varied from one day to three months. The median time from diagnosis to intervention was one month, but varied from one day to 8½ years. Indications for the primary intervention were recurrent ascites with insufficient response to medical treatment with diuretic drugs and anticoagulation. The five patients treated in 2003 to 2008 had a liver vein angioplasty as the primary intervention, and the nine patients treated in 2009 to 2015 had TIPS as the primary intervention. In total, 6/14 patients had some sort of re-inter-vention. The 1-, 3- and 5-year transplantation-free survival was 100%, 100% and 93%, respectively. One patient died due to liver failure, 12 years after the primary intervention and 8 months after TIPS. The median follow-up time from primary intervention was 4 years.

Overall results of TIPS In total, 13 patients had TIPS, all with technical success. The primary TIPS patency rate was 85% at 1 year and 67% at 2 years. The rate of TIPS dysfunc-tion was lower than expected, as the risk of TIPS failure according to BCS-TIPS PI was high (>7 points) in 12 patients and low (<7 points) in one patient. All four patients with TIPS dysfunction had stenosis in the distal end of the stent and they all had stents that did not fully extend to the IVC. De novo episodes of HE occurred in three patients. Risk of death or OLT according to the Rotterdam score was intermediate or high in ten patients, but only one patient died and one patient had an OLT. The median follow-up time for TIPS procedures was 3 years. Results for each patient are presented in Table 5. Results of primary TIPS Nine patients had TIPS as the primary intervention. The only immediate com-plication was transient liver ischemia in one patient. Late complications were de novo episodes of HE in three patients and the recurrence of ascites in three patients, associated with TIPS occlusion in two. Primary patency rates at 3 months, 1 and 2 years were 100%, 83% and 67%, respectively. The 1-, 3- and 5-year transplantation-free survival rate was 100%.

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Table 5. Results of transjugular intrahepatic portosystemic shunt (TIPS) in patients with Budd-Chiari syndrome.

ID Previous Angio-plasty

BCS-PI >7

TIPS-dys-function

Ascites

GI-bleed-ing

De novo HE

Follow-up/end-point, in months

1 Yes x 2 Yes No No No No 33 2 Yes x ? Yes No No No No 35 3 Yes x 1 Yes Yes x 3 Yes* Yes* No 45 OLT 4 Yes x 9 Yes Yes x 1 Yes* No No 8 Dead 5 No No No Yes No No 55 6 No Yes No No No Yes 79 7 No Yes Yes x 1 Yes* No No 29 8 No Yes No No No Yes 47 9 No Yes Yes x 2 Yes No Yes 70 10 No Yes No No No No 38 11 No Yes No No No No 26 12 No Yes No No No No 7 13 No Yes No No No No 48

ID=patient study ID, BCS-PI=Budd-Chiari syndrome prognostic index, * at TIPS dysfunction, GI = gastro-intestinal, HE = hepatic encephalopathy, OLT = orthotopic liver transplant, ?=of unknown number.

Results of liver vein angioplasty/stent Five patients had liver vein angioplasty/stenting as the primary intervention. Angioplasty was the only intervention in one of the patients, with no recurrent symptoms. In another patient, the liver vein re-occluded within one week of stent angioplasty and, after a TIPS procedure and three episodes of TIPS dys-function, the patient eventually had an OLT. The third patient had had liver vein dilatation of an unknown number and surgical resection of thrombotic liver veins at another hospital nine years previously and was referred to our hospital with progressing liver failure. A TIPS procedure was performed and the patient has now remained asymptomatic for almost three years. The fourth and fifth patients were treated in the acute setting with angioplasty and stents. Both experienced repeated dysfunction and had multiple re-interventions be-fore receiving TIPS several years after the primary intervention. One of them had occlusion of the TIPS and died six weeks later. This patient had severe liver disease with cirrhosis and HE prior to TIPS and was one of the two pa-tients with a high risk of death according to the Rotterdam score.

36

Paper III Patients were treated with TT combined with TIPS as primary intervention (n=5) or secondary to surgical thrombectomy and bowel resection (n=1). TT was repeated 0-2 times within 3-14 days. Blood flow was restored in the MPV and the SMV in all six patients. Recanalization of the MPV and the SMV were complete in the patients who had TT and TIPS as the primary intervention, and it was partial in the patient who had had previous surgical treatment. An example is displayed in Fig. 6. Main procedure-related data and outcomes are presented in table 6.

In one patient with primary TT, extensive re-thrombosis and occlusion of the TIPS occurred within 36 hours. Only partial recanalization was achieved with repeated mechanical thrombolysis. Alteplase was thus infused through an in-dwelling catheter in the SMV and MPV. After 24 hours of Alteplase infusion recanalization was complete, and it persisted at second-look after 48 hours.

The patient who had had a surgical thrombectomy and bowel resection prior to TT and TIPS never recovered. Even though blood flow was restored after repeated TT, bowel necrosis extended. Further surgery and bowel resection were performed, but the patient died of multi-organ failure eight months after admittance.

Three of the four patients treated with Alteplase had transient episodes of hae-maturia between interventions. Four of the five patients with primary TT and TIPS improved promptly and could be discharged within two weeks of admis-sion. The fifth patient suffered from persistent mild abdominal pain for two weeks and was hospitalized for seven weeks due to recurrent septicaemia orig-inating in the urinary tract. To prevent re-thrombosis, all patients were pre-scribed systemic anticoagulation which was continued for at least six months. Follow-up was 8-23 months. The two patients with liver cirrhosis had one episode each of transient HE, at 1 and at 4 months after the TIPS insertion respectively. HE was concurrent with obstipation in both patients and it was successfully treated with laxatives. None of the surviving patients experi-enced any PMVT relapse and all were free of symptoms.

37

Fig. 6. Coronal computed tomography image showing acute extensive portomesen-teric vein thrombosis (PMVT) with bowel wall oedema in a 48-year-old man (A) and transhepatic portal venogram showing PMVT prior to (B) and restored blood flow after (C) mechanical transjugular thrombolysis in combination with the estab-lishment of a transjugular portosystemic shunt in the same patient.

38

Table 6. Interventional details and outcome of transjugular thrombectomy (TT) through a transjugular intrahepatic portosystemic shunt (TIPS) created in the same session.

No

Admin-istration of Acti-lyse

No of re-in-terven-tions

Restored blood flow in the MPV and the SMV

Complications In-hos-pital time

Dead

1 None 1 Yes None 12 days No 2 At pri-

mary, and at the two repeated, interven-tions

2 Yes Transient hematu-ria

11 days

No

3 At pri-mary in-tervention

1 Yes Transient hematu-ria, transient en-cephalopathy

5 days No

4 At pri-mary in-tervention + delayed continu-ous infu-sion

2 Yes Transient hematu-ria

10 days No

5 At pri-mary in-tervention

0 Yes DVT, transient encephalopathy

7 weeks No

6 None 2

Yes Not related to TIPS or TT

8 months Yes

No=patient number, MPV=main portal vein, SMV=superior mesenteric vein, DVT=deep venous thrombosis.

39

Paper IV One hundred sixteen of the 131 patients had liver cirrhosis and the most com-mon causes of cirrhosis were alcohol and viral disease. In patients with liver cirrhosis the majority had severe liver disease prior to treatment with TIPS, 90% were classified as CP B or C and the mean MELD score was 13 (range 5-30). The most common cause of PHT in the 15 non-cirrhotic patients were PVT, idiopathic liver trauma and inflammatory bowel disease. The site of bleeding was oesophageal in close to 80% of the patients and gas-tric, stomal, rectal or caput medusa in the rest. All patients had pharmacologic and endoscopic treatment prior to TIPS and more than half of the patients had had repeated episodes of variceal bleeding. Covered stent grafts, 10 mm in diameter, were used in all patients. After TIPS the mean PSG dropped from 18 mmHg to 5 mmHg. The mean follow-up was 35 months (range 4-108 months).

Of the 131 patients, 58 were treated with TIPS after or during their first vari-ceal bleeding, and 24 of them within 72 hours from bleeding onset. Fifty of the patients were treated within 72 hours from bleeding onset regardless of whether it was their first bleeding episode or not. There were no significant differences in 1-year, 2-year or overall mortality, or in the frequency of re-bleeding, between any of these subsamples. Neither was there a significant difference in patients with or without liver cirrhosis nor in a subsample of patients with Child-Pugh B and C treated with TIPS later than 72 hours after the variceal bleeding. Overall survival in patients with liver cirrhosis was 92%, 70% and 57% at 6 weeks, 1 year and 2 years, respectively (Fig. 7) and 100% at 2 years in non-cirrhotic patients. None of the patients in CP class A, or non-cirrhotic patients, died of a liver-related cause while the majority of patients with more severe liver disease died of causes related to the liver disease.

40

Fig. 7. Probability of survival in patients with liver cirrhosis, divided into Child-Pugh classes.

In a simple unadjusted analysis, an increased overall mortality was associated with having a higher Child-Pugh score, a higher MELD score, with having liver cirrhosis and with the occurrence of severe HE within 12 months from TIPS. These associations remained for Child-Pugh, MELD, and HE when ad-justed for age, but nor for liver cirrhosis. In a multiple regression analysis of these parameters, a higher Child-Pugh score and having severe HE within 12 months from TIPS were independently related to an increased mortality (Ta-ble 7). There was no difference in mortality in patients with a MELD score above 18 compared to in those with a MELD score below 18.

41

Table 7. Simple and multiple regression analysis of factors associated with overall mortality in patients treated with transjugular intrahepatic portosystemic shunt (TIPS).

Alive

(n=73) Deceased

(n=58) p-value (simple

analysis)

p-value (multiple analysis)

Age, mean ± SD (years) 53 ± 14 62 ± 8 0.0002 0.015 Child-Pugh, mean ± SD 8 ± 2 9 ± 2 0.0006 0.025 MELD score, mean ± SD 12 ± 5 14 ± 5 0.021 0.74 Confirmed liver cirrhosis, number (%) 60 (82) 56 (97) 0.01 - Severe HE within 12 months from TIPS 2 (3) 10 (17) 0.004 0.02 MELD=model of end-stage liver disease. HE=hepatic encephalopathy

Re-bleeding occurred in five patients (4%) within 6 weeks and in 10 patients (8%) within 12 months after TIPS. Re-bleeding was associated with TIPS dys-function and occurred less frequently in patients with a post-TIPS PSG below 5 mmHg than in patients with a post-TIPS PSG of 5 mmHg or above.

Overall, 13 patients had one or more episodes of TIPS dysfunction, the ma-jority within 12 months (n=10). The TIPS could be restored at re-intervention in 11 of the 13 patients. When the TIPS procedure images were reviewed, the dysfunction appeared to be caused by the TIPS stent being too short, not fully reaching the vena cava, in 10 of the 13 patients.

Overall, 47 (40%) of the patients had HE within 12 months after TIPS, the majority had mild HE (79%). Severe HE after TIPS occurred more frequently in patients that had a history of HE prior to TIPS than in those without HE prior to TIPS. In four of the 10 patients with severe HE after TIPS the diameter of the shunt was reduced in an attempt to treat HE. Two of the four patients died within a month of the shunt diameter reduction (of progressive liver fail-ure) and the other two had a liver transplant within 12 months. Severe HE after TIPS was associated with increased mortality. There were no correlations be-tween the pre-TIPS MELD score, diameter of the TIPS, or the post TIPS PSG and the reduction of PSG, and severe HE within 12 months after TIPS. Apart from HE, eight patients (6%) had major procedure-related complications. These were septicaemia (n=2), pneumonia (n=3), pulmonary embolism (n=1) and transient liver ischemia (n=2). None of these complications was fatal and all could be treated without sequel.

42

Discussion

Interventional radiology in portal vein thrombosis (PVT) In patients with PVT endovascular intervention and TIPS may be effective in recanalization and the reduction of portal hypertension (50). The risk of com-plications with more aggressive techniques (such as continuous thrombolysis) must be balanced with the risk of the disease with its complications such as variceal bleeding, ascites, and intestinal ischemia. The different aetiology, on-set and extension of the thrombi made the study population very heterogene-ous, so to make the results a bit more comprehensible we chose to present them divided into sub-groups with somewhat more uniformity.

Chronic portal vein thrombosis Patients with chronic PVT may present with abdominal pain, but the throm-bosis may also be an incidental finding in patients with liver cirrhosis induced PHT (48,50,90). Patients with complications of PHT may benefit from a TIPS irrespective of the presence of specific thrombosis symptoms (91). Extensive thrombi is a negative predictor for complete recanalization and long-term prognosis (50), and due to the fibrotic transformation of vessels it is hard to completely differentiate vessels from thrombogenic tissue. Due to post-thrombotic changes in the vessels, recanalization may be difficult, but when successful it may lead to clinical improvement (90). In paper I, the decompression of varices with the use of a TIPS was achieved with great tech-nical success in patients with chronic PVT. This was in spite of including pa-tients with acute variceal bleeding, for whom high procedure-related mortality has been reported (92). Of the 13 patients in whom a shunt was attempted, the procedure failed in only two, both non-cirrhotic patients with extensive chronic PVT. This supports earlier studies showing that TIPS can be a safe method for decompressing varices in both cirrhotic and non-cirrhotic patients with PVT (48–50). In the present study, the cirrhotic sub-group had a lower survival rate than patients without liver cirrhosis (73% vs 100% at 12 months). However, both overall survival and survival in patients with liver cirrhosis improved compared to a national multicentre study with less interventional

43

treatment (39). The results suggest that TIPS is a safe procedure and may pro-long survival in patients with chronic PVT.

Acute portomesenteric venous thrombosis (PVMT) In paper I, four non-cirrhotic patients with acute PVMT had signs of insipient bowel ischemia. Treatment with primary continuous local thrombolysis, in three of them in combination with TIPS, achieved only partial recanalization and re-occlusion soon followed. However, thrombolysis was discontinued prematurely in three of the patients, due to complications with haemorrhaging, which may have affected the degree of recanalization, as well as delaying post-interventional anticoagulation treatment. Whether the aggressive treat-ment had any impact on the disease’s progress remains unclear, but three pa-tients recovered clinically and were alive more than six years after interven-tion. Even though symptom relief was achieved in the surviving patients with acute PMVT treated with primary continuous thrombolysis in paper I, the rate of complications was very high and one patient died. Another treatment re-gime was called for, but in the literature there was no perfect choice. Continuous thrombolysis through the transhepatic and transcolic route may be associated with risk of bleeding (59,62). Treatment with indirect thrombolysis through the SMV has been successful in some studies (93–95), but recanali-zation may be limited because combined thrombectomy cannot be performed (59,62). Transjugular thrombectomy (TT) and continuous thrombolysis are effective for symptom relief, but may be associated with a high risk of bleed-ing and recanalization may only be partial (96–98). There are studies of TIPS combined with TT and primary continuous thrombolysis with few complica-tions (57,61,99–102), but recanalization is not always achieved (57,100,101). The best option seemed to be a combination of creating a TIPS and TT, which has been associated with effective symptom relief and low rates of complica-tions, but not always complete recanalization. Very few cases are reported and the method varies slightly in the case reports (57,58,61,63). The study of six patients with acute PMVT (paper IV) demonstrates that it is possible to effectively recanalize extensive PMVT with repeated TT through a TIPS. This method was effective for recanalization, symptom relief and sur-vival in five patients with TIPS and TT as the primary intervention. In the sixth patient, TT was performed after surgical thrombectomy and bowel re-section and although recanalization was achieved the disease’s progress could not be stopped and the patient eventually died of multi-organ failure. The re-sults, with near complete recanalization and few complications in the majority

44

of patients, are in agreement with the previously reported cases using similar techniques (57,58,61,63). Primary continuous thrombolysis was avoided because of the risk of haemor-rhage previously experienced in similar patients who were treated with transhepatic and transjugular thrombolysis (35,59). In the present study, no procedure-related haemorrhage occurred. Therefore, the use of pulse-spray in-jections of Alteplase instead of continuous infusion during the primary proce-dure seems to be effective and have less risk of haemorrhaging. This might be because the half-life of Alteplase in plasma is short (4-5 min) and so it was already eliminated by the time the patients left the endovascular theatre. In addition to less haemorrhaging, the time to symptom relief and in-hospital time in the five patients with TIPS and TT as the primary intervention was reduced compared to patients treated with the method described in paper I. This implies that repeated mechanical TT through the TIPS was a more effec-tive way of recanalization than primary continuous thrombolysis. The long-term patency of TIPS, and absence of re-thrombosis, may be partly explained by the fact that an unconstrained outflow of blood is achieved through the TIPS, allowing thrombi to be eliminated more effectively. The TIPS also pro-vides easy transjugular access to the portal vein, allowing repeated procedures without further trauma to the liver parenchyma. This reduces the need for gen-eral anaesthetics during repeated interventions. Adding systemic corticoster-oids, in order to reduce the inflammatory reaction, (103) to the treatment re-gime could be discussed. The patient who had TIPS and TT secondary to surgical thrombectomy and bowel resection presented with thrombus extension similar to that of the other patients. As in all other patients, the initial treatment was heparin. However, three weeks after admission he was diagnosed with antithrombin III insuffi-ciency, and was thus resistant to heparin. The inadequate anticoagulation and prolonged time to effective treatment may partly explain treatment failure in this patient. Although there are case reports of successful transjugular mesen-teric vein recanalization secondary to resection of necrotic intestines and sur-gical thrombectomy (100), the patient in the present study may have benefitted from having an earlier TT through a TIPS before surgery was attempted. A potential risk with TT through a TIPS is embolization to the pulmonary arteries. However, there were no clinical signs of pulmonary embolism in any of the patients treated with this method.

45

To the best of our knowledge, the regime used in paper III of creating a TIPS, performing repeated TT through a maintained transjugular access with con-stant heparin infusion between the TT sessions to treat acute PMVT has not been described before.

Budd-Chiari Syndrome BCS is a rare but serious condition with poor prognosis if not treated (67). The present study reports 14 patients with BCS treated with interventional radiol-ogy. The overall 1- and 5-year transplantation-free survival was 100% and 93%, respectively. In the primary TIPS group, both the 1- and 5-year transplantation-free survival was 100%. In a previous national study in which patients were mainly treated medically, the 1- and 5-year transplantation-free survival rates were 47% and 28%, respectively (65). The dramatic improvement in transplantation-free sur-vival in the present study clearly demonstrates the value of combining medical treatment with endovascular intervention.

The outcome after TIPS in patients with BCS may be estimated using the BCS-TIPS PI score (69) and the Rotterdam score (88). In the present study, 11 and 12 (of the 13 patients treated with TIPS) had an intermediate to high risk of death or OLT according to the Rotterdam score and BCS-TIPS PI score respectively. However, very high survival rates were achieved. Although the only patient who died in our study had a high BCS-TIPS score, all of the other 11 patients with high scores survived. Whether these prognostic indexes should be used to estimate the value of treatment with TIPS or not needs fur-ther evaluation. Although the study population was very limited, the results indicate better pa-tency and less mortality with a primary TIPS procedure than with primary angioplasty. Survival rates were higher than the 78-87% shown in larger sim-ilar studies (69–71). Post-TIPS occurrence of HE was as expected (69,104). The results of better efficiency with primary TIPS than with liver vein angio-plasty, and much lower mortality than with only medical treatment, support the recent suggestions of early TIPS in symptomatic BCS patients (72). There may be reasons to reconsider the present recommendations (7) for a step-wise approach in the treatment of patients with BCS.

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TIPS in variceal bleeding Variceal bleeding is a serious condition with poor outcome and high mortality (7). TIPS has proven to be an efficient complementary treatment with less re-bleeding than endoscopic and pharmacological methods (52,105,106). Over-all survival rates of 70% and 57% at 1 and 2 years respectively in patients with liver cirrhosis and 100% at 2 years in patients without cirrhosis in the present study, are comparable with other cohorts treated with TIPS (52,105,107–109). As expected, the Child-Pugh score was correlated to survival.

Early TIPS, within 72 hours of onset of primary oesophageal variceal bleed-ing, has been shown to improve survival and reduce the rate of re-bleeding in patients with a high risk of treatment failure (29,30). In the present study there was no difference in survival or re-bleeding between patients who were treated with early TIPS compared to those who were treated with TIPS later, nor after multiple bleeding episodes. These results suggest that receiving a TIPS at all may be of greater importance than receiving it within 72 hours or at the first bleeding episode. A MELD score of 18 or above has been associated with higher mortality after TIPS than a lower MELD score (89,110–112). In the present study, the MELD score did not correlate with mortality in the multivariate analyse. In addition, the outcome in the surviving patients with a MELD score of 18 or above was good, none had re-bleeding or TIPS dysfunction (mean follow-up 12 months). This implies that some patients with a high MELD score may benefit from treatment with TIPS. A pressure gradient of 12 mmHg after TIPS is often recommended to avoid HE (113,114). However, as variceal bleeding occurs at pressure gradients above 12 mmHg (8) the interval of the optimal pressure gradient is very lim-ited. In the present study of TIPS in 131 patients with variceal bleeding, the mean post TIPS PSG was lower than what is usually recommended. On the other hand, the rate of re-bleeding (8% at 12 months) was lower than what could have been expected with conventional treatment (52,105) and the oc-currence of HE after TIPS was not associated with the PSG. Re-bleeding was associated with TIPS dysfunction which is discussed below.

With the aim to further reduce re-bleeding TIPS is sometimes combined with embolization of varices (107,115). There are studies reporting less re-bleeding with the combination of TIPS and variceal embolization compared to TIPS alone (116) but other studies report no difference in re-bleeding rates (117). In the present study of variceal bleeding (paper IV) embolization of collaterals

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was performed in only one patient, this patient was one of the few that expe-rienced re-bleeding (when the TIPS occluded). Whether embolization of var-ices is effective or not remains uncertain. In patients with gastric variceal bleeding a treatment option is balloon-oc-cluded retrograde transvenous obliteration (BRTO) of the varices. There are reports of BRTO being as effective as TIPS in preventing re-bleeding, and with less occurrence of post procedural HE, in patients with isolated gastric variceal bleeding (118,119). However, when the gastric varices are occluded there is a potential risk of developing oesophageal variceal bleeding (120). To combine BRTO and TIPS in patients with gastric variceal bleeding may be more effective than embolization alone (121), or TIPS alone (122), but the combination may prolong the procedures and increase the risk of complica-tions (123) without affecting survival (121).

TIPS dysfunction In the early years of treatment with TIPS the rate of TIPS dysfunction was very high due to neointimal proliferation which reduced the diameter of the uncovered stents (108) but the occurrence of TIPS dysfunction dropped mark-edly with the introduction of covered stents (106,124,125). Dysfunction in TIPS with covered stents has been associated with severe inflammation in the liver tissue and a high MELD score (85) and stenosis in the distal (hepatic venous) end of the stent (126). When the TIPS procedures of the presented studies were reviewed, the major causes of TIPS dysfunction were re-thrombosis in patients with PVT prior to TIPS, and stenosis of the distal end of the TIPS stent graft. In 18/19 patients with stent stenosis the stent appeared to be too short, not fully reaching the IVC. An example is provided in Fig.8. TIPS dysfunction due to stents not reaching the IVC has been reported by others (127). These observations sug-gest that the rate of TIPS dysfunction might be lowered if the TIPS stent def-initely reaches all the way to the confluence of the hepatic veins and the IVC or into the IVC. As a consequence, as re-bleeding was associated with TIPS dysfunction (paper IV), the rate of re-bleeding might be further reduced.

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Fig. 8. To the left: a transjugular intrahepatic portosystemic shunt (TIPS) at inser-tion. The fully expanded TIPS stent (black arrow) does not reach the confluence to the inferior vena cava (IVC) (thin white arrow). To the right: in-stent stenosis in the same patient in the distal end of the stent (thick white arrow).

Hepatic encephalopathy Hepatic encephalopathy after TIPS is a dreaded complication as it is associ-ated with higher risk of death (84), occurred at the expected rate in all four papers (50–52,91,107). The majority of patients had mild HE and could be treated easily, but severe HE after TIPS was associated with higher mortality in paper IV.

Treatment with TIPS is considered a risk factor for HE, but as HE can be induced by liver cirrhosis and portal hypertension per se (6,84), the TIPS can-not be the sole explanation. In a recent study of patients with refractory ascites, there was no difference in the occurrence of HE in patients treated with TIPS and patients treated with pharmacological and endoscopic methods (81). In one study of variceal bleeding there was an initial difference in the frequency of HE in patients treated with TIPS and patients treated with pharmacological and endoscopic methods, but this difference diminished after 12 months (107). It has been suggested that a post-TIPS pressure gradient of 12 mmHg or lower is associated with HE (86,87,128). However, there was no correlation be-tween the post-TIPS PSG, nor the diameter or length of the stent graft, and

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HE in the largest study population in the presented papers (paper IV). Further studies are needed to determine the optimal post-TIPS pressure gradient.

As reported previously (87), patients with episodes of HE prior to TIPS were at higher risk of severe HE after TIPS. However, as in paper IV, not all patients with HE before TIPS had recurrent episodes after TIPS. In a life-threatening situation with extensive variceal bleeding or insipient bowel ischemia, treat-ment with TIPS may be worth a chance even in patients with a history of HE.

Importance and limitations of the portal pressure gradient The portal pressure gradient is used to determine the degree of PHT and to estimate the risk of complications (7,8) and as such, is considered a key to treating patients with PHT. The gradient has, as discussed above, been asso-ciated with the development of HE after TIPS (86,87,128) and great care is taken not to reduce the gradient too much when creating a TIPS. However, in the present study of variceal bleeding (paper IV) a low post TIPS PSG seemed favourable in order to avoid re-bleeding while there were no correlation be-tween the PSG and HE at all. Several factors have been suggested to affect the gradient; it may differ de-pending on the measurement technique (10) and whether the measurement was obtained during general anaesthesia or sedation (13) (as described in the background section of the thesis). Recently, it has also been suggested that stent grafts used for the TIPS procedure may expand over time, possibly re-sulting in a reduction of the gradient (129,130). It remains uncertain whether these possible changes to the PSG are of any clinical importance. However, more uniformity in procedures when measuring the gradient may possibly fa-cilitate the search for the optimal gradient for avoiding HE, as well as the re-currence of PHT related symptoms, after TIPS.

Limitations The biggest limitation in all the studies is the retrospective format. The first three studies were also limited by the small number of patients. Since both BCS and PMVT are rare conditions, the number of patients that can be col-lected is limited, making it difficult to effectively study these conditions.

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Future work The major clinical concern with TIPS is the occurrence of post-intervention HE. A review of all patients treated with TIPS in the PHT registry, irrespective of clinical presentation, might reveal one or more common factors in patients that develop HE after TIPS. A prospective study of patients with refractory ascites considered for treatment with TIPS has also been initiated to try to identify risk factors for HE. The importance of the method used to obtain the gradient between the portal vein and the systemic venous pressure needs fur-ther evaluation. Recently, Swedish centres that perform TIPS have started to register their pa-tients in the PHT registry. This may improve national treatment uniformity and facilitate further studies of patients with rare conditions such as BCS and PMVT. Since the short-term results of the recently introduced treatment re-gime in acute PMVT were very promising, further patients may be treated with the same method and follow-up should continue.

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Conclusions

Interventional radiology, mainly TIPS, seems to be safe and effective for the treatment of patients with complications of PHT, regardless of the underlying causes of disease and sites of venous blood flow obstruction. HE may occur more frequently after TIPS than medical and endoscopic treatment, but is of-ten mild and easily treated. In selected patients with PHT, TIPS may improve survival.

Paper I In patients with PVT and threatening symptoms of portal hypertension, endo-vascular recanalization and TIPS should be considered. TIPS can be accom-plished in a safe and effective way to decompress portal hypertension, even in challenging cases with PVT, which reduces the risk of life-threatening com-plications like variceal bleeding and bowel ischemia.

Paper II TIPS seems to be a safe and effective treatment for symptomatic BCS and there is an obvious improvement in transplantation-free survival compared to conservative medical treatment. It should therefore be considered early, as a first-line intervention, in patients with insufficient response to medical treat-ment.

Paper III TT in combination with TIPS seems to be safe and effective for primary re-canalization and symptom-relief in cirrhotic, as well as non-cirrhotic, patients with acute extensive PMVT and insufficient response to systemic anticoagu-lation therapy. The TIPS allows an effective outflow of blood and access for repeated procedures. This treatment strategy can reduce the complication rate and the in-hospital time compared to continuous transhepatic thrombolysis.

Paper IV TIPS was safe and effectively prevented re-bleeding in patients with variceal bleeding, regardless of occurrence of liver cirrhosis; Child-Pugh class; of how

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soon after bleeding onset the TIPS procedure was performed; and of the di-ameter and the length of the TIPS stent A post-TIPS PSG below 5 mmHg was associated with a decreased risk for re-bleeding and there was no correlation between the post-TIPS PSG and the occurrence of HE. Effective treatment, and reduced risk of stenosis, may be obtained by assuring that the TIPS stent reaches the IVC and allowing a low PSG. This might invalidate the need for collateral embolization.

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Acknowledgements

As a child I dreamt about being a scientist and doing research, but the dream faded as the years passed. However, it took me just a few weeks in the De-partment of Interventional Radiology at Uppsala University Hospital to start thinking about it again, so when Professor Rickard Nyman asked if I was in-terested in doing some research he didn’t have to ask twice. My supervisor: Rickard Nyman. I am forever grateful for all the hard work you have done in to make it possible for me to fulfill my childhood dream. You have always supported me in a way that have made me feel I could do it. You have spent countless evenings and weekends helping me and guiding me through what sometimes felt like a maze. Your patience is astonishing and you have truly been a perfect supervisor. My associate supervisors, Fredrik Rorsman and Lars-Gunnar Eriksson, you have kept me going with your cheerful support and a positive attitude, even when I felt desperate. Thank you for pushing me with a firm but gentle hand! Charlotte Ebeling Barbier, a friend all along and an associate supervisor dur-ing the second half of my journey to this thesis. I don’t think I would have pulled it off without you! I may not always have been smiling, but I am very grateful for all you have done to help me learn and improve. Thank you for always being there! My co-writers Per Sangfelt and Reza Sheikhi, I am thankful for the way you (together with Fredrik Rorsman) introduced me to the fascinating world of hepatology. Your expertise in the field has invaluable and I have enjoyed learning from you. My colleagues, Bengt and Jakob, who introduced me to interventional radiol-ogy in the first months of my radiology residency. Thank you for sharing your enthusiasm in such a way that I immediately knew I had chosen the right field to specialize in.

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My dear friends and colleagues in the Department of Radiology in Västerås, thank you all for creating an atmosphere of friendship and collaboration de-spite a workload that never seems to ease. Katri, Ulrika and Therese, Wednes-days are special and you know why. My colleagues in the Department of Radiology in Uppsala, thank you for shar-ing your enthusiasm and keeping me going! The head of the Department of Radiology in Uppsala, Adel Shalabi, and in Västerås, Jonas Cederberg. Thank you for making it possible for me to finalize this thesis. I would like to thank Christl Richter-Frohm, Monica Åhman and Elin Eriks-son for helping me with the hassle of applications and documentation, and Håkan Pettersson for helping me with pictures for the papers and the structure of this thesis. I would not be writing these words without your help. Dear Clare, thank you for helping me to make the English language in the papers and the thesis make sense. My beloved parents Björn and AnnMargret, and sister Karin, your support means the world to me. You always are, and have always been, there for me. I cannot express in words how grateful I am. My two sons, Anton and Oskar. Thank you for having patience with me! You are the joy of my life and I will always love you. To all my friends in the running community, thank you for sharing the trails with me, for helping me relax and to think of nothing but the moment.

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