University of Medicine and Pharmacy [627889]

University of Medicine and Pharmacy
“Iuliu Hațieganu” Cluj-Napoca
Faculty of General Medicine
LICENSE THESIS
On the “topic” of
TIPS
Pre- and Postinterventional Changes in
Laboratory Parameters and Complications
Coordinator: MD PhD Bogdan Procopet,
Iiliu Hatieganu University of Medicine and Pharmacy,
Regional Institute of Gastroenterology and Hepatology

Graduate: Sebastian Nolle
2019

Table of Contents
1. General Review ………………………………………………………………………………… 4
1.1 Introduction ……………………………………………………………………………….. 4
1.2 Liver Anatomy ……………………………………………………………………………. 4
1.2.1 Liver Surface Anatomy and anatomical Relations ………………………4
1.2.2 Functional Subdivision of the liver …………………………………………… 6
1.2.3 Blood Vessels of the Liver …………………………………………………….. 6
1.3 Liver Physiology ………………………………………………………………………….. 8
1.4 Pathophysiology …………………………………………………………………………. 9
1.5 TIPS Procedure …………………………………………………………………………. 11
1.6 Indications of TIPS in specific clinical conditions …………………………….. 12
1.7 Contraindications to TIPS …………………………………………………………… 15
1.8 TIPS Complications …………………………………………………………………… 16
2. Special Review……………………………………………………………………………….. 23
2.1 Introduction………………………………………………………………………………. 23
2.2 Materials and Methods ……………………………………………………………….. 23
2.3 Descriptive Statistics ………………………………………………………………….. 25
2.3.1 Gender and Age …………………………………………………………………. 25
2.3.2 Etiology of Cirrhosis ……………………………………………………………. 26
2.3.3 Indication for TIPS ……………………………………………………………… 27
2.3.4 Type of TIPS ………………………………………………………………………. 27
2.3.5 TIPS Dysfunction ………………………………………………………………… 28
2.3.6 Patients Death ……………………………………………………………………. 28
2.4 Analytical Statistics ……………………………………………………………………. 29
2.4.1 Analysis of TIPS Dysfunction ………………………………………………… 29
2.4.1.1 Laboratory Values at Admission ……………………………………… 29
2.4.1.2 Laboratory Values at 48h after TIPS procedure …………………29
2.4.1.3 Laboratory Values at discharge ……………………………………… 30
2.4.1.4 Laboratory Values at 1 month revision …………………………….. 30
2.4.1.5 Hemodynamic Parameters at the first Procedure ………………31
2.4.1.6 Delta Values Transaminases ………………………………………… 31
2.4.1.7 Delta Values Gamma-GT and Alkaline Phosphatase ………….32
2.4.1.8 Delta Values Platelets and Sodium …………………………………. 32
2.4.1.9 Delta Values Bilirubin and Creatinine ………………………………. 32
2.4.1.10 Delta Values Albumin, INR and CRP …………………………….. 33
2.4.2 Analysis of Survival ……………………………………………………………. 33
2.4.2.1 Laboratory Values at Admission ……………………………………… 33
2.4.2.2 Laboratory Values at 48 hours ……………………………………….. 34
2.4.2.3 Laboratory values at discharge ………………………………………. 35
2.4.2.4 Laboratory Values at the first Revivsion …………………………… 36
2.4.2.5 Hemodynamic Parameters at TIPS Insertion …………………….37
2.4.2.6 Hemodynamic Parameters after TIPS Insertion ………………..37
2.4.2.7 Delta Values Transaminases ………………………………………… 38
2.4.2.8 Delta Values Gamma-GT and Alkaline Phosphatase ………….38
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2.4.2.9 Delta Values Platelets and Sodium …………………………………. 39
2.4.2.10 Delta Values Bilirubin and Creatinine …………………………….. 39
2.4.2.11 Delta Values Albumin and INR ……………………………………… 40
2.4.2.12 Delta Values CRP ………………………………………………………. 40
2.4.3 Cirrhosis Etiology and Gender ………………………………………………. 41
2.4.4 TIPS Indication and Gender …………………………………………………. 42
2.4.5 TIPS Dysfunction and Gender ………………………………………………. 43
2.4.6 TIPS Dysfunction and Survival ……………………………………………… 43
2.4.7 TIPS Indication and Dysfunction ………………………………………….. 44
2.4.8 TIPS Indication and Survival ………………………………………………… 45
2.4.8 Cirrhosis Etiology and Survival ……………………………………………… 46
2.4.9 Cirrhosis Etiology and Dysfunction ……………………………………….. 47
3. Discussion …………………………………………………………………………………….. 47
4. Conclusion ……………………………………………………………………………………. 48
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1. General Review
1.1 Introduction
Liver disease is an increasing problem amongst the population worldwide and
therefore also the need for therapeutic measurements rises. Especially the
Complications of chronic Liver Disease and Cirrhosis are of high Importance
and may even result in death. Transjugular intrahepatic portosystemic shunt
(TIPS) offers a method for portal decompression and therefore an excellent
tool to increase the patient's survival.
This studies aim is to establish, what complications patients have after the pro –
cedure, and to see how they evolve after the intervention.
1.2 Liver Anatomy
1.2.1 Liver Surface Anatomy and anatomical Relations
The liver is a large, accessory digestive gland, mainly located in the right upper
quadrant of the abdomen. It has two surfaces, the diaphragmatic and the vis –
ceral surface, which are separated anteriorly by its inferior border.
The diaphragmatic surface of the Liver is dome shaped and is covered by vis –
ceral Peritoneum. Superiorly it relates to the Diaphragm. Posteriorly there ex –
ists an area which is not covered by visceral Peritoneum, that is called the bare
area of the Liver. It has a groove through which the Inferior Vena Cava passes.
The visceral surface of the Liver is also covered by visceral Peritoneum. The
exceptions to this are the porta hepatis and the fossa for the gallbladder. The
porta hepatis is transverse fissure that contains the Portal Triad (Hepatic
Artery, Hepatic Vein and Bile Duct), as well as the Hepatic Plexus and Hepatic
4

ducts.
Next to the porta hepatis are two sagittal fissures, the right sagittal and the left
sagittal fissure. These 2 fissures are formed by their surrounding anatomical
structures, for the right those being posteriorly the vena cava and anteriorly the
gall bladder, and for the left posteriorly the ligamentum venosum and anteriorly
the round ligament. Those two sagittal fissures together with the porta hepatis
form a “H-like” Appearance.
There are Subphrenic and Hepatorenal recesses. The subphrenic recesses
are extensions of the greater sac and are divided into left and right subphrenic
recess respectively by the falciform ligament. The Hepatorenal Recess, also
called Morrison Pouch, is a space located between the right kidney, suprarenal
gland and their respective visceral liver surface. The Morrison Pouch is of spe –
cial importance since it drains the fluid from the omental bursa and represents
an area of fluid collection.
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1.2.2 Functional Subdivision of the liver
Functionally the Liver is divided into the left and right Lobe (except for the cau –
date lobe: segment I), which may function independent from each other. Those
2 lobes are similar in size (despite their difference in anatomical size). Both of
them receive their own Vascularization through a branch of the hepatic artery,
portal vein and are drained through their own hepatic duct. By this Definition
one might consider the caudate lobe an independent third lobe since it also
matches those criteria.
Further subdivision are being made considering the secondary or tertiary vas –
cularization of the liver, which allow for a further subdivision into 4 divisions or
respectively 8 surgical resectable divisions. (1)
1.2.3 Blood Vessels of the Liver
The Liver receives up to 1,5l/min blood via two sources, the hepatic artery and
the portal vein.
The hepatic artery delivers blood mainly to non-parenchymal structures, espe –
cially the bile structures. At the porta hepatis the hepatic artery divides into its
right and left branches to supply its respective lobes.
The portal vein accounts for most of the blood delivered, accounting for roughly
75-80% of the livers blood supply. This portal blood is able able to oxygenate
the parenchyma due to its unsual high oxygen content for venous blood, which
is approximately 40%. The blood delivered from the portal vein is also rich in
monosaccharides, amino acids, bile salts, urobilinogen, bilirubing and GI hor –
mones. It also carries along the nutrients that were absorbed from the GI tract
with the exceptions of lipids. The portal vein is formed by the junction of the in –
ferior mesenteric vein, the superior mesenteric vein and also the splenic vein.
At the portal triad, the portal vein bifurcates and further branches out into the
liver in its segmental pattern.
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Anastomoses between the portal system and the systemic circulation are
called portal-systemic anastomoses. There is the anastomoses in the perium –
bilical area, aswell as an anastomoses in the submucosa of the anal canal or
the inferior esophagus. There are also anastomoses of secondarily retriperi –
toneal viscera or the liver. In case of diminished portal flow due to a disease,
this blood can get into the inferior vena cava via these anastomoses. However
if the amount of blood is too high, varices may form.
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1.3 Liver Physiology
The liver is a major digestive gland in the body weighing approximately 1-
1,5kg. It has both, excretory and secretory functions. The functional Unit of the
liver is called hepatic lobule and has a honeycomb-like structure. The hepatic
lobule consists of hepatocytes, which are arranged in two columns and in be –
tween them is a bile canaliculus. This is called a hepatic plate. In between
those plates sinusoids are present. The sinoids are surrounded by portal triads
where they receive their blood supply from and drain their bile.
With being the major digestive gland in the body, the liver has numerous func –
tions, which are contributing to the bodies homeostasis.
The Liver is involved in detoxifying the body, this involves the inactivation of
certain drugs and hormones and also the reticuloendothelial cells, also known
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as Kupffer Cells. The Kupffer cells can either phagocytose foreign bodies, or
synthesizre Interleukins and Tumor necrosis factors. To detoxify the liver can
transform toxic materials into non toxic substances by conjugating them with
sulfates or glucoronic acid.
The Liver also has a hematopoietic and hemolytic Function. It stores the nec –
essary Iron and Vit. B12 and produces Thrombopoietin. Its Kupffer Cells are re –
sponsible for its hemolytic function, they destroy the Red blood cells after their
life span of 120 days.
The Liver also acts as a storage Organ for multiple other substances, such as
glycogen, iron, folic acid, amino acids, vit. A, vit. B12. and vit. D. It is also the
organ where most of the metabolic processes occur, like protein, fat and carbo –
hydrate metabolism. This also makes it on of the organs where high amounts
of heat are produced.
1.4 Pathophysiology
In liver disease multiple processes are occuring, like necrosis, fibrosis and in –
flammation go on at the same time. It is usually caused by chronic toxic stimuli,
especially alcoholism, which accounts for 50% of the cirrhosis worldwide. But
the cirrhosis can also be caused by a viral infection, where it represents the
end stage form of the disease. The Pathogenesis of cirrhosis occurse in multi –
ple steps. The dead Hepatocytes release lysosomal Enzymes which together
with the dead cells activate the Kupffer cells. They also attract inflammatory
cells. Those inflammatory cells and the Kupffer cells release growth hormones,
which convert the stellate cells into myofibroblasts, convert monocytes into
macrophages and induce the proliferation of fibroblasts. (2)
The decreased proteinsynthesis in liver disease leads to hypoalbuminemia
which leads to ascites and peripheral edema. Because of this relative loss in
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plasma volume, the body develops a secondary hyperaldosteronism, which in
addition leads to an Hypokalemia.
The portal Hypertension further aggravates the ascites and causes
splenomegaly and esophageal varices. The splenomegaly leads to Thrombo –
cytopenia. The lack of coagulation factors and platelets in addition to the de –
velepmont of varices expose a very high risk of severe bleeding. In advanced
stages, the portal hypertension causes a condition called exsudative enteropa –
thy. This enhances ascites and promotes protein migration into the intestines.
This leads to a further increase in ammonia levels.
The hyperammonemia is responsible for the hepatic encephalopathy. In liver
insufficiency it gets further aggravated by the fact that, fresh blood from the
varices gives extra protein to digest and the liver isn't capable to transform am –
monia to urea.The cholestasis not only leads to jaundice, it also increases the
patients risk of bleeding, since less bile is entering the intestine to form mi –
celles and therefore decreases the absorption of vitamin K. (2)
Jaundice is a yellowish discoloration of the skin and mucous membranes due
to elevated blood bilirubin levels. It occurs when the Bilirubin levels in the blood
exceed 2mg/dl. Jaundice can be subdivided into three different types, Prehep –
atic, Hepatic and Posthepatic Jaundice. Prehepatic Jaundice occurs due to ex –
cessive red blood cell destruction, which leads to a rise in unconjugated biliru –
bin. In prehepatic jaundice the excretory liver function is normal, but the
amaount of bilirubin excreted rises. Causes include Infection, Hemoglobin dis –
orders, drug abuse or autoimmune diseases. Hepatic Jaundice occurs due to
liver cells damage. The damage prevents the already conjugated bilirubin to
leave the liver and therefore return back into the bloodstream. Causes include
Infections leading to hepatitis, alcoholic liver disease, liver cirrhosis, toxin expo –
sure. Posthepatic Jaundice is caused by a bile flow obstruction, which forces
the bile salts and pigments to enter circulation. Causes include Gall stones and
biliary or pancreatic cancer. (3)
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1.5 TIPS Procedure
Transjugular intrahepatic portosystemic shunt (TIPS) is a radiologic procedure,
in which a stent is placed in the middle of the liver to reroute the blood flow
from the portal circulation into the the systemic circulation. During the Interven –
tion, a cutenous acces is created via the right jugular vein. Via this access, the
catheter is moved into the inferior vena cava and into the right hepatic vein.
Then a tunnel between the hepatic and intrahepatic portion of the portal vein is
created. To dilate the tunnel ballon angioplasty is performed and the stent is
placed. The stent then is dilated until the pressure gradient between the Portal
vein and hepatic vein is less than 12mmHg.
The Procedure is performed within the vessels in the X-Ray room under X-Ray
guidance.
Figures 1 and 2 below illustrate the TIPS Procedure.
Figure 1:
Portal Hypertension causes blood flow to be forced backward, causing veins to
enlarge and varices to develop across the esophagus and stomach from the
pressure in the portal vein. The backup of pressure also causes the spleen to
become enlarged.
11Fig. 1
Fig. 2

Figure 2:
A radiologist makes a tunnel through the liver with a needle, connecting the
portal vein to one of the hepatic veins. A metal stent is placed in this tunnel to
keep the track open.
The shunt allows the blood to flow normally through the liver to the hepatic
vein. This reduces portal hypertension, and allows the veins to shrink to normal
size, helping to stop variceal bleeding. (4)(5)
1.6 Indications of TIPS in specific clinical conditions
TIPS is used to reduce the portal venous pressure in specific clinical scenarios.
Those scenarios might range from acute life threatening conditions to refracto –
ry chronic conditions. It is used in the following clincal conditions.
Primary Prevention of Esophageal Variceal Bleeding:
Acute Variceal Bleeding: TIPS can be used in acute variceal bleeding instead
of endoscopic variceal ligation (EVL) to decrease the treatment failure rates
and overall survival. TIPS also offers the advantage of lowering the re-bleeding
risk compared with EVL.
Refractory acute Variceal Bleeding: The standard treatment for Refractory
acute variceal bleeding is represented by EVL, antibiotics and vasoactive
drugs. Patients that have survived an acute variceal bleeding are at a high risk
of re-bleeding. Risk factors for re-bleeding include present comobrbidities such
as liver disease, renal disease, age or even the severity of the initial bleeding.
Another risk factor is a Hepatic venous pressure gradient >20mmHg which pre –
disposes patient to re-bleed or fail initial treatment with medication or EVL.
Multiple studies have investigated the use of TIPS versus endoscopic therapy,
with the results being, that TIPS decreases re-bleeding risk, but also increases
the risk of developing hepatic encephalopathy.
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There are also studies that have compared TIPS to Pharmacotherapy in the
Treatment of recurrent variceal Hemorrhage. The re-bleeding rates in the TIPS
group were significantly lower where as survival was about the same, except
for the Child Pugh C Group, where the Pharmacotherapy showed increased
survival rates. Refractory Bleeding from gastric varices and hypertensive portal
Gastropathy: Other Therapies for bleeding gastric varices besides TIPS consist
of Vasoconstrictor Therapy, Glue Therapy and cyanoacrylate Therapy. Studies
have compared those Methods to TIPS and found that TIPS was effective in
treating fundal varices unresponsive to vasoconstrictors, with achieving Home –
ostasis in 90% of cases with active bleeding. In comparison to cyanoacrylate
13

therapy it was more effective in reducing re-bleeding rates (11%) compared
with (38%). Survival rates among both groups were similar.
Refractory Ascites: Refrcatory Ascites is managed via two ways, large volume
paracentesis (LVP) and (TIPS). Studies have shown an improved control of the
refractory ascites by TIPS (Mean 64%) compared to LVP (Mean 24%), without
effects on survival.
Refractory Hepatic Hydrothorax: Standard treatment for Hepatic Hydrothorax
consists of Medical Therapy, repeated Thoracocentesis, chest tube placement
and diaphragmatic repair. For Refractory Hepatic Hydrothorax the only thera –
peutic Options are TIPS and video-assisted Thorascopic Surgery (VATS), if
14

the patient isn't suited for transplantion. There are small studies which are eval –
uating the use of TIPS in refractory hepatic hydrothorax. TIPS achieved a re –
sponse rate from 59-82%. Survival was reported with a 30-day Mortality of 5-
25% and a 1year survival of 64% and 48%, which makes TIPS a therapeutic
Option.
Hepatopulmonary Syndrome: Due to only transient improvement in a minority
of study patients, TIPS is not recommended for the treatment of hepatopul –
monary syndrome.
Hepatorenal Syndrome: There have been four small studies, that evaluated the
use of TIPS in Hepatorenal Syndrome. They found an increase in renal func –
tion after the TIPS procedure and also a decrease in Plasma Creatinine and al –
dosterone. TIPS may act as a bridging therapy between vasoconstrictor thera –
py and liver transplantation.
Budd-Chiari Syndrome: It is due to Obstruction or thrombosis of the hepatic
portion of the inferior vena cava or hepatic veins. In one larger study (127 peo –
ple) of the usage of TIPS in severe Budd-Chiari Syndrome unresponsive to
medical treatment, 5-year survival was 84% and transplant-free survival at 1
and 5 years at 88% and 78%.
Hepatic Veno-occlussive Disease: It is most likely encountered after a bone
marrow transplant. In a few studies it has shown to improve the liver disease,
but not influence the survival rate. (6)
1.7 Contraindications to TIPS
Absolute Contraindications: The absolute Contraindications for TIPS include:
•Congestive Heart Failure
•Severe tricuspid regurgitation
15

•Severe pulmonary Hypertension
•Multiple Hepatic Cysts
•Uncontrolled systemic Infections, Sepsis
•Unrelieved biliary Obstruction
•Primary Prevention of variceal Hemorrhage
Relative Contraindications
•Hepatocellular Carcinoma, especially centrally located
•Obstruction of all hepatic Veins
•Portal vein thrombosis
•Moderate pulmonary Hypertension
•Severe coagulopathy (INR > 5)
•Thrombocytopenia <20.000/cm³
•Hepatic encephalopathy (5), (6)
1.8 TIPS Complications
Complications regarding TIPS can be classified into Intraprocedural Complica –
tions, early postprocedural complications and delayed complications.
Acute hemorrhage can occur as a result of an arterial puncture during the ac –
cess of the jugular vein. To avoid this complication, the access should by per –
formed under Ultrasound or fluoroscopic guidance. Arterial punctures may re –
sult in hemorrhages, fistulas, arterial occlusions or pseudoaneurysm formation.
If the patient presents with Symptoms leading to the suspicion of an arterial
puncture, measures must be taken immediately to prevent potentially fatal
complications from hemorrhage. Symptoms include abdominal pain, he –
16

matemesis and hemodynamic instability. If an arterial Source of the Bleeding is
suspected, one should immediately perform angiography, and use stents or
embolization to treat the hemorrhage. Blood loss can also be a cause of portal
venous system injuries. In portal venous injuries venography may be used to
establish the etiology. Also the TIPS insertion itself is an effective treatment in
itself. In rare cases portal vein dissection may occur, in which cases the TIPS
stent must be extended to also cover the dissection flap and maintain the flow.
Another Intraprocedural complication is non-target TIPS insertion. To avoid this
complication, a contrast injection before the dilation of the tract is recommend –
ed. If this is not done, the stent may be placed in the common hepatic duct or
hepatic artery by accident.
Excessive Procedural time may not represent a true complication by itself, but
also carries risks. The main difficulty in performing TIPS lies in the blind punc –
ture or the left or right portal vein at the appropriate site. For successful punc –
ture, wedged hepatic portography has been proposed. Two contrast media ex –
ist, carbon dioxide and iodinated contrast. The former has an incidence of con –
trast extravasation of 1,8% and the latter 7,5%, which makes carbon dioxide
the preferred contrast medium. A rare complication of wedged hepatic venogra –
phy is represented by hepatic laceration. Hepatic laceration appears to occur
more often with the use of iodinated contrast media, rather than carbon diox –
ide. Due to the complications of wedged hepatic venography the recommend –
ed procedure is a balloon occlusion catheter with carbon dioxide hand injec –
tion. If liver laceration is suspected, arteriography should be performed with
subsequent embolization of the bleeding artery. Another suggested method to
reduce procedure time and unintentional needle punctures is transabdominal
and intravascular ultrasound. Also intravascular ultrasound has been proven to
facilitate TIPS needle passage. In a comparison of 25 TIPS procedures by
Farsad et al with 75 blind pass TIPS, no significant reduction in procedure time
has been shown. It still may be useful for patients suffering from Budd Chiari
17

Syndrome, distorted vascular anatomy or portal vein thrombi.
Another intraprocedural Complication may be the liver capsule transgression. It
can occur in 33% of cases with the needle/ catheter combination, with a risk of
intraperitoneal hemorrhage in about 1-2% of the cases. In case the capsule of
the liver is breached, the most likely organ to be punctured is the gallbladder.
This results in Cholangitis, hemobilia and/ or intrabiliary clots. Also other or –
gans may be affected (Duodenum, hepatic flexure of colon, right kidney).
Tabletop TIPS Maldeployment is a complication caused by unintended prema –
ture maldeployment of the stent prior to its insertion into the access sheath.
During the preparation and the deployment of the stent, two major errors may
occur. The first one is the removal of the plastic access sleeve, which may be
mistaken for a protective covering. The second error happens when the clear
sleeve is being advanced through the hemostatic valve of the introducer
sheath. If the sleeve isn't completely loaded into the sheath, a partial malde –
ployment can occur, which results in the inability to further advance the stent.
As a result the stent can no longer be used and must be removed.
Early Postprocedural Complications include arterial complications. Reported
cases of postprocedural arterial complications include acute intra-abdominal
hemorrhage and liver laceration. Also three cases of intrahepatic hematomas
have been reported, but all of which received anticoagulative treatment at that
specific time. If the formation of a postprocedural hematoma is suspected, CT
should be performed to establish the diagnosis and source of bleeding. As a
precaution, antiplatelet and anticoagulative treatment should be stopped and
reversed. If the source of bleeding is suspected to be of arterial origin, hepatic
angiography and embolization is the recommended course of action. Hepatic
infarction caused by arterial compression by the TIPS stent, can be treated
with antibiotics and supportive care.
In 5-35% of the cases, acute hepatic encephalopathy occurs after TIPS inser –
tion. Cases have been reported within a period of 1-210 days after the proce –
18

dure has taken place. Up to 95% of those cases can be controlled via
branched chain amino acids, a protein restrictive diet, or lactulose. In 1-3% of
patients a severe and disabling hepatic encephalopathy occurs. In severe per –
sistent hepatic encephalopathy or in acute liver failure, one should consider oc –
cluding the TIPS stent. This can be done by inflating an angioplasty balloon for
a minimum of 12 hours inside of the stent. If TIPS occlusion is performed it is
necessary to monitor the patient closely, as important hemodynamic changes
after TIPS occlusions have been reported. In severe cases TIPS occlusion re –
sulted in the death of the patients. It is also important to note that the symp –
toms of portal hypertension will reoccur, such as Varices and Ascites. In the
case of variceal hemorrhage, the embolization of the varices shall be per –
formed prior to the occlusion of the stent. If the indication of TIPS was ascites,
peritovenous shunting or aggressive medical therapy should be considered. To
combat encephalopathy a reduction of the stent diameter can also be per –
formed. Several techniques exist, but all involve the use of a covered stent
within the original TIPS. In the study of Madoff et al, a suture was used to con –
strain a seld epxanding stent to decrease TIPS flow in 6 patients. Improvement
was shown in 5 out of the 6 patients. Fanelli et al used a constrained balloon
technique in patients, that was highly successful in managing hepatic en –
cephalopathy. Monnin-Bares et al used a “lasso technique” in 5 patients. Im –
provement of hepatic encephalopathy was shown in 4 out of 5 patients. Maleux
et al used a “parallel technique” in 17 patients. Improvement was shown in
76% of the patients.
Another early postprocedural complication is acute hepatic failure. It is a rare
but severe complication with a poor prognosis. The typical presentation is with
elevated liver function test values, severe hepatic encephalopathy and severe
coagulopathy. To minimize the occurrence of acute hepatic failure after TIPS
insertion, a proper preprocedural assessment and patient selection are crucial.
In patients with decreased hepatic function, a target portosystemic gradient
may be choosen, since a large drop may precipiate acute liver failure. Current
19

recommendations are that for patients with a Child-Pugh Score >10 or Meld
score >14 should not have their portosystemic gradient reduced to less than
5mmHg. Hepatic Failure usually involves an already diseased liver and the fol –
lowning mechanisms:
1.Decrease of the portal perfusion pressure due to TIPS insertion, which
can also reverse portal vein flow, resulting in ischemia
2.TIPS stent may be responsible for the compression or occlusion of the
hepatic artery and/ or portal vein branches, resulting in ischemia or in –
farction
3.Occlusion of the hepatic veins by the covered portion of the stent, re –
sulting in a Budd Chiari type ischemia and acute hepatic failure
For establishing the etiology of post-TIPS acute hepatic failure, contrast en –
hanced CT may be used. It is helpful to identify thrombosis or vessel occlu –
sions and if no such lesion is present, the most likely cause of the hepatic fail –
ure is due to altered portal venous hemodynamics. In this case, the stent
should be occluded rapidly, or atleast a flow reduction technique should be at –
tempted. The only effective therapy for acute hepatic failure due to TIPS inser –
tion still remains liver transplantion.
Also biliary obstruction may be a result of TIPS insertion. Injury to bile ducts
may occur in patients with and without dilated bile ducts. If a bare metal stent is
used and during the procedure a biliary tract is perforated, a biliary venous fis –
tula may result. Clinical manifestions are numerous, including TIPS occlusion,
anemia, multiorgan failure and sepsis. However, when using covered stents,
those fistulas should theoretically not occur.
Early acute Occlusion is a complication that requires reinterventions in 70-90%
of the patients within 2 years of TIPS insertion. If a patient presents with a re –
current thrombotic TIPS it is important to rule out underlying risk factors such
as hypercoagulopathy. Acute Occlusion is reported in less than 5% of TIPS in –
20

sertions. When using bare metal stents, the occlusion of the TIPS is often
thought to be a result of a biliary-venous fistula. The occlusion rate of covered
stents is therefore much lower than the rate of bare metal stents. With the use
of the Viatorr endoprosthesis, early acute thrombosis of TIPS rarely occurs,
causes include suboptimal TIPS postioning or stent migration. Treatment of
acute occlusion includes mechanical thrombectomy or catheter directed throm –
bolysis. For malpositioned stents, the use of another stent may be considered
to extend the current TIPS. If this is not possible, a new TIPS must be inserted.
Delayed Complications of TIPS include the Recurrency of portal Hypertension
symptoms. In the era of bare metal stents, recurrent variceal bleeding ap –
peared in 23-40% of patients during a 2-year period. Due to the introduction of
the covered stents, shunt patency has greatly improved. When recurrent symp –
toms appear, a angiography should be performed and the portosystemic gradi –
ent shall be measured. Stenosis of the hepatic vein at the TIPS margin is the
most common site of pathology. It is treated with a balloon angioplasty as well
as the intra-TIPS thrombosis. Sometimes hepatic vein or intra-TIPS stenosis
may be difficult to verify with angiography, but if the portosystemic gradient is
significantly elevated, an empiric angioplasty is indicated. If the lesion is non-
responsive, a new stent shall be inserted. If the high portosystemic gradient
persists despite empiric angioplasty and stent insertion, a arterial-portal shunt
must be ruled out. If the shunt is absent the placement of a second TIPS could
be considered. He et al placed such “parallel” TIPS without complications. In
patients with portal hypertensive ectopic varices a high risk of re-bleeding ex –
ists. The rate of re-bleeding can be reduced significantly if the embolization of
the varices is performed together with TIPS insertion.
Another Complication is Hernia Incarceration in patients undergoind TIPS pro –
cedure for refractory ascites. The increased risk is estimated to be up to 25%.
The complication is due to anatomical alterations of the abdominal cavity, after
the removal of massive ascites because of the TIPS insertion. This results in
21

the bowels being entrapped in hernias.
Also Infection of the stents may occur. It may be suspected in patients with
sustained and unexplained bacteremia. Treatment includes lifelong antibiotics
or liver transplant. (7)
22

2. Special Review
2.1 Introduction
Portal venous stasis is a serious complication of liver cirrhosis. To combat the
consequences of portal hypertension, TIPS has shown be effective for various
indications. The goal of the TIPS intervention is to re-establish blood flow and
to reduce or reverse the complications arising from the portal hypertension.
The purpose of this study is to establish, whether an early TIPS dysfunction
can be detected by laboratory parameters or if even parameters exist, that may
indicate an increased risk of dying after TIPS procedure.
2.2 Materials and Methods
The data for this study was collected in the regional institute for
gastroenterology and hepatology “Prof. Dr. Octavion Fodor”. This study
contains a total of 85 patients from the 24.11.2011 until the 21.3.2019. The
laboratory values obtained from these Patients are:
•Transaminases
•Blilirubin
•Alkaline Phosphatase
•Gamma-GT
•Platelets
•Sodium
•Creatinine
•Albumin
•INR
•C-reactive Protein
All these laboratory Parameters were collected at the following time stamps:
•before the TIPS intervention
•48h after the TIPS was inserted
•at the patient's discharge
•when the patient came for the TIPS check-up 1 month after the
procedure
23

Also the hemodynamic parameters measured during the intervention are
included in the Study:
•Right Atrium Pressure
•IVC Pressure
•Portal venous Pressure
•Portal Pressure Gradient
The hemodynamioc parameters were measured before and after the stent is
inserted. At the one month check-up, we can detect if the TIPS is functional
according to those hemodynamic parameters.
We included all Patients in this study, that underwent the TIPS procedure in the
given time interval.
The statistical review was done with SPSS. The statistical test to detect if there
is a correlation between the laboratory parameters and an early TIPS
dysfunction or death is the Mann-Whitney-U test. A p-value of less than 0,05
was considered statistically significant.
The Null-Hypothesis is, that there is no correlation between the laboratory
parameters and an early TIPS dysfunction or death. The alternative Hypothesis
is that there exists a correlation.
24

2.3 Descriptive Statistics
2.3.1 Gender and Age
Age
MeanStandard
DeviationCount
GenderMale54958
Female56827
We have a total of 85 Patients, 58 of whom are male and 27 are female. The
mean age for the male patients is 54 with the standard deviation being 9. The
mean age for females is 56 with the standard deviation being 8. Below there is
a table with the exact age distribution.
25

2.3.2 Etiology of Cirrhosis
The main Etiology of Cirrhosis in this study was Alcohol with 48,2%, with a
mean age of 56 and a standard deviation of 8. Of the 41 patients with an
alcoholic cirrhosis, 34 are male and 7 are female.
The second most common etiology is the hepatitis C virus with 20%, with a
mean age of 53 and a standard deviation of 8. Out of the 17 patients with HCV
7 are male and 10 are female.
26

2.3.3 Indication for TIPS
The main Indication for the TIPS procedure in this study was Esophageal
bleeding (52,9%). The second most common indication was Esophageal
Bleeding together with refractory ascites (17,6%) followed by refractory ascites
(16,5%).
2.3.4 Type of TIPS
27

2.3.5 TIPS Dysfunction
Out of the 85 patients, 64 underwent the check-up catheterization, whereas in
21 patients no check-up was performed. In 31 patients there was a dysfunction
present and in 33 patients there was no dysfunction present at the check-up.
2.3.6 Patients Death
Among our Patient selection, 21 Patients died during our given time period.
Patients died between 0 to 43 months, with the mean being 7 months.
The main cause of death was Sepsis or Multiorgan Failure, followed by Liver
Failure. 15% of the Patients died of unknown cause and 1 patient each died of
heart attack and variceal bleeding.
28

2.4 Analytical Statistics
2.4.1 Analysis of TIPS Dysfunction
2.4.1.1 Laboratory Values at Admission
The laboratory values before the TIPS procedure show no significant
correlation between their respective values and early TIPS dysfunction,
therefore we have to accept the H0 Hypothesis.
2.4.1.2 Laboratory Values at 48h after TIPS procedure
29

The laboratory values 48 hours after the TIPS procedure show no significant
correlation between their respective values and early TIPS dysfunction,
therefore we have to accept the H0 Hypothesis.
2.4.1.3 Laboratory Values at discharge
The laboratory values at the Patients discharge show no significant correlation
between their respective values and early TIPS dysfunction, therefore we have
to accept the H0 Hypothesis.
2.4.1.4 Laboratory Values at 1 month revision
Most of the laboratory values at the 1 month revision show no significant
correlation between their respective values and early TIPS dysfunction,
therefore we have to accept the H0 Hypothesis.
For the Sodium level p < 0,05 therefore there exists a significant correlation.
The effect size for sodium is 0,352 which means that there is a medium effect
size. This means, that we can reject the H0 Hypothesis and accept the H1
Hypothesis, that there is a significant correlation between Sodium Levels at the
1 month revision and early TIPS dysfunction.
30

2.4.1.5 Hemodynamic Parameters at the first Procedure
The hemodynamic parameters at the TIPS insertion show no significant
correlation between their respective values and early TIPS dysfunction,
therefore we have to accept the H0 Hypothesis.
2.4.1.6 Delta Values Transaminases
The Delta Values of the Transaminases show no significant correlation
between their respective values and early TIPS dysfunction, therefore we have
to accept the H0 Hypothesis.
31

2.4.1.7 Delta Values Gamma-GT and Alkaline Phosphatase
The Delta Values of Gamma-GT and Alkaline Phosphatase show no significant
correlation between their respective values and early TIPS dysfunction,
therefore we have to accept the H0 Hypothesis.
2.4.1.8 Delta Values Platelets and Sodium
The Delta Values of Platelets and Sodium show no significant correlation
between their respective values and early TIPS dysfunction, therefore we have
to accept the H0 Hypothesis.
2.4.1.9 Delta Values Bilirubin and Creatinine
The Delta Values of Bilirubin and Creatinine show no significant correlation
between their respective values and early TIPS dysfunction, therefore we have
to accept the H0 Hypothesis.
32

2.4.1.10 Delta Values Albumin, INR and CRP
The Delta Values of Albumin, INR and CRP show no significant correlation
between their respective values and early TIPS dysfunction, therefore we have
to accept the H0 Hypothesis.
2.4.2 Analysis of Survival
2.4.2.1 Laboratory Values at Admission
33

Most of the laboratory values before the TIPS procedure show no significant
correlation between their respective values and survival, therefore we have to
accept the H0 Hypothesis.
For sodium the p value is <0,05 therefore there is a significant correlation
between sodium levels before TIPS insertion and survival. The effect size is
0,305, which is a medium effect size.
For CRP the p value is <0,05 therefore there is a significant correlation
between CRP levels before TIPS insertion and survival. The effect size is
0,461 which is a medium effect size.
This means, that we have to reject the H0 hypothesis for Sodium and CRP and
accept the alternative Hypothesis that there is a significant correlation between
their laboratory values at 48h after TIPS insertion and survival.
2.4.2.2 Laboratory Values at 48 hours
Most of the laboratory values at 48 hours after the TIPS insertion show no
significant correlation between their respective values and survival, therefore
we have to accept the H0 Hypothesis.
For GGT the p value is <0,05 therefore there is a significant correlation
between GGT levels at 48 hours after the TIPS insertion and survival. The
effect size is 0,320, which is a medium effect size.
For Sodium the p value is <0,05 therefore there is a significant correlation
between sodium levels at 48 hours after the TIPS insertion and survival. The
effect size is 0,369, which is a medium effect size.
For INR the p value is <0,05 therefore there is a significant correlation between
34

INR levels at 48 hours after the TIPS insertion and survival. The effect size is
0,461, which is a medium effect size.
For CRP the p value is <0,05 therefore there is a significant correlation
between CRP levels at 48 hours after the TIPS insertion and survival. The
effect size is 0,409, which is a medium effect size.
This means, that we have to reject the H0 hypothesis for GGT, Sodium,INR
and CRP and accept the alternative Hypothesis that there is a significant
correlation between their laboratory values at 48h after TIPS insertion and
survival.
2.4.2.3 Laboratory values at discharge
Some of the laboratory values at discharge show no significant correlation
between their respective values and survival, therefore we have to accept the
H0 Hypothesis for ALT, GGT, ALP, Albumin and CRP.
For AST the p value is <0,05 therefore there is a significant correlation between
AST levels at discharge and survival. The effect size is 0,265, which is a
medium effect size.
For Platelets the p value is <0,05 therefore there is a significant correlation
between Platelets levels at discharge and survival. The effect size is 0,362,
which is a medium effect size.
For Sodium the p value is <0,05 therefore there is a significant correlation
between sodium levels at discharge and survival. The effect size is 0,258,
which is a medium effect size.
35

For Bilirubin the p value is <0,05 therefore there is a significant correlation
between Bilirubin levels at discharge and survival. The effect size is 0,329,
which is a medium effect size.
For Creatinine the p value is <0,05 therefore there is a significant correlation
between Creatinine levels at discharge and survival. The effect size is 0,366,
which is a medium effect size.
For INR the p value is <0,05 therefore there is a significant correlation between
INR levels at discharge and survival. The effect size is 0,602, which is a strong
effect size.
This means, that we have to reject the H0 hypothesis for AST, Platelets,
Sodium, Bilirubin, Creatinine and INR and accept the alternative Hypothesis
that there is a significant correlation between their laboratory values at
discharge and survival.
2.4.2.4 Laboratory Values at the first Revivsion
Most of the laboratory values at the first revision show no significant correlation
between their respective values and survival, therefore we have to accept the
H0 Hypothesis.
For Sodium the p value is <0,05 therefore there is a significant correlation
between Sodium Levels at discharge values and survival. The effect size is
0,372, which is a medium effect size.
For Albumin the p value is <0,05 therefore there is a significant correlation
between Albumin levels at discharge and survival. The effect size is 0,341,
36

which is a medium effect size.
For CRP the p value is <0,05 therefore there is a significant correlation
between CRP levels at discharge and survival. The effect size is 0,372, which
is a medium effect size.
This means, that we have to reject the H0 hypothesis for Sodium, Albumin and
CRP and accept the alternative Hypothesis that there is a significant
correlation between their laboratory values at discharge and survival.
2.4.2.5 Hemodynamic Parameters at TIPS Insertion
The hemodynamic parameters at TIPS insertion show no statistical
significance between their value and survival. Therefore we have to accept the
H0 Hypothesis.
2.4.2.6 Hemodynamic Parameters after TIPS Insertion
The hemodynamic parameters after TIPS insertion show no statistical
significance between their value and survival. Therefore we have to accept the
H0 Hypothesis.
37

2.4.2.7 Delta Values Transaminases
The Delta Values of the Transaminases show mostly no statistical significance
between their value and survival, therefore we have to accept the H0
Hypothesis.
For Delta AST between 48h and admission, p<0,05 therefore there is a
statistical significance for the Delta of AST between 48h and admission and
survival. The effect size is 0,272, which is a medium effect size.
This means that for Delta AST between 48h and admission we have to reject
the H0 Hypothesis and accept the alternative Hypothesis.
2.4.2.8 Delta Values Gamma-GT and Alkaline Phosphatase
The Delta Values of Gamma-GT and Alkaline Phosphatase show no statistical
significance between their value and survival, therefore we have to accept the
H0 Hypothesis.
38

2.4.2.9 Delta Values Platelets and Sodium
The Delta Values of Platelets and Sodium show mostly no statistical
significance between their value and survival, therefore we have to accept the
H0 Hypothesis.
For Delta Platelets between 48h and admission, p<0,05 therefore there is a
statistical significance for the Delta of Platelets between 48h and admission
and survival. The effect size is 0,286, which is a medium effect size.
For Delta Platelets between discharge and admission, p<0,05 therefore there
is a statistical significance for the Delta of Platelets between discharge and
admission and survival. The effect size is 0,420, which is a medium effect size.
This means that for Delta Platelets between 48h and admission and Delta
Platelets between discharge and admission we have to reject the H0
Hypothesis and accept the alternative Hypothesis.
2.4.2.10 Delta Values Bilirubin and Creatinine
The Delta Values of Bilirubin and Creatinine show mostly no statistical
significance between their value and survival, therefore we have to accept the
H0 Hypothesis.
For Delta Bilirubin between discharge and admission, p<0,05 therefore there is
a correlation between the Delta Bilirubin between discharge and admission
values and survival. The effect size is 0,288, which is a medium effect size.
39

This means, that for Delta Bilirubin between discharge and admission, we
have to reject the H0 Hypothesis and accept the alternative Hypothesis.
2.4.2.11 Delta Values Albumin and INR
The Delta Values of Albumin and INR show mostly no statistical significance
between their value and survival, therefore we have to accept the H0
Hypothesis.
For Delta INR between 48h and admission, p<0,05 therefore there is a
correlation between the Delta INR between discharge and admission values
and survival. The effect size is 0,496, which is a medium to strong effect size.
For Delta INR between discharge and admission, p<0,05 therefore there is a
correlation between the Delta INR between discharge and admission values
and survival. The effect size is 0,674, which is a strong effect size.
This means, that for Delta INR between 48h and admission and Delta INR
between discharge and admission, we have to reject the H0 Hypothesis and
accept the alternative Hypothesis.
2.4.2.12 Delta Values CRP
40

The Delta Values of CRP show no statistical significance between their value
and survival, therefore we have to accept the H0 Hypothesis.
2.4.3 Cirrhosis Etiology and Gender
We performed a Chi-Square test to test for significance between Gender and
Cirrhosis Etiology. The Chi-Square Score is 23,073 with 9 degrees of freedom
and a p-value = 0,06. This means, that there is a statistical significance
between gender and Cirrhosis Etiology.
41

2.4.4 TIPS Indication and Gender
We performed a Chi-Square test to test for significance between Gender and
TIPS Indication. The Chi-Square Score is 6,3 with 7 degrees of freedom and a
p-value = 0,505. This means, that there is no statistical significance between
gender and TIPS dysfunction.
42

2.4.5 TIPS Dysfunction and Gender
We performed a Chi-Square test to test for significance between Gender and
TIPS Dysfunction. The Chi-Square Score is 2,4 with 2 degrees of freedom and
a p-value = 0,301. This means, that there is no statistical significance between
gender and TIPS dysfunction.
2.4.6 TIPS Dysfunction and Survival
We performed a Chi-Square test to test for significance between TIPS
Dysfunction and Survival. The Chi-Square Score is 23,073 with 9 degrees of
freedom and a p-value = 0,006. This means, that there is a statistical
significance between TIPS dysfunction and Survival.
43

2.4.7 TIPS Indication and Dysfunction
We performed a Chi-Square test to test for significance between TIPS
indication and TIPS Dysfunction. The Chi-Square Score is 14,048 with 14
degrees of freedom and a p-value = 0,446. This means, that there is no
statistical significance between TIPS indication and TIPS dysfunction.
44

2.4.8 TIPS Indication and Survival
We performed a Chi-Square test to test for significance between TIPS
Indication and Survival. The Chi-Square Score is 12,752 with 12 degrees of
freedom and a p-value = 0,078. This means, that there is no statistical
significance between TIPS indication and Survival.
45

2.4.8 Cirrhosis Etiology and Survival
We performed a Chi-Square test to test for significance between Cirrhosis
Etiology and Survival. The Chi-Square Score is 3,916 with 9 degrees of
freedom and a p-value = 0,917. This means, that there is no statistical
significance between Cirrhosis Etiology and Survival.
46

2.4.9 Cirrhosis Etiology and Dysfunction
We performed a Chi-Square test to test for significance between Cirrhosis
Etiology and TIPS Dysfunction. The Chi-Square Score is 15,694 with 18
degrees of freedom and a p-value = 0,614. This means, that there is no
statistical significance between Cirrhosis Etiology and TIPS Dysfunction.
3. Discussion
Persons that undergo the TIPS Procedure already suffer from severe
Complications of Liver Disease. This is why it is of Importance to identify early
TIPS Dysfunctions to reestablish blood flow and minimize further
complications.
Because those patients are at such a high risk, we performed this study to
establish whether there are any connections between Laboratory Parameters,
Hemodynamic Parameters and early TIPS dysfunction and/ or survival.
As seen above, 58 patients were male and 27 patients are female. This raises
the question if male patients are more likely to develop cirrhosis or if male
patients are more likely to develop complications that require the TIPS
47

intervention. According to our performed Chi-Square test, we established that
this observation is due to the higher prevalence of liver cirrhosis due to alcohol
consumption in men.
We also tried to establish if there are correlations between the Indication of
TIPS and Gender, and the development of TIPS dysfunction and Gender, but
in both performed Chi-Square tests, there was no statistical significance found.
4. Conclusion
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