Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_51_библиотеки_им_акад_М_И_Перельмана
.pdf
[182] Albillos AGJ, Arroyo-Manzano D, Zamora J, Ahmad I, de la Pena J, Garcia-Pagan JC, et al. Prevention of recurrent variceal hemorrhage
individual patient meta-analysis of outcomes with current therapy based on the severity of cirrhosis. Hepatology. 2015;62(Suppl 1):581A.
[183] Perez-Ayuso RM, Pique JM, Bosch J, Panes J, Gonzalez A, Perez R, et al. Propranolol in prevention of recurrent bleeding from severe
portal hypertensive gastropathy in cirrhosis. Lancet. 1991;337(8755):14314.
[184] Wang T, Kaumann AJ, Brown MJ. ()-Timolol is a more potent antagonist of the positive inotropic effects of ()-adrenaline than of
those of ()-noradrenaline in human atrium. Br J Clin Pharmacol 1996;42(2):21723.
[185] Merkel C, Zoli M, Siringo S, van BH, Magalotti D, Angeli P, et al. Prognostic indicators of risk for first variceal bleeding in cirrhosis: a
multicenter study in 711 patients to validate and improve the North Italian Endoscopic Club (NIEC) index. Am J Gastroenterol 2000;95
(10):291520.
[186] Gluud LL, Krag A. Banding ligation vs beta-blockers for primary prevention in oesophageal varices in adults. Cochrane Database Syst
Rev 2012;8:CD004544.
[187] Tripathi D, Ferguson JW, Kochar N, Leithead JA, Therapondos G, McAvoy NC, et al. Randomized controlled trial of carvedilol vs vari-
ceal band ligation for the prevention of the first variceal bleed. Hepatology. 2009;50(3):82533.
[188] Shah HA, Azam Z, Rauf J, Abid S, Hamid S, Jafri W, et al. Carvedilol vs. esophageal variceal band ligation in the primary prophylaxis
of variceal hemorrhage: a multicentre randomized controlled trial. J Hepatol 2014;60(4):75764.
[189] Albillos A, Zamora J, Martinez J, Arroyo D, Ahmad I, De-la-Pena J, et al. Stratifying risk in the prevention of recurrent variceal hemor-
rhage: results of an individual patient meta-analysis. Hepatology. 2017;66(4):121931.
[190] Mookerjee RP, Pavesi M, Thomsen KL, Mehta G, Macnaughtan J, Bendtsen F, et al. Treatment with non-selective beta blockers is associ-
ated with reduced severity of systemic inflammation and improved survival of patients with acute-on-chronic liver failure. J Hepatol
2016;64(3):57482.
[191] Pereira GHBC, Victor L, Piedade J, Guimaraes L, Rocha T, Veiga Z, et al. Use of non selective beta blockers in cirrhotic patients with
bacterial infections is associated with lower frequency of sepsis, but not of acute-on-chronic liver failure or survival. Results of a pro-
spective study. Hepatology. 2016;64(2):S264.
[192] Bhutta AQG-TG, Reddy R, Tandon P, Wong F, O’Leary JG, Acharya C, et al. Beta blocker use in hospitalized cirrhotic patients with
ascites is associated with a lower MELD, inflammation and an improved survival. Gastroenterology. 2016;150(4):S10845.
[193] Mishra SR, Sharma BC, Kumar A, Sarin SK. Primary prophylaxis of gastric variceal bleeding comparing cyanoacrylate injection and
beta-blockers: a randomized controlled trial. JHepatol 2011;54(6):11617.
[194] Mishra SR, Chander SB, Kumar A, Sarin SK. Endoscopic cyanoacrylate injection vs beta-blocker for secondary prophylaxis of gastric
variceal bleed: a randomised controlled trial. Gut. 2010;59(6):72935.
[195] Hung HH, Chang CJ, Hou MC, Liao WC, Chan CC, Huang HC, et al. Efficacy of non-selective beta-blockers as adjunct to endoscopic
prophylactic treatment for gastric variceal bleeding: a randomized controlled trial. J Hepatol 2012.
[196] Ripoll C, Garcia-Tsao G. The management of portal hypertensive gastropathy and gastric antral vascular ectasia. Dig Liver Dis 2011;43
(5):34551.
[197] Conn HO. Propranolol in the treatment of portal hypertension: a caution. Hepatology. 1982;2(5):6414.
[198] Serste T, Melot C, Francoz C, Durand F, Rautou PE, Valla D, et al. Deleterious effects of beta-blockers on survival in patients with cir-
rhosis and refractory ascites. Hepatology. 2010;52(3):101722.
[199] Mandorfer M, Bota S, Schwabl P, Bucsics T, Pfisterer N, Kruzik M, et al. Nonselective beta blockers increase risk for hepatorenal syn-
drome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):168090 e1.
[200] Serste T, Njimi H, Degre D, Deltenre P, Schreiber J, Lepida A, et al. The use of beta-blockers is associated with the occurrence of acute
kidney injury in severe alcoholic hepatitis. Liver Int 2015;35(8):197482.
[201] Krag A, Wiest R, Albillos A, Gluud LL. The window hypothesis: haemodynamic and non-haemodynamic effects of beta-blockers
improve survival of patients with cirrhosis during a window in the disease. Gut. 2012;61(7):9679.
[202] Njei B, McCarty TR, Garcia-Tsao G. Beta-blockers in patients with cirrhosis and ascites: type of beta-blocker matters. Gut. 2016;65
(8):13934.
[203] Chirapongsathorn S, Valentin N, Alahdab F, Krittanawong C, Erwin PJ, Murad MH, et al. Nonselective beta-blockers and survival in
patients with cirrhosis and ascites: a Systematic review and meta-analysis. Clin Gastroenterol Hepatol 2016;14(8):1096104.
[204] Giannelli V, Roux O, Laouenan C, Manchon P, Ausloos F, Bachelet D, et al. Impact of cardiac function, refractory ascites and beta block-
ers on the outcome of patients with cirrhosis listed for liver transplantation. J Hepatol 2020;72(3):46371.
[205] Tergast TL, Kimmann M, Laser H, Gerbel S, Manns MP, Cornberg M, et al. Systemic arterial blood pressure determines the therapeutic
window of non-selective beta blockers in decompensated cirrhosis. Aliment Pharmacol Ther 2019;50(6):696706.
[206] Tergast TL, Maasoumy B. Editorial: pressure to close the therapeutic window of non-selective beta blockers? Authors’ reply. Aliment
Pharmacol Ther 2019;50(8):95860.
[207] Garcia-Tsao G, Abraldes JG, Berzigotti A, Bosch J. Portal hypertensive bleeding in cirrhosis: risk stratification, diagnosis, and manage-
ment: 2016 practice guidance by the American Association for the study of liver diseases. Hepatology. 2017;65(1):31035.
[208] European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL Clinical
Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol 2018;69(2):40660.
[209] Garcia-Tsao GAJ, Berzigotti A, Bosch J. Reply to: does the dose and type of NSBBs really matter? Hepatology. 2017;66(1):3023.
64 4. Drugs at the crossroads of heart and liver
I. Liver and heart
https://t.me/medicina_free
CHAPTER
5
Obstruction of the liver circulation
Xuefeng Luo, Oana Nicoar
˘
a-Farc
˘
au, Marta Magaz, Fabian Betancourt,
Guillem Soy, Anna Baiges, Fanny Turon, Virginia Herna
´
ndez-Gea and
Juan Carlos Garcı
´
a-Paga
´
n
Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clı
´
nic, Institut de Investigacions Biome
`
diques
August Pi i Sunyer (IDIBAPS), Centro de Invetsigacio
´
n Biome
´
dica en Red de Enfermedades Hepa
´
ticas y Digestivas
(CIBERehd), Instituto de Salud Carlos III, Universidad de Barcelona, Health Care Provider of the European Reference
Network on Rare Liver Disorders (ERN-Liver), Madrid, Spain
Introduction
Obstruction of the liver circulation refers to a series of vascular disorder s of the liver, including BuddChiari
syndrome (BCS), noncirrhotic nontumoral portal vein thrombosis (NCPVT), sinusoidal obstruction syndrome
(SOS), and Hepatic artery thrombosis. A commo n characteristic of these disorders is that patients are usually
young with an otherwise normal life expectancy that may be significantly reduced if timely diagnosis or disease-
specific management was not provided. Despite the rarity of obstruction of the liver circulation, interest for these
disorders has increased and a lot of important studies assessing epidemiology, natural history, pathogenesis,
diagnosis, and management have been published. The purpose of this chapter is to provide clinicians with
approaches to diagnose and manage the disorders based on current evidence.
BuddChiari syndrome
BCS is a rare vascular disorder characterized by the obstruction of hepatic venous outflow [1]. This obstruction
could be found from the small hepatic veins to the entrance of the inferior vein cava (IVC) into the right atrium.
BCS should be distinguished from other conditions causing hepatic outflow obstruction, such as cardiac disease,
pericardial disease, or SOS. BCS is classified as primary when the obstruction originates in the vein or secondary
when the obstruction is due to external compression (e.g., tumor).
Risk factors
Although some risk factors are specifically related to only BCS or only NCPVT, most of them are shared
by both disorders. Therefore the work-up for the risk factors could be applied to both BCS and NCPVT
(
Table 5.1) [1]. A comprehensive and continuing survey is vital since multiple prothrombotic conditions are
common and new risk factors could be found, thanks to the improvement of the detection techniques.
Indeed, in an European study of 157 patients with splanchnic thrombosis, reanalysis during follow- up identi-
fied additional etiological factors in 12 previously unclassified patients
[2]. A much higher prevalence of pro-
thrombotic disorders has been reported in Western than in Eastern countries
[3]. However, a high prevalence
65
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00004-8 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
of hypercoagulability conditions has been recently described in an Indian study, requiring more studies to
uncover the causes of BCS in other regions of Asia
[4,5].
A meta-analysis revealed that the mean prevalence of myeloproliferative neoplasm (MPNs) in BCS patients was
40.9%
[6].MostofthemareJAK2V617F positive (79.5%), and a very small fraction Calreticulin positive (5.1%) [7].In
current studies, no Exon-12 or myeloproliferative leukemia virus oncogene mutations were found in patients with
MPN and splanchnic vein thrombosis
[1]. Therefore it is currently recommended to initially test patients for
JAK2V617F.IfJAK2V617F and if negative, the patients are then tested for calreticulin. However, due to the low prev-
alence of calreticulin positive patients, it has been suggested to test only patients with spleen length $ 16 cm and
platelet count . 150 3 10
9
/L [7,8]. Nevertheless, there is a fraction of patients negative for these two mutations that
TABLE 5.1 Investigations for risk factors in patients with Budd-Chiari Syndrome and NCPVT.
Thrombotic risk factors Work-up
Systemic factors
Acquired conditions
MPN Test JAK2V616F in all patients
Test for CALR mutations in patients without JAK2V617F, but with spleen height $ 16 cm and
platelet count .150 3 10
9
/L.
In the remaining patients, MPN diagnosis relies on bone marrow biopsy performed on a case-by-
case basis. Role of Next Generation Sequencing (NGS) still not determined.
PNH CD55 and CD59 deficient clone
Antiphospholipid syndrome Diagnosis based on repeatedly detectable anticardiolipin antibodies at high level, or lupus
anticoagulant, or antibeta2 glycoprotein 1 antibodies. Be aware that patients with vascular liver
disease may have nonspecific fluctuating, low titer antiphospholipid antibodies in the absence of a
real antiphospholipid syndrome.
Inherited conditions
Factor V Leiden Test for factor V Leiden mutation
Factor II gene mutation Test for G20210A mutation
Protein C deficiency Decreased protein C activity levels
Protein S deficiency Decreased free protein S levels
Antithrombin deficiency Decreased antithrombin activity levels. Role of antithrombin sequencing still not validated.
Hyperhomocysteinemia Increased serum homocysteine level prior to disease
External factors
Recent pregnancy Medical history
Recent oral contraceptive use Medical history
Other systemic disease
Behc¸et disease Diagnosis based on a set of conventional criteria. To be routinely considered in patients with IVC
thrombosis, or originating from endemic areas, or having extrahepatic features suggestive for the disease
HIV infection Antihuman immunodeficiency virus antibodies
Celiac disease Antitransglutaminase antibodies
Sarcoidosis Serum angiotensin-convertingenzyme level; Biopsy
Cytomegalovirus infection Anti-CMV IgM
Local factors
Inflammatory intra-abdominal lesions Medical history, imaging and biochemical results
Abdominal surgery or trauma Medical history
BCS, Budd-Chiari syndrome; IVC; inferior vena cava; MPN, myeloproliferative neoplasms; PNH, paroxysmal nocturnal hemoglobinuria.
Adapted from Hernandez-Gea V, De Gottardi A, Leebeek FWG, Rautou PE, Salem R, Garcia-Pagan JC. Current knowledge in pathophysiology and management of Budd-Chiari
syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis. J Hepatol. 2019;71(1):175199.
66 5. Obstruction of the liver circulation
I. Liver and heart
https://t.me/medicina_free
still have an underlying MPN. Next generation sequencing (NGS), a DNA sequencing technology that perform
sequencing of millions of small fragments of DNA in parallel, have been suggested to be included in the diagnostic
algorithms of patients with MPN especially those that are negative for the previously mentioned mutations.
Inclusion of NGS in the diagnostic workout of patients with splanchnic vein thrombosis may facilitate the diagnosis
of an unrecognized underlying MPN. This high prevalence of MPN has also been found in India, Turkey, and
Egypt
[912], although it seems much less common in Chinese patients with BCS [3,13].
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematologi cal disorder which is strongly asso-
ciated with an increased risk of venous thrombosis
[14]. PNH is more frequent in patients with BCS [14] than in
those with NCPVT where PNH is a very infrequent cause.
Systemic thrombophilic disorders are common in patients with BCS. Prevalence of factor V Leiden is twice as
high in European BCS patients than in the general population. However, it is commonly associated with other pro-
thrombotic risk factor
[15,16]. Studies from India, Turkey, and Egypt except China also confirmed this finding [12].
Factor II gene mutation seems to play a minor role for BCS. On the contrary, in NCPVT Factor V Leiden mutation
is less frequently found that Factor II gene mutations. Diagnoses of protein C, protein S, or antithrombin deficien-
cies are primarily based on the determination of its plasma levels. These coagulation inhibitors are synthesized by
the liver and therefore the diagnosis of a real congenital deficit is a challenge in the presence of altered liver func-
tion
[17]. It has been recently proposed to include a genetic study of SERPINC1 (the gene encoding antithrombin)
and a study of post-translational defects of antithrombin (such as alterations in N-glycosylation pathways)
[18].
This has been shown to improve the capacity to detect antithrombin deficiencies
[18].
Local risk factors, such as local trauma, inflammatory diseases, and abdominal infections, seem to be relatively
rare in patients with BCS
[19]. In the European BCS cohort, the presence of local factors was only reported in
11% of patients
[19], although 25% in more recent data from a French survey [20].
Natural history
Clinical presentations of BCS are extremely heterogeneous and vary from asymptomatic forms, incidentally
diagnosed, to severe forms of acute liver failure. In an European cohort of 163 patients with BCS, ascites (83%),
hepatomegaly (67%), and abdominal pain (61%) were the most common symptoms
[19] and esophageal varices
were found in 58% of patients
[19]. Typical biochemical results are the elevation of transaminases and decrease
in prothrombin time.
The varied forms of clinical manifestations are thought to correlate with extension and speed of thrombosis
development. Obstruction of one hepatic vein or IVC may lead to the formation of collaterals aimed to bypass
the occluded vein, decompressing the portal venous system partially and keeping the patient asymptomatic.
Conversely, an extensive and rapid thrombosis may cause a severe form of acute liver failure and death if not
adequately and timely treated.
In the West, hepatic veins are the most frequent site of thrombosis
[2,19], whereas in Asia IVC obstruction
(mainly from membrane or web) or combined IVC-HV obstr uction are the most frequent BCS type
[21].
Accordingly, the presence of abdominal varices and lower limb edema or ulcers is more frequently described in
the East
[4].
Benign hepatic regenerative nodules are very frequent in BCS patients with a reported prevalence of around
60%70%
[2225]. These nodules are usually small (under 34 cm in diameter), multiple (more than 10 lesions),
hypervascularized, and disseminated throughout the liver. Hepatic benign nodules have the macro- and micro-
scopic histological alterations of focal nodular hyperplasia (FNH) and are usually called FNH-like lesions
[26,27].
Although less frequently, chronic BCS patients may also develop hepatocellular adenomas
[28] or hepatocellular
carcinoma (HCC)
[29]. A systematic review reported an HCC prevalence in BCS ranging from 2%46.2% [30].
Probably more informative are the data from the study by Moucari and colleagues reporting a 7% five-year
cumulative incidence of HCC in a large cohort of BCS patients
[29]. Although a higher prevalence of HCC has
been reported in patients with long-term IVC obstruction, the risk factors for HCC occurrence are not clearly
defined
[29,31].
Radiological characteristics of HCC in BCS patients are heterogeneous and not specif ic enough. Thus the value
of observing washout, very useful in HCC in cirrhosis, is limited in BCS because close to one-third of patients
with benign nodules greater than 1 cm had washout
[32]. Recently, it has been suggested that lesions showing
homogeneous hypointensity at magnetic resonance imaging (MRI) using hepatobiliary contrast may be highly
suspicious of HCC especially if alpha-fetoprotein is higher than 15 ng/mL
[33]. However, the number of patients
67Natural history
I. Liver and heart
https://t.me/medicina_free
with HCC was very small (n 5 4) and these findings need to be validated. Therefore HCC diagnosis in BCS
patients is still a challenge and should never rely only on imaging criteria and should require histological confir-
mation. It is important to recognize that benign nodules may also increase in numbe r and in size during follow-
up and therefore these facts are not synonymous of malignancy
[22]. Routine surveillance for HCC in patients
with BCS using ultrasound at six months of interval as in cirrhosis is strongly recommended
[34].
Staging and prognosis
BCS should be considered in patients with acute or chronic liver disease, especially when there is not a clear
etiology for the liver alteration and/or a prothrombotic condition exists. Doppler ultrasound has a sensitivity
higher than 75% and should be the first choice diagnostic tool
[34]. Contrast-enhanced computed tomography
(CT) and MRI are also useful for revealing intra- and extrahepatic collaterals, identifying associated portal vein
thrombosis (PVT), and planning future treatments. It should be noted that short membrane obstruction of IVC
could be missed from cross-sectional imaging. Direct imaging features of BCS include visualization of the
occluded veins, presence of thrombosis in the involved veins, and stagnant or inverted venous flow in the portal
vein which is usually associated with acute forms
[35,36]. Indirect signs such as hypertrophy of the caudate lobe
and concomitant atrophic lobes, caudate vein greater than 3 mm, parenchymal heterogeneity, dysmorphic liver,
and hepatic benign regenerative nodules are commonly seen in chronic BCS
[35,36]. Generally, angiography
should not be performed only for diagnostic purposes.
Histological changes in BCS are variable and nonspecific, including congestion, coagulative necrosis or simple
loss of hepatocytes without inflammatory infiltrates, and/or fibrosis that in chronic forms can be severe or even
real cirrhosis.
BCS due to small intrahepatic vein obstruction in the presence of preserved large veins on imaging techniques
can only be diagnosed by liver biopsy
[34]. Otherwise, liver biopsy is generally unnecessary for diagnosis.
Prognosis of BCS has markedly changed in the last 23 decades mainly because of earlier diagnosis and better
available treatments. Thus three-year mortality of BCS patients in the 1960s was as high as 90%
[37], whereas the
current expected 5-year survival is higher than 80%
[2,19]. The largest prospective multicenter cohort of 157 con-
secutive patients diagnosed with BCS within a 2-year period reported a 5-year survival of 85%
[2]. The improved
prognosis of BCS was attributed to early diagnosis of the disease and the application of a step-wise treatment
strategy of progressive invasiveness (see below)
[2].
Child-Pugh
[38], model for end-stage liver disease score [39], and BCS specific prognostic scores (e.g., Clichy PI,
new Clichy PI, Rotterdam BCS index, and transjugular intrahepatic portosystemic shunt (TIPS)-BCS prognostic
index) (
Table 5.2) [37,4042] are useful for predicting survival and have been externally validated [2,43]. However,
none of these scores has enough discrimination capacity to guide individualized BCS management
[2,43].
Treatment and management of complications
Stepwise treatment strategy
Although most current evidence regarding management of BCS are based on case reports, retrospective stud-
ies, and expert opinions, the stepwise treatment strategy has been widely accepted. The initial treatment includes
the use of anticoagulation, medical management of the underlying disease, and the treatment of portal
hypertension-related complications as recommended for cirrhotic patients
[34,44].
Anticoagulation
All patients with BCS should receive anticoagulation therapy immediately after diagnosis, whether there is or
not an underlying prothrombotic disorder. The use of anticoagulation rarely achieves recanalization of the occluded
veins but prevents the extension of thrombosis
[19,42,45]. Low molecular weight heparin (LMWH) and vitamin K
antagonists (VKA) are the most common treatment options for anticoagulation therapy. BCS patients have a high
risk of heparin-induced thrombocytopenia when receiving unfractionated heparin and therefore it is not recom-
mended for BCS patients
[46]. Direct oral anticoagulants (DOACs) could be considered in BCS patients with good
liver and renal function; however, more data about the efficacy and safety in this indication are required.
68 5. Obstruction of the liver circulation
I. Liver and heart
https://t.me/medicina_free
Thrombolysis
There are anecdotal cases of successful recanalization of hepatic veins after infusion of recombinant tissue plasminogen
activator, streptokinase, or urokinase via a peripheral vein or locally after catheterization of the thrombosed vein
[47].
Bleeding complications of thrombolysis can be life-threatening
[48]. Therefore thrombolysis should be avoided if patients
have a potentially hemorrhagic condition or underwent an invasive procedure in the previous 24 hours. In conclusion,
thrombolysis should only be attempted in selected patients with acute/subacute BCS at experienced centers
[34].
Recanalization
Percutaneous endovascular angioplasty with or without stenting is an effective and safe invasive interventional
technique to restore the physiological hepatic outflow in BCS patients with partial or segmental stenosis or thrombo-
sis (
Fig. 5.1) [49]. Restenosis is more frequent if angioplasty is used, requiring additional angioplasties and/or the
use of a stent. Stenting could reduce restenosis risk. However, stent misplacement may cause severe complication
(e.g., cardiac perforation) and make future TIPS or liver transplantation (LT) more challenging. A recent randomized
controlled trial (RCT) enrolling 88 patients with BCS with membranous obstruction or short-length stenosis (#4cm),
[50] suggested that patients treated with angioplasty plus routine stenting had a significantly lower proportion of
restenosis than those only treated with angioplasty. It is important to take into account that 60% of patients treated
with angioplasty alone did not develop restenosis and had excellent survival. Therefore angioplasty is still an effec-
tive treatment, reserving stenting for those cases where angioplasty alone is not effective
[51].
In summary, in patients with BCS due to membranous obstruction or short-length stenosis, angioplasty should
be attempted once the diagnosis is established. In case of restenosis, a new angioplasty procedure or stenting is
recommended. In Asia, where IVC with or without hepatic vein obstruction predominates, the applicability of
angioplasty is higher than in Western countries where this BCS type is much less frequent
[2].
TABLE 5.2 Budd-Chiari Syndrome specific prognostic index.
Score Formula Cut-off vaule Predicted outcome Reference
Clichy PI Ascites score 3 0.75 1 (Pugh score 3 0.28) 1
(age 3 0.037) 1 (creatinine 3 0.0036)
5.4 (range: 3.49.1) 5-year survival
# 5.4: 95%
. 5.4: 62%
[37]
New Clichy PI 0.953 ascites
a
score 1 0.35 3 Pugh
score 1 0.047 3 age 1 0.0045 3 serum
creatinine 1 2.2 3 type III
b
—2.6
5.1 (range: 2.09.7) 5-year survival
, 5.1: 100%
$ 5.1: 65%
[40]
Rotterdam BCS index 1.27 3 encephalopathy 1 1.04 3 ascites 1
0.72 3 prothrombin time 1 0.004 3 bilirubin
class I: 01.1
class II: 1.11.5
class III: $ 1.5
(range: 0.024.03)
5-year survival
class I: 89%
class II: 74%
class III: 42%
[41]
TIPS-BCS PI Age (years) 3 0.08 1 bilirubin (mg/dL) 3 0.16 1
international normalized ratio (INR) 3 0.63
7 1-year OLT-free
survival
# 7 95%
. 7 12%
[56]
BCS-intervention-free
survival prognostic score
Ascites (yes 5 1, no 5 0) 3 1.675 1 ln creatinine
(umol/L) 3 0.613 1 ln bilirubin (umol/ L) 3 0.440
Interval I: # 5
Interval 2: 56
Interval 3: $ 6
Intervention-free
survival
Interval I: 78.3%
Interval 2: 27.8%
Interval 3: 6.8%
[2]
BCSurvival score Age/10 3 0.370 1 ln creatinine (umol/L) 3 0.809 1
ln bilirubin (umol/L) 3 0.496
Interval I: # 7
Interval 2: 78
Interval 3: $ 8
Probability survival
87.5%
63.3%
42.9%
[2]
a
Ascites score: 1, absent with free sodium intake and no diuretic agents; 2, easy to control with sodium restriction or diuretic agents; and 3, resistant to this treatment because of
hyponatremia or functional renal failure.
b
Type III’ is a binary variable coded as 1 for patients with clinicopathological findings of acute injury superimposed on chronic lesions, and 0 for the other patients.
BCS, Budd-Chiari syndrome; OLT, orthotopic liver transplantation.
Adapted from Hernandez-Gea V, De Gottardi A, Leebeek FWG, Rautou PE, Salem R, Garcia-Pagan JC. Current knowledge in pathophysiology and management of Budd-Chiari
syndrome and non-cirrhotic non-tumoral splanchnic vein thrombosis. J Hepatol. 2019;71(1):175199.
69Treatment and management of complications
I. Liver and heart
https://t.me/medicina_free
Transjugular intrahepatic portosystemic shunt
For patients who have failed the above-mentioned treatments, TIPS is the first choice shunting procedure.
TIPS is associated with increased patency rates and lower morbidity and mortality than derivative surgery
[34,44]. Difficult to treat ascites and recurrent variceal bleeding are the common indications for TIPS in BCS
patients. TIPS should also be considered in patients with acute/subacute liver failure
[46].
Prognosis of BCS patients following TIPS is excellent with 1-year cumulative survival rate of 80%100% and
5-year cumulative survival rate of 74%78%
[52,53]. TIPS procedure-related complications ranged from 0% to
56%, including liver capsule perforation, IVC and portal vein injury, contrast induced nephropathy, and stent
migration. This high range of complications is probably related to the expertise and the number of patients with
BCS treated with TIPS in a given center. Therefore TIPS in BCS must be done in centers with high expertise.
A prognostic score (BCS-TIPSS PI) with a good discriminative capacity (area under the curve, 0.86) was devel-
oped for patients with BCS treated with TIPS. Patients with a BCS-TIPSS PI greater than 7 had a worse outcome
after TIPS and it was suggested that these patients might be considered for lT. However, this suggestion has not
been validated.
In a multicenter European prospective cohort, 157 BCS patients treated following this stepwise treatment strat-
egy had an excellent 5-year survival
[2]. The median time from diagnosis of BCS to TIPS was one month (range:
038 m). No differences in survival were observed in patients treated with TIPS before or after the first month
after diagnosis and similar results were observed when the cut-off time was 3 or 6 months. This study suggests
that the stepwise strategy is effective and safe, as long as the patients are followed closely, reserving TIPS for
those patients who progress or fail to respond to medical treatment.
Although TIPS is currently considered the shunting technique of choice, surgical portosystemic shunts may
still be considered in places where there is not enough experience/availability for TIPS or even LT. Shunting
may be used in cases of preserved hepatic function. In the presence of a IVC compression, an infrahepatic cava
vein pressure of . 20 mmHg or a gradient between the right atrium and the cava vein . 15 mmHg predict
a shunt dysfunction unless the IVC compression is previously corrected. Mesocaval or latero-lateral portocaval
shunts that allow transforming the portal vein to an outflow tract to decompress the liver are the preferred
shunts. A mesoatrial shunt could be a choice when the IV C obstruction cannot be resolved
[54].
FIGURE 5.1 Patient with short segment hepatic vein obstruction (A) before and (B) after angioplasty restoring physiological hepatic out-
flow. Source: This image was kindly provided by the West China Hospital affiliated with Sichuan University.
70 5. Obstruction of the liver circulation
I. Liver and heart
https://t.me/medicina_free
Liver transplantation
LT is the last step in the stepwise treatment strategy of BCS. LT should be always be considered in patients with
acute fulminant liver failure and those with advanced decompensated cirrhosis. Even in these situations, TIPS
should still be considered because it may foster fast improvement and potentially avoid LT
[55]. Remarkably, previ-
ous TIPS did not worsen post-LT prognosis
[56,57].
Although data come from small series of cases, living donor liver transplant resulted in acceptable survival
rates ( . 70% at 5 years)
[58,59].
Because of the presence of retroperitoneal fibrosis related to hepatic vein thrombosis, liver enlargement, and adhesions,
LT may be technically challenging for transplantation in BCS patients. In addition, the classical “piggyback” technique
for anastomosis becomes more difficult due to the enlarged caudate lobe and occlusion of the HV ostia. In addition, the
underlying prothrombotic disorders may affect post-transplantation outcome. Although MPN is not a contraindication
for LT, patients should be treated with anticoagulant drugs and/or aspirin, and with antiproliferative treatment
(hydroxyurea) after transplantation to avoid early rethrombosis. In patients with high risk of bleeding, it is suggested to
give at least aspirin and antiproliferative treatment. LT may be even more challenging in patients with PNH, as they
may develop aplastic anemia, requiring an allogenic stem cell transplant, thereby increasing the risk of infection.
Noncirrhotic nontumoral portal vein thrombosis
NCPVT refers to the presence of a thrombus in the main portal vein trunk and/or the left or right intrahepatic
portal branches that may extend to the splenic vein and/or the superior or inferior mesenteric veins
[1]. Isolated
splenic or mesenteric vein thrombosis will not be discussed here.
Risk factors
Since numerous systemic and local risk factors are shared by BCS and NCPVT, work-up for identifying these
risk factors should follow the same strategy as in patients with BCS (
Table 5.1) [7,8,60]. We will here describe a
few additional more specific issues for NCPVT.
Systemic risk factors
In a meta-analysis with 855 patients with NCPVT, mean prevalence of MPNs and JAK2V616F was 31.5% and
27.7%, respectively
[6]. Notably, PVT is often the first symptom of an underlying MPN, enforcing the need for
thorough screening for this disorder
[61]. Obesity is a systemic inflammatory disorder that predisposes to arterial
and venous thrombosis
[62]. The overall odds ratio for the first episode of venous thromboembolism was 2.3 in
obese patients in a meta-analysis
[63]. One study has also suggested an association between central obesity and
an increased risk for NCPVT
[64].
Local factors
Local risk factors are frequently found in patients with NCPVT. Imaging studies need to be reviewed carefully to
look for the signs of gastrointestinal (appendicitis, diverticulitis, intra-abdominal abscesses, or infections) or biliopan-
creatic pathologies including pancreatic pseudocysts and gallbladder alterations. In a European cohort including 102
patients with acute NCPVT, a local factor was found in 21% of patients
[65]. However, around 30% of patients with a
local risk factor, also had a systemic prothrombotic disorder. Therefore even patients with a recognized local factor
should be exhaustively investigated for the presence of a concomitant prothrombotic systemic disorder
[65,66].
If there is no obvious risk factor for PVT and when cirrhosis has been excluded, especially if there are liver
test abnormalities and/or hepatic dimorphism at imaging, liver biopsy could be considered to exclude the pres-
ence of porto-sinusoidal vascular disorder formerly known as idiopathic portal hypertension. Porto-sinusoidal
vascular disorder is a frequent cause for NCPVT. In patients with porto-sinusoidal vascular disorder, the annual
risk of developing NCPVT is 9%
[67]. Previous variceal hemorrhage and HIV associated porto-sinusoidal vascu-
lar disorder have been suggested as risk factors for developing PVT
[67].
71Risk factors
I. Liver and heart
https://t.me/medicina_free
Diagnosis and staging
Ultrasound is a reliable noninvasive imaging technique with an excellent accuracy for the detection of PVT and is
the first-line choice for surveillance. On grayscale ultrasound, acute portal vein thrombus typically reveals hypere-
choic material in the vessel lumen with distension of the portal vein and its tributaries. However, a recently formed
PVT is frequent anechoic, requiring the use of Doppler ultrasound for its demonstration
[68]. Overall sensitivity and
specificity for detection of PVT using color Doppler imaging were 89% and 92%, respectively [69]. The advantage of
CT -scan and MRI, especially when contrast is used, is to improve the capability to detect extension of thrombus, evi-
dence of bowel infarction and identify possible local risk factors. Noncontrast CT scan may show hyper-attenuating
material in the vessel lumen if PVT occurred within a month
[70]. With iodinated contrast injection, acute PVT on CT
appears with increased attenuation and lack of luminal enhancement, with or without inhomogeneities in portal
venous and parenchymal hepatic perfusion. MRI scan is an equally good imaging modality for PVT.
In patients with chronic NCPVT, imag ing studies usually identified a myriad of collateral channels in the por-
ta hepatis, the so-called portal cavernoma, aimed to bypass the occluded portal vein. Portal cavernoma, if recana-
lization is not achieved, may develop within a few weeks. Therefore the presence of cavernoma does not
necessarily imply chronicity of this condition.
Several classification models have been proposed to stage chronic NCPVT; Yerdel’s classification in four degrees
of severity is one of the most frequently used, based on localization and extension of thrombosis
[71].Grade1is
partial occlusion of the portal trunk, grade 2 occlusive thrombosis of the portal trunk, grade 3 with extension to
splenomesenteric confluence, and grade 4 affecting all the portosplenicmesenteric axis
[71]. Recently, Sarin et al.
proposed a new classification, which takes into account not only the location and extension of the thrombosis, but
also the onset of the thrombosis (recent or chronic), its type of presentation, and its possible underlying liver dis-
ease (cirrhosis or normal liver)
[72]. The purpose of this definition and classification of PVT is to provide a uniform
reporting system for clinicians, define clear endpoints, and the efficacy of therapies in trials (
Table 5.3).
Natural history
NCPVT can be detected when it has recently occurred (manifesting with abdominal pain), when it is already
chronic (with the initial acute episode pauci or asymptomatic and therefore being frequently diagnosed by the
existence of portal hypertension) or sometimes, often being confused as a recent NCPVT, as a rethrombotic event
in a patient with a previous unrecognized chronic NCPVT.
The initial symptoms of recent NCPVT, but maybe also the manifestation of rethrombosis extending to mesen-
teric vessels in a patient with previous chronic PVT, are acute abdominal pain and fever as a manifestation of
TABLE 5.3 Morphological, functional, and clinical classification of NCPVT.
Site of PVT Type 1: trunk only
Type 2: branch only; 2a, one branch; 2b, both branches
Type 3: trunk and branches
Degree of occlusion O: occlusive: no flow visible in PV lumen on imaging/Doppler study
NO: nonocclusive: flow visible in PV lumen through imaging/Doppler study
Duration and
presentation
R: recent (first time detected in previously patent PV, presence of hyperdense thrombus on imaging, absent or limited
collateral circulation, dilated PV at the site of occlusion)
Ch: chronic (no hyperdense thrombus; previously diagnosed NCPVT on follow-up, portal cavernoma and clinical
features of PHT)
As: asymptomatic
S: symptomatic: features of acute NCPVT (with or without acute bowel ischemia) or features of portal hypertension
Extent of PVT S: splenic vein
M: mesenteric vein SM: both
Underlying liver
disease
Cirrhotic, noncirrhotic liver disease, post-liver transplant, HCC, local malignancies, and associated conditions
HCC, hepatocellular carcinoma; NCPVT, noncirrhotic nontumoral portal vein thrombosis; PHT, portal hypertension; PV, portal vein; PVT, portal vein thrombosis.
Adapted from Sarin S.K., Philips C.A., Kamath P.S., Choudhury A., Maruyama H., Nery F.G., et al. Toward a comprehensive new classification of portal vein thrombosis in
patients with cirrhosis. Gastroenterology. 2016;151(4):574577.”
72 5. Obstruction of the liver circulation
I. Liver and heart
https://t.me/medicina_free
intestinal ischemia. In these patients, intestinal ischemia leading to bowel infarction is the most severe complica-
tion. Resection of small intestine is sometimes required and might be associated with a high risk of short bowel
syndrome. Therefore early initiation of anticoagulant therapy is vital to reduce the incidence of this severe com-
plication
[65]. In a cohort of 95 consecutive prospectively collected patients with recent PVT receiving anticoagu-
lation, only two patients developed intestinal infarction requiring limited resection. Persistent acute abdominal
pain despite anticoagulant treatment, sign s of organ failure (shock, renal failure, metabolic acidosis with elevated
arterial lactate), and/or the presence of blood in stool must evoke the diagnosis of mesenteric infarction. Patients
suffering from recent NCPVT and having an underlying type 2 diabetes have an increased risk of requiring intes-
tinal resection
[73]. Ascites is usually rare, mostly mild, transient, and visible only on imaging studies [74]. Liver
function is usually preserved or mildly impaired, probably because increased hepatic arterial perfusion compen-
sates for the diminished portal inflow.
If recanalization is not achieved patients will develop chronic NCPVT. In patients with chronic NCPVT, com-
plications of portal hypertension are the most common clinical presentations. Gastroesophageal varices may
develop in nearly half of patients, whereas other complications, including splenomegaly, ectopic varices, and
large spontaneous portosystemic collaterals, are also frequently found
[60]. Liver functi on is usually preserved.
The mo st frequent clinical manifestations are variceal bleeding, biliary complications, and recurrent thrombosis.
Ascites and hepatic encephalopathy are generally rare and most often transient, probably triggered by events
such as gastrointestinal bleeding or infections
[75]. If specifically looked for, minimal hepatic encephalopathy is
commonly present in patients with NCPVT but their clinical impact is unknown
[76,77].
The recurrence or extension of PVT is a frequent event, especial ly if patients with a recognized prothrombotic
disorders are not adequately treated (anticoagulation, cytoreduction in MPN...). This event is probably more fre-
quent than recognized because rethrombosis is not always associated with abdominal pain but may worsen the
complications of portal hype rtension. Although more frequent in patients with an untreated underlying pro-
thrombotic disorder, rethrombosis can also occur in patients without recognized underlying prothrombotic disor-
der, that do not receive long-term anticoagulation. In these patients, routinely scheduled imaging studies to
identify asymptomatic rethrombosis are more relevant because this may prompt the initiation of long-term
anticoagulation.
Portal biliopathy is characterized by abnormalities of the intrahepatic and extrahepatic biliary duct in patients
with portal cavernoma
[78]. It is the consequence of the extrinsic compression of bile ducts by the porto-portal
collaterals of the cavernoma. However, it cannot be discarded that fibrous scarring of por ta hepatis and/or of an
ischemic injury of the bile ducts by thrombosis of the venous plexus of the biliary tree is also playing a role
[79].
If specifically looked for using MRI-colangiography, portal biliopathy is found in more than 80% of patients with
portal cavernoma. However, portal biliopathy is often asymptomatic or may be only causing mild abnormalities
of liver enzymes, particularly elevation of alkaline phosphatase and gamma glutamyl transferase. Severe biliary
manifestations including biliary colic, cholecystitis, obstructive jaundice, cholangitis, and pancreatitis, are rare,
found in only 5%30% of cases
[7981], but usually severe if they occur.
Treatment of recent nontumoral portal vein thrombosis
The aim of treatment for recent NCPVT is to achieve portal vein recanalization, prevent the extension of the
thrombus to mesenteric veins and intestinal infarction, and treat complications of established PVT.
Anticoagulation
Anticoagulation forms the cornerstone of treatm ent for recent NCPVT and should be initiated as soon as possi-
ble. A large European prospective multicenter study enrolled 102 patients with acute thrombosis of the portal
vein or intrahepatic branches
[65]. Ninety-five patients were treated with early administration of LMWH, and
rapidly replaced with VKA, targeting the international normalized ratio (INR) at a range of 23. Complete recan-
alization of the portal vein was achieved in one-third of the patients following 6 months of continued anticoagu-
lation therapy. Interestingly, there was no further recanalization of the portal vein with a prolongation of
anticoagulation therapy, but continued recanalization of the splenic or superior mesenteric vein was observed up
to 12 months of treatment. Forty percent of patients had a permanent obstructio n and the presence of portal
cavernoma one year after the onset of NCPVT. These findings were consistent with several retrospective reports
73Treatment of recent nontumoral portal vein thrombosis
I. Liver and heart
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана