Up-date in Budd-Chiari syndrome

Dr Aurélie Plessier

Centre de Référence des Maladies Vasculaires du Foie

Service d’Hépatologie

Hôpital Beaujon - Clichy

I have not financial relationships to disclose within the past 12

months relevant to my presentation

AND

My presentation does not include discussion off-label or

investigational use

Epidemiology of BCS

Sweden°

1990-

2003

France

2010

Korea

2009-2013

NPL

1990-1992

Incidence(/ 106/ yr) 0.8 0,68 0,87 2.50

Prevalence(/ 106)

1.4 4 5,3 NA

Rare disease = < 1/2000

Shresta J Gastro Hepato 1996. Rajani Liver Int 2008, Ollivier EASL 2014, Ki Liv Intern 2016

Gender specific incidence rate in

Northwestern Italy

Overall gender-specific incidence rates

• for PVT

– 3.78 per 100,000 inhabitants in males

– 1.73 per 100,000 inhabitants in females

• for BCS

– 2.0 in males

– 2.2 per million inhabitants in females

Ageno Thromb Haemost 2017

HEPATIC VEIN OBSTRUCTION LEADS TO ASCITES FORMATION

BCS defined as Obstruction of venous

outflow

Sinusoidal perfusion

Sinusoidal pressure

Portal and splanchnic pressure

A multifactorial systemic disorder

• At least one condition 87%

• Multiple conditions 48%

• Local factor 5%

EN-Vie BCS Cohort. Darwish Murad Ann Intern Med 2009

Cause varies according to

geographic origins

% Europe

N=157

Algeria

N=115

China

N=92/127

MPN/Jak2 + 49/29 34 4

APLS 37 22 NA

V Leiden 19 11 0

PNH 15 4 1,6

Coeliac /Behcet 1/4 12/3-9 NA

Oral contraceptive 33 34 4

Pregnancy 6 4 NA

Darwish Murad Ann Int Med 2009, Afredj World J Hep 2015,

Seijo Hepatology,2014 Qi. J Gastroenterol Hepatol 2012, D’amico int J vasc med 2014;

De Stefano 2011

Primary Budd-Chiari SyndromeSite Specificity in Prothrombotic Disorders

• Behcet’s D. • V Leiden • Poverty

• MPD• OC

• PNHValla J Hepatol 2009,

Riggio JTT 2013

MPD specificity in Splanchnic vein

thrombosis

Plt > 200 000 et SPM > 16cm

Highly predictive of MPD

312 splanchnic vein thrombosis

(99 Budd-Chiari, 212 PVT)

MPD JAK2V617F+

N=58 (20%)JAK2V617F-

(N=254)

Spleen ≥ 16 cm and

platelets > 200/µL

(N=9)

Spleen< 16 cm and

platelets< 200/µL

(N=234)

MPD N=7 85%

(CALR mutation N=5

BM N=2)

MPD N=8

3%

No MPD

(N=226)

Rautou EASL 2015

Spleen? N=11

CALR mutations testing can be restricted to patients with

splanchnic vein thrombosis having a spleen height ≥ 16

cm and a platelet count > 200 G/L and no JAK2V617F

Causes specificity in Splanchnic vein

thrombosis

Plt > 200 000 et SPM > 16cm

Highly predictive of MPD

Treating cause well tolerated and may improve

BCS outcome

Thrombosis can recure in anticoagulated patients

Chait 2005 Br J Hem, Killadjian Blood 2008, Jasper Blood 2012, Pieri Am J Hematol 2017,Desbois Orphanet J Rare Dis. 2014,De Stefano,Blood Cancer Journal 2016

Recurrent thrombosis in patients

with splanchnic vein thrombosis and

MPD• incidence rate of 4.2 per 100 pt-years

• Significantly higher risk of recurrence

– BCS (hazard ratio (HR): 3.03),

– history of previous thrombosis (HR: 3.62),

– splenomegaly (HR: 2.66)

– leukocytosis (HR: 2.8)

• Vitamin K-antagonists (VKA) 85% of patients

– recurrence rate 3.9 per 100 pt-years,

– no VKA 7.2 per 100 pt-yearsDe Stefano,Blood Cancer Journal 2016

Treating the cause

• MPD PEG: IFN-a, anti-JAK2, Hematopoietic SCT

• PNH: Eculizumab, Hematopoietic SCT

• Behcet: Corticoids, Endoxan,..

• Coeliac disease: Gluten free diet

Available treatments

Chait 2005 Br J Hem, Killadjian Blood 2008, Jasper Blood 2012, pieri Am J Hematol 2017,Desbois Orphanet J Rare Dis. 2014, De stefano 2016

EASL guidelines -causes

1. Investigate underlying local and systemic

prothrombotic factors. Identification of one risk

factor should not deter from looking for additional

risk factors. (A1)

2. Work-up consists of diagnosis for inherited and

acquired thrombophilia factors, myeloproliferative

neoplasms, paroxysmal nocturnal haemoglobinuria

and auto-immune disorders. (A1)

3. Investigate patients with both BCS and PVT for

local risk factors, including intra-abdominal

inflammatory conditions and abdominal

malignancies. (A1)

Journal of Hepatology 2016

EASL guidelines 2015-causes 1. Thrombophilia screening includes protein S, protein C and

antithrombin levels, FVL mutation, prothrombin G20210A

gene variant and anti-phospholipid antibodies (APA). In

case of APA positivity, this should be repeated after 12

weeks. (A1)

2. Test for MPN in SVT patients, also when normal peripheral

blood cell counts by testing for JAK2V617F mutation (A1).

In JAK2V617F mutation negative patients, Cal R mutation

screening and if both negative bone marrow histology

should be considered. Patients have to be referred to a

haematologist. (B2 )

3. Treat the underlying condition as appropiate. In case of

MPN, anticoagulation indefinetely(B1).

Journal of Hepatology 2016

Primary BCS – Natural History

100

50

0

1 53

Su

rviv

al %

1960-1970

Ascites with emaciation

GI bleeding due to PHT

Liver failure

Adapted from Tavill.

Gastroenterology 1975

years

9,5%

42%

29%

12%

6%2,5%

1-7 days Fortuitus8 d - 1 month >1-6 months 6 months – 1 year > 1 year

Time of diagnosis in 158 patients

48,7%

Allaire, Ollivier EASL 2014

Ascites 83 %

Pain 61%

Oesophageal varices

Upper GI bleeding

58%

5%

Hepatomegaly 67 %

Splenomegaly 52 %

Murad Ann int med 2009

BCS at diagnosis

When should we suspect BCS?

1. Acute liver failure and hepatomegaly

2. Acute liver failure and ascites

3. Ascites and hepatomegaly

3. Refractory ascites but PT >60%

4. Known prothombotic state and liver disease

5. Any liver disease (because it can be cured)

Murad, ann int med 2009, Plessier, Hepatology,

2006

Valla, D-C Gut 2008;57:1469-1478

Diagnostic Strategy

Any patient with acute or chronic,

symptomatic or asymptomatic

liver disease

C

B

D

A

•Consider diagnosis of BCS in any symptomatic

or asymptomatic patient with acute or chronic

liver disease

•US-Doppler is the first line investigation for BCS.

MRI and CT have to be used for diagnostic

confirmation

•Reevaluate with expert radiologist negative

imaging studies patients with high BCS suspicion.

•Refer patients with BCS to expert centers on

this disease

EASL guidelines 2015-diagnosis

Prognosis-risk factors pejorative

outcome

Prognosis-risk factors pejorative

outcome

Italian guidelines Senzolo Dig &liver dis 2011, Ageno thromb haemost 2017

Age & Haematological cancer associated to mortality. In-hospital mortality 5%

Prognosis-risk factors pejorative

outcome

Symptoms NoAnticoagulation

Anticoagulation

Treat cause and

PHT

TIPS

Transplantation

Angioplasty/

Stent

yes

Treatment failure

Treatment failure

Baveno 2009 and 2015, AASLD guidelines 2009, EASL guidelines 2015

At least one 1 criteria Day 15

• Significant ascites

• Factor V < 40%

• C Bilirubin > 15µmol/L or not decreasing

• Upper GI bleeding from PHT

• Infection

• BMI remaining < 20 kg/m2

• No natriuresis with diuretics

Treatment failure criteria

Plessier Hepatology 2006

Patient outcome

• Yes 6l/week

• Factor V 36%

• Conjugate Bilirubin > 18 µmol/L

• No

• No

• Denutrition

• Na u< 20 /24h despitespironolactone and furosemide

BCS - Improved survival over 50 years

Copyright ©2008 BMJ Publishing Group Ltd. Valla, D-C Gut 2008;57:1469-1478

1960-1970

BCS - Improved survival over 50 years

Copyright ©2008 BMJ Publishing Group Ltd. Valla, D-C Gut 2008;57:1469-1478

1960-1970

ANTICOAGULATION Rx

EN-Vie cohort. Seijo. Hepatology 2013

Hepatic Vein Thrombosis - Survival

26% †

13% LTx

39% TIPS

27% Tt méd.

Recanalisation

• Partial or segmental stenoses present in:

– 60% with IVC obstruction,

– 25–30% with hepatic vein obstruction

• In the West, performed 25% of patients

• In the East, performed 80-90%

– Low morbidity

– Low recurrence rate BCS 15%

Plessier hepatology 2006, eapen gut 2006, Han WJG 2014, Munkund WJR 2011, Li Eur Rad 2017

Valla, Gut 2008

Plessier, Hepatology 2006

Eapen, Gut 2006

Darwish Murad, Ann Intern 2009

TIPS? To whom? when? how ?

Indication for TIPS placement % Garcia Pagan Ronot

Ascites 59 93

Liver failure 22 31

Upper Gi bleed from PHT 10 7

Other 10 17

Median/Mean Meld 17 (16-19) 14+4 (6-25)

Garcia-Pagan Gastroenterology 2008, Ronot, Radiology 2016

Indication for TIPS

Stratégie thérapeutique

Valla, Gut 2008

Plessier, Hepatology 2006

Eapen, Gut 2006

Darwish Murad, Ann Intern 2009

15 days

TIPS : How ?

A challenging procedure Barcelona Clichy

Transcaval % 57 92

Hyperarterialisation % 80-100 80-100

Number of stents 1/2/3/4 37/50/10/3 36/49/13/2

Portal vein thrombosis % 10 6

Anticoagulants ~100 100

Thrombophilia MPD/APLS

%

56/12 52/13

Success ITT/per prot 84/93 93/98

Garcia-Pagan Gastroenterology 2008, Ronot Radiology 2016

TIPS– learning curve

Plessier Hepatology 2006

Alternative attitude?

TIPS is the mostly used treatment for BCS… However,timing for TIPS was not stated.

Due to the rarity of BCS, management guidelines comefrom experts opinion, are empirical and notevidence-based

Given that benefit of treatments for BCS is not underdebate, I wonder if anticipating invasive treatments,before no response to medical therapy appears, coulddecrease hepatic fibrosis development, diseaseprogression and finally improve outcome

Mancuso, Hepatology 2013

Budd-Chiari Syndrome

Current Challenges

• Complications of therapy

• Pregnancy

• Regenerative nodules and HCC

Per procedure and acute TIPS

complications 20 to 30% % Garcia

pagan

N=124

Ronot

N=54

Death 2 4

Bleeding (hematoma, hemobilia) 12 14

Cardiac 4 NA

Other (thrombosis) 3 12

Garcia-Pagan Gastroenterology 2008, Ronot, Radiology 2016

Late complications : encephalopathy

1-year HE 21-25%

Transient 18-20

Recurring 2-4*

*Rifaximin efficient

Garcia-Pagan Gastroenterology 2008, Ronot, in press Radiology 2016

Late complications: TIPS dysfunction

Garcia-Pagan, Gastroenterology 2008

Factors associated with dysfunction 42% (27

months)

Number of stents initially placed > 2

HR = 3,90, p = 0,027

Early complications (< 7 days)

HR = 11,34, p = 0,009

Myeloproliferative neoplasm

HR = 8,18, p = 0,017

Technical factors

Longer tracks

Complex procedures

Ronot radiology 2016

N N Death

Prolonged Anticoagulation 139 89%

Bleeding 24 17% 3 2%

Portal hypertension 14 2

Intracranial 3 1

Other 7 0

Seijo. Hepatology 2013

BCS - Bleeding on Anticoagulation Therapy

N N Death

Prolonged Anticoagulation 139 89%

Bleeding 24 17% 3 2%

Portal hypertension 14 2

Intracranial 3 1

Other 7 0

Seijo. Hepatology 2013, Rautou J Hepatol 2010

Severe bleeding Incidence 24%p.yr vs 7%

Budd-Chiari Syndrome

Current Challenges

• Complications of therapy

• Pregnancy

• Regenerative nodules and HCC

VTE in pregnancy• Pregnant women are at an increased risk for venous thromboembolic

disease (VTE)

– 2-4 fold increase compared to non-pregnant state

– 1 in 1000 pregnancies

– Cesarian delivery > vaginal delivery

– 2/3 of DVT occur antepartum (equally distributed among all three trimesters)

– 43-60% of PE occur 4-6 weeks after delivery

– Daily risk of PE and DVT highest following delivery than antepartum

• PE is a major non-obstetric cause of maternal mortality

– 2/100 000 pregnancies

Courtesy of A Berzigotti

Effects of PH/VLD on the mother and child

Pregnancy in patients with known VLD

Effects of pregnancy on PH/VLD

Courtesy of A Berzigotti

Circulatory changes occurring during pregnancy

Increased plasma and RBC volumeIncreased venous capacity (estrogen) Decreased systemic vascular resistance (peripheral vasodilation due to prostacyclin and NO)

Net effect: worsening of hyperdynamic

circulation

P= R * Q

Mechanical effect of pregnancy

Increase in intrabdominal pressure increases portal pressure

Pregnancy in Budd-Chiari syndrome (BCS) women

Rautou, J Hepatol 2009

16 BCS women with 1 pregnancy during follow-up

(24 pregnancies)

BCS

diagnosis

1st conceptionMedian age: 33 yrs

All well-

controlled

Anticoagulation (n=17)

Antiplatelet (n=4)

No antithrombotic (n=3)• 11 invasive therapies

• 2 ovulation induction therapy:no complication

Median: 57 months

Rautou, J Hepatol 2009

Pregnancy in BCS women: Fetal outcomeN

um

ber

of pre

gnancie

s

weeks of gestation

Miscarriage/

ectopic

pregnancy

Early

preterm

Preterm

Term

24 pregnancies 16 alive

No sequelae

1 stillbirth

Rautou, J Hepatol 2009

Pregnancy in BCS women: Maternal outcome

Ascites in 2 patients:

- 1 portal vein thrombosis

- 1 TIPS obstruction

- Intrahepatic cholestasis (n=3)

- Intrauterine hematoma (n=3)

- Preeclampsia (n=1)

- Placenta praevia (n=1)

- Postpartum bleeding (n=4)

Gestational

course and

perinatal complications

Liver-related complications

Favorable:

- But screen for bleeding and pre eclampsia

- healthy infant born after gestation week 32

Pregnancy in BCS women: Outcome

• No maternal death (follow-up: 34 months after last delivery)

Rautou, J Hepatol 2009

What to do in patients with BCS in childbearing age

• Ask regularly if a pregnancy is desired

• If it is, anticipate actions to avoid problems:

• Re-evaluate the status of the underlying liver disease: discourage pregnancy if LD not stable/recompensated; optimise primary/secondary prophylaxis of variceal bleeding if needed

• Explain that there is a high risk of early fetal loss (> BCS) decreasing after 20 weeks, that prematurity is likely and explain risk for the mother (> BCS)

• LMWH is safe in pregnancy: if on OAC shift to this class as soon as conception might have occurred (test ASAP). Close anti Xa surveillance with haematologist

• Collaboration haematologist, obstetrician and haepatologist

• Vaginal delivery whenever possible

Budd-Chiari Syndrome

Current Challenges

• Complications of therapy

• Pregnancy

• Regenerative nodules and HCC

T1

T2

Cazals-Hatem. Hepatology 2003

Regenerative changes

Macronodules

Budd-Chiari Syndrome

BCS complicated by HCC

Han, WJS 2012

1988-2008 N

Primary BCS 67

HCC 17

BCS and Hepatocellular Carcinoma

WithoutNoduleN = 68

BenignNoduleN = 25

HCC

N = 9

Follow-up yrs 5 7 9

Age yrs 37 36 34

Male% 29 24 67

Blocked IVC % 7 0 78OR 78 [95% CI 11-560]

Moucari. Gut 2008. 102 consecutive patients without nodules at inception, 1995-2005

T2 2004 T2 2006

T2 2008 T2 2010

BCS and Hepatocellular Carcinoma

BenignN = 25

HCCN = 9

P

Largest diameter - cm 2 8 .0001

Number of nodules 5 1 .001

% Heterogeneous 0 100 .0001

AFP > 10 ng/ml - % 0 78 .0001

Moucari. Gut 2008. 102 consecutve patients without nodules at inception, 1995-2005

allowing to

• differentiate

FNH from FNH-like

FNH from adenoma

• classify adenoma in different subtypes

characteristicbiomarkers**

*Zucman-Rossi et al Hepatology 2006; Rebouissou et al J Hepatol 2008

** Bioulac-Sage et al Hepatology 2007; Liver Int 2008; Seminars Liver diseases 2011; WHO book 2011

Can hepatocellular adenoma bio markers help for the

characterization of nodules in BCS ?

Courtesy from Paulette Bioulac Sage

Retrospective multicenter survey

45 cases of liver vascular disease (mainly

explanted livers)2015

11 adenomas:

• 9 previously diagnosed were

subtyped using the

immunohistochemical panel

• 2 additional adenomas come

from reclassification of

LRN/FNH-like

Hepatocellular adenomas-patho-molecular

classification in vascular liver disease

Hepatocellular adenomas-patho-molecular

classification in BCS

N Outcome

HNF1 alpha inactivatedadenoma

loss of LFABP2

1 malignanttransformation/1

borderline

Beta catenin mutatedadenomas

Glutamine synthase strong2

Inflammatory cellular adenomaCRP +

2

Sempoux J Hepatol 2015

1. All subtypes of adenomas are seen in

vascular liver diseases and BCS

2. Adenomas are associated with HCC for all

subtypes, even in subtypes which usually

have low degenerative profile

3. HCC focus can be observed inside the

adenoma

4. Other regenerative nodules can be

associated

Nodules in vascular liver disease

1. Initiate therapy for complications of portal

hypertension as in cirrhosis (C2).

2. Treat all patients with BCS with

anticoagulation, in the absence of major

contraindications (A1).

3. Adequately treated portal hypertension

complications are not a contraindication for

anticoagulation (B1)

EASL guidelines 2015-Treatment

EASL guidelines 2015-Treatment and outcome

4. Consider brief interruption of anticoagulation for invasive procedure,

including paracentesis (B1)

5. Consider angioplasty/stenting first in patients with short hepatic vein

stenosis or IVC stenosis (A1).

6. Closely monitor these patients for early detection of liver deterioration.

Treat patients who do not respond to initial therapy or that are not

candidates, or do not respond to angioplasty/stenting with portal

derivative techniques (A1). TIPS, using PTFE-covered stents, is the

derivative treatment of choice (A1). Discuss surgical shunting when

TIPS is not feasible or fails (B1).

7. Propose liver transplantation as salvage treatment when derivative

techniques failed (A1). Anticoagulation needs to be continued after most

liver transplantation. (B1).

8. Screen patients for HCC. Distinct benign /malignant liver nodules is

very difficult (A1).

• Underlying blood disorder is the rule in the west, with myeloproliferative neoplasm in the first place.

• BCS to be considered – and assessed withDoppler-US – in any patient with liver disease.

Summary

Summary

• Good results of a therapeutic strategy based on minimal invasiveness and stepwise approach.

• Prognostication at baseline is not satisfactory.

• Long-term outcome jeopardized by malignancy(underlying blood disease and HCC).