SINUSOIDAL OCCLUSION SYNDROME:

A RARE AND SEVERE DISEASE

Marco SenzoloMultivisceral Transplant Unit, Gastroenterology

University Hospital of Padua, Italy

19th AISF Pre-Meeting Course“Vascular diseases of the liver”

DEFINITION

Non thrombotic obstruction of sinusoids due to toxic injury of the sinusoidal wall which

could be clinically identical to Budd-Chiari syndrome

First case of VOD (Bras et al. 1954) due to exposure to Pyrrolizidine alkaloids – traditional

herb remedy in south Africa

1950s: hepatic veno-occlusive disease because diagnosis was made only if occlusion of

the central vein was present

1990s: only 55%-75% of moderate/severe SOS have central vein involvement (Shulman

1994)

2000s: changed in Sinusoidal Occlusion Syndrome (De Leve)

GroupNumber of

Studies

Total Number

of Patients

Number of Patients

with VOD MeanIncidence,

% 95% CI

Min,%

Max,%

Median,%

1. Allpatients

135 24,920 3425 13.7% 13.3–14.1 0 62.3 13.3

2. Baltimore 33 5261 503 9.6% 8.8–10.4 0 28.9 8.6

3. Seattle 78 14,798 2565 17.3% 16.7–17.9 0 62.3 17.0

4. Auto-SCT 19 3967 344 8.7%*

7.8–9.4 1.5 44.1 6.2

5. Allo-SCT 67 11,285 1453 12.9%*

12.3–13.5 0 62.3 12.0

6. Pre-1994 50 10,943 1260 11.5†

10.9–12.1 1 62.3 9.3

7. Post-1994 74 12,234 1805 14.6†

14.0–15.2 0 53.3 15.4

Descriptive Statistics for VOD Incidence from 135 Publications*P < .001.†P < .05.

Incidence of SOS after HSTC

Mortality – old series

Incidence of SOS after Solid Organ Transplantation (SOT)

AuthorCases

LiverRisk factor Treatment Outcome

Sterneck (1991) 2 Azathioprine Azathioprine withdrawalComplete recovery

Recurrence after re-challenge

Dhillon (1994) 9 Azathioprine NA NA

Martins (2007) 1 Azathioprine Re-LT Recurrence after 3y that required a second Re-LT

Mion (1993) 1 Azathioprine Azathioprine withdrawal Complete recovery

Mor (2001)

2

(2nd

liver-

Kidney)

Azathioprine and Tacrolimus Defibrotide (3 weeks)1st complete recovery

2nd died 2 months later

Fiel (1999) 1 Azathioprine and Tacrolimus Re-LTRecurrence after 1 month that required a second Re-

LT

Chen (2013) 1 TacrolimusMethylprednisolone, alprostadil,

Danhong injections and TIPS.Complete recovery

Izaki (2004) 1 Tacrolimus Urgent re-LDLT Complete recovery

Marin-Gomez

(2015)1 Tacrolimus Re-LT Complete recovery

Nakanuma

(2015)1 Tacrolimus Tacrolimus withdrawal Re-lister for LT but died before

Shen (2015) 1 Tacrolimus Tacrolimus withdrawal Complete recovery

Shen (2016) 1 Tacrolimus Re-LT Complete recovery

Campos-Varela

(2012)1 Tacrolimus/HIV TIPS Complete recovery

Katajima (2009) 2Tacrolimus, donor liver, ischemic

riperfusion injuryTIPS

1st Complete recovery

2nd ascites worsened, Re-LT was necessary.

Nakazawa (2003) 1 Acute rejection and Tacrolimus Intensified immunosuppression Deceased of MOF

Takamura (2014) 2 2 x AR / IR injury None specific for SOS Both deceased for graft failure

Yamada (2012) 1 Antibody-mediated rejection

Mycophenolate mofetil, high-dose

intravenous immunoglobulin,

anticoagulant therapy.

Complete recovery

Senzolo (2006) 2 Acute rejection Defibrotide and TIPS Complete recovery

Bernstine

(2004)2 NA Defibrotide for 3 weeks.

1st lister for LT, but died before

2nd Complete recovery

Walter (2002) 1Terbinafine initiated for

onychomycosis

Extracorporeal liver assistance device,

TIPS

Died of non PH related gastrointestinal

bleeding

Author (year) Patients Risk factor Treatment Outcome

Adler (1987)2

(Kidney)Azathioprine Azathioprine withdrawal

1st Complete recovery

2nd died 3 years later from liver

failure

Azoulay (1998)1

(Kidney)Azathioprine Emergency TIPS

Complete recovery but TIPS

complications

Eisenhauer (1984)1

(Kidney)Azathioprine

Azathioprine withdrawal and

portacaval shuntComplete recovery

Hola (1996)1

(Kidney)Azathioprine NA NA

Katzka (1986)3

(Kidney)Azathioprine Azathioprine withdrawal

2 Complete recovery

1 died of MOF

Kohli (2011)1

(Kidney)Azathioprine Azathioprine withdrawal

Expired 10months after, but

histological regression of VOD was

documented

Marubbio (1975)1

(Kidney)Azathioprine Azathioprine withdrawal Died

Read (1986)4

(Kidney)Azathioprine and CMV NA Fulminant liver failure and death

Jeffries (1998)1

(Kidney)

Azathioprine, Cyclosporine and

HCVCombined liver-kidney transplant. Complete recovery

Vallet-Pichard (2003)3

(Kidney)

Azathioprine, Tacrolimus,

Valaciclovir and HCV

Withdrawal of azathi oprine,

tacrolimus and valaciclovir.Complete recovery

Liano (1989)5

(Kidney)

Azathioprine and previous

hepatotropic viral infectionNA NA

de Fontbrune (2007)1

(Lung)Azathioprine and Tacrolimus

Tacrolimus and Azathioprine

withdrawalComplete recovery

Shah (2006)1

(Lung)Tacrolimus Tacrolimus withdrawal Complete recovery

Wang (2013)1

(Pancreas)Tacrolimus Tacrolimus discontinuation Complete recovery

1,023 patients transplanted over a 9-year period (protocol biopsies)

VOD was histologically diagnosed if there was total or subtotal fibrous obliteration of hepatic veins by

connective tissue and centrilobular hemorrhagic necrosis.

19 VOD/SOS (1-9%) (mean presentation time 30d) without clinical symptoms of outflow obstruction

17/19 previous AR (greater incidence of chronic rejection in the study group)

All AZA therapy

Despite azathioprine withdrawal, zone 3 changes persisted in 57% of patients.

Significance of Isolated VOS/SOS after liver transplantation

2000-2008: 2724 LB (protocol or for clinical indications)

31 (2.4%) VOD/SOS ((sub)total obliteration of CL veins by connective tissue

with/without haemorragic necrosis)

16/31 previous/concurrent AR (earlier onset 4m versus late onset 65m)

No correlation with CNI

Presentation with abnormal LFTs in all but 2 and ascites in 25/31

Sebagh, Liver Transplantation 2011

Significance of Isolated VOS/SOS after liver transplantation

Increase in IS was efficient in 14/18 versus 4/12 with no increase in

IS, p=.024)

2 underwent TIPS placement

Sebagh, Liver Transplantation 2011

Is Sinusoidal Occlusion a “thrombotic” disease ?

Coagulation and Sinusoidal Occlusion Syndrome

- Endothelial activation after HSCT conditioning, particularly in the allogeneic setting, is

associated with a prothrombotic state, demonstrated by an increase of von Willebrand

factor expression and platelet adhesion (Palomo 2010)

- Genetic polymorphism ( Heparanase in children – Seifert 2015)

- Deficit in antithrombine – Lee 1998, or tissue plasminogen activator – Bearman 1992,

- Resistance to the activated C protein – Lee 1998 are associated with increased risk of

SOS/VOD

- Hyperfibrinolysis at diagnosis

Is Sinusoidal Occlusion Syndrome a DILI ?

• Actinomycin D• Azathioprine• Busulfan• Carmustine• Cytosine arabinoside• Cyclophosphamide• Dacarbazine• Gemtuzumab-ozogamicin• Melphalan• Mercaptopurine• Mitomycin• Oxaliplatin• Pyrrozoliidine alkaloids• Urethane• Terbinafine• Traditional Herbs remedy• 6-mercaptopurine• 6-thioguanide• Calcineuin inhibitors• Post BMT• Total body irradiation• Hepatic irradiation high dose• Platelet transfusion containing ABO incompatible

plasma

Why endothelial injury ?

1. Drugs are absorbed in PV blood, thus SECs are exposed to higher blood levels than

systemic concentrations

2. Significant P450 activity

3. Due to gradient concentration SECs are exposed to higher concentration of toxic

metabolites than CVs

4. Susceptible to depletion of GSH

Parameters Between Days 4 and 8 after monocrotaline exposure

Day Ascites (mL) T Bil (dBil) (mg/dL) Hct WBC

4 1.86±0.4 0.1 (<0.1); 0.1 (<0.1) 39.5 6±0.5 10,000; 13,000

5 4.36±0.2 3.3 (2.1); 3.3 (2.2) 24.5 6±0.5 70,000; 100,000

6 5.06±0.6 9.8 (6.8); 10.0 (6.9) 24.3 6±2.5 100,000; 120,000

7 4.46±0.7 9.4 (6.7) 3.3 (2.1); 30.5 6±0.4 50,000; 70,000

8 5.26±0.9 6.3 (4.2) 3.0 (1.9); 24.0 6±1.4 90,000; 100,000

2d monocrotaline

5d monocrotaline

7d monocrotaline

Rat model of SOS, De Leve 1999

Immusuppression in the pathogenesis of SOS

Carmona, Biol BMT 2013No change in Viscolelastic test

Ischemic reperfusion injury and extravasated PLT aggregation in the risk of SOS (Miyashita 2015)

SOS+PORTAL HYPERTENSION

Clinical diagnostic criteria of SOS

Modified Seattle Criteria (Shulman 1992)

2 of the following criteria within 20d after HSCT

Bilirubin > 2mg/dL

Hepatomegaly or RUQ pain

Weight gain >2% (from pre transplant)

Baltimore Criteria (Jones 1987)

Bilirubin > 2mg/dL within 21d after HSCT and 2 of the follwing criteria

Hepatomegaly

Ascites

Weight gain > 5% (from pre transplant)

Fibrinolytic activity in the diagnostic criteria of SOS

Sartori MT, Ped Blood Cancer 2012

Imaging in SOS

Hepatomegaly and ascites

Reversal HV flow

Gallbladder Thickness

Increase in PV velocity

202 serial US in 48 HSTC patients, 29 developed SOS: no direct correlation with

Gallbladder thickness, PV velociry or HA resistance (McCArville 2001)

Dignan, BJH 2013

Auberger, BMT 2013

Liver Stiffness in predicting SOS

Liver Stiffness in predicting SOS

Colecchia, BMT 2016

22 HSTC

Elastometry T0 – T1 (7-10d) – T2 (17-20d) – T3 (27-30)

No ascites during measurement – efficacy 100%

Transjuguar route in essential !

Transjuguar route in SOS

Liver Histology is needed for diagnosis in ascitic patient

Multiple passes allow better diagnosis in diseases with patchy distribution

In liver transplanted patients an outflow obstruction needs to be excluded (Free

HV-IVC gradient < 6mmHg)

HVPG > 10mmHg 91% specificity and 82% PPV in diagnosis VOD (Shulman 1995)

HVPG > 20mmHg correlated with severe prognosis (Bearman 1993)

Prevention of SOS

- Reduction of patient and transplant risks – ie less busulfan/cyclophosphamide regimens

- RCT Defibrotide 356 children HSTC (108 autologous), defibrotide 6.25mg/Kg x 4 die until +30

- VOD 12% vs 30%, p.048- Decrease in VOD renal failure in treatment arm- Decrease in GvHD in allogenic group in treatment arm- Non difference in survival

- Prostaglandin E1: no consistent results and high toxicity

- Pentoxyfilline: RCTs failed to show benefit

- UDCA: 600mg/die 2 positive, 2 negative RCT. Metanalysis showed RR 0.34 95% CI 0.17-0.66 (Tay 2007)

Prevention of SOS

- Antithrombin – small studies, few evidences

- UFH and LMWH

Imran, BMT 2006

Treatment

Tissue plasminogen activator: 1990s reports with small series; 42 pts 5.4-

120mg ev over 2-4d and 150 u/Kg/d for 10d . 12 (29%) response rate with >

50% reduction bilirubin . 88% bleeding , 25% severe, 3 deaths

N- acetylcisteine: RCT 2008 160 pts. No benefit

Methylprednisolone: 0.5mg/Kg IV bd for 1d - two studies (57 pts, 23 with

MOF), 50% response

Patients (n 102) were given Defibrotide 25 mg/kg per day + UDCA

Specific treatment of the outflow obstruction ?

TIPS FOR HEPATIC VENO OCCLUSIVE DISEASE AFTER LIVER TRANSPLANTATION

Pre TIPS Post TIPS

Senzolo, Liver Transplantation 2006

Clinical case after LT

M 67aa - LT for cryptogenic cirrhosis and HCC

Piggy back technique

1 episode of severe AR rejection 8d ater LT – Cya monotherapy

REFRACTORY ASCITES 6 MONTHS POST OLT WITH ABNORMAL

RENAL FUNCTION

Normal liver function

HVPG and TJLB

• No significant pressure gradient (< 6mmHg) between hepatic

veins and suprahepatic vena cava and between superior and

inferior vena cava

• HVPG was 10 mmHg up to 25mmHg in different hepatic lobes

• Diagnosis of portal hypertension with patchy distribution in the

liver

• TJLB was performed

Van Gieson 20x

Central vein sclerosis

Partial PVT

Defibrotide + LMWH without clinical response

TIPS was placed 14 months after LT

Refractory HE post LT

Reduction stent

Worsening of renal and liver function

Death 19m after LT

Clinical case after LTBAD

Author Patients Etiology Severity VOD Amelioration Mortality

portal hypertension early (<1m) late (>1m)

Azoulay 10 BMT severe 10/10 5/10 4/5

(2000)

Fried 6 BMT severe 6/6 4/6 1/2

(1996)

Annarolo 1 BMT severe yes alive 3 years f-up

(2004)

Zenz 3 BMT severe/moderate 3/3 3/3

(2001)

Shen 1 radiotherapy moderate yes alive 5 months f-up

(1996) pelvis

Levy 1 BMT severe yes yes

(1996)

De la Rubia 1 BMT moderate yes alive 9 months f-up

(1996)

Smith 1 BMT severe yes yes

(1996)

Lerut 1 (series) LT - yes yes

(1999)

Sebagh 1 (series) LT - - re-OLT

(1999)

Senzolo 2 LT severe yes alive 13 months f-up

(2006)

Kitajima 2 LT severe yes alive 21months/reLT

(2010)

Campos Valera 1 LT severe yes alive 20 months f-up

(2012)

TIPS for Sinusoidal Occlusion Syndrome

Is there a role of TIPS to

treat Sinusoidal Occlusion Syndrome ?

TIPS is not indicated in Sinusoidal Occlusion Syndrome in Bone

Marrow Transplanted Patients (C4), but may be considered in

individual basis in Solid Organ Transplant Recipient as stand-alone

treatment or as bridge to liver transplantation in a setting of

multidisciplinary evaluation (4,C)

Fagiuoli et al. Consensus conference on TIPS management: Techniques, indications, contraindications - DLD 2017

VOD suspected

Bilirubin > 2mg/dLAsciteshepatomegaly

TimingAfter HSCT before day 30After LT mean 9 weeks

Diagnosis

Confirm and assess prognosis- Transjugular liver biopsy- HVPG- HV and IVC pressures if LT

Imaging- US and doppler- MRI

Laboratory- AST - Bilirubin- PAI-1, Procollagen III- Ca 125

Medical treatment- Treatment of ascites- Defibrotide+UDCA

failed HSTCLT, KTx, alkaloids

OLTTIPSSenzolo, WJG 2007

Conclusions- SOS is an outflow obstruction disease of the liver due to sinusoidal/centrilobular

vein damage

- SOS is a non-infrequent complication of HSCT, but although not common after

SOT should be considered if PH is present

- Liver histology is essential for diagnosis, thus transjugular route is often needed

because of ascites

- Medical therapy is efficient in 40%-50% of severe SOS after HSTC but no solid

data are available in SOT patients

- TIPS can be considered as an eventual bridge for LT only in toxic/SOT SOS