מחלות כלי דם של הכבד פרופ' ריפעת ספדי מנהל היחידה למחלות כבד מרכז רפואי הדסה ע"כ, י"ם 17-11-2013 safadi@hadassah.org.il

אירועים טרומבוטיים בכבד Hepatic Vein Budd-Chiari Syndrome Veno-occlusive Disease Portal Vein Thrombosis Heptic Artery Thrombosis Peliosis Hepatis Hepatic Artery Aneurysm Hepatic Artery Atherosclerosis Hepatic Artery Gallbladder Portal Vein CBD

Budd-Chiari Syndrome

אירועים טרומבוטיים בכבד Budd-Chiari Syndrome Veno-occlusive Disease Portal Vein Thrombosis Heptic Artery Thrombosis Peliosis Hepatis Hepatic Artery Aneurysm Hepatic Artery Atherosclerosis

Budd-Chiari Syndrome (BCS): Definition Reductions in hepatic venous outflow: From Rt. Atrium To small hepatic venules Including IVC Results from thrombosis of ≥1 Hepatic Veins: Increases sinusoidal pressure/ congestion Portal hypertension Reduced portal vein flow Hepatomegally, ascites……

BCS, Etiology Hypercoagulable States: Infectious (10%): DILI: Antiphospholipids Synd. Antithrombin Def. Factor V Leiden Mutation Lupus anticoagulant MTHFR Myeloproliferative Disorders (PV & Eth) accounts ~50% (JAK2) PNH Postpartum thrombocytopenic Purpura Pregnancy (10%) Prot. S/C Def. Prothrombin mutation G20210A Sickle Cell Disease Aspergillosis Filariasis Hydatid cyst Liver Abscess amebic or pyogenic Pelvic cellulitis Schistosomiasis Syphilis TB In western countries, thrombosis oh hepatic veins is the most common presentation, wherease in Asia & Africa, membraneous obstruction of IVC accounts > 40%. DILI: OC’s, AZA, ChemoTx, HERBS

Spectrum of DILI , Amox-Clav) MTX=methotrexate; AZA=azathioprine; OCP=oral contraceptives pills; chemo Tx=chemotherapy; SOS=sinusoidal obstruction syndrome (veno-occlusive disease; HCC=hepatocellular carcinoma

BCS, Etiology Malignancies (10%): Miscellaneous: Multiple factors: Adrenal Carcinoma Bronchogenic carcinoma HCC Leiomyosarcoma Leukemia Renal cell ca (RCC) Rhabdomyosarcoma Behcet’s Disease Celiac Disease Dacarbazin therapy IBD Lap. Cholecystectomy Membraneous obstruction of vena cava (MOVC): ~70% in Asia & Africa Polycystic Liver disease Sarcoidosis Trauma to hepatic veins Living Related Liver Transplantation Multiple factors: Idiopathic: Accounts 25% Accounts 10%

Clinical Features of BCS Usually: Ages 20-40 Asymptomatic: Thrombosis of one HV Large veneous collaterals Symptomatic Affecting Factors: Extent and Speed of obstruction Extent and Speed of collateral formation

Clinical Features of BCS Fulminant: Rare Preg. & complications Acute 20-30%: Tender Hepatomegally. Ascites Short term mortality 50% Subacute to chronic: Within > 6 months Ascites Develop cirrhosis Hepatosplenomegaly IVC may be occluded Collaterals (flanks & back) Edema Mild LFT’s abnormalities

Pathology Zone 1 – most oxygenated; Zone 3 – least oxygenated Hepatic Vein Hepatic Artery Portal Vein CBD Gallbladder

Zone 3 ischemia / centrilobular necrosis Budd-Chiari Syndrome: Pathology Zone 3 ischemia / centrilobular necrosis

BCS: Diagnosis Liver Function tests: Duppler US Normal Mild elevation Marked elevation (cholestatic) Duppler US Sensitivity & Spec. > 80% HV’s are not visualized No flow signal in HV’s Diagnostic accuracy low in: Large body habitus. Comma-shaped collaterals

39-year-old woman with Budd-Chiari syndrome Contrast-enhanced transverse CT scan obtained during portal phase Brancatelli, G. et al. Am. J. Roentgenol. 2007;188:W168-W176 dilatation of azygos vein Fig. 8A —39-year-old woman with Budd-Chiari syndrome. Contrast-enhanced transverse CT scan obtained during portal phase shows development of intrahepatic (black arrow) and extrahepatic (white arrow) subcutaneous collateral vessels after hepatic venous thrombosis. Ascites and dilatation of azygos vein (arrowhead) are evident. intrahepatic & extrahepatic subcutaneous collateral vessels after hepatic venous thrombosis. Copyright © 2007 by the American Roentgen Ray Society

MRI & CT MRI & CT do not add much to Dupplex US MRI > CT due to: Provides more anatomic HV & IVC details Less nephrotoxic (?) US, CT & MRI are sufficient to diagnose BCS Venography is almost not needed for diagnosis: Pressure measurements Biopsy PTA TIPS

49-year-old woman with Budd-Chiari syndrome Fig. 1A —49-year-old woman with Budd-Chiari syndrome. Unenhanced transverse CT scan shows dysmorphic liver with enlarged left lobe and caudate which has normal attenuation compared with other, low-density portions of liver. Ascites (a) is evident. Brancatelli, G. et al. Am. J. Roentgenol. 2007;188:W168-W176 Copyright © 2007 by the American Roentgen Ray Society

43-year-old woman with Budd-Chiari syndrome Fig. 10A —43-year-old woman with Budd-Chiari syndrome. Contrast-enhanced transverse CT scan obtained during portal phase shows caudate lobe hypertrophy and left lobe atrophy. Central portion of liver is enhanced, and liver periphery is hypoperfused. More cephalic section (not shown) showed hepatic veins as areas of hypoattenuation due to thrombosis. Brancatelli, G. et al. Am. J. Roentgenol. 2007;188:W168-W176 Copyright © 2007 by the American Roentgen Ray Society

25-year-old woman with Budd-Chiari syndrome Fig. 9 —25-year-old woman with Budd-Chiari syndrome. Contrast-enhanced coronal maximumintensity-projection CT scan obtained during portal phase shows patent inferior vena cava with extrinsic compression (arrow) of enlarged caudate lobe (C). Brancatelli, G. et al. Am. J. Roentgenol. 2007;188:W168-W176 Copyright © 2007 by the American Roentgen Ray Society

Symptomatic BCS, Treatment Diuretics: Spironolactone Furosemide Diet Na+ restriction Large Volume Paracentesis Anticoaglation: Heparin Warfarin (INR 2-2.5) Myeloproliferative DO: Hydroxyurea Aspirin

Symptomatic BCS, Treatment Radiologic Intervention: Angioplasty TIPS TIPS: Low mortality Usually successful Intra hepatic VC to HV Useful in HV & VC obstruction. TIPS dysfunction in 70% Covered stents improved patency from 19 to 67%. Transplant complications if protruded to PV

BCS, Surgical Treatment In MOVC cases: Senning procedure: Dorso-cranial liver resection. & Hepatico Atrial Anastomosis. Fingure Fracture Vena Cava Webs resection: Direct Resection or Trans-atrial PS Shunt in classical BCS: Effective Portal Hypertension relief In successful cases: PV became outflow. Hepatomegaly resolves. Histology improves Prolonged survival 90% Shunt thrombosis: Mesocaval 33% in 5 yrs Portocaval 3% over 13 yrs CI in IVC occlusion (Membraneous obstruction of vena cava)

Liver transplantation for Budd–Chiari Fulminant BCS Decompensated cirrhosis (CHILD B&C) BCS recurrence 4-10% Increase risk for HA & PV thrombosis Overall 5 year survival 85% Marco Senzolo et al. (2005) Update on the classification, assessment of prognosis and therapy of Budd–Chiari syndrome Nat Clin Pract Gastroenterol Hepatol 2: 182–190 doi:10.1038/ncpgasthep0143

Veno-occlusive Disease

אירועים טרומבוטיים בכבד Hepatic Vein Hepatic Artery Portal Vein CBD Gallbladder Budd-Chiari Syndrome Veno-occlusive Disease Portal Vein Thrombosis Heptic Artery Thrombosis Peliosis Hepatis Hepatic Artery Aneurysm Hepatic Artery Atherosclerosis

Veno-Occlusive Disease Sinus Obstruction Disease Pathology: Obstruction to HV outflow: Subendothelial swelling & Reticulated collagen Central vein of lobule and branches Endothelial oedema, fibroblastic proliferation, obstruction by fibrosis & thrombosis

Veno-Occlusive Disease Sinus Obstruction Disease After bone marrow transplantation 25% incidence Shortly post BMT Due to toxic endothelial injury: Chemotherapy Radiation therapy Azathioprin & 6MP Plant alkaloids: Senecio Crotalaria

Veno-Occlusive Disease Sinus Obstruction Disease Massive congestive & painful hepatomegaly Ascites Jaundiced, out of proportion. Centrilobular necrosis leads to cirrhosis Mortality 20% to 50% (100% in severe cases)

Veno-Occlusive Disease Sinus Obstruction Disease Symptomatic treatment only for portal HTN Inconclusive data: Ursodeoxycholic acid Heparin & LMWH Prostaglandin E1 High doses of Glucocorticosteroids N-acetylcysteine Anti-Thrombin & Protein C tPA Defibrotide

Veno-Occlusive Disease Sinus Obstruction Disease TIPS: 50% success, 10% long term survival. Liver Transplantation!

Portal Vein Thrombosis

אירועים טרומבוטיים בכבד Hepatic Vein Hepatic Artery Portal Vein CBD Gallbladder Budd-Chiari Syndrome Veno-occlusive Disease Portal Vein Thrombosis Heptic Artery Thrombosis Peliosis Hepatis Hepatic Artery Aneurysm Hepatic Artery Atherosclerosis

Pathogenesis Cirrhosis (10-30%): Cancer:  Portal blood flow  Liver synthetic activity of protein C, S & anti-Thr. III High incidence of concomitant HCC Cancer: Tumor invasion Compression or constriction effect from tumor mass Prothrombogenic changes (cysteine protease)

Etiologies of PVT Local Factors 10-50% Thrombophilia 40-60% Inflammatory Surgical Inherited Acquired Sepsis Liver Transplant FVL Malignancy Pancreatitis Splenectomy Prothrombin Mutation 20210G/A APL syndrome Diverticulitis Colectomy Anti-thrombin III Anti-cardiolipin Appendicitis Umbilical Vein Catheters Protein C/S deficiency Elevated Homocysteine Peptic Ulcer D. Portocaval Shunt OCPs Blunt Trauma Pregnancy IBD Simply stated many things have been known to cause PVT. Above all, PVT is most common in liver disease and cirrhosis. The quoted prevalence being approx 10-30% in all cirrhotics The prevalence rate outside the realm of cirrhosis is unknown due to small numbers of cases reported. The literature does try to categorize the etiologies of PVT into: Local Factors such as surgeries and procedures of the abdomen, as well as inflammatory states of the GI tract. And… Thrombophilic states including the genetically inherited states and other acquired processes that are known to be risk factors for thromboses Local factors thought to attribute anywhere from 10-50% and thrombophillic states accounting for roughly half. Our patient of course was found to have the prothrombin gene mutation Which briefly is a new discovery (1996) by a gentleman named Poort Is thought to raise thrombus risk by 2-4 fold with ethnic predominance in europeans Concerning PVT this mutation is now thought to be a cause in many cases originally thought to be idiopathic The green highlighted items are causes that are also common to many of our Family Medicine patients

Clinical manifestations Acute PVT No definitive time-frame distinguishes acute from chronic PVT (~ 60 days) Abdominal pain, N/V (Mesenteric veins involved) Few clinical consequences: Immediate vasodilation of the hepatic arterial system Rapid development of tortuous collateral veins bypassing (cavernous transformation)

Clinical manifestations Chronic PVT Portal hypertension Hemorrhage of varices (30-70%), Outcome of bleeding is better than with cirrhosis Splenomegaly (50%) & hypersplenism Ascites (10%), Jaundice (<5%), Encephalopathy Abdominal pain when mesenteric veins involved Normal to slightly increased LFT’s 10-year-survival was 81% without cirrhosis, cancer or mesenteric vein thrombosis (Janssen et al. Gut 2001)

Investigation Color doppler ultrasonography Echogenic thrombus within portal vein lumen Dilation proximal to the occlusion Absence of an identifiable portal vein Collateral vessels (cavernous transformation)

Investigation CT scan MR angiography Portal venography Filling defect in contrast-enhanced lumen Train track appearance when totally occluded MR angiography Portal venography Endoscopic ultrasound

Gadolinium-enhanced T1-weighted MR 22-year-old woman with chronic Budd-Chiari syndrome and portal vein occlusion Gadolinium-enhanced T1-weighted MR CT scan obtained during portal phase CT scan obtained during portal phase gallbladder varices Fig. 7A —22-year-old woman with chronic Budd-Chiari syndrome and portal vein occlusion. Gadolinium-enhanced T1-weighted MR image (A) and contrast-enhanced transverse CT scan obtained during portal phase (B) show occlusion of vein (arrow, A and B) draining caudate lobe. Fig. 7C —22-year-old woman with chronic Budd-Chiari syndrome and portal vein occlusion. Contrast-enhanced transverse CT scan caudal in relation to B obtained during portal phase shows cavernous transformation of portal vein (arrow) and gallbladder varices (arrowhead). Ascites is evident. This case is unusual in that caudate lobe has impaired venous drainage with resulting heterogeneous enhancement. occlusion of vein draining caudate lobe cavernous transformation of PV Brancatelli, G. et al. Am. J. Roentgenol. 2007;188:W168-W176 Copyright © 2007 by the American Roentgen Ray Society

Portal and hepatic vein thrombosus Minimun intensity projections Maximum intensity projection

Cavernous Transformation 8

Treatment, General Treat complications: Endoscopy with banding or sclerotherapy Limited evidence for beta-blockers if non-cirrhotic TIPS PS Shunt Mesocaval and splenorenal shunts Sugiura Procedure (esophogastric de vascularization & transection) Broad spectrum antibiotics if pylephlebitis

Acute/ recent-onset Anticoagulation may result in recanalization in more than 80% of cases (Condat et al. Hepatology 2000) High rates of recanalization with thrombolysis compared with conservative treatment (Malkowski et al. Hepatogastroenterology 2003)

Chronic PVT Vague Recommendations with Anticoagulation: The risk of thrombosis is currently as clinically significant as the risk of bleeding. The benefit-risk ratio favors anticoagulant therapy (Condat et al. Gastroenterology 2001) Cohort study with 136 patients, 84 received anticoagulants, followed for median of 46 months. Debate of anticoagulation use in non-cirrhotic PVT - Condat & Sheen: 78-90% show resolution or re-canalization of the thrombus

Anti coagulation PVT Anticoagulation for at least 3-6 months Chronic anticoagulation if: 1) Hypercoagulable state 2) Surgical shunt 3) Concomitant mesenteric vein thrombus Thrombolytics if mesenteric vein involvement or signs of ischemia Broad spectrum antibiotics if pylephlebitis

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