Budd-chiary syndrome,clinical features,radiological and lab diagnosis,managment,guidelines

budd-chiari syndrome,epidemiology,clinical features,acute,subacute,chronic budd-chiari diagnosis and stepwise treatment,anticoagulation,anioplasty,TIPS,DIPS,portosystemic shunt,liver transplantation

1. Budd- chiari syndrome DR. VIJAYA K.C. DM RESIDENT DEPARTMENT OF GASTROENTEROLOGY DATE: MONDAY, FEB 24,2025

2. Anatomy-Hepatic veins Three large vessels that drain the venous blood from the liver into IVC Hepatic veins: RHV, MHV, LHV Others: Several smaller and rarely inconsistent caudate lobe veins Hepatic veins arise from small central veins  that drain the liver sinusoids. Mean diameter of 15 mm

3. Right Hepatic vein Longest hepatic veins, formed anteriorly near the inferior border of the liver. Demarcates the border between the segments VI and VII and segments V and VIII Drains segments VI and VII ± parts of segments V and VIII.

4. Middle Hepatic vein Runs in the middle hepatic fissure, between the right and left lobes of the liver.  Border between the segments V and VIII and segments IVa and IVb   Drains segments IV,V and VIII. Occasionally, anastomoses with the right hepatic vein. Usually joins the left hepatic vein and forms a short common trunk before draining into IVC About 10% it drains directly into IVC.

5. Left Hepatic vein Demarcates the border between the segments IVa and IVb anteriorly, and segments II and III posteriorly.  Drains segments II, III ± segment IV Receives its major tributary, the umbilical vein Draining into IVC, mostly forming common trunk with MHV.

6. Veins of the caudate lobe Drain the segment I of the liver( caudate lobe) Terminate by draining directly into IVC  When sonography reveals a caudate vein equal to or larger than 3 mm in diameter in the appropriate clinical setting, one should strongly suspect budd-chiari syndrome.

7. Historical background George budd , a british internist, described three cases of hepatic vein thrombosis due to abscess-induced phlebitis in 1845 Hans Chiari, an Austrian pathologist, added the first pathologic description of a liver with “obliterating endophlebitis of the hepatic veins” in 1899.

8. Introduction Defined as hepatic venous outflow obstruction at any level from the small hepatic veins to the junction of the inferior vena cava and the right atrium, regardless of the cause of obstruction. Outflow obstruction caused by hepatic veno -occlusive disease and cardiac disorders is excluded from this definition. Aka Hepatic Venous Outflow Obstruction or Obliterative Hepatocavopathy Rare disease with a potentially dismal outcome if not treated optimally.

9. Classification -BCS Classified according to etiology, site of obstruction, manifestations and duration of the disease. Br J Radiol;91:20180441

10. classification Br J Radiol;91:20180441 Journal of Clinical Medicine Research 2022

11. classification Br J Radiol;91:20180441 Journal of Clinical Medicine Research 2022

12. Subtypes of primary BCS Classical( Hepatic venous occlusion) BCS Hepatic Venacava -BCS Small vessel types BCS Small vessel-BCS, an incredibly rare form of BCS, is challenging to diagnose. It has been described in the context of primary or secondary antiphospholipid syndrome (APS) or PNH.They are usually asymptomatic.

13. Classical vs HVC-BCS Okuda et al.(1998) proposed that primary hepatic venous thrombosis (classical BCS) and thrombosis of the IVC at the level of the IVC were two separate syndromes. Classical BCS common in wastern population,HVC -BCS common asian . Classical BCS have acute onset of symptoms, and a greater severity of symptoms requiring a different therapeutic approach, than HVC-BCS. Hepatology. 1998;28:1191–1198

14. Fig: 37-year-old female with hydatid cyst. A.Contrast -enhanced CT at portal venous phase shows a large cyst compressing the inferior vena cava and the right and middle hepatic veins (white arrow). B .The compression is responsible for the development of intrahepatic venous collaterals connecting the right to the middle hepatic veins (white arrows) Secondary Budd–Chiari syndrome

15. Epidemiology Rare disease. Sweden(1990-2001), incidence in 1.4 per million population. Northwest Italy (2002-2012), the 2 per million in males and 2.2 per million in females. Median age at diagnosis -38  17% of hospital admissions for liver-related disease in kathmandu , nepal (1990 to 1992)

16. World J Hepatol 2016 June 8; 8(16): 691-702

17. Etiology N Engl J Med 2023;388:1307-16

18. Etiology-primary BCS Myeloproliferative disorders ≅ 41% of patients Myeloproliferative disorder, PNH, and OCP-common in west China: hyperhomocysteinemia and the C677T polymorphism of MTHFR. ≅ 7% cases of BCS a/w pregnancy or the puerperium.

19. Etiology- Seconday BCS 1) Invasion by a malignant tumor or alveolar echinococcosis 2) Compression by cysts or focal nodular hyperplasia. 3) Compression and inflammation due to PCLD or liver abscesses. 4) Blunt abdominal or thoracic trauma

20. Pathogenesis ≥2 major hepatic veins territory obstruction→ clinical manifestations. Thrombosis →vein transformed into fibrous cord/wall thickening →narrowing of vein Occlusion of vein→collaterals develop on intra- and extrahepatic veins Increased hepatic venous and sinusoidal pressures→sinusoidal distensions/ congestion→decrease in hepatic blood flow→ischemic coagulative necrosis and apoptosis→regenerative changes & Fibrosis→Venocentric cirrhosis. Segment I (caudate lobe) hypertrophy due to preserved blood supply

21. Chronic (>6 months )

22. Clinical features Asymptomatic disease ALF-rare Fulminant Subacute disease Chronic liver disease

23. Clinical features N Engl J Med 2023;388:1307-16

24. Bashir H, Mazhar M, Seerat I, et al. ( Novem ber 07, 2023) Clinical Manifestations and O utcomes of Budd-Chiari Syndrome in Children: A Single-Centre Study.

25. World J Hepatol . 2016 Jun 8;8(16):691–702.

26. Differential diagnosis Sinusoidal obstruction syndrome Constrictive pericarditis Cirrhosis

27. BCS vs cirrhosis Hepatomegaly Dilated veins on back Encephalopathy rare LFTs preserved Platelet count can be high High protein/ high SAAG ascites Hypercoagulable state Rare: except for few causes Absent May be seen low albumin Low Low protein/high SAAG ascites Absent

28. BCS should be suspected when there is.. Sudden onset of ascites and painful hepatomegaly Massive ascites with relatively normal liver functions Sinusoidal dilation in liver biopsy without heart disease Fulminant hepatic failure along with hepatomegaly and ascites Unexplained chronic liver disease(nonalcoholic, HBV and HCV negative) Liver disease with a thrombogenic disorder HVT-BCS should be considered in any patient with liver disease (recent or chronic) of unknown etiology. Suspicion should be even higher in a patient with a recognized prothrombotic disorder.

29. Diagnosis Doppler USG Triphasic CT or MRI Venography Liver biopsy

30. Diagnosis-Lab Bilirubin rise - varying extent Transamnitis > 5 times- acute type ALP rise- varying extend Serum albumin ↓ High SAAG ascites > 1.1gm/dl, high protein >2.5 gm/dl.

31. Abdominal imaging with doppler US, CT, or MRI (1) lack of visibility of hepatic veins (2) dilatation upstream due to a complete or partial obstruction of the terminal portion (3) diffuse narrowing and irregularity (4) transformation into a cord-like remnant. Additional findings 1) a combination of liver sectorial atrophy and hypertrophy, including segment I Enlargement (2) ascites, portosystemic collaterals, and enlargement of the spleen 3) patchy enhancement in the arterial and portal phases, which disappears at the late phase, a pattern indicating decreased portal perfusion due to stasis (4) a marked nodular enhancement in the arterial phase with disappearance in the portal and late phases, without washout,

32. Diagnosis

33. Doppler USG Showing hepatic venous outflow tract obstruction is excellent Depends mostly on operator’s experience and clinical suspicion First investigation of choice • Sensitivity & specificity > 85% • CE-USG: superior to gray scale & CD for Detection/ characterisation of HV thrombosis • HV patency and size/IVC thrombosis Doppler ultrasound, performed by an experienced operator, is the first-line imaging study for HVT/ BCS. MR or CT can be used for diagnosis confirmation and interventional planning. • Lack of visibility • Reversal of flow • Diffuse narrowing and irregularity • Transformed into cord like remnant • Collateral veins- hepatic/ extrahepatic

34. CECT-abdomen Venous anatomy - patent IVC, PV, HV and non visualisation of HV. Caudate lobe hypertrophy (fan shaped enhancement) Collaterals, ascites Liver Necrtotic areas Altered parenchymal perfusion pattern Early homogenous central enhancement Delayed patchy enhancement of periphery of liver Prolonged retention of contrast in the periphery Regenerative nodules Not useful in showing web in IVC

35. Nutmeg liver Nutmeg liver refers to the mottled appearance of the liver as a result of hepatic venous congestion. Radiologically, it is most appreciable on portovenous phase imaging on cross-sectional imaging. It is named after the cut appearance of the nutmeg seed.

36. MRI- Abdomen Particularly beneficial in non-diagnostic USG Liver morphology and regional perfusional disorders : similar to CECT. parenchymal lesions such as benign regeneration nodules (>10 in no, <4 cm & hypervascular ), hemorrhagic necrosis and perfusions disorders: MRI is better than CECT. Useful in differentiating regenerative nodules from HCC. MR angiography- before selecting a treatment modality

37. Bashir H, Mazhar M, Seerat I, et al. ( Novem ber 07, 2023) Clinical Manifestations and O utcomes of Budd-Chiari Syndrome in Children: A Single- Centre Study.

38. Liver biopsy Not required for diagnosis Cirrhosis with thrombosed small veins Differentiating benign regenerative macronodules from HCC Differentiates veno -occlusive disease & cirrhosis of other origin Histochemical staining (hematoxylin-eosin and masson trichrome) showed hepatocyte degeneration, bridging fibrosis, sinusoidal dilatation, and areas of fibrous tissue with substantial hyperplasia . 

39. Left-Normal and Right-BCS liver biopsy Sinusoidal dilation and congestion, with coagulation necrosis of hepatocytes around a small hepatic vein , and midlobular sinusoidal dilation; portal areas are well preserved.

40. Transient elastrography / fibroscan  Noninvasive method for estimating liver fibrosis. Although previously thought to be inappropriate for bcs due to liver congestion, ls is now thought to be capable of monitoring treatment outcomes in bcs after balloon angioplasty, albeit without correlating with liver fibrosis. Utility of te in the diagnosis, staging, and follow-up of liver fibrosis in patients with bcs before and after the endovascular intervention. In addition, te was used to determine if there is a correlation between the preintervention fibrosis stage and posttreatment lsm There was significant drop in liver stiffness measurements (LSM) measured three months post-intervention indicating improvement of liver fibrosis after relieving liver congestion but still not correlated to the METAVIR scores measured in the liver biopsy. Liver congestion has high impact on liver stiffness measurement giving overestimation which improves significantly after decongestion of the liver by the endovascular intervention.

41. IVC venography Delineates the level of obstruction Extensive collateral veins that eventually drain into the SVC Simultaneous catheterization of IVC and SVC - length of obstruction Pressure gradient (significant > = 5mm hg) Infra-hepatic IVC to right atrium pressure gradient >15mm hg - mesoatrial shunt

42. Hepatic venography Direct (transhepatic) Retrograde ( transjugular ) Never needed for making the diagnosis Venography allows percutaneous therapy Occluded / narrow hepatic veins Spider web pattern by intrahepatic collaterals Wedge hepatic venous- IVC gradient >10mm hg 

43. Role of venography TIPS placement, Catheter-directed thrombolysis Mechanical thrombectomy Balloon angioplasty Recanalization of an occluded hepatic vein or venacava with stent placement. Transjugular liver biopsy. Essential guide and road map for surgical therapy in BCS.

44. Laborator y JAK2 V617F mutation Calreticulin gene mutations (spleen length >16 cm, platelet count >200,000/mm3) Flow cytometry of blood cells for PNH Factor V leiden Prothrombin G20210A gene mutations Lupus anticoagulant and anti- β2- glycoprotein I antibodies for antiphospholipid syndrome. Antithrombin, protein c, and protein s levels At the time of HVT/BCS diagnosis, an full thrombophilia workup is recommended, and even when one causal factor is identified, additional factors should be investigated. Consultation with a hematologist is recommended

45. Primary BCS workup Gut 2008;57:1469–1478. doi:10.1136/gut.2007.133637

46. Natural history Not well known in the late phase Earlier studies ,90% of the patients would die within 3 years of diagnosis. Asymptomatic disease have an excellent medium- and long-term outcome. IVC obstruction at high risk of developing HCC.

47. Management

48. Goals of therapy  Prevent the propagation of the clot Restore patency of thrombosed veins Decompress the congested liver Prevent or manage complications

49. Treatment Primary BCS: anticoagulation and specific therapy for the underlying disease. Anticoagulation therapy as like VTE. Portal hypertension (ascites, variceal bleeding, encephalopathy) :medical or endoscopic therapy  Symptomatic patients: percutaneous angioplasty Symptomatic and angioplasty is not feasible : TIPS Symptomatic and failure to PTCA,TIPS,ALF patient: LT Treatment of the underlying disease : MPN, PNH or Behçet’s syndrome Multidisciplinary team of hepatologist, haematologist and specialists in systemic disorders.

50. Correcting HVOTO: stepwise treatment Anticoagulation Restoring hepatic venous outflow thrombolysis Percutaneous angioplasty with or without stenting Derivative techniques: TIPS,DIPS, portosystemic shunt Liver transplantation J Hepatol . 2019 Jul;71(1):175-199 A progressive “step-up” therapeutic strategy according to the clinical response from less to more invasive therapies is recommended for HVT/BCS. Early referral to tertiary care centers with expertise in this disorder is recommended

51. Anticoagulation Attempt to achieve recanalization but mainly to prevent thrombosis progression Anticoagulation for all patients with BCS, even pt without prothrombotic disorder or asymptomatic. Long-term anticogulation ; 5-year intervention free survival with disease-control in 25–30%. Anticoagulation alone is sufficient in only 10% of patients (mild disease). LMWX,Vit K antagonist, DOAC INR goal between 2 and 3 After TIPS, surgical portosystemic shunt or liver transplant, anticoagulation will be required. All patients with HVT/BCS, even in the absence of a recognized prothrombotic disorder, should receive therapeutic anticoagulation.

52. Clinical Gastroenterology and Hepatology 2023;21:978–987

53. Thrombolysis-restoring hepatic venous outflow Little benefit in clinical practice Recombinant tissue plasminogen activator, streptokinase or urokinase Instilled through a peripheral vein or locally after catheterization of the thrombosed vein. Usually combined with angioplasty Indications: acute or sub-acute BCS, at experienced centres . Major ADR : bleeding Drugs used in Thrombolysis Streptokinase - loading dose of 250,000 units intravenously over 30 mins. followed by 100,000 units/hour for 72 hours. (systemic IV infusion) Urokinase - 240,000 U per hour for 2 hours, followed by 60,000 U per hour  rt-PA - 0.5 to 1.0 mg per hour Urokinase & rt-PA, infused directly into thrombosed hepatic vein of about 25 hrs by transferal or transjugular route.

54. Radilogical managment Angioplasty Stenting TIPS ( transjugular intrahepatic portosystemic shunt) DIPS (direct intrahepatic portosystemic shunt) Local thrombolysis

55. Percutaneous angioplasty PTCA (Balloon angioplasty) with or without stenting Effective and safe approach for restoring the physiological hepatic outflow Useful in focal or segmental stenosis of HV/ suprahepatic IVC. Asian (HVC BCS) and combne angioplasty & stenting, achieve patency in >80% of patients at 5 years. Post-angioplasty re-stenosis : subsequent angioplasties

56. Angioplasty

57. Derivative techniques Since 90’s surgical shunts have been replaced by the less-invasive TIPS in most places. Tips: more effective in maintaining patency and is associated with lower morbidity and mortality than surgery TIPS primary patency rate using PTFE-covered stents is 67% at 2-year followup . TIPS or DIPS using PTFE-covered stents is the treatment of choice for HVT/BCS when medical therapy or angioplasty fail or are not feasible.

58. tips Successful treatment option in BCS. Percutaneous image-guided procedure that creates a portocaval shunt in liver parenchyma. Option for secondary prevention of a variceal bleed and refractory ascites. Tips patency has also significantly improved since the use of polytetrafluoroethylene (PTFE)-covered stents Success rate of TIPS placement is 80% in BCS as compared >90% for cirrhosis Failure to recanalization therapies (thrombolytic therapy, angioplasty or stenting)  Good long-term outcome ,success rate of 93% .

59. Journal of Vascular and Interventional Radiology Volume 33, Issue 11 , November 2022, Pages 1301-1312.e13

60. Gastroenterology Volume 135, Issue 3 , September 2008, Pages 808-815

61. Portosystemic shunts Shunt is to convert the portal vein into an outflow tract, thereby decompressing the hepatic sinusoids Technically difficult when there is caudate lobe hypertrophy Perioperative mortality is 25% Late shunt patency is only 70% Survival benefit resulted in this treatment option falling out of favor Surgical shunts should only be considered if TIPS/ DIPS is not feasible or fails.

62. Liver transplantation for BCS About 10%–20% of patients show progressive liver deterioration despite medical management, revascularization strategies and TIPS. Five-year survival rates varying between 71% and 89.4%.  Survival benefit of OLT in more in those BCS patients with worse baseline characteristics Early initiation and persistent anticoagulation after OLT Indications Cirrhosis with progressive liver failure Failure of portosystemic shunt/stents  Unshuntable / unstentable (rare) Acute fulminant hepatic failure (rare) G. Mentha et al. / Journal of Hepatology 44 (2006) 520–528 LT is reserved for HVT/BCS patients in whom the medical and vascular interventional approaches fail. LT may be the first step in patients with acute liver failure. In this situation, TIPS/DIPS should be considered while waiting for transplant because it may improve liver function and potentially avoid the need for transplantation.

63. G. Mentha et al. / Journal of Hepatology 44 (2006) 520–528

64. Recommended treatment strategy-primary BCS Gut 2008;57:1469–1478. doi:10.1136/gut.2007.133637

65. Pregnancy with BCS RCT show: good maternal outcome in treated patients with BCS during pregnancy. The risk of miscarriage or premature birth is increased. Once the pregnancy reaches 20 weeks of gestation, birth of a live baby possible Pregnancy is not contraindicated Anticoagulant therapy throughout pregnancy and in the postpartum period. LMWX indicated. Vaginal delivery, with the use of forceps or a vacuum device Screening for EV during 2 nd trimester, to introduce bete blocker therapy

66. A proposed diagnostic and therapeutic work-up for the patient with Budd Chiari syndrome (BCS). Source: United European Gastroenterol . 2015 Dec;3(6):489–500

67. Surveillance for HCC Surveillance for HCC in patients with chronic HVT/BCS is recommended as in the general cirrhosis population, with ultrasound every 6 months with or without alpha-fetoprotein determination. Because of the perturbed vascularity of the liver, HCC diagnosis in these patients should not rely on imaging criteria alone and should require histological confirmation.

68. Prognosis BCS is associated with high mortality (>80% at 3 years). Risk markedly changes if the diagnosis is established early and adequate management. Well manmaged BCS, survival at 5 years exceeds 80%. Several prognostic scores have been developed Transaminitis >5 times lasting for few days a/w poor prognosis.

69. Journal of Clinical Medicine Research 2022

70. 5-year survival rates

71. Poor prognostic factors For classical BCS patients include: Severe BCS e.g ., ascites requiring diuretics or paracentesis pleural effusion higher Clichey score Older age Cirrhosis at diagnosis of BCS Chronic kidney disease For HVC-BCS patients Development of cirrhosis or Hepatocellular carcinoma (HCC )

72. Take home notes BCS is a rare disease primarily affecting young adults. Many patients with BCS harbour several prothrombotic disorders Myeloproliferative disease (V617F JAK2 mutation)account for 50% of BCS patients Because of its high lethality and good response to therapy, BCS should be considered in any patient with liver disease. Treatment for BCS consists of the successive implementation of anticoagulation, PTCA, TIPS/DIPS and, finally, liver transplantation. Using this progressive therapeutic strategy, overall 5-year survival rates currently approach 90%.

73. references J Hepatol 2009; 50: 195–203. Br J Radiol . 2018 Dec;91(1092):20180441 Khan, Faisal et al. Journal of Translational Internal Medicine  6 (2018): 97 - 104. H.L.A. Janssen et al. / Journal of Hepatology 38 (2003) 364–371 Journal of Hepatology 2016 vol. 64 j 179–202 N Engl J Med 2023;388:1307-16 Journal of Clinical Medicine Research World J Hepatol 2016 June 8; 8(16): 691-702 Sleisenger and fordtran’s gastrointestinal and liver disease, 11th Edition Aasld practice guidelines 2020 Baveno VII guideline 2021 Outcome of Budd-Chiari Syndrome Patients Treated With Direct Oral Anticoagulants: An Austrian Multicenter Study