Hepatic Venous Outflow Tract Obstruction: Causes, Natural History, and Treatment

Abbreviations

HCC

hepatocellular carcinoma

HV

hepatic vein

HVOTO

hepatic venous outflow tract obstruction

IVC

inferior vena cava

TIPS

transjugular intrahepatic portosystemic shunt

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An impediment to hepatic venous outflow anywhere from the small hepatic venules to the cavoatrial junction because of a wide spectrum of etiologies results in Budd‐Chiari syndrome, also known as hepatic venous outflow tract obstruction (HVOTO). By definition, this does not include hepatic portosinusoidal vascular disease and cardiac disorders causing back‐pressure‐related changes. ¹ HVOTO is a rare vascular disease of the liver. The exact incidence and prevalence of HVOTO is unknown. However, meta‐analyses have estimated the pooled annual incidence of HVOTO to be around 1 per 1 million, and the pooled prevalence to be around 11 per 1 million population. ² We briefly review the causes, the natural history, and the available treatment options in the management of HVOTO.

Causes

HVOTO is primarily classified into primary and secondary groups, based on the etiopathogenesis (Table 1). Primary HVOTO is the result of an intrinsic endoluminal pathology (such as thrombosis or phlebitis), while secondary is due to extrinsic disorders originating outside the vein (such as neoplasms, infections, trauma, and iatrogenic causes) and causing secondary compression or invasion of the veins. Primary HVOTO is secondary to acquired or inherited prothrombotic diseases. The prevalence of these prothrombotic risk factors varies widely among different populations, and this is confounded by varying testing rates because of the high costs. Protein C, protein S, and antithrombin deficiency are more common among Indians, while antiphospholipid antibodies, hyperhomocystinemia, and Janus kinase mutations are more common among Europeans (Table 2). ³ , ⁴ These risk factors predispose these patients to recurrent thrombosis even after treatment for HVOTO necessitating long‐term anticoagulation and regular follow‐up. There is a well‐documented geographical difference in the pattern of obstruction. Thrombosis, long‐segment isolated involvement of the hepatic veins (HVs), is more common in Western countries, while short‐segment membranous obstruction with more frequent involvement of the inferior vena cava (IVC) is more common in Asian and African countries. Isolated HV involvement is far less common in eastern countries such as China and Japan compared with Western countries, while the corresponding figure is intermediate in the Indian population (Table 3). ³ , ⁴ , ⁵ , ⁶

TABLE 1.

Risk Factors and Causes of HVOTO

Primary	Secondary
Inherited prothrombotic diseases	Neoplasias
Factor V Leiden mutation	HCC
Protein C deficiency	Adrenal carcinoma
Protein S deficiency	Primary hepatic hemangiosarcoma
Antithrombin deficiency	Epithelioid hemangioendothelioma
Prothrombin G20210A mutation	Sarcoma of the IVC
C677T MTHFR gene mutations	Right atrial myxoma
Acquired prothrombotic diseases	Metastases
Myeloproliferative neoplasms	Infectious diseases
Antiphospholipid syndrome	Hydatid cysts
Paroxysmal nocturnal hemoglobinuria	Amebic or pyogenic abscess
Hyperhomocysteinemia	Aspergillosis
Behçet disease	Sarcoidosis
Other factors	Trauma
Oral contraceptives	Abdominal surgery
Pregnancy, puerperium
Hypereosinophilic syndrome
Inflammatory bowel disease

TABLE 2.

Comparisons of Prothrombotic Risk Factors Between Indian and European Patients With HVOTO

Risk Factors	Indian Population 3	European Population 4
Protein C deficiency	29/85 (34%)	5/117 (4%)
Protein S deficiency	7/85 (8%)	3/108 (3%)
Antithrombin III deficiency	10/72 (14%)	3/112 (3%)
Factor V Leiden mutation	4/51 (8%)	18/147 (12%)
Janus kinase (JAK 2)	11/69 (16%)	35/121 (29%)
ANA (antinuclear antibodies)	5/120 (4%)	—
LAC (lupus anticoagulant)	9/182 (5%)	—
APLA (antiphospholipid antibodies)	5/137 (4%)	37/150 (25%)
B2GP1 (beta2 glycoprotein 1)	8/92 (9%)	—
Hyperhomocysteinemia	2/56 (4%)	28/129 (22%)
MHTFR (methylenetetrahydrofolate reductase)	2/25 (8%)	—

TABLE 3.

Comparison of Site of Obstruction in Patients With HVOTO in Different Countries

Author	Country of Study	Patients (n)	IVC	HV	Combined
Hemachandran et al. 3	India	510	33 (6.5%)	207 (40.6%)	270 (52.9%)
Zhou et al. 5	China	338	8 (2.4%)	45 (13.3%)	285 (84.3%)
Darwish Murad et al. 4	Europe	163	4 (2.4%)	80 (49.1%)	79 (48.5%)
Darwish Murad et al. 6	Europe and United States	237	17 (7.2%)	147 (62.0%)	73 (30.8%)

Clinical Presentation and Natural History

The clinical presentation of HVOTO can range from total absence of symptoms to fatal fulminant liver failure. This primarily depends on the temporal profile and the extent of the obstruction. Thus, it may present as acute, subacute, chronic, or acute‐on‐chronic forms. The subacute and the chronic forms are the most common form of presentation in both Western and Asian countries. Such patients most commonly present with abdominal pain, hepatomegaly, ascites, lower‐extremity edema, gastrointestinal bleeding secondary to varices, or hepatic encephalopathy. ⁷ Subcutaneous collaterals in the anterior abdominal wall are uncommon, but it is a specific sign of IVC obstruction (Fig. 1).

FIG 1.

Clinical photograph of a 35‐year‐old man with IVC obstruction showing multiple subcutaneous anterior abdominal and chest wall collaterals.

If left untreated, HVOTO leads to the development of chronic liver disease and its associated complications secondary to portal hypertension, such as variceal bleeding and hepatic encephalopathy. These patients may also develop acute‐on‐chronic episodes, further worsening the outcomes. ⁸ Most patients experience development of benign regenerative nodules or nodular regenerative hyperplasia characterized by multiple hypervascular well‐defined nodules. The risk for hepatocellular carcinoma (HCC) is also increased in patients with HVOTO (Fig. 2). This risk is higher in patients with IVC involvement and also among those treated patients who experience recurrent disease. ⁹ Patients with HVOTO are also at risk for development of portal vein or portomesenteric thrombosis due to the additive effect of slow flow in the portal circulation and the preexisting prothrombotic risk factors. Such patients have a worse prognosis.

FIG 2.

HCC (arrows) in the background of HVOTO. Axial precontrast T1‐weighted image shows (A) a well‐demarcated hypointense lesion that shows nonrim arterial‐phase hyperenhancement (B) and washout with capsule formation in venous (C) and delayed (D) phases. Heterogeneous diffuse mottled enhancement of the background of the liver is seen in the portal venous phase (dashed arrow in C) secondary to the underlying HVOTO.

Treatment

The treatment strategy is three‐pronged. First is symptomatic management for acute presentations with variceal bleed or hepatic encephalopathy. Second is anticoagulation for the management of the prothrombotic state. Oral vitamin K antagonists, such as warfarin, are commonly used. However, recently, other direct‐acting oral anticoagulants, such as dabigatran, have also shown similar stent patency rates and complications. ¹⁰ Third is the definitive treatment for relieving the obstruction. The definitive treatment has undergone a paradigm shift over the years. Liver transplantation was the most common form of treatment in the early 1980s. The creation of surgical shunts gained favor over transplantation in the later part of the decade. However, endovascular interventions became increasingly popular over the next two decades. Currently, endovascular interventions have a high technical success and favorable long‐term outcomes, and thus play a pivotal role in the management of HVOTO. Available endovascular treatment options include recanalization procedures, such as angioplasty, stenting, and transjugular intrahepatic portosystemic shunt (TIPS) (Fig. 3). There are significant variations in the management protocols. In western countries, a step‐up approach is advocated in which anticoagulation is used first, followed by TIPS for patients who do not improve with anticoagulation alone. In Asian countries, because of the higher prevalence of membranous obstruction, recanalization procedures are more commonly used, with TIPS being performed only in patients with no recanalizable HVs. Recent studies have shown comparable long‐term patency rates with recanalization procedures and TIPS. In a recently published study based on the Indian population, the 5‐year cumulative patency rates were 74% and 68% in the recanalization and TIPS groups, while the 5‐year survival rates were 89% and 76%, respectively. ³ Surgical treatment is primarily in the form of liver transplantation, which is limited for patients with advanced cirrhosis and those who had unsuccessful endovascular procedures because of technical failure and in some patients with fulminant liver failure.

FIG 3.

Endovascular procedures in HVOTO in three different patients: IVC angioplasty (A‐C), HV stenting (D‐F), and TIPS (G‐I). IVC angiogram through the transfemoral route (A) shows complete occlusion of the IVC with filling up of the collaterals. After successfully negotiating the guidewire across the occlusion, a 20‐mm balloon angioplasty (B) was performed, after which there was free flow of contrast into the right atrium (C). Right HV angiogram through transjugular route (D) shows short‐segment complete occlusion of the HV with multiple tortuous collaterals. A 10‐mm balloon mounted stent was deployed (E), after which there was free flow of contrast from the HV into the IVC (F). In a patient with diffuse HV disease, portal vein was punctured through the transjugular route (G). The tract was dilated and the stent deployed across the tract extending from the portal vein to the IVC (H), after which there is free flow of contrast from the portal vein through the shunt into the IVC (I).

Studies have shown that the presence of ascites, encephalopathy, deranged prothrombin time, class C according to Child‐Pugh score, and the response to treatment are factors that affect patient outcome. Various prognostic scores, such as Rotterdam index, Budd‐Chiari syndrome ‐ Transjugular intrahepatic portosystemic shunt prognostic index, and All India Institute of Medical Sciences HVOTO score, have been devised for the same purpose. ⁷ Irrespective of the mode of treatment, all these patients need to be under long‐term follow‐up and surveillance for the diagnosis of recurrence and complications such as HCC. However, currently, there are no established surveillance recommendations for patients with HVOTO.

Conclusion

HVOTO is a rare vascular disease of the liver. Although rare, it is a treatable cause of chronic liver disease and thus should be identified and treated promptly to avoid the associated long‐term complications. There are significant geographical differences in the prothrombotic risk factors and pattern of obstruction between Asian and Western populations. Endovascular interventions are the primary mode of treatment and have favorable long‐term outcomes.