Liver is a highly vascular organ with dual blood supply from hepatic artery and portal vein (PV). Normal hepatic blood flow is about 1500 mL/min. PV blood contributes approximately 70% of the flow and 50% of the oxygen consumed by liver. Blood from hepatic artery at about 100 mm Hg pressure and PV at about 10 mm Hg pressure mixes in the hepatic sinusoid. In contrast to other capillaries whose endothelial linings are continuous, the sinusoidal capillaries are lined by discontinuous layer of endothelium that has pores of about 30–50 nm in size called fenestrae grouped into sieve plates (1). The liver sinusoids are also noted by the absence of a demonstrable basement lamina. Thus, the endothelium is highly permeable and largely supported by a carpet-like pile formed by liver cell microvilli separated by the space of Disse. Hepatic microcirculation is characterized by low outflow resistance. The ratio of pre- to post-capillary resistance in skeletal muscle is 4:1 compared to 49:1 in the liver, which results in a very low outflow resistance (2). Maintenance of low sinusoidal pressure is important for normal hepatic function. This is helped by another unique interrelationship between the sinusoidal pressure and the hepatic arterial flow. Increase in sinusoidal pressure results in reflex decrease in hepatic arterial flow (3). Thus, despite increase in portal venous flow during digestion, the sinusoidal pressure is maintained low. The size of the pore in hepatic sieve plate is just right at normal sinusoidal pressure to maintain an oncotic gradient that prevents loss of protein into interstitial space. The anatomy of hepatic microcirculation is adjusted to allow the hepatocytes a close contact with the incoming PV blood rich in nutrients and hormones, a process that facilitates liver to play its role in body metabolism.

Sinusoidal blood that drains into terminal hepatic vein (HV) is collected in lobular and sublobular veins that join to form medium-sized veins. Medium-sized veins join to form large HVs. Three large and nearly 20 small HVs drain the liver blood into inferior vena cava (IVC), which carries it to the right atrium of the heart. Hepatic venous outflow obstruction (HVOO) may occur at the level of the sinusoids, at HVs, or IVC at the HV outlets. Orifices of large HVs are considered by some as part of the IVC system (4). HVs have no valve and any increase in IVC pressure is directly transmitted to the liver. Thus, cardiac condition such as constrictive pericarditis mimics HVOO (5).

The clinical manifestation of HVOO largely depends on the extent and speed of obstruction, its cause, and the development of compensatory mechanisms. Obstruction of a few medium-sized HVs or a large HV may not cause any symptom. Insidiously developing multiple HV obstruction that allows development of collaterals also remains asymptomatic. HV obstructions thus may largely remain asymptomatic for variable period, till a large part of hepatic outflow tract is obstructed, resulting in sudden increase in sinusoidal pressure. Sinusoidal hypertension manifests clinically as ascites. Sinusoidal hypertension and ascites occur and reoccur at any time in the course of the diseases of HV and IVC.

At present, the eponym BCS is used synonymously for HVOO (26–29). In the past, it had been used for various entities, as some used it for thrombosis of large HVs, others for both thrombotic and non-thrombotic lesions of large HVs and IVC between the liver and right atrium, and a few used it even when the obstruction was in the right atrium. As the term “BCS” became ambiguous that neither identifies the morphology nor the site of obstruction nor the etiology of the disease, Ludwig et al in 1990 suggested dropping the use of the term (4) which was supported by Okuda (30). In their original papers, Budd described three cases of hepatic vein thrombosis (HVT) subsequent to abscess-induced phlebitis which he ascribed to sepsis and alcoholism or syphilis (31), and Chiari (1898) described another three cases of “phlebitis obliterans” where microscopic lesion had extended to adjacent segment of IVC (20). Similar cases were described by Raynaud in 1827 (32) before Budd, and by many including Wilks (33) and Osler (34) before Chiari. Justification for the continued use of the eponym thus appears tenacious. However, an international panel from Europe in 2003 advocated retaining BCS because of its long usage and defined it as HVOO wherever the level or mechanism of obstruction, with exclusion of SOS and cardiac and pericardial diseases (26). BCS was divided into primary BCS when related to a primarily venous disease (thrombosis or phlebitis), and secondary BCS when related to compression or invasion by a lesion originating outside the vein (benign or malignant tumor, abscess or cyst). Further classifications according to its location (small HVs, large HVs, IVC, and combination obstruction of large HVs and IVC) have been suggested. And it has become a common practice to classify HVOO based on the level of obstruction into HV block, IVC block, and combined HV and IVC block (35–38). Classifying HVOO on the basis of the site of obstruction is not helpful as the site of obstruction in the HVOO tract does not differentiate primary diseases of HVOO and it does not influence the management. In BCS, lesions develop not only in large HVs but also in medium, small, and terminal HVs (21, 22) and now it appears even at the level of sinusoid. Similarly, in HVCS, besides primary lesion in IVC, lesions develop at different levels in HVs as in BCS (23). Patients or livers, both in BCS and HVCS have multiple lesions not only at different levels in HVs but also in PV and its branches (21–23). There was also a suggestion to classify HVOO as due to thrombotic and non-thrombotic lesions; in non-thrombotic group, webs and membrane were included with tumor or other obstructive anomalies (4). It is now well recognized that not only webs, membrane, and stenosis but even calcification of the lesions in HV and IVC is the sequel of initial thrombosis or thrombophlebitis (21–23), and their presence indicates the duration of the disease process.

HVOO is rare in the West where it is predominantly due to HVT caused by a combination of inherited and acquired thrombogenic conditions of which myeloproliferative disorder is the common (26, 39, 40). HVOO is common in the East where it is an important cause of portal hypertension (41, 42), ascites (6), and LC (11, 15, 43), and is predominantly due to the disease of the hepatic portion of IVC (43–59). Okuda and colleagues in 1998 established this disease as a distinct clinical entity (60). The epidemiology, etiology, and clinical course of the disease of IVC are different from HVT (61) and it is now renamed HVCS and a new concept of pathogenesis of the disease based on bacterial infection etiology has recently been put forth (7). In India, both HVCS and HVT occur. In practice, Western investigators had been using the term “BCS” to mean HVT due to thrombogenic conditions, whereas investigators in the East used it for HVCS and HVT. Vascular surgeons in the East used it for HVCS (38, 59). The term “BCS” thus continued to be used by different people to mean different things. Interpretation of the results of the studies and assessment of prognosis and treatment of BCS from different centers are thus not comparable. Inclusion of HVT and HVCS together under BCS has been a source of confusion that resulted in patients from developing countries with HVCS subjected to costly investigations for thrombotic disorders. To avoid these confusions, need is felt to redefine the term “BCS” and suggest a meaningful classification of HVOO.

Ascites is an important clinical manifestation of the primary diseases of HVOO. Sudden development of hepatomegaly and ascites with high protein content (usually >2.5 g/dL), and high serum-ascitic albumin gradient is due to HVOO. SOS is the likely cause when this type of ascites develops in a patient on myeloablative therapy or persons using herbal tea. US/CD shows enlarged liver with no abnormality in HV and IVC. SOS had occurred as epidemic outbreaks in underdeveloped areas of developing countries, especially during periods of draught. Outbreak of jaundice with ascites in such circumstances indicates to SOS caused by pyrrolizidine alkaloids. Even dogs in the affected area are known to develop ascites during the outbreak.

HVCS develops in any age group of either sex. Ascites in HVCS is common in persons with poor nutrition or history of alcohol abuse, in whom it is usually precipitated by bacterial infection like puerperal sepsis, chronic diarrhea, and fever or by surgery. Even infants on parenteral nutrition develop this condition. Dilated superficial veins in abdomen with upward blood flow are observed (Figure 4). US/CD examination is diagnostic (75). It shows hepatomegaly and ascites often with evidence of bacterial peritonitis, free-floating particles that settle on standing, acute peritonitis and thick peritoneum with adhesions, loculations, or evidence of perihepatitis indicating chronic peritonitis (Figure 5). Segmental stenosis of medium-sized intra-HVs and prominent main HVs with obstruction to blood flow at the HV outlets will be demonstrated in US/CD. IVC at the site of HV outlet shows stenosis with thick posterior wall with recent and old organized thrombi of different ages along its posterior wall (Figure 6). Gallbladder wall is thick and edematous. Neutrophil leukocytosis or left shift and high level of CRP are common at the onset. Bedside inoculations of blood and ascitic fluid in aerobic blood culture bottle during the initial visit are likely to yield positive culture. Hypersplenism is common in patients with HVCS. Such patients presenting with acute ascites may have normal or slightly elevated WBC count but low platelet count. Levels of serum bilirubin, alanine, and aspartate aminotransferase will be elevated. Cavogram and liver biopsy are not necessary for diagnosis. HVCS patient without ascites usually have normal levels of bilirubin, alanine, and aspartate aminotransferase, but US/CD examination shows IVC with localized stenosis with thick echoic posterior wall in at the level of HV outlet and old organized thrombi along the posterior wall of the distal dilated segment.

Acute onset of high-protein-content ascites in young female patients, especially Caucasians with risk factor for thrombosis, is likely to be due to BCS. BCS patients with myeloproliferative disorders have, on average, higher platelet counts and a larger spleen. US/CD imaging of liver will show features of HV obstruction similar to HVCS, but IVC will be normal or narrowed by caudate lobe enlargement without organized thrombus along its posterior wall, bacterial peritonitis or edematous gallbladder wall.

US and CD imaging should be the first diagnostic tests performed in patients suspected of HVOO. These tests are not only sensitive and specific but also relatively low cost, widely available, and non-invasive with complete lack of harm and minimal technical difficulty. Limitations lie in the patients’ body habitus that may preclude complete sonographic evaluation and the lack of experience on the part of the examiner in diagnosis of HVCS. US and CD help in the differential diagnosis of patients presenting with ascites in developing countries when combined with simple laboratory tests such as WBC and platelet counts; CRP, bilirubin, and alanine/aspartate aminotransferase estimations; ascitic fluid examination for protein, albumin; and bedside culture inoculation in aerobic culture bottle.

In the West, where alcoholic cirrhosis is common, ascites develops late and is considered an indication of hepatic decompensation and liver transplantation. According to Epstein, there is no connection between hepatic decompensation and disturbance in renal sodium handling leading to ascites (76). In developing countries, HVCS is a common comorbid condition in patients with LC and HCC related to chronic hepatitis B and C or alcohol (77). Development of ascites in LC patient may be due to severe AE of associated HVCS that responds to medical treatment. Therefore, LC patient in developing countries who develops ascites and jaundice should not straightaway be referred for liver transplantation.

HVOO is classified into primary and secondary. Three primary diseases of HVOO are recognized: SOS, BCS, and HVCS. Almost all cases of HVOO seen in clinical practice belong to these three primary diseases. Among these, SOS and BCS are rare and seen exclusively in a particular subset of population: SOS in patients on myeloablative therapy and BCS in young women with hypercoagulable state. HVCS is endemic in developing countries where it is a common cause of ascites and LC.