Sinusoidal Hypertension: A Cause of Liver Cirrhosis in Developing Countries

Special Article - Liver Cirrhosis

Austin J Gastroenterol. 2017; 4(3): 1085.

Sinusoidal Hypertension: A Cause of Liver Cirrhosis in Developing Countries

Shrestha SM*

Liver Foundation, Nepal

*Corresponding author: Santosh Man Shrestha, Liver Foundation Nepal, Kathmandu, Nepal

Received: May 29, 2017; Accepted: June 13, 2017; Published: June 29, 2017


Three primary diseases of the liver that cause hepatic venous outflow obstruction (HVOO) are recognized: sinusoidal obstruction syndrome (SOS), Budd-Chiari syndrome (BCS) and hepatic vena cava syndrome (HVCS). Liver cirrhosis develops in these diseases. This paper discusses the pathogenesis of cirrhosis in HVOO.

HVOO results in sinusoidal hypertension. Because of the unique nature of hepatic sinusoid, sinusoidal hypertension is followed by rapid passage of fluid and macromolecules from sinusoid into the space of the Disse and reflex reduction of hepatic arterial flow. As the space between the endothelial cells widens egression of RBCs follows. Hemorrhage and ischemia result in atrophy and apoptosis of hepatocytes in the congested region around the terminal hepatic vein. Extinction of hepatocytes is followed by fibrosis which ultimately leads to development of venocentric cirrhosis. Sinusoidal hypertension also causes reversal of blood flow in portal vein. In BCS and HVCS thrombosis/ thrombophlebitis develops in portal vein and its branches. Atrophy and extinction of hepatocytes supplied by the obstructed portal vein branches lead to development of veno-portal type of cirrhosis in some.

HVCS is endemic in some Asian and African countries. It is a disease related to poor hygienic living condition and caused by bacterial infection. HVOO may develop at anytime in the course disease precipitated by bacterial infection. It is followed by rapid development of ascites and cirrhosis. HVCS induced cirrhosis is characterized by distinctive clinical, histological and ultrasonographic/color Doppler features. HVCS may be a common cause of cirrhosis in developing countries.

Keywords: Sinusoidal hypertension; Liver cirrhosis; Hepatocellular carcinoma


Cirrhosis is defined as the presence of fibrous septa throughout the liver that subdivide the hepatic parenchyma into hepatocellular nodules [1]. Cirrhosis results from parenchymal extinction usually caused by obliteration of small portal and hepatic veins. Fibrosis that is formed during acute stage is rapidly removed leaving collapsed preformed stroma. Regenerative activity of the surviving liver cells leads to development of hepatic nodules. The architectural distortion of the liver results in derangement of the blood supply to the hepatic parenchyma. Saline perfusion studies done in hepatic artery showed that whereas in normal liver most of the fluid escaped through hepatic vein, in cirrhotic liver it escaped largely through the portal vein with concomitant rise in portal venous pressure [2]. Similar studies done by perfusing portal vein showed that in normal liver all fluid was recovered from the hepatic vein; but in cirrhotic liver most of it escaped through the collaterals [3]. The perfusion and reconstruction of hepatic vasculature studies in cirrhotic liver also showed presence of anastomotic connections between the hepatic arteries and portal veins that caused transmission of hepatic arterial pressure into portal vein resulting in portal hypertension. Increase portal pressure was further aggravated by resistance to flow caused by narrowing and obliteration of smaller vessels by regenerating nodules [4]. Cirrhosis is thus associated with impaired blood supply to the hepatic parenchyma, development of portal hypertension and opportunity for abnormal growth of liver nodule. Clinical manifestation of cirrhosis is determined by three vectors (a) impairment of parenchymal function, (b) portal hypertension and (c) and features of disease causing cirrhosis, for example that of alcoholic liver disease.

Cirrhosis is a common chronic liver disease throughout the world. Common causes of cirrhosis in different countries vary and it changes in the same country over the course of time. Prevalence of the common cause/s of cirrhosis is determined by geo-cultural factors such as community practice of tattooing, use of alcohol, prevalence of drug abuse and parenteral treatment, living standard and hygiene. In Japan social upheaval that followed the Second World War in late 1940s saw the emergence of intravenous drug abuse that lead to prevalence of hepatitis C infection, which by 1980s had emerged as the major cause of cirrhosis and hepatocellular carcinoma (HCC) replacing alcohol and hepatitis B [5,6]. Similar change in social behavior among youth in 1960-1970s during Vietnam War led to prevalence of hepatitis C through drug abuse that led to its emergence three decades later as an important cause of cirrhosis in USA. The phenomenon was repeated in former Soviet Union after the Afghanistan war [6]. During 1950s veno-occlusive disease due to use pyrrolizidine alkaloid as herbal tea and medication was the common cause of cirrhosis in the West Indies [7]. A peculiar form of cirrhosis called Indian childhood cirrhosis prevailed in India from 1950 to 1990 [8]. In Afro- Asian countries with moderate to high prevalence of chronic hepatitis B, it along with alcohol is regarded as major causes of liver cirrhosis.

Hepatic vena cava syndrome as a common cause of liver cirrhosis

Study done in 1994 showed that prevalence of HBsAg and HCV-RNA among Nepalese patients with cirrhosis was 39% and 8% respectively, and the cause of cirrhosis in Nepal was unknown in approximately 54% of the patients [9]. Further study was done in 2007 [10] to evaluate the role of different known etiological factors of cirrhosis. HBV-DNA was detected in 47%, HCV-RNA in 7% and history of significant alcohol intake (40 g/day in female and 80g/ day in male for 10 years) was obtained in 26% and obstruction of hepatic portion of inferior vena cava (IVC) was detected in 77%. IVC obstruction was a co-morbid condition of patients with chronic hepatitis B and C and alcoholic liver disease. The disease of IVC, later renamed hepatic vena cava syndrome (HVCS) was found to be endemic in Nepal [11]. Long term follow-up of patients showed that 78.5% of the adult patient [12] and 27.5% of children [13] developed cirrhosis. HVCS was thus found to be an important cause of cirrhosis in Nepal.

Hepatic vena cava syndrome (HVCS) is an obliterative disease of the hepatic portion of inferior vena cava, previously known as membranous obstruction of inferior vena cava and was then included under Budd-Chiari syndrome [14]. It was reported from many countries of Asia and Africa [11,15-29]. High incidence of cirrhosis and hepatocellular carcinoma (HCC) was reported in the disease from Japan [15-19] and South Africa [27,28]. HVCS was previously considered a congenital vascular malformation, and diagnosed late in persons with complete obstruction of IVC by cavogram or liver biopsy or detected at autopsy. It is now recognized as a disease related poor hygienic living condition [11,30] and induced by bacterial infection [31]. It usually develops in childhood or young age. A new concept of pathogenesis of the disease has been described recently [32]. Inferior vena cava at the site of opening of the HVs is a junction between upper segment fixed in diaphragm and liver and distal free segment which is prone to micro-endothelial damage and infection. Some persons with bacterial infection develop localized thrombophlebitis at this site which on resolution converts into stenosis or complete obstruction. The circulatory equilibrium is maintained by development of several pathways of cava-caval collateral anastomosis [33]. The obliterative lesion and the collaterals persists the rest of the life. Persons remain asymptomatic for variable periods. Some chronic patients develop hepatomegaly and/or splenomegaly. Persons with splenomegaly may develop features of hypersplenism with thrombocytopenia, leucopenia and anemia.

Acute exacerbations

The abnormal segment however becomes vulnerable to subsequent bacterial infection with deposition of fresh thrombus. The thrombus so formed extends into hepatic veins because of the close proximity of the lesion resulting in acute exacerbations (AE). Minor episodes of AE are recognized by mild jaundice and/or elevation of ALT/AST. Large thrombophlebitis formed during acute stage or severe AE that cause hepatic venous outflow obstruction (HVOO) results in sudden development of ascites from sinusoidal hypertension. About 10% patients develop pleural effusion [34]. Ascites has high protein and high serum albumin ascitic fluid gradient and shows presence of RBC and is invariably associated with mono-microbial bacterial peritonitis due to aerobic organisms like E.coli, Klebsiella or Staphylococcus aureus [35]. Patient with ascites In HVCS has neutrophil leukocytosis, high level of C reactive protein and or bacteremia and has elevated levels of serum bilirubin and ALT/AST. Severe AE may occur at any time in the course of the disease. It commonly occurs in persons with poor nutrition and /or history of alcohol abuse precipitated by chronic diarrhea, puerperal sepsis, surgery or endoscopic procedures [36,37]. Ultrasonography and color Doppler examination of inferior vena cava and liver (Figure 1) is a sensitive and specific method of diagnosis of HVCS [38]. When used with appropriate blood and ascitic fluid tests it also detects minor and severe acute exacerbations.

HVOO is followed by development of cirrhosis from sinusoidal hypertension [12]. Besides HVCS two other primary disease of liver that causes HVOO are recognized (Table 1) where cirrhosis develops from sinusoidal hypertension (Table 1). They are sinusoidal obstruction syndrome (SOS), previously called veno-occlusive disease caused by toxic damage of the sinusoids by pyrrolizidine alkaloids (PA) or myeloablative therapy [39], and Budd-Chiari syndrome (BCS) related to pro thrombotic conditions [40]. This paper describes the prevalence of cirrhosis in the disease of HVOO and discus its pathogenesis, and mentions the distinctive features of cirrhosis due to HBVS, the common cause of HVOO.