Portal Hypertension

Etiology

Numerous causes contribute to portal hypertension, classified by anatomical location as prehepatic, intrahepatic, or posthepatic.

Prehepatic Etiologies

Common prehepatic causes include increased blood flow or obstruction in the portal or splenic veins. Conditions such as idiopathic tropical splenomegaly, arteriovenous malformations, or fistulas may elevate portal inflow. Obstruction may result from thrombosis, tumor invasion, external compression, or portal vein stenosis.[1]

Intrahepatic Etiologies

Intrahepatic causes fall into presinusoidal, sinusoidal, and post-sinusoidal categories. Presinusoidal causes include schistosomiasis, congenital hepatic fibrosis, early primary biliary cholangitis, sarcoidosis, chronic active hepatitis, and toxins such as vinyl chloride, arsenic, and copper. Sinusoidal causes include cirrhosis, alcohol-related hepatitis, vitamin A intoxication, cytotoxic drugs, and advanced primary biliary cholangitis. Postsinusoidal hypertension may result from sinusoidal obstruction syndrome (SOS), also known as veno-occlusive disease (VOD).[1]

Posthepatic Etiologies

Posthepatic causes involve the hepatic vein, heart, or inferior vena cava. Budd-Chiari syndrome, affecting the hepatic vein, represents a major posthepatic etiology. At the cardiac level, increased right atrial pressure from constrictive pericarditis, tricuspid insufficiency, or restrictive cardiomyopathy may contribute. Lesions of the inferior vena cava, eg, stenosis, thrombosis, webs, or tumor invasion, also lead to posthepatic portal hypertension.

Idiopathic Portal Hypertension

Idiopathic portal hypertension, more commonly observed in Japan and India, features elevated portal pressure without histologic cirrhosis or extrahepatic portal vein obstruction. The etiology remains unclear, though proposed factors include septic emboli from the gut, HIV infection, and prior chemotherapy, particularly with oxaliplatin. Affected patients often present with normal liver function tests, marked splenomegaly, and variceal bleeding, while ascites remains uncommon.

Epidemiology

Cirrhosis of the liver is the most prevalent cause of portal hypertension in the Western world.[1] However, schistosomiasis is the most frequent cause in Africa, where schistosomiasis is endemic. About 2.4 % of all deaths worldwide were attributed to cirrhosis in the year 2017, approximately 1.32 million deaths.[2]

Pathophysiology

The liver receives its blood supply from the hepatic artery and the portal vein, most of which is from the portal vein. The superior mesenteric and splenic veins join to form the portal vein, which is 7 to 8 cm long. The portal vein carries blood from the spleen, pancreas, and gallbladder, as well as from the esophagus, stomach, and large and small intestines. It drains into the liver before dividing into the right and left portal veins and goes to the respective parts of the liver. The blood from the portal vein enters the liver sinusoids and drains into the hepatic veins before entering the inferior vena cava and finally into the systemic circulation.

The portal vein pressure is typically between 1 and 4 mm of mercury, more than the hepatic vein pressure. This pressure differential enables blood to flow through the liver into the systemic circulation. The veins do not have valves. Resistance to blood flow in the portal venous tract leads to elevated portal venous pressure, as seen in portal hypertension. The resistance occurs more commonly within the liver, as seen in cirrhosis, but it can also be prehepatic or posthepatic.

The primary reason for the increased vascular resistance is the dysregulation of liver sinusoidal endothelial cells and hepatic stellate cells, or from dynamic changes (ie, vasoconstriction).[3] Structural changes are due to the alteration of hepatic microcirculation. Such alterations result from the activation of hepatic stellate cells, leading to the development of fibrosis, regenerative nodules, vascular occlusion, and angiogenesis. The increased production of endothelial vasoconstrictors (eg, endothelin) and decreased release of vasodilators (eg, nitric oxide) within the liver leads to sinusoidal constriction, thereby increasing hepatic resistance. Portal hypertension stemming from this is augmented and perpetuated by the increased blood flow within the splanchnic circulation. This increased blood flow is attributed to the increased release of splanchnic vasodilators, notably nitric oxide, resulting from increased shear stress and a reduced effective arterial volume. The splanchnic arterial dilatation plays a significant role in the worsening and progression of portal hypertension.[4] Thus, portal hypertension results from increased resistance to portal venous flow and increased portal blood flow due to splanchnic vasodilation.

Persistent elevation in portal pressure prompts the development of collateral veins as a compensatory mechanism to decompress the portal system.[5] Under normal conditions, these collateral vessels carry minimal blood volume and direct flow toward the portal vein. In the setting of portal hypertension, blood flow reverses, moving toward the systemic circulation. Collateral formation typically occurs in 4 primary locations: the distal esophagus and stomach, where gastroesophageal varices form; the umbilicus, through connections between the left portal vein and umbilical vein; the retroperitoneum, involving iliac and ovarian veins; and the anorectal region, between the pudendal and inferior rectal veins, leading to rectal varices.

Collateral circulation and sustained portal hypertension contribute to decreased systemic blood pressure and reduced effective arterial blood volume. This reduction triggers activation of the renin-angiotensin-aldosterone system, resulting in sodium and water retention.[6]

Historically, cirrhosis was viewed solely as a pro-hemorrhagic condition. Current understanding recognizes a complex balance, with both pro-hemorrhagic and prothrombotic tendencies.[7] The prothrombotic state may accelerate hepatic fibrosis and contribute to pulmonary hypertension.[8] In cirrhosis, bacterial translocation from the gut lumen to the systemic circulation occurs frequently, likely due to increased portal pressure.[9] Bacterial products stimulate hepatic stellate cells and Kupffer cells, promoting fibrogenesis and angiogenesis, thereby exacerbating portal hypertension.[10]

Histopathology

A liver biopsy is often performed when evaluating abnormal liver function tests with an unclear etiology. Clinically silent portal hypertension can sometimes be identified in such instances. Changes in liver tissue and vascular structures can precede the clinical signs. Fibrosis changes, increased portal vein branches, and thickened smooth muscle walls can be seen. An increase in lymphatic vessels may also be noted.[11] Liver biopsy is not recommended for the assessment of portal hypertension.

History and Physical

Patients generally remain asymptomatic until complications develop. Hematemesis, resulting from bleeding varices, is the most common clinical presentation. Melena without hematemesis may also occur. Portal hypertension warrants consideration in any patient presenting with gastrointestinal bleeding alongside stigmata of chronic liver disease, such as jaundice, gynecomastia, palmar erythema, spider nevi, testicular atrophy, Dupuytren contractures, parotid enlargement, ascites, pedal edema, or asterixis from hepatic encephalopathy.[3]

Prominent abdominal wall veins may become visible, reflecting an attempt to divert portal blood via paraumbilical veins into the caval system. In caput medusae, blood flows away from the umbilicus, whereas obstruction of the inferior vena cava redirects flow toward the umbilicus to access the superior vena cava. A venous hum may be heard near the xiphoid process or umbilicus.[4] Cruveilhier-Baumgarten syndrome involves dilated abdominal wall veins accompanied by a low-pitched venous murmur at the umbilicus. In contrast, a systolic arterial murmur often points to hepatocellular carcinoma or alcohol-related hepatitis.[4]

Splenomegaly serves as a dependable clinical indicator of portal hypertension.[1] Absence of splenic enlargement on physical exam or imaging should prompt reconsideration of the diagnosis. Pancytopenia due to hypersplenism results from reticuloendothelial hyperplasia associated with splenomegaly and does not resolve with reduction of portal pressure via portocaval shunting. While a firm liver favors cirrhosis, hepatomegaly shows poor correlation with the degree of portal hypertension.

Evaluation

Laboratory Studies

The evaluation requires obtaining a thorough history and utilizing relevant laboratory data. A complete blood count helps distinguish the presence of thrombocytopenia, secondary to hypersplenism and anemia, from gastrointestinal blood loss. A complete metabolic panel identifies renal failure and liver enzyme elevation present in liver disease, viral hepatitis, and hypoalbuminemia. A coagulation profile helps to identify the liver's synthetic function. A prolonged prothrombin time and a low serum albumin level can predict hepatic synthetic function.

Imaging Studies

Ultrasound and computed tomography (CT) scan of the abdomen can identify signs of portal hypertension, which include splenomegaly and portosystemic collaterals, cirrhotic changes in the liver, and ascites.[12] Magnetic resonance imaging (MRI), enhanced with Gadolinium, can detect esophageal varices.[13] Doppler ultrasound of the portal vein can detect the presence of stenosis or thrombosis. The Doppler ultrasound study of the portal vein will show either hepatopetal portal vein flow (toward the liver) or hepatofugal portal vein flow (away from the liver), depending on the degree of portal hypertension. Hepatopetal flow is normal.

Additional Evaluation Modalities

All patients with cirrhosis require evaluation for CSPH. Management with a non-selective beta blocker (NSBB) should be considered in appropriate cases. When NSBB use is not feasible, endoscopic screening for varices becomes necessary.[14] In the absence of varices, repeat screening is recommended every 2 to 3 years, depending on the patient's clinical condition and risk factors.[15] If varices are identified and found to be large, prophylactic therapy should be initiated. Additionally, patients with ascites require diagnostic paracentesis to determine the underlying cause and exclude spontaneous bacterial peritonitis.[16][17]

In cases where clinical features of portal hypertension are evident, direct portal pressure measurement is generally unnecessary. Evaluation of portal and hepatic vein patency can be performed using duplex Doppler ultrasound, magnetic resonance imaging, or computed tomography angiography. Direct measurement, though accurate, involves invasive hepatic vein catheterization to determine free hepatic vein pressure (FHVP) and wedged hepatic vein pressure (WHVP). The hepatic venous pressure gradient (HVPG), calculated by subtracting FHVP from WHVP (HVPG = WHVP - FHVP), serves as the gold standard for diagnosing portal hypertension but remains limited to specialized centers due to its complexity and cost.[18]

Transient elastography provides a noninvasive method for assessing liver stiffness in patients with chronic liver disease. This method helps identify individuals at risk of developing CSPH.[19] Recent updates from the American Association for the Study of Liver Diseases (AASLD) provide criteria to guide the identification and management of individuals with CSPH who may benefit from intervention.[20]

Treatment / Management

Management of Portal Hypertension Etiologies

Management of portal hypertension involves a 2-fold approach. The initial step focuses on identifying the underlying etiology and addressing reversible causes. Correction of the cause should be pursued whenever feasible. For instance, anticoagulation serves as the treatment of choice when thrombosis affects the portal vein or inferior vena cava in the setting of a hypercoagulable state. In cases of hepatitis C infection, initiation of antiviral therapy can prevent disease progression, reduce the risk of hepatocellular carcinoma, and delay the onset of variceal bleeding.

Patients can be treated medically with NSBB, which prevents variceal bleeding. These drugs reduce cardiac output, thereby decreasing splanchnic blood flow and increasing resistance in the splanchnic vascular system, ultimately leading to reduced portal blood flow. The result is a reduction in the HVPG.[2] Carvedilol also promotes nitrous oxide release and subsequently causes a further decrease in portal pressure and is more effective in reducing HVPG than propranolol and nadolol.[21] The suggested starting dosage is 6.25 mg daily, increasing to 12.5 mg daily (in divided doses) if tolerated well after 2 to 3 days. Reducing the dosage should be considered if the systolic blood pressure drops below 90 mm Hg. The most recent AASLD practice guidelines recommend carvedilol as the preferred NSBB.[22](A1)

Risk Management

Management, following identification of the cause of portal hypertension, focuses on preventing complications and treating them when present.

Approximately 40% of patients with cirrhosis and 60% of those with both cirrhosis and ascites develop esophageal varices.[23] Abstinence from alcohol often leads to improved liver function and, in some cases, regression of varices.[24] Variceal bleeding occurs in about 25% of newly diagnosed varices within 2 years. Nearly half of initial variceal bleeding episodes stop spontaneously due to hypovolemia-induced splanchnic vasoconstriction, which lowers portal venous pressure. Rebleeding occurs in approximately 40% of cases within 5 days of the initial hemorrhage.[25]

In cases of variceal bleeding, immediate resuscitation with intravenous fluids and placement of 2 large-bore intravenous (IV) lines is essential, followed by admission to an intensive care unit. Transfusion should be initiated when hemoglobin levels fall below 7 g/dL. Medications that reduce splanchnic blood flow—vasopressin, terlipressin, somatostatin, or octreotide—should be considered.[26][27] Octreotide is typically given as a 50 µg IV bolus followed by a continuous infusion of 50 µg/hour for 3 to 5 days. Somatostatin is administered as a 250 µg bolus followed by an infusion at 250 µg/hour over the same period. Terlipressin is administered as a 2 mg IV bolus, followed by 1 to 2 mg every 4 to 6 hours until hemostasis is achieved, or for up to 5 days.[28]

Prophylactic antibiotics help prevent spontaneous bacterial peritonitis.[29] Ceftriaxone 1 g IV daily is recommended for 7 days, with a potential switch to oral ciprofloxacin 400 mg twice daily or levofloxacin 500 mg daily. Endoscopy should be performed within 12 hours of admission. Endoscopic variceal ligation is indicated for large varices or varices with high-risk stigmata. For ongoing bleeding despite ligation and pharmacologic therapy, placement of a transjugular intrahepatic portosystemic shunt (TIPS) should be considered.[30] TIPS establishes a connection between the intrahepatic branches of the portal and hepatic veins, effectively lowering portal pressure. However, diverting portal blood flow reduces hepatic perfusion, increasing the risk of hepatic encephalopathy.(A1)

Ascites management depends on the severity of liver dysfunction and treatment response. Recommended therapies include dietary sodium restriction, diuretics such as spironolactone in combination with furosemide, large-volume paracentesis, TIPS placement, and liver transplantation.[31] Transplantation remains the definitive treatment for portal hypertension resulting from cirrhosis.(B3)

Differential Diagnosis

Differential diagnoses that should also be considered in the evaluation of portal hypertension include:

• Budd-Chiari syndrome
• Cirrhosis
• Constrictive pericarditis 
• Myeloproliferative disease 
• Polycystic kidney disease
• Sarcoidosis
• Tricuspid regurgitation
• Tuberculosis
• Vitamin A deficiency

Prognosis

The prognosis of portal hypertension largely depends on the underlying etiology, severity of liver disease, and the presence of complications. Patients with CSPH, particularly those with an HVPG ≥10 mm Hg, face a higher risk of decompensation, including ascites, hepatic encephalopathy, and variceal bleeding. Once HVPG reaches ≥12 mm Hg, the likelihood of life-threatening bleeding and other complications increases significantly.

Early identification and management, including NSBB, endoscopic interventions, and treatment of the underlying cause (eg, antivirals for hepatitis C or anticoagulation for thrombosis), can improve outcomes. Abstinence from alcohol may reverse some complications, while persistent or severe disease may require TIPS or liver transplantation, the only definitive cure for cirrhosis-related portal hypertension. Delayed diagnosis or inadequate management leads to increased hospitalization, higher mortality, and a greater need for transplant evaluation.

Complications

Complications of portal hypertension include:

• Thrombocytopenia due to hypersplenism
• Abdominal wall collaterals
• Variceal bleeding secondary to hemorrhage from gastroesophageal, anorectal, retroperitoneal, stomal, and other varices
• Acute bleeding or iron deficiency anemia due to chronic blood loss from portal hypertensive gastropathy, enteropathy, or coagulopathy
• Ascites
• Spontaneous bacterial peritonitis
• Hepatic hydrothorax
• Hepatorenal syndrome
• Hepatic encephalopathy
• Hepatopulmonary syndrome
• Portopulmonary hypertension
• Cirrhotic cardiomyopathy