Portal Hypertension and Varices

• Increased Intrahepatic Resistance as the Primary Driver: In cirrhosis, the architectural distortion of the liver parenchyma by fibrosis and regenerative nodules creates a structural barrier to portal blood flow. The cirrhotic liver loses its normal sinusoidal structure, replacing it with fibrous septa that disrupt the normal architecture. Additionally, cirrhotic hepatocytes produce excess endothelin-1 (a potent vasoconstrictor) and exhibit impaired synthesis of nitric oxide (NO), a vasodilator. These changes activate hepatic stellate cells (myofibroblasts) that express smooth muscle α-actin and actively contract around sinusoids and portal triads, directly increasing resistance to flow. The net result is that portal pressure increases according to the Ohm's law analog: ΔP = Q × R, where increased resistance (R) at constant or increased flow (Q) drives pressure elevation (ΔP). This intrahepatic resistance component explains why portal pressure correlates with disease severity and why measures reducing hepatic vascular tone (vasodilators, transjugular intrahepatic portosystemic shunt [TIPS]) provide benefit.

• Splanchnic Vasodilation and Compensatory Flow Increase: Paradoxically, the cirrhotic liver also exhibits profound splanchnic vasodilation, mediated by elaboration of nitric oxide from endothelial cells in the splanchnic circulation (portal vein, superior mesenteric vessels, spleen). This NO-mediated vasodilation increases portal blood flow by reducing splanchnic vascular resistance, which would normally reduce pressure, but the magnitude of increased flow combined with the fixed intrahepatic resistance paradoxically worsens portal hypertension. The splanchnic vasodilation is triggered by bacterial lipopolysaccharide (LPS) translocation across the damaged intestinal barrier in cirrhosis, which activates Toll-like receptors on endothelial cells and macrophages, upregulating inducible nitric oxide synthase (iNOS). Additionally, the cirrhotic liver fails to clear endotoxin-producing bacteria, further perpetuating this cascade. This splanchnic vasodilation also drives systemic arterial hypotension and activation of compensatory neurohumoral mechanisms (sympathetic nervous system, renin-angiotensin-aldosterone system [RAAS], and vasopressin), which paradoxically worsen renal retention of sodium and fluid, contributing to ascites formation.

• Formation of Portosystemic Collaterals: As portal pressure rises, flow preferentially diverts through low-resistance collateral pathways connecting the portal and systemic circulations. The esophageal varices form at the junction of the left gastric (coronary) vein and esophageal veins, where high-pressure portal blood enters low-pressure azygos venous system. These varices are prone to rupture because they have a thin, non-muscular wall (consisting only of endothelium and submucosa) and are subjected to mucosal trauma from food, gastric reflux, and direct mechanical stress. The varices enlarge based on portal pressure and flow; hemodynamic studies show that variceal hemorrhage risk increases dramatically when HVPG exceeds 12 mmHg (the threshold for clinically significant portal hypertension), and risk of rebleeding correlates with persistent elevation of HVPG above 12 mmHg. Importantly, formation of collaterals temporarily "decompresses" the portal system by providing a pressure relief valve, but these collaterals become the bleeding hazard and shift morbidity from ascites/hepatic encephalopathy to hemorrhage.

• Impaired Hepatic Microcirculation and Sinusoidal Dysfunction: The cirrhotic liver develops impaired sinusoidal endothelial function with increased permeability (fenestration loss), reduced vasoreactivity, and loss of the normal filtration barrier. Reduced production of vascular endothelial growth factor (VEGF) and increased endothelial cell apoptosis further contribute. These changes prevent normal exchange between hepatic sinusoids and hepatic stellate cells, and impaired synthesis of vasodilators (NO, prostacyclin) combined with excess production of vasoconstrictors (endothelin, angiotensin II) creates a pro-contractile hepatic sinusoidal environment that perpetuates increased resistance.

• Dynamic Variceal Changes: Varices are not static structures; they expand and contract based on acute hemodynamic fluctuations. Increased cardiac output (from anemia, infection, portal vein thrombosis) or increased splanchnic blood flow (from portal vein thrombosis, splenic vein occlusion) transiently increases variceal pressure and bleeding risk. Conversely, bleeding itself reduces portal flow and pressure acutely, which is why variceal bleeding sometimes self-limits (though this is unreliable and only occurs in approximately 40-50% of bleeds).

• Intrahepatic Sinusoidal Disease (Most Common): Cirrhosis from any etiology accounts for >90% of portal hypertension cases. The leading causes of cirrhosis vary by geography: in North America and Europe, alcoholic cirrhosis and hepatitis C virus (HCV)-related cirrhosis predominate, while hepatitis B virus (HBV) dominates in Asia and sub-Saharan Africa. Nonalcoholic fatty liver disease (NAFLD)/metabolic-associated fatty liver disease (MAFLD) is an increasingly common cause, particularly in populations with metabolic syndrome (obesity, type 2 diabetes, dyslipidemia). Other intrahepatic sinusoidal causes include autoimmune hepatitis, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, and drug-induced liver injury (DILI) from acetaminophen, methotrexate, or others. The pathophysiology is similar across causes: progressive fibrosis distorts hepatic architecture and increases sinusoidal resistance until the clinical threshold of HVPG >12 mmHg is crossed.

• Intrahepatic Presinusoidal Disease: Portal vein thrombosis (PVT) is the classic presinusoidal cause, occurring acutely or chronically. Acute PVT may result from hypercoagulable states (malignancy, thrombophilia, myeloproliferative neoplasms like polycythemia vera or essential thrombocythemia), surgical manipulation during splenectomy, blunt abdominal trauma, or pancreatitis-related inflammation. Chronic PVT develops insidiously and is often clinically silent until variceal hemorrhage; cavernous transformation of the portal vein (proliferation of small collateral vessels) develops over time. Important clinically: PVT does not typically cause ascites because the liver parenchyma itself is not fibrotic and retains normal synthetic and filtration function; hence, portal hypertension from PVT presents primarily as variceal bleeding without the other stigmata of cirrhosis (hepatic encephalopathy, coagulopathy, hypoalbuminemia). Splenic vein thrombosis is another presinusoidal cause, frequently associated with pancreatitis or splenic pathology; it causes left-sided (segmental) portal hypertension affecting only the left gastric and short gastric venous systems, resulting in gastric varices (particularly fundal varices) without esophageal varices.

• Intrahepatic Postsinusoidal Disease: Budd-Chiari syndrome (BCS), caused by hepatic vein thrombosis, is the classic postsinusoidal cause. Acute BCS presents dramatically with fulminant hepatitis (jaundice, coagulopathy, encephalopathy) and abdominal pain; chronic BCS develops insidiously with progressive cirrhosis and portal hypertension. Risk factors include myeloproliferative neoplasms (present in 40-75% of BCS cases, particularly JAK2 V617F-positive disorders), hypercoagulable states, malignancy (especially hepatocellular carcinoma), pregnancy/oral contraceptive use, antiphospholipid syndrome, and Factor V Leiden. Sinusoidal obstruction syndrome (SOS), formerly called venocclusive disease, occurs after chemotherapy (busulfan, cyclophosphamide in hematopoietic stem cell transplantation), herbal medicines (Senecio alkaloids, contaminated grain), or toxins; pathologically, there is obliteration of hepatic venules without thrombosis.

• Posthepatic Disease: Constrictive pericarditis, restrictive cardiomyopathy, cardiac tamponade, or right ventricular infarction increase hepatic venous and intrahepatic pressure, transmitted retrograde to the portal system. Inferior vena cava (IVC) thrombosis or compression elevates hepatic venous pressures. These posthepatic causes are distinguished by elevated hepatic venous pressure gradients (HVPG) but normal or preserved liver parenchyma on imaging.

• Prehepatic Disease: Portal vein thrombosis (discussed above) is the primary prehepatic cause, though some definitions classify it as presinusoidal. Splenic vein thrombosis is similarly prehepatic/presinusoidal. These entities are characterized by normal liver parenchyma and thus absence of ascites, hepatic encephalopathy, and coagulopathy, distinguishing them from cirrhotic portal hypertension.

• Variceal Hemorrhage as the Most Dramatic Presentation: Acute upper gastrointestinal bleeding from esophageal or gastric varices is the most immediately life-threatening presentation. The classic history is hematemesis (vomiting bright red blood or coffee-ground emesis) often preceded by retching or alcohol use, followed by melena or hematochezia if bleeding is brisk. Patients present with hemodynamic instability (tachycardia, hypotension, syncope), anemia, and signs of shock. The physiologic basis is simple: increased portal pressure distends the esophageal varices, and mucosal ulceration, mechanical trauma, or increased intraesophageal pressure (from retching, increased intrathoracic pressure) precipitates rupture. Approximately 30-40% of cirrhotic patients with varices will experience a bleeding episode within 2 years if untreated. Notably, many patients with varices never bleed; risk is stratified by variceal size (small <5 mm vs large ≥5 mm), presence of red wale signs or hematocystic spots on endoscopy, and degree of hepatic dysfunction (Child-Pugh class).

• Ascites: Progressive accumulation of peritoneal fluid results from multiple mechanisms: (1) portal hypertension increases hepatic sinusoidal hydrostatic pressure, driving fluid transudation across the capsule into the peritoneal cavity; (2) splanchnic vasodilation activates compensatory neurohumoral mechanisms (sympathetic system, RAAS, arginine vasopressin), promoting renal sodium and water retention; (3) impaired hepatic synthesis of albumin (in advanced cirrhosis) reduces oncotic pressure; and (4) lymphatic obstruction from cirrhotic fibrosis impairs drainage. Clinically, patients develop abdominal distension, weight gain, early satiety, dyspnea (from diaphragmatic elevation), and lower extremity edema. On examination, ascites produces dullness to percussion in the flanks that shifts with position changes (shifting dullness), a fluid wave, and loss of abdominal wall definition. Massive ascites can cause respiratory compromise and umbilical hernia protrusion.

• Hepatic Encephalopathy: Portal hypertension combined with cirrhotic hepatic dysfunction produces hepatic encephalopathy through multiple mechanisms: (1) shunting of portal blood through collaterals bypasses the liver, allowing gut-derived ammonia and other neurotoxic substances to reach systemic circulation; (2) impaired hepatic urea cycle function reduces ammonia detoxification; (3) false neurotransmitters (octopamine) and endogenous benzodiazepine-like compounds accumulate; and (4) manganese deposition in basal ganglia occurs. Clinically, hepatic encephalopathy presents as a spectrum from subtle cognitive dysfunction (difficulty with calculation, asterixis) to confusion, disorientation, and coma. The asterixis (flapping tremor) is pathognomonic and results from impaired ability to maintain postural tone; it is best elicited by asking the patient to extend the wrists with fingers splayed and observing irregular jerking movements. Precipitating factors include infection (spontaneous bacterial peritonitis, urinary tract infection), gastrointestinal bleeding, constipation, renal failure, diuretic overuse, and increased dietary protein intake.

• Splenomegaly and Hypersplenism: Splenic enlargement occurs as a consequence of chronic passive congestion from portal hypertension; the splenic vein is a major tributary of the portal vein, and elevated portal pressure is transmitted retrograde to the spleen. On examination, the spleen may be palpable several centimeters below the costal margin (in normal individuals, the spleen is not palpable). Splenic enlargement produces hypersplenism—sequestration of blood cells in the enlarged spleen—resulting in thrombocytopenia (platelet count often 50,000-100,000/μL in moderate-to-severe disease), leukopenia, and anemia. Importantly, hypersplenism is usually mild and does not typically cause bleeding complications unless platelets fall below 10,000-20,000/μL; the thrombocytopenia from hypersplenism is reversible (unlike the thrombocytopenia from hepatic synthetic dysfunction due to impaired thrombopoietin production).

• Hemorrhoids, Anorectal Varices, and Other Collaterals: Portal hypertension causes not only esophageal and gastric varices but also internal hemorrhoids (portal-to-systemic shunting via superior and middle rectal veins), anorectal varices (which can bleed), and even paraumbilical varices (visible as caput medusae around the umbilicus, though this is rare). Some patients with presinusoidal portal hypertension (e.g., splenic vein thrombosis) develop isolated gastric fundal varices without esophageal varices due to preferential flow through the short gastric and left gastric venous systems.

• Portal Hypertensive Gastropathy: Patients with chronic portal hypertension develop mucosal edema, ectasia of small vessels, and friability of the gastric mucosa (particularly in the fundus and greater curve). While rarely causing acute hemorrhage, portal hypertensive gastropathy accounts for chronic intermittent blood loss and iron deficiency anemia in some cirrhotic patients.

• Physical Examination Stigmata of Advanced Liver Disease: Beyond findings specific to portal hypertension, cirrhotic patients often display physical signs of hepatic decompensation: jaundice, palmar erythema, spider angiomas (branching telangiectasias on the trunk), gynecomastia (from altered estrogen metabolism), testicular atrophy, clubbing, and Dupuytren's contracture.

Acute variceal hemorrhage (emergency)

• Airway and access: intubate for massive hematemesis or encephalopathy to prevent aspiration; two large-bore IVs, type and cross.
• Restrictive transfusion: AASLD and Baveno consensus recommend transfusing packed red cells to a hemoglobin target near 7 g/dL. Over-transfusion re-expands splanchnic volume, raises portal pressure, and precipitates rebleeding.
• Splanchnic vasoconstrictor: octreotide (somatostatin analog) IV bolus then infusion, continued 2–5 days. It inhibits glucagon-mediated splanchnic vasodilation, reducing portal inflow and variceal pressure. Terlipressin is used abroad; in the US it is FDA-approved for hepatorenal syndrome–AKI, not as the standard bleeding agent.
• Antibiotic prophylaxis: third-generation cephalosporin (ceftriaxone) for up to 7 days — AASLD gives this a strong recommendation because it reduces infection, rebleeding, and mortality.
• Endoscopy within 12 hours: endoscopic variceal band ligation (EVL) is definitive for esophageal varices; cyanoacrylate injection is the guideline-preferred endoscopic therapy for gastric fundal varices but has limited availability in the US, where TIPS or BRTO is often used instead.

Escalation when bleeding persists

• Balloon tamponade (Sengstaken–Blakemore tube) or a self-expanding covered esophageal stent as a bridge only, for under 24 hours, with a secured airway.
• TIPS: rescue TIPS for failed endoscopic control. Baveno VII and AASLD also endorse early/pre-emptive TIPS within 72 hours in high-risk patients (Child-Pugh C or Child-Pugh B with active bleeding at endoscopy).
• BRTO for gastric varices with a gastrorenal shunt; surgical shunt or transplant evaluation in refractory disease.

Prophylaxis

• Primary: nonselective beta blocker — carvedilol is favored in Baveno VII for clinically significant portal hypertension — or EVL for medium/large varices.
• Secondary: NSBB plus serial EVL until eradication.

Contraindicated/avoid

• Beta blockers during active hemorrhage (they blunt the compensatory tachycardia). Reduce the dose or temporarily hold NSBBs in patients with refractory ascites who develop systolic BP <90 mmHg, serum Na <130 mEq/L, AKI, or SBP; refractory ascites alone is no longer an absolute contraindication (Baveno VII).
• TIPS with overt hepatic encephalopathy, right heart failure, or severe pulmonary hypertension.
• Aggressive crystalloid/blood resuscitation and prolonged balloon inflation.

Complications of portal hypertension

• Rebleeding (emergency): highest risk in the first 5 days; persistent HVPG above the bleeding threshold drives recurrence. Signaled by recurrent hematemesis, melena, or an unexplained hemoglobin drop with tachycardia.
• Spontaneous bacterial peritonitis (emergency): gut bacterial translocation into ascites with poor opsonic activity. Diagnosed by ascitic PMN count ≥250/µL; fever may be absent, so paracentesis is mandatory in any decompensating patient (AASLD).
• Hepatorenal syndrome–AKI: splanchnic vasodilation → effective arterial underfilling → intense renal vasoconstriction. Rising creatinine with bland sediment, very low urine sodium, and no response to albumin challenge.
• Hepatic encephalopathy: portosystemic shunting bypasses hepatic ammonia clearance; asterixis and altered mentation, often precipitated by the bleed itself (blood is a protein load).
• Refractory ascites, hyponatremia, hepatic hydrothorax; portopulmonary hypertension and hepatopulmonary syndrome (platypnea–orthodeoxia).
• Hepatocellular carcinoma in the underlying cirrhosis — surveillance ultrasound every 6 months per AASLD.

Complications of treatment

• Post-band ulceration and delayed bleeding (emergency): sloughing of the ligated varix days later; hematemesis after an initially successful EVL. Esophageal stricture and dysphagia are late sequelae.
• Balloon tamponade injury (emergency): pressure necrosis, esophageal rupture, and airway obstruction from balloon migration — the reason for a secured airway and a strict time limit.
• TIPS complications: new or worsened hepatic encephalopathy (blood bypasses hepatocytes entirely) in a substantial minority; shunt stenosis/thrombosis presenting as recurrent bleeding or ascites; and right-heart volume overload from the abrupt preload increase.
• Octreotide: bradycardia and glucose dysregulation (hyperglycemia more often than hypoglycemia, since somatostatin analogs suppress both insulin and glucagon). Nonselective beta blockers: hypotension, fatigue, and impaired renal perfusion, which is why dose reduction or temporary withdrawal is advised when hypotension, hyponatremia, AKI, or SBP develops.
• Aspiration pneumonia during hematemesis or endoscopy.

• The acute bleed triad: octreotide + ceftriaxone + endoscopy with band ligation within 12 hours. Antibiotics are the intervention students most often omit, yet they independently reduce mortality (AASLD).
• Transfuse restrictively: target roughly 7 g/dL. The classic distractor is transfusing to a "normal" hemoglobin — this raises portal pressure and provokes rebleeding.
• Isolated gastric fundal varices without esophageal varices = think splenic vein thrombosis from pancreatitis (left-sided/sinistral portal hypertension). The curative answer is splenectomy, not TIPS — TIPS decompresses the portal vein and does nothing for an occluded splenic vein.
• SAAG ≥1.1 g/dL identifies ascites from portal hypertension; <1.1 points to peritoneal carcinomatosis, TB, or pancreatic ascites. Total ascitic protein then separates cardiac ascites (high protein) from cirrhosis (low protein).
• The single most tested TIPS association: TIPS relieves bleeding and ascites but precipitates hepatic encephalopathy and is contraindicated when overt encephalopathy is already present.
• Beta blockers are prophylaxis, never rescue. Do not start propranolol, nadolol, or carvedilol during active hemorrhage. Refractory ascites alone is not an absolute contraindication under Baveno VII — instead, reduce the dose or temporarily hold the NSBB when systolic BP falls below 90 mmHg, serum Na falls below 130 mEq/L, or AKI or SBP develops, and restart once the patient stabilizes.
• Balloon tamponade is a bridge, not therapy — under 24 hours, airway secured first, then definitive endoscopy or TIPS.
• HVPG stratification: >5 mmHg defines portal hypertension, ≥10 mmHg is clinically significant portal hypertension (varices form), and ≥12 mmHg is the threshold above which varices bleed. Falling HVPG on NSBB predicts protection from rebleeding.
• A PMN count ≥250/µL in ascites is SBP — treat empirically without waiting for culture, and give albumin to reduce hepatorenal syndrome risk.
• Distractor to avoid: portal vein thrombosis with a healthy liver bleeds from varices but spares synthetic function — no jaundice, no coagulopathy, typically no ascites.