This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g. "portal_hypertension#Increased Intrahepatic Vascular Resistance"). The key conformance target is the central_effector node "Portal Hypertension" - the disorder-agnostic, rate-limiting step every conformer funnels through.
Disorder-specific substitutions at the trigger node, following the standard sinusoidal anatomy: PRESINUSOIDAL resistance in congenital hepatic fibrosis, schistosomiasis, and non-cirrhotic portal fibrosis; SINUSOIDAL resistance in cirrhosis of any aetiology (alcohol-related liver disease, MASLD, chronic viral hepatitis, the cholangiopathies via biliary cirrhosis), which is the commonest route; and POSTSINUSOIDAL resistance in Budd-Chiari syndrome and sinusoidal obstruction syndrome, where hepatic venous outflow is obstructed. Prehepatic portal vein thrombosis raises portal pressure without raising hepatic sinusoidal pressure and therefore conforms at the portal hypertension node and below, not at the intrahepatic-resistance trigger.
Scope and relationships. The module is deliberately haemodynamic: the fibrogenesis that produces sinusoidal resistance in cirrhosis is modelled by `fibrotic_response` (and, for the biliary route, by `cholestatic_liver_injury`, whose terminal biliary-cirrhosis node feeds this module's trigger), and this module picks up where those leave off. It is not an Xogenesis module - portosystemic collaterals arise by dilation and neovascularisation of pre-existing embryonic vascular channels under a pressure gradient, not as a discrete new pathological structure. Note the therapeutic asymmetry a conforming entry should preserve: nonselective beta-blockade acts on the splanchnic inflow arm, and no established pharmacotherapy reverses the intrahepatic resistance arm.
Can the intrahepatic vascular resistance arm of portal hypertension be lowered pharmacologically, as distinct from reducing splanchnic inflow?
KNOWLEDGE GAP
intrahepatic_resistance_undruggable
Attached to:
Increased Intrahepatic Vascular Resistance
The only treatment curated in this module acts on the splanchnic inflow amplifier, and cirrhotic portal hypertension is described in the current review literature as a condition with few pharmacological treatment options. Because part of the intrahepatic resistance is dynamic - sinusoidal endothelial dysfunction and stellate cell contraction rather than fixed fibrosis - it is in principle reversible, but no agent has established clinical benefit by that route. Conforming entries should not present beta-blockade as treating the resistance trigger.
Proposed experiments:
HVPG-endpoint trial of a sinusoidal-endothelial-directed agent
Increased Intrahepatic Vascular Resistance
trigger
The initiating lesion is a rise in the resistance the hepatic vasculature offers to portal blood flow. In cirrhosis this has both a structural component - fibrosis and architectural distortion - and a dynamic, potentially reversible component: liver sinusoidal endothelial cells lose their normal vasodilatory phenotype and hepatic stellate cells contract, raising hepatic vascular tone. The profibrogenic phenotype acquired by these sinusoidal cells is the initial event. In non-cirrhotic conformers the same node is reached instead by obstruction of hepatic venous outflow or by presinusoidal portal-tract fibrosis.
Downstream
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Portal Hypertension
A rise in the resistance of the hepatic vascular bed raises the pressure required to drive portal blood through it.
Show evidence (2 references)
"Existing knowledge indicates that the profibrogenic phenotype acquired by sinusoidal cells is the initial factor leading to increased hepatic vascular tone and fibrosis, which cause increased vascular resistance and portal hypertension."
States the cellular origin of this trigger node - the profibrogenic sinusoidal cell phenotype - and its two consequences, raised vascular tone and fibrosis, both of which increase resistance. Evidence source is OTHER because this is a review synthesizing human and experimental vascular biology.
"there is increase in the intrahepatic resistances and, therefore, decrease in portal venous flow"
Documents the postsinusoidal route into this node, in which hepatic venous outflow obstruction rather than sinusoidal fibrosis raises intrahepatic resistance - the substitution Budd-Chiari syndrome makes. Evidence source is OTHER because this is a clinical review.
Splanchnic Vasodilation and Hyperdynamic Circulation
amplifier
Portal hypertension is not simply a resistance problem. Arterial vasodilation in the splanchnic bed, driven by excess local vasodilators, increases the volume of blood delivered into the portal system, while systemic vasodilation triggers compensatory cardiac output rise and sodium-retaining neurohormonal activation. This hyperdynamic circulatory syndrome aggravates the portal pressure produced by the resistance lesion and is the arm on which nonselective beta-blockade acts.
Downstream
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Portal Hypertension
Increased splanchnic inflow into a high-resistance hepatic bed raises portal pressure further.
Show evidence (1 reference)
"Portal hypertension occurs due to increased resistance of the cirrhotic liver vasculature to portal blood flow and is further aggravated by the hyperdynamic circulatory syndrome."
Establishes the two-arm structure of the module: the resistance trigger plus this hyperdynamic inflow amplifier, which aggravates rather than compensates the pressure rise. Evidence source is OTHER because this is a review.
Portal Hypertension
central effector
Sustained elevation of pressure in the portal venous system, measured clinically as the hepatic venous pressure gradient. This is the disorder-agnostic, rate-limiting node of the module: every conformer, whatever its route to increased resistance, funnels through it, and every downstream complication in this module is a consequence of it rather than of the underlying liver disease directly. It is the primary non-neoplastic complication of cirrhosis and has few pharmacological treatment options.
Downstream
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Portosystemic Collateral Formation and Gastro-oesophageal Varices
The portosystemic pressure gradient opens and dilates collateral channels that decompress the portal system into the systemic circulation.
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Hepatic Decompensation
Raised sinusoidal pressure drives interstitial filtration and ascites, and portosystemic shunting permits gut-derived neurotoxins to bypass the liver, producing hepatic encephalopathy.
Show evidence (2 references)
"Portal hypertension represents the primary non-neoplastic complication of liver cirrhosis and has life-threatening consequences, such as oesophageal variceal bleeding, ascites, and hepatic encephalopathy."
Establishes this node as the central complication of cirrhosis and names the three downstream decompensating events the module terminates in. Evidence source is OTHER because this is a review.
"In this Review, we discuss recent discoveries in the pathophysiology and treatment of cirrhotic portal hypertension, a condition with few pharmacological treatment options."
Records that this node remains largely undruggable, which bounds what a conforming entry may claim for therapy directed at it. Evidence source is OTHER because this is a review.
Hepatic Decompensation
consequence
The clinical endpoint of the module: the appearance of ascites, jaundice, hepatic encephalopathy, infection, or portal-hypertensive haemorrhage marks acute decompensation, a watershed in prognosis. Once decompensation occurs, survival is measured in months to a few years, and further complications - spontaneous bacterial peritonitis, hepatorenal syndrome, acute-on-chronic liver failure - become likely. Conforming entries attach their disease-specific decompensating events here.
Show evidence (3 references)
"Acute decompensation of liver cirrhosis represents a watershed in prognosis and is characterized by the occurrence of clinical complications such as ascites, jaundice, hepatic encephalopathy, infections, or portal-hypertensive hemorrhages."
Defines this consequence node and enumerates its constituent events, including the portal-hypertensive haemorrhage arriving from the varices node. Evidence source is OTHER because this is a review.
"The median survival time following onset of hepatic encephalopathy and ascites is 0.92 and 1.1 years, respectively."
Quantifies the prognostic weight of reaching this node, which is why it is curated as the module's terminal consequence rather than as an incidental finding. Evidence source is OTHER because this is a JAMA narrative review summarising the literature rather than reporting an original cohort.
"Among people with ascites, the annual incidence of spontaneous bacterial peritonitis is 11% and of hepatorenal syndrome is 8%; the latter is associated with a median survival of less than 2 weeks."
Documents the secondary complications that follow from ascites, the link by which this module connects to renal and infectious sequelae in conforming entries. Evidence source is OTHER because this is a narrative review.
Nonselective Beta-Blocker (Carvedilol or Propranolol)
Platform:
Small molecule
Nonselective beta-blockers lower portal pressure by acting on the splanchnic inflow arm rather than on intrahepatic resistance: beta-2 blockade leaves splanchnic alpha-adrenergic vasoconstriction unopposed, reducing portal venous inflow, while beta-1 blockade lowers cardiac output. Carvedilol adds alpha-1 blockade, which also lowers intrahepatic vascular tone. In patients with clinically significant portal hypertension this reduced the risk of decompensation or death against placebo. This is the portal-hypertension drug-target design pattern for conforming disorders - act on the hyperdynamic amplifier, because the resistance trigger has no established pharmacotherapy.
Evidence: 3