Updated: 03/13/08 01:44 PM
HOME HEAL EDUCATE RESEARCH DIRECTORY OUTREACH


Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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R. Portal Hypertension

1. Pathogenesis of Portal Hypertension (Figure 20)

↑ Intrahepatic vascular resistance + ↑ splanchnic inflow   Increased pressure in the portal venous system (portal hypertension) results whenever there is: a) an increased resistance to the flow of blood through the liver, and/or b) a large increase in the amount of blood trying to enter the liver from the splanchnic circulation. Both factors play an important role in the setting of cirrhosis, which is the most common cause of portal hypertension in the developed countries. In cirrhosis, intralobular collaterals connecting the high pressure hepatic arterioles to the portal venules contribute also to the elevated portal pressure.



Figure 20
Pathogenesis of Portal Hypertension in Cirrhosis

Flow diagram of the sequence of changes in the portal and splanchnic circulations that lead to the portal hypertension and systemic hypotension in cirrhosis.

The two major pathways leading to portal hypertension are the increased intrahepatic vascular resistance (left) and the increased inflow from the dilated, hyperdynamic splanchnic circulation (right). In addition, the responsiveness of the splanchnic and portal vessels to vasoconstrictive agents is abnormally diminished in portal hypertension (not shown)

  a. Portal blood flow and pressure,
measurement & regulation










Normal portal pressure gradient = 4-9 mm Hg 		  Portal blood flow is normally 1.0-1.2 L/min. Pressures within the portal venous system can be measured by several different methods: a) wedging a catheter into an hepatic vein via the jugular or femoral veins; b) catheterizing a left intrahepatic branch of the portal vein via the umbilical vein; c) transhepatic portal vein catheterization via a thin needle; or d) inserting a needle into the splenic pulp. The most commonly used method is the hepatic wedge technique. The difference between the "wedged" hepatic (= sinusoidal) pressure (WHVP), and inferior vena caval (IVC) pressure is the portal (sinusoidal) venous pressure gradient. Normal portal venous pressure gradients are roughly 4-9 mm Hg, slightly above resting inferior vena caval pressure.

Gradients in cirrhosis are >10 mm Hg   Gradients of 10-15 mm Hg or higher are seen in cirrhosis; if > 12 mm Hg, they are usually associated with the development of dilated porto-systemic collateral veins (such as esophageal varices), through which portal blood flow is shunted around the liver.

Large increase in portal pressure and flow after eating in patients with cirrhosis   The system is quite dynamic so there are fluctuations of both pressure and flow with changes in respiration, temperature, body position, straining at stool, coughing, and especially eating. During and for several hours after a meal, portal flow increases by 60 –130%. Normally, this increased blood flow is compensated by vasodilation of the portal veins and a decrease in hepatic arterial flow, so that portal pressure rises at most 1-2 mm Hg. In cirrhosis, the rigid hepatic venous vasculature cannot dilate, and portal pressure may rise by 5-6 mm Hg after eating.

  b. Causes of increased resistance
to portal blood flow

Three sites of increased resistance to portal blood flow.   The anatomic location and etiology of the increased resistance to hepatic blood flow determines the clinical problems that result and their prognoses. The anatomic types are labeled presinusoidal, intrasinusoidal, and postsinusoidal, according to the normal direction of blood flow through the liver.



Portal venous obstruction (presinusoidal) 		  i) Increased presinusoidal resistance is usually secondary to blockage of the main portal vein or its downstream tributaries. Worldwide, it is most often due to annular fibrosis of the intrahepatic portal venules secondary to granuloma formation stimulated by eggs released by Schistosoma mansonii residing in the portal veins. This disease is common in Africa and Latin America, and in immigrants from these regions to the USA. If there is no other associated liver disease, the major manifestation is recurrent bleeding from esophageal varices, without ascites or encephalopathy. In the USA, thrombosis is the more common etiology, usually related to therapy with sex hormones or to hypercoagulable states, but often idiopathic.

Sinusoidal and portal venule narrowing in cirrhosis (intrasinusoidal)   ii) Increased intrasinusoidal resistance is one of the two major factors in portal hypertension due to cirrhosis. It is due to sinusoidal narrowing from three causes: subendothelial deposition of collagen in the space of Disse; distortion from regenerating nodules; and constriction due to impaired synthesis of the vasodilator, nitric oxide (NO) and increased release of the vasoconstrictor, endothelin, by the sinusoidal endothelium. The stimulus underlying these changes may be impaired hepatic removal and increased absorption of toxins produced by the ileo-colonic bacterial flora. Compression of sinusoids and small hepatic venules by primary or metastatic tumors is another cause.

Obstruction of the hepatic vein or its tributaries (postsinusoidal)   iii) Increased postsinusoidal resistance occurs in three conditions:
  1. Veno-occlusive disease – multifocal obstruction of the small hepatic venules, often due to irradiation or chemotherapy for malignancies, or to ingested plant toxins (herbal remedies).


  2. Budd-Chiari syndrome – obstruction of the main hepatic veins, or of the inferior vena cava at or above the liver, secondary to thrombosis, endophlebitis, congenital webs, or hepatocellular or renal cancer growing intravascularly.


  3. Severe right-sided congestive heart failure, which raises right atrial pressure and impedes venous return.
  c. Causes of increased flow of splanchnic blood into portal system

Normal arteriolar vasoconstriction is balanced by vaso-dilator influences.




In cirrhosis, vasodilators (NO) ↑ and sensitivity to vaso-constrictors ↓. Hyperdynamic circulation results. 		  Normal splanchnic vascular resistance and flow are maintained by a balance between tonic constriction of the splanchnic arterioles, mediated by norepinephrine, vasopressin and angiotensin II, countered by the vasodilator effects of nitric oxide (NO) and glucagon. In cirrhosis, splanchnic (and systemic) arterial resistance falls and flow increases dramatically, the so-called hyperdynamic circulation. A combination of factors contribute: (i) increased synthesis of NO from arginine by the vascular endothelium, due to enhanced catalytic activity of endothelial nitric oxide synthetase (eNOS). (ii) secondary increases in systemic glucagon concentrations, due to shunting past the liver in porto-systemic collaterals; (iii) decreased sensitivity of the arterioles to the compensatory increase in release of vasoconstrictors; (iv) increased cardiac output. The stimulus for (i) and (iii) may be increased absorption and impaired removal of bacterial toxins produced in the intestinal lumen.

2. Consequences of Portal Hypertension (Figure 21)

  a. Splenomegaly and pancytopenia

Splenomegaly and pancytopenia   Since there are no valves in the portal system, increases of portal vein pressure are transmitted immediately to all venous tributaries, and the spleen, intestines and stomach become congested. The engorged spleen more effectively destroys blood cellular elements, contributing to anemia, leukopenia and thrombocytopenia.

  b. Porto-systemic collaterals

Portal venous collaterals to systemic veins bypass the liver cells   Prolonged portal hypertension causes development of a collateral venous circulation, which partially decompresses the portal venous system. Portal blood flowing through these collaterals, including porto-central anastomoses within the liver acini, bypasses the liver, decreasing access of substances absorbed from the intestine to removal by the liver. Normally, 100% of the portal venous blood flow can be recovered from the hepatic veins, but in cirrhosis, as little as 13% may be recovered. The collaterals are quite variable, but the most common and clinically important is esophageal varices:


Figure 21
Consequences of Circulatory Changes in Cirrhosis

Flow diagram of the complications caused by portal hypertension and systemic hypotension in cirrhosis. Portal hypertension causes splenic congestion and enlargement with pancytopenia, as well as development of porto-systemic shunts. Large collateral veins in the esophagus (varices) may rupture, causing massive GI bleeding. Shunting around the liver of nitrogenous compounds absorbed from the gut causes hepatic encephalopathy. The sodium and water retention and systemic hypotension contribute to the hepato-renal syndrome, and, combined with high portal pressure cause accumulation of fluid in the peritoneal space (ascites). Bacteria and endotoxins, translocated from the gut due to portal hypertension, may circulate into the ascitic fluid, causing spontaneous bacterial peritonitis.

Bleeding from esophageal or gastric varices is a major complication of portal hypertension   i) Gastroesophageal varices

DDilated, tortuous veins (varices) develop in the submucosa of the lower esophagus and gastric fundus. This system is fed by the coronary and short gastric veins (connecting from the spleen) and empties into the azygous system in the thorax. Sudden increases in portal pressure that exceed the wall tension of these fragile vessels causes their rupture into the esophageal or gastric lumen, resulting in sudden, often massive, upper gastrointestinal hemorrhage. In the stomach, smaller submucosal arterio-venous communications may likewise bleed (portal hypertensive gastropathy). Bleeding varices may be occluded by endoscopic ligation or sclerosant solutions.

ii) Rectal varices:

The superior hemorrhoidal branches of the mesenteric veins connect with the middle and inferior hemorrhoidal veins, which drain into the inferior vena cava. Rectal varices often occur and may bleed, and are more frequent after esophageal varices have been endoscopically obliterated.

iii) Other porto-systemic collaterals:

  1. Retroperitoneal veins constitute a major decompressive route which connects the portal and caval circuits at multiple sites, wherever gastrointestinal organs lie retroperitoneally.


  2. Periumbilical veins run in the falciform ligament to the umbilicus where they connect to superficial abdominal veins that may be clearly visible on the abdominal wall (caput medusae).


  3. Diaphragmatic-periesophageal veins: Many small branches in and around the diaphragm connect the portal and systemic circuits.


c. Hepatic encephalopathy

Absorbed toxins bypassing the liver impair brain function   In the presence of porto-systemic collaterals, ammonia and other nitrogenous compounds that are naturally absorbed from the intestine, partially bypass the liver and reach the brain, causing impaired neurologic function. For details, see section T.

d. Hepato-renal syndrome

Functional renal failure in cirrhosis   Functional renal failure due to extreme vasoconstriction of renal afferent arterioles in cirrhotic patients with severe fluid retention.

e. Ascites and edema

Ascites due to high portal pressure + low plasma albumin   Elevated portal venous pressure and a low plasma oncotic pressure due to hypo-albuminemia are key determinants of the accumulation of fluid in the peritoneal cavity (ascites). Compression of the vena cava by the nodular, cirrhotic liver contributes to edema of the legs. For details, see section S.

f. Spontaneous baterial periotonitis (SBP)

Translocated gut bacteria may infect ascitic fluid   The increased portal pressure increases the permeability of the intestinal capillaries. Combined with bacterial overgrowth in the small intestine, this leads to increased translocation of bacteria and their toxins from the gut into the circulation, via which the bacteria may be carried to and infect the ascitic fluid. Except for fever, SBP is often asymptomatic, and detected only by an increased number of polymorphonuclear leukocytes in the peritoneal fluid.

3. Treatment of Portal Hypertension

Reverse both the intrahepatic vasoconstriction and splanchnic vasodilatation.  
  1. Decrease intrahepatic vascular resistance
    2.
    1. NO precursors (e.g. isosorbide mononitrate)
    2. Block angiotensin II & endothelin receptors (Losartan, Bosentan)


  2. Constrict splanchnic arterioles to decrease portal venous inflow
    3.
    1. β-adrenergic antagonists (e.g. propranolol) – also ↓ heart rate
    2. Splanchnic-selective vasopressin analogue (Terlipressin)


  3. Inhibit splanchnic vasodilatation
    4.
    1. Decrease NO synthesis mediated by eNOS
      1. Inhibit eNOS (N-nitro-L-arginine
        2. )
      2. ↓ endotoxin formation in gut (Norfloxacin antibiotic)
    2. Inhibit CCK, VIP & glucagon receptors (somatostatin analogue)


  4. Decrease intravascular volume – Sodium restriction, diuretics
    5.

  5. Decompress portal system by diverting blood to systemic circulation.

    6. This also helps restore depleted central blood volume.
    1. Surgical splenorenal or porto-caval shunt.
    2. Transjugular intrahepatic porto-systemic shunt (TIPS)
Next Section (S): Ascites, Edema and
Renal Failure in Liver Disease »



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