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Tufts OpenCourseware
Author: Fredric D. Gordon

1. Objectives: Cirrhosis

  1. Understand the portal venous system anatomy

  2. To be able to describe the pathophysiology of portal hypertension

  3. Understand how portal hypertension is diagnosed

  4. To be able to describe the classification of portal hypertension as pre-, intra-, and post-hepatic

  5. Understand how esophageal varices develop and how they are diagnosed and treated

  6. Understand the theories of how ascitic fluid develops

  7. To be able to interpret results of analysis of ascites with particular attention to the important serum-ascites albumin gradient

  8. Understand the pathophysiology and treatment of hepatic encephalopathy

  9. Understand the definition and diagnosis of hepatorenal syndrome

2. Portal Hypertension

See Fig. 1-6. Measure ments of the portal vein and its main branches, in centimeters. (From Gilfillan RS. Anatomic study of the portal vein and its main branches. Arch Surg 1950; 61:449.)

2.1. Pathophysiology

  1. Ohm's law states that the change in pressure (ΔP) along a blood vessel is a function of the resistance to blood flow (R) and the rate of blood flow (Q) as expressed in the following equation:
    ΔP = R x Q
    In a healthy individual, the liver is a very low resistance organ which passively receives whatever blood flow is coming from the mesenteric bed, a value that changes over the course of the day. The liver is able to accommodate these changes in blood flow without an increase in portal pressures by decreasing the resistance n the liver through the recruitment of additional hepatic sinusoids. Thus, the ΔP does not change despite an increase in Q because the R is reduced. One needs to understand how changes in both the resistance to blood flow in the portal system and volume of blood flow in the portal system in patients with cirrhosis combine to produce portal hypertension.

  2. Resistance to blood flow is expressed by Poiseuille's law:
    R – 8nL / πr4
    the most important variable affecting resistance is the radius based on the fact it's input is raised to the fourth power. For example, if the radius is reduced by ½ there is a 16-fold increase in resistance. L is the length of the vessel and n is the coefficient of viscosity both of which are constant under physiologic conditions.
    Patients with cirrhosis have an increase in resistance to blood flow through the liver at the level of the sinusoids and the hepatic and portal venules. This is predominantly due to fibrosis and regenerative nodules compressing/obliterating these vessels.
    The increased resistance to blood flow in portal hypertension may be pre-hepatic (such as blockage of the portal vein), intra-hepatic (pre-sinusoidal, sinusoidal, or post-sinusoidal), or post-hepatic (such as blockage of the IVC). See below.

  3. There is also an increased rate of blood flow to the splanchnic circulation in patients with cirrhosis. Patients with cirrhosis have a hyperdynamic circulation marked by low peripheral vascular resistance and high cardiac output. Studies have shown that there is a 50% increase in flow to the GI tract, pancreas, and spleen in patients with cirrhosis. This hyperdynamic circulation is due to an elevated level of vasodilators is due to an elevated level of vasodilators (such as glucagon) in the blood and a decreased vascular sensitivity to vasoconstriction. The elevated levels of vasodilators are due to decreased hepatic metabolism due to shunting around the liver from the presence of collaterals and due to an increase in the production of local vasodilators (such as nitric oxide) by endothelial cells.

  4. Thus, patients with cirrhosis develop portal hypertension both because on increased vascular resistance within the liver and increased splanchnic/portal blood flow.

2.2. Diagnosis

  1. The best measure of portal hypertension is the hepatic vein pressure gradient (HVPG). By definition, portal hypertension is the hepatic vein pressure gradient (HVPG). By definition, portal hypertension is a hepatic venous pressure gradient of greater than 10 mm Hg. This text is done by passing a catheter by either a transjugular or transfemoral approach into the hepatic vein. Then a free hepatic vein pressure (FHVP) is measured. A balloon is then used to wedge the catheter in the hepatic vein and a second pressure is taken. This wedged hepatic vein pressure (WHVP) is the sinusoidal pressure and in most cases a good reflection of the portal pressure. The HVPG is then the WHPG – FHVP. Alternatively, a direct measurement of portal pressure can be obtained by 1) laparotomy and direct placement of a catheter into the portal vein, 2) passing a catheter through the liver into the portal system, 3) splenic pulp pressure (passing a needle percutaneously into the spleen), or 4) umbilical vein catheterization. These methods are rarely used.

  2. An indirect way to assess for portal hypertension is to perform an upper endoscopy. The presence of esophageal varices and/or portal gastropathy indicates the presence of portal hypertension.

  3. Technetium labeled sulfur colloid scan. In the presence of portal hypertension this text demonstrates a shift of colloid from the liver to the spleen and the bone marrow.

2.3. Classification (based on the location of the increased resistance.)

While attempts to categorize portal hypertension in this fashion have proven somewhat useful, these classifications may in many cases be idealized as most liver conditions have more than one site of increased resistance. In general, patients who have involvement of the sinusoids with fibrosis will have elevated HVPGs.

  1. Pre-hepatic (NOTE: these patients have normal HVPG because the WHVP and FHVP will both be normal):

    1. Portal or splenic vein thrombosis

    2. Arteriovenous fistulas in the splanchnic bed or spleen

  2. Intrahepatic:

    1. Pre-sinusoidal (these patients have normal HVPG because the WHVP and FHVP will both be normal):

      1. Schistosomiasis (Inflammatory rxn to eggs in the portal venules:

      2. Sarcoidosis

    2. Sinusoidal (these patients have an elevated HVPG because the WHVP is elevated while the FHVP is normal):

      1. Cirrhosis of any etiology

    3. Post-sinusoidal:

      1. Hepatic vein thrombosis (Budd-Chiari syndrome). These patients are diagnosed not by the presence of changes in the HVPG, but rather by the fact their hepatic veins cannot be cannulated due to the presence of clot.

    4. Post-hepatic (these patients have a normal HVPG because both the WHVP and the FHVP are elevated):

      1. Webs (congenital or acquired) in the inferior vena cava

      2. Cardiac disease – e.g., constrictive pericarditis, mitral stenosis

3. Complications of Portal Hypertension

3.1. Portosystemic Collaterals

  1. Collateral vessels can develop wherever there is a communication between the portal and systemic circulations. Sites include the umbilical vein (resulting in caput medusae), dilated abdominal wall veins, retroperitoneal veins and the clinically most important collateral, esophageal and gastric varices.
    See Fig. 1-8. Diagram of portal circulation. (From Wanless IR. Anatomy and developmental anomalies of the liver. In: fledman M, Scharschmidt BF, Sleisenger MH, eds. Sliesenger and Fordtran's Gastrointestinal and Liver Disease. 6th ed. Philadelphia: WB Saunders, 1997: p. 1057.)

  2. In patients with portal hypertension, bleeding from varices rarely occurs if the HVPG is below 12 mm Hg. While the varices form as a consequence of increased portal pressures, actual rupture of the varices is more related to variceal wall pressure. At equal pressures a large varix has a greater wall stress than a small varix. That is, at equal portal pressures, patients with large varices tend to bleed more often than those with smaller ones.

  3. Treatment of varices

    1. Pharmacologic therapy. Aims at the reduction of portal pressures.

      1. Vasopressin. A vasoconstictive drug which reduces blood flow to the splanchnic circulation thereby reducing portal pressures. Unfortunately, the vasoconstriction is systemic and may cause ischemia elsewhere. Therefore, vasopressin should always be used in conjunction with nitroglycerin which is a vasodilator.

      2. Somtostatin (and its analogue, Octreotide). These cause selective splanchnic vasoconstriction. This is perhaps due to the inhibition of release of splanchnic vasodilators such as glucagon.

      3. Non-selective beta blockers (propranolol and nadolol) are useful both for reducing the risk of the first bleed and preventing rebleeding. NOTE: One must use a non-selective blocker in in order to produce splanchnic vasoconstriction by blocking the vasodilating beta-2 adrenoreceptors.

      4. Oral nitrates are as effective as beta blockers for preventing first bleeding episodes. The combination of a non-specific beta-blocker and a nitrate was better than a beta-blocker alone, suggesting there is an additive benefit.

    2. Endoscopic therapy

      1. Sclerotherapy. The injection of sclerosants directly into the varices. Has a high rate of complications.

      2. Banding ligation. The placement of bands on the varices. Is as effective as sclerotherapy with a lower complication rate.

    3. Other treatments

      1. TIPS (transjugular transhepatic portosystemic shunt). The formation of a direct connection between the portal vein and the hepatic vein through the parenchyma of the liver. Performed by the interventional radiologists.

      2. Surgical shunts. Portocaval, mesocaval, and distal splenorenal shunts are performed less since the TIPS procedure was introduced.

3.2. Ascites

  1. Pathophysiology
    There is considerable evidence which suggests that ascites is related to an increase in hepatic sinusoidal pressure rather than an increase in splanchnic capillary pressure. Patients with pre-sinusoidal portal hypertension rarely develop ascites while those with post-hepatic portal hypertension have ascites as a prominent feature of their illness. An increase in the hepatic sinusoidal pressure in combination with a decreased oncotic pressure results in the increased production of hepatic lymph. When the production of lymph exceeds the ability of the lymphatics and the thoracic duct to return the lymph of the general circulation, ascites results.

    Facilitating and opposing forces in ascites formation
    Facilitating and opposing forces in ascites formation

    Because ascitic fluid is derived from the vascular space, in order for it to continue to be produced, the intravascular space must be continuously replenished. This mainly occurs by the cirrhotic patient inappropriately holding on to urinary sodium (and therefore free water). How this happens is summarized in the figure below:
    The first step in the process appears to be the production of the hyperdynamic circulation described in Section 3.1, 3). The hyperdynamic sate is marked by low peripheral vascular resistance induced by the presence of elevated level of vasodilators (such as glucagon and nitric oxide) in the blood and a decreased vascular sensitivity to vasoconstrictive agents. The body attempts to compensate for apparent decrease in the circulating blood volume by increasing cardiac output and by activation of the rennin-angiotensin system which results in increased renal sodium and free fluid retention. Because of this, the intravascular space continues to be inappropriately replenished and excessive hepatic lymph production/ascites production continues.

    Portal Hypertension Process
    Portal Hypertension Process

  2. Diagnosis
    The presence of ascites does not always mean cirrhosis/portal hypertension. See table below for the various causes of non-portal hypertensive ascites and portal hypertensive ascites:

    1. Work-up of newly identified ascites should include:

      1. Serum-ascites albumin gradient: calculated by subtracting the ascitic fluid albumin from the serum albumin. An albumin of greater than 1.1 gm/dl indicates portal hypertension as the cause in almost all of the cases. Causes of a "low albumin gradient" ascites include infection, malignancy, and pancreatitis among others.

      2. Cell count and ascitic fluid cultures. An ascitic polymorphonuclear cell count of greater than 250/ml of ascitic fluid is diagnostic of bacterial peritonitis.

      3. Ascitic fluid cytology to diagnose malignant ascites.

        Non-portal hypertensive ascites

        Portal hypertensive ascites






        Cardiac-congestive heart failure, pericardial disease


        Veno-occlusive disease

        Bile ascites

        Portal vein thrombosis


        Polycystic liver disease

        Noncirrhotic chylous ascites

        Massive liver metastases

  3. Management

    1. Dietary measures.
      Sodium restriction. Fluid restriction is unnecessary unless the serum sodium drops below 125 mmol per liter.

    2. Diuretics.
      The goal of therapy is to remove 0.5 to 1 kg per fay of weight. More aggressive diuresis is at the expense of the intravascular space and could damage the kidneys.

      1. The agent of choice is spironolactone because it inhibits the effects of aldosterone in the kidney. Some patients require the addition of furosemide which as a different mechanism of action.

    3. Large volume paracentesis, peritoneovenous (Denver) shunts, and transjugular intrahepatic portosystemic shunt (TIPS) are reserved fro patients with ascites that has not responded to diuretics.

3.3. Hepatic Encephalopathy

  1. Definition:
    A metabolic abnormality of CNS function which can occur in either fulminant or chronic liver disease. When it occurs in fulminant liver failure, it carries a poor prognosis.

  2. Clinical features:
    It is often graded on a scale of I (personality changes, reversal of day-night cycle) to IV (frank coma). The diagnosis is made by the presence of asterixis (a flapping tremor of the hands elicited by dorsiflexion at the wrists), constructional apraxia, and an abnormal EEG showing a general slowing.

  3. Pathophysiology:
    Much debate exists, but it is clear that there is some neurotoxic substance escaping decontamination in the liver because of shunting around the liver and a decrease in hepatic function due to the loss of hepatocytes.

    1. Postulated Toxins:

      1. Ammonia. However, there is often a poor correlation between ammonia levels and degree of encephalopathy.

      2. GABA (gamma amino butyric acid). GABA is the principle inhibitory neurotransmitter in the brain. A study suggested that patients with hepatic encephalopathy had excessive amounts of circulating GABA. However, this study could not be reproduced.

  4. Treatment

    1. Vigorous search for precipitating, reversible causes.


      Possible mechanism

      Associated coprecipitant

      GI bleeding

      Nitrogen load,

      hepatic hypoperfusion,

      arterial hypoxemia


      Banked blood transfusion (ammonia),

      Benzodiazeprines (endoscopic procedure)


      Protein catabolism


      Arterial hypotension,


      Hypokalemia (diarrhea, diuretics)

      Ammonia generation

      GI bleeding,


      Dehydration (diuretics, paracentesis, laxatives)

      Hepatic hypoperfusion




      Increased ammonia production (urealysis)

      GI bleeding,


      Acute hepatitis

      Hepatocellular dysfunction,

      Impaired detoxification




      Enhanced CNS sensitivity

    2. Reduction in intestinal ammonia production"

      1. Reduce oral protein intake. Reduces substrate for ammonia production by bacteria in the GI tract. There is no set amount, but a diet with a protein content of less than 40 gm/day will result in negative protein balance. Patients with cirrhosis should eat as much protein as they can tolerate. Typically, one starts at 40 gm/day and titrates upward to find each patient's protein threshold.

      2. Lactulose: a nonabsorbable disaccharide. Lactulose was initially thought to work by reducing the pH in the colon resulting in decreased absorption. Recent studies have challenged this theory. Studies now suggest that lactulose works by altering the metabolism of intestinal microflora resulting in decreased ammonia production in the gut and, therefore, systemically.

      3. Antibiotics: neomycin, metronidazole, vancomycin, and rifaximin. Kills the bacteria (such as bacteroides) which produce ammonia. Neomycin is for the most part not absorbed. However, the small amounts that are absorbed may lead to nephro- and ototoxicity. Metronidazole and vancomycin have been shown to be effective in small trials. Rifaximin has been used successfully in Europe for some time and is both well-tolerated and safe. It is not yet FDA approved.

3.4. Hepatorenal Syndrome

  1. Definition:
    Azotemia and oliguria (less than 500 cc of urine/day) in association with a low urine sodium concentration (less than 10 meq/L) in a patient with advanced liver disease. The condition is marked by severe renal vasoconstriction, the etiology of which is unknown. This occurs without any intrinsic renal disease. In fact, if kidneys from patients with hepatorenal syndrome were removed and put into a patient without cirrhosis they would work perfectly well.

  2. Diagnosis:
    A low urine sodium and high urine osmolarity with a bland urinary sediment. This syndrome may be precipitated by infection (especially SBP [spontaneous bacterial peritonitis]), volume depletion from an overly aggressive diuresis or blood loss, or drugs such as aminoglycosides (antibiotics which are nephrotoxic) or NSAIDs (blocks the renal production of vasodilatory prostaglandins).

  3. Pathophysiology:
    Incompletely understood, but there is felt to be some humoral agent not cleared by the liver which results in persistent vasoconstriction in the kidney.

  4. Treatment:
    Liver transplantation. ?peritoneovenous shunt, ?TIPS. Recent studies have looked at combining a systemic vasoconstrictor (derivatives of vasopressin) with vascular expansion with albumin. While there was a dramatic improvement in some patients, the results were short-lived and the complication rate was high.