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Portal Hypertension and Cirrhosis

The portal vein is the primary vessel leading into the liver; it receives the deoxygen-ated venous blood flow from the splanchnic bed (intestines, stomach, pancreas, and spleen) (Fig. 22-1). Portal flow accounts for approximately 75% of all the blood delivered to the liver. The hepatic artery provides the remaining 25% of the blood supply in the form of oxygenated blood from the abdominal aorta. Normal portal vein pressure is between 5 and 10 mm Hg; this level maintains blood flow to the liver at approximately 1 to 1.5 L/min. Portal hypertension occurs when the hepatic venous pressure gradient (the pressure difference between the portal vein and the inferior vena cava) exceeds 10 to 12 mm Hg.10,11

Portal hypertension is a consequence of increased resistance to blood flow through the portal vein. This is usually due to restructuring of intrahepatic tissue (sinusoidal damage) but may also be caused by presinusoidal damage such as portal vein occlusion from trauma, malignancy, or thrombosis. The third (and the least common) cause of portal hypertension is outflow obstruction of the hepatic vein. This latter damage is posthepatic, and normal liver structure is maintained. This chapter will focus on portal hypertension caused by intrahepatic damage from cirrhosis.

Sinusoidal damage from cirrhosis is the most common cause of portal hypertension. The sinusoids are porous vessels within the liver that surround radiating rows of hepatocytes, which are the basic functional cells of the liver (Fig. 22-2). Progressive destruction of hepatocytes and an increase in fibroblasts and connective tissue surrounding the hepatocytes culminate in cirrhosis. Fibrosis and regenerative nodules of scar tissue modify the basic architecture of the liver, disrupting and reducing hepatic blood flow as well as normal liver function. Reduced hepatic blood flow alters the normal metabolic breakdown processes and decreases protein synthesis within the liver.

Inferior vena cava

Hepatic vein

Portal Vein Anatomy

Inferior vena cava

Hepatic vein

Left gastric vein Stomach

Inferior vena cava Right renal vein

Spleen Left renal vein

Inferior mesenteric vein

FIGURE 22-1. The portal venous system. (From Sease JM, Timm EJ, Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 634, with permission.)

FIGURE 22-1. The portal venous system. (From Sease JM, Timm EJ, Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 634, with permission.)

Portal Hypertension Causes Images

FIGURE 22-2. Relationship of sinusoids to hepatocytes and the venous system. (From Sease JM, Timm EJ, Stragand JJ. Portal hypertension and cirrhosis. In: DiPiro JT, Talbert RL, Yee GC, et al., eds. Pharmacotherapy: A Pathophysiologic Approach, 7th ed. New York: McGraw-Hill; 2008: 634, with permission.)

The sinusoids transport both portal and arterial blood to the hepatocytes. The systemic blood delivered to the liver contains nutrients, drugs, and ingested toxins. The liver processes nutrients (carbohydrates, proteins, lipids, vitamins, and minerals) for either immediate use or for storage, while drugs and toxins are broken down through a variety of metabolic processes. Changes in hepatic blood flow can significantly alter metabolism. Processing of drugs eliminated by first-pass metabolism is reduced, extending the half-life. In the case of prodrugs that are activated by the liver, the time to therapeutic effect is delayed. The liver also processes metabolic waste products for excretion. In cirrhosis, bilirubin (from the enzymatic breakdown of heme) can accumulate; this causes jaundice (yellowing of the skin), scleral icterus (yellowing of the sclera), and tea-colored urine (urinary bilirubin excretion).

Changes in steroid hormone production, as well as changes in the conversion and handling of steroids are also prominent features of cirrhosis. These changes can result in decreased libido, gynecomastia (development of breast tissue in men), testicular atrophy, and features of feminization in male patients. Another deleterious effect of changes in sex hormone metabolism is the development of spider angiomata (nevi). Spider angiomata are vascular lesions found mainly on the trunk. The lesion has a central arteriole (body) surrounded by radiating "legs." When blanched, the lesions fill from the center body outward toward the legs. Spider angiomata are not specific to cirrhosis, but the number and size do correlate with disease severity, and their presence relates to risk of variceal hemorrhage.12

Increased intrahepatic resistance to portal flow increases pressure on the entire splanchnic bed; an enlarged spleen (splenomegaly) is a common finding in cirrhotic patients. Splenic sequestration secondary to splenomegaly is one of the causes of thrombocytopenia in cirrhotic patients. Portal hypertension mediates systemic and splanchnic arterial vasodilation through production of nitric oxide and other vasodilators in an attempt to counteract the increased pressure gradient. Nitric oxide causes a fall in systemic arterial pressure; unfortunately, this activates both the rennin-

angiotensin-aldosterone system (RAAS) and the sympathetic nervous system, as well

as increasing antidiuretic hormone (vasopressin) production. The activation of these systems is an attempt to maintain arterial blood pressure through increases in renal sodium and water retention. Increased systemic and portal pressure put increased pressure on the vascular system. As a consequence, the umbilical vein, which is usually eradicated in infancy, may become patent and increase blood flow to the abdominal veins. These prominent veins, which are visible on the surface of the abdomen, are called caput medusae because they resemble the head of the mythical Gorgon Medusa.

The aim of pharmacologic treatment in portal hypertension is to decrease portal pressure and reduce the effects of sympathetic activation.


Ascites is the accumulation of fluid in the peritoneal space and is often one of the first signs of decompensated liver disease. Ascites is the most common complication of cirrhosis and portends a dire prognosis.14

The pathophysiologic mechanisms of portal hypertension and of cirrhosis itself are entwined with the mechanisms of ascites (Fig. 22-3). Cirrhotic changes and subsequent decreases in synthetic function lead to decreased albumin production (hypoal-buminemia). Albumin is the primary intravascular protein responsible for maintaining oncotic pressure within the vascular system; low serum albumin levels combined with increased capillary permeability allow fluid to leak from the vascular space into body tissues. This results in peripheral edema, ascites, and fluid in the pulmonary system. Obstruction of hepatic sinusoids and hepatic lymph nodes allows fluid to seep into the peritoneal cavity, further contributing to ascitic fluid formation.

Portal Hypertension Ascites
FIGURE 22-3. Factors involved in the development of ascites. (From Chung RT, Podolsky DK. Cirrhosis and its complications. In: Kasper DL, Braunwald E, Fauci AS, et al., eds. Harrison's Principles of Internal Medicine, 17th ed. New York: McGraw-Hill, 2005: 1858-1869, with permission.)

As previously discussed, the nitric oxide released in reaction to portal hypertension dilates the systemic arterial system, causing a decrease in blood pressure. There is also a decrease in renal perfusion from the lowered effective intravascular volume. The kidney reacts by activating the RAAS, which increases plasma renin activity, aldosterone production, and sodium retention. This increase in intravascular volume furthers the imbalance of intravascular oncotic pressure, allowing even more fluid to escape to the extravascular spaces, furthering ascites and peripheral edema.

Vasodilation and decreased arterial pressure are also detected centrally. The sympathetic nervous system is activated to increase blood pressure, which in turn increases portal pressure. Unchecked, these combined effects enable the cycle of portal pressure and ascites to continue, creating a self-perpetuating loop of ascites formation.

Most patients with large ascites also retain sodium and water avidly, partially due to activation of antidiuretic hormone. Patients may become hyponatremic if there is a decrease in free water excretion. Untreated, this can lead to a decrease in renal function and the hepatorenal syndrome (HRS)4,13

Hepatorenal Syndrome

Type 1 HRS is characterized by rapid deterioration of renal function in the presence of decompensated cirrhosis. HRS is not reversible with volume repletion and is rapidly fatal, with a 50% mortality rate at 14 days if left untreated. Renal artery vasoconstriction (stimulated by activation of the sympathetic nervous system) and decreased mean arterial pressure (mediated by nitric oxide) combine to decrease renal perfusion and precipitate renal failure in patients with cirrhosis. The kidneys attempt to counteract this drop in renal perfusion by activating the RAAS. Production of renin stimulates a cascade that causes fluid retention and peripheral vasoconstriction in an attempt to increase blood flow to the kidneys. Production of prostaglandin E2 and prostacyclin are increased to stimulate renal vasodilation. HRS develops when these mechanisms are overwhelmed and renal perfusion drops acutely. SBP is often implicated as a trigger for HRS, and nonsteroidal anti-inflammatory drugs (NSAIDs) can precipitate HRS by inhibiting prostaglandins.


The splanchnic system drains venous blood from the GI tract to the liver. In portal hypertension, there is increased resistance to drainage from the originating organ so collateral vessels (varices) develop in the esophagus, stomach, and rectum to compensate for the increased blood volume. Varices divert blood meant for hepatic circulation back to the systemic circulation; this has the unintended deleterious effect of decreasing clearance of medications and potential toxins through loss of first-pass metabolism. Varices are weak superficial vessels, so any additional increase in pressure can cause these vessels to rupture and bleed.15

Spontaneous Bacterial Peritonitis

SBP is an acute bacterial infection of peritoneal (ascitic) fluid in the absence of intraabdominal infection or intestinal perforation. Estimates of the prevalence of SBP in patients with ascites range from 10% to 30%.16 The peritoneal cavity is usually a sterile space. One proposed mechanism of bacterial contamination is translocation of intestinal bacteria into the peritoneal cavity, which then seeds the ascitic fluid.17 Bacterial translocation correlates with the delay in intestinal transit time and increased intestinal wall permeability observed in cirrhotic patients. Another possible mechanism is the hematogenous spread of bacteria into the peritoneal space.18 Enteric gramnegative aerobes are the most common bacteria isolated from ascitic fluid, usually Escherichia coli or Klebsiella pneumoniae. Streptococcus pneumoniae is the most common gram-positive pathogen associated with SBP.19 Once a bacterial pathogen has been identified, the antibiotic spectrum can be narrowed; SBP is rarely polymicrobial.

Hepatic Encephalopathy

Decreased cognition, confusion, and changes in behavior combined with physical signs such as asterixis (characteristic flapping of hands upon extension of arms with wrist flexion) indicate HE. To objectively stage the degree of impairment, the patient should be assessed in five distinct categories:

1. Level of consciousness

2. Cognition (e.g., attention, memory, and disorientation)

4. Motor function (e.g., coordination, reflexes, and asterixis)

5. Response to psychometric tests

Changes in mental status may be acute and therefore possibly reversible. Identifiable triggers can often be detected and reversed in acute HE. Changes may also be of a more chronic, insidious nature. Patients rarely recover from chronic HE.

Numerous factors, many of them poorly understood, are involved in the development of HE. In severe hepatic disease, systemic circulation bypasses the liver, so many of the substances normally metabolized by the liver remain in the systemic circulation and accumulate to toxic levels. In excess, these metabolic byproducts, espe-

cially nitrogenous waste, cause alterations in CNS functioning.

Ammonia (NH3) is just one of the toxins implicated in HE. It is a metabolic byproduct of protein catabolism and is also generated by bacteria in the GI tract. In a normally functioning liver, hepatocytes take up ammonia and degrade it to form urea, which is later renally excreted. In patients with cirrhosis, this conversion to urea is retarded and ammonia accumulates, resulting in encephalopathy. The decrease in urea formation is manifest on laboratory assessment as decreased blood urea nitrogen (BUN), but BUN levels do not correlate with degree of HE. Patients with HE commonly have elevated serum ammonia concentrations, but again, the levels do not cor-

relate well with the degree of CNS impairment.

False neurotransmitters resulting from increased levels of aromatic amino acids, y-aminobutyric acid and endogenous benzodiazepines have also been implicated in HE. These substances bind to both the y-aminobutyric acid and benzodiazepine receptors and act as agonists at the active receptor sites.20

Patients with previously stable cirrhosis who develop acute encephalopathy often have an identifiable precipitating event that can account for the increased production and/or decreased elimination of these toxins. Infections, variceal hemorrhage, renal insufficiency, electrolyte abnormalities, and increased dietary protein have all been associated with acute development of HE.

Bleeding Diathesis and Synthetic Failure

Coagulopathies signal end-stage liver disease. The liver manufactures coagulation factors essential for blood clotting and maintenance ofblood homeostasis. With advanced disease, the liver is unable to synthesize these proteins, resulting in extended

clotting times (e.g., prothrombin time) and bleeding irregularities. Thrombocytopenia is another coagulation abnormality seen in advanced liver disease. This is a result of decreased platelet production in the bone marrow (triggered by a lack of throm-bopoietin stimulation by the liver) as well as the splenic sequestration of formed platelets. Macrocytic anemia may also occur because of decreased intake, metabolism, and storage of folate and vitamin B12. In individuals who continue to drink, blood abnormalities are also aggravated further because ethanol is toxic to bone marrow.

Alcoholic Liver Disease

The course of alcoholic liver disease moves through several distinct phases from development of fatty liver to the development of alcoholic hepatitis and cirrhosis. Fatty liver and alcoholic hepatitis may be reversible with cessation of alcohol intake, but cirrhosis itself is irreversible. Although the scarring of cirrhosis is permanent, main taining abstinence from alcohol can still decrease complications and slow progression to end-stage liver disease. Continuing to imbibe ethanol speeds the advancement of liver dysfunction and its complications.

Metabolism of ethanol begins even prior to absorption, as alcohol dehydrogenase (ADH) within the gastric mucosa oxidizes a portion of ingested alcohol to acetal-dehyde. The remaining alcohol is rapidly absorbed from the GI tract, and since it is highly lipid soluble, it enters the body tissues quite easily. ADH oxidizes ethanol

in body tissues, primarily the liver, producing hypoxic damage. High levels of ethanol saturate the ADH enzyme system; when the ADH system is overwhelmed, the microsomal ethanol oxidizing system must take over the detoxification process. The microsomal ethanol oxidizing system is an inducible cytochrome P-450 (CYP 450) enzyme system; it participates in phase 1 metabolism and also produces acetaldehyde as its end product. 4,25 Acetaldehyde exerts direct toxic effects on the liver by damaging hepatocytes, inducing fibrosis, and by directly coupling to proteins, interfering with their intended actions. Metabolism of large amounts of ethanol shifts hepatic metabolic processes away from oxidation and toward reduction. These changes in metabolism account for the fatty liver, hypertriglyceridemia, and acidemia observed in alcoholic liver disease.

Less Common Causes of Cirrhosis

Genetics and metabolic risk factors mediate other less common causes of cirrhosis. These diseases vary widely in prevalence, disease progression, and treatment options.

Primary biliary cirrhosis is characterized by progressive inflammatory destruction of the bile ducts. This immune-mediated inflammation of the intrahepatic bile ducts results in remodeling and scarring, causing retention of bile within the liver and subsequent hepatocellular damage and cirrhosis. The number of patients affected with primary biliary cirrhosis is difficult to estimate because many people are asymptomatic; it is often diagnosed incidentally during a routine health care visit.

Nonalcoholic fatty liver disease (NAFLD) begins with asymptomatic fatty liver but may progress to cirrhosis. NAFLD is a disease of exclusion; elimination of any possible viral, genetic, or environmental causes must be made prior to making this diagnosis. NAFLD is directly related to numerous metabolic abnormalities. Risk factors include diabetes mellitus, dyslipidemia, obesity, and other conditions associated with increased hepatic fat.26

Hereditary hemochromatosis is an autosomal recessive disease of increased intestinal iron absorption and deposition in hepatic, cardiac, and pancreatic tissue. Hepatic iron overload results in the development of fibrosis, hepatic scarring, cirrhosis, and hepatocellular carcinoma. Hemochromatosis can also be caused by repeated blood transfusions, but this mechanism rarely leads to cirrhosis.

Wilson's disease is another autosomal recessive disease that leads to cirrhosis through protein abnormalities. The protein that is responsible for facilitating copper excretion in the bile is faulty, so copper accumulates in hepatic tissue. High copper levels within hepatocytes are toxic, and fibrosis and cirrhosis may develop in untreated patients. Those with Wilson's disease usually present with symptoms of liver and/or neurologic disease while still in their teens.

A third autosomal recessive genetic disease is ai-antitrypsin deficiency. Abnormalities in the ai-antitrypsin protein impair its secretion from the liver. ai-Antitrypsin deficiency causes cirrhosis in children as well as adults; adults usually have concomitant pulmonary disease such as chronic obstructive pulmonary disease.

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