potential mechanisms have been invoked to explain the cause of sodium retention and the development

of ascites in cirrhotic patients. The first is the “underfill” theory, whereby portal hypertension causes an

increase in pressure in the splanchnic circulation. Ascites occurs when hepatic lymph production exceeds

lymphatic return, with subsequent contraction of the blood volume and renal sodium retention.116 This

theory was abandoned when it was shown that patients with cirrhosis were found to have increased,

rather than decreased, plasma volume.117 The second is the “overflow” theory, which suggests that the

primary defect is inherent to the kidney. Abnormal renal retention of sodium leads to concomitant

water retention, expansion of plasma volume, and subsequently edema and ascites.117,118 The third and

most currently accepted explanation is the “arterial vasodilation hypothesis,” which suggests that the

responsible defect lies within the vascular system, with arterial hypotension as the primary event.

Arterial vasodilation in the splanchnic circulation leads to relative peripheral hypovolemia and

activation of the renin–angiotensin–aldosterone and sympathetic nervous systems. The effects, in turn,

are a release of antidiuretic hormone (arginine vasopressin), enhancement of sodium and water

conservation, an increase in effective circulating volume, and edema and ascites.119,120

The cause of the splanchnic vasodilation is unclear. Some evidence suggests that nitric oxide may be

the key mediator. Elevations in portal venous nitric oxide have been reported in both animal and human

studies,121,122 and inhibitors of nitric oxide production have been shown to reduce the activity of

vasoconstrictor systems and enhance renal hemodynamics.122 The exact role of nitric oxide activity in

the pathophysiology of renal disease in cirrhosis remains to be determined. Other studies have

demonstrated that extracellular fluid volume expansion precedes vasodilation,123 and that pathologic

activation of intrahepatic vascular sensors is the key mediator for the ensuing renal salt retention.116

Water Retention. Patients with cirrhosis and ascites may have a marked inability to handle free water.

An increased production of antidiuretic hormone, decreased delivery of fluid to the diluting segments of

the nephron, and reduced renal production of prostaglandins all may contribute.117 Retention of water

leads to dilutional hyponatremia (serum sodium 130 mEq/L), which can cause nausea, vomiting,

lethargy, and seizures.124

6 Hepatorenal Syndrome. HRS is a complication of cirrhosis, most often with ascites, characterized by

progressive renal failure in the absence of intrinsic renal disease. Renal dysfunction is thought to occur

in up to 20% of patients hospitalized with cirrhosis and ascites.125 In a large study of two major Spanish

centers, HRS developed in 7.6% of patients admitted for the management of ascites.126 Manifestations

of the disease include progressive oliguria, with urine outputs of 400 to 800 mL/d, a rising serum

creatinine level, increased cardiac output, and decreased arterial pressure. The disease process is highly

variable and is associated with marked renal cortical vasoconstriction induced by activity of the renin–

angiotensin–aldosterone and sympathetic nervous systems. In addition, the powerful endotheliumderived vasoconstrictor endothelin-1, combined with decreased renal production of vasodilator

prostaglandins, may play a role.

HRS may develop as a result of infection, use of nonsteroidal anti-inflammatory drugs, variceal

hemorrhage, or excessive diuretic use in patients who were previously well compensated. The

differentiation of HRS from acute renal failure is possible by the laboratory evaluation of urine and

serum samples. HRS, however, is virtually indistinguishable by laboratory testing from prerenal

azotemia. Both prerenal azotemia and HRS are characterized by extremely low sodium concentrations in

the urine, high urine osmolality, high urine-to-plasma ratios of creatinine, and normal urinary sediment

(Table 59-5). Criteria for the diagnosis of HRS are listed in Table 59-6.

DIAGNOSIS

Table 59-6 Diagnostic Criteria for Hepatorenal Syndromea

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The treatment of ascites in patients with cirrhosis requires sodium and water restriction in addition to

the use of diuretics. Excessive use of these treatment modalities may lead to increases in serum

creatinine that can be difficult to distinguish from those of HRS. A failure to respond to cessation of

diuretics and fluid challenge suggests HRS. If liver transplantation cannot be performed, patients with

HRS usually die within months of the development of severe disease, defined as a serum creatinine level

above 2 mg/dL.113

Management of HRS hinges on a three-pronged approach. First is treatment of the triggering event.

The most common inciting factor is spontaneous bacterial peritonitis, followed by volume contraction

(from multiple etiologies including gastrointestinal bleeding or the overzealous treatment of ascites).

Over 70% of cases of acute HRS have been linked to bacterial infections.127 The other two cornerstones

of HRS treatment are vasoconstrictors and volume expansion with albumin. The vasopressin-analog

terlipressin is commonly used outside the United States. The oral vasopressor midodrine is commonly

used in the United States, where terlipressin is not approved by the FDA. Others have examined

norepinephrine as a substitute for terlipressin.127 A meta-analysis of all randomized controlled trials of

vasopressor use in the treatment of HRS has found a reduction in all-cause mortality when vasopressors

are utilized.128 Although advances in medical therapy have made the reversal of HRS possible in some

patients, many will ultimately require liver transplantation in order to survive.

Pulmonary

Many pathologic processes in patients with cirrhosis affect pulmonary function. Some reflect an

underlying condition that causes both hepatic and pulmonary diseases (i.e., cystic fibrosis, α1

-antitrypsin

deficiency); others are primary pulmonary processes, such as interstitial lung disease, primary

pulmonary hypertension (portopulmonary hypertension [POPH]), and obstructive airway disease. Three

main pulmonary manifestations of cirrhosis are discussed here; one is related to increased intraabdominal pressure secondary to ascites, one is caused by intrapulmonary shunting and is known as the

hepatopulmonary syndrome (HPS), and the last is POPH.

The presence of copious ascitic fluid can lead to pulmonary dysfunction by compromising

diaphragmatic excursion secondary to increases in intra-abdominal and intrapleural pressures. Ascites

may also induce large pleural effusions known as hepatic hydrothorax because of the presence of

lymphatic transdiaphragmatic communications between the abdomen and thorax.129 These small

diaphragmatic defects are typically found on the right side of the body. Effusions can compress the

pulmonary parenchyma and impair gas exchange, so that ventilation–perfusion mismatch and

hypoxemia develop. Patients present with worsening pulmonary symptoms in the setting of increasing

abdominal girth. Pulmonary function testing reveals decreases in functional residual capacity and total

lung capacity.130 Marked improvement in pulmonary function results from medical management of

ascites, large-volume paracentesis, and thoracentesis.131,132 These interventions decrease the work of

breathing and relieve symptoms. With control of ascites, even in the presence of pleural effusions, no

other interventions may be necessary. For patients refractory to the above measures, second- and thirdline strategies such as TIPS, indwelling pleural catheter placement, and pleurodesis have been described,

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although liver transplantation should be pursued in these patients for definitive management.132

HPS occurs in patients with mild to severe hepatic disease and in approximately 10% to 50% of

patients with hepatic dysfunction.133,134 Diagnostic criteria for HPS in patients with cirrhosis include

PaO2 <80 mm Hg or A–a gradient over 15 mm Hg in patients under 65 years old. The A–a gradient

cutoff for patients over 65 is 20 mm Hg.135 Other manifestations include platypnea (increased shortness

of breath with movement from a supine to an erect position) and orthodeoxia (decreased oxygen

tension on moving from a supine to an erect position). These two positional deficits in pulmonary

function are related to the increased number of dilated capillaries in the basal areas of the lung; flow is

increased in these vessels while the subject is standing, so that shunting is increased. Physical findings

include clubbing and cyanosis of the nail beds and spider angiomata.

Although the underlying cause of hypoxemia in these patients is right-to-left intrapulmonary shunting,

ventilation–perfusion mismatch and impaired hypoxic vasoconstriction also play a role. Patients usually

present with dyspnea and worsening hypoxemia without evidence of a primary pulmonary process.

Initial diagnostic tools include pulse oximetry and arterial blood gas analysis. When significant

hypoxemia is found, pulmonary function testing is useful to rule out obstructive or restrictive airway

disease. A definitive diagnosis can be obtained by the use of contrast-enhanced echocardiography

(bubble study) or technetium-macroaggregated albumin (MAA) scanning, which will confirm the

presence of intrapulmonary vascular dilation.136,137 Contrast echocardiography is the most sensitive test,

whereby intrapulmonary vascular dilation is demonstrated by a late appearance of microbubbles in the

left heart three to six cardiac cycles after injection.138 MAA scanning is complementary to contrast

echocardiography in the setting of coexisting intrinsic lung disease with severe hypoxemia, where MAA

shunting of >6% suggests HPS as the major contributor to hypoxemia.139 The only effective therapy for

this disease is orthotopic liver transplantation, and those with HPS and with a PaO2 <60 mm Hg

receive extra priority at listing.138

POPH is defined as a mean pulmonary arterial pressure of greater than 25 mm Hg, pulmonary artery

occlusion pressure <15 mm Hg, and pulmonary vascular resistance >240 dyn/s/cm−5 on right heart

catheterization in the setting of documented portal hypertension.135 It is a relatively rare (<10%)

complication of cirrhosis that, when severe, carries a substantial risk of mortality and is a relative

contraindication to liver transplantation.140,141 Screening of patients with cirrhosis by Doppler

echocardiography will reveal evidence of elevated right heart pressures, which need to be confirmed by

right heart catheterization. Although the high flow state of cirrhosis can elevate right-sided pressures,

fixed obstruction of the pulmonary microcirculation is highly lethal and is not likely to improve with

liver transplantation. The exact pathophysiology behind POPH is not known, but portal hypertension is

a necessary component of the disease process. The hyperdynamic state in portal hypertension may be

the main contributory factor, although the severity of POPH does not correlate with the severity of

portal hypertension.142 Treatment with prolonged intravenous infusion of prostaglandins has been

shown to be effective in improving pulmonary hemodynamics but does not prolong survival.141 The

most commonly used drugs in POPH are oral endothelin receptor antagonists such as bosentan and

ambrisentan. As stated above, severe POPH (mPAP >50 mm Hg) is an absolute contraindication to

liver transplantation. For patients in whom medical therapy can maintain mPAP under 35 mm Hg and

PVR under 400 dyn/s/cm−5, priority listing for liver transplantation is available.143

Hepatic Encephalopathy

7 Etiology. Hepatic encephalopathy is a neuropsychiatric syndrome that occurs in the setting of hepatic

disease. It is characterized by variable alterations in mental status, ranging from deficits detectable only

by detailed psychometric tests to confusion, lethargy, and ultimately frank coma. The disease may

present in association with acute hepatic failure, as a consequence of progression of chronic liver

disease, or after the creation of a surgical portosystemic shunt. Usually, a precipitating cause, such as an

acute variceal hemorrhage or infection, can be found.

The causative agent in hepatic encephalopathy has been the subject of much debate. Most evidence

implicates ammonia in the development of this condition. Ammonia is produced during the bacterial

digestion of proteins in the gut, is absorbed into the portal circulation, and usually undergoes extensive

degradation in the liver.144 Most researchers believe that encephalopathy is caused by products, such as

ammonia, derived from the gastrointestinal tract that are usually metabolized by the liver. These agents

reach the peripheral circulation as a result of poor hepatic metabolism or through portosystemic shunts

that may be physiologic or the result of surgical procedures. In patients with cirrhosis, in addition to the

accumulation of ammonia in the blood, the permeability of the brain to ammonia appears to be

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