increased.145 Other suggested etiologic agents for hepatic encephalopathy include γ-aminobutyric acid

(GABA), endogenous benzodiazepines,146 branched-chain amino acids (BCAAs) (e.g., tryptophan),147

neurotoxic short-chain fatty acids, mercaptans, phenols,148 and endogenous opiates.149

The following observations suggest that ammonia is the key mediator in hepatic encephalopathy: (a)

ammonia levels are increased in 80% to 90% of patients with the condition,150 (b) factors that

precipitate hepatic encephalopathy cause increases in ammonia levels, and (c) treatments that relieve

hepatic encephalopathy lower ammonia levels.151 Arguments against this hypothesis include the

following: (a) levels of ammonia correlate poorly with the severity of hepatic encephalopathy, (b) high

ammonia levels alone do not cause encephalopathy, (c) administration of ammonia to patients with

cirrhosis but not hepatic encephalopathy does not cause encephalopathy, and (d) treatments that reduce

ammonia levels also reduce the levels of other putative toxins.151

Clinical Features. A wide range of neurologic symptoms may occur in patients with hepatic

dysfunction. Subtle deficits may include changes in personality, memory loss, alterations in sleep

patterns, and minor decreases in intellectual function. Defects may be detectable only by detailed

psychometric testing. If no known underlying liver disease is suspected, establishing the cause of an

alteration in mental status may be difficult.

TREATMENT

Table 59-7 Treatment of Hepatic Encephalopathy

With progression of disease, asterixis, a rapid repetitive flexion–extension of the wrist that occurs in

response to sustained extension of the forearm and fingers, may occur. In addition, stigmata of liver

disease are usually evident, including fetor hepaticus and spider angiomas. The combination of asterixis,

elevated ammonia levels, and altered mental status in a patient with known liver disease strongly

suggests the diagnosis. Electroencephalographic changes are nonspecific and may occur in patients with

a variety of other conditions.

Factors that commonly precipitate hepatic encephalopathy include impaired renal function, variceal

hemorrhage, constipation, infection, excessive dietary protein, and drugs, especially benzodiazepines

and barbiturates.

Treatment. Treatment options for hepatic encephalopathy include correction of the precipitating

factors, alterations in diet, bowel cleansing, medications that reduce ammonia production and neutralize

its effects, and medications to treat possible neurotransmitter and nutrient deficiencies.

A search for precipitating factors is imperative and includes cultures of urine, sputum, and ascitic

fluid; determination of electrolyte abnormalities; screening for viral infection; assessment of overall

volume status; drug history; and endoscopy (Table 59-7).

Therapy begins with a trial of volume expansion via intravenous hydration to relieve azotemia and

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reduce concentrations of toxic substances by dilution. The mainstays of treatment are directed at the

removal of nitrogenous compounds from the gut. Most ammonia is produced within the small and large

bowels by bacterial metabolism of dietary and endogenous protein. Orally administered cathartics and

enemas are the best methods to achieve bowel cleansing. While dietary restriction of protein intake was

once a mainstay in the therapy of hepatic encephalopathy, the loss of skeletal muscle, which aids in

breakdown of ammonia, is now recognized as an important contributor to hepatic encephalopathy.

Current recommendations thus favor regular or increased protein diets along with medical therapy for

hepatic encephalopathy. Since patients with cirrhosis often manifest a deficiency of BCAAs compare to

aromatic amino acids (which worsen hepatic encephalopathy); supplementation with BCAAs has been

shown to improve the rate of recovery from episodic hepatic encephalopathy.152 L-carnitine

supplementation has also been demonstrated to improve cognitive deficits and reduce ammonia

levels.153

The cathartic of choice is lactulose, a nonabsorbable disaccharide that reaches the distal ileum and

colon essentially unmetabolized. Many theories regarding the mechanism of action of lactulose have

been proposed. Initially, the presumed mechanism of action was that on reaching the colon, lactulose is

metabolized by colonic bacteria to acidic products that lower the pH of the colon. Lowering the pH

inhibits the growth of ammonia- and urea-producing bacteria and promotes the growth of Lactobacillus,

a bacterium with little proteolytic activity.154 The validity of this theory has been questioned. It appears

now that lactulose alters the metabolism of intestinal bacteria by providing carbohydrate, which

enhances the bacterial uptake of ammonia.155 Combined with the osmotic diarrhea caused by the

cathartic activities of lactulose, this effect leads to an increased excretion of ammonia.

The dosage of lactulose, 45 to 90 g/d, is administered orally, divided into 3 or 4 doses. The dosage

can be adjusted to produce two or three soft stools daily. Hourly doses of 30 to 45 mL can be used to

induce more rapid improvement during the initial phase of therapy. Symptoms usually abate within 24

hours, but more than 48 hours may be required. Doses can be adjusted if side effects such as flatulence,

diarrhea, and electrolyte abnormalities occur.

Nonabsorbable antibiotics have also been used to decrease the number and concentration of ammoniaforming bacteria in the gut. Most experience has accrued for neomycin and metronidazole. These

antibiotics are active against gram-negative anaerobes such as Bacteroides, which are considered to be a

major source of ammonia production.156,157 The dosage of neomycin, 2 to 8 g/d, is divided into 4 doses

and is continued for 4 to 10 days. Multiple double-blinded, randomized trials have determined the

efficacy of antibiotics alone or in combination with lactulose. For acute hepatic encephalopathy, studies

have shown that neomycin for 4 days is equally as effective as lactulose,157 and metronidazole for 7

days is as effective as neomycin.158 In addition, for chronic hepatic encephalopathy, neomycin for 10

days was equal to lactulose.154

Due to the risk of nephrotoxicity and irreversible ototoxicity, neomycin therapy has fallen out of

favor.159 Rifaximin, a minimally absorbed macrolide antibiotic, was approved by the FDA in 2013 for

the maintenance therapy of hepatic encephalopathy and is now frequently used in an off-label fashion

for acute episodes as well. In a recent randomized controlled trial, the addition of rifaximin to lactulose

resulted in a higher proportion of patients experiencing complete reversal of hepatic encephalopathy

(76% vs. 50.8%) and decreased mortality (23.1% vs. 49.1%) compared to lactulose and placebo.160

Thus, based on the most current evidence, the treatment of overt hepatic encephalopathy should consist

of treatment of precipitating factors, followed by lactulose administration. Rifaximin should be added

for patients without improvement in the first 24 hours. Following an episode of overt hepatic

encephalopathy, maintenance therapy with lactulose and/or rifaximin should be administered

indefinitely for secondary prophylaxis.159

PORTAL HYPERTENSION

8 Portal hypertension is defined as a portal vein pressure above the normal range of 5 to 8 mm Hg.

Portal hypertension may also be defined by the hepatic vein–portal vein pressure gradient, which is

greater than 5 mm Hg in portal hypertensive states.161 Pressures in the portal venous system are usually

measured indirectly via the wedged hepatic venous pressure utilizing a technique similar to that used to

determine pulmonary capillary wedge pressure by pulmonary arterial (Swan–Ganz) catheterization.

Anatomy

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The venous anatomy of the portal system is relatively constant, with the “usual” anatomy present in

98% of the population (Fig. 59-5). The portal vein is formed by the confluence of the superior

mesenteric and splenic veins behind the neck of the pancreas. The inferior mesenteric vein most often

joins the splenic vein before the portal vein is formed, but approximately one-third of the time the

inferior mesenteric vein joins the superior mesenteric vein. The superior mesenteric vein may not be

present, and the portal vein may be formed by multiple small branches from the mesenteric system that

join the splenic vein.

Many branches of the portal venous system are affected when portal pressure rises. As pressure

increases, blood flow decreases and the pressure in the portal system is transmitted to its branches. This

transmission of pressure through branches of the portal system is beneficial in that it decreases overall

portal pressure. It also is responsible for many of the complications of portal hypertension, however,

because of the resulting dilation of venous tributaries.

The coronary or left gastric vein becomes highly significant in portal hypertension, by diverting

portal blood to the veins of the lesser curve of the stomach and the esophagus, leading to the formation

of varices. Other important collaterals include the inferior mesenteric vein, which connects with its

rectal branches, which, when distended, form hemorrhoids; the umbilical vein in the ligamentum teres

of the falciform ligament, which joins the left portal vein and causes abdominal wall veins around the

paraumbilical plexus to dilate (caput medusae); the short gastric veins, branches of the splenic vein,

which communicate with gastric veins and contribute to gastric varices; and the retroperitoneal veins of

Retzius, which communicate with the gastrointestinal veins through the bare areas of the liver where no

peritoneal layer separates the abdominal viscera from the retroperitoneum. The retroperitoneal

collaterals can also form large splenorenal shunts that may decompress the portal system but are

associated with severe encephalopathy.

Physiology

As in any vascular bed, portal hypertension is the product of blood flow and resistance. In nearly all

cases, portal hypertension is caused by increased resistance to portal blood flow secondary to cirrhosis,

portal vein thrombosis, or hepatic venous obstruction, though in rare instances, an arterioportal fistula

may cause flow-related hypertension. Normally, the liver offers little resistance to portal flow because

of the porous nature of the hepatic sinusoids and the capacity of the organ to expand. Moreover, the

liver has limited control over portal blood flow; it is primarily a passive recipient of splanchnic flow,

the primary regulation of which occurs at the level of the splanchnic arterioles.162 As discussed earlier,

the deposition of collagen in the space of Disse (capillarization), in addition to the contractile properties

of stellate cells, causes an increased resistance to portal blood flow in cirrhosis. In addition, various

cytokines and hormones contribute to elevated portal pressures by inducing splanchnic vasodilation and

an increase in splanchnic flow.

The increased blood flow through collateral vessels and subsequently increased venous return cause

the characteristic hemodynamic features of portal hypertension, which include an increase in cardiac

output and total blood volume and a decrease in systemic vascular resistance.163 Arteriovenous shunts

within the liver, stomach, and small intestine contribute to the augmented venous return and decreased

peripheral vascular resistance. Early in the course of portal hypertension, blood pressure may be

normal, but with progression of disease, blood pressure usually falls.164

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