Figure 59-11. Interposition mesocaval shunt. A plastic prosthesis or an autogenous internal jugular vein is used for the shunt. One

end is anastomosed to the inferior vena cava, and the other end is anastomosed to the trunk of the superior mesenteric vein. The

shunt curves around the lower edge of the third portion of the duodenum and is sometimes called a C-shunt.

Advantages to this procedure are the following: (a) control of bleeding is excellent in more than 90%

of patients, (b) no dissection of the porta hepatis is required, (c) hepatopetal flow is maintained, and (d)

the incidence of encephalopathy (5% to 24%) and the risk of progressive liver failure are lower.251

Experience with this shunt has revealed that most patients have hepatopetal flow, with 84% of alcoholic

and 90% of nonalcoholic patients having prograde flow at 4 years after surgery.252 Some loss of

prograde portal flow does occur as a result of either portal vein thrombosis (approximately 10% of

patients) or increased flow through collaterals located along the pancreas. This latter mechanism can be

prevented by complete dissection of the splenic vein from the posterior aspect of the pancreas

(splenopancreatic disconnection),253 but this additional technique adds to the complexity of the

operative procedure and to the incidence of complications.

The distal splenorenal shunt is relatively contraindicated in patients with significant ascites. Because

no portal venous decompression occurs, ascites may increase after a distal splenorenal shunt is created.

In addition, ligation of collateral vessels and lymphatics during the procedure contributes to increased

portal pressures and subsequent increase in ascites. Patients with small splenic veins (<8 mm) have a

relatively high incidence of shunt thrombosis.

Several trials comparing side-to-side total shunts with the distal splenorenal shunt found that they are

equally effective (>90%) in stopping variceal hemorrhage.254 The incidence of hepatic encephalopathy

is lower after the distal splenorenal shunt, with rates of 36% and 15% for the total and selective shunts,

respectively. Rates of rebleeding were similar and ranged from 0% to 30%, with no survival advantage

for either procedure.

1524

Figure 59-12. Small-diameter interposition portacaval Sarfeh shunt. A vascular prosthesis measuring 8 to 10 mm in diameter is

interposed between the side of the vena cava and the side of the portal vein. The goal is to reduce portal pressure partially and

thereby prevent variceal hemorrhage but still maintain sufficient pressure to permit the prograde flow of portal blood to the liver.

This procedure is simpler to perform than that for the Warren shunt and theoretically avoids the problem of diversion of an

increasing proportion of portal blood away from the liver over time, as occurs with the Warren shunt.

Figure 59-13. Distal splenorenal Warren shunt. The splenic vein is divided near its junction with the superior mesenteric vein. The

distal end of the splenic vein is anastomosed to the renal vein. Varices are selectively decompressed through the stomach and short

gastric veins into the splenic vein and then into the vena cava through the renal vein. Portal hypertension is maintained in the

portal and superior mesenteric veins to provide enough pressure to drive portal blood through the diseased liver.

1525

Figure 59-14. Transection and reanastomosis of the distal esophagus with the stapling device to control variceal hemorrhage. A: A

stapling device is inserted through a small gastrotomy incision. B: When the device is fired, the esophagus is simultaneously

transected and reanastomosed with staples. C: If the device fires correctly, a complete ring of esophageal tissue is excised.

Investigators have also used the side-to-side nonselective total shunt for the emergency treatment of

bleeding varices. Bleeding stopped in more than 90% of patients with medical therapy alone, although

bleeding often restarted shortly thereafter. Bleeding stopped in all patients after surgery, and 99% of

patients were completely free of episodes of rebleeding. The 5-year survival was approximately 80%,

with the majority of deaths occurring during the first year after surgery as a result of progressive

hepatic failure. Hepatic encephalopathy requiring recurrent intervention, including dietary restriction

and lactulose or neomycin therapy, occurred in 8% of patients. These data support an aggressive,

systematic approach to caring for these patients before, during, and after surgery, though most of these

patients had alcoholic liver disease, which recovers rapidly with withdrawal of the alcohol.

Devascularization Procedures. Devascularization procedures are nonshunting techniques in which the

venous drainage of the stomach and esophagus is disconnected from the liver and intestinal vessels.

These procedures are relatively less technically demanding than shunting procedures and can be

performed in patients with extensive portal thrombosis who preclude other options. They do not

interfere with hepatopetal blood flow and therefore do not increase the incidence of hepatic

encephalopathy.

The procedures range in complexity from simple esophageal transection and reanastomosis with an

end-to-end anastomosis (EEA) stapler combined with ligation of the coronary vein (Fig. 59-14) to the

Sugiura procedure (Fig. 59-15). The Sugiura procedure requires both abdominal and thoracic incisions,

through which a splenectomy, devascularization of the proximal stomach and esophagus, transection of

1526

the esophagus with reanastomosis, and ligation of all gastroesophageal collaterals are performed.255 The

latter procedure can also be performed via a single abdominal incision.256 Bleeding recurs in fewer than

5% of patients in Japan, but rates of rebleeding range from 10% to 54% in other countries.257 Operative

mortality rates range from 10% to 35% and outcomes are certainly related to the severity of liver

disease. In our practice, these procedures are not used in patients with liver disease, but exclusively in

patients with diffuse portomesenteric thrombosis, in whom decompressive shunts cannot be made.

Figure 59-15. Sugiura esophageal transection and devascularization operation.

Hepatic Transplantation. Liver transplantation is the definitive therapy for portal hypertension and

cirrhosis and the complications thereof, but is indicated for the overall management of end-stage liver

disease and has no role in the control of acute variceal bleeding. When successful, transplantation treats

both the underlying disease and any acute complication.

In conclusion, open surgical intervention short of liver transplantation for patients with cirrhosis and

portal hypertension is becoming a rarity. With the advent of TIPS, the indications for surgically created

shunts are dwindling. Although some studies have shown an increased need for reintervention in

patients who have undergone TIPS for variceal bleeding, the overwhelming efficacy and safety of TIPS

has essentially settled the issue and today, even in large liver centers, open portal decompressive

procedures are rarely performed.

Current guidelines recommend nonselective beta blockade at the maximally tolerated dose for

secondary prophylaxis, followed by serial EVL until all varices are obliterated. Patients should then

undergo surveillance EGD every 6 to 12 months to evaluate for recurrent varices. TIPS should be

reserved for Child A or B patients who bleed again despite combination medical and endoscopic

therapy. Shunt surgery remains an option for good risk Child A patients. Those patients who are

candidates should be referred to a transplant center for timely evaluation.198

Gastropathy and Gastric Varices. Approximately 10% of patients with esophageal varices also have

gastric varices. Conversely, about 90% of patients with gastric varices have esophageal varices.197

Bleeding from gastric varices occurs in approximately 25% of affected patients and is usually more

severe than bleeding from esophageal varices. Rebleeding occurs in up to 30% of patients after an initial

bleed.258 The same pharmacologic interventions used for esophageal varices are used to treat gastric

varices. However, sclerotherapy and EVL have proven relatively ineffective for bleeding gastric varices,

and endoscopic variceal obliteration with tissue adhesives such as N-butyl-cyanoacrylate or isobutyl-2-

cyanoacrylate has shown better rates of initial hemorrhage control and prevention of recurrent

bleeding. A large randomized controlled trial demonstrated better prevention of rebleeding following

acute gastric variceal hemorrhage with N-butyl-cyanoacrylate compared to EVL.259 Balloon tamponade

may also be used as a temporizing measure while arrangements for definitive therapy are made. TIPS is

the primary therapy for controlling gastric varices in patients who fail or cannot receive endoscopic

therapy, with bleeding control rates of over 90% reported.198 The distal splenorenal shunt is reserved

1527

for the rare patient who cannot receive TIPS.

Portal hypertensive gastropathy is a condition characterized by dilation of the venules and capillaries

of the gastric mucosa without associated inflammation. The major complication of gastropathy is

bleeding; gastropathy accounts for 4% to 38% of all episodes of acute bleeding in patients with

cirrhosis.260 TIPS may provide therapeutic decompression in this setting as well.

Ascites

One of the most important consequences of hepatic dysfunction in cirrhosis and portal hypertension is

ascites. This development portends a significant worsening of the patient’s condition, with markedly

decreased survival rates. Ascites is defined as the accumulation of free fluid within the abdominal cavity

(normally <150 mL). Causes of ascites are listed in Table 59-12. In cirrhosis, the fluid is derived from a

combination of hepatic (high in protein) and splanchnic (low in protein) lymphs that cannot be absorbed

as a result of the increased hydrostatic pressures within the liver and splanchnic systems secondary to

cirrhosis and capillarization of the space of Disse.261 Because of the loss of sinusoidal fenestrations and a

subsequent decrease in their permeability, splanchnic lymph is more abundant than hepatic lymph in

patients with advancing cirrhosis, so that the protein content of ascitic fluid is relatively low.262 The

main underlying pathophysiology in the development of ascites is renal sodium retention and associated

water retention, which lead to fluid overload. Peripheral vasodilation and lower pressures are thought

to be secondary to the dilator effects of nitric oxide, glucagon, and prostaglandins on nascent

arteriovenous shunts present throughout the splanchnic vascular system, as well as in muscle, skin, and

brain. The severity of liver disease is not uniformly correlated with the presence or absence of ascites.

DIAGNOSIS

Table 59-12 Differential Diagnosis of Ascites

Clinical and Laboratory Features. Ascites may be present in patients with cirrhosis who have no other

overt signs or symptoms. Patients may present with subtle signs of weight gain and an inability to fit

into clothes. Physical examination reveals shifting dullness to percussion (1.5 L of ascitic fluid), fluid

waves (10 L), and bulging flanks.263 With progression of disease and massive ascites, respiratory status

may be compromised secondary to increased intra-abdominal pressure and pleural effusions, which are

often present and usually located on the right side. The progression may be slow or more rapid after an

inciting event, such as a variceal bleed or infection.

Stigmata of poor liver function include peripheral muscle wasting, palmar erythema, spider angiomas,

peripheral edema, a palpable liver, and caput medusae (dilated periumbilical veins). With progressive

ascites and increased abdominal pressure, umbilical and inguinal hernias often develop and may be

difficult to manage. Abdominal distention may be caused by gastrointestinal gas rather than ascites. Gas

can be differentiated from fluid by eliciting hyperresonance to percussion, secondary to gas, as opposed

to dullness with fluid. The most widely used test for the diagnosis of ascites is ultrasonography, which

1528

can also be helpful in determining the best location for therapeutic and diagnostic paracentesis.

Diagnostic Paracentesis. The differential diagnosis of ascites is presented in Table 59-12.

Determination of the character of the ascitic fluid is helpful in establishing the diagnosis. Paracentesis

may be performed in the midline, midway between the umbilicus and the pubic symphysis. The fluid

from patients with cirrhosis is usually straw colored and clear; measurements of protein (usually <2

g/dL), quantitative cell counts, and microbiologic culture and determination of pH, amylase, glucose,

and albumin levels should be obtained. The serum-to-ascitic fluid albumin gradient (SAG) is calculated

by subtracting the albumin concentration in ascites from the level found in serum. This gradient is

helpful in determining the cause of ascites; high values (>1.1 g/dL) are generally associated with portal

hypertension, whereas lower levels may be associated with other disorders, including malignancy.264

Treatment. Initial therapy is usually directed at control of renal sodium and water retention, with bed

rest and dietary manipulation. The upright position exacerbates sodium retention as a result of venous

pooling and relative hypovolemia. Up to 15% of patients respond to this therapy alone with a

natriuresis. A low-sodium diet is a critical part of the management of patients with cirrhosis (1 to 2 g of

sodium per day or 45 to 90 mEq/d). A major problem with a strict low-sodium diet is lack of

palatability and poor compliance. Fluid restriction is also an essential component of therapy in patients

in whom hyponatremia develops (sodium concentration <125 mEq/L), with only 1,000 to 1,500 mL of

fluid allowed each day.

For the 85% to 95% of patients who do not respond to bed rest and fluid and salt restriction, the

mainstay of treatment is diuresis (Table 59-13). The loop diuretic furosemide and the potassium-sparing

diuretic spironolactone are the two most widely used agents, and they can be combined to minimize

side effects and maximize effectiveness. A ratio of 40-mg furosemide to 100-mg spironolactone

generally maintains potassium homeostasis. A diuresis of approximately 500 mL/d is the goal for

patients with mild ascites and of up to 1 to 2 L/d for patients with both ascites and peripheral edema.

More than 90% of patients respond to the combination of dietary manipulation and diuretics.263,265

Complications of the use of spironolactone include painful breast enlargement in males,

hyperkalemia, and metabolic acidosis. Complications of the more potent furosemide include prerenal

azotemia, which occurs in approximately 20% of patients as a result of excessive diuresis and

hypovolemia.274 Additional complications include hyponatremia and encephalopathy.

Large-volume paracentesis (removal of 4 to 6 L of ascitic fluid per day) and total paracentesis are

techniques that can be used for patients with large amounts of fluid who are experiencing symptoms

and are not responding to the aforementioned therapeutic endeavors. Patients requiring paracentesis

usually have severe underlying liver disease and a 1-year survival rate of 25%.266 The technique of

paracentesis involves placing a catheter into the abdominal cavity, either in the lower midline or in one

of the lower quadrants. Care is taken to enter lateral to the rectus muscle and avoid the inferior

epigastric artery. More than 30 L of fluid can be removed by means of total paracentesis, with 6 to 10 g

of albumin infused intravenously for each liter of ascitic fluid removed.263,265,266 The albumin

commonly is administered in the form of 25% albumin (12.5 g/50 mL). Controversy exists regarding

the need for albumin replacement therapy in patients undergoing total paracentesis and repetitive largevolume paracentesis. Patients who have less than 5 L of ascitic fluid removed do not require albumin

replacement.267

TREATMENT

Table 59-13 Treatment of Ascites

1529

The efficacy of paracentesis in the treatment of tense ascites has been studied extensively. Repetitive

large-volume paracentesis has been shown to be as effective as diuretics in the treatment of moderate to

severe ascites, with fewer systemic complications. A decreased length of hospital stay with no increase

in the incidence of spontaneous bacterial peritonitis has been noted.268 Paracentesis has become the

therapy of choice for severe ascites.

Peritoneovenous shunts are surgically placed tubes that connect the peritoneal cavity with the

superior vena cava via the internal jugular vein (Fig. 59-16). The two main types are the LeVeen shunt

and the Denver shunt, both of which have a one-way valve that allows unidirectional movement of

ascitic fluid from the peritoneal cavity into the systemic circulation. Although these shunts are effective

in decreasing the volume of ascitic fluid, a significant number of major complications have been noted,

including disseminated intravascular coagulation, heart failure, and sepsis,266,269 and associated

mortality rates are high (approximately 20%).270 The shunt is occluded in approximately 50% of

patients at 1 year, and no improvement in survival is noted.266 The use of these shunts has drastically

decreased with the development of the TIPS procedure. In addition to the use of TIPS, the placement of

peritoneovenous shunts is now done percutaneously, further increasing the safety of these procedures.

Surgically created portosystemic shunts have been used in the past for the treatment of ascites.

Because of high morbidity and mortality rates, an increase in encephalopathy and progression to liver

failure, and the addition of the TIPS procedure to treatment options, surgically created shunts are now

used infrequently for this indication alone. As discussed earlier, the TIPS is a total nonselective shunt

that decompresses the portal system and reduces pressure at the hepatic sinusoids, thereby eliminating

the drive for the production of ascitic fluid. In a study evaluating the use of TIPS for the treatment of

medically refractory ascites, the ascites resolved completely in almost 75% of patients, and a partial

response was noted in an additional 20%.271 In addition, renal function improved during the 6 months

of follow-up. TIPS in this group of patients, however, was associated with an increase in the number of

cases of encephalopathy. Although survival appears to be unaffected by a TIPS procedure when

compared with large-volume paracentesis, TIPS may simplify the management of the patient while on

the transplant waiting list.

1530

 

critically reducing liver perfusion, which may cause hepatic dysfunction and may accelerate the

progression of cirrhosis. It is possible to readily measure the portal pressure during TIPS, and many

authors have proposed these measurements as a guide to optimal management of the TIPS to balance

control of bleeding with hepatic perfusion. To control bleeding, the therapeutic goal is to reduce the

hepatic–portal venous pressure gradient to below 12 mm Hg. TIPS reduces the portosystemic pressure

gradient to a mean of approximately 9 to 15 mm Hg (average, 10 mm Hg) or to 40% to 62% below

baseline.239–241 A residual portal gradient less than 5 mm Hg has been associated with a deleterious

impact on hepatic flow.242 Earlier studies documented high mortality (40% to 60% at 6 to 7 weeks)

despite the relative noninvasiveness of the procedure, reflecting the gravity of the clinical condition of

most patients requiring this intervention. One potential cause of the high mortality is a delay in

instituting TIPS until multiple unsuccessful attempts at sclerotherapy or banding have been made. Since

well-validated instruments predict the survival of patients after TIPS, the procedure should be used with

caution in patients with high MELD scores, though TIPS has been used successfully to bridge patients to

transplantation.243,244 The use of TIPS in massive variceal bleeding in a patient with a high MELD score

who has contraindications to liver transplant should be regarded as a palliative intervention.

Algorithm 59-1. Suggested treatment options, in order of preference, for patients who fail medical management for variceal

bleeding.

1520

Figure 59-8. Schematic representation of the steps used to create a transjugular intrahepatic portosystemic shunt. A: A needle is

directed from the IVC or hepatic veins into an intrahepatic portal venous branch. B: A guidewire is advanced into the portal

venous system. C: The resulting tract is then balloon dilated. D: A stent is then placed into the dilated tract. E: Completed TIPS

shunt. Arrows indicate direction of blood flow.

As with all portosystemic shunts, a significant complication of TIPS is the development of hepatic

encephalopathy. The rate of hepatic encephalopathy following TIPS is 34%, compared to 19% following

EVL for acute variceal bleeding, although the use of covered stents has reduced the rate of post-TIPS

encephalopathy from when bare metal stents were used primarily.245,246 Although in early series

stenosis or occlusion of the stent developed in up to 50% to 60% of patients in the first year, long-term

patency can be maintained by ongoing surveillance of the shunt with redilatation, as needed. Shunt

stenosis is managed angiographically with thrombolytic therapy, dilation, or replacement of the stent.

The newest shunts are lined with polytetrafluoroethylene (PTFE) and have a much higher patency than

the original permeable wallstents. Primary patency rates are 76% to 89% with shunt dysfunction

occurring in only 15% of patients at 1 year.236 Patients are usually followed at 3-month intervals by

ultrasonography to assess the patency of the shunt. At 6 months of follow-up, 92% of patients had had

no episodes of rebleeding, and 82% were free of hemorrhage at 1 year. It is safe to assert that the TIPS

is now the standard procedure used to halt bleeding in patients who fail medical therapy. The ability to

effectively decompress the portal circulation without open surgery in these critically ill patients has

transformed clinical hepatology. Patients become medically stable and can be evaluated for

transplantation electively. Patients with reversible liver disease (e.g., abstinent alcoholics) may recover

fully without further intervention because the TIPS will slowly close as the liver heals.

Surgical Decompression

Background. Surgeons have been performing shunt procedures since the 1800s. The first was an end-to1521

side portacaval shunt with ligation of the distal portal vein, performed by Nicolai Eck (Eck fistula) in

dogs. In 1945, Whipple247 at the Columbia-Presbyterian Medical Center in New York performed this

shunt for the first time for the indication of variceal bleeding. This group was also responsible for the

development of the tube for the tamponade of bleeding esophageal varices, which adopted the name of

Blakemore, as discussed previously.

11 Surgical interventions for the treatment of bleeding varices are divided into three main types: (a)

liver transplantation, (b) shunt procedures, and (c) devascularization procedures. The only definitive

procedure for the treatment of portal hypertension caused by cirrhosis is orthotopic liver

transplantation, and the success of this option during the past two decades has revolutionized the

treatment of portal hypertension and its complications in patients with end-stage liver disease.

However, for the treatment of portal hypertension in patients without cirrhosis or in those whose liver

function does not warrant a transplant (e.g., patients with portal vein thrombosis), decompressive

surgically created shunts or devascularization procedures may be performed.

Shunts. Portosystemic shunts created operatively can be divided into three categories: (a) totally

diverting (nonselective) shunts, (b) partially diverting shunts, and (c) selective shunts. Total shunts are

created by completely bypassing the flow of blood away from the liver by joining the portal vein to the

vena cava. Examples include the end-to-side portacaval shunt (Eck fistula) (Fig. 59-9) and the largediameter (>10-mm) side-to-side portacaval (Fig. 59-10), mesocaval, and central splenorenal shunts.

Because the pressure in the portal vein is much higher than that in the vena cava (or the renal vein),

large side-to-side shunts divert all blood flow through the path of least resistance, so that flow in the

portal vein is reversed, creating “hepatofugal” flow, out of the liver and decreasing total hepatic

perfusion. One of the causes of ascites in patients with portal hypertension is high pressure at the level

of the hepatic sinusoids with protein-rich fluid leaking directly out of the swollen liver. The main

difference between end-to-side and side-to-side shunts is that maintenance of high pressure with end-toside shunts may worsen ascites, whereas side-to-side procedures effectively relieve this problem by

reducing sinusoidal pressure. Complete portal blood flow diversion lowers portal pressure and is highly

effective in the treatment of bleeding esophageal varices but, as noted earlier, may accelerate hepatic

decompensation.

Figure 59-9. End-to-side portacaval shunt, also referred to as an Eck fistula. The portal vein is divided, the hepatic limb of the

portal vein is ligated, and the splanchnic end of the portal vein is anastomosed end to side to the vena cava. All portal blood is

necessarily diverted into the vena cava, and the hepatic limb of the portal vein cannot serve as an outflow tract.

The main complications of totally diverting shunts are a worsening of liver function and hepatic

encephalopathy as a result of decreased flow through the liver and loss of hepatotropic factors from the

mesenteric venous system. Another disadvantage of portacaval shunts is that the porta hepatis must be

dissected, so that future surgical procedures in the area (e.g., liver transplantation) are more difficult.

1522

Partially diverting shunts allow for the maintenance of hepatopetal flow while decompressing the

high pressures in the portal system. The original shunts were larger than 10 mm in diameter and were

able to create a gradient between the portal vein and vena cava that maintained some prograde hepatic

flow. All these shunts, however, dilated over time and became complete shunts in that the portal vein to

inferior vena cava pressure gradient disappeared. The small-diameter (8-mm) side-to-side mesocaval

(Fig. 59-11) and portacaval (Sarfeh) (Fig. 59-12) shunts are performed with an interposition graft made

of either expanded PTFE or dacron. A significant component of the Sarfeh procedure is ligation of the

coronary (left gastric), gastroepiploic, and other collateral veins. Bleeding from varices resolves in more

than 90% of patients.248,249 This smaller-diameter shunt has a higher resistance than the larger shunt, is

synthetic and therefore does not dilate, can maintain hepatic perfusion, and is associated with a lower

incidence of hepatic encephalopathy. With these shunts, portal pressure gradients can be reduced to the

critical 12 mm Hg while hepatopetal flow is maintained in up to 80% to 90% of patients. In addition,

the maintenance of mesenteric pressure at or relatively close to normal levels may prevent the

hyperammonemia associated with total shunts. One relatively common complication is graft thrombosis,

which occurs in up to 16% of patients.249 Shunt thrombosis can usually be treated angiographically.

Dissection at the porta hepatis leads to the formation of adhesions, which may compromise later liver

transplantation.

Figure 59-10. Side-to-side portacaval shunt. An anastomosis is made between the side of the portal vein and the side of the

inferior vena cava. With a shunt of standard diameter, almost all splanchnic blood is diverted around the liver into the lowpressure vena cava. The hepatic limb of the portal vein serves as an outflow tract from the liver toward the low-pressure vena

cava.

Selective shunts are designed to create two separate drainage systems within the portal venous

network. A high pressure is maintained within the mesenteric system and a low pressure is created in

the esophagogastric system by shunting blood from the latter into the systemic circulation without

decompressing the mesenteric network. The most traditional and most favored selective shunt is the

distal splenorenal shunt (Fig. 59-13).250 The distal splenorenal shunt selectively decompresses the

gastroesophageal venous system through an anastomosis between the distal end of the splenic vein and

the side of the renal vein. Decompression occurs through the short gastric veins, which are in continuity

with the splenic vein. In addition, as in the small side-to-side shunts described earlier, collateral veins

must be ligated.

1523

 

clinical support for the notion that portal diversion accelerated the decline of liver function in patients

with cirrhosis and they are no longer performed for this indication.

Endoscopic Sclerotherapy and Variceal Ligation. In the past, prophylactic sclerotherapy to prevent

variceal bleeding was an accepted practice but technical challenges and esophageal and pulmonary

complications have led to abandonment of endoscopic sclerotherapy (ES) for the primary prevention of

variceal bleeding. Initial investigations of the effectiveness of endoscopic variceal ligation (EVL) as a

method of primary prophylaxis to prevent initial bleeding in high-risk patients with esophageal varices

reported mixed results.218,219 In one study, no statistically significant differences in the incidence of

initial bleeding and mortality were found in a comparison of patients after variceal ligation with

controls,220 though subgroup analysis revealed a significant decrease in the incidence of initial bleeding

for Child–Pugh class B patients.219 Furthermore, there seems to be a significant prognostic divergence

related to variceal size. As data have accumulated, consensus recommendations regarding prophylaxis

have emerged as presented in recent practice guidelines from the AASLD. Briefly summarized, patients

with cirrhosis with small, low-risk varices should be managed with beta-blocker prophylaxis. In those

with medium or large varices with high-risk features (Child B or C, red wale markings), either EVL or

beta blockade is acceptable primary prophylaxis. In the absence of the above high-risk features, beta

blockade is preferred, with EVL reserved for those patients who have contraindications to, or are

intolerant of beta blockers.198

Treatment of Esophageal Variceal Bleeding

Initial Management. Initial management of the patient with acute variceal bleeding includes the

following: (a) establishment and maintenance of an airway; (b) hemodynamic monitoring; (c)

placement of large-bore intravenous lines; (d) full laboratory investigation, including measurement of

hemoglobin and hematocrit, coagulation profile, liver function tests, measurement of electrolytes, and

assessment of renal function; (e) administration of blood products as needed, including packed red cells,

platelets, and fresh frozen plasma; and (f) intensive care unit monitoring. Hemoglobin concentration

should be maintained around 8 g/dL.221,222 Transfusion to higher hemoglobin concentrations has been

associated with higher portal pressure and worse outcomes. Furthermore, as gastrointestinal bleeding is

associated with a high risk of subsequent spontaneous bacterial peritonitis in patients with cirrhosis, a 7-

day course of antibiotics (typically a quinolone such as norfloxacin or ciprofloxacin) is also

recommended as standard therapy for acute variceal bleeding.223

Pharmacologic Therapy. The administration of vasoactive medications can be commenced almost

immediately after patient presentation if the history and physical findings suggest variceal bleeding.

This practice decreases the rate of bleeding and enhances the endoscopic ability to visualize the site(s)

of bleeding.

Vasopressin (antidiuretic hormone) has potent splanchnic vasoconstrictive properties that decrease

portal venous and collateral flow and reduce portal pressure. In randomized prospective trials, as well

as in a meta-analysis, continuous intravenous administration of vasopressin has proved to reduce

variceal bleeding, an observation initially made in 1962.224–226 When vasopressin was compared with

placebo, bleeding stopped in an average of 52% of patients who received vasopressin and 18% of

patients who received placebo. Rates of rebleeding as high as 45% were noted, however. Because of

coronary vasoconstrictive effects, vasopressin is often used in combination with a vasodilator, such as

nitroglycerin. The combination provides protection from adverse cardiac events and increases the

effectiveness of vasopressin by decreasing intrahepatic and collateral resistance.227 A meta-analysis of

three randomized controlled trials confirmed the increased effectiveness of vasopressin and

nitroglycerin in comparison with vasopressin alone.228

Somatostatin and octreotide, its longer-acting eight-amino acid derivative, have been used extensively

for the treatment of variceal bleeding. These agents decrease splanchnic blood flow indirectly by

reducing the levels of other factors, such as glucagon, vasoactive intestinal peptide, and substance P,

rather than by direct vasoconstriction.229 The effects of somatostatin are limited to the splanchnic

circulation, so that side effects are minimized.230 A somatostatin and octreotide combination has proved

to be as effective as vasopressin, sclerotherapy, and balloon tamponade in multiple studies.231–233

Because of the lack of complications related to somatostatin therapy, octreotide is the initial drug of

choice for the treatment of acute variceal hemorrhage. Dosing typically consists of a bolus of 50 μg

followed by an infusion of 50 μg/hr, to be initiated as soon as variceal bleeding is suspected and

continued for 3 to 5 days after the diagnosis has been verified.198

1517

Endoscopic Interventions. Esophageal variceal ligation has become the principal approach to the

initial control and ongoing treatment of variceal bleeding; it is performed at the bedside in acute

bleeding and has replaced variceal sclerosis.

The technique of ligation (Fig. 59-6) includes placing an endoscope over a sheath (which allows

multiple insertions and removal of the endoscope), suctioning of a varix into the lumen of a plastic

channel, and then placing a rubber band around the tissue. The procedure is similar to the ligation of

hemorrhoids. The tissue then sloughs in 1 to 3 days, leaving a shallow ulcer. Up to six bands can be

placed at each session. Newer endoscopes allow for the placement of multiple bands without removal of

the endoscope.

Success rates for variceal ligation range from 80% to 100%, in comparison with 77% to 94% for

sclerotherapy, in controlled trials.234 In patients with profuse bleeding, however, the type of endoscope

used for variceal ligation may make visualization of the bleeding varices difficult leading some

investigators to choose sclerotherapy in these patients, and use variceal ligation once bleeding is

somewhat controlled.

Balloon Tamponade. The vast majority of patients (75% to 90%) with bleeding esophageal varices

respond to endoscopic or pharmacologic therapy. For patients who fail these interventions, balloon

tamponade (Fig. 59-7) is an alternative therapy with a high success rate in controlling bleeding. It

entails the placement of a specialized nasogastric tube with two balloons that can be inflated separately

and to different pressures to apply direct compression to the gastroesophageal junction and the

esophagus. Once the mainstay in the initial management of variceal bleeding, use of these tubes is

becoming a lost art, most suitable for initial stabilization of patients in a facility with limited

availability of endoscopic or radiologic support. Because these tubes are difficult to use, and may cause

fatal complications with esophageal injury, it remains important for surgeons and gastroenterologists

with responsibility for managing gastrointestinal bleeding to understand principles for safe use. The

most commonly used tubes are the Sengstaken–Blakemore tube and the Minnesota tube. The former

consists of a gastric balloon and an esophageal balloon with a sump port for gastric suctioning. The

latter tube has an additional port above the esophageal balloon for the aspiration of saliva and other

material from the esophagus and pharynx.

Figure 59-6. Endoscopic ligation of esophageal varices. The device used for ligation is based on the standard Barron-type ligator

for the treatment of anal hemorrhoids. The esophageal varix is drawn up into the ligating device with suction (A), and the base of

the varix is ligated with an O-ring (B). Up to six varices can be treated at a single session.

1518

Figure 59-7. The Sengstaken–Blakemore tube is used to tamponade acutely bleeding gastroesophageal varices. The tube has three

lumina—one to aspirate the stomach, another to inflate the gastric balloon, and a third to inflate the esophageal balloon. Patients

treated with balloon tamponade should be in an intensive care unit, and endotracheal tubes should be placed in almost all to

prevent aspiration.

Placement of these tubes begins with the establishment of a safe airway by endotracheal intubation.

The tube is then passed through the nose and into the stomach. Radiographic confirmation that the tip

of the tube is in the stomach is required before balloon inflation to prevent inadvertent intraesophageal

inflation of the gastric balloon and resultant perforation. The gastric balloon is inflated with 200 mL of

air and firmly pulled backward against the gastroesophageal junction to tamponade any proximal

gastric bleeding. The esophageal balloon is then inflated to a pressure of 30 to 40 mm Hg, and the tube

is secured to the patient by means of a facemask or helmet to ensure adequate stability of the tube and

prevent inadvertent removal.

Because of the possible complications of balloon tamponade (e.g., aspiration, esophageal and gastric

perforations, necrosis), which occur in 10% to 20% of patients, its use is restricted to approximately 24

hours. Success rates for cessation of bleeding are 70% to 80%, but more than half of all patients rebleed

when the balloons are deflated. Although this method is highly effective in the initial control of

bleeding, with an efficacy similar to that of pharmacologic agents, because of its transient effects it can

be used only as a temporizing measure in anticipation of a more definitive procedure (e.g., TIPS,

placement of a surgical shunt, or transplantation) and is used only after endoscopic and pharmacologic

therapies have failed.

Transjugular Intrahepatic Portosystemic Shunt. In the 10% to 20% of patients who continue to

bleed or who have early rebleeding, a shunt procedure (to bypass the high-pressure hepatic vascular

bed) may be indicated (Algorithm 59-1). The mortality rate associated with failure to control bleeding

can be as high as 90%, and surgically created shunts in this setting are associated with a high morbidity

and mortality rate.

10 The TIPS (Fig. 59-8) has become first-line treatment for bleeding esophageal varices when the

aforementioned attempts fail.235 Absolute contraindications to TIPS include congestive heart failure,

uncontrolled sepsis, multiple hepatic cysts, severe pulmonary hypertension, and uncontrolled biliary

obstruction. Relative contraindications include HCC, hepatic vein obstruction, severe coagulopathy or

thrombocytopenia, and moderate pulmonary hypertension.236 After ultrasonographic confirmation of

patency of the portal vein, the procedure is performed in the interventional radiology suite, where a

wire-guided stent (8 to 12 mm in diameter) is placed percutaneously into the jugular vein. The wire is

then guided through the superior vena cava, right atrium, and inferior vena cava into a hepatic vein,

after which the catheter traverses the hepatic parenchyma and joins the hepatic vein to a portal vein.

This connection effectively creates a side-to-side portacaval shunt. Success rates in the cessation of

variceal bleeding are as high as 90% to 100%, with an incidence of recurrent bleeding of approximately

10%.237,238

As discussed earlier, the ideal portosystemic shunt lowers the pressure in the portal system without

1519

 

Splenic Vein Thrombosis

Splenic vein thrombosis is most often caused by disorders of the pancreas, including acute and chronic

pancreatitis, trauma, pancreatic malignancy, and pseudocysts. This association is related to the location

of the splenic vein behind and close to the pancreas. Other causes include retroperitoneal masses,

abscesses, and inflammatory bowel disease; the remaining cases are idiopathic. Gastric varices are

present in approximately 80% of patients, and esophageal varices in 30% to 40%.187 Isolated “sinistral”

or left-sided portal hypertension occurs in the setting of normal liver function, and patients are readily

cured with splenectomy, although observation for asymptomatic patients is acceptable. The main

indication for splenectomy is variceal hemorrhage.

Complications of Portal Hypertension

9 The most important complications of portal hypertension are gastrointestinal bleeding secondary to

esophageal and gastric varices, ascites, and hepatic encephalopathy. The mortality risk associated with

portal hypertension is primarily related to the functional status of the cirrhotic liver. Child introduced a

scoring system of liver function for the purposes of assessing prognosis after portosystemic shunt

surgery in patients with cirrhosis, which has been subsequently modified several times to the Child–

Turcotte–Pugh (CTP) score (Table 59-9). These indices incorporate clinical and laboratory data as a

means to assess the functional status of the liver, estimate hepatic reserve, and predict morbidity and

mortality. They had been adopted by the United Network for Organ Sharing (UNOS) as a tool for

stratifying pretransplant mortality risk for patients on the waiting list for liver transplantation.188 Over

the last decade, the use of these criteria in transplant has been replaced by the model for end-stage liver

disease (MELD) score, which uses serum bilirubin, creatinine, and the international normalized ratio

(INR) to produce a surprisingly robust prediction of 90-day mortality for patients with cirrhosis on the

transplant list.189 Though the CTP score produces a more complete assessment of the patient, its use of

subjective clinical elements in the score made it unreliable as a verifiable element in assessment

compliance with center behavior in national organ transplant policy.190,191

While the MELD score was initially developed for the prognosis of patients after TIPS, the CTP score

has had long-standing use as a reliable predictor of mortality risk for shunt surgery and, by extension,

mortality risk of patients with cirrhosis undergoing other types of abdominal surgery.192,193 Patients

with normal function, termed “Child A,” have adequate hepatic reserve and survival rates similar to

those of noncirrhotic patients, whereas Child C patients have mortality rates in excess of 50% and may

not tolerate any intervention short of hepatic transplantation.

Varices

One of the most life-threatening complications of portal hypertension is bleeding from esophageal

varices. Esophageal varices are dilated veins found most commonly in the distal 5 cm of the esophagus.

In the normal esophagus, a venous plexus is located in the submucosa; it becomes more superficially

located to the lamina propria in the distal esophagus.194–196 This more superficial location in the distal

esophagus is consistent with the known increased occurrence of bleeding varices in that location. In

addition, 5% to 33% of patients with portal hypertension have gastric varices.197

1514

The pressure in the portal system is an important determinant of the likelihood for varices to develop.

As noted earlier, portal pressure may be estimated from the hepatic vein wedge pressure, and the

gradient between the wedge pressure and the free hepatic vein pressure is an indirect measure of the

resistance across the liver. In general, varices do not develop in persons with hepatic vein–portal vein

gradients below 12 mm Hg. Pressure gradients above 12 mm Hg are invariably present in patients with

varices, but this pressure does not necessarily produce varices in all patients. Other, undetermined

factors must play a role. Gastroesophageal varices are present in 40% of patients with Child A cirrhosis,

and in up to 85% of patients with Child C cirrhosis.198 Varices may also be present in chronic liver

disease without outright cirrhosis. For example, 16% of patients with chronic hepatitis C and bridging

fibrosis have varices.199

In approximately 10% of all patients presenting with acute upper gastrointestinal bleeding,

esophageal varices are the cause of bleeding. Rates of bleeding from varices vary among studies. In a

study of the natural history of varices in which patients were prospectively followed for 6 years,

esophageal varices developed in approximately 8% of patients with cirrhosis each year during the first 2

years of observation; the percentage increased to 30% by 6 years. Of the patients who had small varices

detected at initial endoscopy, large varices developed in 25%.200 Other studies show an incidence of

varices of up to 90% for patients with cirrhosis.201,202 Once varices are present, bleeding occurs in 25%

to 35% of cases, with the highest risk occurring within the first year after diagnosis.202,203 Patients with

large varices are at the highest risk for an initial bleed. Spontaneous bleeding from varices ceases

spontaneously in up to 40% of patients, although mortality and recurrent bleeding remain high.198 Of

patients who survive an episode of bleeding, 30% experience rebleeding within 6 weeks, and 70% at 1

year.203,204 The correlation between severity of varices and derangement of hepatic function is

inconstant, so mortality rates from bleeding varices range from 5% to 50%, with rates of 5%, less than

25%, and more than 50% for Child A, B, and C patients, respectively.204

The propensity for varices to bleed has been extensively studied. When combined with clinical data

such as the presence of active alcohol consumption, certain endoscopic characteristics of varices have

been correlated with initial episodes of bleeding (Table 59-10). These factors include variceal size,

Child–Pugh class, and the presence of red wale markings (longitudinal dilated venules that resemble

whip marks).202 Direct and indirect measurements of portal pressure have been used to predict the

likelihood of bleeding, with hemorrhage occurring only in patients with portal–hepatic venous gradients

above 12 mm Hg.205,206

Table 59-10 Endoscopic Signs That Correlate with Risk for Variceal Rupture

TREATMENT

Table 59-11 Prevention/Treatment Options for Variceal Bleeding

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Diagnosis of Varices and Prevention of Initial Variceal Bleeding. Because of the severe

consequences of variceal bleeding, methods to diagnose varices prior to bleeding and to prevent first

(primary prophylaxis) and recurrent (secondary prophylaxis) episodes of bleeding have been developed.

Esophagogastroduodenoscopy (EGD) is the gold standard for the diagnosis of gastroesophageal varices,

and should be performed in all patients upon the initial diagnosis of cirrhosis. If no varices are present

upon initial screening, an EGD should be repeated in 2 to 3 years for patients with compensated

cirrhosis. If small (<5 mm) varices are present, EGD should be repeated in 1 to 2 years. Patients with

decompensated cirrhosis should undergo yearly screening EGD based on current recommendations from

the AASLD.198 After varices are diagnosed, methods of primary and secondary bleeding prophylaxis

include control of the underlying cause of cirrhosis (i.e., alcohol consumption) and pharmacologic and

surgical interventions to lower portal pressure. The next section discusses methods of primary

prophylaxis to prevent initial episodes of bleeding (Table 59-11).

Beta Blockade. The use of nonspecific β-adrenergic blockade has been studied extensively in

randomized controlled trials of the primary prophylaxis of variceal bleeding. The mechanism of action

of these drugs (propranolol, nadolol) involves effects of both β1

-adrenergic and β2

-adrenergic

blockades, including decreased cardiac output and increased splanchnic arteriolar vasoconstriction as a

result of the loss of opposing β2

-adrenergic dilation.206,207 The combined effects decrease portal blood

flow and subsequently portal pressure.

These drugs are effective in portal hypertension associated with prehepatic, intrahepatic, and

posthepatic conditions,208 regardless of whether ascites is present.209 Not all patients respond to

therapy, however. Two meta-analyses have evaluated seven randomized controlled trials comparing

propranolol or nadolol with placebo in the prevention of initial variceal bleeding. Both analyses

concluded that beta blockade is significantly correlated with a reduced incidence of bleeding.210,211 A

reduction of 40% was noted overall after all trial results were combined, with bleeding developing in

approximately 16% of treated and 27% of untreated patients. The goal of therapy is to reduce the

hepatic vein–portal vein gradient to below 12 mm Hg or to more than 20% below baseline.212 Patients

who meet these goals not only have a lower risk of variceal bleeding, but also of developing ascites,

spontaneous bacterial peritonitis, and death.213 In addition to reducing the number of first episodes of

bleeding, beta blockade therapy has been shown to reduce mortality in most clinical trials.214 A metaanalysis of these studies concluded that mortality from bleeding is reduced in patients with large

varices.

Despite their known benefits, beta blockers are also associated with significant side effects that limit

their universal application in patients with cirrhosis. There is no role for beta blockade to prevent

formation of varices in patients who do not already have them, based on a large randomized study by

Groszmann et al.215 In this study, serious adverse events were significantly more common in patients

undergoing timolol therapy compared to placebo. For patients with small (<5 mm) varices without

high-risk features (decompensated cirrhosis, red wale markings), current guidelines from the AASLD

state that beta blockers may be used, although convincing evidence of substantial benefits in this setting

is lacking.198

Surgical Intervention. In the 1950s and 1960s, surgeons created prophylactic portosystemic shunts in

an attempt to prevent variceal bleeding. These procedures were studied in a randomized controlled

fashion and, although effective in preventing variceal bleeding, they caused an increased incidence of

hepatic failure and encephalopathy and had no effect on overall survival.216,217 These results provided

1516

 

Figure 59-5. Potential venous collaterals that develop with portal hypertension. The veins of Sappey drain portal blood through

the bare areas of the diaphragm and through paraumbilical vein collaterals to the umbilicus. The veins of Retzius form in the

retroperitoneum and shunt portal blood from the bowel and other organs to the vena cava.

The portal venous concentration of nitric oxide, a potent vasodilator, has been shown to be elevated

in patients with cirrhosis and portal hypertension.165 In addition to nitric oxide, many other vasodilators

are elevated in portal hypertension, including prostacyclin, endotoxin, and glucagon.166

Etiology

Many pathologic processes can cause portal hypertension (Table 59-8). These are usually classified as

prehepatic, hepatic, or posthepatic (presinusoidal, sinusoidal, or postsinusoidal) conditions. As noted

above, in prehepatic and posthepatic conditions, portal hypertension is the result of mechanical venous

obstruction at the level of the portal or hepatic veins, respectively, whereas cirrhosis is the main cause

of hepatic portal hypertension.

Budd–Chiari Syndrome and Veno-occlusive Disease

The BCS is caused by hepatic venous obstruction. The name of the syndrome is derived from two

investigators, the first of whom (Budd)167 described the classic presentation of abdominal pain, ascites,

and hepatomegaly, and the second of whom (Chiari)168 described the pathologic characteristics of the

liver. The obstruction may occur at the level of the inferior vena cava, the hepatic veins, or the central

veins within the liver itself and may be the result of congenital webs (most common in Africa and Asia),

acute or chronic thrombosis (most common in the West), and malignancy. With occlusion of the hepatic

veins, pressure increases in the central veins. As a result, centrilobular congestion, necrosis, and, with

chronic disease, fibrosis and cirrhosis with portal hypertension develop.

In the West, the most common causes of this syndrome are hypercoagulable states associated with

polycythemia vera, myeloproliferative disorders, paroxysmal nocturnal hemoglobinuria, and defects in

the coagulation cascade, as in conditions associated with high estrogen levels (e.g., pregnancy, use of

birth control pills).169,170 Neoplasms may cause hepatic venous obstruction by direct invasion and

occlusion of the vessels, or by establishment of a prothrombotic milieu secondary to the malignancy

itself. In the East, the major causes of obstruction of the vena cava and hepatic veins are membranous

webs that directly occlude the vessels. The etiology of vena cava webs is unknown. Veno-occlusive

disease is characterized by obliterative endophlebitis of the intrahepatic veins (Table 59-3). Causes of

veno-occlusive disease include medications, toxins, and pyrrolizidine alkaloids.

BCS may present with acute, subacute, or chronic symptoms and is often misdiagnosed. This is

1511

unfortunate, because early treatment will prevent the development of hepatic fibrosis, which can lead to

end-stage liver disease. Nearly 50% of patients have had symptoms for more than 3 months.171 Acute

symptoms include hepatomegaly, right upper quadrant abdominal pain, nausea, vomiting, and ascites.

In the chronic form of the disease, patients may present with the sequelae of cirrhosis and portal

hypertension, including variceal bleeding, ascites, spontaneous bacterial peritonitis, fatigue, and

encephalopathy. In the chronic form, the entire liver atrophies except for the caudate lobe, which may

hypertrophy because its hepatic vein(s) enters the vena cava separately, so that venous outflow is not

impeded.100 The hypertrophy of the caudate lobe creates a longitudinal narrowing of the retrohepatic

vena cava, which is surrounded by parenchyma, leading to secondary obstruction of the caval flow in

the abdomen.

ETIOLOGY

Table 59-8 Common Causes of Portal Hypertension

Although the diagnosis can be made by ultrasonographic evaluation of the liver and its vasculature

with a sensitivity of 85% to 95%,169 cross-sectional imaging is essential for staging and planning

therapy. Duplex scanning may reveal the location of the obstruction and characterize the flow within

the vena cava and hepatic, portal, mesenteric, and splenic veins. Other common ultrasonographic

findings consistent with BCS include lack of visualization of the hepatic veins, an enlarged caudate lobe

with compressed inferior vena cava, enlarged intrahepatic collaterals, splenomegaly, and ascites.101.

Thrombus within the hepatic veins or inferior vena cava may be directly visualized using contrastenhanced magnetic resonance angiography (MRA).172

Because the vascular obstruction is usually well established at the time of presentation,

anticoagulation alone is rarely sufficient therapy for BCS. Although major open surgery has been

favored in the past, including mesoatrial shunting,173,174 and even liver transplantation,175 minimally

invasive approaches are now preferred.176 The mainstay of therapy is mechanical decompression with a

side-to-side portosystemic shunt, optimally achieved with a percutaneous portacaval shunt (see below).

1512

After shunt placement, the pressure on the vena cava by the caudate lobe is gradually relieved, leading

to restoration of liver function.

A more direct solution, which is necessary in the face of complete caval obstruction, is the creation of

a mesoatrial shunt, which was described by Cameron and Maddrey.173 This radical procedure has been

largely supplanted by percutaneous portacaval shunting (TIPS). The rates of postprocedural

encephalopathy are usually not increased in patients with BCS, because they have anatomically healthy

livers that recover fully if decompression is achieved early prior to the establishment of cirrhosis. In

patients with end-stage liver disease, liver transplantation may be performed.175 The 5-year survival

rate for patients with good hepatic function before the shunt procedure is approximately 60%, with a

34% to 88% survival for patients after liver transplantation.177 Postoperatively, patients are treated

with long-term anticoagulation to prevent recurrent thrombosis.

As noted, minimally invasive treatment using TIPS may be first-line therapy, and it has supplanted

surgical shunting in our practice.178,179 Case reports and small series have suggested efficacy for this

technique,180 and a recent larger study has indicated 1- and 5-year survival rates of 93% and 74%,

respectively.181 Many patients develop shunt occlusion; however, further angiographic manipulation

and long-term anticoagulation are required to maintain patency.

Portal Vein Thrombosis

Portal vein thrombosis is commonly associated with advanced cirrhosis, and may be the ominous

portent of a HCC. Spontaneous portal vein thrombosis in the absence of cirrhosis is the cause of portal

hypertension in fewer than 10% of adult patients but is the most common cause in children.182,183 In

contrast to patients with cirrhosis-induced portal hypertension, these patients have normal liver function

and are not as susceptible to the development of complications such as encephalopathy. Causes of portal

vein thrombosis include umbilical vein infection (the most common cause in children), coagulopathies

(protein C and antithrombin III deficiency), hepatic malignancy, myeloproliferative disorders,

inflammatory bowel disease, pancreatitis, trauma, and previous splenorenal shunt.184 Most cases in

adults are idiopathic.

The diagnosis can be made by sonography, which reveals an echogenic lesion in the lumen of the

portal vein and an absence of portal venous flow on duplex examination.185 With time, cavernous

transformation of the portal vein may occur, in which channels develop within the clotted portal

vein.182 CT and MRI are also useful in establishing the diagnosis. Often, the initial manifestation of

portal vein thrombosis is variceal bleeding in a noncirrhotic patient with normal liver function.

Splenomegaly is another common finding.

The initial therapeutic option for the control of hemorrhage caused by portal vein thrombosis is

esophageal variceal ligation. If unsuccessful, the distal splenorenal shunt has been the traditional

surgical treatment for patients with isolated portal vein thrombosis. In patients whose intrahepatic

portal vein is patent (most commonly children), however, a shunt created by placing an internal jugular

vein graft between the superior mesenteric vein and the patent left portal vein within the parenchyma

of the liver (Rex shunt) may be the optimal therapeutic procedure for reestablishing physiologic portal

flow.186 This is the most elegant solution for portal obstruction because the portal pressure is reduced

by restoring blood flow to the liver, preventing chronic hepatic atrophy and dysfunction, which can

occur in a patient with long-standing portal decompression. In fact, in our practice, the Rex shunt is the

first-line treatment and we reserve splenorenal shunting for patients who have no remnant intrahepatic

portal system to receive the shunted blood.

CLASSIFICATION

Table 59-9 Child–Turcotte Criteria for Hepatic Functional Reserve

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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

1508

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

1509

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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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,

1506

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

1507

 

Metabolic and Genetic Disorders. Some of these diseases are listed in Table 59-1. A description of all

the metabolic disorders causing liver disease is beyond the scope of this chapter.

In hemochromatosis of the liver, an inborn error of metabolism causes an increased absorption of iron

from the gastrointestinal tract. The pathophysiology of iron-induced hepatotoxicity is related to lipid

peroxidation induced by iron in periportal regions of the liver. Activation of stellate cells by cytokines

released from Kupffer cells that have phagocytosed necrotic hepatocytes injured by iron toxicity is also

contributory.93 Over time, the reaction progresses to bridging fibrosis and eventually to a mixed

micronodular–macronodular cirrhosis. Treatment includes reduction of iron intake, repeated

phlebotomy, and orthotopic liver transplantation.94

Wilson disease is an autosomal, recessively inherited disease caused by a deficiency in hepatocyte

transport of copper into the bile. The disease is characterized biochemically by low serum ceruloplasmin

levels and clinically by corneal pigmentation (Kayser–Fleischer rings), neuropsychiatric disease, and

hepatic cirrhosis.95 As copper accumulates in the liver, periportal inflammation develops that leads to

piecemeal and lobular necroses, bridging fibrosis, and a mixed micronodular–macronodular cirrhosis.

Treatment options include chelating agents, such as penicillamine, trientine, zinc salts, and orthotopic

liver transplantation.

Venous Outflow Obstruction. Cirrhosis may also result from obstruction of the hepatic veins. Causes

include chronic right-sided heart failure as a result of severe tricuspid regurgitation, constrictive

pericarditis, and the Budd–Chiari syndrome (BCS).

Hepatic dysfunction secondary to passive vascular congestion in the setting of right-sided heart failure

and increased right-sided heart pressures is caused by the transmission of increased pressure to the

hepatic venous system. This increased pressure leads to sinusoidal congestion, perivenular atrophy,

hemorrhagic necrosis, and distortion and enlargement of sinusoidal fenestrations.96 Increased pressure

also causes perisinusoidal edema that eventually exceeds the clearance capabilities of hepatic

lymphatics, so that ascites develops.97 Grossly, the liver is described as having a “nutmeg” appearance

in which areas of hemorrhage are interspersed with relatively normal yellowish parenchyma.97

Histologically, perivenular fibrosis progresses to bridging fibrosis that spares the portal regions. Portal

sparing is characteristic of “cardiac cirrhosis.” In addition to causing ascites, chronic vascular congestion

can lead to fibrosis in the space of Disse, which compromises nutrient delivery and contributes to portal

hypertension and zone 3 hepatocellular injury.98

5 BCS is a rare disease caused by mechanical obstruction of the hepatic veins (Table 59-3).

Obstruction may occur at the level of the terminal hepatic veins, the major hepatic veins, or the vena

cava and may be caused by obstructing webs or membranes (most commonly in Africa and Asia) or

thrombosis secondary to hypercoagulable states and neoplasms (most commonly in the West).

The range of presentations is wide; some patients are completely asymptomatic, whereas acute

hepatic failure or cirrhosis develops in others.99 These variations in symptoms are related to the degree

and rate of progression of hepatic outflow obstruction. Patients classically present with abdominal pain,

hepatomegaly, and ascites. The diagnosis can be made by duplex Doppler ultrasonography, which has a

sensitivity of 85% to 95%.100 Identification of collateral vessels to subscapular or intercostal vessels on

ultrasonography on ultrasound is a highly sensitive and specific finding.101 Computed tomography (CT)

and magnetic resonance imaging (MRI) offer optimal characterization of intrahepatic vascular anatomy

and are currently used for the planning of complex interventions.102 Medical management consists of

anticoagulation and symptomatic management. Interventional radiologic procedures have now taken

the forefront in management of BCS, in which accessible strictures may be treated with angioplasty or

stenting. For patients unsuitable for reestablishment of hepatic venous outflow through the above

means, transjugular intrahepatic portosystemic shunting (TIPS) is able to decompress both the inferior

vena cava and the portal system.101 In patients with fulminant BCS or in those who develop chronic

decompensated cirrhosis, liver transplantation becomes an option.

ETIOLOGY

Table 59-3 Etiology

1502

Diagnosis

Although cirrhosis can be asymptomatic for decades, significant information can be obtained by

performing a thorough history and physical examination. A history of alcohol abuse, hepatitis, toxin or

drug exposure, upper gastrointestinal bleeding, enlarging hemorrhoids, infections, and alteration in

mental status suggests the possibility of liver disease. Physical findings associated with cirrhosis are

listed in Table 59-4. In addition to these findings, fetor hepaticus, purpura and bruising, decreased body

hair, and white nails are common.

Laboratory tests of liver function are indicated if liver disease is suggested by the history and physical

examination. Although levels of bilirubin, aspartate aminotransferase, alanine aminotransferase, and

alkaline phosphatase are elevated in hepatic disease, the increases are not specific for liver pathology,

and levels may be normal even in the setting of significant disease. A very common finding in patients

with cirrhosis is thrombocytopenia, caused by hypersplenism and portal hypertension. The platelet

growth factor thrombopoietin, which is produced by the liver, has been shown to be decreased in

patients with cirrhosis, and this deficit may contribute to the thrombocytopenia associated with hepatic

disease.103

The definitive diagnosis of cirrhosis usually requires biopsy, either percutaneous or operative, or

gross inspection during laparoscopy or laparotomy. Regardless of the method selected, it is crucial to

obtain a large enough specimen to make the diagnosis. Current recommendations suggest that at least

11 portal tracts need to be assessed.104 Several staging systems exist for the grading of fibrosis and

cirrhosis, including the International Association for Study of the Liver (IASL), Batts–Ludwig, and

Metavir systems. The AASLD recommends the Batts–Ludwig system as it gives a verbal diagnosis rather

than numeric categories, and thus may be easier to interpret.104

DIAGNOSIS

Table 59-4 Physical Findings in Cirrhosis

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Noninvasive methods to diagnose cirrhosis include ultrasonography, CT, and MRI, which generally

reveal an atrophic, nodular liver and an enlarged spleen. More recent work suggests that subtle changes

in the hepatic veins may be early markers of cirrhosis.102 Ultrasonographic criteria for cirrhosis include

the demonstration of multiple nodular irregularities on the ventral liver surface that are clearly separate

from the anterior abdominal wall. Parenchymal texture is altered in the setting of fibrosis, though this

feature can be subtle. When these criteria are used, ultrasonography has been shown to have a

sensitivity, specificity, and accuracy of approximately 90% in the diagnosis of cirrhosis.105 Ultrasoundbased transient elastography, a measure of liver stiffness, is playing an increasingly large role in the

noninvasive assessment of fibrosis, with some studies demonstrating a 95% area under the receiver

operating characteristic curve (AUROC) for diagnosing grade IV fibrosis (cirrhosis).106

More recently, several laboratory indexes have been found to correlate well with histologic grade of

cirrhosis.106,107 The NAFLD fibrosis score, for example, consists of age, BMI, diabetes, platelet count,

albumin level, and AST/ALT ratio.108 The AUROC of this scoring system in diagnosing stage 3 or greater

fibrosis was 85% in a recent meta-analysis.109 The Fibrotest (LabCorp) is a patented panel of biomarkers

consisting of GGT, haptoglobin, bilirubin, apolipoprotein A1, and alpha-2-macroglobulin. The AUROC of

Fibrotest for fibrosis greater than or equal to stage 2 has been shown to be up to 87%.110 Indirect

evidence of cirrhosis includes endoscopically discovered varices of the esophagus, and the presence of

splenomegaly detected by CT or MRI.

Complications

Renal

Renal complications in cirrhosis are intrinsic to functional dysregulation of vascular tone throughout the

body.111 Several elements come into play and renal dysfunction is characterized by avid sodium

retention despite normovolemia or hypervolemia, dilutional hyponatremia secondary to free water

overload, ascites, and ultimately renal failure and the hepatorenal syndrome (HRS). The paradoxical

arterial vasoconstriction of the renal arterial bed in the face of global fluid overload is critical to the

pathophysiology of HRS.112 Among the complications of cirrhosis, HRS confers the highest risk of

mortality.113 Although HRS is the most dramatic renal complication of liver failure, renal dysfunction in

patients with advanced liver disease is generally multifactorial.112 Renal insufficiency may develop in a

patient with cirrhosis as a direct consequence of the underlying condition (i.e., PBC, amyloidosis), as a

consequence of excessive diuretic use in the treatment of ascites and fluid overload, or as a secondary

reaction to the release of cytokines or hormones by the liver that alter renal function.

DIAGNOSIS

Table 59-5 Differential Diagnosis of Acute Azotemia in Patients with Liver Disease

Much progress has been made in the understanding of the pathophysiology of HRS focusing on the

dysregulation of arterial tone in the end stages of liver disease. Empiric observations that support a

functional or “secondary effect” theory include the lack of anatomic renal abnormalities in patients with

cirrhosis-related renal dysfunction, the normal function of previously dysfunctional kidneys transplanted

into otherwise healthy recipients, and resolution of renal abnormalities after successful hepatic

transplantation. Recent clinical studies have defined the critical role of optimizing colloid balance in the

patient with cirrhosis

114 and the exploration of regulators of renal blood flow such as terlipressin in

counteracting the deranged vascular tone.115

Sodium Retention. Patients with cirrhosis who do not have ascites have relatively normal sodiumhandling capabilities. Patients in whom ascites develops have a marked inability to excrete sodium.

Because of this deficit, sodium intake in excess of renal excretion contributes to fluid overload. Three

1504

 

considered, recent reports have identified obesity as a major risk factor for cancer deaths with a 4.5-fold

increase of the relative risk for liver cancer in obese subjects.64

The current understanding of NAFLD and progression to NASH and cirrhosis involves a two-hit model,

which is nicely explained in a review by Bohinc and Diehl.25 In this model, insulin resistance leads to

hepatic steatosis (the first hit), which sensitizes the hepatic parenchyma to environmental and

extracellular insults (the second hit) leading to inflammation, necrosis, and fibrosis.25 Dietary fructose

has been identified as an important culprit in the development of hepatic steatosis by decreasing

intracellular ATP and transforming to lipid in the absence of insulin.65 Ongoing hepatic insults lead to

activation of the inflammasome, a protein scaffold that results in the secretion of the inflammatory

cytokines IL-1β and IL-18, further amplifying hepatic inflammation and injury. Inflammasome

activation is increased by gut-derived bacterial endotoxin. This inflammation promotes increased Hh

signaling and stellate cell activation with resultant fibrosis.66

Therapy for NASH centers on lifestyle modification, with a modest weight loss of 5% to 10%

associated with significant histologic improvements in disease severity.61 Now that the role of gut

microflora is understood to play a major role in the pathogenesis of NASH and other liver diseases, the

use of probiotics, most commonly lactobacilli and bifidobacteria, is being explored in the treatment of

NASH. A recent meta-analysis of four randomized controlled trials demonstrated probiotics significantly

decreased transaminases, total cholesterol, TNF-α, and insulin resistance.67

4 Hepatitis. Viral hepatitis is the most common cause of cirrhosis worldwide, accounting for at least

50% of cases. Hepatitis A, B, C, D, and E have all been proved to cause acute hepatitis, characterized

histologically by lymphocytic parenchymal and portal inflammations, focal necrosis, ballooning

degeneration, cholestasis, Kupffer cell and macrophage hypertrophy and hyperplasia, and lobular

disarray. Only hepatitis B, C, and D have been shown to progress to chronic hepatitis, defined by

persistent liver cell necrosis and inflammation lasting longer than 6 months. Chronic infection with

hepatitis B virus (HBV) develops in fewer than 5% of patients who experience acute HBV infection. The

development of cirrhosis in approximately 10% to 20% of chronically infected persons produces an

overall rate of cirrhosis of approximately 1%. Hepatitis B remains a major public health problem in

Asian countries and Africa, with up to 10% of the population showing evidence of chronic infection. The

widespread use of antiviral medications effective against hepatitis B effectively suppresses viral

replication to undetectable levels in up to 90% of patients, and may reverse fibrosis and even cirrhosis.

Even with effective suppression of viral replication, however, HBV is not truly “cured” since the virus is

incorporated into the host genome. This has important consequences as HCC can still develop in the

noncirrhotic liver of HBV-infected patients.68 In addition, public health strategies with systematic

vaccination of newborns should substantially decrease the incidence of new infections.

In contrast, hepatitis C poses a much higher risk of chronic infection, and therapeutic strategies

eradicate viral replication in a minority of patients. Of patients with hepatitis C virus (HCV), 90%

become chronically infected, and chronic hepatitis develops in 60% of these patients. Among patients

with chronic hepatitis, 30% progress to cirrhosis,46 so that the incidence of cirrhosis in patients initially

infected with hepatitis C is approximately 10%. Standard treatment for HCV was previously based on

the combination of pegylated interferon and ribavirin, with sustained viral response (SVR) rates of up to

80% in patients with genotypes 2 and 3,69 but results for the more common genotype 1 were only 40%

to 50%, with the best reporting an SVR rate of 65%.70 Compounding the limited efficacy of interferonbased therapy is the high rate of adverse events that prevents many patients from completing therapy.

The recent release of a new wave of oral antiviral therapies, termed direct-acting antivirals (DAAs),

and allowing interferon-free regimens, however, has demonstrated more promising results (Table 59-2).

The fixed dose combination of 90-mg ledipasvir and 400-mg sofosbuvir is sold under the trade name

Harvoni (Gilead Sciences) and is recommended as first-line therapy by the American Society for the

Study of Liver Disease (AASLD) for the treatment of HCV genotypes 1a, 1b, and 4.71 Ledipasvir is an

inhibitor of the HCV protein NS5A, which limits viral replication. Sofosbuvir is a nucleotide inhibitor of

the NS5B polymerase that terminates viral replication. In the ION-1 trial that leads to approval of the

combination of these two agents for the treatment of HCV genotype 1, SVR rates of 97% to 99% were

demonstrated after 12 weeks of therapy. No patients who received the 12-week regimen had adverse

effects leading to early treatment discontinuation.72 For treatment of genotype 4, the SYNERGY trial

demonstrated an SVR rate of 95% by intention to treat analysis following 12 weeks of

ledipasvir/sofosbuvir therapy.71 Ledipasvir/sofosbuvir is also recommended as first-line therapy for

genotype 6. Sofosbuvir also has significant activity against genotypes 2 and 3 when combined with

ribavirin, and genotypes 5 and 6 when combined with ribavirin and pegylated interferon.71 Simeprevir

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is a novel NS3/4A protease inhibitor recommended as first-line therapy for HCV for genotypes 1a and

1b when used in combination with sofosbuvir. In the COSMOS trial, combination simeprevir/sofosbuvir

for genotype 1 HCV demonstrated 95% SVR after 12 weeks of therapy in noncirrhotics, and 100% SVR

after 24 weeks of therapy in cirrhotics.73

ETIOLOGY

Table 59-2 Causes of Cholestasis

Another novel all-oral HCV regimen is the combination of ombitasvir, paritaprevir, ritonavir, and

dasabuvir, marketed as the Viekira Pak (AbbVie). Ombitasvir inhibits NS5A, paritaprevir inhibits the

NS3/4A protease, ritonavir is a CYP3A4 inhibitor without any HCV activity used to increase sensitivity

to paritaprevir, and dasabuvir is a nonnucleotide NS5B polymerase inhibitor. The combination is

recommended as first-line therapy for genotype 1a when used with weight-based ribavirin, genotype 1b

(with ribavirin for cirrhotics), and genotype 4 (with ribavirin).71 Against HCV genotype 1, SVR rates of

95.3% to 97% have been demonstrated.74,75

These results represent a revolution in the therapy of HCV that makes cure of HCV a possibility. In

patients who respond to therapy, progression to cirrhosis is eliminated and it is generally thought that

HCC does not develop. In patients who do not respond to therapy, cirrhosis develops in approximately

40%, and HCC develops in 16% of these patients.73

Hepatitis D virus (HDV) is an RNA virus that requires the presence of HBV to be pathogenic.

Superinfection of HBV-positive patients with HDV leads to a more rapid clinical course, with

progression to cirrhosis in 70% to 80% of patients.74 Among patients with compensated cirrhosis of viral

origin, HCC developed in approximately 20% with HCV, 9% with HBV, and 41% with both HBV and

HCV.46 The progressive increase in hepatitis-infected individuals in the United States precedes an

epidemic in HCC, which has been well documented and is expected to peak over the coming decade.75

Cholestasis. Cholestasis, defined as a decrease or absence of bile flow into the duodenum, may be

caused by intrahepatic or extrahepatic biliary obstruction or defects in the ability of hepatocytes to

excrete bile. Causes of cholestasis are presented in Table 59-2. Prolonged biliary obstruction leads to

proliferation of bile ducts, formation of bile lakes caused by disruption of bile ducts, fibrosis, and

ultimately secondary biliary cirrhosis as a result of the direct toxic effects of bile salts on hepatobiliary

elements.

Immune or Inflammatory Cirrhosis. Although cholestasis is a generically toxic insult to the liver that

can cause cirrhosis, several diseases that are characterized by cholestasis seem to be caused by

underlying immune or inflammatory disorders affecting either small (primary biliary cirrhosis [PBC]) or

large (primary sclerosing cholangitis [PSC]) bile ducts. PBC is a chronic, slowly progressive disease that

1500

most commonly affects middle-aged women; it is characterized by portal inflammation, destruction of

intrahepatic bile ducts, and progression to cirrhosis. Approximately 95% of patients are women, and

95% of these women express antimitochondrial antibodies in serum.76 The autoimmune inflammatory

process damages both the bile ducts and, eventually, the hepatocytes as a result of leakage of bile acids

into surrounding parenchyma.77 Patients present with fatigue, jaundice, and pruritus, but as many as

60% of patients may be asymptomatic.78 PBC progresses in the majority of patients; median survival

times are approximately 10 to 15 years in asymptomatic patients and 7 years in symptomatic

patients.79,80 Poor prognostic factors include hyperbilirubinemia, advanced age, hepatosplenomegaly,

and symptomatic disease.

Medical management of PBC is with the exogenous bile acid ursodeoxycholic acid (13 to 15

mg/kg/d). Complete response, as evidenced by normalization of liver enzymes without histologic

progression, is seen in up to 30% of patients and can even lead to a normal life expectancy. Therapy for

nonresponders includes immunosuppression with methotrexate, colchicine, or steroids, although the

efficacy of these medications is in question.81 Liver transplantation is ultimately required as the

definitive treatment in most patients, and the parameters for liver transplantation and its timing are

relatively predictable and have been well studied.82

PSC is a chronic, progressive cholestatic liver disease of unknown cause characterized by diffuse

segmental intrahepatic or extrahepatic biliary ductular strictures with associated fibrosis and

inflammation. The disease has no cure and often leads to secondary biliary cirrhosis, portal

hypertension, hepatic failure, and cholangiocarcinoma if hepatic transplantation is not performed. PSC

is strongly associated with inflammatory bowel diseases, most commonly ulcerative colitis, and

probably shares an underlying disturbance related to disturbed mucosal immunity of the gastrointestinal

tract.83 Approximately 70% of patients with PSC also have ulcerative colitis.83 Conversely,

approximately 5% of patients with ulcerative colitis have PSC, though subtler forms of the disease may

be present but clinically asymptomatic. PSC is thought to be autoimmune in nature; elevated levels of

autoantibodies and an increased expression of human leukocyte antigen (HLA) class II molecules on

biliary epithelial cells have been observed.84,85 Approximately two-thirds of patients are male and

younger than 45 years of age at the time of diagnosis.86 Patients with PSC may be completely

asymptomatic (up to 44%) or have signs of advanced disease at the time of diagnosis.83 Commonly, the

diagnosis is made in symptomatic patients after endoscopic retrograde cholangiopancreatography

(ERCP) has been performed to evaluate elevated liver enzymes, including alkaline phosphatase and γglutamyltransferase. Symptomatic patients have a waxing and waning course and may present with

complaints of fatigue (75%), pruritus (25% to 70%), jaundice (30% to 69%), abdominal pain (16% to

37%), and weight loss (10% to 34%).83 Complications secondary to progression to cirrhosis are less

common and include ascites, variceal bleeding, and acute cholangitis.

The diagnosis of PSC is suggested by a history of inflammatory bowel disease in the setting of

elevated liver enzymes and is established by cholangiography. The disease process may range from a

single dominant stricture to, more commonly, diffuse multifocal sclerosis of the intrahepatic and

extrahepatic bile ducts. Pathologically, bile ductular proliferation, periductal fibrosis and inflammation,

ductopenia, and, less commonly, obliterative fibrous cholangitis may be present. PSC may be considered

a premalignant condition. Like ulcerative colitis, PSC confers a significant risk of malignant

transformation of the biliary mucosa, which is one of the considerations in considering patients for

transplantation.87 Cholangiocarcinoma develops in 1% to 2% of patients per year after the diagnosis of

PSC, with an overall risk of up to 10%.88 Screening for premalignant changes with ERCP and cytologic

examination and serum testing of CA19-9 have been helpful, though both have limited specificity and

sensitivity. Recently, it has been proposed that newer analysis methods of biliary material obtained at

screening ERCP, including fluorescence in situ hybridization (FISH), may be used for chromosomal

abnormalities associated with cancer with an increase in the sensitivity.89

There is no generally accepted medical therapy to treat PSC, so therapeutic efforts are directed

toward complications of the disease. The major complications include biliary obstruction, cirrhosis, and

cholangiocarcinoma. Dominant strictures, defined as stenosis less than 1.5 mm in the common bile duct

or less than 1 mm in the hepatic duct, are readily treated endoscopically by means of dilation and/or

stent placement.90,91 Transplantation should be performed before cancer develops and, generally, the

discovery of cancer has been considered an absolute contraindication to transplantation because of poor

outcomes. Highly selected patients with localized tumors may be transplanted with an acceptable

survival rate with intensive preoperative therapy including radiation and chemotherapy, as proposed by

Shaw and implemented on a larger scale by the Mayo group.92

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