2627Cirrhosis and Its Complications CHAPTER 344

■ BILIARY CIRRHOSIS

Biliary cirrhosis has pathologic features that are different from either

alcohol-associated cirrhosis or posthepatitic cirrhosis, yet the manifestations of end-stage liver disease are the same. Cholestatic liver disease

may result from necroinflammatory lesions, congenital or metabolic

processes, or external bile duct compression. Thus, two broad categories

reflect the anatomic sites of abnormal bile retention: intrahepatic and

extrahepatic. The distinction is important for obvious therapeutic reasons.

Extrahepatic obstruction may benefit from surgical or endoscopic biliary

tract decompression, whereas intrahepatic cholestatic processes will not

improve with such interventions and require a different approach.

The major causes of chronic cholestatic syndromes are primary

biliary cholangitis (PBC), autoimmune cholangitis (AIC), primary

sclerosing cholangitis (PSC), and idiopathic adulthood ductopenia.

These syndromes are usually clinically distinguished from each other

by antibody testing, cholangiographic findings, and clinical presentation. However, they all share the histopathologic features of chronic

cholestasis, such as cholate stasis; copper deposition; xanthomatous

transformation of hepatocytes; and irregular, so-called biliary fibrosis.

In addition, there may be chronic portal inflammation, interface activity, and chronic lobular inflammation. Ductopenia is a result of this

progressive disease as patients develop cirrhosis.

■ PRIMARY BILIARY CHOLANGITIS

PBC is seen in about 100–200 individuals per million, with a strong

female preponderance and a median age of ~50 years at the time of

diagnosis. The cause of PBC is unknown; it is characterized by portal

inflammation and necrosis of cholangiocytes in small- and mediumsized bile ducts. Cholestatic features prevail, and biliary cirrhosis is

characterized by an elevated bilirubin level and progressive liver failure. Liver transplantation is the treatment of choice for patients with

decompensated cirrhosis due to PBC. Ursodeoxycholic acid (UDCA) is

the first-line treatment that has some degree of efficacy by slowing the

rate of progression of the disease.

Antimitochondrial antibodies (AMAs) are present in ~95% of

patients with PBC. These autoantibodies recognize lipoic acid on the

inner mitochondrial membrane proteins that are enzymes of the pyruvate dehydrogenase complex (PDC), the branched-chain 2-oxoacid

dehydrogenase complex, and the 2-oxogluterate dehydrogenase complex. These autoantibodies are not pathogenic, but rather are useful

markers for making a diagnosis.

Pathology Histopathologic analyses of liver biopsies of patients

with PBC have resulted in identifying four distinct stages of the disease

as it progresses. The earliest lesion is termed chronic nonsuppurative

destructive cholangitis and is a necrotizing inflammatory process of the

portal tracts. Medium and small bile ducts are infiltrated with lymphocytes and undergo duct destruction. Mild fibrosis and sometimes bile

stasis can occur. With progression, the inflammatory infiltrate becomes

less prominent, but the number of bile ducts is reduced and there is

proliferation of smaller bile ductules. Increased fibrosis ensues with the

expansion of periportal fibrosis to bridging fibrosis. Finally, cirrhosis,

which may be micronodular or macronodular, develops.

Clinical Features Currently, most patients with PBC are middleaged women diagnosed well before the end-stage manifestations of

the disease are present, and as such, most patients are asymptomatic.

When symptoms are present, they most prominently include a significant degree of fatigue out of proportion to either the severity of

the liver disease or the age of the patient. Pruritus is seen in ~50% of

patients at the time of diagnosis, and it can be debilitating. It might be

intermittent and usually is most bothersome in the evening. In some

patients, pruritus can develop toward the end of pregnancy and can

be mistaken for cholestasis of pregnancy. Pruritus that presents prior

to the development of jaundice indicates severe disease and a poor

prognosis.

Physical examination can show jaundice and other complications

of chronic liver disease including hepatomegaly, splenomegaly, ascites,

and edema. Other features that are unique to PBC include hyperpigmentation, xanthelasma, and xanthomata, which are related to altered

cholesterol metabolism. Hyperpigmentation is evident on the trunk

and the arms and is seen in areas of exfoliation and lichenification

associated with progressive scratching related to the pruritus. Bone

pain resulting from osteopenia or osteoporosis is occasionally seen at

diagnosis.

Laboratory Findings Laboratory findings in PBC show cholestatic liver enzyme abnormalities with an elevation in γ-glutamyl transpeptidase and alkaline phosphatase (ALP) along with mild elevations

in aminotransferases (ALT and AST). Immunoglobulins, particularly

IgM, are typically increased. Hyperbilirubinemia usually is seen once

cirrhosis has developed. Thrombocytopenia, leukopenia, and anemia

may be seen in patients with portal hypertension and hypersplenism.

Liver biopsy shows characteristic features as described above and should

be evident to any experienced hepatopathologist. Up to 10% of patients

with characteristic PBC will have features of AIH (moderate to severe

interphase hepatitis on biopsy, elevated ALT >5× the upper limit of normal, and elevated IgG levels) as well and are defined as having “overlap”

syndrome. These patients are usually treated as PBC patients and may

progress to cirrhosis with the same frequency as typical PBC patients.

Some patients require immunosuppressive medications as well.

Diagnosis PBC should be considered in patients with chronic

cholestatic liver enzyme abnormalities. AMA testing may be negative

in as many as 5–10% of patients with PBC. These patients usually are

positive for other PBC-specific autoantibodies including sp100 or

gp210, although these tests are not universally available. Liver biopsy is

most important in this setting of AMA-negative PBC. In patients who

are AMA negative with cholestatic liver enzymes, PSC should be ruled

out by way of cholangiography.

TREATMENT

Primary Biliary Cholangitis

Treatment of the typical manifestations of cirrhosis is no different for PBC than for other forms of cirrhosis. UDCA has been

shown to improve both biochemical and histologic features of

the disease, thus slowing but not reversing or curing the disease.

Improvement is greatest when therapy is initiated early; the likelihood of significant improvement with UDCA is low in patients

with PBC who present with manifestations of cirrhosis. UDCA

is given in doses of 13–15 mg/kg per d; the medication is usually

well tolerated, although some patients have worsening pruritus

with initiation of therapy. A small proportion of patients may have

diarrhea or headache as a side effect of the drug. About 30–40% of

patients with PBC do not have a satisfactory response to UDCA;

about half of these patients will have significant improvement with

obeticholic acid. Patients with PBC require long-term follow-up by

a physician experienced with the disease. Certain patients may need

to be considered for liver transplantation should their liver disease

decompensate.

The main symptoms of PBC are fatigue and pruritus, and

symptom management is important. Several therapies have been

tried for treatment of fatigue, but none of them has been successful; frequent naps should be encouraged. Pruritus is treated

with antihistamines, narcotic receptor antagonists (naltrexone),

and rifampin. Cholestyramine, a bile salt–sequestering agent, has

been helpful in some patients but is somewhat tedious and difficult

to take. Plasmapheresis has been used rarely in patients with severe

intractable pruritus. There is an increased incidence of osteopenia

and osteoporosis in patients with cholestatic liver disease, and bone

density testing should be performed. Oral calcium and vitamin D

are also recommended. Treatment with a bisphosphonate should be

instituted when bone disease is identified.

■ PRIMARY SCLEROSING CHOLANGITIS

As in PBC, the cause of PSC remains unknown. PSC is a chronic

cholestatic syndrome that is characterized by diffuse inflammation and

fibrosis involving the entire biliary tree, resulting in chronic cholestasis.

2628 PART 10 Disorders of the Gastrointestinal System

This pathologic process ultimately results in obliteration of both the

intra- and extrahepatic biliary tree, leading to biliary cirrhosis, portal

hypertension, and liver failure. The cause of PSC remains unknown

despite extensive investigation into various mechanisms related to bacterial and viral infections, toxins, genetic predisposition, and immunologic mechanisms, all of which have been postulated to contribute to

the pathogenesis and progression of this syndrome.

Liver biopsy changes in PSC are not pathognomonic, and establishing the diagnosis of PSC must involve imaging of the biliary tree.

Pathologic changes occurring in PSC show bile duct proliferation as

well as ductopenia and fibrous cholangitis (pericholangitis). Periductal

fibrosis is occasionally seen on biopsy specimens and can be quite helpful in making the diagnosis. As the disease progresses, biliary cirrhosis

is the end-stage manifestation of PSC.

Clinical Features The usual clinical features of PSC are those found

in cholestatic liver disease, with fatigue, pruritus, steatorrhea, deficiencies of fat-soluble vitamins, and the associated consequences. As in PBC,

the fatigue is profound and nonspecific. Pruritus can often be debilitating and is related to the cholestasis. The severity of pruritus does not

correlate with the severity of the disease. Metabolic bone disease, as seen

in PBC, can occur with PSC and should be treated (see above).

Laboratory Findings Patients with PSC typically are identified

during an evaluation of abnormal liver enzymes. Most patients have

at least a twofold increase in ALP and may have elevated aminotransferases as well. Albumin levels may be decreased, and prothrombin

times are prolonged in a substantial proportion of patients at the time

of diagnosis. Some degree of correction of a prolonged prothrombin

time may occur with parenteral vitamin K. A small subset of patients

has aminotransferase elevations >5× the upper limit of normal and

may have features of AIH on biopsy indicating an overlap syndrome

between PSC and AIH. Autoantibodies are frequently positive in

patients with the overlap syndrome but are typically negative in

patients who only have PSC. One autoantibody, the perinuclear antineutrophil cytoplasmic antibody (pANCA), is positive in ~65% of

patients with PSC. Sixty to eighty percent of patients with PSC have

inflammatory bowel disease, predominately ulcerative colitis (UC);

thus, a colonoscopy is recommended at diagnosis.

Diagnosis The definitive diagnosis of PSC requires cholangiographic imaging. Over the past several years, magnetic resonance

imaging (MRI) with magnetic resonance cholangiopancreatography

(MRCP) has been used as the imaging technique of choice for initial

evaluation. Endoscopic retrograde cholangiopancreatography (ERCP)

should be performed if the MRCP provided suboptimal images or if

there is clinical (newly elevated total bilirubin or worsening pruritus)

or MRCP evidence of a dominant stricture. Typical cholangiographic

findings in PSC are multifocal stricturing and beading involving both

the intrahepatic and extrahepatic biliary tree. These strictures are typically short and with intervening segments of normal or slightly dilated

bile ducts that are distributed diffusely, producing the classic beaded

appearance. The gallbladder and cystic duct can be involved in up to

15% of cases. Gradually, biliary cirrhosis develops, and patients will

progress to decompensated liver disease with all the manifestations of

ascites, esophageal variceal hemorrhage, and encephalopathy.

TREATMENT

Primary Sclerosing Cholangitis

There is no specific proven treatment for PSC. Some clinicians

use UDCA at “PBC dosages” of 13–15 mg/kg per d with anecdotal

improvement, although no study has shown convincing evidence of

clinical benefit. A study of high-dose (28–30 mg/kg per d) UDCA

found it to be harmful. Endoscopic dilatation of dominant strictures

can be helpful, but the ultimate treatment is liver transplantation

when decompensated cirrhosis develops. Episodes of cholangitis

should be treated with antibiotics. A dreaded complication of PSC

is the development of cholangiocarcinoma, which is a relative contraindication to liver transplantation.

■ CARDIAC CIRRHOSIS

Definition Patients with long-standing right-sided congestive heart

failure may develop chronic liver injury and cardiac cirrhosis. This is

an increasingly uncommon, if not rare, cause of chronic liver disease

given the advances made in the care of patients with heart failure.

Etiology and Pathology In the case of long-term right-sided

heart failure, there is an elevated venous pressure transmitted via the

inferior vena cava and hepatic veins to the sinusoids of the liver, which

become dilated and engorged with blood. The liver becomes enlarged

and swollen, and with long-term passive congestion and relative ischemia due to poor circulation, centrilobular hepatocytes can become

necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend

to the periphery of the lobule outward until a unique pattern of fibrosis

causing cirrhosis can occur.

Clinical Features Patients typically have signs of congestive heart

failure and will manifest an enlarged firm liver on physical examination. ALP levels are characteristically elevated, and aminotransferases

may be normal or slightly increased, with AST usually higher than

ALT. It is unlikely that patients will develop variceal hemorrhage or

encephalopathy.

Diagnosis The diagnosis is usually made in someone with clear-cut

cardiac disease who has an elevated ALP and an enlarged liver. Liver

biopsy shows a pattern of fibrosis that can be recognized by an experienced hepatopathologist. Differentiation from Budd-Chiari syndrome

(BCS) can be made by seeing extravasation of red blood cells in BCS,

but not in cardiac hepatopathy. Veno-occlusive disease, now termed

sinusoidal obstructive syndrome, can also affect hepatic outflow and

has characteristic features on liver biopsy. Sinusoidal obstructive syndrome can be seen under the circumstances of conditioning for bone

marrow transplant with radiation and chemotherapy; it can also be

seen with the ingestion of certain herbal teas as well as pyrrolizidine

alkaloids. This is typically seen in Caribbean countries and rarely in

the United States. Treatment is based on management of the underlying

cardiac disease.

OTHER TYPES OF CIRRHOSIS

There are several other less common causes of chronic liver disease that

can progress to cirrhosis. These include inherited metabolic liver diseases such as hemochromatosis, Wilson’s disease, α1

 antitrypsin (α1

AT)

deficiency, and cystic fibrosis. For these disorders, the manifestations

of cirrhosis are similar, with some minor variations, to those seen in

other patients with other causes of cirrhosis.

Hemochromatosis is an inherited disorder of iron metabolism that

results in a progressive increase in hepatic iron deposition, which, over

time, can lead to a portal-based fibrosis progressing to cirrhosis, liver

failure, and hepatocellular cancer. While the frequency of hemochromatosis is relatively common, with genetic susceptibility occurring in

1 in 250 individuals, the frequency of end-stage manifestations due to

the disease is relatively low, and <5% of those patients who are genotypically susceptible will go on to develop severe liver disease from

hemochromatosis. Diagnosis is made with serum iron studies showing

an elevated transferrin saturation and an elevated ferritin level, along

with abnormalities identified by HFE mutation analysis. Treatment is

straightforward, with regular therapeutic phlebotomy.

Wilson’s disease is an inherited disorder of copper homeostasis with

failure to excrete excess amounts of copper, leading to an accumulation

in the liver. This disorder is relatively uncommon, affecting 1 in 30,000

individuals. Wilson’s disease typically affects adolescents and young

adults. Prompt diagnosis before end-stage manifestations become

irreversible can lead to significant clinical improvement. Diagnosis

requires determination of ceruloplasmin levels, which are low; 24-h

urine copper levels, which are elevated; typical physical examination

findings, including Kayser-Fleischer corneal rings; and characteristic liver biopsy findings. Treatment consists of copper-chelating

medications.

α1

AT deficiency results from an inherited disorder that causes abnormal folding of the α1

AT protein, resulting in failure of secretion of that

2629Cirrhosis and Its Complications CHAPTER 344

protein from the liver. It is unknown how the retained protein leads to

liver disease. Patients with α1

AT deficiency at greatest risk for developing chronic liver disease have the ZZ phenotype, but only ~10–20% of

such individuals will develop chronic liver disease. Diagnosis is made

by determining α1

AT levels and phenotype. Characteristic periodic

acid–Schiff (PAS)–positive, diastase-resistant globules are seen on liver

biopsy. The only effective treatment is liver transplantation, which is

curative.

Cystic fibrosis is an uncommon inherited disorder affecting whites

of northern European descent. A biliary-type cirrhosis can occur, and

some patients derive benefit from the chronic use of UDCA.

MAJOR COMPLICATIONS OF CIRRHOSIS

These include gastroesophageal variceal hemorrhage, splenomegaly,

ascites, hepatic encephalopathy, spontaneous bacterial peritonitis

(SBP), hepatorenal syndrome (HRS), and hepatocellular carcinoma

(Table 344-2). There are also more rare complications in the pulmonary system including hepatopulmonary syndrome and portopulmonary hypertension.

■ PORTAL HYPERTENSION

Portal hypertension is defined as the elevation of the hepatic venous

pressure gradient (HVPG) to >5 mmHg. Portal hypertension is caused

by a combination of two simultaneously occurring hemodynamic

processes: (1) increased intrahepatic resistance to the passage of blood

flow through the liver due to cirrhosis, regenerative nodules, and

microthrombi, and (2) increased splanchnic blood flow secondary to

vasodilation within the splanchnic vascular bed. In more advanced

stages, there is also activation of neurohumoral responses and vasoconstrictive systems resulting in sodium and water retention, increased

blood volume, and hyperdynamic circulatory system producing more

portal hypertension. There is usually an initial stage of compensated

cirrhosis with HVPG between 5 and 10 mmHg that can be asymptomatic

and last for ≥10 years, but when clinically significant portal hypertension

develops (defined as a HVPG ≥10 mmHg), there is substantial risk of

decompensation with variceal bleeding, ascites, or hepatic encephalopathy. With decompensation, median mortality is <2 years. Variceal hemorrhage is an immediate life-threatening problem with a 20–30% mortality

rate associated with each episode of bleeding. The portal venous system

normally drains blood from most of the GI tract including the stomach,

small and large intestines, spleen, pancreas, and gallbladder.

The causes of portal hypertension are usually subcategorized as

prehepatic, intrahepatic, and posthepatic (Table 344-3). Prehepatic

causes of portal hypertension are those affecting the portal venous system before it enters the liver; they include portal vein thrombosis and

splenic vein thrombosis. Posthepatic causes encompass those affecting the hepatic veins and venous drainage to the heart; they include

BCS and chronic right-sided cardiac congestion. Intrahepatic causes

account for >95% of cases of portal hypertension and are represented

by the major forms of cirrhosis. Intrahepatic causes of portal hypertension can be further subdivided into presinusoidal, sinusoidal, and

postsinusoidal causes. Postsinusoidal causes include veno-occlusive

disease, whereas presinusoidal causes include congenital hepatic fibrosis and schistosomiasis. Sinusoidal causes are related to cirrhosis from

various causes.

Cirrhosis is the most common cause of portal hypertension in the

United States, and clinically significant portal hypertension is present

in >60% of patients with cirrhosis. Portal vein obstruction may be

idiopathic or can occur in association with cirrhosis or with infection,

pancreatitis, or abdominal trauma.

Coagulation disorders that can lead to the development of portal

vein thrombosis include polycythemia vera; essential thrombocytosis;

deficiencies in protein C, protein S, antithrombin III, and factor V

Leiden; and abnormalities in the gene-regulating prothrombin production. Some patients may have a subclinical myeloproliferative disorder.

Clinical Features The three primary complications of portal

hypertension are gastroesophageal varices with hemorrhage, ascites,

and hypersplenism. Thus, patients may present with upper GI bleeding, which, on endoscopy, is found to be due to esophageal or gastric

varices; with the development of ascites along with peripheral edema;

or with an enlarged spleen with associated reduction in platelets and

white blood cells on routine laboratory testing.

ESOPHAGEAL VARICES Over the past decade, it has become common practice to screen known cirrhotics with endoscopy to look for

esophageal varices. Such screening studies have shown that approximately one-third of patients with histologically confirmed cirrhosis

have varices. Approximately 5–15% of cirrhotics per year develop

varices, and it is estimated that the majority of patients with cirrhosis

will develop varices over their lifetimes. Furthermore, it is anticipated

that roughly one-third of patients with varices will develop bleeding.

Several factors predict the risk of bleeding, including the severity of cirrhosis (Child-Pugh class, Model for End-Stage Liver Disease [MELD]

score); the height of wedged-hepatic vein pressure; the size of the varix;

the location of the varix; and certain endoscopic stigmata, including

red wale signs, hematocystic spots, diffuse erythema, bluish color,

cherry red spots, or white-nipple spots. Patients with tense ascites are

also at increased risk for bleeding from varices.

Diagnosis In patients with cirrhosis who are being followed chronically, the development of portal hypertension is usually revealed by the

presence of thrombocytopenia; the appearance of an enlarged spleen;

or the development of ascites, encephalopathy, and/or esophageal

varices with or without bleeding. In previously undiagnosed patients,

any of these features should prompt further evaluation to determine

the presence of portal hypertension and liver disease. Varices should

TABLE 344-2 Complications of Cirrhosis

Portal hypertension Coagulopathy

Gastroesophageal varices Factor deficiency

Portal hypertensive gastropathy Fibrinolysis

Splenomegaly, hypersplenism Thrombocytopenia

Ascites Bone disease

 Spontaneous bacterial peritonitis Osteopenia

Hepatorenal syndrome Osteoporosis

Type 1 Osteomalacia

Type 2 Hematologic abnormalities

Hepatic encephalopathy Anemia

Hepatopulmonary syndrome Hemolysis

Portopulmonary hypertension Thrombocytopenia

Malnutrition Neutropenia

TABLE 344-3 Classification of Portal Hypertension

Prehepatic

Portal vein thrombosis

Splenic vein thrombosis

Massive splenomegaly (Banti’s syndrome)

Hepatic

Presinusoidal

 Schistosomiasis

 Congenital hepatic fibrosis

Sinusoidal

 Cirrhosis—many causes

 Alcoholic hepatitis

Postsinusoidal

 Hepatic sinusoidal obstruction (veno-occlusive syndrome)

Posthepatic

Budd-Chiari syndrome

Inferior vena caval webs

Cardiac causes

 Restrictive cardiomyopathy

 Constrictive pericarditis

 Severe congestive heart failure

2630 PART 10 Disorders of the Gastrointestinal System

be identified by endoscopy. Contrasted-enhanced abdominal imaging, either by computed tomography (CT) or MRI, can be helpful

in demonstrating a nodular liver and in finding changes of portal

hypertension with intraabdominal collateral circulation. Rarely, the

HVPG is measured by interventional radiology. Patients with a gradient

>12 mmHg are at risk for variceal hemorrhage.

TREATMENT

Variceal Hemorrhage

Treatment for esophageal varices as a complication of portal hypertension is divided into two main categories: (1) primary prophylaxis

and (2) prevention of rebleeding once there has been an initial

variceal hemorrhage. Primary prophylaxis requires routine surveillance by endoscopy of all patients with cirrhosis. Upper endoscopies are recommended at diagnosis of compensated cirrhosis and

then every 2 years if the liver disease is active or every 3 years if

inactive (alcohol cessation, viral hepatitis eradication). Endoscopy

is also recommended at the time of hepatic decompensation. Once

varices that are at increased risk for bleeding are identified, usually

defined as medium or large varices or small varices with high-risk

stigmata or in decompensated cirrhosis, primary prophylaxis can be

achieved either through nonselective beta blockade (NSBB) titrated

with a goal heart rate of 55–60 beats/min with systolic blood pressure >90 mmHg or by variceal band ligation. Numerous placebocontrolled clinical trials of either propranolol or nadolol show a

lower risk of variceal hemorrhage and mortality related to variceal

hemorrhage but no clear benefit on overall survival.

Endoscopic variceal ligation (EVL) has been compared to NSBB

for primary prophylaxis against variceal bleeding, and EVL appears

to have equivalent efficacy. Two more recent trials comparing EVL

to carvedilol, a drug with NSBB and anti–α1

-adrenergic properties,

showed similar efficacy. Thus, either NSSB or EVL is effective for

primary prophylaxis of bleeding, and the choice should be based

on patient and physician preference and tolerability. Once primary

prophylaxis has been initiated, repeat endoscopy for surveillance of

varices is unnecessary.

The approach to patients once they have had a variceal bleed is

first to treat the acute bleed, which can be life-threatening, and then

to prevent further bleeding. Treatment of acute bleeding requires

both fluid and red blood cell replacement to stabilize hemodynamics. A recent randomized trial of restricted transfusion starting when

hemoglobin is <7 g/dL with a goal hemoglobin of 7–9 g/dL, compared to a more liberal strategy, resulted in reduced early rebleeding

and mortality. This strategy is recommended, although adjustments

should be made based on cardiac risks and hemodynamics. Correcting an elevated prothrombin time with fresh frozen plasma is not

recommended unless there is evidence of coagulopathy (bleeding

at other sites such as IV lines). The use of vasoconstricting agents,

usually somatostatin or octreotide, has been shown to improve initial

bleeding control and reduce transfusion requirements and all-cause

mortality. Prophylactic antibiotics, usually with ceftriaxone, started

prior to endoscopy result in reduced infections, recurrent bleeding,

and mortality. Balloon tamponade (Sengstaken-Blakemore tube or

Minnesota tube) can be used in patients who need stabilization prior

to endoscopic therapy or as a bridge to transjugular intrahepatic portosystemic shunt (TIPS) after endoscopic failure. Control of bleeding

can be achieved in the vast majority of cases; however, bleeding

recurs in the majority of patients if definitive endoscopic therapy has

not been instituted. Upper endoscopy is used as first-line treatment

to diagnose the cause of the bleeding and to control bleeding acutely

with EVL. When esophageal varices extend into the proximal stomach or the bleeding varices are entirely within the stomach, band

ligation is often unsuccessful. In these situations, consideration for a

TIPS should be made. This technique creates a portosystemic shunt

by a percutaneous approach using an expandable metal stent, which

is advanced under angiographic guidance to the hepatic veins and

then through the substance of the liver to create a direct portocaval

shunt. Encephalopathy can occur in as many as 20% of patients

after TIPS and is particularly problematic in elderly patients and in

patients with preexisting encephalopathy. TIPS is usually reserved

for individuals who fail or are unable to receive endoscopic therapy,

although there is emerging evidence that patient who are highly

selected to be at high risk for rebleeding may also benefit. TIPS can

sometimes be used as a bridge to transplantation, and all patients

requiring TIPS should be considered for transplant evaluation.

Some gastric varices are associated with a splenorenal shunt and

can be effectively treated with a balloon occluded retrograde transvenous obliteration (BRTO) of varices sometimes in combination

with a TIPS. Prevention of further bleeding is usually accomplished

with repeated variceal band ligation until varices are obliterated in

combination with NSBB. If recurrent variceal bleeding occurs, then

TIPS should be performed for long-term prevention of bleeding.

Once a TIPS has been performed, there is no need for further endoscopies for variceal surveillance; however, the TIPS should be periodically monitored with Doppler ultrasound for stenosis. (Fig. 344-3).

■ PORTAL HYPERTENSIVE GASTROPATHY

Portal hypertensive gastropathy can cause both acute clinical GI

bleeding and chronic bleeding resulting in iron-deficiency anemia. It

is associated with all causes of portal hypertension and is diagnosed by

characteristic endoscopy findings showing a snake skin–like mosaic

pattern of gastric mucosa often with central red or brown spots. When

there is bleeding, treatment is with NSBB and iron repletion. Refractory bleeding may respond to TIPS.

■ SPLENOMEGALY AND HYPERSPLENISM

Congestive splenomegaly with hypersplenism is common in patients

with portal hypertension and is usually the first indication of portal

hypertension. Clinical features include the presence of an enlarged

spleen on physical examination and the development of thrombocytopenia and leukopenia in patients who have cirrhosis. Some patients

will have significant left-sided and left upper quadrant abdominal pain

Recurrent acute bleeding

Endoscopic therapy

+

Pharmacologic therapy

Control of bleeding

Compensated cirrhosis

Child’s class A

TIPS

Consider liver

transplantation

evaluation

Decompensated cirrhosis

Child’s class B or C

Transplant evaluation

Endoscopic therapy or

beta blockers

Consider TIPS

Liver transplantation

FIGURE 344-3 Management of recurrent variceal hemorrhage. This algorithm

describes an approach to management of patients who have recurrent bleeding

from esophageal varices. Initial therapy is generally with endoscopic therapy often

supplemented by pharmacologic therapy. With control of bleeding, a decision

needs to be made as to whether patients should go on to transjugular intrahepatic

portosystemic shunt (TIPS; if they are Child’s class A) or if they should have TIPS

and be considered for transplant (if they are Child’s class B or C).

2631Cirrhosis and Its Complications CHAPTER 344

related to an enlarged spleen. Splenomegaly itself usually requires no

specific treatment.

■ ASCITES

Definition Ascites is the accumulation of fluid within the peritoneal cavity. Overwhelmingly, the most common cause of ascites is

portal hypertension related to cirrhosis; however, clinicians should

remember that malignant, infectious, and cardiac causes of ascites can

be present as well, and careful differentiation of these other causes is

obviously important for patient care.

Pathogenesis The presence of portal hypertension contributes to

the development of ascites in patients who have cirrhosis (Fig. 344-4).

There is an increase in intrahepatic resistance, causing increased portal

pressure, but there is also vasodilation of the splanchnic arterial system,

which, in turn, results in an increase in portal venous inflow. Both

abnormalities result in increased production of splanchnic lymph.

Vasodilating factors such as nitric oxide are responsible for the vasodilatory effect. There is activation of the renin-angiotensin-aldosterone

system with the development of hyperaldosteronism and activation of

the sympathetic nervous system as a consequence of a homeostatic

response caused by underfilling of the arterial circulation secondary to

arterial vasodilation in the splanchnic vascular bed. The renal effects

of increased aldosterone and activation of the sympathetic nervous system lead to sodium retention causing fluid accumulation and expansion of the extracellular fluid volume, resulting in peripheral edema

and ascites. Because the retained fluid is constantly leaking out of the

intravascular compartment into the peritoneal cavity, the sensation of

vascular filling is not achieved, and the process continues. Hypoalbuminemia from decreased synthetic function in a cirrhotic liver results

in reduced plasma oncotic pressure and contributes to the loss of fluid

from the vascular compartment into the peritoneal cavity.

Clinical Features Patients typically note an increase in abdominal girth that is often accompanied by the development of peripheral

edema. The development of ascites is often insidious, and it is surprising that some patients wait so long and become so distended before

seeking medical attention. Patients usually have at least 1–2 L of fluid

in the abdomen before they are aware that there is an increase. If ascitic

fluid is massive, respiratory function can be compromised, causing

dyspnea. Hepatic hydrothorax may also contribute to respiratory

symptoms. Patients with massive ascites are often malnourished and

have muscle wasting and excessive fatigue and weakness.

Diagnosis Diagnosis of ascites is by physical examination and is

often aided by abdominal imaging. Patients will have bulging flanks,

may have a fluid wave, or may have the presence of shifting dullness.

This is determined by taking patients from a supine position to lying

on either their left or right side and noting the movement of the

dullness to percussion. Subtle amounts of ascites can be detected by

ultrasound or CT scanning. Hepatic hydrothorax is more common on

the right side and implicates a rent in the diaphragm with free flow of

ascitic fluid into the thoracic cavity.

When patients present with ascites for the first time, it is recommended that a diagnostic paracentesis be performed to characterize

the fluid. This should include the determination of total protein and

albumin content, blood cell counts with differential, and cultures. In

the appropriate setting, amylase may be measured and cytology performed. In patients with cirrhosis, the protein concentration of the

ascitic fluid is low, usually <2.5 g/dL. The serum ascites-to-albumin

gradient (SAAG), calculated by subtracting the fluid albumin level

from the serum albumin level, has replaced the description of exudative or transudative fluid. When the SAAG is >1.1 g/dL, the cause

of the ascites is most likely due to portal hypertension; this is usually

in the setting of cirrhosis. Cardiac ascites can be identified by SAAG

>1.1 g/dL and ascites protein >2.5g/dL. When the SAAG is <1.1 g/dL,

infectious or malignant causes of ascites should be considered. When

ascitic fluid protein is very low, <1.5 g/dL, patients are at increased risk

for developing SBP. A high level of red blood cells in the ascitic fluid

usually signifies a traumatic tap but can also rarely occur with hepatocellular cancer or a ruptured omental varix. When the absolute level of

polymorphonuclear leukocytes is >250/μL, infection is likely.

TREATMENT

Ascites

Patients with small amounts of ascites can usually be managed

with dietary sodium restriction alone. Most average diets in the

United States contain 6–8 g of sodium per day, and if patients eat at

restaurants or fast-food outlets, the amount of sodium in their diet

can exceed this amount. Thus, it is often extremely difficult to get

patients to change their dietary habits to ingest 2 g of sodium per

day, equivalent to slightly more than three-quarters of a teaspoon

of salt, which is the recommended amount. Sodium educational

pamphlets are helpful. Often, a simple recommendation is to eat

fresh or frozen foods, avoiding canned or processed foods. When

a moderate amount of ascites is present, diuretic therapy is usually

necessary. Traditionally, spironolactone at 100 mg/d as a single dose

is started, and furosemide may be added at 40 mg/d, particularly in

patients who have peripheral edema. Failure of the diuretics suggests that patients may not be compliant with a low-sodium diet.

If compliance is confirmed and ascitic fluid is not being mobilized,

there should be incremental increases in spironolactone to a maximum of 400 mg/d and furosemide to 160 mg/d. If a large amount of

ascites is still present on diuretics in patients who are compliant with

a low-sodium diet, then they are defined as having refractory ascites,

and alternative treatment modalities including repeated largevolume paracentesis (LVP) or a TIPS procedure should be considered (Fig. 344-5). After LVP of ≥5 L, IV 25% albumin at a dose of

~8 g/L of removed ascites should be given to prevent circulatory

dysfunction. Multiple studies have shown that TIPS, although

effective at managing the ascites, does not improve survival. Unfortunately, TIPS is often associated with an increased frequency of

hepatic encephalopathy and must be considered carefully on a caseby-case basis. The prognosis for patients with cirrhosis with ascites

is poor, and some studies have shown that <50% of patients survive

2 years after the onset of ascites. Thus, there should be consideration for liver transplantation in patients with ascites. Patients with

cirrhosis and ascites are at increased risk for renal failure from certain medications including nonsteroidal anti-inflammatory drugs

and aminoglycosides; therefore, these medications should generally be avoided. Angiotensin-converting enzyme inhibitors and

angiotensin receptor blockers should be used cautiously with close

monitoring of blood pressure and renal function.

Cirrhosis

Portal hypertension

Splanchnic vasodilation

↑ Splanchnic pressure Arterial underfilling

Formation of ascites

Lymph formation

Activation of

vasoconstrictors and

antinatriuretic factors*

Sodium retention Plasma volume

expansion

FIGURE 344-4 Development of ascites in cirrhosis. This flow diagram illustrates the

importance of portal hypertension with splanchnic vasodilation in the development

of ascites. *Antinatriuretic factors include the renin-angiotensin-aldosterone

system and the sympathetic nervous system.

2632 PART 10 Disorders of the Gastrointestinal System

■ SPONTANEOUS BACTERIAL PERITONITIS

SBP is a common and severe complication of ascites characterized by

spontaneous infection of the ascitic fluid without an intraabdominal

source. In hospitalized patients with cirrhosis and ascites, SBP can

occur in up to 30% of individuals and can have a 25% in-hospital

mortality rate. Bacterial translocation is the presumed mechanism

for development of SBP, with gut flora traversing the intestine into

mesenteric lymph nodes, leading to bacteremia and seeding of the

ascitic fluid. The most common organisms are Escherichia coli and

other gut bacteria; however, gram-positive bacteria, including Streptococcus viridans, Staphylococcus aureus, and Enterococcus spp., can

also be found. If more than two organisms are identified, secondary

bacterial peritonitis due to a perforated viscus should be considered.

The diagnosis of SBP is made when the fluid sample has an absolute

neutrophil count >250/μL. Bedside cultures should be obtained by

direct injection of ascitic fluid into blood culture bottles. Patients with

ascites may present with fever, altered mental status, elevated white

blood cell count, abdominal pain or discomfort, and acute kidney

injury, or they may present without any of these features. Therefore, it

is necessary to have a high degree of clinical suspicion, and peritoneal

taps are recommended for most cirrhosis patients hospitalized with

ascites and cirrhosis complications or signs of infection. Treatment is

commonly with intravenous third-generation cephalosporin for 5 days.

In addition, intravenous albumin (1.5 g/kg body weight on day and

1.0 g/kg on day 3) has been shown to reduce the risk of renal failure

and to improve survival. In patients with variceal hemorrhage, the frequency of SBP is significantly increased, and prophylaxis against SBP

is recommended when a patient presents with upper GI bleeding. Furthermore, in patients who have had an episode (or multiple episodes)

of SBP and recovered, quinolone antibiotic prophylaxis should be given

to prevent recurrent SBP.

■ HEPATORENAL SYNDROME

HRS is a form of functional renal failure without renal pathology

that occurs in ~10% of patients with advanced cirrhosis or acute liver

failure. There are marked disturbances in the arterial renal circulation

in patients with HRS; these include an increase in vascular resistance

accompanied by a reduction in systemic vascular resistance. The reason for renal vasoconstriction is most likely multifactorial and is poorly

understood. The diagnosis is made usually in the presence of a large

amount of ascites in patients who have a stepwise progressive increase

in creatinine. Type 1 HRS is characterized by a progressive impairment

in renal function and a significant reduction in creatinine clearance

within 1–2 weeks of presentation. Type 2 HRS is characterized by a

reduction in glomerular filtration rate with an elevation of serum creatinine level, but it is stable and is associated with a better outcome than

that of type 1 HRS.

HRS requires exclusion of other causes of acute renal failure,

most notably volume depletion. Diuretics should be stopped, and

infusion of albumin 1 g/kg per day is recommended. Treatment is

with vasoconstrictors such as terlipressin (not currently available in

North America) or low-dose norepinephrine (requires intensive care

unit monitoring). Midodrine, an α-agonist, along with octreotide and

intravenous albumin are also commonly used in the United States.

The best therapy for HRS is liver transplantation; recovery of renal

function is typical in this setting. In patients with either type 1 or type

2 HRS, the prognosis is poor unless transplant can be achieved within

a short period of time.

■ HEPATIC ENCEPHALOPATHY

Portosystemic encephalopathy is a serious complication of chronic

liver disease and is broadly defined as an alteration in mental status and

cognitive function occurring in the presence of liver failure. In severe

acute liver injury, the development of encephalopathy is a requirement

for a diagnosis of acute liver failure and can be seen in association with

life-threatening brain edema, which is not a feature in chronic liver

disease. Encephalopathy is much more commonly seen in patients with

chronic liver disease. Gut-derived neurotoxins that are not removed

by the liver because of vascular shunting and decreased hepatic mass

reach the brain and cause the symptoms known as hepatic encephalopathy. Ammonia levels are typically elevated, but the correlation

between severity of liver disease and height of ammonia levels is often

poor, and most hepatologists do not rely on ammonia levels to make

a diagnosis or follow clinical progress. Other compounds and metabolites that may contribute to the development of encephalopathy include

certain false neurotransmitters and mercaptans.

Clinical Features In acute liver failure, changes in mental status

can occur rapidly. Brain edema can be seen in these patients, with

severe encephalopathy associated with swelling of the gray matter.

Cerebral herniation is a feared complication of brain edema in acute

liver failure, and treatment to decrease edema is with mannitol and

judicious use of intravenous fluids.

In patients with cirrhosis, encephalopathy is often found as a

result of certain precipitating events such as hypokalemia, infection,

an increased dietary protein load, or volume depletion. Patients may

be confused or exhibit a change in personality. They may actually be

quite violent and difficult to manage; alternatively, patients may be

very sleepy and difficult to rouse. Precipitating events are common, so

they should be sought carefully. If patients have ascites, this should be

tapped to rule out infection. Evidence of GI bleeding should be sought,

and patients should be appropriately hydrated. Electrolytes should be

measured and abnormalities corrected. In patients presenting with

encephalopathy, asterixis is often present. Asterixis can be elicited by

having patients extend their arms and bend their wrists back. Patients

who are encephalopathic have a “liver flap”—that is, a sudden forward

movement of the wrist. This requires patients to be able to cooperate

with the examiner. Alternative causes for altered mental status should

also be considered.

The diagnosis of hepatic encephalopathy is clinical and requires

an experienced clinician to recognize and put together all the various

features. Often when patients have encephalopathy for the first time,

they (and/or their caregivers) are unaware of what is transpiring, but

once they have been through the experience, they can identify when

this is developing in subsequent situations and can often self-medicate

to prevent the development or worsening of encephalopathy.

TREATMENT

Hepatic Encephalopathy

Treatment is multifactorial and includes management of the abovementioned precipitating factors. Sometimes hydration and correction of electrolyte imbalance are all that is necessary. In the

past, restriction of dietary protein was used; however, the negative

impact of that maneuver on overall nutrition is thought to outweigh

the benefit, and it is thus strongly discouraged. The mainstay of

Symptomatic ascites

Large-volume paracentesis (LVP) + albumin

Dietary sodium restriction + diuretics

Ascites reaccumulation

Consider TIPS Continue LVP with

albumin as needed

Consider liver

transplantation

FIGURE 344-5 Treatment of refractory ascites. In patients who develop azotemia

in the course of receiving diuretics in the management of their ascites, some will

require repeated large-volume paracentesis (LVP), some may be considered for

transjugular intrahepatic portosystemic shunt (TIPS), and some would be good

candidates for liver transplantation. These decisions are all individualized.

2633 Liver Transplantation CHAPTER 345

treatment for encephalopathy is to use lactulose, a nonabsorbable disaccharide, which results in colonic acidification. Catharsis

ensues, contributing to the elimination of nitrogenous products in

the gut that are responsible for the development of encephalopathy.

The goal of lactulose therapy is to promote two to three soft stools

per day. Patients are asked to titrate their amount of ingested lactulose to achieve the desired effect. Lactulose is usually continued

after the initial episode of encephalopathy. Poorly absorbed antibiotics are often used as adjunctive therapies for patients who have

a difficult time with lactulose. The alternating administration of

neomycin and metronidazole has been used in the past to reduce

the individual side effects of each: neomycin for renal insufficiency

and ototoxicity and metronidazole for peripheral neuropathy. More

recently, rifaximin at 550 mg twice daily has been very effective

in preventing recurrent encephalopathy. Zinc supplementation is

sometimes helpful and is relatively harmless. The development

of encephalopathy in patients with chronic liver disease is a poor

prognostic sign, but this complication can be managed in the vast

majority of patients.

■ LIVER-LUNG SYNDROMES

Hepatopulmonary syndrome (HPS) is characterized by arterial hypoxemia in a patient with cirrhosis without significant lung disease. The

liver disease causes intrapulmonary vascular dilations resulting in

blood shunting past alveoli and significant ventilation-perfusion mismatch. Clinical symptoms include dyspnea and platypnea. HPS is common, occurring in 4–32% of patients with cirrhosis; however, it is often

mild. Diagnosis involves demonstrating hypoxemia, without evidence

of significant lung disease, and shunt on bubble echocardiography.

Treatment is with oxygen supplementation and liver transplantation.

Portopulmonary hypertension (PPHT) is pulmonary hypertension

in a patient with portal hypertension. The portal hypertension results

in the production of vasoconstrictor substances that affect the pulmonary artery. Many patients are asymptomatic, especially early in

the disease; however, they later can develop dyspnea on exertion and

fatigue. PPHT is rare, occurring in ~5% of patients with advanced

cirrhosis. Diagnosis includes initial identification on echocardiogram

and confirmation on right heart catheterization showing elevated mean

pulmonary artery pressure, elevated pulmonary vascular resistance,

and normal pulmonary capillary wedge pressure. Prognosis is poor,

although liver transplantation after effective reduction in pulmonary

artery pressure with vasodilatory medications can be effective.

■ MALNUTRITION IN CIRRHOSIS

Because the liver is principally involved in the regulation of protein

and energy metabolism in the body, it is not surprising that patients

with advanced liver disease are commonly malnourished. Once

patients become cirrhotic, they are more catabolic, and muscle protein is metabolized. There are multiple factors that contribute to the

malnutrition of cirrhosis, including poor dietary intake, alterations in

gut nutrient absorption, and alterations in protein metabolism. Close

attention to food intake is helpful in preventing patients from becoming catabolic. General recommendations include multiple small meals

including a late evening snack with total calories of 25–30 kcal per kg

of ideal body weight per day and 1.2–1.5 g of protein per kg of ideal

body weight per day.

■ ABNORMALITIES IN COAGULATION

Coagulation disorders in cirrhosis are poorly understood, and typical

clinical measures of coagulation, such as the prothrombin time and

international normalized ratio, are not reliable measures of clotting

ability. There is decreased synthesis of both pro- and anticoagulant factors and thus some rebalancing in coagulation; however, the coagulation cascade can easily tip toward thrombosis or bleeding. In addition,

patients may have thrombocytopenia from hypersplenism due to portal

hypertension and some platelet dysfunction, which is counterbalanced

with increased von Willebrand factor. Adequate thrombin formation

can occur with platelet levels from cirrhosis patients >50,000–60,000/L.

Synthesis of vitamin K–dependent clotting factors II, VII, IX, and X

is diminished in patients with chronic cholestatic syndromes because

absorption of vitamin K requires good bile flow. Intravenous or intramuscular vitamin K can quickly correct this abnormality. Overall, the

status of coagulation in a cirrhotic patient needs to be judged clinically

rather than relying on current laboratory tests.

■ BONE DISEASE IN CIRRHOSIS

Osteoporosis is common in patients with chronic cholestatic liver

disease because of malabsorption of vitamin D and decreased calcium

ingestion. The rate of bone resorption exceeds that of new bone formation in patients with cirrhosis, resulting in bone loss. Dual-energy x-ray

absorptiometry (DEXA) is a useful method for determining osteoporosis or osteopenia. When a DEXA scan shows osteoporosis, treatment

with bisphosphonates is effective.

■ HEMATOLOGIC ABNORMALITIES IN CIRRHOSIS

Numerous hematologic manifestations of cirrhosis are present, including anemia from a variety of causes including hypersplenism, hemolysis, iron deficiency, and perhaps folate deficiency from malnutrition.

Macrocytosis is a common abnormality in red blood cell morphology

seen in patients with chronic liver disease, and neutropenia may be a

result of hypersplenism.

■ FURTHER READING

AASLD/IDSA HCV Guidance Panel: Hepatitis C guidance 2019

update: AASLD-IDSA recommendations for testing, managing, and

treating hepatitis C virus infection. Hepatology 71:686, 2020.

Biggins SW et al: Diagnosis, evaluation and management of ascites

and hepatorenal syndrome: 2021 Practice guidance by the American

Association for the Study of Liver Diseases. Hepatology 74:1014,

2021.

Garcia-Tsao G et al: Portal hypertensive bleeding in cirrhosis: Risk

stratification, diagnosis and management: 2016 practice guidance by

the American Association for the Study of Liver Diseases. Hepatology

65:310, 2017.

Terrault NA et al: Update on prevention, diagnosis and treatment of

chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology

67:1560, 2018.

Vilstrup H et al: Hepatic encephalopathy in chronic liver disease:

2014 Practice Guideline by the American Association for the Study

of Liver Diseases and the European Association for the Study of the

Liver. Hepatology 60:715, 2014.

345 Liver Transplantation

Raymond T. Chung, Jules L. Dienstag

Liver transplantation—the replacement of the native, diseased liver by

a normal organ (allograft)—has matured from an experimental procedure reserved for desperately ill patients to an accepted, lifesaving

operation applied more optimally in the natural history of end-stage

liver disease. The preferred and technically most advanced approach

is orthotopic transplantation, in which the native organ is removed and

the donor organ is inserted in the same anatomic location. Pioneered

in the 1960s by Thomas Starzl at the University of Colorado and, later, at

the University of Pittsburgh and by Roy Calne in Cambridge, England,

liver transplantation is now performed routinely worldwide. Success

measured as 1-year survival has improved from ~30% in the 1970s to

>90% today. These improved prospects for prolonged survival resulted

from refinements in operative technique, improvements in organ procurement and preservation, advances in immunosuppressive therapy,

and, perhaps most influentially, more enlightened patient selection and

timing. Despite the perioperative morbidity and mortality, the technical

2634 PART 10 Disorders of the Gastrointestinal System

and management challenges of the procedure, and its costs, liver transplantation has become the approach of choice for selected patients

whose chronic or acute liver disease is progressive, life-threatening,

and unresponsive to medical therapy. Based on the current level of success, the number of liver transplants has continued to grow each year;

in 2020, 8906 patients received liver allografts in the United States. Still,

the demand for new livers continues to outpace availability; as of 2021,

11,710 patients in the United States were on a waiting list for a donor

liver. In response to this drastic shortage of donor organs, many transplantation centers supplement deceased-donor liver transplantation

with living-donor transplantation.

INDICATIONS

Potential candidates for liver transplantation are children and adults

who, in the absence of contraindications (see below), suffer from

severe, irreversible liver disease for which alternative medical or surgical treatments have been exhausted or are unavailable. Timing of the

operation is of critical importance. Indeed, improved timing and better

patient selection are felt to have contributed more to the increased

success of liver transplantation in the 1980s and beyond than all the

impressive technical and immunologic advances combined. Although

the disease should be advanced, and although opportunities for

spontaneous or medically induced stabilization or recovery should be

allowed, the procedure should be done sufficiently early to give the

surgical procedure a fair chance for success. Ideally, transplantation

should be considered in patients with end-stage liver disease who are

experiencing or have experienced a life-threatening complication of

hepatic decompensation or whose quality of life has deteriorated to

unacceptable levels. Although patients with well-compensated cirrhosis can survive for many years, many patients with quasi-stable chronic

liver disease have much more advanced disease than may be apparent.

As discussed below, the better the status of the patient prior to transplantation, the higher will be its anticipated success rate. The decision

about when to transplant is complex and requires the combined judgment of an experienced team of hepatologists, transplant surgeons,

anesthesiologists, and specialists in support services, not to mention

the well-informed consent of the patient and the patient’s family.

■ TRANSPLANTATION IN CHILDREN

Indications for transplantation in children are listed in Table 345-1.

The most common is biliary atresia. Inherited or genetic disorders

of metabolism associated with liver failure constitute another major

TABLE 345-1 Indications for Liver Transplantation

CHILDREN ADULTS

Biliary atresia Primary biliary cholangitis

Neonatal hepatitis Secondary biliary cirrhosis

Congenital hepatic fibrosis Primary sclerosing cholangitis

Alagille’s syndromea Autoimmune hepatitis

Byler’s diseaseb Caroli’s diseasec

α1

 Antitrypsin deficiency Cryptogenic cirrhosis

Inherited disorders of metabolism Chronic hepatitis with cirrhosis

Wilson’s disease Hepatic vein thrombosis

Tyrosinemia Fulminant hepatitis

Glycogen storage diseases Alcohol-associated cirrhosis

Lysosomal storage diseases Chronic viral hepatitis

Protoporphyria Primary hepatocellular malignancies

Crigler-Najjar disease type I Hepatic adenomas

Familial hypercholesterolemia Nonalcoholic steatohepatitis

Primary hyperoxaluria type I Familial amyloid polyneuropathy

Hemophilia

a

Arteriohepatic dysplasia, with paucity of bile ducts, and congenital malformations,

including pulmonary stenosis. b

Intrahepatic cholestasis, progressive liver failure,

and mental and growth retardation. c

Multiple cystic dilatations of the intrahepatic

biliary tree.

indication for transplantation in children and adolescents. In CriglerNajjar disease type I and in certain hereditary disorders of the urea

cycle and of amino acid or lactate-pyruvate metabolism, transplantation may be the only way to prevent impending deterioration of

central nervous system function, despite the fact that the native liver

is structurally normal. Combined heart and liver transplantation has

yielded dramatic improvement in cardiac function and in cholesterol

levels in children with homozygous familial hypercholesterolemia;

combined liver and kidney transplantation has been successful in

patients with primary hyperoxaluria type I. In hemophiliacs with

transfusion-associated hepatitis and liver failure, liver transplantation

has been associated with recovery of normal factor VIII synthesis.

■ TRANSPLANTATION IN ADULTS

Liver transplantation is indicated for end-stage cirrhosis of all causes

(Table 345-1). In sclerosing cholangitis and Caroli’s disease (multiple

cystic dilatations of the intrahepatic biliary tree), recurrent infections

and sepsis associated with inflammatory and fibrotic obstruction

of the biliary tree may be an indication for transplantation. Because

prior biliary surgery complicates and is a relative contraindication

for liver transplantation, surgical diversion of the biliary tree has

been all but abandoned for patients with sclerosing cholangitis. In

patients who undergo transplantation for hepatic vein thrombosis

(Budd-Chiari syndrome), postoperative anticoagulation is essential;

underlying myeloproliferative disorders may have to be treated but are

not a contraindication to liver transplantation. If a donor organ can

be located quickly, before life-threatening complications—including

cerebral edema—set in, patients with acute liver failure are candidates

for liver transplantation. Currently, alcohol-associated liver disease,

chronic hepatitis C, and nonalcoholic fatty liver disease (NAFLD) are

the most common indications for liver transplantation, accounting

for >40% of all adult candidates who undergo the procedure. Patients

with alcohol-associated cirrhosis can be considered as candidates for

transplantation if they meet strict criteria for abstinence and reform;

however, these criteria still do not prevent recidivism in up to a quarter

of cases. In highly selected cases in a limited but growing number of

centers, transplantation for severe acute alcohol-associated hepatitis

has been performed with success; however, because patients with acute

alcohol-associated hepatitis are still actively using alcohol and because

continued alcohol abuse remains a concern, acute alcohol-associated

hepatitis is not a routine indication for liver transplantation. Patients

with chronic hepatitis C have early allograft and patient survival

comparable to those of other subsets of patients after transplantation; however, reinfection in the donor organ is universal, recurrent

hepatitis C had been insidiously progressive, with allograft cirrhosis

and failure occurring at a higher frequency beyond 5 years. Fortunately, with the introduction of highly effective direct-acting antiviral

(DAA) agents targeting hepatitis C virus (HCV), allograft outcomes

have improved substantially. In patients with chronic hepatitis B, in

the absence of measures to prevent recurrent hepatitis B, survival after

transplantation is reduced by ~10–20%; however, prophylactic use of

hepatitis B immune globulin (HBIg) during and after transplantation

increases the success of transplantation to a level comparable to that

seen in patients with nonviral causes of liver decompensation. Specific oral antiviral drugs (e.g., entecavir, tenofovir disoproxil fumarate,

tenofovir alafenamide) (Chap. 341) can be used both for prophylaxis

against and for treatment of recurrent hepatitis B, facilitating further

the management of patients undergoing liver transplantation for endstage hepatitis B; most transplantation centers rely on antiviral drugs

with or without HBIg to manage patients with hepatitis B. Issues of

disease recurrence are discussed in more detail below. Patients with

nonmetastatic primary hepatobiliary tumors—primary hepatocellular

carcinoma (HCC), cholangiocarcinoma, hepatoblastoma, angiosarcoma, epithelioid hemangioendothelioma, and multiple or massive

hepatic adenomata—have undergone liver transplantation; however,

for some hepatobiliary malignancies, overall survival is significantly

lower than that for other categories of liver disease. Most transplantation centers have reported 5-year recurrence-free survival rates in

patients with unresectable HCC for single tumors <5 cm in diameter

2635 Liver Transplantation CHAPTER 345

or for three or fewer lesions all <3 cm comparable to those seen in

patients undergoing transplantation for nonmalignant indications.

Consequently, liver transplantation is currently restricted to patients

whose hepatic malignancies meet these criteria. Expanded criteria for

patients with HCC continue to be evaluated. Because the likelihood

of recurrent cholangiocarcinoma is very high, only highly selected

patients with limited disease are being evaluated for transplantation

after intensive chemotherapy and radiation.

CONTRAINDICATIONS

Absolute contraindications for transplantation include life-threatening

systemic diseases, uncontrolled extrahepatic bacterial or fungal infections, preexisting advanced cardiovascular or pulmonary disease, multiple uncorrectable life-threatening congenital anomalies, metastatic

malignancy, and active drug or alcohol abuse (Table 345–2). Because

carefully selected patients in their sixties and even seventies have

undergone transplantation successfully, advanced age per se is no longer considered an absolute contraindication; however, in older patients,

a more thorough preoperative evaluation should be undertaken to

exclude ischemic cardiac disease and other comorbid conditions.

Advanced age (>70 years), however, should be considered a relative

contraindication—that is, a factor to be considered with other relative

contraindications. Other relative contraindications include portal vein

thrombosis, preexisting renal disease not associated with liver disease (which may prompt consideration of combined liver and kidney

transplantation), intrahepatic or biliary sepsis, severe hypoxemia (Po2

<50 mmHg) resulting from right-to-left intrapulmonary shunts, portopulmonary hypertension with high mean pulmonary artery pressures

(>35 mmHg), previous extensive hepatobiliary surgery, any uncontrolled serious psychiatric disorder, and lack of sufficient social supports. Any one of these relative contraindications is insufficient in and

of itself to preclude transplantation. For example, the problem of portal

vein thrombosis can be overcome by constructing a graft from the

donor liver portal vein to the recipient’s superior mesenteric vein. Now

that combination antiretroviral therapy has dramatically improved the

survival of persons with HIV infection (Chap. 202), and because endstage liver disease caused by chronic hepatitis C and B has emerged

as a serious source of morbidity and mortality in the HIV-infected

population, liver transplantation has now been performed successfully

in selected HIV-positive persons who have excellent control of HIV

infection. Selected patients with CD4+ T-cell counts >100/μL and

with pharmacologic suppression of HIV viremia have undergone

transplantation for end-stage liver disease. HIV-infected persons who

have received liver allografts for end-stage liver disease resulting from

chronic hepatitis B have experienced survival rates comparable to those

of HIV-negative persons undergoing transplantation for the same indication. In contrast, recurrent HCV in the allograft has until recently

limited long-term success in persons with HCV-related end-stage

liver disease. Again, the availability of DAA agents targeting HCV (see

below and Chap. 341) is expected has improved allograft outcomes

significantly.

TECHNICAL CONSIDERATIONS

■ DECEASED-DONOR SELECTION

Deceased-donor livers for transplantation are procured primarily from

victims of head trauma. Organs from brain-dead donors up to age 60

are acceptable if the following criteria are met: hemodynamic stability,

adequate oxygenation, absence of bacterial or fungal infection, absence

of abdominal trauma, absence of hepatic dysfunction, and serologic

exclusion of hepatitis B virus (HBV), HCV, and HIV. Occasionally,

organs from donors with hepatitis B and C are used, particularly for

recipients with prior hepatitis B and C, respectively. Organs from

donors with antibodies to hepatitis B core antigen (anti-HBc) can also

be used when the need is especially urgent, and recipients of these

organs are treated prophylactically with antiviral drugs. Increasingly,

with the early administration of highly effective DAA agents, organs

from donors with hepatitis C have been used successfully in previously

uninfected recipients. Cardiovascular and respiratory functions are

maintained artificially until the liver can be removed. Transplantation of organs procured from deceased donors who have succumbed

to cardiac death can be performed successfully under selected circumstances, when ischemic time is minimized and liver histology

preserved. Encouraging improvements in normothermic ex vivo liver

perfusion techniques may make broader use of these organs possible.

Compatibility in ABO blood group and organ size between donor and

recipient are important considerations in donor selection; however,

ABO-incompatible, split-liver, or reduced-donor-organ allografts can

be performed in emergencies or marked donor scarcity. Tissue typing

for human leukocyte antigen (HLA) matching is not required, and

preformed cytotoxic HLA antibodies do not preclude liver transplantation. Following perfusion with cold electrolyte solution, the donor

liver is removed and packed in ice. The use of University of Wisconsin

(UW) solution, rich in lactobionate and raffinose, has permitted the

extension of cold ischemic time up to 20 h; however, 12 h may be a

more reasonable limit. Improved techniques for harvesting multiple

organs from the same donor have increased the availability of donor

livers, but the availability of donor livers is far outstripped by the

demand. Currently in the United States, all donor livers are distributed

through a nationwide organ-sharing network (United Network for

Organ Sharing [UNOS]) designed to allocate available organs based

on regional considerations and recipient acuity. Recipients who have

the highest disease severity generally have the highest priority, but

allocation strategies that balance highest urgency against best outcomes continue to evolve to distribute deceased-donor organs most

effectively. Allocation based on the Child-Turcotte-Pugh (CTP) score,

which uses five clinical variables (encephalopathy stage, ascites, bilirubin, albumin, and prothrombin time) and waiting time, has been

replaced by allocation based on urgency alone, calculated using the

Model for End-Stage Liver Disease (MELD) score. The MELD score is

based on a mathematical model that includes bilirubin, creatinine, and

prothrombin time expressed as international normalized ratio (INR)

(Table 345-3). Neither waiting time (except as a tie breaker between

two potential recipients with the same MELD scores) nor posttransplantation outcome is taken into account, but use of the MELD score

has been shown to reduce waiting list mortality, to reduce waiting time

prior to transplantation, to be the best predictor of pretransplantation

mortality, to satisfy the prevailing view that medical need should be the

TABLE 345-2 Contraindications to Liver Transplantation

ABSOLUTE RELATIVE

Uncontrolled extrahepatobiliary

infection

Age >70

Active, untreated sepsis Prior extensive hepatobiliary surgery

Uncorrectable, life-limiting congenital

anomalies

Portal vein thrombosis

Active substance abuse Renal failure not attributable to

liver disease (consider dual organ

transplantation)

Advanced cardiopulmonary disease Previous extrahepatic malignancy (not

including nonmelanoma skin cancer)

Extrahepatobiliary malignancy (not

including nonmelanoma malignancy

skin cancer)

Severe obesity

Metastatic malignancy to the liver Severe malnutrition/wasting

Cholangiocarcinoma (except those

tumors that fit into protocols)

Medical noncompliance

AIDS HIV seropositivity with failure to control

HIV viremia or CD4 <100/μL

Life-threatening systemic diseases Intrahepatic sepsis

Severe hypoxemia secondary to rightto-left intrapulmonary shunts (Po2

 <50

mmHg)

Severe pulmonary hypertension (mean

pulmonary artery pressure >35 mmHg)

Uncontrolled psychiatric disorder

2636 PART 10 Disorders of the Gastrointestinal System

decisive determinant, and to eliminate both the subjectivity inherent

in the CTP scoring system (presence and degree of ascites and hepatic

encephalopathy) and the differences in waiting times among different

regions of the country. Data indicate that liver recipients with MELD

scores <15 experienced higher posttransplantation mortality rates than

similarly classified patients who remained on the waiting list. This

observation led to the modification of UNOS policy to allocate donor

organs to candidates with MELD scores exceeding 15 within the local

or regional procurement organization before offering the organ to local

patients whose scores are <15. In 2016, the MELD score was modified

to incorporate serum sodium, another important predictor of survival

in liver transplantation candidates (the MELD-Na score).

The highest priority (status 1) continues to be reserved for patients

with fulminant hepatic failure or primary graft nonfunction. Because

candidates for liver transplantation who have HCC may not be sufficiently decompensated to compete for donor organs based on urgency

criteria alone and because protracted waiting for deceased-donor

organs often results in tumor growth beyond acceptable limits for

transplantation, such patients are assigned disease-specific MELD

points (Table 345–3). Other disease-specific MELD exceptions include

portopulmonary hypertension, hepatopulmonary syndrome, familial

amyloid polyneuropathy, primary hyperoxaluria (necessitating liverkidney transplantation), cystic fibrosis liver disease, and highly selected

cases of hilar cholangiocarcinoma.

■ LIVING-DONOR TRANSPLANTATION

Occasionally, especially for liver transplantation in children, one

deceased-donor organ can be split between two recipients (one adult

and one child). A more viable alternative, transplantation of the right

lobe of the liver from a healthy adult donor into an adult recipient, has

gained increased popularity. Living-donor transplantation of the left

lobe (left lateral segment), introduced in the early 1990s to alleviate

the extreme shortage of donor organs for small children, accounts

currently for approximately one-third of all liver transplantation procedures in children. Driven by the shortage of deceased-donor organs,

living-donor transplantation involving the more sizable right lobe is

being considered with increasing frequency in adults; however, livingdonor liver transplantation cannot be expected to solve the donor

organ shortage; 524 such procedures were done in 2019, representing

only ~4% of all liver transplant operations done in the United States.

Living-donor transplantation can reduce waiting time and cold

ischemia time; is done under elective, rather than emergency, circumstances; and may be lifesaving in recipients who cannot afford to wait

for a deceased donor. The downside, of course, is the risk to the healthy

donor (a mean of 10 weeks of medical disability; biliary complications in ~5%; postoperative complications such as wound infection,

small-bowel obstruction, and incisional hernias in 9–19%; and even, in

0.2–0.4%, death) as well as the increased frequency of biliary (15–32%)

and vascular (10%) complications in the recipient. Potential donors

must participate voluntarily without coercion, and transplantation

teams should go to great lengths to exclude subtle coercive or inappropriate psychological factors as well as outline carefully to both donor

and recipient the potential benefits and risks of the procedure. Donors

for the procedure should be 18–60 years old; have a compatible blood

type with the recipient; have no chronic medical problems or history of

major abdominal surgery; be related genetically or emotionally to the

recipient; and pass an exhaustive series of clinical, biochemical, and

serologic evaluations to unearth disqualifying medical disorders. The

recipient should meet the same UNOS criteria for liver transplantation

as recipients of a deceased donor allograft.

■ SURGICAL TECHNIQUE

Removal of the recipient’s native liver is technically difficult, particularly in the presence of portal hypertension with its associated collateral circulation and extensive varices and especially in the presence

of scarring from previous abdominal operations. The combination of

portal hypertension and coagulopathy (elevated prothrombin time and

thrombocytopenia) may translate into large blood product transfusion

requirements. After the portal vein and infrahepatic and suprahepatic

inferior vena cava are dissected, the hepatic artery and common bile

duct are dissected. Then the native liver is removed and the donor

organ inserted. During the anhepatic phase, coagulopathy, hypoglycemia, hypocalcemia, and hypothermia are encountered and must

be managed by the anesthesiology team. Caval, portal vein, hepatic

artery, and bile duct anastomoses are performed in succession, the last

by end-to-end suturing of the donor and recipient common bile ducts

(Fig. 345-1) or by choledochojejunostomy to a Roux-en-Y loop if the

recipient common bile duct cannot be used for reconstruction (e.g., in

sclerosing cholangitis). A typical transplant operation lasts 8 h, with a

range of 6–18 h. Because of excessive bleeding, large volumes of blood,

blood products, and volume expanders may be required during surgery;

however, blood requirements have fallen sharply with improvements in

surgical technique, blood-salvage interventions, and experience.

As noted above, emerging alternatives to orthotopic liver transplantation include split-liver grafts, in which one donor organ is divided

and inserted into two recipients, and living-donor procedures, in which

part of the left (for children), the left (for children or small adults), or

TABLE 345-3 United Network for Organ Sharing (UNOS)

Liver Transplantation Waiting List Criteria

Status 1 Fulminant hepatic failure (including primary graft nonfunction

and hepatic artery thrombosis within 7 days after transplantation

as well as acute decompensated Wilson’s disease)a

The Model for End-Stage Liver Disease (MELD)-Na score, on a continuous

scale,b

 determines allocation of the remainder of donor organs. This model is

based on the following calculation:

MELD = 3.78 × loge

 bilirubin (mg/100 mL) + 11.2 × loge

 international normalized ratio

(INR) + 9.57 × loge

 creatinine (mg/100 mL) + 6.43.c,d,e

MELD-Na = MELD + 1.32 * (137 – Na [meq/L]) – [0.033 * MELD * (137 – Na [meq/L])

Online calculators to determine MELD scores are available, such as the following:

https://optn.transplant.hrsa.gov/resources/allocation-calculators/meld-calculator/

a

For children <18 years of age, status 1 includes acute or chronic liver failure plus

hospitalization in an intensive care unit or inborn errors of metabolism. Status 1 is

retained for those persons with fulminant hepatic failure and supersedes the MELD

score. b

The MELD scale is continuous, with 34 levels ranging between 6 and 40 (scores

above 40 are categorized as 40). Donor organs usually do not become available unless

the MELD score exceeds 20. c

Patients with stage T2 hepatocellular carcinoma receive

22 disease-specific points. d

Creatinine is included because renal function is a validated

predictor of survival in patients with liver disease. For adults undergoing dialysis twice

a week, the creatinine in the equation is set to 4 mg/100 mL. e

For children <18 years of

age, the Pediatric End-Stage Liver Disease (PELD) scale is used. This scale is based

on albumin, bilirubin, INR, growth failure, and age. Status 1 is retained.

Donor

liver

Suprahepatic

vena cava

Hepatic artery

Portal vein

Infrahepatic vena cava

Common bile duct

FIGURE 345-1 The anastomoses in orthotopic liver transplantation. The anastomoses

are performed in the following sequence: (1) suprahepatic and infrahepatic vena

cava, (2) portal vein, (3) hepatic artery, and (4) common bile duct-to-duct anastomosis.

(From JL Dienstag, AB Cosimi: Liver transplantation—a vision realized. N Engl J Med

367:1483, 2012. Copyright © 2012 Massachusetts Medical Society. Reprinted with

permission from Massachusetts Medical Society.)

2637 Liver Transplantation CHAPTER 345

the right (for adults) lobe of the liver is harvested from a living donor

for transplantation into the recipient. In the adult procedure, once the

right lobe is removed from the donor, the donor right hepatic vein is

anastomosed to the recipient right hepatic vein remnant, followed by

donor-to-recipient anastomoses of the portal vein and then the hepatic

artery. Finally, the biliary anastomosis is performed, duct-to-duct if

practical or via Roux-en-Y anastomosis. Heterotopic liver transplantation, in which the donor liver is inserted without removal of the native

liver, has met with very limited success and acceptance, except in a very

small number of centers. In attempts to support desperately ill patients

until a suitable donor organ can be identified, several transplantation

centers are studying extracorporeal perfusion with bioartificial liver

cartridges constructed from hepatocytes bound to hollow fiber systems

and used as temporary hepatic-assist devices, but their efficacy remains

to be established. Areas of research with the potential to overcome

the shortage of donor organs include hepatocyte transplantation and

xenotransplantation with genetically modified organs of nonhuman

origin (e.g., swine).

POSTOPERATIVE COURSE AND

MANAGEMENT

■ IMMUNOSUPPRESSIVE THERAPY

The introduction in 1980 of cyclosporine as an immunosuppressive

agent contributed substantially to the improvement in survival after

liver transplantation. Cyclosporine, a calcineurin inhibitor, blocks

early activation of T cells and is specific for T-cell functions that result

from the interaction of the T cell with its receptor and that involve

the calcium-dependent signal transduction pathway. As a result, the

activity of cyclosporine leads to inhibition of lymphokine gene activation, blocking interleukins 2, 3, and 4, tumor necrosis factor α, and

other lymphokines. Cyclosporine also inhibits B-cell functions. This

process occurs without affecting rapidly dividing cells in the bone

marrow, which may account for the reduced frequency of posttransplantation systemic infections. The most common and important side

effect of cyclosporine therapy is nephrotoxicity. Cyclosporine causes

dose-dependent renal tubular injury and direct renal artery vasospasm.

Following renal function is therefore important in monitoring cyclosporine therapy and is perhaps even a more reliable indicator than

blood levels of the drug. Nephrotoxicity is reversible and can be managed by dose reduction. Other adverse effects of cyclosporine therapy

include hypertension, hyperkalemia, tremor, hirsutism, glucose intolerance, and gingival hyperplasia.

Tacrolimus, a macrolide lactone antibiotic isolated from a Japanese

soil fungus, Streptomyces tsukubaensis, has the same mechanism of

action as cyclosporine but is 10–100 times more potent. Initially

applied as “rescue” therapy for patients in whom rejection occurred

despite the use of cyclosporine, tacrolimus was shown to be associated

with a reduced frequency of acute, refractory, and chronic rejection.

Although patient and graft survival are the same with these two drugs,

the advantage of tacrolimus in minimizing episodes of rejection, reducing the need for additional glucocorticoid doses, and reducing the

likelihood of bacterial and cytomegalovirus (CMV) infection has simplified the management of patients undergoing liver transplantation.

In addition, the oral absorption of tacrolimus is more predictable than

that of cyclosporine, especially during the early postoperative period

when T-tube drainage interferes with the enterohepatic circulation of

cyclosporine. As a result, in most transplantation centers, tacrolimus

has now supplanted cyclosporine for primary immunosuppression,

and many centers rely on oral rather than IV administration from the

outset. For transplantation centers that prefer cyclosporine, a betterabsorbed microemulsion preparation is available.

Although more potent than cyclosporine, tacrolimus is also more

toxic and more likely to be discontinued for adverse events. The

toxicity of tacrolimus is similar to that of cyclosporine; nephrotoxicity and neurotoxicity are the most commonly encountered adverse

effects, and neurotoxicity (tremor, seizures, hallucinations, psychoses,

coma) is more likely and more severe in tacrolimus-treated patients.

Both drugs can cause diabetes mellitus, but tacrolimus does not cause

hirsutism or gingival hyperplasia. Because of overlapping toxicity

between cyclosporine and tacrolimus, especially nephrotoxicity, and

because tacrolimus reduces cyclosporine clearance, these two drugs

should not be used together. Because 99% of tacrolimus is metabolized

by the liver, hepatic dysfunction reduces its clearance; in primary graft

nonfunction (when, for technical reasons or because of ischemic damage prior to its insertion, the allograft is defective and does not function normally from the outset), tacrolimus doses have to be reduced

substantially, especially in children. Both cyclosporine and tacrolimus

are metabolized by the cytochrome P450 IIIA system, and therefore,

drugs that induce cytochrome P450 (e.g., phenytoin, phenobarbital,

carbamazepine, rifampin) reduce available levels of cyclosporine and

tacrolimus, and drugs that inhibit cytochrome P450 (e.g., erythromycin, fluconazole, ketoconazole, clotrimazole, itraconazole, verapamil,

diltiazem, danazol, metoclopramide, the HIV protease inhibitor

ritonavir, and the HCV protease inhibitors glecaprevir [cyclosporine

only] and grazoprevir) increase cyclosporine and tacrolimus blood

levels. Indeed, itraconazole is used occasionally to help boost tacrolimus levels. Like azathioprine, cyclosporine and tacrolimus appear to

be associated with a risk of lymphoproliferative malignancies (see

below), which may occur earlier after cyclosporine or tacrolimus than

after azathioprine therapy. Because of these side effects, combinations

of cyclosporine or tacrolimus with prednisone and an antimetabolite (azathioprine or mycophenolic acid, see below)—all at reduced

doses—are preferable regimens for immunosuppressive therapy.

Mycophenolic acid, a nonnucleoside purine metabolism inhibitor

derived as a fermentation product from several Penicillium species, is

another immunosuppressive drug being used for patients undergoing

liver transplantation. Mycophenolate has been shown to be better than

azathioprine, when used with other standard immunosuppressive

drugs, in preventing rejection after renal transplantation and has been

adopted widely as well for use in liver transplantation. The most common adverse effects of mycophenolate are bone marrow suppression

and gastrointestinal complaints.

In patients with pretransplantation renal dysfunction or renal deterioration that occurs intraoperatively or immediately postoperatively,

tacrolimus or cyclosporine therapy may not be practical; under these

circumstances, induction or maintenance of immunosuppression with

antithymocyte globulin (ATG; thymoglobulin) or monoclonal antibodies to T cells, OKT3, may be appropriate. Therapy with these agents

has been especially effective in reversing acute rejection in the posttransplantation period and is the standard treatment for acute rejection

that fails to respond to methylprednisolone boluses. Available data support the use of thymoglobulin induction to delay calcineurin inhibitor

use and its attendant nephrotoxicity. IV infusions of thymoglobulin

may be complicated by fever and chills, which can be ameliorated by

premedication with antipyretics and a low dose of glucocorticoids.

Infusions of OKT3 may be complicated by fever, chills, and diarrhea

or by pulmonary edema, which can be fatal. Because OKT3 is such a

potent immunosuppressive agent, its use is also more likely to be complicated by opportunistic infection or lymphoproliferative disorders;

therefore, because of the availability of alternative immunosuppressive

drugs, OKT3 is now used sparingly.

Sirolimus, an inhibitor of the mammalian target of rapamycin

(mTOR), blocks later events in T-cell activation and is approved for

use in kidney transplantation, but it is not formally approved for use

in liver transplant recipients because of the reported association with

an increased frequency of hepatic artery thrombosis in the first month

after transplantation. In patients with calcineurin inhibitor–related

nephrotoxicity, conversion to sirolimus has been demonstrated to be

effective in preventing rejection with accompanying improvements in

renal function. Because of its profound antiproliferative effects, sirolimus has also been suggested to be a useful immunosuppressive agent

in patients with a prior or current history of malignancy, such as HCC.

Side effects include hyperlipidemia, peripheral edema, oral ulcers,

and interstitial pneumonitis. Everolimus is a hydroxyethyl derivative

of sirolimus that, when used in conjunction with low-dose tacrolimus, also provides successful protection against acute rejection, with

decreased renal impairment compared to that associated with standard

2638 PART 10 Disorders of the Gastrointestinal System

TABLE 345-4 Nonhepatic Complications of Liver Transplantation

CATEGORY COMPLICATION

Cardiovascular instability Arrhythmias

Congestive heart failure

Cardiomyopathy

Pulmonary compromise Pneumonia

Pulmonary capillary vascular permeability

Fluid overload

Renal dysfunction Prerenal azotemia

Hypoperfusion injury (acute tubular necrosis)

Drug nephrotoxicity

↓ Renal blood flow secondary to ↑ intraabdominal

pressure

Hematologic Anemia secondary to gastrointestinal and/or

intraabdominal bleeding

Hemolytic anemia, aplastic anemia

Thrombocytopenia

Infection Bacterial: early, common postoperative infections

Fungal/parasitic: late, opportunistic infections

Viral: late, opportunistic infections, recurrent

hepatitis

Neuropsychiatric Seizures

Metabolic encephalopathy

Depression

Difficult psychosocial adjustment

Diseases of donor Infectious

Malignant

Malignancy B-cell lymphoma (posttransplantation

lymphoproliferative disorders)

De novo neoplasms (particularly squamous cell

skin carcinoma)

TABLE 345-5 Hepatic Complications of Liver Transplantation

Hepatic Dysfunction Common after Major Surgery

Prehepatic Pigment load

Hemolysis

Blood collections (hematomas, abdominal

collections)

Intrahepatic

Early Hepatotoxic drugs and anesthesia

Hypoperfusion (hypotension, shock, sepsis)

Benign postoperative cholestasis

Late Transfusion-associated hepatitis

Exacerbation of primary hepatic disease

Posthepatic Biliary obstruction

↓ Renal clearance of conjugated bilirubin (renal

dysfunction)

Hepatic Dysfunction Unique to Liver Transplantation

Primary graft nonfunction

Vascular compromise Portal vein obstruction

Hepatic artery thrombosis

Anastomotic leak with intraabdominal bleeding

Bile duct disorder Stenosis, obstruction, leak

Rejection

Recurrent primary

hepatic disease

tacrolimus dosing. Everolimus and sirolimus share a similar adverse

events profile. The most important principle of immunosuppression is

that the ideal approach strikes a balance between immunosuppression

and immunologic competence. In general, given sufficient immunosuppression, acute liver allograft rejection is nearly always reversible.

On one hand, incompletely treated acute rejection predisposes to the

development of chronic rejection, which can threaten graft survival.

On the other hand, if the cumulative dose of immunosuppressive therapy is too large, the patient may succumb to opportunistic infection.

In hepatitis C, pulse glucocorticoids or OKT3 use accelerates recurrent

allograft hepatitis, although the routine use of DAA therapy to clear

the allograft of HCV should remove this concern. Further complicating

matters, acute rejection can be difficult to distinguish histologically

from recurrent hepatitis C. Therefore, immunosuppressive drugs must

be used judiciously, with strict attention to the infectious consequences

of such therapy and careful confirmation of the diagnosis of acute

rejection. In this vein, efforts have been made to minimize the use

of glucocorticoids, a mainstay of immunosuppressive regimens, and

steroid-free immunosuppression can be achieved in some instances.

Patients who undergo liver transplantation for autoimmune diseases

such as primary biliary cholangitis, autoimmune hepatitis, and primary sclerosing cholangitis are less likely to achieve freedom from

glucocorticoids.

■ POSTOPERATIVE COMPLICATIONS

Complications of liver transplantation can be divided into nonhepatic

and hepatic categories (Tables 345-4 and 345-5). In addition, both

immediate postoperative and late complications are encountered. As a

rule, patients who undergo liver transplantation have been chronically

ill for protracted periods and may be malnourished and wasted. The

impact of such chronic illness and the multisystem failure that accompanies liver failure continue to require attention in the postoperative

period. Because of the massive fluid losses and fluid shifts that occur

during the operation, patients may remain fluid overloaded during the

immediate postoperative period, straining cardiovascular reserve; this

effect can be amplified in the face of transient renal dysfunction and

pulmonary capillary vascular permeability. Continuous monitoring

of cardiovascular and pulmonary function, measures to maintain the

integrity of the intravascular compartment and to treat extravascular volume overload, and scrupulous attention to potential sources

and sites of infection are of paramount importance. Cardiovascular

instability may also result from the electrolyte imbalance that may

accompany reperfusion of the donor liver as well as from restoration

of systemic vascular resistance following implantation. Pulmonary

function may be compromised further by paralysis of the right hemidiaphragm associated with phrenic nerve injury. The hyperdynamic

state with increased cardiac output that is characteristic of patients

with liver failure reverses rapidly after successful liver transplantation.

Other immediate management issues include renal dysfunction.

Prerenal azotemia, acute kidney injury associated with hypoperfusion (acute tubular necrosis), and renal toxicity caused by antibiotics,

tacrolimus, or cyclosporine are encountered frequently in the postoperative period, sometimes necessitating dialysis. Hemolytic-uremic

syndrome can be associated with cyclosporine, tacrolimus, or OKT3.

Occasionally, postoperative intraperitoneal bleeding may be sufficient

to increase intraabdominal pressure, which, in turn, may reduce renal

blood flow; this effect is rapidly reversible when abdominal distention

is relieved by exploratory laparotomy to identify and ligate the bleeding

site and to remove intraperitoneal clot.

Anemia may also result from acute upper gastrointestinal bleeding

or from transient hemolytic anemia, which may be autoimmune, especially when blood group O livers are transplanted into blood group A

or B recipients. This autoimmune hemolytic anemia is mediated by

donor intrahepatic lymphocytes that recognize red blood cell A or B

antigens on recipient erythrocytes. Transient in nature, this process

resolves once the donor liver is repopulated by recipient bone marrow–

derived lymphocytes; the hemolysis can be treated by transfusing

blood group O red blood cells and/or by administering higher doses

of glucocorticoids. Transient thrombocytopenia is also commonly

encountered. Aplastic anemia, a late occurrence, is rare but has been

reported in almost 30% of patients who underwent liver transplantation for acute, severe hepatitis of unknown cause.