Based on the mechanism of injury, liver trauma is classified
as penetrating or blunt. Penetrating wounds, constituting more than
half of cases, are typically due to projectiles (such as bullets
or shrapnel) or knives. In civilian practice, most of these tend
to be clean wounds that are dangerous because of intra-abdominal bleeding
but do not result in much devitalization of liver tissue. In contrast,
high-velocity projectiles are associated with greater energy that
is transferred to the abdominal viscera and can shatter the parenchyma,
even if the projectile does not enter the liver directly.
Blunt trauma can be inflicted by a direct blow to the upper abdomen
or lower right rib cage or can follow sudden deceleration, as occurs
with a fall from a great height. Most often a consequence of automobile
accidents, direct blunt trauma tends to produce explosive bursting wounds
or linear lacerations of the hepatic surface, often with considerable parenchymal
destruction. The stellate, bursting type of injury tends to affect
the posterior and superior aspect of the right liver (segments VI,
VII, and VIII) because of its relatively vulnerable location, convex
surface, fixed position, and concentration of hepatic mass. Damage
to the left lobe is much less common than damage to the right. Injuries
that involve shearing forces can tear the hepatic veins where they
enter the liver substance, producing an exsanguinating retrohepatic
injury in an area difficult to surgically expose and repair. The
staging system described in Table 24–2 is
used to categorize liver injuries and provide a common language
in order to allow comparisons of results of treatment between institutions.
Table 24–2. Liver Injury Scale.1 |Favorite Table|Download (.pdf)
Table 24–2. Liver Injury Scale.1
|I||Hematoma||Subcapsular, nonexpanding, < 10% surface area.|
|Laceration||Capsular tear, nonbleeding; < 1 cm deep in parenchyma.|
|II||Hematoma||Subcapsular, nonexpanding, 10–50% surface
area; intraparenchymal, nonexpanding, < 2 cm in diameter.|
|Laceration||Capsular tear, active bleeding; 1–3 cm deep into
the parenchyma, < 10 cm long.|
|III||Hematoma||Subcapsular, > 50% surface area or expanding; ruptured
subcapsular hematoma with active bleeding; intraparenchymal hematoma
> 2 cm or expanding.|
|Laceration||> 3 cm deep into the parenchyma.|
|IV||Hematoma||Ruptured intraparenchymal hematoma with active bleeding.|
|Laceration||Parenchymal disruption involving > 50% of hepatic
|V||Laceration||Parenchymal disruption involving > 50% of hepatic
|Vascular||Juxtahepatic venous injuries; ie, retrohepatic vena cava
or major hepatic veins.|
The principal surgical goals are to stop bleeding and debride
devitalized liver. Because some degree of liver failure is common
postoperatively, efforts should be made during each step to maintain adequate
oxygenation and perfusion of the liver. Also, when one is debriding liver
tissue, care should be taken to avoid injury to the vascular supply
of adjacent viable parenchyma.
The clinical manifestations of liver injury are those of hypovolemic
shock: hypotension, decreased urinary output, low central venous
pressure, and, in some cases, abdominal distention.
With major injuries, particularly those associated with disruption
of hepatic veins, the rate of blood loss is usually so rapid that
anemia does not develop. Leukocytosis greater than 15,000/μL
is common following rupture of the liver from blunt trauma.
CT scans should be obtained in most stable patients suspected
of having a hepatic injury. The scans demonstrate the extent of
the injury and provide a rough estimate of the amount of blood loss.
The findings are useful for triaging, since minor injuries rarely
require surgical treatment, whereas extensive injuries usually do.
One must exercise caution, however, in using CT estimates of injury grade,
because they correlate poorly (ie, they both understage and overstage) with
what is found at surgery. CT scanning is also useful for identifying
injuries to other organs, which are not uncommon, particularly in
the setting of blunt trauma.
Sonography has not been helpful other than as the rapid abdominal
sonogram to identify fluid in the abdomen. It does not help to define
the injury. Angiography is generally not helpful in the acute setting but
may be used to diagnose and treat specific postinjury problems,
such as hemobilia.
Patients with stable minor liver injuries (and no associated
injuries requiring exploration) may be managed expectantly unless
symptoms or signs of bleeding appear. The CT findings in patients who
may be considered for nonoperative management include contained
subcapsular or intrahepatic hematoma, unilobar fracture, absence
of devitalized liver, minimal intraperitoneal blood, and absence
of injuries to other intra-abdominal organs. Serial CT scans should
be obtained to verify that the lesion is stable rather than expanding.
Most patients have CT or clinical evidence of active bleeding
or a major injury, however, and require prompt exploration. Most
lacerations have stopped bleeding by the time operation is performed.
In the absence of active hemorrhage, these wounds need not be sutured.
Active bleeding should be managed by clipping or direct suture of
identifiable vessels, if possible, rather than by mass ligatures.
Subcapsular hematomas often overlie an active bleeding site or parenchyma
in need of debridement and should be explored even though the injury
appears to be tamponaded and of limited severity. Blunt injuries
associated with substantial amounts of parenchymal destruction may
be particularly difficult to manage. Rarely, a very severe pulverizing
injury requires formal lobectomy.
Temporary occlusion of the hepatic artery and portal vein can
be done quickly by placing a vascular clamp around the entire hepatoduodenal
ligament (Pringle maneuver). This can be done for periods of 15–20
minutes and reduce the hemorrhage sufficiently to permit more accurate
ligation of bleeding vessels. With major hepatic venous injuries,
however, a Pringle maneuver has little effect, and precise repair
of the injury may not be possible. Absorbable gauze mesh (eg, polyglycolic
acid) can sometimes be wrapped around an injured lobe and sutured
in a way that maintains pressure and tamponades the bleeding; this
is difficult to accomplish without rendering the involved liver
ischemic, however, and such an approach is rarely applicable. In
some cases, control of arterial hemorrhage requires ligation of
the hepatic artery or one of the accessible lobar branches in the
The most difficult problems involve lacerations of the major
hepatic veins behind the liver. With such injuries, temporary clamping
of the inflow vessels will not slow the bleeding to allow inspection
and repair of the injured vessels. For persistent bleeding, the
abdominal incision can be extended into a median sternotomy to improve
exposure. An ancillary technique, which is used only rarely, is
to place a tube through the atrial appendage into the inferior vena
cava past the origin of the hepatic veins. Appropriately placed ligatures
around the vena cava permit total isolation of the liver circulation
without interrupting venous return from the lower extremities to
the heart. Resection of the right liver improves exposure of the
retrohepatic vena cava but is a difficult to perform in the face
of overwhelming hemorrhage.
In many cases, when bleeding is difficult to control and especially
when other injuries must be addressed, the best strategy is to pack
the liver to achieve hemostasis. The packs are generally left in
place for 48–72 hours, during which time the patient remains
sedated and intubated in the intensive care unit where adequate
resuscitative measures are undertaken. The packs are removed in the
operating room; if persistent bleeding is noted, definitive repair
of the injury can then be performed.
The majority of patients who come to operation require little
in the way of surgical intervention to control bleeding; drainage
of substantial liver lacerations and other injuries is reasonable,
since bile leakage can occur. Suture ligation of bleeding hepatic
vessels and debridement of devitalized tissue are indicated in about
30% and 10% of cases, respectively. More extensive
procedures are indicated even less often.
Penetrating injuries that also involve the small bowel or colon
may result in contamination of perihepatic fluid or devitalized
liver tissue, leading to a subhepatic abscess. Placement of drains
may help prevent this problem, but a high index of suspicion should
With present techniques, hemorrhage at laparotomy is rarely uncontrollable except
with retrohepatic venous injuries. Patients who rebleed from the
liver wound after initial suture ligation should be treated by reexploration
or packing; rarely is a major resection required. Angiography and
CT scanning may provide useful diagnostic information preoperatively
in such patients. Subhepatic sepsis develops in about 20% of
cases; it is more frequent if lobectomy has been done.
Hemobilia may be responsible for gastrointestinal bleeding in
the postoperative period and can be diagnosed by selective angiography.
Treatment consists of embolization through the arteriography catheter.
The death rate of 10–15% following hepatic
trauma depends largely on the type of injury and the extent of associated
injury to other organs. About one third of patients admitted to
the emergency department in shock cannot be saved. Only 1% of penetrating
civilian wounds are lethal, whereas a 20% death rate attends
blunt trauma. The death rate in blunt hepatic injury is 10% when
only the liver is injured. If three major organs are damaged, the
death rate is close to 70%. Bleeding causes more than half
of deaths associated with liver trauma.
Carrillo EH et al: Non-operative management of
blunt hepatic trauma. Br J Surg 1998;85:461.
Chen RJ et al: Factors determining operative mortality of grade
V blunt hepatic trauma. J Trauma 2000;49:886.
David Richardson J et al: Evolution in the management of hepatic
trauma: a 25-year perspective. Ann Surg 2000;232:324.
Leone RJ Jr, Hammond JS: Nonoperative management of pediatric
blunt hepatic trauma. Am Surg 2001;67:138.
Oniscu GC, Parks RW, Garden OJ: Classification of liver and
pancreatic trauma. HPB 2006;8:4.
Pryor JP, Stafford PW, Nance ML: Severe blunt hepatic trauma
in children. J Pediatr Surg 2001;36:974.
Yanar H et al: Nonoperative treatment of multiple intra-abdominal
solid organ injury after blunt abdominal trauma. J Trauma 2008;64:943.
Liver malignancy may arise from hepatocytes (hepatocellular carcinoma,
the most common) or biliary epithelial cells (intrahepatic cholangiocarcinoma).
Tumors arising from both cell types (mixed hepatocellular carcinoma/cholangiocarcinoma) have
also been described. Neonates may also develop a variant of hepatocellular
carcinoma called hepatoblastoma because it is morphologically similar
to fetal liver and the occasional presence of hematopoiesis. Primary
malignancy arising from other liver cell types (endothelial cells,
stellate cells, neuroendocrine cells, or lymphocytes) is exceedingly rare.
Primary hepatic cancer is relatively uncommon in the United States,
but its incidence is increasing. In Asia and Africa, however, primary
liver cancer is extremely common and in some areas represents the
single-most frequent abdominal tumor and the most common cause of
cancer-related death. The etiologic factors in these high-risk areas
are environmental or cultural, since persons of similar racial background
in the United States are at only slightly greater risk than Caucasians.
About 9000 cases—distributed equally between men and women—occur
in the United States each year. Most arise in persons over age 50, but
a few are found in children, mainly under 2 years of age.
Chronic hepatitis B and C virus (HBV and HCV) infection is the
principal etiologic factor worldwide for hepatocellular carcinoma.
Patients chronically seropositive for HBsAg constitute a high-risk
group for development of hepatocellular carcinoma, which in some
cases may be detected early by screening for serum α-fetoprotein
(AFP) levels. Hepatitis B virus DNA has been detected integrated
into the genome of host hepatocytes and hepatoma cells and has a
direct oncogenic effect. Patients with chronic hepatitis B infection
may therefore develop hepatocellular carcinoma in the absence of
cirrhosis; by contrast, hepatocellular carcinoma arising in the
setting of chronic hepatitis C infection is typically associated
with cirrhotic change. Cirrhosis from almost any cause (eg, alcoholism,
hemochromatosis, α1-antitrypsin deficiency,
or primary biliary cirrhosis) is associated with an increased risk
of hepatocellular carcinoma, and the great majority of these tumors
arise in the setting of chronic underlying liver disease. Certain
fungal metabolites called aflatoxins have been shown experimentally
to be capable of producing liver tumors. These substances are present
in staple foods (eg, ground nuts and grain) in some parts of Africa
where hepatomas are common.
Unlike hepatocellular carcinoma, intrahepatic cholangiocarcinoma
is infrequently associated with cirrhosis. Primary sclerosing cholangitis
is a predisposing condition in a small minority of patients. Widespread
infection with liver flukes (Clonorchis sinensis)
is at least partly responsible for the higher incidence of these
tumors in some parts of Asia. Emerging evidence has implicated chronic
hepatitis C infection, obesity, diabetes mellitus, chronic liver disease,
and cigarette smoking as risk factors for intrahepatic cholangiocarcinoma.
In Western centers, the vast majority of intrahepatic cholangiocarcinomas
are sporadic. Intrahepatic cholangiocarcinoma generally presents
as a large mass within the liver and is therefore clinically distinct
from cholangiocarcinoma arising from the extrahepatic biliary tree.
Hepatomas constitute about 85–95% of primary
hepatic cancers. Previously, differences in morphology were used
to separate tumors into three types: mass-forming type,
characterized by a single predominant mass clearly demarcated from
the surrounding liver, occasionally with small satellite nodules; nodular type, composed
of multiple nodules, often distributed throughout the liver; and
a diffuse type, characterized by infiltration of tumor
throughout the remaining parenchyma. A number of staging systems
for hepatocellular carcinoma are in current use: American Joint
Commission on Cancer tumor-node-metastasis (TNM) staging system,
Okuda, and Cancer of the Liver Italian Program (CLIP); none fully
accounts for extent of disease and underlying hepatic parenchymal
function, which is an important predictor of outcome.
About 50% of resectable tumors are surrounded by a fibrous
capsule, which develops as a result of compression of adjacent liver
stroma. Encapsulated tumors exhibit a lower incidence of tumor microsatellites
and venous permeation compared with nonencapsulated tumors, and
the finding is a favorable sign. An uncommon variant, fibrolamellar
hepatocellular carcinoma, contains numerous fibrous septa
and may resemble focal nodular hyperplasia. Fibrolamellar hepatoma
occurs in a younger age group (average 25 years) and is not associated
with cirrhosis or hepatitis B virus infection.
A large proportion of patients will have intrahepatic or extrahepatic
metastases at presentation. Multiple intrahepatic tumors can arise
as a result of infiltration of the portal venous system with subsequent
dissemination of tumor cells. Vascular invasion is more common with larger
tumors (> 5 cm). The extrahepatic sites most commonly involved with
metastatic disease include the hilar and celiac lymph nodes and
the lungs; metastases to bone and brain are less common, and peritoneal
disease (ie, carcinomatosis) is distinctly unusual. Major portal
or hepatic veins are often invaded by tumor, and venous occlusion
may occur as a result.
Microscopically, there is usually little stroma between the malignant
cells, and the tumor has a soft consistency. The tumor may be highly
vascularized, a feature that rarely can result in massive intraperitoneal
hemorrhage following spontaneous rupture.
Cholangiocarcinoma makes up a small fraction of primary liver
cancers, although several reports have documented a marked increase
in incidence worldwide. Histologically, these tumors are most often
invasive adenocarcinomas, although rare variants have been reported.
Intrahepatic or extrahepatic spread of disease is not uncommon by
the time the tumor is detected. These tumors infrequently cause
symptoms at early stages and therefore often grow to a large size before
they become apparent, frequently because of pain. Infrequently,
these tumors may contain cells of both cholangiocellular and hepatocellular
origin. These mixed tumors are similar to intrahepatic cholangiocarcinoma
in that they are infrequently associated with chronic liver disease.
Angiosarcoma of the liver, a rare fatal tumor, has been seen
in workers intensively exposed to vinyl chloride for prolonged periods
in polymerization plants.
The diagnosis at early and more treatable stages is often difficult,
since symptoms are often absent. Screening and surveillance of high-risk
patients (with cirrhosis, chronic hepatitis, etc) is helpful in this
regard. Patients with more advanced tumors may have epigastric or
right upper quadrant pain, which may be associated with referred
pain in the right shoulder. Weight loss may be present. Jaundice
is rare in patients with small tumors and good liver function; the
presence of jaundice suggests either very advanced cancer or deteriorating
liver function or both.
Hepatomegaly or a mass is palpable in many patients. An arterial
bruit or a friction rub may be audible over the liver. Intermittent
fever may be a presenting feature. Ascites or gastrointestinal bleeding
from varices indicates advanced disease, and ascites fluid with
blood should always suggest hepatoma. An acute deterioration in
a previously well-compensated cirrhotic patient should also raise
the suspicion of hepatocellular carcinoma.
The patterns of presentation can thus be extremely variable and
may include (1) pain with or without hepatomegaly; (2) sudden deterioration
of the condition of a cirrhotic patient with the onset of hepatic
failure, bleeding varices, or ascites; (3) sudden, massive intraperitoneal
hemorrhage; (4) acute illness with fever and abdominal pain; (5)
symptoms related to distant metastases; and (6) no clinical findings
Depending on the disease extent and underlying hepatic function,
laboratory values may range from entirely normal to suggestive of
impending liver failure. Serum transaminase levels (AST and ALT)
and alkaline phosphatase may be increased but are nonspecific and
often seen in patients with chronic liver disease without hepatocellular
carcinoma. The presence of a moderate to large liver tumor may bring
about an increase in the serum alkaline phosphatase in the absence
of underlying liver disease. An elevated serum bilirubin is a more
ominous finding and reflects some degree of liver dysfunction, either
from the underlying chronic liver disease or from a large volume
of cancer within the liver. Tumor extension within the portal venous
system is not uncommon, and involvement of the right and left portal
trunks or the main portal vein may result in jaundice due to compromised
portal venous inflow. Less often, jaundice is the result of tumor
involvement of the biliary confluence by direct compression or by
intrabiliary tumor extension. Other signs of compromised hepatic
function include hypoalbuminemia, coagulopathy, and thrombocytopenia.
A large number of patients will be positive for HBsAg or HCV antibody;
the proportions of each will vary somewhat by geography.
CT scans, ultrasound scans, and MRI scans demonstrate the principal
lesion in nearly all patients. MRI scans with MR angiography or
CT angiography may provide more detail regarding vascular involvement.
A triple-phase, contrast-enhanced helical CT scan generally provides
the best images of disease extent within the liver and will also
assess for extrahepatic spread.
Diagnostic angiography was previously used often to assess liver
tumors but is now rarely needed for this purpose; it is reserved
primarily for treatment (ie, chemoembolization). Hepatomas are supplied
primarily by the hepatic artery, and the vast majority are more
vascular than adjacent parenchyma (hypervascular). In some cases,
the center of the tumor has become necrotic, and only the peripheral
areas are hypervascular. Arterial branches supplying the tumor have an
irregular appearance compared to the native hepatic artery, and
arterial-venous shunting may be seen. By contrast, cholangiocarcinomas
usually appear less vascular than adjacent tissue. Hemangiomas have
a distinctive pattern of peripheral nodular enhancement and patchy vascular
pooling. Other benign tumors, particularly adenomas and focal nodular hyperplasia,
are more difficult to diagnose based on angiographic features alone.
The venous phase of a superior mesenteric arterial injection may
show invasion or occlusion of the portal vein by tumor.
Angiography may be equivocal in small tumors, which may be demonstrated
with greater certainty by a selective injection of iodized oil (Lipiodol)
followed 1–2 weeks later by CT scanning. In a normal liver,
the contrast medium is cleared quickly but hepatomas retain it and
The diagnosis can be established by percutaneous core biopsy
or aspiration biopsy. Fine-needle aspiration biopsy is associated
with an approximately 30% false-negative rate. A negative
result therefore does not rule out malignant disease, and a core
biopsy should be pursued if the index of suspicion is high. Percutaneous
biopsy carries some risk of bleeding, although this is rare in experienced
hands; tumor dissemination resulting from a biopsy has been reported
but is uncommon. In patients with cirrhosis, the presence of a hypervascular
mass larger than 2 cm on two different imaging studies (ultrasound,
CT, MRI, or angiography) or a hypervascular mass larger than 2 cm
on one imaging study combined with a serum AFP level higher than
400 ng/mL is diagnostic of hepatocellular carcinoma, and
a biopsy is generally not required.
In high-risk patients, surveillance with periodic imaging studies
is recommended in order to detect early hepatocellular carcinoma,
which is more amenable to treatment. The optimal type and timing
of imaging studies is the subject of debate, but such programs have proved
useful in areas with a high incidence of chronic hepatitis, such
as Asia, where a large proportion of patients are now identified
with a mass 2 cm in diameter or smaller; other studies in high-risk patients
have also proved valuable.
AFP, a glycoprotein normally present only in the fetal circulation,
is present in high concentrations in the serum of many patients
with primary hepatomas and testicular tumors. Increased levels are
rarely seen as a product of other tumor types, such as the lung,
stomach, pancreas, and biliary tree.
The upper limit of normal in the serum is 20 ng/mL;
values above 200 ng/mL are suggestive of hepatoma, while
levels above 400 ng/mL in a cirrhotic patients with a hypervascular
liver mass larger than 2 cm in diameter are diagnostic. Levels in
the intermediate range are nonspecific and may occur with benign
liver diseases, such as cirrhosis and chronic hepatitis, where they
represent a manifestation of liver cell proliferation. As imaging
methods have improved, the diagnosis of liver cancer is being made earlier,
when AFP levels may be normal or only minimally elevated. Additionally, some
patients may have normal AFP levels despite the presence of advanced disease.
In general, AFP levels correlate with tumor size and vascular invasion, and
a number of studies have shown a correlation between high AFP levels
and recurrent cancer after resection. AFP levels can also provide
a measure of tumor response in patients treated nonoperatively.
The clinical picture is often nonspecific, and the presenting
symptoms may provide little in the way of diagnostic clues. Primary
liver cancer may initially be confused with metastatic cancer arising
from other abdominal sites. The presence of cirrhosis and findings
consistent with chronic liver disease make hepatocellular carcinoma
the leading diagnosis, and this is often confirmed with further
testing. In patients without cirrhosis or normal AFP levels (or
both), a hypervascular mass in the liver should raise other diagnostic
considerations, such as hepatic adenoma, which can be difficult
to distinguish from hepatocellular carcinoma on the basis of imaging
alone. In addition, certain types of cancer may give rise to hypervascular
liver metastases, including melanoma, neuroendocrine carcinoma,
and renal cell carcinoma.
When complications develop suddenly in a cirrhotic patient, the
possibility of hepatoma must always be considered. In rare instances,
primary hepatocellular cancer is associated with metabolic or endocrine
abnormalities such as erythrocytosis, hypercalcemia, hypoglycemic attacks,
Cushing syndrome, or virilization.
Sudden intra-abdominal hemorrhage may occur from spontaneous
bleeding. Obstruction of the portal vein may produce portal hypertension,
and obstruction of the hepatic veins may produce the Budd-Chiari
syndrome. Liver failure is a common cause of death in these situations.
Resection is the most effective therapy and is the treatment
of choice in selected patients without cirrhosis or in cirrhotics with
well-preserved hepatic function. Initial diagnostic laparoscopy,
immediately prior to planned laparotomy, may identify previously
undetected spread of tumor within the liver or abdominal cavity
that would preclude resection; however, with better imaging, the
yield of laparoscopy has decreased. The minimal criteria of resectability
that must be met are (1) disease confined to the liver and (2) disease
amenable to a complete resection. Multiple tumors in the liver and
tumor invasion into major portal or hepatic veins are bad prognostic findings,
even if resection is technically feasible; such patients generally
are not good candidates for resection. For small and peripherally
placed lesions, particularly in cirrhotics, sublobar, segmental
resections are preferred if technically feasible. Anatomical segmentectomies
are preferred to nonanatomical resections. Larger or more central
tumors will require more extensive resections. In Western centers,
about 25–30% of patients with hepatocellular carcinoma
prove to be candidates for resection; this proportion is over 60% in
Japan due largely to widespread surveillance programs.
If gross tumor is left behind or if the margins of resection
are involved microscopically, progressive disease is the rule. After
a complete resection, the prognosis is best for patients with a
solitary, small, and asymptomatic tumor and well-preserved hepatic
function. Several adverse predictors of outcome have been identified,
which vary somewhat among studies. However, the presence of vascular invasion
(even if microscopic) has been identified in nearly all studies
to predict recurrent cancer and poor outcome. Large tumor size (>
5 cm), the presence of satellite tumors, and markedly elevated AFP
(> 2000 ng/mL) are also associated with a worse outcome,
in part because of their correlation with vascular invasion. Additionally,
patients with coexistent hepatocellular disease (ie, cirrhosis)
tend to do worse, and this is especially true in the face of significant hepatocellular
dysfunction or portal hypertension.
In general, cirrhosis constitutes the major obstacle to resection
in patients with hepatocellular carcinoma. Careful patient selection
(Child-Pugh A, no portal hypertension) is critical in order to avoid
acute liver failure. In addition to this immediate perioperative
concern, cirrhotic patients have a late risk of death from progression
of the underlying liver disease (bleeding esophageal varices or
liver failure) and a high rate (> 75%) of new tumors developing
in the residual liver. For these reasons, highly selected patients
may be better treated with liver transplantation rather than resection.
Overall, the rate of tumor recurrence is approximately 70% at
5 years (although it is higher, as mentioned above, in patients
with cirrhosis). Some patients may be candidates for repeat resection or
ablative procedures. The 5-year survival rate is approximately 40% but
is lower for patients with cirrhosis.
After surgery, patients should be followed by periodic physical
examinations and blood work to assess liver function. Imaging studies
and AFP measurements (if elevated before resection) at regular intervals
may help identify early, localized recurrences that may be amenable to
repeat resection or palliative therapy.
Hepatocellular carcinoma is the only solid neoplasm for which
transplantation plays a significant role. Liver transplantation
has the advantage of treating not only the malignant disease but
also the underlying cirrhosis. Previously, the selection criteria
for transplanting hepatoma patients were broad and included patients
with very advanced disease. Consequently, 5-year survival rates
were less than 40%, too low to justify use of a scarce
resource. The lessons learned from this early experience have allowed
identification of patients most likely to benefit, specifically
those with a single tumor no larger than 5 cm in diameter or up
to three tumors with none exceeding 3 cm in diameter and no major
vascular invasion. Using these strict criteria (the Milan criteria),
5-year survival rates of 70% can be achieved. It should
be emphasized that the benefit of transplantation is realized only
when the waiting time for a new graft is under 6 months. Since waiting
times can exceed 12 months in many centers, up to 50% of patients
will develop cancer progression or otherwise become ineligible.
This problem has led a number of centers to adopt living donor transplantation
as a means of increasing the donor pool, an approach that remains
controversial because of donor-related morbidity and mortality.
A major concern of transplantation in cancer patients has been
that the immunosuppressive therapy required to support the graft
would remove an important defense mechanism against progression of
residual microscopic disease. Indeed, calculated tumor doubling
times for lesions in transplanted patients have been shown to be
greater compared to patients not on immunosuppressive agents. Despite
this possibility and although the logistical problems and expense
are enormous, transplantation is a reasonable option in patients
with cirrhosis who are not candidates for resection and have limited
malignant disease, as specified in the selection criteria.
At present, transplantation has no role in patients with intrahepatic
cholangiocarcinoma outside of controlled clinical trials, since
the results to date have been poor.
Percutaneous ablative techniques are a reasonable option in patients
with small, unresectable hepatocellular carcinoma, of which ethanol
injection is the cheapest, easiest, and least morbid. Using ultrasound
or CT guidance, 95% ethanol (5–20 mL) is injected
through a 22-gauge needle directly into the tumor. This approach
can achieve complete necrosis in 90–100% of tumors
small than 2 cm, but its efficacy declines rapidly as the tumor
size increases. The patient is followed up and retreatment given
for residual or new primary tumors. In one multi-institutional series
from Italy, survival 1, 2, and 3 years after treatment for patients
with solitary, small tumors was 90%, 80%, and
Radiofrequency ablation (RFA) is another percutaneous ablative
approach, useful for treating selected patients with unresectable,
small tumors. RFA has generally supplanted ethanol injection as the
percutaneous treatment of choice. Under ultrasound or CT guidance,
a needle is used to access the lesion; the needle is attached to
a radiofrequency generator that generates thermal energy to bring
about tumor destruction. RFA can be used percutaneously, laparoscopically,
or at laparotomy.
The goal of RFA is the same at that of ethanol injection: to
achieve complete tumor necrosis. The efficacy of RFA is limited
by tumor size but may be somewhat greater than ethanol injection
in this regard; RFA is less effective for tumors adjacent to major
vascular structures. A randomized study comparing the two techniques
found no differences in survival, although RFA may offer better
local tumor control rates. In carefully selected patients, 5-year
survival rates of 30–40% have been reported.
Hepatic artery embolization is another ablative technique that
is more broadly applicable than RFA or ethanol injection. This approach
takes advantage of the fact that primary liver cancers derive disproportionately
greater blood supply from the hepatic arterial circulation compared to
the surrounding liver. The strategy is to combine selective hepatic
arterial injection of cancer chemotherapeutic agents with arterial
embolization, the latter to produce tumor necrosis and slow the
washout of the drugs. Embolization can be used in patients with
much larger tumors than can be effectively treated with percutaneous
procedures, and the procedure can be staged to treat bilobar disease.
Patients must have adequate liver function; those with Child-Pugh
C cirrhosis or thrombosis of the portal vein are not suitable candidates.
A variety of techniques have been used. Embolization is often
performed with Gelfoam, which dissolves after a few weeks, but other
inert agents are also used. Doxorubicin, mitomycin, and cisplatin
in various combinations are the drugs most often given. Lipiodol,
which lodges in the tumor, has occasionally been used as a carrier
for the drugs. It remains unclear if the addition of chemotherapeutic
agents provides much benefit beyond the necrosis produced by occlusion
of the hepatic arterial supply. Many patients require multiple treatments,
although the optimal schedule is ill defined. Embolization achieves
partial responses in up to 55% of patients. The best 3-year
survival rates are approximately 50%. Histologic studies
of tumors resected shortly after treatment reveal viable neoplastic
cells in the tumor capsule, which receives blood from the portal
vein as well as the hepatic artery.
A recent randomized prospective trial showed that the combination
of RFA and chemoembolization provides superior disease control rates
than either technique alone.
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with cirrhosis in the era of liver transplantation. Ann Intern Med
Patel T: Increasing incidence and mortality of primary intrahepatic
cholangiocarcinoma in the United States. Hepatology. 2001;33:1353.
Trevisani F et al: Randomized control trials on chemoembolization for
hepatocellular carcinoma: is there room for new studies? J Clin
Tung-Ping Poon R, Fan ST, Wong J: Risk factors, prevention,
and management of postoperative recurrence after resection of hepatocellular
carcinoma. Ann Surg 2000;232:10.
Weber SM et al: Intrahepatic cholangiocarcinoma: resectability,
recurrence pattern and outcome. J Am Coll Surg 2001:193;384.
Welzel TM et al: Risk factors for intrahepatic and extrahepatic
cholangiocarcinoma in the United States: a population-based case-control
study. Clin Gastroenterol Hepatol 2007;5:1221.
of the Liver
In Western countries, metastatic cancer is much more common than
primary tumors in the liver. Nearly all solid tumors can potentially
give rise to liver metastases; primary cancers of the gastrointestinal
tract (colon, pancreas, esophagus, stomach, neuroendocrine), breast,
lung, genitourinary system (kidney, adrenal), ovary and uterus,
melanoma, and sarcomas account for the overwhelming majority of
cases. Spread to the liver may be via the systemic or portal venous
circulation. The cirrhotic liver, which often gives rise to primary hepatic
tumors, seems to be less susceptible than normal liver to implantation of
Individual tumor types have characteristic patterns of spread.
For example, colorectal cancer spreads to the liver as the first
site of metastatic disease in a very high proportion of patients;
the lung is the next most common site, but bone, brain, or adrenal
metastases are distinctly unusual. By contrast, metastatic lung cancer
to the liver typically occurs concomitantly with spread to other
sites, with brain, bone, and adrenal among the most common. In general,
the vast majority of patients with metastases to the liver also have
disease at other sites. A notable exception is colorectal cancer,
which in many cases involves the liver only for a prolonged period.
In the past, approximately 20% of patients with hepatic metastases
had additional tumor deposits in the liver not seen on preoperative imaging
studies. As imaging technology has improved, however, this proportion has
become increasingly smaller.
The signs and symptoms will vary with the clinical scenario,
the disease extent within the liver, and the presence or absence
of metastatic disease to other sites. Patients with an undiagnosed
primary tumor may come to attention because of symptoms caused by
the metastatic disease. Weight loss, fatigue, pain, and anorexia
are the presenting general complaints in many such patients. Signs
of liver failure, such as ascites and jaundice, are uncommon and suggestive
of very advanced cancer. Fever without demonstrable infection is present
in 15% of cases. By contrast, patients with a known history
of cancer undergoing routine surveillance often develop liver metastases
that cause no symptoms; in a small proportion of cases, liver metastases
are found on studies done for unrelated reasons.
Physical examination is frequently unrevealing. Hepatomegaly
or a palpable tumor in the upper abdomen may be present, and either
may be tender. Portal hypertension may be manifested by abdominal
venous collaterals or splenomegaly. A friction rub is sometimes heard
over the liver.
Laboratory values may be entirely normal or at most reflect only
minor nonspecific changes. Patients with advanced cancer will have
anemia and hypoalbuminemia. The alkaline phosphatase is increased
in most patients. More significant derangements in liver function
will occur in patients with a large volume of liver disease, although
this is uncommon at initial presentation. Tumor marker levels (carcinoembryonic
antigen [CEA], cancer antigen [CA] 19-9,
CA-125) are often elevated, depending on the tumor type, and may
be helpful for monitoring treatment.
The diagnosis can be established in most cases by CT-guided or
ultrasound-guided percutaneous liver biopsy or fine-needle aspiration
for malignant cells.
The detection of liver metastases relies on CT and/or
MRI scans; ultrasonography will identify tumors in the liver and will
distinguish solid from cystic lesions but cannot provide the same
degree of anatomical detail. MRI provides useful additional information
and may help distinguish benign from malignant disease. However,
a high-quality triple phase CT scan with intravenous and oral contrast
medium provides excellent assessment of disease extent in the liver
and elsewhere in the abdomen. In the past, CT portography was superior
to ordinary contrast-enhanced CT and was obtained routinely in patients
being considered for hepatic resection, but this is no longer the
case. Positron emission tomography using 14-fluorodeoxyglucose (FDG-PET)
is a commonly used staging study and may help identify extrahepatic
disease, a finding that could change the treatment recommendations.
During surgery, intraoperative ultrasound is used to assess the
liver for disease not appreciated on imaging studies.
For most patients with metastatic liver disease, chemotherapy
is the only treatment option, particularly with coexisting metastases
outside the liver. Such therapy is usually not curative but rather
palliative in most cases. A notable exception is metastatic colorectal
cancer, for which resection or other treatments aimed at the liver
disease are effective and potentially curative; the recent advent
of several active chemotherapeutic agents has further improved the
results of treatment. Carefully selected patients with metastases
from other primary tumors (sarcoma, breast, ovary, lung, neuroendocrine)
may also benefit from resection but represent a small minority of
Hepatic resection is most commonly indicated in patients with
metastatic colorectal cancer. Of the approximately 130,000 patients
diagnosed with colorectal cancer annually in the United States,
approximately 50% either have liver metastases at diagnosis
or develop liver metastases at some point. In 40% of the
latter group, the liver is the only demonstrable site of disease.
Hepatic metastases from colorectal cancer thus affect approximately 20,000
patients per year, which is comparable to the annual incidence of
pancreatic or esophageal carcinoma.
After a complete resection, the 5-year survival rate has historically
been 25–40%; systemic or regional chemotherapy
or both are frequently given after resection and appear to enhance
the results of surgery, with more recent series reporting 5-year
survival figures of approximately 50%. The presence of
extrahepatic metastases and inability to achieve a complete resection
are contraindications to resection in most cases. However, as more
effective chemotherapeutic options have emerged, the indications
for resection have expanded to include selected patients with multiple
bilobar tumors and even some with extrahepatic metastatic disease.
Extensive use of chemotherapy prior to surgery can cause changes
in the liver, particularly steatosis and steatohepatitis, which
can impair the liver’s normal regenerative response. Caution
is therefore needed when considering such patients for major hepatic
resections, since operative morbidity and mortality may be increased;
preoperative portal vein embolization may reduce the incidence of
serious postoperative complications.
The following variables are associated with a worse prognosis
after resection: (1) original tumor with involved lymph nodes (stage
III or Dukes C), (2) multiple liver lesions, (3) less than 1 year
since resection of the colon primary (disease-free interval), and
(4) CEA level higher than 20 ng/mL. Variables that do not influence
the outcome include (1) histologic grade of the tumor, (2) bilateral rather
than unilateral disease, (3) site of the primary tumor within the
large intestine, and (4) the gender of the patient. The mortality
rate for resection of hepatic metastases is 1–2% in
hospitals where this operation is performed frequently.
The liver is the most common site of cancer recurrence after
a complete resection. A small proportion of patients with hepatic
recurrence may be amenable to a second resection. The use of adjuvant hepatic
arterial chemotherapy appears to reduce the risk of intrahepatic
The efficacy of liver resection for colorectal cancer has been
clearly established and is the most common indication for this procedure.
By contrast, for most other tumor types, particularly those arising
from the gastrointestinal tract other than the colon or rectum,
the benefit of liver resection is much more limited. Rare patients
with metastases from renal cell carcinoma, ovarian cancer, adrenocortical
carcinoma, or sarcomas appear to derive the most benefit; by contrast, liver
resection for metastatic esophageal, gastric or pancreatic cancer
is almost never warranted. In selecting patients with noncolorectal
liver metastases for resection, the most important factors are (1)
long disease-free interval, (2) solitary resectable liver tumor,
and (3) absence of extrahepatic metastases.
Neuroendocrine carcinomas (pancreatic islet cell tumors, carcinoids)
represent a unique class of tumors that often give rise to liver
metastases. Unlike patients with other metastatic tumor types, those with
neuroendocrine tumors often survive for many years. Multiple liver metastases
are the rule with this disease, so complete resection is usually not
possible. However, debulking liver resections are sometimes indicated
to palliate tumor-related pain or hormonal symptoms. Partial hepatectomy
is also sometimes worthwhile to extirpate a tumor invading directly
from a contiguous organ.
RFA has been used to treat metastases to the liver from a variety
of tumor types. The indications for this procedure remain ill defined.
The best candidates are those with a limited number of small liver lesions
with no evidence of extrahepatic cancer.
In a large proportion of patients with metastatic colorectal
cancer, the liver is the only evident site of disease. If the lesions cannot
be resected, regional intrahepatic chemotherapy can be given by
placing a catheter in the gastroduodenal artery (at its origin with
the common hepatic artery) connected to an implantable, subcutaneous
infusion pump, which allows the delivery of much higher concentrations
of drug to the tumor than is possible with systemic administration.
This regimen is generally not used for metastases from other kinds
of tumors. The pump is primed with floxuridine, which is delivered
by continuous infusion (0.1–0.2 mg/kg/d)
for 14-day periods alternating with 14-day rests. Systemic chemotherapy
is usually given concomitantly. The discovery of extrahepatic lesions
at laparotomy for pump placement is a relative contraindication
to proceeding with this approach. Treatment is continued until disease
progression or excessive toxicity is seen or, rarely, until the
response is complete. Toxicity consists mainly of gastroduodenal
erosions (caused by unintentional perfusion of these areas), chemical
hepatitis, or chemical sclerosing cholangitis. Survival is related
principally to the initial amount of liver involvement by tumor,
objective response to treatment (which is seen in about 60% of
patients), and extent of prior chemotherapy. The median survival of
patients with less than 30% of liver replaced by tumor
is 24 months, compared with 10 months if the extent of replacement
exceeds 30%. There is a general perception that hepatic
artery infusion therapy improves survival, but the objective evidence
is inconclusive. Cure is not a realistic objective.
Hepatic artery infusion chemotherapy may be a useful adjunctive
therapy after complete tumor resection or RFA. Studies of this option
are under way.
Systemic chemotherapy (eg, with fluorouracil, irinotecan, or
oxaliplatin) after liver resection has not been proved to improve
survival, although it is often prescribed.
Hepatic artery ligation or angiographic embolization of the tumor
has been of benefit in a few patients with hepatic metastases from
specific tumor types, particularly neuroendocrine tumors.
Survival varies with the site of origin of the primary tumor
and the extent of metastatic disease. Patients with extensive hepatic
replacement by multiple lesions have a dismal outlook, with a survival measured
in months, compared to perhaps 2–3 years for patients with
small solitary lesions. The range of treatment options and effective
chemotherapeutic agents is greatest for metastatic colorectal cancer
compared to most other tumor types, and survival is generally better
in this group.
Adam et al: Two-stage hepatectomy: a planned strategy
to treat irresectable liver tumors. Ann Surg 2000;232:777.
Andres A et al: Improved long-term outcome of surgery for advanced
colorectal liver metastases: reasons and implications for management
on the basis of a severity score. Ann Surg Onc 2007;15:134.
Cho CS et al: Histologic grade is correlated with outcome after resection
of hepatic neuroendocrine neoplasms. Cancer 2008; 113:126.
DeMatteo RP et al: Results of hepatic resection for sarcoma
metastatic to liver. Ann Surg 2001;234:540.
Fong et al: Clinical score for predicting recurrence after hepatic
resection for metastatic colorectal cancer: analysis of 1001 consecutive
cases. Ann Surg 1999;230:309.
Heslin MJ et al: Colorectal hepatic metastases: resection, local
ablation, and hepatic artery infusion pump are associated with prolonged
survival. Arch Surg 2001;136:318.
Kokudo N et al: Anatomical major resection versus nonanatomical
limited resection for liver metastases from colorectal carcinoma.
Am J Surg 2001;181:153.
Lambert LA, Colacchio TA, Barth RJ Jr: Interval hepatic resection
of colorectal metastases improves patient selection. Arch Surg 2000;135:473.
Nagakura S, Shirai Y, Hatakeyama K: Computed tomographic features
of colorectal carcinoma liver metastases predict posthepatectomy
patient survival. Dis Colon Rectum 2001;44:1148.
Nordlinger B et al: Perioperative chemotherapy with FOLFOX4
and surgery versus surgery alone for resectable liver metastases
from colon cancer (EORTC Intergroup trial 40983): a randomized controlled
trial. Lancet 2008;371:1007.
Primrose JN: Treatment of colorectal metastases: surgery, cryotherapy,
or radiofrequency ablation. Gut 2002;50:1.
Strasberg SM et al: Survival of patients evaluated by FDG-PET
before hepatic resection for metastatic colorectal carcinoma: a
prospective database study. Ann Surg 2001;233:293.
Tomlinson JS et al: Actual 10-year survival after resection
of colorectal liver metastases defines cure. J Clin Oncol 2007;
Vauthey JN et al: Chemotherapy regimen predicts steatohepatitis
and an increase in 90-day mortality after surgery for hepatic colorectal
metastases. J Clin Oncol 2006;24:2065.
Weitz J et al: Partial hepatectomy for metastases from non-colorectal,
non-neuroendocrine carcinoma. Ann of Surg 2005;241:269.
& Cysts of the Liver*
Hemangioma is the most common benign hepatic tumor, and except
for the skin and mucous membranes, the liver is the most common
site of origin. Women are affected more often than men—in some
series, up to 75% of patients are female. Histologically,
hepatic hemangiomata are of the cavernous type rather than the capillary
type. Most are small, solitary subcapsular growths that are found
incidentally during laparotomy or autopsy or on imaging studies.
Rarely, hemangiomata grow to very large dimensions (giant hemangiomata)
and cause abdominal pain or a palpable mass. Most are small to moderate-sized
lesions, however; pain is uncommon in tumors smaller than 8–10
cm in diameter.
Rare complications of liver hemangiomata include hemorrhagic
shock resulting from spontaneous rupture and the Kasabach-Merritt
syndrome, which is usually seen in children and is associated with thrombocytopenia
and a consumptive coagulopathy; both of these complications are
exceedingly uncommon. Large congenital hemangiomas of the liver
may be associated with others in the skin. Large hemangiomata may
also give rise to large-volume arteriovenous shunting, resulting
in cardiac hypertrophy and congestive heart failure.
Large-bore needle biopsy is hazardous due to bleeding risks;
aspiration biopsy with a fine needle is safe but rarely helpful.
Fortunately, biopsy is very rarely indicated, since the diagnosis
can be made with certainty in most cases by contrast-enhanced CT
or MRI scans. The hallmark features of hemangiomata are nodular
peripheral enhancement with progressive central enhancement on the more
delayed images. MRI is a particularly good study for hemangiomata, which
appear very bright on the T2-weighted images. Angiography is unnecessary,
and nuclear scans lack sufficient sensitivity and specificity.
The only reasons to resect hemangiomata are for symptoms, most
commonly pain, or diagnostic uncertainty. Symptomatic hemangiomas
should be excised by lobectomy or enucleation. Even large lesions
can be safely removed. Radiotherapy or embolization via a catheter
in the hepatic artery may be tried in patients who are poor candidates
for surgery, but the efficacy of these approaches is limited. The
natural history of asymptomatic hemangiomas, whether large or small,
is benign. The vast majority of incidentally discovered hemangiomata
remain stable in follow-up, do not give rise to symptoms, and therefore
do not require resection. Progressive growth of asymptomatic hemangiomata
over a relatively short time interval, particularly in young patients,
is considered a relative indication for resection.
Bykov S et al: The role of hepatobiliary scintigraphy
in the follow-up of benign liver tumors secondary to oral contraceptive
use. Clin Nucl Med 2001;26:946.
Charny CK et al: The management of 155 patients with benign
liver tumours. Br J Surg 2001;88:1.
Cherqui D et al: Laparoscopic liver resections: a feasibility
study in 30 patients. Ann Surg 2000;232:753.
Clarke D et al: Hepatic resection for benign non-cystic liver
lesions. HPB 2004;6:115.
Popescu I et al: Liver hemangioma revisited: current surgical
indications, technical aspects, results. Hepatogastroenterology
Terkivatan T et al: Indications and long-term outcome of treatment
for benign hepatic tumors: a critical appraisal. Arch Surg 2001;136:1033.
Van den Bos IC et al: Magnetic resonance imaging of liver lesions:
exceptions and atypical lesions. Curr Probl Diagn Radiol 2008;37:95.
A number of different cystic lesions may affect the liver. Simple
hepatic cysts, the most common, are unilocular fluid-filled lesions
that generally produce no symptoms. The occasional large cyst may present
as an upper abdominal mass or discomfort. Small, simple cysts may
be difficult to diagnose on CT and may be confused for metastatic
disease; ultrasound and MRI are better modalities to assess the
character of cystic lesions. Many patients have multiple simple cysts,
which should not be confused with polycystic liver disease, a progressive condition
characterized by cystic replacement of virtually the entire liver. Polycystic
liver disease is associated in about half of cases with polycystic
renal disease. The possibility of echinococcosis (see Chapter 8) should be considered in patients with cystic liver lesions
and the appropriate exposure history, although their radiographic
appearance is usually quite distinctive.
Most simple cysts have a serous lining and a smooth, thin wall.
Intracystic hemorrhage can occur, which can confuse the radiographic
appearance. Solitary cysts lined with cuboidal epithelium are classified
as cystadenomas and should be resected, since they are premalignant.
Cystadenomas are characterized radiographically as complex, with internal
septae, an irregular lining, and papillary projections. Complex,
multilocular (septated) cysts (if not echinococcal) are often neoplastic
and should be resected. However, cystadenomas and cystadenocarcinomas
are rare, while internal hemorrhage into a simple cyst is a more common
entity and may have a similar appearance. Nevertheless, complex
cysts of the liver must be approached with some caution in order
to avoid inappropriate interventions. There are few indications
for aspirating hepatic cysts—simple cysts reaccumulate
fluid quickly, neoplastic cysts must be excised, and parasitic cysts
might rupture and the parasite thus be allowed to spread. It is
possible to eliminate small cysts by aspiration of the contents
followed by an injection into the lumen of 20–100 mL of
absolute alcohol; however, small cysts almost never cause symptoms
and generally require no treatment.
Large symptomatic cysts are difficult to eradicate with alcohol
injections, and serious superinfection of the cyst cavity may occur.
The simplest method of treatment consists of laparoscopic cyst fenestration
(wide excision of the cyst wall). A tongue of omentum is fixed so
it lies in the residual cyst cavity as an ancillary measure to prevent
the edges from coapting. The operation is curative in nearly all
Multiple, small, simple cysts do not usually require treatment,
but large polycystic livers that cause discomfort or are associated
with obstructive jaundice can be managed by partial resection or
surgically unroofing the cysts on the surface of the liver and creating
windows between superficial cysts and adjacent deep cysts. The opened
cysts are allowed to drain into the abdominal cavity. The results
of surgery for polycystic liver disease are often disappointing,
with quick return of symptoms in many patients.
Cowles RA, Mulholland MW: Solitary hepatic cysts.
J Am Coll Surg 2000;191:311.
Del Poggio P, Buonacore M: Cystic tumors of the liver: a practical
approach. World J Gastroenterol 2008;14:3616.
Hansen P, Ludemann R, Swanstrom LL: Minimally invasive approaches
to hepatic surgery. Hepatogastroenterology 2001;48:37.
Inaba Y et al: Focal attenuation differences in pericystic liver
tissue as seen on CT hepatic arteriography and CT arterial portography:
observation using a unified helical CT and angiography system. Abdom
Hepatic adenomas occur predominantly in women and appear to be
related to the use of oral contraceptives. Mestranol-containing
compounds have been associated with a disproportionate number of cases,
but mestranol has been in use longer than the other agents.
The tumors are soft, yellow-tan, well-circumscribed masses that
are usually of moderate size (range of 2–15 cm in diameter).
Most of those that cause symptoms are in the 8–15-cm range. Two
thirds of hepatic adenomas are solitary; other benign tumors (such
as focal nodular hyperplasia, see next section) are present in some
cases. Transition from benign hepatic adenoma to hepatocellular
carcinoma may occur, with liver cell dysplasia as an intermediate
step. Histologically, hepatic adenomas consist of an encapsulated
homogeneous mass of normal-appearing hepatocytes without bile ducts
or central veins. Intratumoral hemorrhage or central necrosis may
About half of patients are asymptomatic. Most of those with symptoms
present with right upper quadrant pain. Spontaneous hemorrhage into
the substance of the tumor with subsequent rupture and intraperitoneal
bleeding is a well-known potential complication of adenomas; patients
with this life-threatening problem present with acute pain or even
hemorrhagic shock. There is a strong association of acute bleeding
episodes with pregnancy.
Liver function tests and AFP levels are usually normal or minimally
deranged. Adenomas typically appear hypervascular compared to the
surrounding liver parenchyma, a feature that is apparent on contrast-enhanced
CT or MRI scans or angiography. Adenomas can be difficult to distinguish
from focal nodular hyperplasia, another benign tumor often found
in young women. Differences in tumor vascularity may be demonstrated on
angiography; however, MRI is probably the best study for differentiating
these lesions. Adenomas often cannot be distinguished from well-differentiated
hepatocellular carcinoma on imaging studies and even on biopsy specimens.
Needle biopsy is generally safe but often inconclusive and is associated
with a small risk of bleeding.
The general recommendation is that adenomas should be resected
because of the risks of malignant change and spontaneous hemorrhage.
Unfortunately, the true likelihood of these events is difficult
to estimate, since most series include only treated patients. Symptomatic
and large asymptomatic adenomas clearly should be resected. Emergent
resection or hepatic artery embolization should be undertaken in
patients with evidence of hemorrhage. Small peripheral lesions may
be removed with wedge excisions, but larger tumors require more
extensive resections. Small adenomas may regress when oral contraceptive
agents are discontinued, and close follow-up with imaging studies
is not unreasonable in such cases; however, any change in symptoms
or imaging characteristics (growth, hemorrhage) should prompt resection.
The possibility that a presumed adenoma is actually a well-differentiated
hepatocellular carcinoma or contains a focus of malignancy must
always be kept in mind; there is no completely reliable means of making
the differentiation other than pathologic analysis of the resected
Most patients recover without sequelae after surgical removal;
recurrence is rare. Oral contraceptives should be discontinued permanently
in all cases. Radiotherapy and chemotherapy are of no value, but elective
hepatic artery embolization may be helpful in patients who are not
surgical candidates. Embolization may be particularly helpful in
the very rare patient with multiple hepatic adenomas (hepatic adenomatosis),
since resection is usually not possible.
Focal nodular hyperplasia is a benign lesion with no malignant
potential. Like hepatic adenoma, focal nodular hyperplasia is much
more common in young women. The average age is about 40 years, but
the tumor can occur at any age. Unlike hepatic adenoma, however, the
use of oral contraceptive agents does not appear to predispose to
the development of focal nodular hyperplasia, although it has been
suggested that these agents may stimulate growth.
Grossly, the tumor is a well-circumscribed, firm, tan, usually
subcapsular mass measuring 2–3 cm in diameter. In patients
with symptoms, the lesions are much larger, usually around 10 cm.
Multiple tumors can occur; 80% are solitary. The gross
appearance on cut section is quite characteristic, consisting of
a central stellate scar (which is actually an aggregation of blood
vessels) with radiating fibrous septa that compartmentalize the
lesion into lobules. Histologically, there are nodular aggregations
of normal-appearing hepatocytes without central veins or portal
triads. Bile duct proliferation is present in the nodules.
Most patients with focal nodular hyperplasia are asymptomatic.
The few with symptoms present with a right upper quadrant discomfort.
Unlike hepatic adenomas, these lesions rarely, if ever, bleed, and
the natural history of asymptomatic lesions is benign. Very rare patients
with diffuse focal nodular hyperplasia develop portal hypertension.
Hepatic function tests and AFP levels are usually normal. Hepatic
scintiscans usually do not show a filling defect but are of little
practical value. CT scans demonstrate the tumor and may also show
the central stellate scar. The arteriographic pattern is one of
hypervascularity. In most cases, the diagnosis of focal nodular
hyperplasia can be made with noninvasive studies, although distinguishing focal
nodular hyperplasia from hepatic adenomas can be difficult, even
for experienced radiologists. MRI scanning is the best modality,
but the imaging features of both tumors overlap somewhat, and they occur
in similar patient populations. Fine-needle aspiration biopsies
are generally not helpful.
Symptomatic lesions should be removed, while asymptomatic tumors
(the majority) should be left undisturbed, provided that the diagnosis
has been made confidently. In the latter circumstance, a period
of observation with imaging studies is recommended to ensure stability. Inability
to distinguish focal nodular hyperplasia from adenoma or malignant disease
is an indication for resection in some patients. Discontinuation
of oral contraceptives probably has no impact. Focal nodular hyperplasia
can be reliably identified on examination of frozen sections.
Bioulac-Sage P, Balabaud C, Wanless IR: Diagnosis
of focal nodular hyperplasia: not so easy. Am J Surg Pathol 2001;25:1322.
Bonney GK et al: Indication for treatment and long-term outcome
of focal nodular hyperplasia. HPB 2007;9:368.
Cho SW et al: Surgical management of hepatocellular adenoma:
take it or leave it. Ann Surg Oncol 2008; in press.
Kim YI, Chung JW, Park JH: Feasibility of transcatheter arterial
chemoembolization for hepatic adenoma. J Vasc Interv Radiol 2007;18:862.
Leconte I et al: Focal nodular hyperplasia: natural course observed
with CT and MRI. J Comput Assist Tomogr 2000;24:61.
Terkivatan T et al: Indications and long-term outcome of treatment
for benign hepatic tumors: a critical appraisal. Arch Surg 2001;136:1033.
Terkivatan T et al: Treatment of ruptured hepatocellular adenoma.
Br J Surg 2001;88:207.
*Echinococcal cysts are discussed in Chapter 8.
The major causes of portal hypertension are listed in Table 24–3. In all but a few instances,
the basic lesion is increased resistance to portal flow. Those associated
with increased resistance can be subclassified according to the
site of the block as prehepatic, hepatic, and posthepatic; hepatic
causes of portal hypertension are further subclassified as presinusoidal,
sinusoidal, and postsinusoidal. Cirrhosis accounts for about 85% of
cases of portal hypertension in the United States, most commonly
from heavy alcohol use. Postnecrotic cirrhosis is next in frequency,
followed by biliary cirrhosis. The other intrahepatic causes of
portal hypertension are relatively rare in Western countries, although
in some parts of the world, hepatic schistosomiasis constitutes
the largest single group. Idiopathic portal hypertension occurs
with greater frequency in southern Asia.
Table 24–3. Causes of Portal Hypertension. |Favorite Table|Download (.pdf)
Table 24–3. Causes of Portal Hypertension.
|I. Increased resistance to flow|
|A. Prehepatic (portal vein obstruction)|
|1. Congenital atresia or stenosis|
|2. Thrombosis of portal vein|
|3. Thrombosis of splenic vein|
|4. Extrinsic compression (eg, tumors)|
|a. Portal cirrhosis (nutritional, alcoholic,
|b. Postnecrotic cirrhosis|
|c. Biliary cirrhosis|
|d. Others (Wilson disease, hemochromatosis)|
|2. Acute alcoholic liver disease|
|3. Chronic active hepatitis|
|4. Congenital hepatic fibrosis|
|5. Idiopathic portal hypertension (hepatoportal
|1. Budd-Chiari syndrome (hepatic vein thrombosis)|
|2. Veno-occlusive disease|
|3. Cardiac disease|
|a. Constrictive pericarditis|
|b. Valvular heart disease|
|c. Right heart failure|
|II. Increased portal blood flow|
|A. Arterial-portal venous fistula|
|B. Increased splenic flow|
|1. Banti syndrome|
|2. Splenomegaly (eg, tropical splenomegaly,
After cirrhosis, extrahepatic portal venous thrombosis or occlusion
is the most common cause of portal hypertension in the United States.
Patients with this condition are generally younger than cirrhotics,
and many are children. Posthepatic obstruction due to Budd-Chiari syndrome
or constrictive pericarditis is rare.
Portal hypertension is defined as a portal pressure gradient
greater than 5 mm Hg. Since pressure in the portal venous system
is determined by the relationship Pressure = Flow × Resistance,
portal hypertension could result either from increased volume of
portal blood flow or increased resistance to flow. In practice, however,
the liver has tremendous reserve capacity to accommodate increased
blood flow, and portal hypertension due to this mechanism is extremely
uncommon. Nearly all clinically relevant cases result from increased
resistance, although the site of the resistance varies in different
diseases. A pathophysiologic classification of the causes of portal
hypertension is given in Table 24–3.
Portal venous pressure normally ranges from 7 to 10 mm Hg. In
portal hypertension, portal pressure exceeds 10 mm Hg, averaging
around 20 mm Hg and occasionally rising as high as 50–60
In alcoholic liver disease, the abnormal resistance is predominantly
postsinusoidal, as indicated by the results of wedged hepatic vein
The causes of increased resistance in this disease are thought
to be (1) distortion of the hepatic veins by regenerative nodules
and (2) fibrosis of perivascular tissue around the hepatic veins
and the sinusoids.
Even in the absence of cirrhosis, acute alcoholic hepatitis can
raise portal pressure by producing centrilobular swelling and fibrosis.
Sinusoidal resistance to flow is also increased by engorgement of adjacent
hepatocytes with fat and resultant distortion and narrowing of vascular channels.
Documented cases of normalization or reduction in portal pressure have
occurred with resolution of the pathologic changes.
Schistosomiasis can produce a unique form of presinusoidal obstruction
to blood flow from deposition of parasite ova in small portal venules.
The subsequent chronic inflammatory reaction leads to fibrosis and
cirrhosis. Many patients with schistosomiasis are also at risk for
chronic hepatitis, which can exacerbate the liver damage.
Fluctuations in the level of portal hypertension may occur in
conjunction with changes in blood volume. This is almost never a
problem in patients with a normal liver. However, administration
of colloid solutions to a patient with underlying liver disease
and a normal or expanded blood volume could theoretically aggravate
the clinical manifestations of portal hypertension.
Budd-Chiari syndrome (hepatic vein thrombosis) results
from obstruction of flow through the hepatic veins. The resulting
sinusoidal hypertension produces prominent ascites and hepatomegaly.
Conditions (veno-occlusive disease, inferior vena cava obstruction
by tumor or congenital webs, right-sided heart failure) that reduce
flow through the hepatic veins will result in a similar clinical
Banti syndrome was defined as liver disease secondary to
primary splenic disease and was incorrectly considered as the cause
of portal hypertension now known to result from cirrhosis and other
hepatic disorders rather than a consequence of such conditions.
Portal hypertension from splenomegaly and increased splenic vein flow
has been described in patients with hematologic diseases or tropical
splenomegaly and apparently normal liver function. This is extremely
uncommon, however, and given the great reserve of the liver to handle
increases in portal flow, many such patients probably have some
component of liver disease. In cirrhosis, the increased splenic
blood flow accompanying “congestive” splenomegaly
may occasionally be great enough to warrant splenic artery ligation
or splenectomy to decrease portal pressure and improve symptoms,
but this situation is rare.
Increased flow may contribute to portal hypertension in patients
with arterial-portal venous fistulae (traumatic, congenital). When
an arteriovenous fistula occurs, portal hypertension and its clinical
manifestations usually do not appear for several months, because
sinusoidal capacity is so great that the immediate rise in portal
pressure is only moderate. With time, however, sinusoidal sclerosis develops,
resistance increases, and portal pressure gradually reaches high
levels, leading to the formation of varices.
The average portal flow in cirrhotic patients with complications
of portal hypertension is about 30% of normal, ranging
from 0 to 700 mL/min. Hepatic arterial flow is usually
reduced by a similar proportion. The range of portal flow rates
in different patients may vary greatly; in some, blood in the portal
vein moves sluggishly or the direction of flow may even be reversed
(hepatofugal) so that the portal vein functions as an outflow tract
from the liver. These states of low flow predispose to spontaneous thrombosis
of the portal vein, a complication of cirrhosis that usually is
associated with acute clinical deterioration and renders the portal
vein unsuitable for a shunt to decompress the portal venous system. Along
with these changes, blood flow through the splanchnic vascular bed increases
as a result of decreased resistence, the consequence of increased
production of local vasodilators (eg, nitric oxide) and mesenteric
The obstacle to flow through the liver promotes expansion of
collateral channels between the portal and systemic venous systems.
As the pathologic process develops, portal pressure increases until
a level of about 40 cm H2O (30 mm Hg) is reached. At this
point, increasing hepatic resistance, even to the point of occlusion
of the portal vein, diverts a greater fraction of portal flow through
collaterals without significant increments in portal pressure.
The type of collateral that develops depends partly on the cause
of the portal hypertension. In extrahepatic portal vein thrombosis
(without liver disease), collaterals in the diaphragm and in the
hepatocolic, hepatoduodenal, and gastrohepatic ligaments transport
blood into the liver around the occluded vein (hepatopetal). In
cirrhosis, collateral vessels circumvent the liver and deliver portal
blood directly into the systemic circulation (hepatofugal); these
collaterals give rise to esophageal and gastric varices. Other common spontaneous
collaterals are through a recanalized umbilical vein to the abdominal
wall, from the superior hemorrhoidal vein into the middle and inferior
hemorrhoidal veins, and through numerous small veins (of Retzius)
connecting the retroperitoneal viscera with the posterior abdominal
Isolated thrombosis of the splenic vein causes localized splenic
venous hypertension and gives rise to large collaterals from spleen
to gastric fundus. From there, the blood returns to the main portal system
through the coronary vein. In this condition, gastric varices are
often present without esophageal varices.
Of the many large collaterals that form as a result of portal
hypertension, spontaneous bleeding is relatively uncommon except
from those at the gastroesophageal junction; spontaneous bleeding from
gastric varices can sometimes occur. Compared with adjacent areas
of the esophagus and stomach, the gastroesophageal junction is especially
rich in submucosal veins, which expand disproportionately in patients
with portal hypertension. The cause of variceal bleeding is most
probably rupture due to sudden increases in hydrostatic pressure.
Esophagitis is usually mild or absent.
*A catheter wedged in a tributary of the hepatic
vein permits estimation of the pressure in the afferent veins to
the sinusoid. The gradient between the wedged pressure and that
in the hepatic vein reflects resistance at any point between the
wedged position and the periphery of the sinusoid. The current view
holds that the site of principal resistance in normal persons is
in reasonably large hepatic veins. In cirrhosis, it is probably
in the sinusoids as well as the hepatic veins.
Debernardi-Venon W et al: CO2
hepatic venography in the evaluation of portal hypertension. Gut 2000;46:856.
Krige JE, Beckingham IJ: ABC of diseases of liver, pancreas,
and biliary system. Portal hypertension—1: varices. BMJ
Krige JE, Beckingham IJ: ABC of diseases of liver, pancreas,
and biliary system: portal hypertension—2. Ascites, encephalopathy,
and other conditions. BMJ 2001;322:416.
Sanyal AJ et al: Portal hypertension and its complications.
Hepatic cirrhosis remains a major public health problem worldwide,
with and annual mortality of approximately 23,000 per year in the
United States alone. The incidence of cirrhosis is increasing, due in
large measure to hepatitis C, and at present is the third-most common
cause of death in men in the fifth decade of life.
Alcohol abuse remains the leading cause of cirrhosis in most
Western countries. Alcohol exerts direct toxic effects on the liver
that are magnified in the presence of protein and other dietary
deficiencies that are often present. Even still, cirrhosis develops
in a small minority of patients who abuse alcohol. Alcohol induces
a specific cytochrome P450 in the liver (ie, P450 2E1) that participates in
its metabolism to acetaldehyde, which has a number of deleterious
effects, including antibody formation, decreased DNA repair, enzyme
inactivation, and alterations in microtubules, mitochondria, and
plasma membranes. Acetaldehyde also promotes glutathione depletion,
free radical–mediated toxicity, lipid peroxidation, and
hepatic collagen synthesis. Hepatic steatosis and alcoholic hepatitis are
stages of alcoholic liver injury that may precede cirrhosis. Alcoholic
hyalin, a glycoprotein, accumulates in centrilobular hepatocytes
of patients with alcoholic hepatitis. There is some evidence that
immunologic responses to alcoholic hyalin may be important in the
pathogenesis of cirrhosis.
Collagen deposition in cirrhosis results from increased fibroblastic
activity as well as from repair following hepatocellular injury
and necrosis. The ultimate result is a liver containing regenerative nodules
and connective tissue septa linking portal fields with central canals.
The natural history of cirrhosis is difficult to predict. Once
the diagnosis has been established, up to 30% of patients
die within a year from hepatic failure or complications of portal
hypertension, of which bleeding esophageal varices is the most feared.
In newly diagnosed cirrhotics, the chances of dying within the subsequent 2–3
years are influenced by the status of liver function (as reflected
by the Child-Pugh classification), the presence of varices, and
the portal pressure. A group of cirrhotics with varices followed
by the Boston Interhospital Liver Group experienced a 1-year death
rate of 66%. Cirrhotics without varices may benefit substantially
by abstaining from alcohol. Bleeding episodes occur in up to 40% of all
patients with cirrhosis, and the initial episode of variceal hemorrhage
is fatal in 50% or more. At least two thirds of those who
survive their initial hemorrhage will bleed again, and the risk
of dying from the second is similarly high. It is principally for
such patients that portal decompressive procedures are recommended.
Varices will develop in 5–15% of cirrhotic patients
per year. Most patients with cirrhosis will develop varices, but
only about one third will experience variceal hemorrhage. Each bleeding
episode is associated with a mortality rate of up to 25%,
and 70% of untreated patients will die within a year of
the first episode. This high death rate reflects not only the massive
hemorrhage but also the frequent presence of severely compromised
liver function and other systemic disease that may or may not be
related to alcohol abuse. Malnutrition, pulmonary aspiration, infections,
and coronary artery disease are frequent coexisting conditions. Additional
complicating factors in this patient population include lack of
cooperation with treatment and acute alcohol withdrawal, which in
its worst manifestation (delirium tremens) adds greatly to the already
high mortality rate.
The initial management of the patient with massive gastrointestinal
hemorrhage is discussed in Chapter 23. Critical
initial steps include airway protection, particularly in patients
with altered mental status or those with hemodynamic instability,
and resuscitation with fluid and blood products; correction of coagulopathy
and thrombocytopenia should also be initiated early. Patients admitted
with variceal hemorrhage are often bacteremic as a result of a concomitant
infectious process (spontaneous bacterial peritonitis, urinary tract
infection, or pneumonia). Clinical trials have shown better outcomes
when empiric antibiotic therapy is initiated, usually a third-generation
cephalosporin such as ceftriaxone.
It must be emphasized that bleeding from varices cannot be accurately
diagnosed on clinical grounds alone even though the history or the
appearance of the patient may strongly suggest the presence of cirrhosis
or portal hypertension. Most patients with bleeding varices have
alcoholic cirrhosis, and the diagnosis may seem obvious in a patient
with hepatomegaly, jaundice, and vascular spiders who admits to
recent binge drinking. Splenomegaly, the most constant physical
finding, is present in 80% of patients with portal hypertension
regardless of the cause. Ascites is frequently present. Massive
ascites and hepatosplenomegaly in a nonalcoholic would suggest the
much less common Budd-Chiari syndrome. If cirrhosis or varices have
been documented on previous examinations, hematemesis would strongly
suggest bleeding varices as the cause.
Most patients with alcoholic liver disease and acute upper gastrointestinal
bleeding have compromised liver function. The bilirubin is usually
elevated, and the serum albumin is often below 3 g/dL.
The leukocyte count may be elevated. Anemia may be a reflection
of chronic alcoholic liver disease or hypersplenism as well as acute
hemorrhage. The development of a hepatoma by a cirrhotic may first
manifest by hemorrhage from varices; CT scan and marked elevation of
the serum α-fetoprotein will make the diagnosis. Thrombocytopenia
and coagulopathy are common.
Emergency esophagogastroscopy is the most useful procedure for
diagnosing bleeding varices and should be performed as soon as the patient’s
general condition is stabilized by blood transfusion and other supportive
measures. Endotracheal intubation is usually necessary for airway
control. Varices appear as three or four large, tortuous submucosal
bluish vessels running longitudinally in the distal esophagus. The
bleeding site may be identified, but in some cases the lumen fills
with blood so rapidly that the lesion is obscured.
A barium swallow outlines the varices in about 90% of
affected patients, but barium studies are neither as sensitive nor as
specific as endoscopy, and they are difficult and dangerous studies
to perform in the bleeding patient.
The general goal of treatment is to control the bleeding as quickly
and reliably as possible using methods with the fewest possible
side effects. The methods currently in use for acute variceal bleeding
are listed in Table 24–4.
Table 24–4. Measures to Control Acute Bleeding from
Esophageal Varices. |Favorite Table|Download (.pdf)
Table 24–4. Measures to Control Acute Bleeding from
|1. Vasopressin, terlipressin|
|2. Somatostatin analogues|
|3. Balloon tamponade|
|4. Endoscopic sclerotherapy|
|5. Transhepatic embolization and sclerotherapy|
|6. Emergency portasystemic shunts|
|7. Esophageal transection and reanastomosis|
|8. Esophagogastric devascularization|
|9. Suture ligation of varices|
The patient’s condition is stabilized to the extent
possible by following the general guidelines for treating major
upper gastrointestinal bleeding described in Chapter 23. Other therapy should include measures to treat or prevent
encephalopathy, parenteral vitamin K to correct a prolonged prothrombin
time, intravenous antibiotics, and electrolyte replacement (especially
potassium) as required to restore electrolyte balance.
Vasoactive drugs aimed at reducing portal pressure (vasopressin
and terlipressin, somatostatin and its analogues) and endoscopic
variceal ablation (sclerotherapy and banding) are the most commonly used initial therapies. In general,
vasoactive compounds should be used immediately in all patients,
since control of bleeding can be achieved in 80–85% of episodes.
Endoscopic intervention in the very acute setting can be equally
effective but requires a skilled endoscopist; banding has been shown
to be more effective and is considered the treatment of choice,
although very profuse bleeding makes ligation a challenge, and sclerotherapy
is useful in this setting. A meta-analysis showed that combined
endoscopic and pharmacologic treatment is more effective in controlling
acute bleeding than after endoscopic treatment alone. Balloon tamponade
is no longer used routinely but is rather reserved for special situations
when other methods fail.
These measures are successful in approximately 90% of
cases, but the early rebleeding rate is about 30%. When
bleeding continues after initial treatment and if the patient is
a good operative risk, an emergency shunt procedure should be considered.
Death rates rise rapidly in patients requiring more than 10 units
of blood, and in general, patients still bleeding after 6 units—or
those whose bleeding is still unchecked 24 hours after admission—should
be considered for portal decompression procedures. Even when the bleeding
is brought under control by the initial intervention, the mortality
rate remains high (about 35%) as a result of liver failure
and other complications.
Sclerotherapy or Ligation
Via fiberoptic endoscopy, 1–3 mL of sclerosant solution
is injected into the lumen of each varix, causing it to become thrombosed.
Variations in the type of endoscope or sclerosant solution or whether or
not the varices are physically compressed appear to have little
influence on the outcome. Endoscopy is usually repeated within 48
hours and then once or twice again at weekly intervals, at which
time any residual varices are injected.
Sclerotherapy controls acute bleeding in 80–85% of
patients, and rebleeding during the same hospitalization is about
half (25% versus 50%) the rebleeding rate of patients
treated with a combination of vasopressin and balloon tamponade. Even
though controlled trials show improvement in the control of bleeding with
sclerotherapy, the evidence for increased patient survival is conflicting.
A similar effect is achieved by endoscopic ligation of the varices.
The varix is lifted with a suction tip, and a small rubber band
is slipped around the base. The varix necroses to leave a superficial
ulcer. Several controlled trials have reported rubber band ligation
to be more effective in controlling long-term bleeding episodes
compared to sclerotherapy, although comparisons in the acute setting
are limited. Band ligation is associated with fewer complications
and fewer procedures are needed for complete eradication and has
thus emerged as the initial endoscopic treatment of choice.
and Terlipressin (Triglycyl Lysine Vasopressin)
Vasopressin and terlipressin lower portal blood flow and portal
pressure by directly constricting splanchnic arterioles, thereby
reducing inflow. Vasopressin or terlipressin alone controls acute
bleeding in about 80–85% of patients, and this
rate is increased when combined with endoscopic therapy or balloon
tamponade. Cardiac output, oxygen delivery to the tissues, hepatic
blood flow, and renal blood flow are also decreased—effects
that occasionally produce complications such as myocardial infarction,
cardiac arrhythmias, and intestinal necrosis. These unwanted side effects
may sometimes be prevented without interfering with the decrease
in portal pressure by simultaneous administration of nitroglycerin
or isoproterenol. Terlipressin, a long-acting synthetic vasopressin
analogue, has fewer untoward cardiovascular side effects than vasopressin.
Although the results are somewhat contradictory, controlled trials
generally indicate that vasopressin plus nitroglycerin is superior
to vasopressin alone and that vasopressin alone is superior to placebo in
controlling active variceal bleeding. Survival is not increased,
however. In fact, while several vasoactive agents effectively stop
acute hemorrhage, only terlipressin has been shown to improve survival
after an acute event. Vasopressin is given as a peripheral intravenous
infusion (at about 0.4 units/min), which is safer than
bolus injections. Nitroglycerin can be given intravenously or sublingually.
Terlipressin undergoes gradual conversion to vasopressin in the body
and is safe to give by intravenous bolus injection (2 mg intravenously
every 6 hours).
Somatostatin infusion reduces portal pressure without any impact
on systemic hemodynamics. By contrast, octreotide (a longer lasting somatostatin
analogue) appears to have less of an impact on portal pressure. Somatostatin
has been shown, in a prospective randomized trial, to effectively control
acute bleeding, although other studies have had equivocal results.
A meta-analysis of all studies using somatostatin or its analogues
did show a significant risk reduction in control of hemorrhage.
The efficacy of octreotide remains uncertain, but it appears to reduce
the rebleeding rate when used in conjunction with endoscopic therapy.
It should be emphasized that no study of somatostatin or octreotide
has shown improved survival after an acute bleeding episode. Somatostatin
is typically administered as a bolus of 250 micrograms followed
by an infusion of 250 μg/hour for 24 hours.
Octreotide is given as an initial bolus of 50–100 μg
followed by a continuous infusion of 25–50 μg/h
for 24 hours.
See Figure 24–6. Tubes designed
for tamponade have two balloons that can be
inflated in the lumen of the gut to compress bleeding varices. There
are three or four lumens in the tube, depending on the type: two
are for filling balloons within the stomach and the esophagus, and
the third permits aspiration of gastric contents. A fourth lumen
in the Minnesota tube is used to aspirate the esophagus orad to
the esophageal balloon. The main effect results from traction applied
to the tube, which forces the gastric balloon to compress the collateral
veins at the cardia of the stomach. Inflating the esophageal balloon
probably contributes little, since barium x-rays suggest that it
does not actually compress the varices.
Sengstaken-Blakemore tube with both gastric and esophageal
The most common serious complication is aspiration of pharyngeal
secretions and pneumonitis. Another serious hazard is the occasional
instance of esophageal rupture caused by inflation of the esophageal
balloon. The esophageal balloon is therefore infrequently used.
About 75% of actively bleeding patients can be controlled
by balloon tamponade. When bleeding has stopped, the balloons are
left inflated for another 24 hours. They are then decompressed, leaving
the tube in place. If bleeding does not recur, the tube should be
withdrawn. The efficacy of other therapies combined with potential
complications associated with balloon catheters have led to a marked
reduction in the use of the latter approach, which is now reserved
as a salvage treatment in patients who fail initial measures.
Intrahepatic Portasystemic Shunt (TIPS)
TIPS is a minimally invasive means of creating a portasystemic
shunt by creating a direct communication between the portal and
hepatic venous systems within the liver parenchyma. A catheter is
introduced through the jugular vein and, under radiologic control,
positioned in the hepatic vein. From this point, the portal vein
is accessed through the liver, the tract is dilated, and the channel
is kept open by inserting an expandable metal stent, which is left
in place. This technique is of great value in controlling portal
hypertension and variceal bleeding and can be used to stop acute
bleeding or to prevent rebleeding in a patient who has recovered
from an acute episode. The shunts remain open in most patients for
up to a year, at which point intimal overgrowth lead to thrombosis
and occlusion in many cases. The use of polytetrafluoroethylene
(PTFE)-covered stents may improve the patency rate.
TIPS is used most commonly as a salvage procedure in patients
who continue to bleed after treatment with pharmacologic agents
and endoscopic banding or sclerotherapy. TIPS has proved most useful
as a bridge to transplantation. It should not be regarded as definitive
therapy, however, even though the shunt will usually remain patent
for many months. Thus, patients with advanced liver disease are
the principal candidates for TIPS, whereas those with less severe cirrhosis
should be considered for beta-blocker therapy or surgery (shunt
or devascularization procedure).
The operative procedures to control active bleeding are emergency
portasystemic shunt and variceal ligation or esophageal transection.
Emergency Portacaval Shunt
An emergency portasystemic shunt has a 95% rate of success
in stopping variceal bleeding. Like TIPS, surgical intervention
in the acute setting is generally used to salvage patients with
persistent hemorrhage. The death rate of the operation is not insignificant,
generally related to the status of the patient’s liver function
(eg, Child-Pugh classification; Table 24–1)
as well as the rate and amount of bleeding and its effects on cardiac,
renal, and pulmonary function. Some patients with advanced liver
disease, especially those with severe encephalopathy and ascites,
have an extraordinarily poor survival regardless of the treatment.
In such patients, surgery is usually not warranted, even in the
face of continued bleeding. On the other hand, patients with good
liver function usually recover after an emergency shunt. A controlled trial
showed that the death rate in acutely bleeding Child-Pugh C patients
was insignificantly lower after endoscopic sclerotherapy (44%)
than after emergency portacaval shunt (50%).
For active bleeding, an end-to-side portacaval shunt or H-mesocaval
shunt is most commonly performed.
The distal splenorenal (Warren) shunt is usually too time-consuming
for use in emergency operations. The central splenorenal shunt is
more complicated than an end-to-side portacaval shunt and has no
specific advantages. A side-to-side portacaval shunt might be preferable
in an acutely bleeding patient with severe ascites, and this approach
(or a variant such as an H-mesocaval shunt) would be required for
someone with Budd-Chiari syndrome.
Hepatic failure is the cause of death in about two thirds of
those who die after an emergency portacaval shunt. Renal failure,
which is often accompanied by ascites, is another potentially lethal
problem. Metabolic alkalosis and delirium tremens are not uncommon
postoperatively in alcoholics.
Varices may be obliterated by firing the end-to-end stapler in
the distal esophagus after tucking a full-thickness ring of tissue
into the cartridge with a circumferential tie. This procedure has
gained popularity in the past decade, and in many surgical units
it is the first choice for therapy when nonsurgical methods fail.
If transection is performed, it must be done as soon as it is recognized
that a second attempt at sclerotherapy or band ligation has failed.
As a last-ditch effort—after many units of blood have been transfused—death
from liver failure is all but certain. The results (eg, survival)
are better in patients with nonalcoholic cirrhosis. Stapled transection
has replaced the older technique of direct suture ligation of the
varices. Transection must be viewed as an emergency measure to stop
persistent bleeding—not as definitive treatment—since
the underlying portal hypertension is not corrected and varices
recur months later in many patients.
Bambha K et al: Predictors of early re-bleeding
and mortality after acute variceal hemorrhage in patients with cirrhosis.
Gut 2008; 57:814.
Bendtsen F, Krag A, Moller S: Treatment of acute variceal bleeding.
Dig Liver Dis 2008;40:328.
Cales P et al: Early administration of vapreotide for variceal
bleeding in patients with cirrhosis. French Club for the Study of
Portal Hypertension. N Engl J Med 2001;344:23.
Gerbes AL et al: Transjugular intrahepatic portosystemic shunt
(TIPS) for variceal bleeding in portal hypertension: comparison
of emergency and elective interventions. Dig Dis Sci 1998;43:2463.
Mercado MA et al: Comparative study of 2 variants of a modified
esophageal transection in the Sugiura-Futagawa operation. Arch Surg
Orozco H et al: A comparative study of the elective treatment
of variceal hemorrhage with beta-blockers, transendoscopic sclerotherapy,
and surgery: a prospective, controlled, and randomized trial during
10 years. Ann Surg 2000;232:216.
Shibata D et al: Transjugular intrahepatic portosystemic shunt
for treatment of bleeding ectopic varices with portal hypertension.
Dis Colon Rectum 1999;42:1581.
Toubia N, Sanyal AJ: Portal hypertension and variceal hemorrhage.
Med Clin N Am 2008;92:551.
Woods JE, Kiely JM: Short-term international medical service.
Mayo Clin Proc 2000;75:311.
Patients with varices that have never bled have a 30% chance of
bleeding at some point; of those who bleed, 50% die. For patients
who do not bleed during the first year after diagnosis of varices,
the risk of bleeding subsequently decreases by half and continues
to drop thereafter. Patients who have bled once from esophageal
varices have a 60–70% chance of bleeding again,
and about two thirds of repeat bleeding episodes are fatal.
and Pressure Measurements
Measurements of pressure and flow in the splanchnic vasculature
have been used for diagnosis and as a guide to therapy and prognosis
in portal hypertension. Portal pressure can be measured directly
at surgery or preoperatively by any of the following techniques:
(1) Wedged hepatic venous pressure (WHVP) accurately reflects free
portal pressure when portal hypertension is caused by a postsinusoidal
(or sinusoidal) resistance, as in cirrhosis. The portal pressure
can be determined with the catheter in the wedged position, corrected
by subtracting the free hepatic venous pressure (FHVP); the hepatic
venous pressure gradient (HVPG, the pressure gradient from the portal
to the hepatic venous systems) can also be determined. This is the
most commonly used technique. (2) Direct measurement of splenic
pulp pressure is obtained by a percutaneously placed needle. (3)
Percutaneous transhepatic catheterization of the intrahepatic branches
of the portal vein is the method of choice in patients thought to
have presinusoidal block or Budd-Chiari syndrome. (4) Catheterization
of the umbilical vein is accomplished through a small incision,
and the catheter is threaded into the portal system. With each of
these methods, one may also obtain anatomic information by performing
angiography through the catheter.
HVPG predicts decompensation and death. Reduction in the HVPG,
either spontaneously or after therapy, may help predict the risk
of rebleeding in some patients. It has therefore been suggested that
HVPG can be used to guide therapy. However, its value currently
has been shown primarily in alcoholic liver disease. Also, it is
an invasive study that requires special expertise and is not always
readily available. Duplex ultrasonography is an accurate noninvasive means
of assessing the amount and direction of flow in the portal vein.
Preoperatively, duplex ultrasonography is useful to determine patency
of the portal vein and direction of flow. Because of spontaneous
thrombosis, about 10% of patients with cirrhosis have a
portal vein unsuitable for a portacaval shunt. If flow in the portal
vein is reversed (hepatofugal), a selective shunt is not recommended, because
it compromises the ability of portal tributaries to serve as an
outflow tract for liver blood. Duplex ultrasonography can also be
used to follow changes in portal perfusion after shunt operations.
The portal venous anatomy is often studied preoperatively by
angiographic techniques. The objectives are to determine the patency,
location, and size of the veins tentatively chosen for a shunt,
to demonstrate the presence of varices, and to estimate the degree
of prograde portal flow. Some of this information can now be obtained
less invasively by duplex ultrasonography. When a splenorenal shunt
is contemplated, the left renal vein should be opacified, either
by injection of the renal artery or renal vein.
The treatment options consist of expectant management, endoscopic
sclerotherapy, nonselective beta-blocker (eg, propranolol, nadolol),
portasystemic shunts, devascularization of the esophagogastric junction,
and miscellaneous rarely used operations. The treatment of patients
with varices that have never bled is usually referred to as prophylactic therapy
(eg, prophylactic sclerotherapy or prophylactic propranolol). By
convention, procedures performed on patients who have bled previously
are referred to as therapeutic (eg, therapeutic shunts).
Prophylactic therapy is of value, since the mortality rate of
variceal bleeding is high (25%), the risk of bleeding in patients
with varices is relatively high (30%), and varices can
often be diagnosed before the initial episode of bleeding. In patients
who have never had a bleeding episode, the following have been shown
to be related to the risk of hemorrhage: Child-Pugh classification, the
size of the varices, and the presence of red wale markings (longitudinal
dilated venules resembling whip marks) on the varices. This information
can be used to identify high-risk patients (up to 65% risk of
bleeding within a year) who are most likely to benefit from prophylactic
In patients who have never bled but have a high risk (medium
to large varices or small varices with red wale markings and/or
decompensated cirrhosis), treatment in the form of nonselective
beta-blocker or endoscopic band ligation is recommended. Both of
these therapies are effective in this setting. It has been suggested
that beta-blocker therapy should be the first-line treatment, with endoscopic
variceal ligation (EVL) used in patients who cannot tolerate or
have contraindications to beta-blockade. Endoscopic sclerotherapy
is no longer routinely used as primary prophylaxis.
Patients WHO Have Bled Previously
As noted earlier, patients who recover from an episode of variceal
bleeding an approximately 60–70% chance of bleeding
again. Much effort has been expended to ascertain the best treatment for
these patients. The methods of greatest interest include beta-blocker
therapy, endoscopic band ligation, and portasystemic shunts.
As with patients who have never bled, nonselective beta-adrenergic
blocking agents (propranolol, nadolol) effectively reduce the risk
of recurrent bleeding episodes. These agents work by decreasing cardiac
output and splanchnic blood flow and consequently portal blood pressure. Chronic
propranolol therapy, 20–160 mg twice daily (a dose that
reduces resting pulse rate by 25%), decreases by about 40% the
frequency of rebleeding from esophageal or gastric varices, deaths from
rebleeding, and overall mortality. The benefits are greater in Child-Pugh
A and B than in Child-Pugh C cirrhotics. Beta-blocker therapy has
been compared to endoscopic sclerotherapy, with no difference in
rebleeding or mortality seen but with higher complications in the sclerotherapy
group. The addition of isosorbide mononitrate to beta-blocker therapy
appears to result in a greater reduction of portal pressure compared
to beta-blockade alone. Abstinence from alcohol should always be
emphasized and may help prevent further bleeding but may not necessarily
decrease the mortality related specifically to variceal hemorrhage,
as was previously thought.
Endoscopic band ligation, as described earlier, is an effective
means of preventing recurrent bleeding episodes and has been shown
to be superior to sclerotherapy in this regard. Both band ligation
and beta-blocker therapy appear to be similarly effective in preventing
rebleeding. However, the combination of both therapies has been
shown to significantly reduce not only the risk of rebleeding but also
the recurrence of varices. Thus, combination therapy appears to
be the most effective treatment after an initial bleeding episode.
The technique of endoscopic sclerotherapy was described earlier
in this chapter. Sclerotherapy was previously used routinely to
reduce the risk of rebleeding but has been replaced by band ligation.
Intrahepatic Portasystemic Shunt
The TIPS technique is described in the preceding section. TIPS
is effective in preventing rebleeding episodes, more so than either
endoscopic or pharmacologic therapy alone. However, this advantage
is offset by its higher morbidity and mortality rate from the development
of hepatic encephalopathy and liver failure. For this reason, as
well as the lack of a clear survival or cost-benefit advantage,
TIPS is used mainly to salvage patients who fail endoscopic and/or pharmacologic
TIPS has generally superseded shunt surgery in most patients
who fail first-line therapy. A recent large multicenter randomized
trial showed that TIPS and surgical shunts had similar rates of rebleeding,
encephalopathy, and mortality in Child-Pugh A and B cirrhotic patients.
There was a higher incidence of shunt dysfunction in the TIPS patients, perhaps
because of the type of stent used. Given the similar outcomes but more
durable patency compared to TIPS, surgical shunts still have a role
in the management of these patients.
The objective of surgical procedures used to treat portal hypertension
is either to obliterate the varices or to reduce blood flow and
pressure within the varices (Table 24–5).
A third option, particularly in patients with advanced cirrhosis,
is liver transplantation.
Table 24–5. Surgical Procedures for Esophageal Varices. |Favorite Table|Download (.pdf)
Table 24–5. Surgical Procedures for Esophageal Varices.
|A. Direct variceal obliteration|
|1. Variceal suture ligation|
|2. Esophageal transection and reanastomosis|
|a. Suture technique|
|b. Staple technique|
|3. Variceal sclerosis|
|4. Variceal resection|
|b. Subtotal esophagectomy|
|B. Reduction of variceal blood flow and pressure|
|1. Portasystemic shunts|
|1. Side-to-side portacaval|
|3. Central splenorenal|
|2. Selective shunts|
|a. Distal splenorenal (Warren)|
|b. Left gastric vena caval (Inokuchi)|
|3. Reduction of portal blood flow|
|b. Splenic artery ligation|
|4. Reduction of proximal gastric blood flow|
|a. Esophagogastric devascularization|
|b. Gastric transection and reanastomosis (Tanner)|
|5. Stimulation of additional portasystemic venous
|b. Splenic transposition|
|C. Measures to preserve hepatic blood flow after portacaval shunt|
|1. Arterialization of portal vein stump|
Any relatively young patient with cirrhosis who has survived an
episode of variceal hemorrhage should be considered a candidate
for liver transplantation, since any other form of therapy carries
a much higher (about 80%) mortality rate within the subsequent
1–2 years as a result of repeat bleeding or complications
of hepatic failure. Obviously, continued alcohol use is a contraindication
to transplantation in most patients. The good transplantation candidates,
however, should not be subjected to portasystemic shunts or other procedures
if it appears that they will come to transplantation in the near future.
In general, Child-Pugh A patients are candidates for portal decompression; Child-Pugh
C patients are candidates for a transplant. A transjugular intrahepatic shunt
(see previous section) is an excellent way to control bleeding while
the patient is being prepared for a transplant.
The advent of TIPS has resulted in a marked decline in the number
of shunt operations performed. However, surgical shunts are much
more durable than TIPS, and good risk patients appear to benefit
from theses procedures.
Portasystemic shunts can be grouped into those that shunt the
entire portal system (total shunts) and those that selectively shunt
blood from the gastrosplenic region while preserving the pressure-flow relationships
in the rest of the portal bed (selective shunts). All of the shunt
operations commonly used today reduce the incidence of rebleeding
to less than 10%, compared with about 75% in unshunted patients.
Unfortunately, the price of this achievement is an operative mortality rate
of 5–20% (depending on the Child-Pugh classification [Table 24–1]), further impairment
of liver function, and an increase in encephalopathy (greater with
total shunts). Therefore, since shunts have these potential drawbacks,
clinical trials are needed to pinpoint their place within an overall treatment
In one well-designed trial, patients who had bled previously
were randomized to chronic sclerotherapy or a distal splenorenal
shunt (Warren shunt). Patients randomized to chronic sclerotherapy
who had recurrent episodes of bleeding during treatment (ie, treatment
failures, which amounted to 30% of the sclerotherapy group)
were then treated surgically (ie, shunted). The results showed that 2-year survival was
better among those originally randomized to sclerotherapy (90%)
than among those originally assigned to the shunt group (60%).
This trial supports a general treatment plan consisting initially
of endoscopic therapy and reserving portasystemic shunts for the
patients in whom the former fails to control bleeding adequately.
The choice of shunt has been the subject of much debate and several
randomized trials. The principal question in recent years has been
whether encephalopathy and survival are better with a selective
shunt (eg, a distal splenorenal shunt) than with a total shunt (eg,
a mesocaval or an end-to-side portacaval shunt). The results are
conflicting, but in general they support the contention that there
is about half as much severe encephalopathy following selective
shunts. None of the trials have shown any particular shunt to be
associated with longer survival.
of Hepatic Disease and Operative Risk
The immediate death rate of an elective shunt procedure can be
predicted from the patient’s hepatic function as reflected by
the Child-Pugh classification (Table 24–1).
In addition to operative death rate, the figures also correlate
with the death rate in the first postshunt year. Thereafter, survival
curves of the different risk classes become reasonably parallel.
The severity of histopathologic changes in liver biopsies correlates
with the immediate surgical death rate, the most ominous findings
being hepatocellular necrosis, polymorphonuclear leukocyte infiltration,
and the presence of Mallory bodies. The extent of histologic change also
correlates with the more easily obtained data in the Child-Pugh
classification (ie, severe changes occur in class C patients), so
results of biopsies have no independent predictive value.
Types of Portasystemic Shunts
Figure 24–7 depicts the various
shunts in use currently. Although they differ technically, physiologically
there are only three different types: end-to-side, side-to-side,
Types of portacaval anastomoses: A: Normal. B: Side-to-side. C: End-to-side. D: Mesocaval. E: Central
splenorenal. F: Distal splenorenal (Warren). The H-mesocaval
shunt is not illustrated.
The end-to-side shunt completely disconnects the liver from the
portal system. The portal vein is transected near its bifurcation
in the liver hilum and anastomosed to the side of the inferior vena cava.
The hepatic stump of the vein is oversewn. Postoperatively, the
WHVP (sinusoidal pressure) drops slightly, reflecting the inability
of the hepatic artery to compensate fully for the loss of portal
inflow. The side-to-side portacaval, mesocaval, mesorenal, and central
splenorenal shunts are all physiologically similar, since the shunt
preserves continuity between the hepatic limb of the portal vein,
the portal system, and the anastomosis. Flow through the hepatic limb
of the standard side-to-side shunt is nearly always away from the
liver and toward the anastomosis. The extent to which hepatofugal
flow is produced by the other types of side-to-side shunts listed
previously is not known.
The end-to-side portacaval shunt gives immediate and permanent
protection from variceal bleeding and is somewhat easier to perform
than a side-to-side portacaval or central splenorenal shunt. Encephalopathy
may be slightly more common after side-to-side than end-to-side
portacaval shunts. Side-to-side shunts are required in patients
with Budd-Chiari syndrome or refractory ascites (when the latter
is treated by a portasystemic shunt).
The mesocaval shunt interposes a segment of prosthetic graft
or internal jugular vein between the inferior vena cava and the
superior mesenteric vein where the latter passes in front of the
uncinate process of the pancreas. The mesocaval shunt is particularly
useful in the presence of severe scarring in the right upper quadrant
or portal vein thrombosis, and in some cases it may be technically
easier than a conventional side-to-side portacaval shunt if a side-to-side type
of shunt is necessary. In most cases, portal flow to the liver is
lost after this shunt. Evidence has been presented, however, that
by limiting the diameter of the prosthetic graft to 8 mm (compared
with 12- to 20-mm grafts), prograde flow is preserved in the portal
vein, which decreases the incidence of postoperative encephalopathy
while still preventing variceal hemorrhage.
Selective shunts lower pressure in the gastroesophageal venous
plexus while preserving blood flow through the liver via the portal
The distal splenorenal (Warren) shunt involves anastomosing the
distal (splenic) end of the transected splenic vein to the side
of the left renal vein, plus ligation of the major collaterals between the
remaining portal and isolated gastrosplenic venous system. The latter
step involves division of the gastric vein, the right gastroepiploic
vein, and the vessels in the splenocolic ligament. The operation
is more difficult and time consuming than conventional shunts and
except for the experienced operator is probably too complex for
emergency portal decompression. If mobilization of the splenic vein
is hazardous, the renal vein may be transected and its caval end
joined to the side of the undisturbed splenic vein. The segment
of splenic vein between the anastomosis and the portal vein is then ligated. Surprisingly,
this seems to have little permanent effect on renal function as
long as the remaining tributaries are preserved on the oversewn
renal vein stump.
In contrast to total shunts, the Warren shunt does not improve
ascites and should not be performed in patients whose ascites has
been difficult to control. Preoperative angiography should be performed
to determine if the splenic vein and left renal vein are large enough and
close enough together for performance of this shunt. Recent pancreatitis may
preclude safe dissection of the splenic vein from the undersurface
of the pancreas.
Another type of selective shunt (Inokuchi shunt) consists of
joining the left gastric vein to the inferior vena cava by a short segment
of autogenous saphenous vein. The procedure has not become popular, perhaps
because of its technical complexity.
Selective shunts tend to become less selective over several years
as new collaterals develop between the high-pressure and low-pressure
regions of the portal system. This is accompanied by a gradual decrease
in portal pressure (measured by WHVP) and evolution of the procedure
into a version of side-to-side total shunt. The enlargement postoperatively
of small venous tributaries entering the distal splenic vein from
the pancreas suggests that this is the path by which nonselectivity
develops. It is possible that this can be avoided by mobilizing
the splenic vein all the way to the hilum (dividing these small
vessels) before performing the splenorenal anastomosis.
A reasonable approach to shunt selection is as follows: The distal
splenorenal shunt is the first choice for elective portal decompression.
If ascites is present or the anatomy is unfavorable, an end-to-side
portacaval shunt is preferred. Side-to-side shunts would be done
for patients with severe ascites or Budd-Chiari syndrome. The H-mesocaval
and central splenorenal shunts are reserved for special anatomic situations
in which the above operations are unsuitable. An end-to-side shunt
or H-mesocaval shunt is performed for emergency decompression.
Portacaval and distal splenorenal shunts are often followed by
a rise in platelet count in patients with secondary hypersplenism.
The response is unpredictable, however, and hypersplenism need not necessarily
dictate the type of shunt since it rarely produces clinical manifestations.
A central splenorenal shunt, in which splenectomy is performed,
should not be considered preferable to other kinds of shunt just
because the patient has a low platelet count.
Results of Portasystemic Shunts
Over 90% of portasystemic shunts remain patent, and
the incidence of recurrent variceal bleeding is less than 10%.
The 5-year survival rate after a portacaval shunt for alcoholic
liver disease averages 45%. Some degree of encephalopathy
develops in 15–25% of patients. Severe encephalopathy
is seen in about 20% of alcoholics following a total shunt; its
occurrence is not related to the severity of preshunt encephalopathy.
The objective of devascularization is to destroy the venous collaterals
that transport blood from the high-pressure portal system into the
veins in the submucosa of the esophagus.
The Sugiura-Futugawa procedure is done in two stages. In the
first stage, performed through a thoracotomy, the dilated venous
collaterals between esophagus and adjacent structures are divided,
and the esophagus at the level of the diaphragm is transected and
reanastomosed. The second stage, a laparotomy, is performed immediately
after the thoracotomy if the patient is actively bleeding but is deferred
4–6 weeks in elective cases. In the second stage of the
operation, the upper two thirds of the stomach is devascularized,
and selective vagotomy, pyloroplasty, and splenectomy are performed.
It is possible in some cases to perform the entire operation through
the left chest. An analogous operation has been described that consists
of splenectomy, gastroesophageal devascularization, and resection
of a 5-cm segment of the gastroesophageal junction. Continuity of
the gut is restored by esophagogastrostomy with pyloroplasty.
In studies from Japan, where these operations originated, operative
mortality is around 5%, variceal rebleeding is 2–4%, and
5-year survival is approximately 80%. Operations of this
type performed in patients with alcoholic cirrhosis in North America
have had poor results, owing to a high rate (40%) of late rebleeding.
Attempts have also been made to decrease portal pressure by decreasing splanchnic
inflow through splenectomy or splenic artery ligation. Diseases
characterized by marked splenomegaly may rarely be associated with
portal hypertension as a consequence of increased splenic blood
flow, which has been known to reach levels as high as 1000 mL/min.
Splenic blood flow may occasionally be increased enough in patients with
cirrhosis to contribute significantly to the portal hypertension.
However, splenectomy or splenic artery ligation in cirrhosis most
often gives only a transient decrease in portal pressure, and over half
of patients having these operations bleed again. Some workers have
suggested that the absolute size of the splenic artery (a crude
index of splenic flow) correlates with the clinical effectiveness
of splenic artery ligation, a good result being predictable if the
diameter of the artery is 1 cm or greater.
Berzigotti A, Garcia-Pagan JC: Prevention of recurrent
variceal bleeding. Dig Liv Dis 2008;40:337.
de Franchis R: Updating consensus in portal hypertension: report
of the Baveno III Consensus Workshop on definitions, methodology
and therapeutic strategies in portal hypertension. J Hepatol 2000;33:846.
Garcia-Tsao G, Bosch J, Groszmann RJ: Portal hypertension and
variceal bleeding: unresolved issues. Summary of an AASLD and EASLD
single topic conference. Hepatology 2008;47:1764.
Gentilini P et al: Ascites and hepatorenal syndrome during cirrhosis:
two entities or the continuation of the same complication? J Hepatol
Gonzalez R et al: Combination endoscopic and drug therapy to
prevent variceal rebleeding in cirrhosis. Ann Intern Med 2008;149:109.
Henderson JM et al: Distal splenorenal shunt versus TIPS for
refractory variceal bleeding: a prospective randomized controlled
trial. Gastroenterology 2006;130:1643.
Krige JE, Beckingham IJ: ABC of diseases of liver, pancreas,
and biliary system. Portal hypertension—1: varices. BMJ
Masson S et al: Hepatic encephalopathy after transjugular intrahepatic
portosystemic shunt insertion: a decade of experience. QJM 2008;101:493.
Sarin SK et al: Comparison of endoscopic ligation and propranolol
for the primary prevention of variceal bleeding. N Engl J Med 1999;340:988.
Suzuki H, Stanley AJ: Current management and novel therapeutic
strategies for refractory ascites and hepatorenal syndrome. QJM
Vlachogiannakos J et al: Angiotensin converting enzyme inhibitors
and angiotensin II antagonists as therapy in chronic liver disease.
Portal Venous Occlusion
Extrahepatic portal vein obstruction is one of many causes of
noncirrhotic portal hypertension, the other common cause being noncirrhotic
portal fibrosis. These disorders are distinct but appear to share several
similar etiological and pathogenetic features, the most notable
of which is the clinical manifestation of portal hypertension in
the absence of significant hepatic parenchymal dysfunction.
Idiopathic portal vein thrombosis (in the absence of liver disease)
is a relatively common cause of portal hypertension in developing
countries but is less prevalent in the West. This diagnosis accounts for
most cases of portal hypertension in childhood (80–90%)
and for a smaller proportion of cases in adults. Neonatal septicemia,
omphalitis, umbilical vein catheterization for exchange transfusion,
and dehydration have all been incriminated as possible causes, but
collectively they can be implicated in less than half of cases.
The causes of portal vein thrombosis in adults include hepatic tumors,
cirrhosis, trauma, pancreatitis, pancreatic pseudocyst, myelofibrosis, thrombotic
states (eg, protein C deficiency), and sepsis; in particular, cirrhosis
and/or hepatocellular carcinoma need to be considered in
Although clinical manifestations may be delayed until adulthood,
80% of patients present between 1 and 6 years of age with
variceal bleeding, although hemorrhage from ectopic varices at other
locations in the gastrointestinal tract is not uncommon. About 70% of
hemorrhages are preceded by a recent upper respiratory tract infection.
Some of these children first come to medical attention because of
splenomegaly and pancytopenia. Failure to recognize the underlying problem
has occasionally led to splenectomy, with the result that portal
decompression using the splenic vein is precluded. Ascites is uncommon
except transiently after bleeding. Liver function is either normal
or only slightly impaired, which probably accounts for the low incidence
of overt encephalopathy. There is an increased frequency of neuropsychiatric problems,
which may be a subtle form of encephalopathy.
Portal biliopathy refers to abnormalities of the extrahepatic
bile ducts, usually the result of bile duct compression from large,
dilated venous collaterals within the porta hepatis. These changes
result in marked irregularities of the biliary wall that can progress
to strictures and even obstructive jaundice and cholangitis in some
cases; secondary biliary cirrhosis has been reported. Biliopathy
is commonly seen on imaging studies, but most patients remain free
of related symptoms.
Because the patient’s general condition and liver function
are good, the death rate for sudden massive bleeding is below that
for other types of portal hypertension. The diagnosis can be confirmed with
cross-sectional imaging or direct mesenteric angiography. WHVP is
normal to slightly elevated; liver biopsies are normal or may show
mild to moderate periportal fibrosis.
Bleeding episodes in children under age 8 are usually self-limited
and often do not require endoscopic sclerotherapy, administration
of vasopressin, or balloon tamponade. Even if such interventions are
necessary, however, the bleeding episodes are self-limited and uncommonly
fatal, so emergency operations are rarely necessary.
Thrombosed portal veins are unsuitable for shunt procedures.
Cavomesenteric shunts are best for young children, whose vessels
are small. In older individuals, treatment should be started with
sclerotherapy; if that fails to control the bleeding, a distal splenorenal
shunt is preferred. Splenectomy alone has no permanent effect and
sacrifices the splenic vein, which might be needed later for a shunt
operation. Shunts in small children have a high rate of spontaneous
thrombosis and should be avoided, if possible, until approximately
8–10 years of age, when the vessels are of larger caliber.
Even still, using precise technique, some surgeons have obtained
a high rate of anastomotic patency in the very young. Encephalopathy
and hepatic dysfunction many years after a total shunt may be improved
if converted to a selective shunt.
Splenectomy alone is never indicated in this disease, either
for hypersplenism or in an attempt to reduce portal pressure, because
the rebleeding rate is 90% and fatal postsplenectomy sepsis
is not uncommon. If it is not possible to construct an adequate
shunt, expectant management is the best strategy. Repeated severe
bleeding episodes should be treated by transendoscopic sclerosis.
Esophagogastrectomy with colonic interposition may be effective
but should be considered a last resort.
Janssen HL et al: Extrahepatic portal vein thrombosis:
aetiology and determinants of survival. Gut 2001;49:720.
Sarin SK, Kumar A: Noncirrhotic portal hypertension. Clin Liver
Sheen CL et al: Clinical features, diagnosis and outcome of
acute portal vein thrombosis. QJM 2000;93:531.
Valla DC, Condat B: Portal vein thrombosis in adults: pathophysiology,
pathogenesis and management. J Hepatol 2000;32:865.
van’t Riet M et al: Diagnosis and treatment of portal
vein thrombosis following splenectomy. Br J Surg 2000;87:1229.
Budd-Chiari syndrome is a rare disorder resulting from obstruction
of hepatic venous outflow, which can arise at several different
levels, from the small hepatic venous tributaries within the liver parenchyma
to the major hepatic venous trunks to the inferior vena cava up
to the level of the right atrium. Most cases are caused by spontaneous
thrombosis of the hepatic veins, often associated with myeloproliferative
disorders (polycythemia vera, essential thrombocytosis) or the use
of birth control pills. Other common associated conditions include factor
V Leiden and factor II gene mutations. Other predisposing factors
include protein C and S deficiencies, antiphospholipid syndrome,
antithrombin III deficiency, paroxysmal nocturnal hemoglobinuria,
Behçet syndrome, and trauma. Some patients present with
idiopathic membranous stenosis of the inferior vena cava located
between the hepatic veins and right atrium, which is usually associated
with secondary thrombosis of the hepatic veins; this condition appears
to be more common in Asia than in Western countries. Many patients
with Budd-Chiari syndrome are HBsAg-positive, and others have malignancies
(eg, hepatocellular carcinoma). Vena caval webs were once thought
to be congenital, but more recent evidence suggests that they are
the consequence of thrombus formation. Primary Budd-Chiari syndrome
originates from within the lumen of the hepatic veins or venules,
and occlusion results from thrombosis, webs, or endophlebitis. By contrast,
secondary Budd-Chiari syndrome results from extrinsic compression of
the venous outflow tract, usually related to a neoplasm or abscess.
Veno-occlusive disease and congestive hepatopathy are two conditions
that can cause hepatic venous outflow obstruction, and although
the clinical picture of both may be indistinguishable from that of
Budd-Chiari syndrome, they differ in the level of obstruction and
in predisposing conditions. Veno-occlusive disease is primarily
a problem affecting the sinusoids and terminal venules, while congestive
hepatopathy reflects a problem at the level of the heart.
Posthepatic (postsinusoidal) obstruction raises sinusoidal pressure,
which is transmitted proximally to cause portal hypertension. Because
the parenchyma is relatively free of fibrosis, filtration across
the sinusoids and hepatic lymph formation increase greatly, producing marked
Symptoms usually begin with a mild prodrome consisting of vague
right upper quadrant abdominal pain, postprandial bloating, and
anorexia. After weeks or months, a more florid picture develops
consisting of gross ascites, hepatomegaly, and hepatic failure.
At this stage, the AST is usually markedly increased, the serum
bilirubin is slightly elevated, and the alkaline phosphatase is
Except in patients with membranous obstruction of the vena cava,
liver scans (CT or MRI) usually demonstrate a marked perfusion abnormality
throughout most of the liver except for a small central area representing
the caudate lobe, whose venous outflow is spared (it goes directly
to the vena cava through multiple small tributaries). CT scans show
pooling of intravenous contrast media in the periphery of the liver;
patent hepatic veins cannot be seen on ultrasound scans. An enlarged
azygos vein may be seen on chest x-rays of patients with caval obstruction.
Liver biopsy reveals grossly dilated central veins and sinusoids,
pericentral necrosis, and replacement of hepatocytes by red blood cells.
Centrilobular fibrosis develops late. The clinical diagnosis should
be confirmed by venography, which shows the hepatic veins to be
obstructed, usually with a beaklike deformity at their orifice. The
inferior vena cava should be opacified to verify its patency, which
is a requirement for a successful portacaval shunt. Previously,
direct venography was used, but the required information may now
be obtained using noninvasive methods, such as CT or MR angiography.
The x-rays may show compression of the intrahepatic cava by the
In patients without cancer and in whom the obstruction is confined
to the hepatic veins, a side-to-side portacaval or mesocaval shunt
can be considered; TIPS is not an option in this situation because the
hepatic veins are not patent. Focal membranous obstruction of the
suprahepatic cava may be treated by excision of the lesion with
or without the addition of a patch angioplasty. Some cases may be managed
nonsurgically by percutaneous transluminal balloon dilation of the
Occlusion of the inferior vena cava by thrombosis or compression
from the liver requires a mesoatrial shunt using a prosthetic vascular
graft. Because the incidence of graft thrombosis is relatively high,
it may be advisable to perform a second-stage side-to-side portacaval shunt
a few months after mesoatrial shunt decompression of the liver in patients
with hepatic vein thrombosis whose vena cava was originally blocked by
a congested liver. Development of hepatocellular carcinoma is common
in patients with membranous obstruction of the vena cava. The postoperative
results are excellent in patients without malignant neoplasms.
Liver transplantation is indicated in patients with advanced
hepatic decompensation either from cirrhosis or as part of the acute
syndrome. The results are excellent, and the risk of later hepatocellular
carcinoma is eliminated.
Bayraktar UD, Seren S, Bayraktar Y: Hepatic venous
outflow obstruction: three similar syndromes. World J Gastroenterol 2007;13:1912.
Garcia-Pagan JC et al: TIPS for Budd-Chiari syndrome: long-term
results and prognostic factors in 124 patients. Gastroenterology
Horton JD, San Miguel FL, Ortiz JA: Budd-Chiari syndrome: illustrated
review of current management. Liver Int 2008; 28:455.
Olzinski AT, Sanyal AJ: Treating Budd-Chiari syndrome: making
rational choices from a myriad of options. J Clin Gastroenterol
Orloff MJ et al: A 27-year experience with surgical treatment
of Budd-Chiari syndrome. Ann Surg 2000;232:340.
Ascites is a common manifestation of chronic liver disease, resulting
from sinusoidal hypertension as the specific pathophysiologic abnormality.
Ascites in hepatic disease results from (1) increased formation
of hepatic lymph (from sinusoidal hypertension), (2) increased formation
of splanchnic lymph (from splanchnic vasodilatation), (3) hypoalbuminemia,
and (4) salt and water retention by the kidneys. Before therapy
is started, paracentesis should be performed and the following examinations
made on a sample of ascitic fluid: (1) Culture and leukocyte count:
Spontaneous bacterial peritonitis is common and may be clinically
silent. A white count above 250/μL is
highly suggestive of infection. (2) LDH levels: A ratio of LDH in
ascites to serum that exceeds 0.6 suggests the presence of cancer
or infection. (3) Serum amylase: A high level suggests pancreatic
disease. (4) Albumin: The ratio of serum to ascites albumin concentrations
is above 1.1 in liver disease and below 1.1 in malignant ascites.
(5) Cytology: This is pertinent only in patients with a cancer diagnosis
or a suspicion of cancer.
In general, the intensity of medical therapy required to control
ascites can be predicted from the pretreatment 24-hour urine Na+ output
as follows: A Na+ output below 5 meq/24
h will require strong diuretics; 5–25 meq/24 h,
mild diuretics; and above 25 meq/24 h, no diuretics. Initial
treatment is usually with spironolactone, 200 mg/d. The
objective is to stimulate a weight loss of 0.5–0.75 kg/d
except in patients with peripheral edema who can mobilize fluid
faster. If spironolactone alone is insufficient, another drug such
as furosemide should be added. A loop diuretic (eg, furosemide,
ethacrynic acid) should be given only in combination with a distally
acting diuretic (eg, spironolactone, triamterene). Alternatively,
massive ascites may be treated by one or more large volume (eg,
5-L) paracenteses; this is often accompanied by an intravenous infusion of
albumin, although the benefits of albumin remain controversial.
Close monitoring of serum electrolytes should be done. Salt or water
restriction is recommended in refractory cases. Caution is required
in patients with evidence of renal dysfunction, since aggressive
fluid removal can result in renal failure.
A history of ascites that has been easy to control need not influence
the choice of shunt operation intended to treat variceal bleeding.
When ascites has been severe, however, a side-to-side shunt (eg,
side-to-side portacaval, H-mesocaval, central splenorenal) may be
considered, because it reduces sinusoidal as well as splanchnic
venous pressure. A side-to-side portacaval shunt is rarely indicated
just to treat ascites (eg, in patients in whom several LeVeen shunts
have thrombosed), although the incidence of severe postoperative encephalopathy
is high under these circumstances. TIPS is another effective intervention
for refractory ascites, probably a better option than repeated paracentesis
in good-risk patients, although there is an associated risk of hepatic encephalopathy.
Shunt (LeVeen Shunt, Denver Shunt)
Refractory ascites can be treated with a LeVeen shunt—a subcutaneous
Silastic catheter that transports ascitic fluid from the peritoneal
cavity to the jugular vein. A small unidirectional valve sensitive
to a pressure gradient of 3–5 cm H2O prevents
backflow of blood. A modification called the Denver shunt contains
a small chamber that can be used as a pump to clear the line by
external pressure. In practice, Denver shunts become blocked more
often than LeVeen shunts.
In patients with ascites due to cirrhosis, use of a LeVeen shunt
should be confined to those who fail to respond to high doses of
diuretics (eg, 400 mg of spironolactone and 400 mg of furosemide
daily) or who repeatedly develop encephalopathy or azotemia during diuretic
Peritoneovenous shunts may also be used for ascites associated
with cancer. The best results occur in patients whose ascitic fluid
contains no malignant cells. A LeVeen shunt is of benefit in Budd-Chiari
syndrome but is ineffective for chylous ascites. Because the incidence
of complications and early shunt thrombosis is high, a LeVeen shunt
is relatively contraindicated if the ascitic fluid is grossly bloody, contains
many malignant cells, or has a high protein concentration (> 4.5
g/dL). The incidence of tumor embolization is low (5%).
The ascitic fluid should be cultured a few days before the shunt
is inserted. Antibiotic coverage should be given for the procedure.
The operation can be done with local anesthesia.
Postoperatively, the patient is outfitted with an abdominal binder
and instructed to perform respiratory exercises against mild pressure
to increase abdominal pressure and flow through the shunt. Dietary
salt should not be restricted. A functioning LeVeen shunt alone
is unable to fully eliminate the ascites, but it improves symptoms
related to distention and renders the patient much more responsive
to diuretics. Therefore, furosemide should be administered postoperatively.
An average of 10 kg of weight is lost during the first 10 days
after the operation, and eventually the abdomen assumes a normal
configuration. Nutrition and serum albumin levels often improve
postoperatively. Urinary sodium excretion increases promptly, and
renal function may improve in patients with the hepatorenal syndrome.
Serious complications and deaths are most common in patients with
advanced hepatorenal syndrome or a serum bilirubin level greater
than 4 mg/dL. Although some patients eventually bleed from
varices following insertion of a LeVeen shunt, the shunt itself
does not increase the risk of bleeding and actually decreases portal
pressure. Thus, a previous episode of variceal bleeding is not a contraindication
for this procedure. Disseminated intravascular coagulation (manifested
by increased fibrin split products, decreased platelet count, etc) occurs
in more than half of cases but is clinically relevant in only a
few. The frequency and severity of disseminated intravascular coagulation
may be minimized by emptying most of the ascitic fluid from the
abdomen during operation and partially replacing it with Ringer
lactate solution. Lethal septicemia may occur if the ascitic fluid
is infected at the time the shunt is inserted. In about 10% of
cases, the valve becomes thrombosed and must be replaced.
Hydrothorax, usually on the right side, may develop in patients
with cirrhosis and ascites. The fluid reaches the chest through
a pinhole opening in the membranous portion of the diaphragm, a pathway
that can be demonstrated by aspirating the thoracic fluid, injecting technetium 99mTc
colloid into the ascites fluid, and observing rapid accumulation
of the label in the chest. Treatment consists of a peritoneovenous
shunt and injection of a sclerosing agent into the pleural cavity after
it has been tapped dry. If a leak persists, it may be closed surgically
Helton WS et al: Transjugular intrahepatic portasystemic
shunt vs surgical shunt in good-risk cirrhotic patients: a case-control comparison.
Arch Surg 2001;136:17.
Krige JE, Beckingham IJ: ABC of diseases of liver, pancreas,
and biliary system: portal hypertension-2. Ascites, encephalopathy,
and other conditions. BMJ 2001;322:416.
Kuiper JJ, van Buuren HR, de Man RA: Ascites in cirrhosis: a
review of management and complications. Neth J Med 2007;65:283.
Laffi G et al: Is the use of albumin of value in the treatment
of ascites in cirrhosis? The case in favour. Dig Liv Dis 2003;35:660.
Rossle M et al: A comparison of paracentesis and transjugular
intrahepatic portosystemic shunting in patients with ascites. N
Engl J Med 2000;342:1701.
Suzuki H, Stanley AJ: Current management and novel therapeutic
strategies for refractory ascites and hepatorenal syndrome. QJM
Zervos EE, Rosemurgy AS: Management of medically refractory
ascites. Am J Surg 2001;181:256.
Central nervous system abnormalities may be seen in patients
with chronic liver disease and are especially likely after portocaval
shunts. Portasystemic encephalopathy, ammonia intoxication, hepatic
coma, and meat intoxication are older terms used to refer to this
condition. The manifestations range from lethargy to coma—from
minor personality changes to psychosis—from asterixis to paraplegia.
Hypothermia and hyperventilation may precede coma. The changes may
be quite subtle and detectable only with the use of neuropsychological
or neurophysiological testing.
Hepatic encephalopathy is a reversible metabolic neuropathy that
results from the action of chemicals absorbed from the gut on the
brain. Increased exposure of the brain to these agents is the result of
impaired hepatic metabolism due to cirrhosis or spontaneous or surgically created
shunts of portal venous blood around the liver and increased permeability
of the blood-brain barrier. The chemical agents responsible for
encephalopathy form from the action of colonic bacteria on protein
within the gut. Potential aggravating factors include gastrointestinal
hemorrhage, constipation, azotemia, hypokalemic alkalosis, infection,
excessive dietary protein, and sedatives (Table
24–6). Four main chemical mediators of this syndrome
currently attract the most attention. Low-grade cerebral edema appears
to be a major component of the pathophysiologic process.
Table 24–6. Factors Contributing to Encephalopathy. |Favorite Table|Download (.pdf)
Table 24–6. Factors Contributing to Encephalopathy.
|A. Increased systemic toxin levels|
|1. Extent of portal-systemic venous shunt|
|2. Depressed liver function|
|3. Intestinal protein load|
|4. Intestinal flora|
|B. Increased sensitivity of central nervous system|
|1. Age of patient|
|5. Sedatives, narcotics, tranquilizers|
|7. Hypoxia, hypoglycemia, myxedema|
Gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter
in the brain, produces a state similar to hepatic encephalopathy
when given experimentally. It is normally synthesized in the brain
and by bacteria within the colon; GABA in the gastrointestinal tract
is normally degraded by the liver and is found in increased levels
in the serum of patients with hepatic encephalopathy. The passage
of GABA across the blood-brain barrier is increased in hepatic encephalopathy.
Experiments also indicate the presence of increased numbers of GABA
receptors in encephalopathy and increased GABA-ergic tone, perhaps
due to a benzodiazepine receptor agonist ligand on the receptor
complex (GABA/benzodiazepine receptor). This has raised
the possibility of treating encephalopathy with benzodiazepine antagonists,
and the drug flumazenil has shown promise in preliminary trials.
Ammonia is produced in the colon by bacteria and is absorbed and
transported in portal venous blood to the liver, where it is extracted
and converted to glutamine. Ammonia concentrations are elevated
in the arterial blood and cerebrospinal fluid of patients with encephalopathy,
and experimental administration of ammonia produces central nervous
According to this theory, cerebral neurons become depleted of
normal neurotransmitters (norepinephrine and dopamine), which are
partially replaced by false neurotransmitters (octopamine and phenylethanolamine).
The result is inhibition of neural function. Serum levels of branched-chain
amino acids (leucine, isoleucine, valine) are decreased, and levels
of aromatic amino acids (tryptophan, phenylalanine, tyrosine) are
elevated in patients with encephalopathy. Because these two classes
of amino acids compete for transport across the blood-brain barrier,
the aromatic amino acids have increased access to the central nervous
system, where they serve as precursors for false neurotransmitters. Trials
of therapy with supplements of branched-chain amino acids have given conflicting results.
This theory postulates that ammonia, mercaptans, and fatty acids,
none of which accumulate in the brain in amounts capable of producing
encephalopathy, have synergistic effects that produce the full-blown
syndrome in patients with liver disease.
Encephalopathy is a major side effect of portacaval shunt and
is to some extent predictable. Elderly patients are considerably
more susceptible. Patients with alcoholic liver disease fare better
than those with postnecrotic or cryptogenic cirrhosis, apparently
owing to the invariable progression of liver dysfunction in the
latter. Good liver function partially protects against encephalopathy.
If the liver has adapted to complete or nearly complete diversion
of portal blood before operation, a surgical shunt is less apt to depress
liver function further. For example, patients with thrombosis of
the portal vein (complete diversion and normal liver function) rarely
experience encephalopathy after portasystemic shunt. Encephalopathy
is less common after a distal splenorenal (Warren) shunt than after other
kinds of shunts.
Increased intestinal protein, whether of dietary origin or from
intestinal bleeding, aggravates encephalopathy by providing more
substrate for intestinal bacteria. Constipation allows more time
for bacterial action on colonic contents. Azotemia results in higher
concentration of blood urea, which diffuses into the intestine,
is converted to ammonia, and is then reabsorbed. Hypokalemia and
metabolic alkalosis aggravate encephalopathy by shifting ammonia
from extracellular to intracellular sites where the toxic action
Arterial ammonia levels are usually high, although encephalopathy
can certainly be present with a normal ammonia level. The presence
of high levels of glutamine in the cerebrospinal fluid may help
distinguish hepatic encephalopathy from other causes of coma. Electroencephalography
is more sensitive than clinical evaluation in detecting minor involvement.
The changes are nonspecific and consist of slower mean frequencies.
Studies performed at different times can be compared to assess the
effects of therapy.
Acute encephalopathy is treated by controlling precipitating
factors, halting all dietary protein intake, cleansing the bowel
with purgatives and enemas, and administering antibiotics (neomycin
or ampicillin) or lactulose. Neomycin may be given orally or by
gastric tube (two to four times daily) or rectally as an enema (1% solution
one or two times daily). At least 1600 kcal of carbohydrate should be
provided daily, along with therapeutic amounts of vitamins. Blood
volume must be maintained to avoid prerenal azotemia. After the
patient responds to initial therapy, dietary protein may be started
at 20 g/d and increased by increments of 10–20
g every 2–5 days as tolerated.
Chronic encephalopathy is treated by restriction of dietary protein,
avoidance of constipation, and elimination of sedatives, diuretics,
and tranquilizers. To avoid protein depletion, protein intake must
not be chronically reduced below 50 g/d. Vegetable protein
in the diet is tolerated better than animal protein. Lactulose,
a disaccharide unaffected by intestinal enzymes, is the drug of
choice for long-term control. When given orally (20–30
g three or four times daily), it reaches the colon, where it stimulates bacterial
anabolism (which increases ammonia uptake) and inhibits bacterial enzymes
(which decreases the generation of nitrogenous toxins). Its effect
is independent of colonic pH. A related compound outside the United
States, lactitol (β-galactoside sorbitol), is also
effective and appears to work faster. As a powder, it is easier
to use than liquid lactulose. Intermittent courses of oral neomycin
or metronidazole may be given if lactulose therapy and preventive
measures are inadequate.
Butterworth RF: Hepatic encephalopathy: a neuropsychiatric
disorder involving multiple neurotransmitter systems. Curr Opin Neurol
Haussinger D, Schliess F: Pathogenetic mechanisms of hepatic
encephalopathy. Gut 2008;57:1156.
Lockwood AH: Early detection and treatment of hepatic encephalopathy.
Curr Opin Neurol 1998;11:663.
Hepatic abscesses may be bacterial, parasitic, or fungal in origin.
In the United States, pyogenic abscesses are the most common, followed
by amebic abscesses (see Chapter 8). Unless
otherwise indicated, the remarks in this section refer to bacterial abscesses.
Cases are about evenly divided between those with a single abscess
and those with multiple abscesses. About 90% of right lobe
abscesses are solitary, while only 10% of left lobe abscesses
In most cases, the development of a hepatic abscess follows a
suppurative process elsewhere in the body. Many abscesses are due
to direct spread from biliary infections such as empyema of the gallbladder
or protracted cholangitis. Abdominal infections such as appendicitis
or diverticulitis may spread through the portal vein to involve
the liver with abscess formation. About 40% of patients
have an underlying malignancy. Other cases develop after generalized sepsis
from bacterial endocarditis, renal infection, or pneumonitis. In
25% of cases, no antecedent infection can be documented
(“cryptogenic” abscesses). Rare causes include
secondary bacterial infection of an amebic abscess, hydatid cyst,
or congenital hepatic cyst.
In most cases, the organism is of enteric origin.
Escherichia coli, Klebsiella pneumoniae, bacteroides,
enterococci (eg, Streptococcus faecalis), anaerobic
streptococci (eg, Peptostreptococcus), and microaerophilic streptococci
are most common. Staphylococci, hemolytic streptococci, or other gram-positive
organisms are usually found if the primary infection is bacterial endocarditis
When liver abscess develops in the course of another intra-abdominal
infection such as diverticulitis, it is accompanied by increasing
toxicity, higher fever, jaundice, and a generally deteriorating clinical
picture. Right upper quadrant pain and chills may appear.
In other cases, the diagnosis is much less obvious, since the
illness develops insidiously in a previously healthy person. In
these, the first symptoms are usually malaise and fatigue, followed after
several weeks by fever. Epigastric or right upper quadrant pain
is present in about half of cases. The pain may be aggravated by
motion or may be referred to the right shoulder.
The course of fever is often erratic, and spikes to 40–41
°C are common. Chills are present in about 25% of cases.
The liver is usually enlarged and may be tender to palpation. If
tenderness is severe, the condition may be confused with cholecystitis.
Jaundice is unusual in solitary abscesses unless the patient’s
condition is worsening. Jaundice is often present in patients with
multiple abscesses and primary disease in the biliary tree and in
general is a bad prognostic sign.
Leukocytosis is present in most cases and is usually over 15,000/μL.
A small group of patients, usually the most seriously ill, may fail
to develop leukocytosis. Anemia is present in most. The average
hematocrit is 33%.
Serum bilirubin is usually normal except in patients with multiple
abscesses or biliary obstruction or when hepatic failure has supervened.
Alkaline phosphatase is often elevated even in the presence of a normal
X-ray changes present in the right lung in about one third of cases
consist of basilar atelectasis or pleural effusion. The right diaphragm
may be elevated and less mobile than the left.
Plain films of the abdomen are usually normal or show only hepatomegaly.
In a few patients, an air-fluid level in the region of the liver
reveals the presence and location of the abscess. Distortion of the
contour of the stomach on upper gastrointestinal series may be seen
with large abscesses involving the left lobe.
Ultrasound and CT scans are the most useful diagnostic tests,
providing accurate information regarding the presence, size, number,
and location of abscesses within the liver. CT scans have the added advantage
of being able to demonstrate abscesses or neoplasms elsewhere in the
abdomen. The radioisotope liver scintiscan is able to demonstrate
most liver abscesses but is nonspecific, gives little other useful
information, and is therefore not helpful.
In many cases, early findings may be so vague that hepatic abscess
is not even considered. The multiple other causes of malaise, weight
loss, and anemia would enter into the differential diagnosis. With spiking
fevers, one must consider all the causes of fever of unknown origin.
Failure to entertain the idea of hepatic abscess and to obtain the
necessary scans leads to most errors in diagnosis.
Once imaging tests have demonstrated the abscess, the responsible
organisms must be identified. Amebiasis should be considered in
cases of a solitary abscess. Compared with amebic abscesses, pyogenic
liver abscesses are seen more often in patients older than 50 years
and are associated with jaundice, pruritus, sepsis, a palpable mass,
and elevated bilirubin and alkaline phosphatase levels. Patients
with amebic abscesses more often have been to an endemic area and
have abdominal pain and tenderness, diarrhea, hepatomegaly, and
positive serologic tests for amebiasis.
Intrahepatic spread of infection may create multiple additional
abscesses and is responsible for some failures after treatment of
an apparently solitary abscess. As the untreated abscess expands,
rupture may occur into the pleural or peritoneal cavity, usually
with catastrophic results. Septicemia and septic shock are common
terminal complications of diffuse hepatic infection. Hepatic failure may
develop in addition to uncontrolled sepsis, or it may predominate
over signs of infection.
Hemobilia may follow bleeding from the vascular wall into the
abscess cavity. In this case, hepatic artery embolization or ligation
may be required to control bleeding.
Antibiotics should be started promptly. Initial coverage, before
culture results are available, should be adequate for E
coli, K pneumoniae, bacteroides, enterococci, and yanaerobic
streptococci and consequently would usually include an aminoglycoside,
clindamycin or metronidazole, and ampicillin. The regimen may be
modified later according to the results of cultures.
About 80% or more of patients with liver abscesses are adequately
treated by drainage catheters inserted percutaneously under ultrasound
or CT guidance. Whether the patient has a single abscess or multiple
abscesses, this is usually the most appropriate initial therapy.
The catheters can be removed in 1–2 weeks after output
becomes nonpurulent and scant.
In about 40% of patients, the catheters do not drain
well following initial placement and must be repositioned. The principal
advantage of percutaneous drainage is lower morbidity compared to open
drainage, although not necessarily lower mortality. It is easier
to provide thorough drainage surgically, so when difficulties are
encountered with percutaneous drainage, laparotomy should be performed
promptly. Surgical intervention is more often necessary in cases
of multiple, loculated collections or when the abscess cavity contains
a large amount of necrotic debris. In such cases, open debridement
should be considered early. Likewise, early surgical intervention
is indicated for patients who are seriously ill (APACHE II score
≥ 15). Rarely, multiple abscesses are confined to a single lobe and
can be cured by lobectomy. Biliary obstruction or other causes of
sepsis must also be corrected.
The overall mortality rate of 15% is more closely related
to the underlying disease than to any other factor. The mortality rate
is about 40% in patients with malignant disease. Pleural effusion,
leukocytosis over 20,000/μL, hypoalbuminemia,
and polymicrobial infection correlate with a poor outcome. In the
United States, whether the abscess is solitary or multiple no longer has
a major influence on survival, but where benign biliary disease
remains a major cause of this disease, multiple hepatic abscesses
are associated with a worse prognosis. Death is rare in patients
with a cryptogenic liver abscess.
Chen SC et al: Predictors of mortality in patients
with pyogenic liver abscess. Neth J Med 2008;66:183.
Hsieh HF et al: Aggressive hepatic resection for patients with pyogenic
liver abscess and APACHE II score ≥ 15. Am J Surg 2008;196:346.
Johannsen EC, Sifri CD, Madoff LC: Pyogenic liver abscesses. Infect
Dis Clin North Am 2000;14:547.
Molle I et al: Increased risk and case fatality rate of pyogenic
liver abscess in patients with liver cirrhosis: a nationwide study
in Denmark. Gut 2001;48:260.