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Chapter 7
These recurrences responded partially to systemic
chemotherapy, and patients were alive with disease
at 1480 and 1881 months following hepatectomy.
Thus, although rarely feasible, hepatectomy followed by hepatic arterial chemotherapy may provide a limited survival benefit in chemosensitive
oesophageal cancer with isolated liver metastases.
Gastric adenocarcinoma is the second most common cause of cancer-related death worldwide, and the
liver is a major site of spread in 9% of cases, generally in a bilobar distribution.82 Overall 5-year survival
in patients with liver metastases ranges from 0% to
10% and the role of surgery is unclear in this setting.
A recent study of patients with isolated synchronous
or metachronous liver metastases reported that surgery was performed if the tumour burden was deemed
completely resectable, while lesions <5 cm were considered for RFA. Overall 5-year, survival in this cohort
was 27% with a median survival of 48 months. In
a comparison of patients who were not offered the
above treatment modalities, no patients survived to
5 years, with a median survival of 9 months.82 These
results appear comparable to previously published
studies.83 Data regarding independent predictors of
survival are limited and appear to correlate with absence of serosal invasion of the primary tumour and
the presence of a solitary liver metastasis.
Primary small-bowel malignancies represent an
exceedingly rare but histologically diverse subgroup
accounting for 2% of all GI malignancies.84 Smallbowel adenocarcinoma (SBA) represents the majority of these tumours and is seen in up to 5% of
patients with familial adenomatous polyposis (FAP).
By virtue of its non-specific clinical presentation and
the limitations of radiological and endoscopic diagnostic modalities to examine the small bowel, approximately 80% of patients present with advanced
disease. In addition, the low prevalence of SBAs limits
our understanding of the natural history of tumour
spread, restricting the development of clear treatment guidelines. A French multicentre retrospective
study examining the efficacy of chemotherapy in 93
patients with advanced SBA compared various chemotherapeutic regimens for progression-free survival
(PFS) and overall survival (OS). Median PFS and OS
were 6.6 and 15.1 months, respectively, with best
outcomes seen with FOLFOX therapy.85 Negative
prognostic factors include a poor baseline WHO performance status, elevated carbohydrate antigen (CA)
19-9/carcinoembryonic antigen (CEA) levels and the
presence of a duodenal primary. The ability of surgery to prolong PFS in hepatic SBA metastases has
only been described in a single case report of an FAP
patient with a PFS of 3 years following neoadjuvant
chemotherapy and surgery.84 As such, future studies
examining liver resections in metastastic SBA will
provide further guidance as to its role in this disease.
Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all histological subtypes of pancreatic cancer and confers the worst overall prognosis.86
Over the last 50 years, PDAC has continued to rank
as the tenth most common cancer in the western
world and the fourth leading cause of cancer death.
PDAC presents in a non-specific manner, often when
disease is already at an advanced stage. Improvements
in chemotherapy, surgical technique and knowledge
of tumour biology have translated into marginal
improvements in survival. Currently, only 15–20%
of patients present with disease amenable to curative resection, of which 20% are alive at 5 years.86
The overall average 5-year survival for unresectable
PDAC is 5%, with a median survival of 6–9 months.
Due to the dismal prognosis in patients with localised resectable disease, surgery in metastatic PDAC
has been contraindicated. Yamada et al. examined
the role of partial hepatectomy in non-neuroendocrine pancreatic cancer, including five patients with
PDAC, one with adenosquamous carcinoma and one
with cystadenocarcinoma.87 Patients were chosen for
surgery if complete excision of intrahepatic disease
was deemed feasible, reliable control of the primary
disease was possible and the liver was the only site
of spread. Overall 5-year survival in this cohort was
16.7%; however, five patients experienced a recurrence and subsequently died of their disease within
4–52 months. Prognostic factors appear to correlate
with disease-free interval from primary to metastasis and the presence of negative surgical margins at
metastasectomy. Although the authors highlight the
potential role of liver resection in metastatic PDAC,
they acknowledge the need for future studies to clarify the true benefit of this approach.
The available evidence for hepatectomy in the
management of metastases from non-colorectal,
non-neuroendocrine (NCRNNET) GI primaries is
limited, and few meaningful statements can be
made as to the utility of this treatment strategy.
With improvements in safety of liver resections
coupled with encouraging results from other
malignancies metastasising to the liver, future
prospective studies will shed light on the role of
hepatic metastasecotomy in NCRNNETs.
Testicular cancer
Metastasectomy is well established in the management of disseminated non-seminomatous germ
cell testicular carcinoma that does not completely
respond to chemotherapy. Although it can be difficult to differentiate active residual tumour from
post-treatment fibrosis or necrosis, the probability
of achieving cure by surgical resection is high.
140
Non-colorectal hepatic metastases
Residual teratoma has the potential for sarcomatous transformation and thus lymphadenectomy
and visceral resection are performed whenever there
is radiographic evidence of residual disease. The
overall 10-year survival is 62% from diagnosis of
hepatic metastasis.
A single institution experience of 57 liver resections performed over the last two decades has demonstrated that surgery for hepatic metastases is safe
and efficacious, depending on the histopathological
characteristics of the resected specimen. Based on
the presence and type of tumour in the liver, 40–
70% of patients remain disease free at 20 months.89
Negative prognostic indicators included viable tumour in the resected specimen, metastases greater
than 3 cm in diameter and pure embryonal carcinoma in the primary lesion.
88
Urothelial cancer
Data for metastasectomy in the management of disseminated urothelial cancer are sparse, and no studies specifically address the role of hepatectomy. Of
those patients treated for primary urothelial cancer
30% will recur, of which 75% will be with distant
spread. Five-year survival of 28% has been reported
following resection of lung, brain, adrenal, smallbowel or lymph node metastases with variation in
the use of adjuvant chemotherapy.90 Metastasectomy
has also been employed for palliation.
Lung cancer
The management of metastatic lung cancer is largely
restricted to radiation and chemotherapy. Although
the surgical management of hepatic metastasis remains controversial, most cases have been reviewed
within the broader context of NCRNNET. Hepatic
metastases appear most commonly in right-sided
non-small-cell lung tumours with concomitant bone
metastases. A small case series of highly selected patients with one to two liver lesions has shown that
surgery may confer a marginal survival benefit.91
Nevertheless, the role of surgery as well as other
treatment modalities (RFA, TAE/TACE) cannot be
definitively made with current evidence.
Adrenocortical tumours
Adrenocortical tumours with liver metastases are
rare, and literature on the management of this
disease scenario is mostly anecdotal. Case reports
have provided no clear guidance regarding the role
of surgical or ablative strategies. It is possible that
patients who develop metachronous liver metastases
with a disease-free interval >1 year from primary to
metastasis may derive benefit from surgery.
92
Endometrial cancer
Metastatic endometrial cancer is usually multifocal
and rarely managed operatively. A recent singlecentre report described the results in five patients
who developed metastatic disease to the liver ranging from 11 months to 10 years after primary resection. All patients underwent hepatic surgery, with
disease-free survival between 8 and 66 months.
Based on these results, the authors advocate referral
to a hepatobiliary specialist with the intent of pursuing surgery.93 Other isolated reports of long-term
survivors exist within the context of larger studies
focused on NCRNNET hepatic metastasis.
Conclusion
The recent success of an aggressive surgical approach in the management of CRC liver metastases
has, in part, provided the impetus for liver resection
in non-colorectal cancer hepatic metastatic disease.
Extrapolating surgical strategies from one malignancy to another is reasonable in some cases; however, fundamental biological differences between
various neoplasms require thoughtful consideration
of differences in the natural history and non-surgical
treatment modalities that are available for each tumour site. Unfortunately, strong evidence-based data
are lacking and it is therefore necessary for the treating surgeon to have a good working knowledge of the
biology and management of various malignancies. In
many cases, this is augmented by the availability of
multidisciplinary tumour boards and a critical mass
of subspecialists to assist in decision-making.
It is worth emphasising that in most cases liver resection should be performed with curative intent.
Exceptions include liver metastases from NETs, epithelial ovarian cancer and testicular malignancies,
where ‘debulking’ is considered useful as a palliative
manoeuvre to improve overall survival. The case for
resection of breast cancer metastases is evolving,
with some liver surgeons advocating resection in a
selected patient population responsive to preoperative chemotherapy. There is no strong evidence that
non-curative intent surgery is helpful for patients
with liver metastases from gastrointestinal tract primaries, lung and other cancers.
The presence of extrahepatic disease is almost always a contraindication to liver resection, except
within the context of a prospective trial or for specific malignancies such as ovarian cancer. The critical
141
Chapter 7
variables that usually predict cure after liver resection of secondary cancer of almost all types include
prolonged disease-free interval from resection of the
primary tumour, negative resection margins and performance status.
Future efforts should be directed toward the conduct
of randomised trials designed to test the role of liver
surgery for the common non-colorectal malignancies,
and the discovery of genetic and proteomic signatures
as better prognostic and predictive markers.
Key points
• The majority of patients with non-colorectal liver metastases have disseminated disease and are
not candidates for hepatectomy.
• Treatment decisions must take into account clinical surrogates of tumour biology. Patients with
synchronous liver metastases, a short disease-free interval and extrahepatic disease are believed to
have more aggressive tumours and are less likely to gain significant survival benefit from liver resection.
• With few exceptions, liver resection for metastatic disease should be performed with curative
intent. The ability to achieve negative resection margins is a significant prognostic factor.
• Debulking surgery including liver resection has been shown to significantly improve survival
in metastatic neuroendocrine tumours. Aggressive cytoreduction, often using a multimodality
approach, is indicated in most cases of metastatic NETs.
• Cytoreduction including hepatectomy, followed by intraperitoneal chemotherapy, appears to
improve survival in stage III/IV ovarian adenocarconima. New studies are now focusing on
combination adjuvant i.v./i.p. chemotherapy as well as combination surgery and HIPEC.
• Patients with breast cancer liver metastases that respond to preoperative chemotherapy appear to
gain a survival benefit from hepatectomy.
• Level I and II evidence regarding hepatectomy for the treatment of non-colorectal liver metastases
is lacking, and the indications for surgery are evolving.
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8
Portal hypertension
Geoffrey H. Haydon
John Isaac
John A.C. Buckels
Simon P. Olliff
Introduction
The management of portal hypertension has evolved
from a surgical discipline into one with the majority of patients successfully treated by medical and
radiological therapies. Surgery still has a distinct
role for a limited number of patients, chiefly those
with extrahepatic portal hypertension and those
suitable for liver transplantation (which can cure
both the complications and the underlying liver disease). As patients with gastrointestinal (GI) bleeding
will often be referred for a surgical opinion, it is important that the surgeon has a good understanding
of the pathophysiology of variceal bleeding as well
as the treatment options.
Portal hypertension itself does not require treatment, but intervention is indicated when the risk
of bleeding from varices is present or when complications such as actual variceal haemorrhage or
the formation of ascites occur. The management
of many patients commences with a herald variceal bleed, which requires effective therapy before
a plan can be made for longer-term treatment. A
significant choice of options is now available, many
of which are evidence based. These include: pharmacotherapy to both prevent and treat variceal
bleeding; endoscopic options of injection therapy or
variceal ligation; radiologically placed transjugular
intrahepatic portosystemic shunts (TIPS); and surgical options (surgical shunts and liver replacement).
The selection of these options needs to be tailored
to the individual patient, taking into account their
general fitness, including severity of any underlying
liver disease and the local medical facilities and expertise available.
This chapter will briefly outline the causes, pathophysiology and natural history of portal hypertension, but will concentrate on the evaluation and
management of both asymptomatic patients and
patients who present with an acute bleed, together
with longer-term strategies. In addition, specific recommendations will be made for the management of
ascites and for patients with hepatic venous outflow
obstruction due to Budd–Chiari syndrome.
Aetiology and pathophysiology of portal hypertension
Traditionally, portal hypertension has been classified
as prehepatic, intrahepatic or posthepatic, with the
intrahepatic causes subdivided into presinusoidal,
sinusoidal and postsinusoidal (Table 8.1). Prehepatic
causes are usually due to portal vein thrombosis,
which is discussed later in this chapter. The main
cause of portal hypertension in the West is cirrhosis.
This is a sinusoidal obstruction to portal flow with
varying causes. Viral hepatitis and alcoholic liver
disease are the most common causes, but others include primary biliary cirrhosis, primary sclerosing
146
Portal hypertension
Table8.1 • Causes of portal hypertension
Presinusoidal Sinusoidal Postsinusoidal
Extrahepatic Cirrhotic Budd–Chiari
syndrome
Portal vein
thrombosis
Splenic vein
thrombosis
Increased splenic
flow (tropical
splenomegaly,
myelofibrosis)
Intrahepatic Chronic active
Schistosomiasis Haemochromotosis
Congenital
hepatic fibrosis
Sarcoidosis Non-cirrhotic
Acute alcoholic
Cytotoxic drugs
cholangitis and haemochromatosis. Presinusoidal
obstruction due to hepatic fibrosis occurs in schistosomiasis. Worldwide, this is one of the commonest causes of portal hypertension and, as it is usually
associated with normal liver function, has a better
prognosis. The main causes of postsinusoidal portal
hypertension are hepatic venous thrombosis (Budd–
Chiari syndrome) and veno-occlusive disease.
Experimental studies have demonstrated that
the initial factor in the pathophysiology of portal
hypertension is the increase in vascular resistance
to portal blood flow. In cirrhosis, this increase
in resistance occurs in the hepatic microcirculation (sinusoidal portal hypertension), and is a
consequence of both a ‘passive’ and an ‘active’
component. The ‘passive’ component is the mechanical consequence of the hepatic architectural
disorder resulting from histological cirrhosis, and
the ‘active’ component is the active contraction
of portal/septal myofibroblasts, activated stellate cells and portal venules. The increase in intrahepatic tone is probably a consequence of an
imbalance between an increase in the endogenous
vasoconstrictor substances, such as endothelin,
noradrenaline, leukotrienes and angiotensin II, and
a relative decrease in the endogenous vasodilator
nitric oxide.1 Vasodilatory drugs (for example,
calcium channel blockers) may restore the equilibrium in intrahepatic tone, although they are not
used for this indication in clinical practice.
Postviral (B, C) Veno-occlusive
disease
Alcoholic Caval web
Cryptogenic
Primary biliary
cirrhosis
Primary sclerosing
cholangitis
hepatitis
Wilson's disease
hepatitis
Constrictive
pericarditis
The other major pathophysiological factor contributing to portal hypertension is an increase
in portal venous blood flow through the portal
circulation resulting from splanchnic arteriolar
vasodilatation caused by an excessive release of
endogenous arteriolar vasodilators (endothelial,
neural and humoral). This can be corrected by
means of splanchnic vasoconstrictors such as terlipressin and non-selective beta-blockers. Many
drugs that lower portal pressure both reduce intrahepatic vascular resistance and decrease portal
venous inflow.
An important but rare form, segmental or left upper quadrant portal hypertension, occurs in patients
with splenic vein thrombosis. This should be suspected in patients with bleeding gastric varices but
normal liver function, particularly if there is a history of either acute or chronic pancreatitis.
The natural history of portal hypertension
The prevalence of oesophageal varices in patients
with cirrhosis and portal hypertension is high.
When cirrhosis is diagnosed, varices are present in
40% of compensated and 60% of decompensated
cirrhotics.2 After the initial diagnosis of cirrhosis,
varices develop with an incidence of 5% per year;
subsequently, they may progress from small to large
at an incidence of 10–15% per year.3 Rapid progression of hepatic decompensation is associated with a
rapid increase in size, whilst improvement in liver
function, particularly when associated with removal
of the injurious agent (e.g. abstinence from alcohol),
may result in a decrease in size or disappearance of
the varices.
The overall incidence of variceal bleeding following diagnosis is of the order of 25% in unselected patients. The most important predictive
factors of variceal bleeding are severity of liver
dysfunction, size of varices and intravariceal
wall pressure (which although difficult to measure may correlate at endoscopy with the presence of red spots or red weals).6 Traditionally,
liver dysfunction has been classified using the
Child–Pugh score7 (Table 8.2), but a more recent
scoring system, the MELD (Model for End-stage
Liver Disease), may be a better prognostic indicator (Box 8.1).8 Variceal size may be the best
single predictor of variceal bleeding and generally it is used to decide whether a patient should
be given prophylactic therapy or not. Whether a
patient dies from a variceal bleed depends on the
severity of the accompanying liver failure; those
with a high Child–Pugh or MELD score have
been reported to have as high a risk of mortality
4,5
147
Chapter 8
(
)
éù
ëû
éù
ëû
Table8.2 • Child–Pugh classification
Number of points
1 2 3
Bilirubin (μmol/L)* <34 34–51 >51
Albumin (g/L) >35 28–35 <28
Prothrombin time
prolonged by (s)
Ascites None Slight to
Encephalopathy None Slight to
Grade A 5–6 points; Grade B 7–9 points; Grade C 10–15 points.
* In primary biliary cirrhosis, the point scoring for bilirubin level is
adjusted as follows: 1, <68; 2, 68–170; 3, >170.
Box8.1 • Model for End-stage Liver Disease (MELD)
MELD is calculated for patients over the age of 12 based on
the following variables:
• Serum creatinine (mg/dL)
• Total bilirubin (mg/dL)
• INR (international normalised ratio).
The formula incorporates these variables as:
MELD = 3. 7 8 Ln serum bilirubi n mg/ dL
+ 11.2 Ln INR + 9.57
The following rules must be observed when using this
formula:
• 1 is the minimum acceptable value for any of the three
variables.
• The maximum acceptable value for serum creatinine is 4.
• The maximum value for the MELD score is 40. All values
higher than 40 are given a score of 40.
• If the patient has been dialysed twice within the last
7 days, then the value for serum creatinine used should
be 4.0.
In being considered for liver transplantation, patients with a
diagnosis of liver cancer are assigned a MELD score based
on how advanced the cancer is, using the TNM staging
system.
as 30–50% within 6 weeks of the index bleed.9
However, a more realistic figure would be 20%
at 6 weeks with an immediate mortality from
uncontrolled bleeding as low as 5–8%. Indeed,
in 40–50% of patients who bleed and develop
hypotension, variceal bleeding stops spontaneously, probably as a result of reflex splanchnic
vasoconstriction with associated reduction in
<3 3–10 >10
moderate
moderate
( )
Ln serum creatinine mg/ dL + 6 .4 3
(
)
Moderate to
severe
Moderate to
severe
portal pressure and blood flow; this beneficial
response is nullified by over-transfusing the
patient.
The incidence of re-bleeding ranges between 30%
and 40% within the first 6 weeks; this risk peaks in
the first 5 days following the index bleed. Bleeding
gastric varices, active bleeding at emergency endoscopy, low serum albumin levels, renal failure and a
hepatic venous pressure gradient >20 mmHg have all
been reported as significant indicators of an early risk
of re-bleeding.
variceal bleeding have a very high risk of re-bleeding
(63%) and death (33%), and this is the basis for
treating all patients to prevent further bleeding.
10–12
Patients surviving a first episode of
9
Presentation
Portal hypertension may present acutely with
variceal bleeding or be discovered during the
investigation of a patient with liver disease.
Varices are usually easily diagnosed at endoscopy
and patients will then be investigated systematically. A classification of the grading of varices is
given in Table 8.3. Presentation of patients with
liver disease is variable and ranges from nonspecific tiredness to advanced encephalopthy with
decompensation. External features of advanced
liver disease such as spider naevi, palmar erythema
and ascites are easy to detect, although these signs
will be lacking in many patients. Splenomegaly is
probably the most useful physical sign, although
some patients will have the classic sign of dilated
umbilical vein collaterals (caput medusae).
Imaging
Doppler ultrasonography is a useful and easily obtained initial imaging modality for patients with
suspected portal hypertension. Spleen size and the
state of the liver parenchyma can be assessed together with portal and hepatic vein patency and
flow velocity, and the presence or absence of varices
can often be inferred. Computed tomography (CT)
and magnetic resonance imaging (MRI) now give
detailed roadmaps of vascular anatomy prior to any
surgical intervention with no need for invasive angiography in most cases.
Management of varices
The management of oesophageal varices will be
considered in three sections: the prevention of
bleeding in patients with varices who have never
bled (primary prophylaxis); the longer-term management of patients who have bled to prevent
148
Portal hypertension
Table8.3 • Classification of oesophageal and gastric varices
Classification of varices
Oesophageal varices Grade 0 (or absent)
Grade 1 (or small) Varices that collapse on insufflation of oesophagus with air
Grade 2 (or medium) Varices that do not collapse on air insufflation
Grade 3 (or large) Varices that are large enough to occlude the lumen
Gastric varices GOV1 Gastro-oesophageal varices extending <5 cm from the
oesophagus across gastro-oesophageal junction
GOV2 Gastro-oesophageal varices extending into the fundus across
gastro-oesophageal junction
IGV1 Isolated gastric varices in the fundus
IGV2 Isolated non-fundic varices
future bleeding episodes (secondary prophylaxis); and the emergency resuscitation and initial control of the acute bleeding episode. Though
the emergency management of many patients
will be in a district general hospital, patients
may require referral to specialised centres with
expertise in liver diseases and where recourse to
specialised radiological intervention is available.
As pharmacological therapy is employed in the
majority of cases, the treatment aims of this will
be discussed first.
Therapeutic aims for pharmacological therapy in portal hypertension
The hepatic venous pressure gradient (HVPG)
reflects accurately portal pressure in sinusoidal portal hypertension and is readily measured by hepatic
vein catheterisation.
Varices do not develop until the HVPG
increases to 10–12 mmHg and the HVPG must
be greater than 12 mmHg for the appearance
of complications such as variceal bleeding
and ascites.13 Longitudinal studies of patients
with complications of portal hypertension have
demonstrated that when an HVPG decreases
to less than 12 mmHg with pharmacological
therapy, TIPS or an improvement in liver
function, variceal bleeding is prevented and
varices may decrease in size or disappear
altogether.14 When this target is not reached, a
substantial reduction in portal pressure by more
than 20% still offers protection against variceal
bleeding15 and thus these two parameters are
regarded as the end-points to therapeutic
strategies to lower portal pressure.
Recent evidence suggests that these therapeutic
end-points may also reduce the risk of other complications of portal hypertension, including ascites,
spontaneous bacterial peritonitis and hepatorenal
syndrome.
16,17
Oesophageal varices
Primary prophylaxis for the prevention of variceal haemorrhage
All patients with cirrhosis should be screened
for varices at the time of first diagnosis of their
cirrhosis. In patients with grade I varices at index
endoscopy, a follow-up endoscopy should be performed after 12 months to detect the progression
from grade II to III varices. Patients without varices
should be re-evaluated 2–3 years after their index
endoscopy.
The mainstay of primary prophylactic therapy
in the prevention of variceal haemorrhage is the
non- selective β-adrenergic receptor blocker (betablocker). Twelve trials using beta-blockers in this
context have been reported.
A meta-analysis has indicated that
indefinite treatment with propanolol or nadolol
significantly reduces the bleeding risk from 25%
with non-active treatment or placebo to 15% with
beta-blockers over a median follow-up period of
24 months; there was no significant reduction
in mortality.3 The benefit of therapy was only
proven in those patients with grade II (or larger)
varices; there was no evidence to support the use
of primary prophylactic therapy in patients with
grade I varices.
149