Book on hepatitis from page 346 to 355

Book on hepatitis from page 346 to 355

346  Hepatology 2012
Therapeutic management of additional risk factors such as obesity and poorly
controlled diabetes mellitus provide additional chances for prophylactic measures to
reduce the risk of HCC development. Finally, consumption of two or more cups of
coffee per day seems to reduce the risk of liver cancer by 40-50% in patients with
chronic viral hepatitis (Gelatti 2005, Bravi 2007, Larsson 2007, Wakai 2007).
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348  Hepatology 2012
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Update in Transplant Hepatology  349
22. Update in Transplant Hepatology
S. Beckebaum, G. Gerken, V. R. Cicinnati
Introduction
The first attempt at heterotopic grafting of a liver in a dog was reported more than
50 years ago (Welch 1955). The first known experimental orthotopic liver
transplantation (LT) was reported in 1956 at the University of California (Cannon
1956). In the early sixties, a human-to-human LT was performed in a 3-year-old
child with congenital biliary atresia who died intraoperatively (Starzl 1963). The
next two transplant recipients lived for 22 days and 1 week, respectively (Starzl
1963). Starzl finally transplanted several patients with success in 1967 (Starzl
1968).
With the advances in immunosuppression, surgical techniques, organ preservation
and improvements in patient management, LT has become the gold standard in the
treatment of advanced chronic liver disease and fulminant hepatic failure. This
chapter focuses on important issues in the field of transplant hepatology and may
provide helpful information to physicians involved in the care of adult LT
recipients. It includes indications for LT, current organ allocation policy,
pretransplant evaluation, management while on the waiting list, living donor liver
transplantation (LDLT), and management of early and long-term complications
post-LT.
Timing and indications for liver transplantation
Appropriate selection of candidates and timing of LT is crucial in reducing
mortality and improving outcomes in LT recipients. A patient is considered too
healthy to undergo LT if the expected survival is greater without LT. Therefore,
criteria are needed in order to select patients who can most benefit from
transplantation. In 2002, the  Organ Procurement and Transplantation Network,
along with the United Network of Organ Sharing (UNOS), developed a new system
based on the model for end-stage liver disease (MELD) (Table 1) to prioritize
patients on the waiting list. In the Eurotransplant countries, the Child-Pugh Turcotte
score was replaced by the MELD score in December 2006.
350  Hepatology 2012
The lab MELD score is a numerical scale using the three laboratory parameters
depicted in Table 1 and ranging from 6 (less ill) to 40 (severely ill).
In a large study (Merion 2005) investigating the survival benefit of LT candidates,
those transplanted with a MELD score <15 had a significantly higher mortality risk
as compared to those remaining on the waiting list, while candidates with a MELD
score of 18 or higher had a significant transplant benefit.
Table 1. Calculation of the MELD* Score.
MELD Score = 0.957 x log (creatinine mg/dL)
0.378 x log (bilirubin mg/dL)
1.120 x log (INR**)
+ 0.643
*Model of End-stage Liver Disease
**International Normalized Ratio
However, the MELD score does not accurately predict mortality in approximately
15-20% of patients. Therefore MELD-based allocation allows exceptions for
patients whose score may not reflect the severity of their liver disease. These
exceptions include hepatocellular carcinoma (HCC), non-metastatic
hepatoblastoma, adult polycystic liver degeneration, primary hyperoxaluria type 1,
small for size syndrome, cystic fibrosis, familial amyloid polyneuropathy,
hepatopulmonary syndrome, portopulmonary hypertension, urea cycle disorders,
hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu disease),
hemangioendothelioma of the liver, biliary sepsis, primary sclerosing cholangitis
(PSC) and cholangiocarcinoma. Patients with standard exceptions will be assigned a
higher MELD score (match MELD) than that assigned by the patient’s laboratory
test results (lab MELD). This results in an increasing proportion of patients
transplanted for HCC and other exceptions over time (Massie 2011).
MELD has proved to be accurate as a predictor of waiting list mortality, but has
shown to be less accurate to predict post-transplant outcome. For instance, MELD
allocation resulted in decreased waiting list mortality; whereas post-transplant
morbidity has increased due to transplantation of a higher proportion of sicker
recipients with MELD scores >30 (Dutkowski 2011). Moreover, since the
introduction of MELD, the quality of donor organs has been impaired and the
threshold for organ allocation has increased from a match MELD of 25 to 34
(Schlitt 2011).
A potential modification of the MELD allocation system currently under
investigation is to allocate organs by not only taking into account pretransplant
mortality but also donor-related factors for estimation of the donor risk index (DRI)
(Feng 2006) and post-transplant mortality.
Furthermore, standardization of laboratory assays and variants of MELD
including incorporation of parameters such as sodium or cholinesterase have been
proposed to overcome the limitations of the current scoring system (Choi 2009,
Weissmüller 2008).
Candidates for LT must have irreversible acute or chronic end-stage liver disease.
Hepatitis C virus (HCV)- or alcohol-induced liver disease account for the most
common disease indications in adults with liver cirrhosis  (http://www.eltr.org)
(Figure 1). Other indications include cholestatic liver disorders (primary biliary
Update in Transplant Hepatology  351
cirrhosis [PBC], PSC), hepatitis B virus (HBV) infection, autoimmune hepatitis
(AIH), inherited metabolic diseases (Wilson’s Disease, hemochromatosis, α-1-antitrypsin deficiency), nonalcoholic steatohepatitis, HCC, and acute or acute-on-chronic hepatic failure. In children, biliary atresia and metabolic liver diseases are
the most common indications. Contraindications for LT include active alcohol and
drug abuse, extrahepatic malignancies, sepsis, uncontrolled pulmonary
hypertension, and coexistent medical disorders such as severe cardiopulmonary
condition, technical or anatomical barriers such as thrombosis of the entire portal
and superior mesenteric venous system. Previous malignancy history must be
carefully considered and likelihood of recurrence estimated.
Figure 1. Indications for liver transplantation (LT). Primary diseases leading to LT in Europe
1988 - 2010 (Data kindly provided from European Liver Transplant Registry,
http://www.eltr.org).
Patient evaluation
Evaluation of a potential transplant candidate is a complex and time-consuming
process that requires a multidisciplinary approach. Requirements for evaluation may
differ slightly between transplant centers. The evaluation process must identify
extrahepatic diseases that may exclude the patient from transplantation or require
treatment before surgical intervention. The protocol we use for evaluation of
potential transplant candidates is shown in Table 2.
Pretransplant management issues
In cases of recurrent variceal hemorrhage despite prior interventional endoscopic
therapy (and non-selective beta-blockade) or refractory ascites, transjugular
intrahepatic portosystemic shunts (TIPS) have been used as an approach to lower
portal pressure and as a bridging therapy for transplant candidates. The
identification of predisposing factors and the application of lactulose, nonabsorbed
antibiotics and protein-restricted diets remain essential for prophylaxis and
management of hepatic encephalopathy (HE).
352  Hepatology 2012
Table 2. Evaluation protocol for potential transplant candidates.
  Physical examination
  Diagnostic tests (baseline laboratory testing; serologic, tumor/virologic, and
microbiological screening; autoantibodies; thyroid function tests)
  Ultrasonography with Doppler
  Abdominal MRI or CT scan
  Chest X-rays
  Electrocardiogram (ECG), stress ECG, 2-dimensional echocardiography (if
abnormal or risk factors are present: further cardiological screening)
  Upper and lower endoscopy
  Pulmonary function testing
  Mammography (females >35 years)
  Physician consultations (anesthesiologist, gynecologist, urologist, cardiologist,
neurologist, dentist, ENT physician)
  A meticulous psychosocial case review (medical specialist in psychosomatic
medicine, psychiatry or psychology)
Hepatorenal syndrome (HRS) represents a complication of end-stage liver disease
and is a risk factor for acute kidney injury (AKI) in the early postoperative phase
(Saner 2011). It is classified into type 1 HRS characterized by a rapid impairment of
renal function with a poor prognosis; type 2 HRS is a moderate steady renal
impairment. Vasoconstrictors including commonly used terlipressin in combination
with volume expansion, have been shown to be effective for restoration of arterial
blood flow and serve as a bridging therapy to LT. Extracorporeal liver support
systems based on exchange or detoxification of albumin have been successfully
employed in indicated cases. After wait-listing, laboratory values must be updated
according to the recertification schedule shown in Table 3.
Table 3. Recertification schedule of MELD data.
Score  Recertification  Lab values
≥25  every 7 days  ≤48 hours old
24-19  every 30 days  ≤7 days old
18-11  every 90 days  ≤14 days old
≤10  every year  ≤30 days old
Special attention regarding specific, disease-related therapy prior to surgery
should be given to transplant candidates undergoing LT for HCC or virally-related
liver diseases.
Waiting list monitoring of hepatitis B liver transplant
candidates
The goal of antiviral therapy in HBV patients on the waiting list is to achieve viral
suppression to undetectable HBV DNA levels using sensitive tests (Figure 2)
(Cornberg 2011). Several studies have demonstrated clinical benefits under viral
suppression in patients with decompensated cirrhosis as reflected by a decrease in
CPT score, improvement of liver values and resolution of clinical complications
(Kapoor 2000, Schiff 2007, Nikolaidis 2005).
Update in Transplant Hepatology  353
Figure 2. Management of HBV patients prior to liver transplantation (LT). In all viremic
patients awaiting LT for HBV-related liver damage, efficient antiviral therapy is required.
Suppression of HBV DNA may lead to clinical stabilisation resulting in removal from the waiting
list or in a delay in the need for LT. Neg., negative, pos., positive.
A major concern of long-term lamivudine (LAM) therapy is the emergence of
mutations in the YMDD motif of the DNA polymerase which could result in clinical
decompensation in patients with liver cirrhosis (Beckebaum 2008, Beckebaum
2009). Therefore potent nucleos(t)ide analogs (entecavir [ETV] or tenofovir [TDF])
with a high resistance barrier are preferred.
Waiting list monitoring and treatment of hepatitis C liver
transplant candidates
The number of studies investigating the tolerability and efficacy of antiviral therapy
in HCV patients before LT is limited (Crippin 2002, Iacobellis 2007, Everson 2005,
Triantos 2005). Wait-listed patients who have a viral response on antiviral therapy
have a lower reinfection rate and better outcome after LT (Thomas 2003, Picciotto
2007). Thus, there is an indication for therapy with pegylated interferon (PEG-IFN)
plus ribavirin (RBV) in patients with compensated HCV cirrhosis on the waiting
list. Results from antiviral clinical studies show sustained viral response (SVR) rates
between 20% and 40% (Melero 2009). Adverse effects are frequent including
cytopenias, bacterial infections and hepatic decompensation requiring dose
reduction or treatment withdrawal. Hematopoietic growth factors have shown to
increase patient compliance and to avoid dose reductions, but it remains
questionable whether they result in higher SVR rates. Antiviral therapy in
decompensated cirrhosis and with MELD score ≥18 should be restricted to selected
cases and monitored by a transplant center.
Adjunctive treatment and staging of HCC transplant
candidates
Under MELD allocation, patients must meet the Milan criteria (one tumor ≤5 cm in
diameter or up to three tumors, all ≤3 cm) to qualify for exceptional HCC waiting
list consideration. Diagnosis of HCC is confirmed if the following criteria are met
according to the German Guidelines for Organ Transplantation
(Bundesärztekammer 2008): (1) liver biopsy-proven or (2) AFP >400 ng/mL and
hypervascular liver lesion detectable in one imaging technique (magnetic resonance
354  Hepatology 2012
imaging [MRI], spiral computed tomography [CT], angiography) or (3)
hypervascular liver lesion detectable in 2 different imaging techniques. Patients are
registered at a MELD score equivalent to a 15% probability of pretransplant death
within 3 months. Patients will receive additional MELD points equivalent to a 10%
increase in pretransplant mortality to be assigned every 3 months until these patients
receive a transplant or become unsuitable for LT due to progression of their HCC.
The listing center must enter an updated MELD score exception application in order
to receive additional MELD points. The  US National Conference on Liver
Allocation in Patients with HCC recommended the introduction of a calculated
continuous HCC priority score, that incorporates the MELD score, AFP level and
rate of tumor growth, for identifying patients with a good vs. a poor outcome
(Pomfret 2010). Further investigations are necessary to determine the survival
benefit of HCC patients considering these features.
Pre-listing, the patient should undergo a thorough assessment to rule out
extrahepatic spread and/or vascular invasion. The assessment should include CT
scan or MRI of the abdomen, pelvis and chest. We perform trimonthly routine
follow-up examinations (MRI or CT scan) of wait-listed HCC patients for early
detection of disease progression. It has been shown that waiting list drop-out rates
can be reduced by the application  of bridging therapies such as transarterial
chemoembolisation or radiofrequency ablation (Roayie 2007). Recently,
transarterial radionuclide therapies such as Yttrium-90 microsphere transarterial
radioembolisation (TARE) have been tested for bridging therapy in selected cases
(Toso 2010, Khalaf 2010). Bridging therapy should be considered in particular in
patients outside of the Milan criteria, with a likely waiting time of longer than 6
months and those within the Milan criteria with high-risk characteristics of HCC.
Sorafenib has been administered in a few studies before LT to investigate the safety
and efficacy of this oral multikinase inhibitor in the neoadjuvant setting (Fijiki
2011, Di Benedetto 2011).
Accurate discrimination of HCC patients with good and poor prognosis by
specific criteria (genomic or molecular strategies) is highly warranted to select
appropriate treatment options (Tournoux-Facon 2011, Marsh 2003, Finkelstein
2003). In patients with alcohol-related liver disease and HCC, a multidisciplinary
approach and thorough work-up of both the alcoholic and oncologic problem is
mandatory (Sotiropoulos 2008a).
Living donor liver transplantation: indications,
donor evaluation, and outcome
LDLT was introduced in 1989 with a successful series of pediatric patients
(Broelsch 1991). Adult-to-adult LDLT (ALDLT) was first performed in Asian
countries where cadaveric organ donation is rarely practiced (Sugawara 1999,
Kawasaki 1998). LDLT peaked in the US in 2001 (Qiu 2005) but therafter the
numbers declined by 30% over the following years (Vagefi 2011). A decline over
time was also observed in Europe, although LDLT activity increased in Asia (Moon
2011).
The evaluation of donors is a cost-effective although time-consuming process.
Clinical examinations, imaging studies, special examinations, biochemical
parameters, and psychosocial evaluation prior to donation varies from center to
Update in Transplant Hepatology  355
center and has been described elsewhere (Valentin-Gamazo 2004). Using Germany
as an example, the expenses for evaluation, hospital admission, surgical procedure,
and follow-up examinations of donors are paid by the recipient’s insurance. Due to
the increasing number of potential candidates and more stringent selection criteria,
rejection of potential donors has been reported in about 69-86% of cases (Valentin-Gamazo 2004, Pascher 2002). The advantages of LDLT include the feasibilty of
performing the operation when medically indicated and the short duration of cold
ischemia time.
The surgical procedures for LDLT are more technically challenging than those for
cadaver LT. In the recipient operation, bile duct reconstruction has proven to be the
most challenging part of the procedure with biliary complications ranging from 15%
to 60% (Sugawara 2005).
Regarding donor outcome, morbidity rates vary considerably in the literature
(Patel 2007, Beavers 2002). Possible complications include wound infection,
pulmonary problems, vascular thrombosis with biliary leaks, strictures, and
incisional hernia. Biliary complications are the most common postoperative
complication in LDLT and occur in up to 7% of donors (Perkins 2008, Sugawara
2005). Liver regeneration can be documented with imaging studies and confirmed
by normalization of bilirubin, liver enzymes, and synthesis parameters. LDLT
should be performed only by established transplant centres with appropriate medical
expertise.
Perioperative complications
Cardiac decompensation, respiratory failure following reperfusion, and kidney
failure in the perioperative LT setting constitutes a major challenge for the intensive
care unit. Early dialysis has been shown to be beneficial in patients with severe
acute kidney injury (AKI) (stage III according to the classification of the Acute
Kidney Injury Network) (Bellomo 2004), whereas treatment with dopamine or loop
diuretics have shown to be associated with worse outcome. Preventative strategies
of AKI include avoidance of volume depletion and maintenance of a mean arterial
pressure >65 mmHg (Saner 2011).
Despite advances in organ preservation and technical procedures, postoperative
complications due to preservation/reperfusion injury have not markedly decreased
over the past several years. Typical histological features of preservation and
reperfusion injury include centrilobular pallor and ballooning degeneration of
hepatocytes. Bile duct cells are more sensitive to reperfusion injury than
hepatocytes (Washington 2005) resulting in increased levels of bilirubin, gamma-glutamyl transpeptidase (GGT) and alkaline phosphatase (AP). Vascular
complications such as hepatic artery thrombosis (HAT) occur in 1.6-4% of patients.
Thus, Doppler exams of the hepatic artery and portal vein are frequently performed
in the early postoperative setting. HAT in the early postoperative period can be
managed with thrombectomy. Late HAT with complication of bile duct strictures is
managed by interventional endoscopic retrograde cholangiography (ERC) but
requires retransplantation in the majority of patients. Early portal vein thrombosis is
rare (<1%) but may lead to graft loss if not revascularized.
Primary non-functioning graft (PNFG) may be clinically obvious immediately
after revascularization of the allograft. Early signs of liver dysfunction include
prolonged coagulation times, elevated liver enzymes (transaminases, cholestasis

Book on hepatitis from page 338 to 345

Book on hepatitis from page 338 to 345

338  Hepatology 2012
21. Diagnosis, Prognosis & Therapy of
Hepatocellular Carcinoma
Ulrich Spengler
Classification of HCC
Tumors are classified in order to stratify patients with respect to their survival
prognosis, to select and offer optimised therapeutic options at any tumor stage. In
HCC the Barcelona Clinic Liver Cancer (BCLC) Classification has been adopted as
the international standard, which is recommended by both the American Association
for the Study of Liver Diseases (AASLD) and the European Association for the
Study of the Liver (EASL) (Table 1). The BCLC classification takes into account
several aspects of the disease: the patient’s general state of health, the severity of the
liver disease as well as the extent of tumor spread (Llovet 1999). Patients in stages
BCLC 0 and A have a considerably better prognosis than patients in advanced
stages of liver cancer (Mazzaferro 1996). Nevertheless approximately only 25% of
patients with liver cancer are diagnosed at an early stage. Both EASL and AASLD
guidelines also provide recommendations regarding which therapy is best suited to
treat patients at each stage of the BCLC classification. Unlike classification schemes
in other types of malignancies, the BCLC classification is particularly helpful
because it is entirely based on clinical parameters - molecular characteristics are not
yet able to reliably assess individual prognosis of patients with HCC.
Table 1. Barcelona Clinic Liver Cancer (BCLC) Classification.
Tumor stage  General state of health  Tumor characteristics  Child stage
0 Very early  Good  Single nodule <2 cm  A & B
A Early  Good  Single nodule <5 cm,
3 nodules <3 cm
A & B
B Intermediate  Good  Large, multiple nodules  A & B
C Advanced  Reduced  Vascular invasion,
extrahepatic secondaries
A & B
D Terminal  Severely reduced  Any form  C
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma  339
Epidemiology
HCC constitutes the sixth most frequent form of cancer worldwide, and it holds
third place concerning malignancy-related mortality (Parkin 2005). Incidence rates
of HCC are steadily rising both in Europe and the US.
Chronic hepatitis B is the major risk factor for developing HCC in Africa and
Asia, while in the US, Europe and Japan chronic hepatitis C is the leading cause of
HCC. Eighty percent of liver cancers are found in cirrhotic livers, which themselves
carry a high risk for HCC. Chronic carriers of hepatitis B virus (HBV) have a 100-fold increased risk as compared to a non-infected healthy reference population.
Recent reports from Taiwan indicate a direct link between HBV viral loads and the
risk of developing liver cancer within 10 years (Chen 2006, Iloeje 2006). The risk of
HCC is significantly increased once HBV viral loads exceed 2000 IU/ml
irrespective of the degree of hepatic inflammation. In developing countries exposure
to aflatoxins further increases this risk of HCC.
Approximately 130-170 million people are infected with the hepatitis C virus
worldwide, 20 to 30% of whom will develop liver cirrhosis, which carries a 3-5%
annual risk of ultimately progressing to liver cancer. In practical terms this means
that approximately one third of cirrhotic patients with hepatitis C will go on to
develop HCC. Unlike hepatitis B a close relationship between HCV viral loads and
the risk of developing HCC apparently does not exist (Bralet 2000). As a general
rule patients will not develop liver cancer in chronic hepatitis C before their disease
has progressed to the stage of cirrhosis. Consumption of alcohol or tobacco
enhances the risk of HCC (Donato 2002, Gelatti 2005). Beyond that, obesity (Calle
2003) and diabetes mellitus (Davila 2005) must be considered neglected but
nevertheless pivotal factors that can multiply the risk of liver cancer in western
countries resulting in 4 to 40-fold increased HCC rates among patients with chronic
viral hepatitis. Finally a genetic polymorphism in the adiponutrin gene seems to
predispose patients with alcoholic and non-alcoholic fatty liver disease to develop
cirrhosis and HCC (Fallet 2011, Nischalke 2011)
Surveillance of patients at high risk and early HCC
diagnosis
Surveillance is cost effective if the expected HCC risk exceeds 1.5% per year in
hepatitis C and 0.2% per year in hepatitis B. Surveillance has to be based on
ultrasound examination at 6-month intervals. When 3- versus 6-month surveillance
intervals were compared in a randomized study involving 1200 patients, there was
no evidence that the shorter interval improved rates of early diagnosis and
therapeutic outcomes. However, if patients with cirrhosis harbour nodular lesions,
the 3-month control interval is preferred due to the high potential of malignancy and
growth characteristics of such lesions (Yao 2006). Alpha-fetoprotein (AFP) has
insufficient sensitivity and specificity, and thus is no longer recommended for HCC
surveillance. The consistent use of ultrasound in patients with a high risk for HCC
enables us to diagnose early carcinoma in 30% of patients who then have a
reasonable chance of curative therapy.
340  Hepatology 2012
Diagnosis
The diagnosis of HCC can either be made by detecting malignantly transformed
hepatocytes in a liver biopsy or by dynamic contrast-enhanced radiological imaging
techniques demonstrating intense arterial uptake followed by wash-out of contrast in
the delayed venous phases reflecting arterialised perfusion of the tumor. Contrast-enhanced ultrasound may falsely suggest HCC in some patients with
cholangiocarcinoma, and it should not be used as the only diagnostic tool for HCC
(Vilana 2010). Nevertheless, novel diagnostic algorithms enable the diagnosis of
HCC in a cirrhotic liver without histopathology or reference to elevated tumor
markers.
The distinction between a dysplastic nodule and early HCC poses a particularly
challenging task for the pathologist. Staining for glypican 3, heat shock protein 70,
and glutamine synthetase is advised in this situation, and positivity for any two of
these three markers confirms the presence of HCC (International Working Party
2009).
Radiological diagnosis of HCC uses detection of hyper-vascularized nodular
lesions. Contrast-enhanced computed tomography (CT) or nuclear magnetic spin
resonance tomography (MRT) are considered to be equivalent diagnostic tools, and
international consensus guidelines accept a diagnosis of HCC without
histopathology if the patient with a nodular lesion in a cirrhotic liver exhibits the
following sequence of events: in the arterial phase, HCC enhances more intensely
than the surrounding liver, because arterial blood in the liver is diluted by venous
blood from the portal venous circulation, whereas HCC contains only arterial blood.
In the venous phase, HCC enhances less than the liver, reflecting the fact that HCC
does not have a portal venous blood supply and that the arterial blood flowing into
the lesion no longer contains contrast. This phenomenon is termed “washout”. In the
delayed phase “washout” persists, and occasionally HCC can only be detected in
this phase of a dynamic study. Thus, a four-phase dynamic study is needed to
reliably make a diagnosis of HCC (unenhanced, arterial, venous and delayed venous
phases). Contrast enhancement in the early arterial phase, which disappears in the
late venous phase, is highly specific for HCC.
The current recommendations for the diagnosis of HCC are summarized in Figure
1. For lesions smaller than 1 cm detailed investigation is not recommended because
most lesions will represent regenerative nodules rather than HCC. However, close
follow-up in 3-month intervals should be offered using the same imaging technique
that detected the lesion in the first place.
For lesions larger than 1 cm, either dynamic MRI or multidetector CT scans
should be performed. If findings are characteristic for HCC as described above, a
firm diagnosis of HCC can be made and no further studies are necessary. If the
findings are not typical for HCC, then the alternative dynamic imaging technique
should be applied. If this supplementary radiological investigation yields typical
features, the diagnosis of HCC is confirmed. Otherwise, a guided biopsy of the
lesion should be performed. Contrast-enhanced CT and MRI exhibit excellent
diagnostic sensitivity and specificity if the rules regarding early hypervascularity
and washout are strictly applied. The presence of arterial hypervascularisation alone
is not sufficient for a diagnosis of HCC, which requires the presence of venous
washout as an essential second diagnostic component. In equivocal situations the
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma  341
diagnosis must be clarified by biopsies, which may have to be repeated within a
short period of time.
Figure 1. Diagnostic algorithm for the diagnosis of hepatocellular carcinoma depending
on tumor size.
Stage-adapted therapy for liver cancer
Patients with early HCC have excellent chances for curative cancer treatment. They
can achieve 5-year survival rates of 50-70% by surgical resection, liver
transplantation or percutaneous ablative procedures. With more advanced HCC,
local transarterial embolisation and multikinase inhibitor therapy can still prolong
life. Figure 2 gives a summary and concise overview of stage-adapted therapy for
hepatocellular carcinoma.
Potentially curative therapy in BCLC stages 0-A
Surgical resection constitutes the backbone of curative treatment in patients with
early HCC. It is the treatment of choice in patients with localised tumor spread and
small-sized cancers and tumors in a non-cirrhotic liver (evidence grade IIIA).
Prognosis after surgical resection is excellent, if the tumor is not larger than 2 cm in
diameter (5-year survival rates 70-90% with rates of tumor recurrence below 10%).
Excluding patients with poor liver function keeps perioperative mortality below 5%.
Favourable criteria for surgical resection comprise single nodules less than 5 cm in
size or a maximum of 3 nodules in a single liver lobe. Patients should be carefully
selected to diminish the risk of postoperative liver failure. Patients should have only
moderately impaired liver function (cirrhosis stage Child’s A), should not have
342  Hepatology 2012
portal hypertension (hepatic-portal-vein pressure gradient >10 mm Hg, presence of
esophageal varices or splenomegaly together with reduced  platelet counts
<100,000/µl) and should have a serum bilirubin in the normal range. Right
hepatectomy in cirrhotic patients has a higher risk of inducing hepatic
decompensation than left hepatectomy.
Liver transplantation is an alternative therapeutic option, if the liver cancer
cannot be cured by local resection due to anatomical reasons, if residual liver
function after resection is anticipated to be poor, or if there is multi-nodular tumor
spread into both liver lobes (evidence grade IIIA). Commonly patients with HCC
are selected for liver transplant according to the so-called Milan criteria, i.e., the
patient has a single nodule of less than 5 cm in diameter or at most 3 nodules, none
of which exceeds 3 cm in diameter (Mazzaferro 1996). Milan criteria patients
usually achieve survival rates of 80% and 70% one and five years after liver
transplantation. However, it has been demonstrated that selected patients with more
extensive stages of liver cancer can be transplanted with reasonable long-term
outcomes (Yao 2001). Selection of patients according to the so-called San Francisco
criteria comprises solitary large nodules up to 6.5 cm as well as multi-nodular HCC
with a maximum of 3 nodules, each of which must be smaller than 4.5 cm with a
total sum of all nodule diameters below 8 cm. Patients who remain within these
extended selection criteria can still reach 70-80% five-year survival rates after liver
transplantation. However, there is very limited data to support extending selection
criteria for liver transplantation (Pomfret 2010).
A central issue in liver transplantation is the process of fair organ allocation.
Shortage of donor organs is particularly critical in patients with liver cancer,
because the tumor will continue to expand while the patient is on the waiting list,
and can ultimately reach a stage that makes liver transplantation a futile option. It
has been estimated that after one year on the waiting list approximately 40% of
patients can no longer be cured by liver transplant (Poon 2007). In the
Eurotransplant registry donor livers are allocated to patients according to their
MELD scores. To circumvent the problem that patients with early HCC who are
eligible for liver transplantation have rather low MELD scores, Eurotransplant
accepts the diagnosis of HCC within the Milan criteria as a so-called standard
exemption, allocating additional points on top of the patient’s lab-MELD score in an
incremental time-dependent fashion.
Most transplant centres treat liver cancers locally while the patient is on the
waiting list, mostly using transarterial chemoembolisation. This strategy probably
also facilitates patient selection for liver transplantation, because those with stable
disease after chemoembolisation achieve a greater than 90% five-year survival rate
after liver transplantation, while only 35% of patients in the group with progressive
tumor expansion survive five years post-liver transplantation (Otto 2006).
Radiofrequency ablation can also cure HCC that is limited to a distinct region of
the liver and is especially applied in older patients or patients with significant co-morbidity. A cohort study on percutaneous radiofrequency ablation demonstrated
that complete ablation of lesions smaller than 2 cm is possible in more than 90% of
patients with local recurrence in less than 1% (Livraghi 2008). In larger tumors five-year survival rates are somewhat lower, at 70-80% for nodules less than 3 cm in
diameter, and 50% for tumors between 3 and 5 cm (Lopez 2006). A cumulative
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma  343
meta-analysis has suggested that survival is better after radio frequency ablation
than after ethanol injection (Cho 2009).
Adjuvant therapy, in the context of resection, liver transplantation or local-ablative procedures, does seem to offer additional benefits. Thus far, antiviral
treatment of hepatitis B with nucleos(t)ide analogs remains the single approved
treatment after removal or local destruction of HCC.
Tumor recurrence is frequent after putatively curative treatment of HCC. The
best predictors of HCC recurrence are microvascular invasion and/or additional
tumor sites besides the primary lesion. There is no effective adjuvant therapy to
reduce recurrence rates. However, it is noteworthy that even the most modern CT
and MRT scanner still underestimate the extent of vascular invasion in 30% of
patients with early HCC. Treatment of recurrence is a poorly studied area. Solitary
nodules might be amenable to repeat resection, but HCC recurrence is frequently
multifocal owing to intrahepatic dissemination of the tumor. Some patients with
HCC recurrence after primary resection might benefit from salvage transplantation.
Palliative therapy in BCLC stages B and C
Palliative treatment remains the only therapeutic option for patients with advanced
stages of liver cancer that cannot be controlled by local therapy.
Arterial chemoembolisation is the most frequent palliative intervention offered
to patients with HCC and is considered for patients with non-surgical HCC that are
also not suited for percutaneous ablation and do not have extrahepatic tumor spread.
HCC exhibits intense neoangiogenic activity, so that even well-differentiated HCCs
become highly dependent on arterial blood supply. Thus, hepatic arterial obstruction
is performed either by angiographic transarterial embolisation or transarterial
chemoembolisation. Usually lipiodol combined with an embolising agent such as
gelatin or microspheres is mixed with cytostatic drugs and applied to the liver via an
intra-arterial catheter. Suitable cytotoxic agents are doxorubicin, mitomycin and cis-platinum, but the optimal combination of drugs and treatment schedules has not
been established. In randomised studies demonstrating a benefit of
chemoembolisation, doxorubicin or cis-platinum were administered in 3-4
angiographic sessions per year. Chemoembolisation carries the risk of ischemic
damage to the liver, potentially leading to fulminant liver failure. To minimize this
risk chemoembolisation should be offered only to patients with good residual
hepatic function, who have asymptomatic multi-nodular liver cancer without
vascular invasion or extrahepatic tumor spread. Vice versa patients with
decompensated liver disease (liver cirrhosis, Child’s B or C) or imminent hepatic
failure should not undergo chemoembolisation. The side effects of interarterial
chemoembolisation are the same as for systemic chemotherapy and comprise
nausea, vomiting, bone marrow depression, alopecia and renal damage. As a
complication of hepatic ischemia, more than 50% of patients also develop a so-called post-embolisation syndrome with fever, abdominal pain and a moderate
degree of ileus. Fasting and fluid replacement is mandatory, but the post-embolisation syndrome is usually self-limited and patients can be discharged safely
after 2 days.
Objective response rates vary between 16% and 60%, but less than 2% of patients
achieve complete remission. Residual tumor cells recover their blood supply and the
tumors continue to grow. Thus, repeated therapy is needed.
344  Hepatology 2012
Chemoembolisation is currently the only palliative treatment demonstrated to
significantly improve patient survival in controlled studies (Llovet 2002). However,
it cannot be offered to patients with portal vein thrombosis or HCC-induced portal
vein occlusion.
Radiotherapy  applyingYttrium-90 microspheres  has been developed as a
novel alternative palliative treatment of liver cancer with unexpectedly impressive
anti-tumoral activity in selected individual cases (Sangro 2006, Jacobs 2007, Salem
2006, Liu 2004). Of note, unlike chemoembolisation, some types of microspheres
do not occlude the blood vessels and can also be applied in the presence of portal
vein thrombosis. Radioembolisation has been shown to induce tumor necrosis.
However, there are no data comparing its efficacy to other palliative treatment
modalities.
Molecular-targeted therapeutic strategies  offer new hope for effective
palliative therapy in liver cancer. Sorafenib (Nexavar®) is an orally available multi-kinase inhibitor acting on several distinct tyrosine kinases (VEGFR2, PDGFR, c-kit
receptor) as well on serine/threonine kinases (b-Raf and p38). Thus, by inhibiting
angiogenesis and cellular proliferation, sorafenib can block two of the major
signalling pathways of HCC expansion. In a Phase III study (the SHARP trial)
involving 602 patients, sorafenib 400 mg BID was well tolerated and associated
with improved survival in 44% of patients resulting in 3 months extended survival
in treated patients (10.7 months in the sorafenib arm versus 7.9 months in the
control arm). Diarrhea, weight loss, hand-foot syndrome and hypophosphatemia
were the most important side effects in patients on sorafenib. The efficacy of
sorafenib has been confirmed in a second randomized placebo-controlled trial,
mostly involving patients with HBV-associated HCC (Cheng 2009). Sorafenib has
established itself as first option in patients with HCC who can no longer be treated
with potentially more effective local therapies. The SHARP trial largely included
patients with preserved liver function. Although the pharmacologic profile is
favourable, data in Child-Pugh class B patients are scarce (Abou Alfa 2011). It has
been demonstrated that sorafenib can be safely combined with chemoembolisation
therapy (Pawlik 2011), although it remains unclear if this strategy actually offers
any clinical benefit to the patients. Finally, further antagonists targeting VEGFR,
EGFR, ERBB2, Akt/mTor or Wnt/β-catenin signal transmission pathways are
currently under evaluation in Phase II studies.
Systemic chemotherapy  has been proven repeatedly not to offer survival
benefits, whether given as a single agent or as part of combination chemotherapy
(Llovet 2003). Likewise, anti-hormonal therapy with tamoxifen or octreotide has
not provided improved patient survival when studied under controlled conditions
(Gallo 2006, Yuen 2002).
Diagnosis, Prognosis & Therapy of Hepatocellular Carcinoma  345
Figure 2. Overview of stage-adapted therapy of liver cancer relative to the BLCL criteria.
Prophylaxis of liver cancer
Despite conspicuous progress concerning the diagnosis and therapy of HCC, its
prognosis has not improved very much over time. Thus, prophylactic measures are
of pivotal importance. Vaccination against HBV, as is now recommended by many
national vaccination councils, has been proven in Taiwan to markedly reduce HBV
infection rates along with the incidence of HCC as a complication of chronic
hepatitis B in later life (Lok 2004).
Patients with chronic HBV and patients with chronic hepatitis C should be offered
antiviral therapy as effective secondary prophylaxis of HCC. Although HBe-antigen-positive (van Zonneveld 2004) and HBe-antigen-negative patients with
chronic hepatitis B showed reduced incidence rates of HCC when successfully
treated with interferon (Papatheoridis 2001,  Brunetto 2002,  Lampertico 2003),
antiviral therapy with nucleos(t)side analogs seems to reduce the risk of HCC less
convincingly (Papatheoridis 2010, Papatheoridis 2011). Also several meta-analyses
suggest that successful interferon therapy will reduce the risk of HCC in chronic
hepatitis C (Camma 2001, Paptheoridis 2001a, Veldt 2004). However, patients who
have cirrhosis prior to starting antiviral therapy should be maintained on close HCC
surveillance programs, since the risk of developing liver cancer remains high in
these patients even after sustained virologic elimination is achieved (Yu 2006).

Book on hepatitis from page 328 to 337

Book on hepatitis from page 328 to 337

328  Hepatology 2012
patient procedures, since >90% of complications are detected within the first 24
hours (Piccinino 1986).
Transjugular puncture of the liver via cannulation of a hepatic vein is an
alternative, which can be performed in patients with severe coagulation deficiencies.
It is resource intensive and carries a risk of intrahepatic hemorrhage or capsule
perforation with intraabdominal bleeding. Complication rates are lower as compared
to percutaneous biopsies and range from 2.5% (Mammen 2008) to 6.5% with a
reported mortality rate of up to 0.09% in high-risk groups (Kalambokis 2007).
However, the quality of specimens from transjugular biopsies may be lower because
of the higher fragmentation of specimens and the lower numbers of portal fields in
transjugular biopsies (Cholongitas 2006).
Laparoscopy and mini-laparoscopy are even more invasive procedures  for
obtaining liver biopsies. A recent randomized trial showed a higher detection rate of
liver cirrhosis as compared to percutaneous biopsies with lower complication rates
for laparoscopy (Denzer 2007). No data is available for detection of lesser fibrosis
stages. Thus, we recommend this procedure only in selected cases if the results will
have an impact on the clinical management of the patient (Helmreich-Becker 2003).
The quality and reliability of fibrosis staging via histopathological assessment of
liver biopsy specimens depends largely on the size of the specimen and the number
of portal fields. The biopsy should be 20-25 mm long and more than 11 portal tracts
should be visible (Bedossa 2003, Cholongitas 2006, Rousselet 2005). However, in
daily practice these requirements may not be easy to achieve; and even if a large
enough biopsy is acquired, the specimen only reflects about 1/50,000 of the whole
liver. Thus, liver biopsies are particularly prone to sampling errors and may – like
non-invasive markers – have difficulties in discriminating between adjacent stages
of fibrosis (i.e., F1 vs. F2 or F2 vs. F3). Recent studies report up to one stage
difference between specimens from the right and the left lobe in up to 38% of
biopsies (Regev 2002, Siddique 2003). Discrepancies of more than one stage are
rare (Regev 2002,  Siddique 2003,  Skripenova 2007). Intra-  and inter-observer
variability may be unaffected by specimen sizes but can lead to discrepancies in up
to 20% of cases, even if one stage difference between estimates is accepted
(Gronbaek 2002, Petz 2003). Standardized automatic staging via image analysis
may improve interobserver variability (Hui 2004, Calvaruso 2009).
All staging systems for liver fibrosis are based on the definition of categorical
stages of liver fibrosis that describe the increase of deposition of collagen and the
progressive destruction of liver architecture ranging from no fibrosis to cirrhosis
with a variable number of intermediate stages (Table 1). The use of categories
decreases interobserver variation, but also results in a loss of information that may
be covered by more detailed scoring systems (Standish 2006).
Whereas the METAVIR score is considered best in HCV fibrosis, there is a wide
variability in the use of other staging systems in patients with chronic viral hepatitis.
In Germany, current guidelines recommend the staging system defined by Desmet
& Scheuer (Table 1) (Batts 1995,  Desmet 1994,  Ishak 1995,  Knodell 1981,
Schirmacher 2004, French Cooperative Study Group 1994).
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  329
Table 1. Commonly used liver fibrosis staging scores.
Staging System  Fibrosis stages  Remark
METAVIR Score  F0, F1, F2, F3, F4 Best evaluated in
HCV fibrosis
(The French METAVIR
Cooperative Study Group
1994)
Knodell Score  F0, F1, F3, F4  No intermediate
stage
(Knodell 1981)
Desmet
& Scheuer
Analogous to
METAVIR
Recommended by
German
guidelines for the
assessment of
liver fibrosis
(Desmet 1994, Schirmacher
2004)
Batts & Ludwig  Similar to METAVIR    (Batts 1995)
Ishak Score  F0, F1, F2, F3, F4,
F5, F6
(Ishak 1995)
Surrogate markers of liver fibrosis in chronic viral
hepatitis
Liver fibrosis develops as a continuous process rather than in a stepwise manner.
Thus, so-called surrogate markers, which are also continuous variables, may provide
more precise information. Surrogate makers can be subdivided into direct and
indirect markers. Direct markers reflect changes in the content of extracellular
matrix proteins (such as collagen) in the liver. In contrast, indirect markers reflect
alterations in hepatic function, increase in portal hypertension with subsequent
splenic enlargement, and/or grade of hepatic inflammation that may correlate with
liver fibrosis stage (Table 2)  (see http://hepatologytextbook.com/link.php?id=7).
Direct and indirect markers may be used alone or -  more commonly -  in
combination (“composite scores”). The calculation of such scores can be simple or
based on complicated formulas (e.g., Fibrotest/Fibrosure) (Table 2). Most studies of
non-invasive markers were performed in HCV patients, while studies in HBV or
coinfected cohorts are sparse (Pinzani 2008). Primary endpoints of the studies that
evaluated surrogate markers vary from discrimination of no fibrosis and cirrhosis to
the determination  of fibrosis stages. However, for the clinical management of
patients with chronic viral hepatitis both are needed. Whereas the former is needed
to identify patients in need of urgent treatment, the latter may separate those patients
with an indication for antiviral treatment due to significant fibrosis from those with
no or minor fibrosis in whom treatment may be postponed.
From the whole range of surrogate markers only a few are in clinical use. The
simple APRI score has been widely studied in HCV and HBV  as well as in
coinfected patients (Cacoub 2008, Lebensztejn 2005, Vallet-Pichard 2008, Wai
2006). A recent comprehensive meta-analysis of the performance of the APRI test
showed that its major strength is the exclusion of significant fibrosis, defined as F2-F4, or cirrhosis with cut-offs of 0.5 and 1.0, respectively. However, the authors
conclude that using this marker alone, only about one third of all biopsies can be
avoided. Importantly, the test performance varied with the quantity of advanced
fibrosis in the different patient groups (Shaheen 2007, Shaheen 2008). Fibrotest has
also achieved some clinical significance. However, this test may not be available for
all patients. Recent meta-analyses of the predictive performance of Fibrotest
330  Hepatology 2012
summarize that the reliability for the detection of advanced fibrosis or cirrhosis is
adequate for clinical practice, and a cut-off of 0.6 has been suggested (Poynard
2007, Shaheen 2008, Shaheen 2007). Of note, the reliability for the detection of
earlier fibrosis stages appears to be relatively low (Poynard 2007, Shaheen 2008). In
summary, surrogate markers may support the clinical decision making process, but a
single surrogate marker or score cannot replace the liver biopsy. On the other hand,
attempts have been made to combine different surrogate markers and biopsy in
clinical decision algorithms that aim to reduce the need for liver punctures (Table
2). Increasingly efforts are made to combine surrogate markers with transient
elastography, and it seems that some progress can be expected in precise prediction
of different fibrosis stages, which may eventually replace liver biopsy for fibrosis
staging.
Transient elastography
Transient elastography (TE) is a non-invasive technique to assess liver fibrosis
(Sandrin 1999). TE allows the assessment of liver fibrosis by calculating the
velocity of a low-frequency transient shear wave produced by a mechanical probe
that is placed directly on the skin of the patient. The velocity of the wave that
penetrates the liver tissue depends on the actual stiffness of the liver, which in turn
correlates with the extent of liver fibrosis. In practice, a probe is placed in an
intercostal space at a position that is comparable to the position for standard liver
biopsy. Ten successful measurements are usually necessary for the assessment of
liver stiffness. This can be done in less than 5 minutes. At present TE machines are
exclusively available from Echosense (FibroScan
®
). Liver stiffness is expressed in
kilo Pascal (kPa). The method is easy to learn, quick, results are available
immediately, and a technical assistant can perform the procedure. TE displays
robust intra- and inter-observer variability (Fraquelli 2007) and may be applied in
children and adults (de Ledinghen 2007). Recently a special S probe for testing
children and patients with small intercostals spaces was introduced, and normal
reference values for different ages were defined (Engelmann 2011).
Evaluation of liver stiffness in subjects without apparent liver disease shows that
liver stiffness is influenced by gender and body mass index (BMI). In general, liver
stiffness is higher in men than in women (5.81±1.54 vs. 5.23±1.59 kPa) (Roulot
2008). Interestingly, TE may be used as a screening tool for the general population
to identify patients with unrecognized liver disease (Roulot 2011).
It is important to note that the applicability of TE is limited to relatively lean
patients (BMI <28 kg/m
2
), patients without ascites, and “cooperative” patients. A
special probe for obese patients has recently broadened the applicability of TE and
is recommended for patients with a skin-caspular distance of >2.5 cm but below 3.5
cm (Myers 2011). In addition, TE is hampered in those with acute liver injury such
as acute viral or alcoholic hepatitis, or chronic viral hepatitis flares, which may lead
to an overestimation of liver fibrosis (Arena 2008, Coco 2007, Sagir 2008). Unlike
liver histology, no published data is available on the variability (“sampling error”)
of TE results. TE correlates well with other surrogate markers of liver fibrosis such
as APRI and FIB-4 (Vidovic 2010). In patients with chronic liver disease eligible
for TE, liver stiffness values correlate well with the stage of fibrosis, irrespective of
the underlying disease etiology. TE has been evaluated in patients with chronic viral
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  331
hepatitis, PBC, PSC, and NASH. Due to high acceptance by patients, it can easily
be used to monitor progression or regression of fibrosis in patients under
observation or on therapy (Wilson 2006, Wong 2011). TE has been evaluated for
the detection of liver fibrosis in patients with acute and chronic viral hepatitis and
has also been positively evaluated for HIV/HCV-coinfected patients and in patients
with HCV reccurrence post-transplantation (Carrion 2006,  de Ledinghen 2006,
Maida 2007). In chronic viral hepatitis, it is unknown whether there is a difference
in TE results between patients with chronic HBV, HCV, and/or HIV/HCV-coinfected patients.
In some clinical situations, e.g., older patients or patients with risk factors for
therapy, a positive decision for treatment of chronic hepatitis B and C is guided by
the diagnosis of significant fibrosis. The presence of F2 fibrosis indicates significant
liver fibrosis, which justifies treatment according to treatment guidelines for chronic
hepatitis B, C and coinfected patients (Sarrazin 2010).
Recent studies comparing TE with liver biopsy demonstrate both high sensitivity
and specificity for the detection of advanced fibrosis and cirrhosis. However, TE
performance is less reliable for the detection of fibrosis stages ≥2 as compared to
more advanced stages of liver fibrosis (sensitivity 56-67%), resulting in moderate
negative predictive values. Thus, assessment of liver fibrosis by TE alone may
result in the underestimation of liver fibrosis in some patients. Vice versa, if TE
predicts significant fibrosis, a biopsy will not be necessary. One drawback in
clinical practice is that the different TE studies suggest slightly different cut-off
values (Table 3). A recent meta-analysis that evaluated the predictive performance
of TE in patients with chronic liver disease suggested that the optimal cut-off value
for the diagnosis of significant fibrosis is 7.65 kPa and 13.01 kPa for cirrhosis
(Friedrich-Rust 2008). This cut-off proved to be robust, especially in patients with
chronic HCV infection.
In addition to the assessment of liver fibrosis stages, TE may also be used to
predict the presence of portal hypertension and thus the need to evaluate the patient
for the presence of esophageal varices (Rockey 2008). Whether TE is reliable
enough to predict the stage of cirrhosis is still debatable and needs further studies
(Foucher 2006).
Increasing knowledge from studies on transient elastography also revealed a
number of conditions that may produce false positive results the user should be
aware of. These conditions include acute and chronic cardiac failure, valsalva
maneuver, hepatitis flair, pulmonary hypertension, amyloidosis, cholestasis,
pregnancy and steatosis, with the latter being more relevant for HCV than for HBV-infected patients (Fraquelli 2007, Arena 2008).
Another relevant artifact is the examination of a patient within 2 hours after a
meal, which may increase resistance by up to 2 kPa (Mederacke 2009).
The spectrum of interpretation of elevated TE results has been broadened
recently. For instance, a cut-off value of >25 kPa has been associated with >45-fold
increased risk to develop HCC in viral hepatitis. However, the risk seems  to
increase in a linear fashion starting from a cut-off of 10 kPa (Fung 2011, Masuzaki
2009). Furthermore, TE values >21.1 are associated with portal hypertension as well
as the risk of portal hypertension-related complications and suggest endoscopy to
confirm or exclude esophageal varices and to initiate or decline the need for primary
prophylaxis with propranolol (Castera 2011, Robic 2011).
332  Hepatology 2012
Table 3. Cut-off values for transient elastography in different study populations.
Study  Population  Cut off (kPa)
F=0  F≥1  F≥2  F≥3  F=4
Castera  HCV
N=183
n.d.  n.d.  7.1
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
9.5
Se: 0.73
Sp: 0.91
PPV: 0.87
NPV: 0.81
12.5
Se: 0.87
Sp: 0.91
PPV: 0.77
NPV: 0.97
Ziol  HCV
N=327
n.d.  n.d.  8.8  9.6  14.6
n.d.  n.d.
Se: 0.56
Sp: 0.91
PPV: 0.88
NPV: 0.56
Se: 0.86
Sp: 0.85
PPV: 0.71
NPV: 0.93
Se: 0.86
Sp: 0.96
PPV: 0.78
NPV: 0.97
Foucher  HCV / HBV
N=711
n.d.  n.d.  7.2
Se: 0.64
Sp: 0.85
PPV: 0.90
NPV: 0.52
12.5
Se: 0.65
Sp: 0.95
PPV: 0.90
NPV: 0.80
17.6
Se: 0.77
Sp: 0.97
PPV: 0.91
NPV: 0.92
Ogawa  HCV / HBV
N=229
3.5  6.4  9.5
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
11.4
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
15.4
Se: 0.67
Sp: 0.95
PPV: .95
NPV: .48
6.3  6.7  9.1
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
13.7
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
26.4
Se: 0.67
Sp: 0.95
PPV: 0.95
NPV: 0.48
Arena  HCV
N=150
7.8
Se: 0.83
Sp: 0.82
PPV: 0.83
NPV: 0.79
10.8
Se: 0.91
Sp: 0.94
PPV: 0.89
NPV: 0.95
14.8
Se: 0.94
Sp: 0.92
PPV: 0.73
NPV: 0.98
De
Ledinghen
HIV/HCV
N=72
n.d.  n.d.  4.5
Se: 0.93
Sp: 0.18
PPV: n.d.
NPV: n.d.
n.d.  11.8
Se: 1.0
Sp: 0.93
PPV: n.d.
NPV: n.d.
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  333
Other imaging techniques for the
assessment of liver fibrosis
A number of different imaging techniques such as conventional ultrasound, real-time elastography, acoustic radiation force imaging (ARFI), portal venous transit
time, NMR imaging and CT have been used for the assessment of liver fibrosis.
None of these methods has yet achieved an overall clinical acceptance regarding the
detection of early liver fibrosis, either due to low sensitivity and/or specificity, or
high costs. The most promising candidate for everyday usability may be the ARFI
technique that has been integrated in high-end ultrasound machines. This technique
allows the measurement of liver fibrosis in an area of interest rather than a global
assessment as with the transient elastography method. This may be an advantage as
different regions of the liver may be studied separately but may – like histology –
also be a source of “sampling bias” and low reproducability. Compared to transient
elastography the available data from large populations is sparse. A recent meta-analysis managed to combine data from 518 individuals. Nevertheless, in this
analysis the overall accuracy for the prediction of fibrosis stage ≥F2, ≥F3 and
cirrhosis as determined by ROC analysis were 0.87, 0.91. 0.93, respectively
(Friedrich-Rust 2012).
Clinical decision algorithms
Until now, no non-invasive marker for the staging of liver fibrosis has been able to
replace the liver histology as the gold standard. This is largely due to the fact that
outcome studies with clear endpoints like mortality have not been performed and
that a clear differentiation of fibrosis stage by non-invasive strategies has been
unreliable. But the advantages of these non-invasive tests in comparison to liver
biopsy are striking. In order to overcome test limitations and to benefit from their
specific advantages, a frequent strategy is to combine different noninvasive tests,
thereby using liver biopsy only in case of doubt. However, former algorithms vary
greatly in performance and acceptance. Whereas some authors have calculated a
reduction in liver biopsies of 30%, others have estimated reductions of up to 80%
(Leroy 2007, Sebastiani 2004, Sebastiani 2006, Sebastiani 2007). New strategies
with sophisticated algorithms may overcome all these limitations and combination
of TE with FibroMeter achieved results that may give detailed and reliable
information on liver fibrosis stage without any need for histology. However, only
one study from France has described this method, which needs to be cross-validated
by independent groups (Boursier 2011a, Boursier 2011b).
334  Hepatology 2012
Figure 1. Potential clinical decision algorithm for safer liver biopsies in patients
with chronic viral hepatitis.
Summary
Non-invasive tests have not replaced liver biopsies today, but smart combinations of
non-invasive tools can save many patients from the more invasive procedure.
Whatever the current standard of care, the patient should be informed about the non-invasive tests, their applicability and their limitations. The decision to biopsy should
ultimately be made together with the informed patient.
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Book on hepatitis from page 322 to 327

Book on hepatitis from page 322 to 327

2005).
322  Hepatology 2012
Cirrhosis
Higher rates of cirrhosis have been demonstrated in HBV/HCV-coinfected patients.
In comparison to patients with HBV monoinfection, higher rates of cirrhosis (44%
vs. 21%) and decompensated liver disease (24% vs. 6%) were demonstrated in
coinfected patients (Fong 1991). Compared to HCV monoinfected patients a higher
rate of cirrhosis (95% vs. 49%) and more decompensated liver disease (Child-Pugh
class C 37% vs. 0%) were found in HBV/HCV-coinfected patients (Mohamed Ael
1997).
Hepatocellular carcinoma
In many studies coinfection with HBV and HCV has been shown to be associated
with an increased risk of HCC development (Kaklamani 1991, Mohamed Ael 1997).
In one longitudinal study incidence of HCC was 6.4 per person years in
HCV/HBV-coinfected patients compared to 2.0 in HBV and 3.7 in HCV
monoinfection. The cumulative risk of developing HCC after 10 years was 45% in
HBV/HCV-coinfected patients compared to 16% in HBV-  and 28% in HCV-monoinfected patients (Chiaramonte 1999). HBV/HCV-coinfected patients should
undergo a screening routine for HCC with liver ultrasound and α-fetoprotein levels
in serum at least every 6 months.
Treatment of HBV and HCV coinfection
Currently there are no well-established treatment guidelines for HBV/HCV-coinfected patients. Generally, treatment guidelines for monoinfected patients
should be applied to coinfected patients. In patients with HBV/HCV coinfection
treatment should be initiated when inclusion criteria for standard treatment
guidelines of HBV and HCV monoinfection are met (see Chapter 9 on therapy of
HBV and Chapter 13 on treatment of HCV). As with HBV and HCV
monoinfection, treatment of coinfected patients should be started in patients with
active chronic hepatitis or cirrhosis before liver decompensation occurs. Due to the
variety of virological profiles in HBV/HCV coinfection it is important to assess the
dominant virus prior to initiating therapy.
Due to loss of viral suppression from the successfully treated dominant virus,
deterioration of liver disease has been reported (Yalcin 2003), thus caution must be
exercised upon initiation of therapy.
In coinfected patients with dominance of HCV infection, treatment with IFN
(Weltman 1995, Villa 2001, Utili 1999) and IFN plus ribavirin (Chuang 2005, Hung
2005, Liu 2003) has been well-studied and proven effective. However, more recent
studies show that combination therapy with pegylated IFN and ribavirin are even
more efficient in inducing virological results (see Table 2).
HCV RNA response was similar to results seen in HCV monoinfection with up to
83% in HCV genotype 2/3 and 72% in HCV genotype 1 achieving sustained
virological response (Liu 2009). In one small study including 17 HCV/HBV-coinfected patients these successful results were not confirmed (Senturk 2008).
Importantly, HBV replication may become detectable in up to 36% of patients with
undetectable pretreatment HBV DNA levels (Potthoff 2009, Liu 2009). Thus, close
monitoring of both viruses is recommended during and after combination therapy.
HBV/HCV Coinfection  323
Table 2. Peg-IFN plus ribavirin treatment trials in HBV/HCV-coinfected patients.
Patients (n)  HCV SVR (%) HBV DNA
negative (%)
HBsAg loss
(%)
HBV
reactivation #
(%)
Reference
19  74  33  0  31  Potthoff, 2008
161  72*, 83**   56  11  35  Liu, 2009
17  6  na  na  na  Senturk, 2008
50  40*, 75**  100  0  24  Yu, 2009
*HCV GT1,** HCV GT2/3, na=not applicable, # HBV DNA negative pretreatment
In patients with dominance of HBV disease IFN +/- HBV polymerase inhibitors
are an option, although until now there is only data for lamivudine in a small cohort
of 8 HBV (HBeAg and HBV DNA-pos) and HCV (HCV RNA-pos) coinfected
patients (Marrone 2004). In this study, clearance of HBeAg was found in 3/8, two
patients showing HBeAg seroconversion, and clearance of HBV DNA was observed
in 3/8 at the end of therapy. HBV DNA became detectable again in 2 patients at the
end of follow-up. HCV clearance was observed in 50%. Based on these
observations nucleos(t)ide analogs such as tenofovir, adefovir, entecavir  and
telbivudine showing a higher genetic barrier in combination with PEG-IFN are a
possible treatment option. However, studies are needed to estimate the treatment
value of these newer drugs in this clinical scenario.
Conclusion
Coinfection with HBV and HCV is not uncommon, especially within areas of high
hepatitis B prevalence. HBV/HCV coinfection is a challenge for clinicians due to
the complex interaction of HBV and HCV, and the propensity for developing severe
liver disease. No treatment standard has been established for HBV/HCV-coinfected
patients. Treatment decisions must be made based upon identification of the
dominant virus. Combination therapy of PEG-IFN plus ribavirin has been shown to
be highly effective in inducing virological response of HCV in patients with
HBV/HCV coinfection. The availability of direct acting antivirals against HCV will
open new pathways in treatment, which should be replicated in HBV/HCV
coinfection. However, to date, in coinfection of HBV/HCV no treatment experience
with these new agents has been reported. Finally, caution must be exercised in
treating coinfected patients, as flares of the untreated virus may occur.
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326  Hepatology 2012
20. Assessment of Hepatic Fibrosis in
Chronic Viral Hepatitis
Frank Grünhage and Frank Lammert
Introduction
Non-invasive methods for the assessment of liver fibrosis are increasingly being
used versus invasive liver biopsy thanks to patient acceptance and the low but ever-present morbidity of biopsies. Non-invasive tests should be able to discriminate
between non-significant (stages F0-F1) and significant (stages ≥F2) fibrosis to help
either delay or initiate antiviral treatment. In addition, non-invasive markers should
be able to reliably predict liver cirrhosis in order to initiate further diagnostics to
exlude portal hypertension and to initiate surveillance strategies with progressive
fibrosis. Non-invasive strategies are also warranted for monitoring the disease while
on therapy and ideally document a regression of fibrosis in the long term.
Yet, despite recent advances in the use of surrogate markers and the development
of new technical developments such as elastography, liver histology remains the
gold standard for fibrosis staging (Goodman 2007). Currently an intense debate
regarding non-invasive tests is going on and a number of participants of this
discussion have suggested to not accept the claim of liver histology as the gold
standard and define the role of histology as the best available standard (Bedossa
2009). Nevertheless, until today most experts agree that non-invasive techniques
will not replace liver biopsies completely although they will help reduce the number
of biopsies required (Leroy 2007,  Pinzani 2005,  Sebastiani 2006). While non-invasive fibrosis tests are suitable for the diagnosis of liver cirrhosis, they have been
questioned for clinical practice as they lack the potential to discriminate the stages
of fibrosis. This specific dogma is now being questioned, and entirely non-invasive
algorithms have been developed that include a differentiation of the stages of
fibrosis (Boursier 2011a, Boursier 2011b).
Assessment of Hepatic Fibrosis in Chronic Viral Hepatitis  327
Mechanisms of liver fibrosis in chronic viral
hepatitis
Liver fibrosis is characterised by the loss of hepatocytes, destruction of hepatic
(micro)architecture, proliferation of hepatic (myo)fibroblasts, and excess deposition
of extracellular matrix components (Friedman 2008). Endstage liver fibrosis
(cirrhosis) may include insufficient detoxification, hepatocellular carcinoma, portal
hypertension, renal and pulmonary failure, and is associated with excess mortality.
In chronic viral hepatitis, fibrosis develops as a consequence of the host
immunological response. This immunological response activates antiviral defence
mechanisms that aim to clear infected hepatocytes. The mechanisms underlying
fibrogenesis in HBV or HCV are complex (Friedman 2007).
A key feature of hepatic fibrosis is the activation and proliferation of hepatic
stellate cells. Quiescent hepatic stellate cells store vitamin A and reside in the
subendothelial space of Disse. Chronic liver injury leads to activation of these cells,
which become contractile, produce extracellular matrix components and secrete pro-inflammatory cytokines and chemokines like transforming growth factor ß. The
activation of these cells is believed to represent the key event in hepatic fibrogenesis
(Friedman 2008). Hepatic stellate cell activation depends on signalling by Kupffer
cells, endothelial cells, hepatocytes, and platelets. The deposition of the
extracellular matrix is constantly opposed by degradation of these proteins. In
progressive liver fibrosis, this balance is skewed in favour of excess extracellular
matrix deposition. Matrix metalloproteinases and their regulators (tissue inhibitors
of metalloproteinases, TIMPs) control matrix deposition and degradation. In liver
fibrogenesis, TIMP-1 is also produced by activated hepatic stellate cells.
Liver histology, by helping visualise the fibrosis, has been considered the gold
standard for assessment and measurement of progression of fibrosis. However, the
disadvantages of this method have motivated researchers and clinicians to look into
more non-invasive strategies. These strategies are based either on single serum
surrogate markers, compositional scores derived from combinations of different
surrogate markers, or modifications of imaging techniques.
Liver biopsy – the gold standard for staging of
liver fibrosis
In the majority of liver centres worldwide, liver biopsy is performed as a “blind” or
ultrasound-guided puncture, as either an out-  or in-patient procedure. Liver
punctures are considered to be relatively safe procedures with complication rates
ranging from 0.75% up to 13.6% (Myers 2008, Piccinino 1986, van der Poorten
2006). The most frequent complications are minor bleeding or pain. After efficient
substitution with clotting factors, percutaneous liver biopsy is also possible in
patients with inherited bleeding disorders with no obvious increase of complication
rates (DiMichele 2003,  Schwarz 2008). Procedure-related mortality rates are
reported to range from 0.001 to 0.003% (Piccinino 1986). Of note, excess rates with
severe bleedings and biopsy related deaths have been reported after percutaneous
biopsy in populations with advanced fibrosis, cirrhosis, or hepatic tumors (Terjung
2003). Thus, liver biopsies in these patients should always be performed as in-