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Blood, Vol. 91 No. 4 (February 15), 1998:
pp. 1173-1177
A Prospective Multicenter Study of Hepatocellular Carcinoma in
Italian Hemophiliacs With Chronic Hepatitis C
By
F. Tradati,
M. Colombo,
P.M. Mannucci,
M.G. Rumi,
C. De Fazio,
G. Gamba,
N. Ciavarella,
A. Rocino,
M. Morfini,
A. Scaraggi,
E. Taioli, and
the Study Group of the Association of Italian Hemophilia
Centers
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center,
Fondazione Italiana Ricerca Cancro-University Research
Unit on Liver Cancer, Institute of Internal Medicine, and Epidemiology
Unit, University of Milan, Maggiore Hospital, Milan; Clinical Medicine
2, Instituto Ricovero e Cura a Carattere Scientfico Policlinic
Hospital, Pavia; Hemophilia and Thrombosis Center, Policlinic Hospital,
Bari; Department of Hematology, Nuovo Pellegrini Hospital, Naples;
Department of Hematology and Hemophilia Center, Careggi Hospital,
Florence; and Clinical Medicine and Department of Infectious Diseases,
Policlinic Hospital, Bari, Italy.
 |
ABSTRACT |
To assess the risk factors, natural history, and eligibility for
curative treatment of early-detected hepatocellular carcinoma (HCC),
385 hemophiliacs who were treated with blood or plasma derivates for at
least 10 years and had persistently elevated aminotransferase values
underwent an annual screening with an abdominal ultrasound examination
and measurement of the serum alpha-fetoprotein (AFP) level. Of these,
355 had serum antibody to hepatitis C virus (anti-HCV), 29 had anti-HCV
and hepatitis B surface antigen (HBsAg), and one had HBsAg alone; 141 had serum antibody to human immunodeficiency virus (anti-HIV). During
48 months of follow-up study, six patients developed HCC. All HCC patients had a HCV-related cirrhosis and had been exposed to HCV risk
at a median age of 40 years. All patients had a multicentric tumor,
which was not eligible for curative treatment. Univariate analysis
showed age, cirrhosis, and baseline AFP levels to be significantly
associated with an increased risk of HCC. By multivariate analysis, the
risk of HCC was infinite in patients with cirrhosis, 31.0 for those
with baseline AFP higher than 11 ng/mL, and 17.9 for those more than 45 years of age. In conclusion, the risk of cancer was greater for
patients infected later in life, particularly those with cirrhosis and
high AFP. Annual screening of hemophiliacs with ultrasound and AFP
fails to identify potentially curable tumors because the diagnosis is
made at a late stage of the disease.
| |
INTRODUCTION |
SEQUENTIAL DEVELOPMENT of cirrhosis and
hepatocellular carcinoma (HCC) has been documented in nonhemophilic
patients with chronic liver disease due to hepatitis C virus (HCV) or
hepatitis B virus (HBV).1,2 Preliminary evidence suggests
that this is also true for hemophilic patients who acquired chronic
viral hepatitis subsequent to replacement therapy with large-pool
clotting factor concentrates infected with blood-borne hepatitis
viruses.3-5
In a questionnaire-based survey of 11,801 multitransfused hemophiliacs
from 54 centers in the United States and Europe, 10 cases of HCC were
reported that were invariably associated with cirrhosis due to either
HBV or HCV.4 In the survey, the crude rate of HCC in
hemophiliacs was 30 times the background incidence of the tumor in the
countries of origin of the patients, and in most instances the tumors
were so advanced they could not be successfully treated with surgery.
The only exceptions were three patients, two of whom had undergone
studies with abdominal ultrasound examination and/or
measurement of serum markers of HCC such as alpha-fetoprotein (AFP), in
whom HCC was less advanced and could be treated with chemotherapy or
surgery.4 These findings suggest that screening may enhance
the chance of early HCC detection in patients with chronic viral
hepatitis, although it remains unclear whether survival is improved by
early diagnosis.2,6-8
Multitransfused hemophiliacs offer a unique model for studying the
sequelae of chronic hepatitis C. The duration of hepatitis risk can be
calculated virtually in all patients: most of the older patients have
had exposure to blood, plasma, or cryoprecipitates that had a high risk
of transmitting HCV.9 In the 1970s, practically all
patients treated with non-virus-inactivated concentrates became infected with HCV after their first infusion of concentrates prepared from a large plasma pool.10 Another peculiar feature of HCV infection in hemophiliacs is that the course of hepatitis may be
aggravated by multiple virus infections and impaired immunity as a
consequence of repeated infusions with infected
concentrates.11,12 To assess the natural history of HCC and
whether screening enhances early detection and improves the chances of
curative treatment, we began in 1992 to prospectively study 385 multitransfused hemophiliacs with a long history of elevated
aminotransferases (ALT) using an annual abdominal ultrasound
examination and serum AFP measurement.
| |
MATERIALS AND METHODS |
Participating centers.
In January 1992, all hemophilia centers in Italy were invited to
participate in a prospective study aimed at the early diagnosis of HCC
through an annual screening program. Eleven Centers agreed, six in
Northern Italy, one in Central Italy, and four in Southern Italy.
Enrollment and follow-up study.
Patients were enrolled if they had been treated with large-pool
clotting factor concentrates for at least 10 years before the start of
the study and had serum aminotransferase activity greater than 1.5 times the upper limit of normal at three consecutive tests 6 months
apart. At enrollment, all patients underwent a full clinical
examination and routine liver chemistry analysis. Patients were
also tested for serum markers of HBV and HCV (hepatitis B surface
antigen [HBsAg] and anti-HCV, second-generation ELISA; Ortho
Diagnostics, Raritan, NJ) anti-HIV (ELISA; Ortho), and AFP (ELISA; Abbott Laboratories, Chicago, IL). Abdominal ultrasound examination was performed using conventional real-time equipment. Every
6 months, all patients repeated the clinical examination and routine
liver chemistry analysis. Every 12 months, patients were also studied
with abdominal ultrasound examination and serum AFP measurement.
Cirrhosis was established on the basis of clinical signs of portal
hypertension (platelet count <100,000/µL, albumin level <3.5 g/L,
and serum cholinesterase activity <4.5 U/L), endoscopic signs
(esophageal varices and portal hypertensive gastropathy), and/or abdominal ultrasound examination (irregular margins of the liver, dilated portal vein axis, and splenomegaly). The clinical stage of the disease was classified according to the Child-Pugh score13: 1, bilirubin less than 2 mg/100 mL, albumin
greater than 3.5 g/dL, prothrombin time 2 to 4 seconds longer than
normal, and no ascites or encephalopathy; 2, bilirubin between 2 and 3 mg, albumin between 2.8 and 3.5 g, prothrombin time 4 to 6 seconds longer, first- to second-degree encephalopathy, and modest ascites; 3, bilirubin greater than 3 mg, albumin less than 2.8 g, prothrombin time at least 6 seconds longer than normal, third- to fourthdegree encephalopathy, and severe ascites; 5 to 6, Child-Pugh class A; 7 to 9, Child-Pugh class B; and greater than 9, Child-Pugh class C.
Diagnosis of HCC.
HCC was diagnosed on the basis of abdominal ultrasound identification
of a focal lesion in a patient with serum AFP higher than 400 ng/mL.
Patients with a focal lesion on abdominal ultrasound and serum AFP
less than 400 ng/mL were considered suspect for HCC and underwent a
diagnostic liver biopsy with an echo-guided thin needle (21-gauge
Tru-cut needle; Travenol, Hyland, Los Angeles, CA).
Tumor staging.
To assess the number of tumor nodes, tumor size, and extrahepatic
metastasis, patients with potentially operable HCC were further investigated with chest x-ray, abdominal computed tomographic (CT) scan, bone scintiscan, and Lipiodol hepatic
arteriography (Lipidol Ultrafluide, Laboratoire Guerbet,
Aulnay-Sous-Bois, France). The disease was classified as unicentric
when a single tumor node was detected with ultrasound and confirmed
with CT after Lipiodol hepatic arteriography. It was considered
multicentric when more than one node was detected with abdominal
ultrasound and/or other imaging techniques. To calculate tumor
size, the two main diameters of the lesion(s) were measured by CT scan.
Treatment options.
The following therapeutic algorithm was developed. Orthotopic liver
transplantation was thought to be the best option for an
anti-HIV-seronegative patient who had cirrhosis, was younger than 60 years, and had a single tumor less than 3 cm in diameter. Patients who
did not have cirrhosis or did not fit the general criteria for
transplantation were considered for hepatic resection or transhepatic
arterial chemoembolization with doxorubicin. Patients who were not
eligible for any of these treatments were given palliative treatment
such as analgesics, antipyretics, or corticosteroids if required.
Statistical analysis.
Student's t test was used to compare means and the chi-square
test to compare proportions. Unconditional logistic regression was
used to calculate the odds ratio (OR) of HCC according to age, AFP
level, and presence of cirrhosis. Survival estimates from birth to the
age at development of HCC were calculated by Kaplan-Meier curves and
compared by the Wilcoxon test and log-rank test. Conditional
risk ratios were calculated using the proportion hazard regression
(PHREG) procedures, taking into consideration the following variables:
sex, AFP more than 11 ng/mL (95th percentile of the control
distribution), duration of follow-up study (<90, 190 to 240, or
>240 months), and type of hemophilia.
| |
RESULTS |
Of 1,675 patients attending the 11 participating centers, 385 (22.9%)
met the inclusion criteria. There were 377 males and eight females aged
10 to 83 years (median, 31); 311 patients had hemophilia A, 60 had
hemophilia B, and 14 had von Willebrand disease. Patients had been
treated with blood, plasma, cryoprecipitates, or clotting factor
concentrates for a median of 240 months (range, 120 to
588); 355 patients had serum anti-HCV alone, 29 had both serum anti-HCV
and HBsAg, and one had HBsAg alone; 141 (36.6%) patients had serum
anti-HIV; and 40 patients (10.3%) had cirrhosis (Table
1). Eleven patients had Child-Pugh A
cirrhosis, nine Child-Pugh B, and 20 Child-Pugh C. The prevalence of
cirrhosis was similar in anti-HIV-positive and anti-HIV-negative
patients (13.4% v 8.6%, P = .09). During a 48-month
follow-up study, 36 patients (9.3%) died. Twenty died of HIV-related
events; six anti-HIV-positive patients died of liver failure. Among
the anti-HIV-negative patients, nine, including four with HCC, died of
liver failure and one died of causes unrelated to the liver. Overall,
15 hemophiliacs (3.9%) died of liver-related disease.
Six patients developed HCC, with an incidence rate of 390 cases per
100,000 per year. Table 2 summarizes the
main epidemiologic and clinical features of the six patients with HCC.
The median age at which these patients were first exposed to blood or
plasma concentrates was 40 years (range, 22 to 50), compared with 12 years (range, 0 to 53) for the other patients (P < .0001).
In all cases, HCC was associated with HCV-related cirrhosis due to infection with genotype 3a in two, 3a and 1a in one, 1a in one, and 1b
in another. For one patient, no serum sample was available for
genotyping. In all cases, the tumor was multicentric: when the tumor
was first detected, two patients had two nodes and four had more than
three. At diagnosis, serum AFP was higher than 400 ng/mL only in one
patient (case no. 1) and was above the upper-normal limit (7 ng/mL) but
less than 400 ng in five patients (no. 2 to 6). Liver function was good
in three patients (no. 3, 5, and 6), but was impaired in the remaining
three. None of the patients met the criteria for surgery or treatment
with arterial chemoembolization. One patient was unsuccessfully treated
with intravenous mitoxantrone. The survival time from diagnosis to
death was 4 to 19 months (Table 2).
Univariate analysis found that the age, presence of cirrhosis, and AFP
level at enrollment were significantly associated with an increased
risk of HCC (Table 3). Multivariate
analysis showed that the risk of HCC was infinite in patients with
cirrhosis, 31.0 (confidence interval [CI], 4.8 to 199.2) in patients
with AFP more than 11 ng/mL, and 17.9 (CI, 1.9 to 173.3) in patients older than 45 (Table 4). Figure 1 shows the survival
estimates from birth to the age of development of HCC for patients with AFP less than 11 ng/mL at baseline and for those with higher baseline AFP. Comparative analysis of the two curves shows that HCC developed earlier in patients with AFP greater than 11 ng/mL
(P < .0001). The conditional risk ratio of HCC in patients
with baseline AFP higher than 11 ng/mL was 70.4 (CI, 3.6 to
1,374.7).
View larger version (8K):
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| Fig 1.
HCC-free survival of hemophilic patients. (---)
Survival of patients with serum AFP <11 ng/mL; ( ) survival of
patients with serum AFP >11 ng/mL.
|
|
| |
DISCUSSION |
This prospective study confirms previous retrospective
surveys4,5 showing that HCC is an important cause of death
in both anti-HIV-negative and anti-HIV-positive hemophiliacs with chronic hepatitis C. The risk of liver cancer is particularly high in
hemophiliacs with cirrhosis and elevated AFP, being higher in patients
infected late in life than in those infected earlier.
The yearly HCC incidence rate of 390 cases per 100,000 in our patients
is much higher than the calculated yearly age-adjusted incidence of HCC
in the general population in Italy, which is approximately seven cases
per 100,000.14 The incidence rate of HCC in these
prospectively studied hemophiliacs was also higher than in our previous
retrospective study.4 That study enrolled all unselected
patients with hemophilia, whereas this prospective study focused on
patients with chronic ALT abnormalities, who have a high risk of
cirrhosis and HCC.15,16 All six patients with HCC had
clinical or histologic features of cirrhosis due to chronic infection
with HCV.
Persistent hepatocellular inflammation is a well-recognized triggering
factor for HCC in patients with chronic hepatitis C.1,2,16 Every year, 3% to 6% of prospectively evaluated patients with HCV-related cirrhosis develop liver cancer.1,2,8,16,17 Thus, the low annual rate (0.4%) of HCC detected in our hemophiliacs might simply reflect the small proportion of patients with cirrhosis enrolled. Although the lack of histologic studies could underestimate the real prevalence of cirrhosis in hemophiliacs, our finding of 10%
of the patients showing clinical or ultrasound signs of cirrhosis
agrees with several cross-sectional and a few prospective studies in
hemophilia indicating that only 20% to 30% of all hemophiliacs with
chronic HCV infection ultimately develop cirrhosis.5,18 However, considering that in patients with transfusion-transmitted hepatitis C HCC is a disease that may take up to 30 years to
develop,19 in hemophiliacs this tumor might be less
frequent than expected because these patients had a shorter survival
than the nonhemophilic population as a consequence of the HIV
epidemic.20,21
We also found that a direct relationship exists between the HCC risk
and the age at which hemophiliacs became infected with HCV. In line
with this observation are two recent studies in multitransfused patients showing a direct correlation between the age when patients become infected and the risk of developing a preneoplastic condition such as cirrhosis.22,23 Why hemophiliacs infected late in
life are at a higher risk of HCC is unknown. An increased exposure to
environmental factors responsible for cirrhosis or liver cancer or an
increased vulnerability of the older liver to genotoxic agents are
possible explanations.
The serum AFP level at enrollment was another important predictor of
HCC risk in our patients that was identified by multiple regression and
conditional risk ratio analysis. When the predictive power of serum AFP
was assessed in a prospective fashion, it was found to be higher in
population-based versus clinic-based studies, as a consequence of the
many false-positive results in patients with cirrhosis.1,24
In our setting, the predictive power of AFP was high, probably because
of the low prevalence of patients with cirrhosis (10.3%).
The pattern of HCV genotypes among hemophiliacs with HCC paralleled the
genotype distribution among Italian hemophiliacs, with a predominance
of genotypes 1a and 3a, as reported elsewhere.25 Thus,
genotype 1b, which in nonhemophilic patients with HCV-related cirrhosis
was shown to be an important risk factor for HCC,26 in this
study was not the predominant strain among HCV-infected hemophiliacs
who developed HCC.
The main clinical goal of this study was to assess whether an annual
screening with abdominal ultrasound examination and serum AFP
measurement could help to reveal the tumor at an early, potentially treatable stage. Unfortunately, all six patients with HCC had multicentric disease at diagnosis, which was not amenable to surgical or radiologic treatment. The absolute rate of multicentric tumors in
our patients is far higher than the prevalence (8% to 35%) reported
in nonhemophilic cirrhotics.1,2,8,17 This might reflect
differences in the natural history of HCC between hemophiliacs and
nonhemophilic patients. In hemophiliacs, HCC may originate as multiple
distinct clones of tumor disease as a consequence of multiple HCV
infections acquired by multiple infusions of large-pool concentrates.
However, since multiple infusions with allogeneic proteins may also
impair immunity in these patients,11,12 HCC could initially
develop as a monoclonal cancer and spread early within the liver to
cause multinodal disease.
Whatever the biologic cause of multicentric HCC in hemophiliacs, it
detracts from the potential utility of a screening program based on
annual abdominal ultrasound examination and AFP assay, because
multicentric tumors rarely respond to curative treatments. More
aggressive schedules of screening might improve the early detection of
HCC,24,27 and thus we are now conducting a prospective study of multitransfused hemophiliacs with chronic hepatitis C based on
6-month screening intervals.
| |
FOOTNOTES |
Submitted July 7, 1997;
accepted October 6, 1997.
Supported by the Fondazione Italiana Ricerca Cancro.
Address reprint requests to M. Colombo, MD, Institute of
Internal Medicine, University of Milan, Via Pace 9, 20122 Milan, Italy.
The publication costs of this article were defrayed in part by page
charge payment. This article must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. section 1734 solely
to indicate this fact.
| |
ACKNOWLEDGMENT |
Other members of the Study Group are as follows: F. Baudo, Talamona
Division of Hematology, Niguarda Hospital, Milano; G. Castaman,
Division of Hematology, Ospedale Civile, Vicenza; P.G. Mori, Division
of Pediatrics, Gaslini Hospital, Genoa; A.R. Tagliaferri, 5th Division
of Medicine, Hemostasis Disease Center, Policlinic Hospital, Parma; G. Muleo and R. Santoro, Hemophilia Center, Hematology Division, Ospedale
Civile Pugliese, Catanzaro; and M. Schiavoni, Hemophilia and Thrombosis
Center, Policlinic Hospital, Bari.
| |
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The natural history of chronic hepatitis C in a cohort of HIV-negative Italian patients with hereditary bleeding disorders
Blood,
September 15, 2001;
98(6):
1836 - 1841.
[Abstract]
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E. Santagostino, M. Colombo, D. Cultraro, M. Muca-Perja, A. Gringeri, and P.M. Mannucci
High Prevalence of Serum Cryoglobulins in Multitransfused Hemophilic Patients With Chronic Hepatitis C
Blood,
July 15, 1998;
92(2):
516 - 519.
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Abstract
Introduction
Abstract