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Andrea
Horvath, Aniko Folhoffer, Peter Laszlo Lakatos, Ferenc Szalay, 1st
Department of Medicine of Semmelweis University, Budapest, Hungary
Judit Halász, Gyorgy Illyés, Zsuzsa Schaff, 2nd
Department of Pathology of Semmelweis University, Budapest, Hungary
Kornelia Tekes, Department of Pharmacodynamics of Semmelweis
University, Budapest, Hungary
Monika Beatrix Hantos, Neurochemical Research Unit of
Hungarian Academy of Sciences, Budapest, Hungary
Correspondence to: Szalay Ferenc, MD, PhD, 1st Department of
Medicine, Semmelweis University, Korányi St. 2/A, H-1083 Budapest,
Hungary. szalay@bel1.sote.hu
Telephone: +36-1-210-1007
Fax: +36-1-210-1007
Received: 2003-09-23
Accepted: 2003-11-16
Abstract
AIM: Although liver cirrhosis is a predisposing factor for
hepatocellular carcinoma (HCC), relatively few reports are available
on HCC in primary biliary cirrhosis. High plasma nociceptin (N/OFQ)
level has been shown in Wilson disease and in patients with acute
and chronic pain.
METHODS:
We report a follow-up case of HCC, which developed in a patient with
primary biliary cirrhosis. The tumor appeared 18 years after the
diagnosis of PBC and led to death within two years. Alfa fetoprotein
and serum nociceptin levels were monitored before and during the
development of HCC. Nociceptin content was also measured in the
tumor tissue.
RESULTS:
The importance and the curiosity of the presented case was the novel
finding of the progressive elevation of plasma nociceptin level up
to 17-fold (172 pg/mL) above the baseline (9.2±1.8 pg/mL), parallel
with the elevation of alpha fetoprotein (from 13 ng/mL up to 3 480
ng/mL) during tumor development. Nociceptin content was more than
15-fold higher in the neoplastic tissue (0.16 pg/mg) than that in
the tumor-free liver tissue samples (0.01 pg/mg) taken during the
autopsy.
CONCLUSION:
Results are in concordance with our previous observation that a very
high plasma nociceptin level may be considered as an indicator for
hepatocellular carcinoma
Horvath
A, Folhoffer A, Lakatos PL, Halász J, Illyés G, Schaff Z, Hantos
MB, Tekes K, Szalay F. Rising plasma nociceptin level during
development of HCC: A case report. World J Gastroenterol
2004; 10(1): 152-154
http://www.wjgnet.com/1007-9327/10/152.asp
INTRODUCTION
The incidence of hepatocellular carcinoma (HCC) in primary
biliary cirrhosis (PBC) is reported to range from 0.5% to 4.2%,
which is somewhat less frequent than that in liver cirrhosis from
other etiologies[1,2]. However, recent reports have shown
an increasing trend. The incidence of HCC was found higher in stage
III/IV than in stage I/II patients[1,3,4].
Relatively
few prospective and comprehensive studies are available on HCC in
PBC, and the number of case reports is also limited. Summarizing the
data of the literature, 126 of 6 188 PBC patients (2.0%) were found
to have HCC. Since HCC usually develops many years after the
diagnosis of PBC, screening of HCC has clinical importance and
offers best with hope for early detection. Serum AFP is a widely
accepted marker of HCC[5]; however, using the
conventional cut-off value of 500 ng/mL, it has a sensitivity of
about 50% and a specificity of more than 90% in detecting HCC in a
patient with coexisting liver disease[6]. The average
survival of patients with HCC improved in the last decades[7].
Female HCC patients often have a better prognosis than male patients[8].
Because of the lack of sensitive markers of malignant hepatic
tumors, HCC is usually recognized in the advanced stage.
We
reported a follow-up case of HCC in a PBC patient. The importance of
this case is the novel finding of progressive elevation in plasma
nociceptin (N/OFQ, formerly named as orphanin FQ) up to 17-fold
above the baseline, parallel with the elevation of alpha fetoprotein
(AFP) during tumor development. Moreover, high nociceptin content
was found in the tumor tissue as well.
Nociceptin,
a newly discovered neuropeptide of 17 aminoacids, is the natural
agonist of NOP receptor, earlier named opioid receptor-like 1 (ORL1)
receptor. N/OFQ is a neuropeptide that is endowed with
pronociceptive activity in vivo. Both the long and the short splice
variants of the OP4 receptor mRNA were isolated in rat liver[9];
however, there are no data about its physiological or
pathophysiological role in liver function. To date only few clinical
studies on nociceptin were reported, and only one of them dealt with
liver disease.
Findings
of the presented case are in concordance with our previous
observation that a high plasma NC level may be an indicator of HCC.
CASE
REPORT
A 47-year-old woman was admitted for fatigue, itching,
hepatomegaly, high alkaline phophatase and gamma-GT levels. Primary
biliary cirrhosis was diagnosed based on the clinical symptoms,
laboratory findings, AMA M2 positivity, normal US and ERCP pictures.
Liver biopsy revealed stage II/III. There was no family history of
liver disease or autoimmune disease, and all other confounding risk
factors including alcohol, HBV and HCV infections were excluded. The
patient was a heavy smoker. The past surgical history was
significant only for an appendectomy and two caesarean sections. Her
menopause started at the age of 38. Bone mineral density was
slightly below the normal range at the time of diagnosis of PBC.
Ursodeoxycholic acid (Ursofalk) treatment, calcium and vitamin D
supplementation were introduced.
Severe
progression of osteoporosis was observed during the following years.
Five years after the diagnosis of PBC significantly decreased bone
mineral density was shown both on the femoral neck (T-score: -5.12,
Z score: -3.38) and on the lumbar vertebrae (T-score: -5.44,
Z-score: -3.9). At the age of 57 despite the calcium, vitamin-D
supplementation, calcitonin and bisphophonate (Fosamax) treatment,
the severe osteoporosis led to hip fracture and multiple vertebral
collapses, which made the patient lifelong disabled.
Progression
of PBC to stage IV occured. She was monitored by yearly US, by
regular laboratory tests and AFP every 3-4 months. For different
reasons we collected blood samples for plasma nociceptin level
determination as well. Sampling was done in conformity to accepted
ethical standards and was approved by the regional ethical
committee.
Hepatocellular
carcinoma developed 18 years after the diagnosis of PBC. Regular
follow-up US investigations revealed a focal lesion of 2.5 cm in
diameter, which increased rapidly in segment V of the liver. Fine
needle biopsy findings proved hepatocellular carcinoma. After the
HCC diagnosis a continuous and rapid increase in the size of the
tumor, an elevation of ALP, GGT, plasma nociceptin and AFP levels
and clinical deterioration were observed.
Figure
1(PDF) Serum alpha
fetoprotein and plasma nociceptin levels before and during the
development of hepatocellular carcinoma in the presented patient
with primary biliary cirrhosis.
Figure 2 Hepatocellular
carcinoma in the presented patient with primary biliary cirrhosis. A:
Gross view of liver at autopsy. Grayish nodules of carcinoma
protrude on the surface of the cirrhotic liver. Bar=1 cm. B:
The focal red staining on the histologic picture of the
hepatocellular carcinoma shows the immunohistochemical reaction of
AFP. Original magnification 400×.
The AFP value had been within the normal range one year
before the tumor was detected (13 ng/mL), but it was elevated at the
time of the diagnosis of HCC (426 ng/mL) and rose up to 3 480 ng/ml.
The plasma nociceptin measured by radioimmunoassay
125I-Nociceptin-kit, Phoenix Pharmaceuticals, Phoenix, CA, USA (10.6
pg/mL) was within the normal range (9.2±1.8 pg/mL) in the
tumor-free stage, while progressive elevation was detected during
the tumor development (15.8, 65.8, 103.7, 128.0, 172.2 pg/mL),
reaching the highest value before death (Figure 1). Higher
nociceptin content was measured in the tumor tissue (0.16 pg/mg)
compared to the tumor-free liver tissue sample (0.01 pg/mg) taken
during the autopsy. The patient refused any surgical or other
systemic or local tumor treatment. The size of the tumor increased
up to 12 cm in diameter and involved segments V, VII, VIII and
partly IV. No metastasis was detected, but necrosis developed in the
central region of the tumor. The patient received supportive
treatment, analgetics, and died of tumorous cachexia 19 months after
the discovery of HCC. The autopsy confirmed both PBC stage IV and
HCC. Focal presence of AFP was shown in the tumor by
immunohistochemistry (Figures 2 A and B).
A
nociceptin content in the HCC tissue (0.16 pg/mg) was 15-fold higher
than that in the tumor free liver tissue sample (0.01 pg/mg) taken
during the autopsy.
DISCUSSION
The presented case is a further example of the occurrence of HCC
in PBC, and it supports previous observations that HCC usually
develops in stage III/IV patients[3]. The tumor developed
18 years after the diagnosis of PBC and led to the death of the
patient within two years. Furthermore, severe osteoporosis is a
common disorder in PBC, although recently it is considered as a
non-specific complication[10,11 ]. In our patient the
early menopause together with PBC resulted in many bone fractures
causing lifelong disability. The low serum osteocalcin level
indicated a low turnover osteoporosis. High serum osteoprotegerin
and low RANKL have been reported in PBC[12], and we found
the same alteration in this patient. Progression of bone loss was
detected despite the serum osteoprotegerin was two-fold higher than
normal, which suggested that inflammatory process in the liver could
also contribute to the elevation of osteoprotegerin.
This
is the first follow-up case in which progressive elevation of plasma
nociceptin level was detected in parallel with the elevation of AFP
during tumor development, and high N/OFQ content was found in the
tumor tissue.
Nociceptin
is the endogenous agonist of a G-protein coupled, naloxon
insensitive opioid-like 1 receptor (ORL1) recently named as OP4.
Although nociceptin is structurally related to opioid peptides,
especially to dynorphin A, it does not interact with m,
d
and k
receptors. N/OFQ/OP4 system is a newly discovered peptide-based
signalling pathway, involved in the modulation of pain and
cognition. Opioid antagonists were successfully used for the
treatment of pruritus in patients with PBC[13]. These
results together with the data that high plasma N/OFQ level has been
reported in Wilson disease and in patients with chronic pain, led us
to measure plasma nociceptin level in primary biliary cirrhosis[14].
Our motivation was reinforced by an accidental observation that we
found extremely high N/OFQ in a Wilson patient with advanced HCC.
The
nociceptin levels in blood samples collected in the pre-tumor stage
and during the tumor development period clearly showed that the
elevation of N/OFQ was parallel with that of AFP and the clinical
deterioration. When the tumor was first detected the N/OFQ level was
6-fold higher than that in healthy controls (65.8 versus 9.2±1.8
pg/mL, n=29) and in other PBC patients without HCC (12.1±3.2pg/mL,
n=21). When the tumor reached 11 cm the N/OFQ level was 17-fold
higher than normal. Since N/OFQ content was 15-fold higher in tumor
tissue than in tumor free parts of the liver, the question arose
whether nociceptin was produced by HCC tissue or it accumulated in
the tumor by passive binding or via increased nociceptin receptor
expression.
Further
research is needed to clarify the mechanism and clinical
significance of the highly elevated N/OFQ level in HCC. Since N/OFQ
transcripts are expressed in immune cells[15], the high
N/OFQ level may also be an indicator of altered reaction of the body
including immunological, cytokine and other mechanisms.
Elevated
N/OFQ level might represent a compensatory mechanism in the N/OFQ/OP4
system to modulate pain perception in the central nervous system.
This mechanism could explain why some patients with a very high
plasma N/OFQ level did not have pain despite advanced stage of
malignant liver tumor. It is remarkable that the N/OFQ was 3-fold
higher in our patient than the highest values reported in patients
with chronic pain without malignant disease[16].
In
conclusion, the novel finding of this study is that progressive
elevation of plasma nociceptin was detected in parallel with the
elevation of AFP during tumor development, as well as high N/OFQ
content was found in the tumor tissue in a PBC patient with
hepatocellular carcinoma. This is in concordance with our previous
observation that high plasma N/OFQ level might be considered as an
indicator of HCC.
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Edited
by Zhang
JZ
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