*Corresponding author: Elsayed Ibrahim Elshayeb, Internal Medicine Department, Faculty of Medicine, Menoufiya University, 477 Elhorria Street, Bolkly, Egypt, Tel: 0021002502062; Email:firstname.lastname@example.org
How to cite this article: Elsayed I E, Mohamed Abdel R K, Nada F E, Mohamed A H, Ehab Ahmed A-E. Serum Serotonin as a Novel Marker for Hepatocellular Carcinoma. Adv Res Gastroentero Hepatol. 2016; 1(5): 555571. DOI: 10.19080/ARGH.2016.01.555571
Aim of the Work: To investigate the role of serum serotonin as a novel marker for diagnosis of Hepatocellular carcinoma In comparison with serum alpha fetoprotein.
Introduction: Hepatocellular carcinoma is the most common liver cancer and is a disease with poor prognosis. In addition to its function as a neurotransmitter and vascular active molecule, Serotonin is also a mitogen for hepatocytes and promotes liver regeneration and may be involved in tumorigenesis of HCC.
Methods: The study conducted on 136 patients and 20 healthy subjects as control group. Patients classified into two groups, 68 Cirrhotic with HCC as group I and 68 only cirrhotic without HCC as group II. Patients and controls underwent through history taking, full clinical examination with Child pugh score laboratory. Investigations including Complete blood count, Liver function tests, Creatinine, serum AFP and Serotonin levels in addition to abdominal ultrasound and Triphasic CT abdomen.
Results: Cirrhotic Patients presented with HCC showed significantly higher levels of serotonin, alpha fetoprotein, albumin and white blood cell count compared to pure cirrhotic group without HCC, however, HCC patients showed lower levels of AST, ALT, bilirubin and platelet count compared to cirrhotic patients. HCC patients were more in elder, associated with male gender and showed shorter prothrombin. A significant positive correlation between serum AFP and serotonin. r=0.594, P<0.001 AFP at 0.5 ng /ml is a cutoff with sensitivity 100%, specificity 70%, PPV 91.9% and Accuracy 97.6% respectively for diagnosis of HCC while Sr. Serotonin >510ng/ml is a cutoff with 89.71% sensitivity, 85% specificity, 95.3 % PPV, 70.8 % NPV and 96.6 % accuracy respectively for diagnosis of HCC.
Conclusion: Serotonin could be a novel maker for diagnosis of HCC and may be used together with serum AFP for screening of HCC in cirrhotic patients.
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules leading to loss of liver function. Cirrhosis is most commonly caused by hepatitis B and C, alcoholism, and fatty liver disease, but has many other possible causes . In developing countries viral hepatitis is the leading cause of cirrhosis and in the developed countries alcoholic liver disease (ALD), HCV and non-alcoholic steatohepatitis (NASH) are the most significant causes of cirrhosis . Some studies have demonstrated that patients who present with cirrhosis related complications (for example, hepatic encephalopathy, esophageal varices, bleeding and HCC) have a decreased survival rate compared with those without complications .
Liver biopsy is the only definite method for confirming a diagnosis of cirrhosis. It also helps to determine its cause,treatment possibilities, the extent of damage, and the long-term
outlook. For example, hepatitis C patients who show no significant
liver scARGHing when biopsied may have a low risk for cirrhosis.
The histopathological landmarks of cirrhosis are nodularity
(regenerating nodules), fibrosis (deposition of connective
tissue creates pseudolobules), abnormal hepatic architecture,
and hepatocellular abnormalities (pleomorphism, dysplasia,
and regenerative hyperplasia) . Because Liver Biopsy is an
uncomfortable and sometimes risky procedure, it is unsuitable
to incorporate it into the routine follow-up examinations of
chronic liver disease patients. There is therefore a demand for
serum markers that can routinely assess progression of liver
fibrosis and reliably detect the stage of liver cirrhosis. Models
such as Fibro test, which is based on a range of clinical chemistry
analytes, have recently been intensively studied for these
Serotonin is known as 5-hydroxytryptamine (5-HT), a
biogenic amine that function as a ligand for a large family of
5-HT receptors.  The majority of serotonin in the body (90%)
is synthesized by enterochromaffin cells of the gastrointestinal
(GI) tract, where it regulates intestinal motility . It plays a
major role in neurotransmission within the central nervous
system (CNS) and the autonomic nervous system (ANS), In the
CNS serotonin is known to control mood, behavior, learning,
sleep and anxiety. Peripherally, serotonin is able to mediate
vascular contraction and relaxation, cell proliferation, apoptosis
and platelet aggregation . Serotonin is actively taken up by
cells expressing the Na+/Cl− dependent serotonin transporter
(SERT) where it is stored in intracellular vesicles and released
in response to various stimuli. Once bound to target receptors or
taken up by the SERT, internalised serotonin can be metabolised
by monoamine oxidase (MAO) leading to the generation of
5-hydroxyindoleacetaldehyde (5-HIAA) which is excreted in
urine . Liver cirrhosis is one of various pathological conditions
in which serotonin homeostasis can change. In cirrhotic patients,
secondary changes in the GI tract occur. In the altered intestinal
wall, disturbances in serotonin synthesis and metabolism are
observed. Serotonin leakage to systemic circulation cannot be
excluded. It could be manifested by anxiety, sleep disorders, and
other emotional disturbances. Then, the liver should play the
role of a filter, where serotonin is catabolized. This mechanism
fails in the case of liver diseases .
The chronic hepatic insufficiency gives rise to serotonin
system changes, contributing to the development of hepatic
encephalopathy, portal hypertension, and hyperdynamic
circulation. In patients with liver cirrhosis, low whole-blood
serotonin levels depend probably on reduced uptake, retention
of serotonin by platelets, and low platelet number. Also,
concentration of circulating serotonin in liver cirrhosis can be
influenced by other factors, such as altered serotonin co-oxidase
and impaired metabolism of tryptophan, as a precursor of serotonin . Patients with cirrhosis are known to have platelet
storage pool defects, significantly lower intraplatelet serotonin
concentrations when compared to healthy individuals. It is
therefore tempting to propose that the haemorrhagic tendency
of cirrhotic patients . Each year, hepatocellular carcinoma
(HCC) (SEER 2010) is diagnosed in more than half a million
people worldwide, including approximately 20,000 new cases in
the United States. Liver cancer is the fifth most common cancer
in men and the seventh in women. Most of the HCC cases (85%)
are present in developing countries.  Incidence of HCC in
Egypt is currently increasing, which may be the result of a shift in
the relative importance of HBV and HCV as primary risk factors
in addition to exposure to aflatoxin as an additional risk factor
. HCC is the second most frequent cause of cancer incidence
and mortality among men in Egypt . Egypt has the highest
prevalence of HCV in the world, with estimates ranging from 6
to 28% and a reported average of ∼ 13.8%, also investigations
in Egypt have also shown the increasing importance of HCV
infection in the etiology of HCC, account for 40-50% of cases .
Hence platelets are not expected to function properly in
diseased liver. Platelets harbour important growth factors for
liver regeneration, e.g. Hepatocyte growth factor (HGF). Platelets
contain transforming growth factor α (TGF-α), which is required
for termination of liver regeneration. Thus, it is plausible that
platelets may participate in orchestrating liver regeneration
through stimulation and inhibition of growth-related signals.
The ability of serotonin to modulate all of these factors renders
it crucial in times of hepatic injury and repair . Platelet
derived serotonin has been shown to be beneficial in terms of
stimulating hepatocyte proliferation following hepatic ischaemia
in mice . In addition over proliferation of hepatocytes can
lead to HCC and this would raise the possibility that serotonin
may play a role in HCC pathogenesis . Serotonin is emerging
as a mediator of different pathological conditions. It contributes
to liver fibrosis, mediates oxidative stress in nonalcoholic
steatotic hepatitis, and aggravates viral hepatitis promoting
the progression of steatohepatitis by oxidative stress . It
promotes tumor growth in a mouse model of subcutaneous colon
cancer allografts. 5HT deficiency led to decreased vascularity
and increased necrosis reflecting cell death of the tumor.
This study conducted on 136 patients and 20 healthy subjects
as control group, Subjects selected from the outpatient of our
Menoufia University Hospital and after oral and written consent
from all, Patients and control subjects classified into 3 groups
temperatures are 280C and 110C respectively.
Patients with any active infection including spontaneous
Patients with evident neurotic or psychiatric disorders
other than Hepatic encephalopathy
Patients who are taking benzodiazepines, narcotics,
or other agents that can alter gastrointestinal motility such
as prokinetic agents like metoclopramide, erythromycin,
cisapride, opioids, adsorbents like bismuth subsalicylate and
anti-emetic drugs like promethazine.
Patients with cardiopulmonary, renal and endocrinal
All patients were subjected to the following:
I-Thorough history taking with special emphasis on the
Age and Sex.
Manifestations of liver cirrhosis history of bleeding,
encephalopathy and previous medication.
II-Thorough physical examination with special emphasis
Signs of liver cell failure (e.g. jaundice, pallor, ascites,
hepatomegaly, splenomegaly, and lower limb edema).
Signs of hepatic encephalopathy: all patients will be
examined carefully for the presence of asterixis
The present study was conducted 136 patient and 20 healthy subjects as control group classified as follows:
G1: 68 Cirrhotic patients , 38 males and 30 females with age
53.51±7.21, classified according to child pugh classification into
child A 11patients , child B 10 patients and child C 47 patients.
G 2: 68 patients Cirrhotic with HCC 55 males and 13 females
with age 57± 8
G3: 20 health control subjects 14 males and 6 females with
Etiology of liver cirrhosis in cirrhotic group was HCV in 60
patients ( 88.24%), HBV in 8 patients (11.76%), 21 patients
(30.8%) with history of melena, 10 patients (14.71%) had history
of hematemesis and 2 patients (2.94%) had bleeding gum, 40
patients had history of encephalopathy, 10 patients (14.71%)
had mild ascites, 15 patients (22.06%) had moderate ascites,
33patients (48.53%) had history of tense ascites, 64patients
(92.65%) with enlarged spleen, 4 patients (5.88%)have normal
size spleen, according to child pugh classification, there were
11 patients class A, 10 patients class B and 47 patients class C.
Etiology of liver cirrhosis in HCC group HCV 78% (n=53) with
schistosomiasis in 18% (n=12), hepatitis B virus in 4 %(n=3),
55 males and 13 females in HCC group, 43% child A (n=29), 38%
(n=26) are child class B and 19 % (n=13) are child class C. In HCC
group 76% (n=52) have focal lesion in R lobe, 22.5% (n=15) have
focal lesion in left lobe and 1.5% (n=1) have focal lesions in both
R and L lobes and 5 patients have distant metastases in lungs,
colon and bone.
Patients presented with HCC showed significantly higher
levels of serotonin, alpha fetoprotein, albumin and white blood
cell count compared to cirrhotic groups. However, HCC patients
showed lower levels of AST, ALT, bilirubin and platelet count
compared to cirrhotic patients. However, HCC patients were
of older age associated with male gender and showed shorter
prothrombin time compared to cirrhotic patients (Table 1).
Serum serotonin was significantly higher in HCC patients
with metastases than patients without metastases (Table 2)
with Mean± SD 1134±140.641 compared to that of isolated
HCC without metastases 852.524± 283.965. Serotonin level
in patients with isolated HCC and patients with metastasis are
shown in Table 2. Serotonin level in different etiology of liver
cirrhosis is shown in Table 3. Correlation between serotonin
and different parameters in HCC patients are shown in Table 4.
Comparison between Cirrhotic patients groups (A,B,C)according
to Child classification as regard blood serotonin shown in Table
5. Sensitivity, specificity and accuracy for AFP and serotonin HCC
group are shown in Table 6. ROC curve for α fetoprotein level in
HCC patients is shown in Figure 1. AFP at cutoff 5 ng/ml in the
area under ROC curve showing high sensitivity and specificity.
ROC curve for serotonin level in HCC group is shown in Figure
2. Sr .Serotonin at cutoff > 510 under ROC curve showed high
sensitivity and specificity in HCC group.
Serotonin (5HT) a well known neurotransmitter within the
central nervous system, also regulate a wide range of physiological
actions in the gastrointestinal tract . 5HT a potent mitogen
for many different cell types including hepatocytes . Within
the liver 5HT has the ability to regulate hepatic blood flow at
both portal vein and sinusoidal levels and it may play a role in
hepatic regeneration . Serotonin has been shown to mediate
the pathology of many liver diseases, such as steatohepatitis,
chronic cholestasis, viral hepatitis and liver cirrhosis . All
these conditions are involved in the tumorigenesis of HCC .
Although Serotonin promoting liver regeneration, it is involved in
many liver diseases and tumors such as steatohepatitis, chronic
cholestasis, development of portal hypertension, aggrevation of
viral hepatitis and progression of hepatic fibrosis and facilitate
tumor growth as cholangiocarcinoma and HCC .
HCV infection was the main etiology of liver cirrhosis in
the majority of our cases, about 60 patients (88.2%) and HBV
in 8 patients (11.76 %) of cirrhotic group while 78% and 4%
respectively in HCC group. In our study Serotonin level was
correlated with degree of portal hypertension, splenic size and
portal vein diameter as with statistically significant difference
between serotonin level in cirrhotic patients and healthy control
subjects and between cirrhotic and HCC groups. Abdu Elmoety et al.  found that ROC curve for serotonin cut off 75ng /ml,
93.33 % sensitivity with 100% PPV and 100 % specificity with
83.3% NPV and 95% accuracy, in the present study sensitivity
of serotonin 95.27 % and specificity 88.24%, PPV 97.1% and
accuracy 97.6% for liver cirrhosis. Farintai et al.  concluded
that AFP was not a sensitive marker to detect the presence of
HCC. Also, the prognostic value of AFP is limited, but correlated
with the overall survival in untreated patients. AFP is less specific
and can be elevated in liver cirrhosis and other malignancies, it
is recommended that it is no longer be used for diagnosis of HCC
In our study, Sr. serotonin was significantly higher in Child A
cirrhotic patients than child C (p< 0.005) and also with statistical
significant difference between HCC group and cirrhotic patients.
We found serum serotonin is also correlated with liver synthetic
capacity, child score, sr. bilirubin and prothrombin time. Abdo –
Elmoety et al.  found in the cirrhotic group that ROC for AFP
at cut off 10 ng /ml the area under ROC curve was 0.733, p=0.074
showing 51.11% sensitivity, 100% PPV and 31.25% NPV and 60
% accuracy .Found also serotonin AUROC with cut off 75ng /ml
(0939) p=0.031 showed 86.67% sensitivity and 100% specificity
with 62.50 % NPV and 89.09% accuracy. And serotonin in the
HCC group at cut off 75ng/ml by ROC the diagnostic performance
ARGHived 100%. In the present study sensitivity of serotonin
89.71%and specificity 85%and sensitivity of AFP is 100% and
Combined use of serotonin and AFP is better in diagnosis
of HCC. A significant positive correlation was found between Sr.
serotonin and AFP in HCC patients (r =0.954), p<0.001.So higher
AFP is associated with higher serotonin and this signify the
association between AFP and serotonin and so the importance
of sr. Serotonin as marker of HCC and together with the result
of ROC curve can be considered as a good marker for diagnosis