INTERPLAY OF RISK FACTORS ON DEMOGRAPHICS AND PATIENT PRESENTATION IN

HEPATOCELLULAR CARCINOMA, A 8 YEAR-REVIEW

*

Njihia BN BSc MBChB, **Mutiso SK BSc MBChB, Lule GN MBChB, MMed PGDip MSc FRCP (Edinburgh)
*

Affiliations: Medical Officer Intern at Kiambu District Hospital and Program Administrator at the Kenya Oncological Research Database
**

Project;
Medical Officer Intern at the Kikuyu Mission Hospital;
Professor of Medicine and Head of Division of Gastroenterology,
Department of Clinical Medicine and Therapeutics, University of Nairobi

Abstract
Introduction: Liver cancer is the third leading cause of cancer-related death in the world. Sub-Saharan
Africa is one of three geographical regions where hepatocellular carcinoma occurs very commonly. Men
are far more likely to develop HCC and this sex difference has been linked to differing hepatitis B carrier
states among other risk factors. Although patients who develop hepatocellular carcinoma usually have no
symptoms other than those related to their chronic liver disease, suspicion for hepatocellular carcinoma
should be heightened in patients with previously compensated cirrhosis who develop features of
decompensation such as ascites and jaundice. The interplay of risk factors and their influence on patient
demographics and presentation in Kenya have however not been described in this Sub-Saharan
population.
Objective: To describe the demographics, risk factor profile and presentation of patients with HCC at a
tertiary referral institution in Kenya during the period of 2002 2010
Methods: This was a cross-sectional, retrospective observational study. All patients with a diagnosis of
HCC over the eight year period between January 2002 and December 2010 admitted to the Kenyatta
National Hospital, whose files could be retrieved were included in the study. Descriptive statistics and
Chi-square analyses were carried out.
Results: A total of 286 patient files were reviewed and included in the study. Overall male to female ratio
was 1.92:1. The age of diagnosis varied with the youngest patient being diagnosed at 7 years and the
oldest at 84 years (Mean= 48.81years, SD=16.027). Moreover, 31.5% of the patients were aged below 40
years. The most common districts of origin of the patients were Murang'a, Kiambu, Makueni, Machakos,
Thika. Abdominal pain was the most common presenting complaint with 81.8% (n=234) of the patients
reporting it.On cross-tabulation analyses, statistical significance was found for right upper quadrant pain
with abdominal mass and ascites. Only 2 (0.7%) had received vaccination against hepatitis B. Of 170
patients who had Hepatitis B surface antigen assay done, positivity was reported in only 38.5% of males
and 26.4% of females. Whereas 14% of patients had a history of possible aflatoxin exposure, statistical
significance was established only for Makueni and Machakos Districts. HIV, hypertension and diabetes as
comorbidities were present in only 5.2%, 4.2% and 3.1% of patients respectively.
Conclusion: The burden of hepatocellular carcinoma in Kenya presents a high percentage of young
patients and a broad range of risk factors that include alcohol abuse, cigarette smoking and possible
aflatoxin exposure. The weak association of traditional risk factors in some of the high-prevalence
districts calls for future studies to elaborate on other possible modifiers in these regions. This study also
makes a case for the development of adaptable screening programs in the high-prevalence areas in order
to reduce the burden of HCC.

Introduction
The International Agency for Research on Cancer estimates that worldwide, by 2020 there will be 15
million new cases of cancer a year, 70% of which will occur in developing countries (Parkin et al., 2005).
It is feared that most cases of cancer in Africa will be diagnosed at advanced or metastatic stages
(Higginson, 2006; Tomatis, 2006). Liver cancer is the third leading cause of cancer-related death in the
world (Parkin et al., 2005). Sub-Saharan Africa is one of three geographical regions, apart from East Asia
and North America, where hepatocellular carcinoma (HCC) occurs very commonly. This high incidence
has been attributed to the high rates of primary infection with Hepatitis B or C virus coupled with the
impact of the risk factors of HCC in the regions (Venook et al., 2010). The most recently published
accounts from the Nairobi Cancer Registry in Kenya place liver malignancy (not exclusively HCC) as the
7th most common neoplasm in males (5.7% of overall cases) and 9 th amongst females (2.1%).
Hepatocellular carcinoma constitutes 70% of these liver malignancies (Mutuma and Rugutt-Korir, 2006).
Men are far more likely to develop HCC (CDC, 2010). Although not fully understood, the differences in
sex distribution have been thought to be due to variations in hepatitis carrier states, exposure to
environmental toxins, and the trophic effect of androgens (Okuda, 1992). Additionally, risk factors for
development of HCC vary depending on geographical location and degree of development of a country
(Bosch et al., 2004). With regard to risk factor prevalence in the United States and Europe, Hepatitis C,
alcohol consumption, Hepatitis B infection and tobacco smoking predominate. However, in Africa and
Asia Hepatitis B infection has been shown to be the most common risk factor with tobacco smoking,
Hepatitis C infection and alcohol consumption following respectively (Bosch et al., 2004; Shariff et al.,
2009). This is underscored by the findings of the Gambia Liver Cancer Study where HBV carriage was
present in 61% of recruited HCC patients (Kirk et al., 2004).Other environmental risk factors identified
for HCC include: aflatoxin exposure, microcystin-contaminated water and betel nut chewing (Chen et al.,
1996; Ueno et al., 1996; Tsai et al., 2001).
Patients who develop HCC usually have no symptoms other than those related to their chronic liver
disease. Suspicion for HCC should be heightened in patients with previously compensated cirrhosis who
develop decompensation such as ascites, jaundice, or variceal bleeding. These complications are often
associated with extension of the tumor into the hepatic or portal veins or arteriovenous shunting induced
by the tumor (Altekruse et al., 2009). This study therefore sought to describe demographics and patient
presentation in patients presenting with HCC at a tertiary referral centre in Kenya between January 2000
and December 2010.
2

Objective
To describe the demographics, risk factor profile and presentation of patients with HCC at a tertiary
referral institution in Kenya during the period of 2000 2010

Study Design
Cross-sectional, retrospective study.
Setting
Kenyatta National Hospital, an 1800-bed a national tertiary teaching and referral institution in Nairobi,
Kenya
Methodology
All patients with a diagnosis of HCC over the eight year period between January 2002 and December
2010 admitted to the Kenyatta National Hospital, whose files could be retrieved were included in the
study. The eight year period was chosen due to the inability to obtain patients files predating 2002 from
the registry which had discarded inactive files previous to that year. The files included were a
combination of admissions and out patients seen in the Liver and Oncology clinics. Of the total number of
patients seen, simple random sampling was used to obtain the sample size required for the study. As a
result only 286 files out of a total of 562 files were reviewed in the study. The study definition of HCC
was based on a combination of both clinical features and ultrasound findings suggestive of HCC. Ethical
approval was obtained from the Kenyatta National Hospital/University of Nairobi Ethics and Research
Committee. Data capture was paper-based with pre-formatted questionnaires filled by the authors (BNN,
SMK) and a colleague. The pro-forma questionnaires were drafted based on factors identified on
literature review and data included demographics of the patients, characteristics of pain at presentation
where applicable and the presence of jaundice, distension, ascites or a palpable mass per abdomen.
Summary data was also collected on possible risk factors as captured by Senior House Officer clerkship
notes: history of alcohol/smoking, possible aflatoxin exposure, prior history of cirrhosis and Hepatitis B
vaccination. Data analysis was carried out using the Statistical Package for Social Science, version 17.
Descriptive statistics were employed to summarize categorical data; Chi-square was used to determine
relationships among the different categorical risk factors and outcomes.
Results
Patient demographics
A total of 286 patient files were reviewed and included in the study. The year with the highest index of
patients seen was 2006 (Figure 1). Overall male to female ratio was 1.92:1 with 65.7% (n=188) of the

patients being male and 34.3% (n=88) being females (Figure 2). The age of diagnosis varied with the
youngest patient being diagnosed at 7 years and the oldest at 84 years (Mean= 48.81years, SD=16.027).
Moreover, 31.5% of the patients were aged below 40 years (Figure 3). The most common district of
origin of the patients were Muranga (n=35), Kiambu (n=22), Makueni (n=19), Machakos (n=16), Thika
(n=15), Nyeri, Meru and Kitui all had 12 patients. Of the 5 most common districts of origin, male to
female ratios varied from 1.14 2.8: 1. (Figure 4)

Figure 1: Distribution of index admissions over the study period

Figure 2: Sex distribution of patients with hepatocellular carcinoma

4

Figure 3: Distribution of age at diagnosis of patients

Table 1: Sex ratio of patients in the 5 most common districts of origin

District
Male:Female Ratio
Makueni
2.8:1
Kiambu
2.7:1
Machakos
1.7:1
Murang'a
1.5:1
Thika
1.14:1

Clinical presentation
Abdominal pain was the most common presenting complaint with 81.8% (n=234) of the patients reporting
it. In 189 (80.8%) of the patients presenting with pain, it was located in the right upper quadrant of the
abdomen. One hundred and ten (n=110, 47%) of the patients had pain in the epigastric region of the
abdomen. Of the patients with right upper quadrant pain (n=189), 65 (34.4%) of them also had epigastric
pain. However of the patients with epigastric pain (n=110), 45 (40.9%) had an isolated epigastric pain,
while 65 (59.1%) had an associated right upper quadrant pain. In 20.9 % (n=49) the abdominal pain was
located in the other regions of the abdomen plus the right upper quadrant and epigastric regions. This is
summarized in Table 2.

Table 2: The distribution of location of abdominal pain in the patients

Abdominal Pain
location
Right upper quadrant
only
Epigastric only
RUQ and Epigastric

Present

Total

234

Absent

124
45
65
52

In the other presenting complaints, 68.5 % (n=195) of the patients had gross abdominal distention while
86 % (n=246) of the patients had a palpable abdominal mass. Jaundice was observed in 177 (61.9%) of
the patients, while the presence of ascites was demonstrated in 36 % (n=102) of the patients as illustrated
in table 3. On cross-tabulation analyses, statistical significance was found for right upper quadrant pain
with abdominal mass and ascites (p=0.002 and p=0.020 respectively, Table 4).
Table 3: The distribution of other presenting complaints in the patients
Symptom / Sign
Abdominal Distention
Abdominal Mass
Jaundice
Ascites

Present
195 (68.5%)
246 (86.0%)
177 (61.9%)
102 (38.1%)

91
40
109
184

Absent
(31.5%)
(14.0%)
(38.1%)
(64.0%)

Table 4: Cross-tabulation analyses for right upper quadrant pain and other symptoms
SYMPTOM

Right
upper
quadrant
pain

2, (p)
Abdominal
mass

Ascites

Jaundice

Abdominal
distension

9.580 (0.002)

7.853 (0.020)

0.387
(0.534)

2.059 (0.357)

Risk Factor Profile

In all the patients, only 2 (0.7%) had received vaccination against hepatitis B. Some of the patients had
laboratory tests for Hepatitis B and C done. The tests analyzed from the files in the present study
included: Hepatitis B surface antigen (HBsAg), Hepatitis B surface antibody (Anti-HBS), Hepatitis B
core antibody (Anti-HBc) Hepatitis B encaspid antigen (HBeAg) and Hepatitis C antibody (Anti-HCV).
HBsAg was not done in 116 of the patients. In males 38.5% (n=45) had a positive HBsAg result while
6

26.4% (n=14) of the females had a positive result. Anti-HBS was not done in all the patients. Anti-HBc
was not done in 242 patients and of the ones done only 6.5% (n=2) of the males were positive and all the
females tested negative (n=13). HBeAg was only done in 1 of the males and it was a negative result. AntiHCV was not done in 165 of the patients. In the ones who Anti-HCV was done, 5.8% (n=5) of the males
had a positive result while only 2.9% (n=1) of the women had a positive result. This information is
summarised in Table 5.
Nine (3.1%) of the patients had a previous history of liver cirrhosis and 14 %( n=14) had a positive
history of probable aflatoxin exposure. A positive history of smoking was present in 48 (16.8%) of the
patients with 238(83.2%) of patients reporting to have never smoked cigarettes. A family history of
hepatocellular carcinoma was present in 9 (3.1%) of the patients. As shown in Table 7, Chi-square
analyses were statistically significant only for possible aflatoxin exposure in Makueni and Machakos
Districts (2=11.413, p=0.009; 2=14.715, p=0.005 respectively). In the patients co-morbidities, 5.2%
(n=15) had an associated diagnosis of HIV/AIDS while 3.1% (n=9) had diabetes mellitus and 4.2%
(n=12) had Hypertension. Other co-morbidities were observed in 25 (8.7%) of the patients with 9 (3.1%)
of them having a communicable disease and 16 (5.6%) having a non-communicable disease as a
comorbid (Table 6).
Table 5: Laboratory tests done for Hepatitis B and C
Sex
Positive
Negative
Not done
Total

HBsAg
Male
Female
45(38.5
%)
72(62.5
%)
71
188

14(26.4
%)
39(73.6
%)
39
98

Anti-HBc
Male
Female
2 (6.5%)
29(93.5
%)
157
188

0(0%)
13(100
%)
85
98

HBeAg
Male
Femal
e
0(0%)
1(100
%) 98
187

5(5.8%)
81(94.2
%)
102

1(2.9%)
34(97.1
%)
63

188

188

98

98

Table 6: Risk factor profile of the patients

Risk Factor
Hepatitis B vaccination
Liver cirrhosis
Aflatoxin Exposure
Cigarette Smoking
Alcohol Abuse
Family History of HCC

Present
2 (0.7%)
9 (3.1%)
14 (4.9%)
48 (16.8%)
100 (35.0%)
9 (3.1%)

Co-morbidities
HIV/AIDS
Diabetes Mellitus
Hypertension

15 (5.2%)
9 (3.1%)
12 (4.2%)

284
277
272
238
186
277

Absent
(99.3%)
(96.8%)
(95.1%)
(83.2%)
(65.0%)
(96.9%)

271 (94.8%)
277 (96.9%)
274 (95.8%)

Anti-HCV
Male
Female

DISTRIC
T

2, (p)
Alcohol
Abuse

Murang'
a
Kiambu
Makueni
Machak
os
Thika

0.445 (0.505)
1.153 (0.283)
0.103 (0.749)
1.685 (0.194)
2.349 (0.125)

Aflatoxin
Exposure

Smoking
History

2.053 (0.231)
1.227 (0.268)

11.413 (0.009)
14.715 (0.005)
0.815 (0.367)

2.278 (0.131)
1.878 (0.171)
4.105 (0.051)

Table 7: Crosstabulation analyses

for key risk factors
with district of
origin

0.223 (0.998)
1.107 (0.293)

Discussion
There were more male than female patients over the review period. This is in keeping with GLOBOCAN
estimates in 2002, where the overall male: female incidence ratio was 2.4, with this ratio even higher in
areas of greater HCC risk (Parkin et al., 2002). Indeed, Makueni and Kiambu Districts exhibit higher
ratios at 2.8:1 and 2.7:1 respectively. Theories advanced to explain the sex discrepancy include the
androgen-receptor theory (Wu et al., 2010) and differential expression of apolipoprotein A-1 (Yang et al.,
2010). Both theories focus on modulation of the hepatitis-B carcinogenic pathways and as the current
study demonstrates, there might be need to explore the influence of other factors on the development of
hepatocellular carcinoma in Kenya.
Peak age of HCC prevalence in the current study was 41-50 years. These findings are in contrast to the
West, where highest prevalence is seen among those aged over 65 years (El-Serag, 2007; Parikh and
Hyman, 2007). Of note is that 31.5% of patients were aged 40 years and younger. Younger patients have
been shown to have poorer prognosis at 1 year (Chien-Hung et al., 2006) and this may have implications
on the high overall mortality seen locally (Unpublished data, Njihia et al.,). Stuart et al., (1996) also note
that younger age at presentation is found in patient populations where hepatitis and alcohol exposure are
significant contributors. This situation may obtain in the current study, although it may not apply to the
entire spectrum of patients as elaborated below.
8

Right-upper-quadrant pain was reported by 80.8% of patients whereas an abdominal mass was palpable in
86% of patients (p=0.002). Although ascites was present in only 38.1% of patients, it was significantly
associated with right-upper-quadrant pain (2=7.853, p=0.020). Whereas the presence of right-upperquadrant pain with presence of an abdominal mass and ascites may be highly suggestive of hepatocellular
carcinoma, it would be associated with advanced disease (Llovet et al., 1999), hence limiting clinical
utility.
Regarding risk factors for HCC, there is paucity of population-based data on Hepatitis B carrier state.
Baseline screening of adult African volunteers in East Africa (n= 2,107) reported a prevalence of 38%
(Stevens et al., 2008). Although Hepatitis B is recognized as an important risk factor in the development
of HCC, only 0.7% of patients had a history of immuni zation. This study further found HBsAg positivity
to be 38.5% (n=45) in males and 26.4% (n=14) in females. Of the 170 patients who had assays for
HBsAg done, only 5.6% (n=6) were positive for both HBsAg and HIV though this was not statistically
significant (p=0.104). Whereas this prevalence is lower than previous accounts from the same catchment
area (Ogutu et al., 1990) it is noteworthy that the latter study had a smaller sample size (n= 41 versus
170). Higher prevalence of HBV/HIV co-infection has however been reported in the Western region subpopulation of Kenya (Otedo, 2004). HCV/HIV co-infection was rare (0.9%, n=1) a finding that is similar
to studies that have reported prevalence of 0.02% and 3.7% (Karuru et al., 2005a; Karuru et al., 2005b).
These findings imply that Hepatitis B and C infection may not play as significant a role as risk factors in
the central/eastern Kenyan population as described elsewhere (Otedo, 2004; Parikh and Hyman, 2007). A
similar situation may obtain with HIV co-infection as the local rates are much lower than reported in the
rest of sub-Saharan Africa (Burnett et al., 2005).
In the African setup, cirrhosis and aflatoxin-exposure are key risk factors for HCC (Kuniholm et al.,
2008; Turner et al., 2005). The current study showed that the 3 most common risk factors locally are
alcohol abuse, cigarette smoking and possible aflatoxin-exposure (35%, 16.8% and 4.9% respectively).
Probable aflatoxin exposure was however shown to be statistically significant only for Makueni and
Machakos Districts. This is in keeping with the findings of Mwihia et al. (2008) reporting high levels of
aflatoxin in maize for consumption in Makueni District. An inherent bias in this analysis however exists
as clinicians would restrict active interrogation of aflatoxin exposure as a risk factor in patients from these
districts. These findings however also beg the question, What risk factors would then account for the
high prevalence of patients from Muranga, Kiambu and Thika Districts? We posit that other factors not
analysed in the present study such as the high intake of illicit brew in these regions, prepared and stored
in iron drums, may be associated with iron overload that predisposes the population to HCC (Moyo et al.,
1997; Moyo et al., 1998). Genetic factors may also have a role to play (Marrogi et al., 2001).
9

Only 3.1% (n=9) of patients had diabetes as a co-morbidity. Diabetes has been found to increase the risk
of developing chronic liver disease and HCC (El-Serag et al., 2004) by as much as two-fold (Blonski et
al., 2010). With the prevalence rate of diabetes set to increase to 4.5% by 2025, its significance as a risk
factor may increase in the near future.
In conclusion, the current study has highlighted several issues that HCC poses in the central and eastern
regions of Kenya. Health-seeking behaviour may account for the low percentage of patients on follow-up
for liver cirrhosis and is a call to action with regard to the diagnostic work-up of patients by clinicians.
The weak association of traditional risk factors in some of the high-prevalence districts calls for future
studies to elaborate on other possible etiologies in these regions. We believe that this study also makes a
case for the future evaluation of hepatitis B vaccination coverage in adults with the advent of the
pentavalent vaccine in the KEPI schedule starting 2011.
Acknowledgements
We are thankful to the Records Department of Kenyatta National Hospital for their help in file retrieval
with a special thank-you to Messrs Kariuki and Jared. We are also grateful to Dr. Esther Mokaya for her
help in data abstraction and to Prof. Saidi Hassan for his insight in the analysis process.

10

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