Clinical Characteristics and Difference at First Detection among … · 2007. 3. 13. · among Hepatocellular Carcinoma Patients with Hepatitis B-, C- Virus, ... TNM stage by liver

Bulletin of the Osaka Medical College 53（1）：21-32, 2007 21

Address correspondence to:Akira Fukuda, M.D., Department of Internal Medicine I, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-city, Osaka 569-8686, JapanPhone: +81-72-683-1221 Fax: +81-72-683-1801 E-mail: [email protected]

〈Original Article〉

Clinical Characteristics and Difference at First Detection

among Hepatocellular Carcinoma Patients

with Hepatitis B-, C- Virus, and Diagnosed as Non-B Non-C type

Toshiaki TANABE, Akira FUKUDA, Rina OOHASHI, Hideo FUKUI,

Yasuhiro TSUDA, Kazuhisa TERAMURA and Toshiaki HANAFUSA

Department of Internal Medicine I, Osaka Medical College,

Takatsuki-city, Osaka 569-8686, Japan

Key Words：hepatocellular carcinoma, hepatitis B virus, hepatitis C virus,

Non-B Non-C type

ABSTRACT

To investigate characteristic differences of hepatocellular carcinoma (HCC), 45 HCC patients

with hepatitis B virus (HCC-B), 216 with hepatitis C virus (HCC-C) and 28 diagnosed as Non-B Non-

C type (HCC-N) were studied retrospectively. There was a male dominant difference irrespective of

causes. The mean age for HCC-B, HCC-C, and HCC-N were 58 ± 9 years, 67 ± 8, and 71 ± 6,

respectively. The detection age of HCC-B was younger with wider range, in contrast to older age

with narrow range among HCC-C or HCC-N. Although the underlying liver status among HCC-B was

broad spectrum from carriers without liver injury to cirrhosis, that among HCC-C was likely to be

cirrhosis with liver damage in many cases. In contrast, many HCC-N had normal liver function

except for heavy drinkers. HCC-B or-C was detected at relatively earlier stage through periodic

screening, but HCC-N was often incidentally detected at an advanced stage. Considering these

characteristic differences among each type of HCC, periodical screening including tumor markers

and imaging studies should be performed for early HCC detection in hepatitis-B or -C carriers. It is

also desirable for patients that are heavy drinkers, obese, or diabetic to undergo the same screening

at least once a year, in consideration of rare but possible HCC.

Introduction

Hepatocellular carcinoma (HCC) is one of themost common malignant diseases in the generalpopulation worldwide (1-3). In Japan, more than30,000 people die of HCC every year and theincidence of HCC is increasing. Early detection of

HCC is a high priority in the medical care of liverdisease.

HCC in Japan is frequently complicated bychronic liver disease, especially liver cirrhosis,caused by hepatitis B (HBV) or C virus (HCV) inthe majority of cases (4-7). These HBV or HCVcarriers have been recognized the high risk group

of HCC onset. It should be noted, however, thatthere are a reasonable number of cases of non-B,non-C type (NBNC) HCC, which tests negative formarkers of these viruses, and that non-alcoholicsteatohepatitis (NASH) has recently drawnattention as a disease underlying HCC (8).

Clinical experience indicates that thecharacteristics of HCC vary depending on thecause of underlying liver disease. For example,HBV carriers occasionally suffer from HCC whenthey are relatively young or have normal liverfunction. In contrast, HCC in HCV carriers isoften observed with liver cirrhosis. On the otherhand, NBNC HCC is often detected incidentally.

Hence, a key to time- and cost-efficientscreening of HCC patients for chronic liverdiseases in medical check-up resides in gaining anunderstanding of the clinical characteristics anddifferences of each type of HCC. However, therehave been very few reports identifying andcomparing the clinical characteristics of HCC bycauses of underlying liver disease.

The purpose of this study is to investigateclinical characteristics and differences of HCCrelated with HBV, HCV, and NBNC at firstdetection by analyzing retrospectively, andpropose points for consideration that may help inthe early detection of the disease.

Patients and Methods

Patients

We reviewed the medical records of HCCpatients admitted to the Liver Unit at theDepartment of Internal Medicine (I), OsakaMedical College Hospital during the period fromAugust 1991 to June 2005. The data on clinicalfindings at the time of first detection of HCC in atotal of 289 consecutive patients were analyzedretrospectively.

The diagnosis of HCC was made by analysis ofimages from abdominal ultrasonography (US),computed tomography (CT), magnetic resonanceimaging (MRI), and hepatic angiography and/orhistological findings from targeted needle biopsyfrom the tumor under US guidance.

Viral markers, biochemical liver function tests,and screening markers of HCC at time of the firstdetection were evaluated. Serum hepatitis Bsurface antigen (HBs Ag), anti-hepatitis Cantibody (HCV Ab) and HCV-RNA detected by thepolymerase chain reaction (PCR) were assayedusing commercially available assays. Thefollowing biochemical liver function parameters

Bulletin of the Osaka Medical College 53（1）：21-32, 2007

Toshiaki TANABE et al.22

were measured using a standard multi-channelauto chemical analyzer: serum albumin (Alb),total bilirubin (T.B), aspartate aminotransferase(AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP) and alkalinephosphatase (ALP). Platelet count (PLT) andprothrombin time (PT) were also assayed.

The definition of HBV-related HCC (HCC-B)was based on a finding of persistently positive HBsAg, and the definition of HCV-related HCC (HCC-C) was based on the presence of HCV Ab andHCV-RNA. In the present study, HCC without HBsAg, HCV Ab, and HCV-RNA was defined as NBNCHCC (HCC-N). HCC-N patients included thosewith alcoholic liver disease, but there were nopatients who had any other chronic liver diseasessuch as autoimmune hepatitis, primary billiarycirrhosis, drug-induced liver injury, Wilson’sdisease or other congenital metabolic liverdiseases.

Severity of liver function was graded by theChild-Pugh classification (9) on the basis of theclinical data.

The number and the distribution of intra-hepatic tumors, the presence of portal thrombosis,and the existence of ascites were assessed by US,CT, MRI, and angiography. The size of tumor wasestimated by CT. The presence of distantmetastasis of HCC was ascertained by severalimaging techniques including chest X-rayexamination and bone scintigraphy.

Informed consent was obtained from eachpatient in accordance with the HelsinkiDeclaration.

Screening Markers for Detection of HCC

Serum alpha-fetoprotein (AFP) and proteininduced by absence of vitamin K or antagonist-II(PIVKA-II) were taken as representativescreening markers for the detection of HCC, andwere examined using commercially available kitsat the time of first detection of HCC. The markerswere taken to be definitely positive when theirlevels were above the upper limit of the normalrange.

Evaluation of the Degree of Liver Damage

and TNM Stage of HCC

In the present study, we evaluated HCCpatients according to tumor node metastasis(TNM) staging and liver damage (LD) grade basedon the General Rules for the Clinical andPathological Study of Primary Liver Cancer set bythe Liver Cancer Study Group of Japan (LCSGJ)


Characteristics and difference of HCC 23

(10). The TNM staging of the LCSGJ shown inTable 1 includes four grades (stage I, II, III, andIV) as follows; stage I (fulfilling the following threeconditions: solitary, less than below 2cm, no vesselinvasion), stage II (fulfilling two of the threeconditions), stage III (fulfilling one of the threeconditions), stage IV (not fulfilling any of thethree conditions), respectively.

The liver disease stage of the LCSGJ shown inthe Table 2, called the liver damage classification,includes three grades (liver damage grades A, B,and C) (11). These classifications have been usedcommonly in Japan, and are very useful toprecisely determine the residual liver function andcancer spared, separately.

Medical Check-ups in Screening of HCC

To evaluate the clinical significance of periodicmedical check-ups for HCC by screening formarkers of HCC at least every 3 months, withabdominal US and/or CT examination at leastevery 6 months, HCC patients were classified intothree groups according to patterns of medicalcheck-ups as follows: “regular check”, wherepatients had visited a medical institution regularlyand undergone periodic HCC check-ups; “irregularcheck”, where patients had visited a medicalinstitution regularly or irregularly but had notundergone a periodic medical HCC check-ups; “nocheck”, where patients had not visited a medicalinstitution and had not received any medicalcheck-ups.

T category

N category

M category

Criteria 1 Number of tumors: solitary

2 Tumor diameter: no more than 2 cm

3 No vascular or bile duct invasion: Vp0, Vv0, B0

T1 All three criteria are fulfilled

T2 Two of the three criteria are fulfilled

T3 One of the three criteria is fulfilled

T4 None of the three criteria is fulfilled

N0: Absence of lymph node metastasis

N1: Presence of lymph node metastasis

M0: Absence of distant metastasis

M1: Presence of distant metastasis

TNM Stage of Hepatocellular Carcinoma

T category N category M category

Stage I

Stage II

Stage III

Stage IV-A

Stage IV-B

T1

T2

T3

T4

T1,T2,T3,T4

T1,T2,T3,T4

N0

N0

N0

N0

N1

N0,N1

M0

M0

M0

M0

M0

M1

Table 1. TNM stage by liver Cancer Study Group of Japan Criteria


Toshiaki TANABE et al.24

Statistical Analysis

Non-parametric analysis (Mann Whitney’s Utest, Kruskal-Wallis test) was used to evaluateamong clinical variables in each HCC group. A Pvalue of <0.05 was considered as statisticallysignificant.

Results

Demographic and Clinical Features of HCC

Patients

Among 289 HCC patients, 45 patients (15%)were defined as HCC-B, 216 patients (75%) asHCC-C, and 28 patients (10%) as HCC-N. Therewere no HCC patients who were positive for bothHBs Ag and HCV Ab in this study (Table 3).Among 28 HCC-N patients, 12 (43%) had a long-term history of alcohol consumption (ethanolintake >80 g/day for 10 years), 11 (39%) had type2 diabetes mellitus, and 7 (25%) were obese(body mass index >25 kg/m2).

The proportion of men was similarly high(70%) in each HCC group, and there wassignificant male-dominant difference in each threegroups. The age at detection of HCC was 58 ± 9years for HCC-B, 67 ± 8 years for HCC-C, and 71 ±

6 years for HCC-N. Figure 1 shows thedistribution of age at detection of HCC. Onaverage, age was 10 years lower at detection ofHCC-B than age at detection of HCC-C, with awide range, from 30 to 76 years. In contrast,about 80% of HCC-C patients were more than 60years old. Among the HCC-N patients, none wereaged less than 60 years old and most were over 70years old.

Laboratory Characteristics at Detection of

HCC

In comparison of the laboratory data among thethree HCC groups (Table 4), the mean serum Alblevel was found to be lower and the mean serumAST and ALT levels were elevated to a greaterextent in HCC-C patients than in the otherpatients. The levels of γ-GTP and ALP were moresignificantly elevated than HCC-C patients.Platelet count in HCC-C patients was significantlylower than that in HCC-B or -N patients.

It is well-known that the level of serum ALT isa sensitive marker for the degree of necro-inflammation of hepatocytes and that plateletcount is a marker for the degree of liver fibrosis.Child-Pugh classification is widely used for the

Clinical and laboratory findings Grade

BA C

Ascites

SerumBilirubin(mg/dl)

Serumalbumin(g/dl)

ICGR15(%)

Prothrombinactivity(%)

None

<2.0

>3.5

<15

>80

Controllable

2.0-3.0

3.0-3.5

15-40

50-80

Uncontrollable

>3.0

<3.5

>40

<50

Each clinical and laboratory findings listed in the chart is classified into one of three grades. The severity of each finding is evaluated separately. Degree of liver damage is recorded as A, B, or C, based on the highest grade containing at least 2 findings.

Table 2. Degree of liver Damage of Liver Cancer Study group of Japan

Table 3. Demographic Features of HCC Patients

Group No. of patients (%) Age (range) Male (%) : Female

HCC-B

HCC-C

HCC-N

45 (16%)

216 (74%)

28 (10%)

58 ± 19 ( 30-76 )

67 ± 18 ( 48-86 )

71 ± 16 ( 60-85 )

31 (69%) : 13

151 (70%) : 65

19 (68%) : 9

* HCC-C vs. HCC-B; P<0.001, HCC-C vs. HCC-N; P<0.05, HCC-B vs. HCC-N; P<0.001



evaluation of liver function. In addition, theclassification of liver damage by LCSGJ was usedfor the evaluation of liver function in HCC patientsin this study. As shown in Table 5, 19 (42%) of 45patients with HCC-B were asymptomatic HBVcarriers with a normal ALT level; however, 161(75%) of 216 patients with HCC-C had anabnormal ALT level and 30% had ALT×2 timesthe upper limit of normal. The ALT level in 20(71%) of 28 patents with HCC-N was within thenormal range.

Of the patients with HCC-C, 174 (80%) had a

below normal level of PLT and 57% had levelslower than 12 × 104/µml. However, in patientswith HCC-N, more than half of the patients (54%)had normal PLT counts.

Regarding liver function at the time of HCCdetection, most patients in each of the threegroups were classified as Child-Pugh class A andwith liver damage grade A on LCSGJ, but the liverfunction in HCC-C patients was slightly decreasedcompared with that in HCC-B or -N patients.

Fig. 1 Age distribution of the total number of HCC among patients with HBV (A), HCV (B), and Non-BNon-C (C). The age at detection of HCC was 58 ± 9 years for HCC-B, 67 ± 8 years for HCC-C, and71 ± 6 years for HCC-N, respectively. Detection age of HCC-C and –N patients was significantlyolder than that of the HBV patients. (Each P < 0.05).

HCC-B HCC-C HCC-N P

T.B(mg/dl)

Alb(g/dl)

AST(IU/l)

ALT(IU/l)

γ-GTP(IU/l)

ALP

PLT

PT(%)

1.0 ± 0.7

3.8 ± 0.5

68 ± 62

57 ± 59

100 ± 112

346 ± 216

15.2 ± 8.1

83 ± 17

1.0 ± 0.7

3.5 ± 0.5

73 ± 43

70 ± 50

105 ± 101

373 ± 234

12.3 ± 6.2

83 ± 12

1.1 ± 1.0

3.7 ± 0.6

47 ± 18

43 ± 42

252 ± 265

519 ± 371

17.8 ± 8.8

87 ± 17

0.8391

<0.0004

<0.0001

<0.0001

<0.0001

0.0196

0.0003

0.068

Data represent mean ± SD.

Table 4. Laboratory Findings of HCC Patients at Detection

Tumor Features at Detection of HCC

The characteristics of the tumor at the time ofHCC detection are demonstrated in Table 6. Thedetection of a single nodule less than 2 cm,defined as the early stage of HCC, occurred in 10(22%) of 45 cases of HCC-B, 62 (29%) of 216cases of HCC-C, but in only 1 (4%) of 28 cases ofHCC-N. Six (21%) of 9 cases of HCC-N had alarge (>5 cm) tumor, even if it was detected as asingle nodule.

In comparison with HCC-B or HCC-C cases, thedetection of a mutifocal or diffuse type was morefrequent in HCC-N cases. The rate of vascularinvasion in HCC-C cases was less than that inHCC-B or HCC-N cases.

Regarding TNM staging, 64% of HCC-B caseswere stage I and II, and 63% of HCC-C cases werestage I and II. Of the 28 cases of HCC-N, 23 (82%)were stage III and IV, with most of the HCC-Npatients already having advanced HCC at the timeof tumor detection.

Screening Markers at Detection of HCC

Detection of HCC using screening markers isdemonstrated in Figure 2. In HCC-B and HCC-Cpatients, approximately 60% of positive caseswere detected when screening was conductedusing AFP or PIVKA-II individually. However,when the two markers were used together,approximately 80% of positive cases weredetected. In HCC-N patients, however, thedetection rate was only 36% using AFP solely,increasing to 64% using a combination of the twomarkers.

Table 7 shows the relationship between TNMstage assessed by LCSGJ and the screeningmarkers in the three HCC groups. Tumordetection at stage I that is the detection of a singleHCC nodule of less than 2 cm without vascularinvasion and extra-hepatic metastasis was seen in7 (70%) of 44 cases of HCC-B and 24 (45%) of188 cases of HCC-C, but no cases of HCC-N weredetected at stage I. Regardless of the type ofHCC, the percentage of cases of HCC detected bythe use of screening markers was proportional tothe degree of TNM staging for both AFP andPIVKA-II.

26


Toshiaki TANABE et al.

HCC-B HCC-C HCC-N P

SerumALTlevels(IU/l)

＜ 40

40 ≦　＜ 80

80 ≦

19(42)

17(38)

9(20)

55(25)

97(45)

64(30)

20(71)

5(18)

3(11)

0.0001

PlateletCounts(×104)

＜ 12

12 ≦　＜16

16 ≦

18(40)

11(24)

16(36)

124(57)

49(23)

43(20)

9(32)

4(14)

15(54)

0.0024

Child-PughClassification

A

B

C

37(82)

7(16)

1(2)

161(75)

46(21)

9(4)

22(79)

4(14)

2(7)

0.7021

LiverDamagebyLCSGJ

A

B

C

33(73)

10(22)

2(4)

137(63)

67(31)

12(6)

21(75)

5(18)

2(7)

0.4427

The values represent number with the percentage in parentheses.

Table 5. Serum ALT Levels, Platelet Counts, and Degree of Liver Damage of HCC



HCC-B(n=45)

HCC-C(n=216)

HCC-N(n=28)

P

Tumortype

Monofocal

≦ 2cm

2cm＜　≦cm

5cm＜

MutifocalorDiffuse

27(60)

10(22)

14(31)

3(7)

18(40)

108(50)

62(29)

37(17)

9(4)

108(50)

9(32)

1(4)

2(7)

6(21)

19(68)

0.0266

Vascularinvasion

No/Yes 30(67) / 15(33) 175(81) / 41(19) 7(61) / 11(39)

0.0266

TNMStagebyLCSGJ

I

II

III

IV

10(22)

20(44)

6(13)

9(20)

59(27)

78(36)

51(24)

28(13)

0(0)

5(18)

11(39)

12(43)

＜0.0001


Table 6. Characteristics and Stage of HCC at Detection

Fig. 2 Detection of HCC among HBV, HCV, and Non-B Non-C patients using AFP (A), PIVKA-II (B), andthe combination of these markers (C). Approximately 60% in HCC-B and HCC-C cases weredetected using AFP or PIVKA-II solely, and the use of two markers was more effective forscreening of HCC. In HCC-N patients, the detection rate was 36% using AFP solely andsignificantly lower than that of HCC-B or HCC-C. The detection rate was 64% using acombination of the two markers. (*P < 0.05, ** Not significant)

Detection of HCC in Relation to the Pattern

of Medical Check-Ups

Stage of HCC in relation to the pattern ofmedical check-ups is shown in Table 8.Approximately half of HCC-B and HCC-C patientsreceived regularly medical check-ups, but 19(68%) of the 28 HCC-N patients had not receivedregularly medical check-ups.

In each HCC group, many of cases where HCCwas detected at the earlier stages (stages I and II)were receiving regularly medical check-ups, butcases detected at more advanced stages (stages IIIand IV) were mainly in patients who had notreceived any medical check-ups. This tendencywas particularly striking in HCC-B and HCC-Cpatients. Among patients who had regularlycheck-ups for HCC, 9 (39%) cases of HCC-B weredetected at stage I, with 13 cases (57%) of HCC-Bdetected at stage II. For HCC-C, 49 (47%) and 42cases (40%) were at stage I and stage IIrespectively.

Among patients who had not received anymedical check-ups, however, only one (5%) and 3cases (4%) were detected at stage I for HCC-Band HCC-C, respectively. In contrast, no cases ofHCC-N were detected at stage I, regardless of thepattern of medical check-ups, and most caseswere detected at more advanced stages.

Discussion

The present study confirmed clinical character-istics and difference among HCC related withHBV, HCV, and Non-B Non-C according to sex-related differences, mean age and age distribution,status of the underlying liver disease, tumor stageat the time of first detection, and opportunity ofHCC detection. These results showed that theregularly medical check-ups with tumor markersand imaging study should be performed based onrecognizing clinical characteristics and differenceamong each HCC for early detection.

28



HCC-B(n=44)

HCC-C(n=188)

HCC-N(n=27)

Total(n=259)

Screening Marker

TNM Stage

I(n=63)

II(n=92)

III(n=59)

IV(n=45)

5(50)

12(63)

4(67)

7(78)

3(30)

10(53)

5(83)

9(100)

7(70)

15(79)

5(83)

9(100)

AFP PIVKA-II and / or

22(42)

42(63)

32(73)

18(72)

18(35)

30(45)

32(73)

25(100)

24(45)

54(79)

39(93)

25(100)


0(0)

0(0)

4(36)

6(55)

0(0)

2(40)

7(64)

9(82)

0(0)

2(40)

7(64)

9(82)


27(43)

54(59)

40(75)

31(69)

21(33)

42(46)

44(75)

43(96)

31(49)

71(77)

51(86)

43(95)



Table 7. TNM Stage and Detection of HCC by Screening Makers

HCC-B

Medical Check

Stage of HCC

I(n=63)

II(n=92)

III(n=59)

IV(n=45)

9(39)

13(57)

1(4)

0(0)

0(0)

1(50)

1(50)

0(0)

1(5)

6(30)

4(20)

9(45)

Regular

(n=23)

Irregular

(n=2)

No

(n=20)

HCC-C

49(47)

42(40)

13(12)

1(1)

7(17)

15(36)

16(38)

4(9)

3(4)

21(31)

22(32)

23(33)

Regular

(n=105)

Irregular

(n=42)

No

(n=69)

HCC-N

0(0)

2(22)

6(67)

1(11)

0(0)

3(30)

2(20)

5(50)

0(0)

0(0)

3(33)

6(67)

Regular

(n=9)

Irregular

(n=10)

No

(n=9)

The value srepresent number with the percentage in parentheses.

Table8. Stage of HCC in Relation to the Medical Check Pattern



It is widely known that sex-related differencesexist between HCC-B and HCC-C, with a greaterprevalence in males (1-3). In the present study,males were over-represented (about 70%) in allgroups of HCC patients, including HCC-N,irrespective of the cause of the disease. Bugianesiet al. investigated the clinical characteristics ofHCC as a complication of cryptogenic livercirrhosis (LC) and reported it to be moreprevalent among males irrespective of the cause ofthe disease (12). Additionally, a study of HCCthat developed as a complication of non-alcoholicsteatohepatitis (NASH) in Japan revealed atendency for male dominance (8).

Age at first HCC detection varied widely, with amean age of 58 ± 9 years for HCC-B, including anumber of patients who were relatively young atonset. For HCC-C, however, the mean age of thepatients was 67 ± 8 years, with most patients inthis group aged over 60. Among patients withHCC-N, elderly patients over 70 were prevalent.Shiratori et al. reported that the mean ages of theHCC-B and HCC-C patients in Japan were 52 ± 13and 62 ± 7 years, respectively (13). Our studyrevealed higher mean ages, by about 5 years forboth groups, compared with these figures. Sincethey reported the age of patients in their studybetween 1990 and 1993, it may be that HCCpatients in Japan are gradually aging. Theyevaluated the age distribution of their studypopulation and pointed out the same tendencythat we found, i.e., HCC-C was detected in olderpatients over a narrow age range, whereas HCC-Bwas detected in younger patients over a wide agerange (13). The mean age of the HCC-N patientswas 71±6 years, and they were older at the time offirst detection than that of the HCC-B and HCC-Cpatients. Bugianesi et al. reported that patientswith HCC underlying cryptogenic LC weresignificantly older than HCC-B and HCC-Cpatients (12). Likewise, Ratziu et al. reported thatHCC patients with cryptogenic LC were older byabout 8 years than HCC-C patients (14).Although our HCC-N patients included those withalcoholic liver disease, 16 (57%) of them had HCCbased on cryptogenic liver disease, showingsimilar characteristics to those mentioned above.

One of the major characteristics of HCC inJapan is that the majority of patients have chronicliver disease caused by HBV or HCV, as anunderlying disease (4,7). In our study, the HCC-Bpatients had a broad spectrum of underlying liverpathologies, ranging from asymptomatic HBVcarriers (ASC-B) with normal liver function to LC,

whereas many of the HCC-C patients were basedon LC with necro-inflammatory activity. Shiratoriet al. also pointed out similar differences betweenthe patients with HCC-B and HCC-C (13). Thisfinding is considered to reflect the difference inthe mechanism of carcinogenesis between them.HBV is a DNA virus thought to be incorporatedinto the liver cell nuclei (15), contributing directlyto carcinogenesis (16-19). Hence, HCC can occurin HBV carriers, irrespective of age and thepresence or absence of liver cell injury. Incontrast, HCV is an RNA virus thought to beassociated with carcinogenesis due to chronicpersistent liver cell injury; it has been reportedthat the risk of carcinogenesis with this virusincreases with the progression of fibrosis (20). Inthe present study, the majority of the HCC-Cpatients had serum ALT abnormalities and plateletcount reductions, which suggested underlying LC.Another noticeable finding in the HCC-C patientswas decreased reserved liver function. Incontrast, many of the HCC-N patients had normalliver function except for those with alcoholic liverdisease. A previous report of HCC based oncryptogenic LC revealed a higher prevalence ofpatients with normal ALT level (12). Someauthors consider that cases of cryptogenic LC aremostly derived from NASH (21); this condition isconsidered to progress more slowly and to beassociated with better liver function than viralliver disease.

ALT levels provide a highly sensitive marker ofthe activity of necroinflammatory of liver cells,whereas platelet counts indicate the degree ofliver fibrosis; these are easily measured onhematological examination. In the present study,about 70% of the HCC-N patients and about 40%of the HCC-B patients were with normal ALT. Onthe other hand, the majority of the HCC-Cpatients had ALT abnormalities. As for the HCC-Npatients, more than half had normal plateletcounts, whereas 80% of the HCC-C patients hadreduced platelet counts. These results suggestedthat special attention should be paid to possibleHCC in HBV carriers even with normal ALT andplatelet counts, and in HCV carriers with reducedplatelet counts.

AFP and PIVKA-II are widely known as HCC-specific tumor markers (22). In the present study,the positivity rate at the first detection of HCCwas about 60% for each of these markers whenused separately and about 80% when the twowere used in combination, showing generallysimilar rates to those obtained previously (23).

30


Interestingly, for HCC-N, the AFP positivity ratewas significantly lower. Although the positivityrate increases with the combination of the twotumor markers, these markers serve asupplementary purposes; it should be noted that areasonable number of cases of HCC are negativefor these markers.

Regarding the tumor stage at first detection,HCC-B and HCC-C were often detected relativelyearly. In Japan, there has recently been increasedmedical awareness of the fact that HBV and HCVcarriers represent a population at increased risk ofHCC (3,4), and this seems to have contributed tothe trend for early detection of the disease.However, even in cases where the disease isdetected with a small tumor size, intrahepaticmulti metastasis is often found; this is unique tothe mutifocal onset of HCC, distinguishing thedisease from malignant tumors of other organs. Incontrast, HCC-N was frequently detected in theadvanced stages. This is probably because itremains unknown which types of underlying liverdisease represent increased risks of carcino-genesis in NBNC patients.

Analysis of opportunities of detection of thedisease reconfirmed the importance of recognizingpopulations at increased risk of HCC, andperforming regularly medical check-ups, for theearly detection of the disease. Shiratori et al.emphasized the importance of periodical medicalchecks for HBV and HCV carriers, as the clinicaldisease stage and prognosis of HCC are influencedby the presence or absence of such checks (13).On the other hand, HCC-N was shown to be quitedifficult to detect early. Marrero et al. reported ontheir follow-up study in which the detection ratewas 23% for HCC based on cryptogenic LC,showing a significantly lower rate than HCC basedon other causes (61%) (24). In fact, in themajority of cases of HCC-N in the present study,HCC was detected incidentally by screening US inmedical check-ups or in response to the patient’scomplaint of symptoms.

To facilitate the early detection of HCC,periodical medical check-ups by hematologicalexamination including tumor markers and imagingtests such as US or CT at intervals of 3 to 6months, have been recommended (25). It is alsoimportant to identify populations at high risk ofcarcinogenesis, taking into consideration theclinical characteristics of each of underling liverdisease, and to perform medical examinationperiodically. HBV and HCV carriers representincreased risks for HCC, necessitating regular

medical check-ups. Suggested risk factors ofcarcinogenesis in HBV carriers include HBeantigen positive, existence of HBV-DNA, andadvanced liver fibrosis; special attention should bepaid to patients with these factors (16). Anotherpoint to note for HBV carriers is possiblecarcinogenesis even in the young and in thosewith normal liver function (26). For HCV carriers,in contrast, the attending physician should bevigilant to persistent liver cell damage and plateletcount reductions, with special attention to the riskof carcinogenesis in cases of progressed fibrosis(20).

For HCC-N, it is necessary to identifypopulations at high risk of HCC onset. In recentyears, NASH has been drawing attention as anunderlying disease in LC and HCC. Aside forcases of LC of known causes such as excessalcohol drinking, autoimmune or metabolic liverdiseases, the majority of cases of cryptogenic LCare considered to be due to NASH (21). A reportis available showing that the incidence of HCCbased on cryptogenic LC did not differ from thatbased on HCV related LC (14). The incidence ofHCC-N appears to be increasing; it has beensuggested that the incidence of HCC is likely torise with the increase in NASH in Europe and theUS (24). The present study revealed some casesof HCC-N with underlying conditions such as non-alcoholic fatty liver, obesity, hyperlipidemia,impaired glucose tolerance or type 2 diabetesmellitus, hypertension, as well as alcoholic liverdisease. In future, more detail analysis in largepopulation is necessary to clarify the high riskgroups of HCC-N patients because of littleinformation for available. It is desirable thatpatients with fatty liver accompanying theseconditions should receive the screening tests withtumor markers and US as part of medicalexamination for health care at least once a year, inconsideration of the likelihood of NASH and rarebut possible HCC.

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Received September 7, 2006Accepted November 7, 2006


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