Diarrhea as a presenting symptom of hepatocellular carcinoma

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Digestive Diseases and Sciences, Vol. 35, No. 6 (June 1990), pp. 681-685

Diarrhea as a Presenting Symptom of Hepatocellular Carcinoma JORDI BRUIX, MD, ANTONI CASTELLS, MD, XAVIER CALVET, MD, FAUST FEU, MD, C O N C E P C I 0 BRU, MD, M A N E L SOLId, MD, MIQUEL B R U G U E R A , MD, and JOAN RODt~S, MD

The clinical manifestations of hepatocellular carcinoma (HCC) are highly nonspecific since they usually mimic those of hepatic cirrhosis, which frequently underlies this neoplasm. The fact that some HCC patients present with severe diarrhea, an unusual symptom in liver cirrhosis, prompted us to determine the prevalence of diarrhea in a series of 23 consecutive HCC patients and compare it with that of a control group formed by cirrhotic patients without HCC, matched by age, sex, and etiology of the liver disease. All the patients were interviewed about the existence of diarrhea (defined as the presence of three or more loose stools per day appearing over three or more days) in the three months prior to admission. Both groups of patients were similar in regards to the degree of liver failure and presence of diarrhea-favoring factors. By contrast, diarrhea was significantly more frequent among HCC cases than among cirrhotics without HCC (47.8% vs 8.7%, P < 0.005). HCC patients with diarrhea exhibited higher alkaline phosphatase and bilirubin levels and worse liver function, assessed by the Child-Pugh' s classification, than patients without diarrhea. However, neither tumor size, vascular invasion, or the degree of tumor differentiation were significantly different between these two groups of HCC patients. These results show that diarrhea is a frequent manifestation of HCC in patients with cirrhosis. Therefore, the development of HCC in these patients should be suspected upon the appearance of diarrhea. KEY WORDS: diarrhea; hepatocellular carcinoma; paraneoplastic manifestations.

Hepatocellular carcinoma (HCC) is a neoplasm that usually complicates hepatic cirrhosis (1). Therefore, the symptoms of this tumor frequently mimic those of chronic liver disease (2), thus being highly nonspecific. In addition, clinical manifestations of HCC appear only in advanced phases of the disease when only palliative treatment can be Manuscript received August 9. 1989" revised manuscript received February 21, 1990; accepted March 2, 1990. From the Liver Unit and Departments of Radiology and Pathology, Hospital Clfnic i Provincial, University of Barcelona, Spain. This work was supported by the Fundaci6 Catalana per a l'Estudi de les Malalties del Fetge. X. Calvet had a research grant from the Department d'Ensenyament de la Generalitat de Catalunya. Address for reprint requests: Dr. J. Bruix, Liver Unit, Hospital Clfnic i Provincial, C/Villarroel, 170, Barcelona 08036, Spain.

applied. This has led to the concept that the early diagnosis of HCC should be based mainly in imaging techniques and tumoral marker determination [namely, ultrasonography (US) and alphafetoprotein (AFP)] (3). However, there are some clinical manifestations of HCC not usually seen in patients with liver disease and therefore could be helpful in clinically raising the suspicion of HCC. In that regard, there are several case reports describing HCC patients with severe diarrhea associated to the appearance of the tumor (4-6). Moreover, Lai et al (7), in a retrospective analysis of 211 HCC patients, noted that this abnormality could be detected in 21% of the cases 9 The present study was aimed to ascertain prospectively the prevalence of diarrhea in a series of

Digestive Diseases and Sciences, Vol. 35, N o . 6 (June 1990) 0163-2116/90/0600-0681506.00/0 9 1990 Plenum Publishing Corporation



Age (years) Male/female Etiology of liver disease Cryptogenic Alcoholic Posthepatitic Clinical manifestations Ascites Hepatic encephalopathy Bilirubin (mg/dl) ASAT (IU/liter) ALAT (IU/liter) Alkaline phosphatase (IU/liter) Albumin (g/liter) BUN (mg/dl) Prothrombin index (%) Child-Pugh classification Group A Group B Group C Diarrhea-favoring factors Diabetes Active alcoholism Lactulose treatment

65.5 • 18/5

Group B


62.5 • 18/5

12 8 3

12 8 3

9 1 2.4 + 111.0 • 85.4 • 268.9 • 32.5 • 21.2 • 74.1 •

13 4 3.9 • 69.9 • 67.4 • 310.3 • 28.2 • 24.7 • 68.7 •

P value




9 11 3 NS 2 1

1.8 77.3 62.5 167.4 6.7 12.5 18.8

5.2 37.1 44.1 193.8 5.1 15.9 18.6

NS 0.02 NS NS 0.02 NS NS

4 12 7

*NS, nonsignificant difference. H C C p a t i e n t s a n d c o m p a r e it with that of a c o n t r o l g r o u p o f cirrhotic p a t i e n t s w i t h o u t H C C . MATERIALS


Twenty-three consecutive patients with confirmed HCC and 23 control subjects were included in the study. Twentytwo of the HCC cases were confirmed by biopsy or aspirative cytology, whereas the remaining case was confirmed by increased AFP levels. In all the cases HCC complicated liver cirrhosis, which was confirmed by liver biopsy in eight cases and by clinical, biochemical, and US findings in the remaining 15. The control group was formed by 23 cirrhotic patients admitted to the hospital at the same time as the HCC cases and matched for age (+5 years), sex, and the etiology of the underlying liver disease. In these cases the absence of HCC was checked by US examination and AFP determination, while liver cirrhosis was diagnosed by liver biopsy in nine cases or by clinical, biochemical, and US criteria in the remaining patients. All patients had a complete medical examination including renal and liver function tests, hematological parameters, and HBsAg and A F P determination. Both patients and controls answered a preestablished questionnaire to ascertain the existence of diarrhea in the three months prior to admission. Diarrhea was arbitrarily defined as the presence of three or more loose stools per day appearing over three or more consecutive days. The frequency and intensity of diarrhea, macroscopic characteristics (mucus, blood), the existence of associated symptoms (abdominal pain, fever, rectal tenesmus), the presence of nocturnal diarrhea, and the response to dietetic management were also recorded. Finally, factors


such as diabetes, active alcoholism, or treatment with lactulose, all factors favoring the development of diarrhea, were also determined. The tumor size in the HCC patients was assessed according to the US findings, thus dividing HCC into four groups: uninodular 5 cm, multinodular, and diffuse. In the 22 cases with cytological or histological confirmation, the degree of differentiation of the tumor was estimated as follows: In the 11 patients diagnosed by histology, tumor differentiation was graded according to the criteria of Edmondson and Steiner (8). In the remaining cases, diagnosed by cytological criteria, the tissue specimen contained a reduced number of cells. The classification of Edmondson and Steiner was not feasible in these patients and, therefore, tumor differentiation was graded as well, moderately, or poorly differentiated according to previously published criteria (9). In order to group patients stratified by these criteria and those divided by the criteria of Edmondson and Steiner, cases with grade I and II from the latter classification were considered as well differentiated, grade III as moderately differentiated, and grade IV as poorly differentiated. The chi-square test and the Fischer exact test were applied to compare proportions between groups. Mean values of the different characteristics of the patients were compared using the Student's t test and the ANOVA test when required. Results are given as mean -+ standard deviation. RESULTS T h e c l i n i c a l c h a r a c t e r i s t i c s o f t h e p a t i e n t s are s u m m a r i z e d i n T a b l e 1. E i g h t e e n o f 23 H C C Digestive Diseases and Sciences, Vol. 35, No. 6 (June 1990)



Age (years) Male/female Clinical manifestations Ascites Hepatic encephalopathy Bilirubin (mg/dl) Alkaline p h o s p h a t a s e (IU/liter) A l b u m i n (g/liter) B U N (mg/dl) Prothrombin index (%) Child's classification Group A Group B Group C Factors favoring diarrhea Diabetes Active alcoholism Lactulose treatment H C C characteristics Size Uninodular < 5 cm Uninodular > 5 cm Multinodular Diffuse Portal vein invasion Differentiation degree Good Moderate Poor I n c r e a s e d alpha-fetoprotein (>100 ng/ml)

Group A-1

Group A-2

P value

62.4 9/2

68.2 -+ 6.6 9/3

NS* NS 0.03

3.1 343.1 30.0 26.7 71.3


7 1 -+ 2.2 -+ 211.2 -+ 5.2 -+ 15.1 -+ 21.4 2 6 3

2 1.7 200.9 34.9 16.1 76.7

--- 0.9 -+ 70.3 - 7.3 --- 6.8 - 16.5

NS 0.03 NS 0.03 NS NS

7 5 NS

2 1 NS 1 2 6 2 1

5 1 5 1 1

4 6 1

4 3 4




*NS, nonsignificant difference.

patients were male and five female. Mean age was 65.5 --- 7 years (range 45-77), being no different from the mean age of the control group (62.5 --- 8 years, range 40-77). Both cases and controls had liver cirrhosis, whose etiology was cryptogenic in 52%, a l c o h o l i c in 35%, and p o s t h e p a t i t i c (HBsAG § in 13%. In the three months prior to admission, 11 patients with HCC (47.8%) had at least one episode of diarrhea, while this was observed in only two patients (8.7%) of the control group (P < 0.005). Three of the HCC patients had only one episode of diarrhea. Five patients had repeated episodes of acute diarrhea (three or more) and another three had chronic diarrhea of 12, six, and four, weeks of evolution. Diarrhea was severe (more than five depositions per day) (thus being their chief complain) in four cases, moderate (four to five depositions per day) in five cases and light (three depositions per day) in the remaining two. Only one patient reported the passage of mucus, with no cases reporting passage of blood or pus. Four Digestive Diseases and Sciences, Vol. 35, No. 6 (June 1990)

patients had nocturnal diarrhea, with associated symptoms being rare: one patient complained of abdominal pain and another had fever. Diarrhea responded to dietary management in only one of the six patients who was counseled. The clinical data and liver function tests of the patients are depicted in Table 1. There were no differences in regards to the presence of clinical manifestations of liver disease or in the ChildPugh's classification (10). The only significant difference found was in ASAT serum levels, which were significantly lower in HCC patients, and in albumin concentration, which was significantly lower in cirrhotic patients without HCC (Table 1). Finally, there were no differences in the presence of factors favoring diarrhea (Table 1). When comparing HCC patients with diarrhea and those without, the former patients had poorer liver function (higher incidence of clinical manifestations; higher levels of alkaline phosphatase, bilirubin, and BUN; and worse Child-Pugh classification) (10); and a higher proportion of increased AFP



levels (Table 2). By contrast, neither tumor size nor the degree of tumor differentiation or the presence of factors favoring diarrhea were found to be significantly different between these two groups (Table 2). DISCUSSION The present study demonstrates that diarrhea is a common manifestation of HCC in patients with liver disease, since nearly 50% of the cases of this series had had diarrhea in the three months prior to the diagnosis of HCC. Up to now, little attention has been paid to diarrhea as a paraneoplastic manifestation of HCC. There are few case reports of HCC patients with severe diarrhea (4-6), while Lai et al (7) and Okuda (ll) are the only authors who have examined the prevalence of diarrhea in large series of HCC patients. Lai et al found that 21% of their 211 patients presented diarrhea (7). However, only four (2%) reported diarrhea as their chief complaint, which is comparable with the 3.7% prevalence of diarrhea or constipation as early symptoms described in the historical series of 134 HCC patients performed by Okuda (11). However, it must be noted that these studies were done retrospectively and were not specifically aimed at ascertaining the prevalence of diarrhea. Therefore, selflimited episodes of loose stools may not be registered in the medical records. In fact, the diarrhea of these patients does not have specific characteristics and, as shown in our study, its intensity varies from patient to patient and may even be intermittent. Thus, only four patients of our series presented a severe diarrhea of more than five loose stools per day, while in the other seven cases diarrhea was classified as moderate or light. Probably, these less severe cases could have been missed in a retrospective analysis of the clinical records, possibly explaining the high prevalence of diarrhea in our series. The mechanism of HCC-associated diarrhea is not known. The results of the current investigation suggest that impairment of liver function because of the tumor may play a role in the appearance of diarrhea. As shown in Table 2, HCC patients with diarrhea had higher bilirubin and alkaline phosphatase levels than HCC patients without diarrhea, probably reflecting tumor-induced cholestasis, which could favor the development of diarrhea. However, if HCC-associated diarrhea is due to cholestasis, its presence would be related to


tumor growth and probably would not be intermittent. Nevertheless, the statistical analysis of HCC characteristics (size, portal vein invasion, differentiation degree) reflecting tumor evolution argues against this possibility. Probably, the development of diarrhea is due to the production of some substances, such as gastrin, vasoactive intestinal polypeptide, and prostaglandins. Our study cannot confirm this hypothesis since it was not designed to determine the mechanism of diarrhea. However, the case reports described by Steiner et al (4), Saban et al (5) and Solinas et al (6) clearly favor the role of active agents, especially prostaglandins, in the appearance of this manifestation. In the case report of Steiner et al (4) the immunohistochemical study revealed VIP, gastrin, and prostaglandin E 2 immunoreactivity in the tumoral cells. In addition, the surgical ablation of the HCC was followed by the disappearance of the diarrhea (4). In the other two reported HCC cases with severe diarrhea, this was controlled by giving nonsteroidal antiinflammatory drugs (5, 6), further supporting the role of prostaglandins. The present investigation is of interest since it demonstrates that diarrhea is a frequent clinical manifestation of HCC in patients with liver cirrhosis. Accordingly, the development of HCC should be suspected after the appearance of loose stools in these patients. ACKNOWLEDGMENTS

The authors are most grateful to Ms. Eul~tlia Ventura for secretarial assistance. REFERENCES 1. Johnson PJ, Williams R: Cirrhosis and the aetiology of hepatocellular carcinoma. J Hepatol 4:140-147, 1987 2. Kew MC: Clinical manifestations and paraneoplastic syndromes of hepatocellular carcinoma. In Neoplasms of the Liver. K Okuda, KG Ishak (eds). Tokyo, Springer-Verlag, 1987, pp 199-214 3. Okuda K. Early recognition of hepatocellular carcinoma. Hepatology 6:729-738, 1986 4. Steiner E, Velt P, Gutierrez O, Schwartz S, Chey W: Hepatocellular carcinoma presenting with intractable diarrhea. Arch Surg 121:849-851, 1986 5. Saban J, Boixeda D, Moreno A, Barcena R, Serrano-Rios M: Long survival of diarrhea-associated hepatocarcinoma treated with adriamycin and indomethacin. J Clin Pathol 86:241-247, 1986 6. Solinas A, Biscarini L, Morrelli A, Del Favero A: Hepatocellular carcinoma and the watery diarrhea syndrome. Arch Surg 123:124, 1988 Digestive Diseases and Sciences, Vol. 35, No. 6 (June 1990)

DIARRHEA AND HCC 7. Lai CL, Lam KC, Wong KP, Wu PC, Todd D: Clinical features of hepatocellular carcinoma: Review of 211 patients in Hong Kong. Cancer 47:2746-2755, 1981 8. Edmondson HA, Steiner PE: Primary carcinoma of the liver: A study of 100 cases among 48,900 necropsies. Cancer 7:462-503, 1954 9. Calvet X, Pons F, Bruix J, Bru C, Lomefia F, Herranz R, Bruguera M, Faus R, Rod6s J: Technetium-99m DISIDA hepatobiliary agent in diagnosis of hepatocellular carci-

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