Characteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma

doi:10.1016/j.cgh.2011.01.023

Clinical Gastroenterology and Hepatology

Volume 9, Issue 5, May 2011, Pages 428-433

https://doi.org/10.1016/j.cgh.2011.01.023 Get rights and content

Background & Aims

Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC.

Methods

In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed.

Results

Obesity (body mass index ≥25 kg/m²), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008).

Conclusions

Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.

Section snippets

Patients

We retrospectively identified and reviewed 87 Japanese patients with NASH, who developed HCC between 1993 and 2010, at 15 hepatology centers that belong to the Japan NASH Study Group¹⁸ and their affiliated hospitals in Japan. The diagnosis of NASH was based on (1) the histologic features of steatohepatitis, (2) negligible alcohol consumption, and (3) exclusion of liver diseases of other etiology. To determine alcohol consumption as accurately as possible, we reviewed medical records in our

Results

The characteristics of the 87 NASH patients who developed HCC are summarized in Table 1. The median age was 72 years (25th percentile, 69; 75th percentile, 75); the mean age (standard deviation) was 71.2 (6.7) years. There were 54 male patients (62%) and 33 female patients (38%); the male:female ratio was 1.6:1. The median BMI was 26.0 kg/m², and 54 patients (62%) were obese (BMI ≥25 kg/m²). Diabetes, dyslipidemia, and hypertension were present in 51 (59%), 24 (28%), and 47 (55%) patients,

Discussion

In this cross-sectional multicenter study in Japan, we showed the clinical features of a relatively large number (n = 87) of NASH patients with HCC. The male:female ratio was 1.6:1. Men have higher HCC rates than women in almost all populations, with male:female ratios usually averaging between 2:1 and 4:1.² In the latest nationwide survey of HCC in Japan,²⁷ this ratio was 2.5:1. The reasons underlying higher rates of HCC in men might relate to sex-specific differences in exposure to risk

References (39)

D.M. Parkin
Global cancer statistics in the year 2000
Lancet Oncol
(2001)
H.B. El-Serag et al.
Hepatocellular carcinoma: epidemiology and molecular carcinogenesis
Gastroenterology
(2007)
H.P. Cotrim et al.
Nonalcoholic steatohepatitis and hepatocellular carcinoma: natural history?
Am J Gastroenterol
(2000)
M. Shimada et al.
Hepatocellular carcinoma in patients with non-alcoholic steatohepatitis
J Hepatol
(2002)
J.A. Marrero et al.
NAFLD may be a common underlying liver disease in patients with hepatocellular carcinoma in the United States
Hepatology
(2002)
E. Bugianesi et al.
Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma
Gastroenterology
(2002)
V. Ratziu et al.
Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis
Hepatology
(2002)
L.A. Adams et al.
The natural history of nonalcoholic fatty liver disease: a population-based cohort study
Gastroenterology
(2005)
T. Kuzuya et al.
Report of the Committee on the classification and diagnostic criteria of diabetes mellitus
Diabetes Res Clin Pract
(2002)
C.A. Matteoni et al.
Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity
Gastroenterology
(1999)

E.M. Brunt et al.

Non-alcoholic steatohepatitis: a proposal for grading and staging the histological lesions

Am J Gastroenterol

(1999)

E. Bugianesi

Non-alcoholic steatohepatitis and cancer

Clin Liver Dis

(2007)

B.A. Neuschwander-Tetri et al.

Nonalcoholic steatohepatitis: summary of an AASLD single topic conference

Hepatology

(2003)

R.E. Bullock et al.

Association of non-alcoholic steatohepatitis without significant fibrosis with hepatocellular carcinoma

J Hepatol

(2004)

H.L. Bonkovsky et al.

Non-alcoholic steatohepatitis and iron: increased prevalence of mutations of the HFE gene in non-alcoholic steatohepatitis

J Hepatol

(1999)

G.C. Farrell et al.

Nonalcoholic fatty liver disease: from steatosis to cirrhosis

Hepatology

(2006)

P. Angulo

Nonalcoholic fatty liver disease

N Engl J Med

(2002)

E.E. Powell et al.

The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years

Hepatology

(1990)

Y. Zen et al.

Hepatocellular carcinoma arising in non-alcoholic steatohepatitis

Pathol Int

(2001)

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: This article has an accompanying continuing medical education activity on page e50. Learning Objectives—At the end of this activity, the learner should identify the clinical features of patients with nonalcoholic steatohepatitis who develop hepatocellular carcinoma and the role of hepatic fibrosis in the development of hepatocellular carcinoma.

: Conflicts of interest The authors disclose no conflicts.

: Funding This work was supported by a grant from the Ministry of Health, Labour and Welfare of Japan (H20-hepatitis-008 to Takeshi Okanoue).

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Original article—liver, pancreas, and biliary tractCharacteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma

Background & Aims

Methods

Results

Conclusions

Section snippets

Patients

Results

Discussion

Lancet Oncol

Gastroenterology

Am J Gastroenterol

J Hepatol

Hepatology

Gastroenterology

Hepatology

Gastroenterology

Diabetes Res Clin Pract

Gastroenterology

Am J Gastroenterol

Clin Liver Dis

Hepatology

J Hepatol

J Hepatol

Nonalcoholic fatty liver disease: from steatosis to cirrhosis

Hepatology

Nonalcoholic fatty liver disease

N Engl J Med

The natural history of nonalcoholic steatohepatitis: a follow-up study of forty-two patients for up to 21 years

Hepatology

Hepatocellular carcinoma arising in non-alcoholic steatohepatitis

Pathol Int

Original article—liver, pancreas, and biliary tract
Characteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma