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Overweight & Fatty Liver Accelerates Activity and Progression of HCV
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“Overweight and obesity, hepatic steatosis, and progression of chronic hepatitis C: a retrospective study on a large cohort of patients in the United States”
Journal of Hepatology, January 2004, 40 (2004) 147–154
Ke-Qin Hu, Namgyal L. Kyulo, Eric Esrailian, Thompson, Resa Chase, Donald J. Hillebrand, Bruce A. Runyon
Division of Gastroenterology/Hepatology, University of California, Irvine, Orange, CA, USA, Department of Medicine, USC Keck School of Medicine, Los Angeles, CA, USA, Department of Pathology, Loma Linda University Medical Center, Loma Linda, CA, USA, Department of Pathology, Jerry L. Pettis Memorial VA Medical Center, Loma Linda, CA, USA, Division of Gastroenterology/Hepatology, Loma Linda University Medical Center, Loma Linda, CA, USA
ABSTRACT/SUMMARY
Hepatic steatosis has been associated with chronic hepatitis C (CHC), but its prevalence, risk factors, and clinical significance remain to be determined.
The present study determined the frequency of, and risk factors for hepatic steatosis and its association with activity and progression of CHC in a large cohort of U.S. patients.
This is a retrospective study that utilized systematic chart review and statistical analyzes to investigate 324 U.S. patients with CHC from a university medical center and a regional VA medical center.
- The frequency of hepatic steatosis was 66.0%.
- We demonstrated that not only being obese, but also overweight (i.e. body mass index ≥25 kg/m2) was independently associated with hepatic steatosis.
- In our cohort of patients with CHC, hepatic steatosis, especially grade II/III steatosis, was significantly associated with elevated aspartate aminotransferase at entry, persistently elevated alanine aminotransferase, and stage III/IV fibrosis.
- Grade II/III steatosis, was significantly associated with a higher histology activity index as well. The presence of steatosis, especially grade II/III steatosis, was independently associated stage III/IV fibrosis
- Multivariate analysis indicated that steatosis, especially grade II/III steatosis, was independently associated with stage III/IV fibrosis. Taken together, our results indicate that the presence of grade II/III steatosis may accelerate progression of fibrosis in U.S. patients with CHC.
The authors concluded that being overweight/obese serves as an independent risk factor for hepatic steatosis in U.S. patients with CHC. Steatosis accelerates activity and progression of CHC, and is independently associated with stage III/IV hepatic fibrosis in these patients.
These data indicate that in patients with CHC, a higher grade of steatosis is more associated with an active and progressive CHC.
For the first time, our data demonstrated that even being overweight can contribute to hepatic steatosis in patients with CHC. Furthermore, multivariate analyzes confirmed that this association was independent of age, ethnicity, a past history of alcohol use, DM, hypertriglyceridemia, and HCV-3a infection. Although both being overweight and obese were associated with hepatic steatosis, this association was more significant in patients with obesity. Thus, a higher BMI carries higher risk for hepatic steatosis in patients with CHC.
It remains controversial whether hepatic steatosis may accelerate fibrosis by stimulating activity of CHC. Some have reported a possible association of a higher grade of hepatic steatosis with higher levels of ALT and HAI, but others were unable to establish this association. Through a thorough univariate analysis, we found that the grade II/III steatosis was significantly associated with a higher HAI, the most reliable histological evidence of active liver injury. In addition, the presence of steatosis, especially grade II/III steatosis, was associated with persistently elevated ALT and elevated AST and AFP at entry, a series of clinical parameters representing active liver injury. Thus, our data provide additional evidence that a higher grade of hepatic steatosis may promote HCV-mediated liver injury. This steatosis-related ongoing liver injury may accelerate progression of hepatic fibrosis and result in an increased incidence of advanced fibrosis in these patients.
Consistent with our findings, an effective weight loss is associated with reduction in steatosis, ALT elevation, and fibrosis stage in patients with CHC.
BACKGROUND
Chronic hepatitis C virus (HCV) infection affects 170 million people worldwide, including 2.7 million of U.S. individuals. Although a great deal of progress has
been made, factors affecting disease progression and development of cirrhosis in these patients remain incompletely defined.
Hepatic steatosis is a well-documented histological feature during HCV infection. Most studies have suggested that obesity is associated with steatosis in patients with chronic hepatitis C (CHC).
However, a general threshold of body mass index (BMI) for steatosis and association of BMI with grade of steatosis remain to be determined. Besides obesity, type 2 diabetes mellitus (DM) and hypertriglyceridemia have also been associated with hepatic steatosis in patients with non-alcoholic fatty liver disease.
Increased frequency of type 2 DM has been reported in patients with CHC. A recent study included 7.7% patients with DM, but could not directly associate DM with hepatic steatosis. In addition, the effect of hypertriglyceridemia on hepatic steatosis in HCV-infected patients has not been systematically examined.Therefore, it is important to determine whether DM and/or hypertriglyceridemia alone, or in combination with obesity, contribute to development of hepatic steatosis in these patients.
Expression of HCV proteins has been associated with hepatic steatosis in transgenic mice. These results were further supported by findings that HCV genotype 3a(HCV-3a) is associated with both higher prevalence and grade of hepatic steatosis in patients with CHC. However, this association remains to be further defined.
Several studies have reported an association of steatosis with advanced hepatic fibrosis in patients with CHC. However, it remains unknown whether a higher grade of steatosis is more associated with a higher stage of hepatic fibrosis. In addition, it remains controversial whether BMI affects progression of fibrosis directly. A few studies have reported that hepatic steatosis is associated with higher levels of alanine aminotransferase (ALT) and histological activity index (HAI), but these findings were not supported by other studies. Thus, it is necessary to re-examine these issues in a large cohort of HCV-infected patients.
The aims of this retrospective study were to determine the prevalence of and the risk factors for hepatic steatosis and to assess the association of being overweight/obese and steatosis with activity and progression of CHC in U.S.patients.
Patient population
The present study retrospectively included 324 consecutive patientsfrom two Liver Clinics at Loma Linda VA Medical Center (n=112) andLoma Linda University Medical Center (n=212) between July 1999 andApril 2002.
Inclusion criteria were: (1) positive HCV RNA reverse transcriptionpolymerase chain reaction (RT-PCR) for at least 6 months; (2) a liverbiopsy to stage CHC; (3) abstinence from alcohol use for >6 months forthose with daily alcohol use of >30 g; (4) negative serology for hepatitis Bsurface antigen and anti-HIV; (5) absence of other causes of chronic liverdisease, history of prior anti-HCV treatment or recent use of steatosis-inducingagents; and (6) no history of hepatic decompensation defined as the presence of ascites, jaundice (total bilirubin >3 mg/dL or 51 mmol/l), variceal bleeding, or hepatic encephalopathy.
Patients who had a history of daily alcohol consumption of >30 g prior to study entry were considered to have alcohol use. According to National Institute of Health criteria, patients with a BMI between 25 and 29.9 kg/m2 were categorized as overweight, and patients with a BMI ≥30 kg/m2 were categorized as obese.
Hypertriglyceridemia were defined as ≥200 g/l. Patients were considered to have type 2 DM if using insulin or oral hypoglycemic agents in adulthood or if they had a fasting plasma glucose level of >126 mg/dL (i.e. 7.0 mmol/l) at the time of enrollment.
Hepatic histology
Knodell’s scoring system was used to stage hepatic fibrosis. While stage 0
represented the absence of hepatic fibrosis, stage III/IV represented advanced hepatic fibrosis. HAI (i.e. total Knodell score – fibrotic score) was used to grade activity of CHC. In the present study, an HAI ≥7 was considered active liver injury. Steatosis was graded on a scale of 0–3: 0=absence of steatosis; grade 1=30% of hepatocytes affected; grade 2=30 to about 70% of hepatocytes affected; grade 3=70% of hepatocytes affected.
Results
Baseline demographic findings
Of the 307 patients with recorded BMI, the mean BMI was 28.5±5.3 (17–47) kg/m2. Overweight was seen in 122/307 (39.7%) cases, and obesity was seen in 116/307(37.8%) patients. Overall, 238/307 (77.5%) patients were overweight or obese. In 250 patients with documented information of drinking, 69.6% reported a past history of alcohol use. In 189 patients with recorded duration of sobriety, 32.8% have been sobered for 6–12 months and 67.2% have been sobered for >12 months.
Biochemically, 267 (83.9%) had elevated ALT. Longitudinally, 40/317 (12.6%) had persistently normal ALT, 216/317 (68.1%) had persistently elevated ALT, and61/317 (19.2%) had fluctuating elevated ALT levels. Two hundred thirty-six (73.3%) had elevated AST. Forty-seven (15.3%) had hypoalbuliminemia (35.0 g/l) and70 (21.8%) had platelet counts <130x109/l. In 257 cases who received an AFP assay, 29 (11.3%) had AFP ≥20 mg/l, but negative abdominal CT for liver mass lesions.
Histologically, 186 (57.4%) had CHC and stage 0–2 fibrosis, while 74 (22.8%) and 64 (19.8%) had stage III and IV fibrosis, respectively. In the present study, patients with stage III and IV fibrosis were combined as a group with advanced fibrosis. Of the 226 patients with recorded HAI, the medium score was 4 with range of 0–12. Fifty-two (23.0%) had HAI $7 and 174 (76.1%) had HAI <7. Of the 324 patients, 214 (66.0%) showed histological evidence of hepatic steatosis including 117 (36.1%) with grade I, 65 (20.1%) with grade II, and 32 (9.9%) with grade III steatosis. Because of the relatively small number of patients with grade II and III steatosis, these patients were combined for statistical analysis. Positive hepatic iron staining was seen in 46 (16.0%) patients.
Risk factors for hepatic steatosis
Although the frequency of steatosis was significantly associated with a BMI ≥25 kg/m2, it was more significantly associated with a BMI ≥30 kg/m2 as indicated by a higher odds ratio (OR). In addition, when these patients were further divided
based on BMI, the frequency of steatosis was significantly higher in individuals with a BMI ≥30 kg/m2 (83.6%, n=116) than in those with a BMI $25 and ,30 kg/m2
(60.9%, n=122, P=0:0009). Thus, hepatic steatosis was more significantly associated with being obese than overweight. Multivariate analysis revealed that after adjusting for age, ethnicity, history of alcohol use, DM, hypertrigly-ceridemia, and HCV-3a infection, being overweight/obese (i.e. BMI ≥25 kg/m2) remained an independent risk for presence of and grade II/III hepatic steatosis.
In our cohort of patients, a history of DM or hypertriglyceridemia was not statistically associated with steatosis. Both univariate and multivariate analyzes did not reveal association of past history of alcohol use and duration of sobriety with hepatic steatosis in these patients. Although HCV-3a infection was more
frequently seen in patients with hepatic steatosis, this difference was not statistically significant by both univariate and multivariate analyzes. Steatosis was
not associated with age at entry, gender, ethnicity, or high HCV load.
Association of hepatic steatosis with the parameters of activity and stage of CHC
To test the association of steatosis with parameters related to activity and stage of CHC, univariate analysis was used to assess 12 clinical and biochemical parameters. The presence of steatosis was significantly associated with elevated level of AST at entry and longitudinally persistent elevation of ALT, which are
biochemical surrogates indicating active CHC.
In addition, steatosis was significantly associated with stage III/IV fibrosis, the most important histological criteria for advanced CHC. However, steatosis was not associated with elevated serum ALT, AFP and ferritin at entry, hypoalbuminemia,
and hepatic iron staining.
To further examine the pathogenic role of steatosis on CHC progression, the same univariate analysis was also performed to compare patients lacking steatosis to those with grade II/III steatosis. All three variables that had been associated with the presence of steatosis were even more associated with grade II –III steatosis as indicated by higher ORs. Furthermore, grade II/III steatosis was also significantly associated with a higher HAI, a histological indicator of active CHC, and elevated AFP, a reported surrogate of advanced hepatic fibrosis. Grade II/III steatosis was not associated with age at the exposure, elevated ALT and ferritin at entry, hepatic iron staining, hypoalbuminemia, thrombocytopenia, and splenomegaly. A multivariate analysis revealed that after adjusting for ALT and AST levels, ALT pattern, hypoalbuminemia, thrombocytopenia, and HAI, the presence of steatosis, especially grade II/III steatosis, was independently associated stage III/IV fibrosis. These data indicate that in patients with CHC, a higher grade of steatosis is more associated with an active and progressive CHC.
To further define the association of steatosis with fibrosis, two additional analyzes were carried out. First, the mean fibrosis score was 1.7 ^ 1.3 in patients without
hepatic steatosis, which was increased to 2.4±1.2 (P=0.001) in patients with grade II/III steatosis. Second, in patients without hepatic steatosis, 30.9% had stage III/IV
fibrosis. However, in patients with grade II/III steatosis, 58.8% (P=0.0002) had stage III/IV fibrosis.
Discussion
The present study investigated a large cohort of US patients with CHC and demonstrated that the frequency of steatosis was as high as 66.0% in these patients. Hourigan et al. reported that 20.0% of Australian patients with CHC
have grade II/III steatosis. Using the same scoring system, grade II/III steatosis was seen in 30.0% of our patients with CHC. Therefore, hepatic steatosis, especially a
higher grade of steatosis, is a very common presentation in U.S. patients with CHC. Although it is well accepted that obesity is associated with hepatic steatosis in patients with CHC, the threshold BMI for hepatic steatosis has not been reported. In our cohort of patients, BMI ≥25 kg/m2 has been significantly
associated with hepatic steatosis. Thus, for the first time, our data demonstrated that even being overweight can contribute to hepatic steatosis in patients with CHC. Furthermore, multivariate analyzes confirmed that this association was
independent of age, ethnicity, a past history of alcohol use, DM, hypertriglyceridemia, and HCV-3a infection.
Although both being overweight and obese were associated with hepatic steatosis, this association was more significant in patients with obesity. Thus, a higher BMI carries higher risk for hepatic steatosis in patients with CHC. It should be
noted that the mean BMI in our cohort of patients and the other U.S. studies (19 and Hu et al. unpublished data) is higher than that reported from other countries. This may contribute to a relatively higher prevalence of steatosis in the U.S. patients with CHC. Interestingly, we also found that BMI ≥25 kg/m2 was associated with any grade of steatosis, indicating that being overweight/obese may not
affect grade of steatosis in these patients. Taken together, our data indicate that being overweight/obesity plays an independent pathogenic role in the development, but not grade of hepatic steatosis in HCV-infected US patients.
Alcohol use can cause hepatic steatosis. In the present study, 69.6% reported a past history of alcohol use defined as >30 g/day, but all had achieved 6-month sobriety prior to enrollment. Our data did not reveal an association of past
history of alcohol use with hepatic steatosis. In addition, the prevalence of steatosis was not different in patients who were sobered for 6–12 vs. >12 months. Although our data provided additional support to previous findings that a history of alcohol use may not be associated with hepatic steatosis in HCV-infected patients, a larger prospective study will be needed to further address this issue.
In transgenic mice, expression of HCV proteins has been associated with hepatic steatosis. Some studies have also revealed a higher frequency and grade of hepatic
steatosis in patients with HCV-3a infection. A recent study indicated that effective HCV treatment is associated with reduced steatosis in patients with HCV-3
infection. However, this association remains controversial. The present study involved a small group of such patients and did not reveal an association between
HCV-3a infection and either presence or grade of hepatic steatosis. Furthermore, a recent study reported that a high prevalence of hepatic steatosis (40.1%) was seen in patients with chronic hepatitis B virus infection as well. Clearly, additional studies, including utilization of HCV replication system, will be required to disclose the association of HCV-3 infection with steatosis.
A recent study revealed that both DM and hypertrigly-ceridemia may not directly associated with hepatic steatosis in HCV-infected patients. Consistent with these results, we observed relatively higher, but not statistically different frequencies of DM and hypertriglyceridemia in HCV-infected patients with hepatic steatosis. The present study did not reveal an association of steatosis with age, gender, ethnicity, HCV-load, serum ferritin, and hepatic iron.
Several studies have indicated an association between steatosis and progression of hepatic fibrosis in different ethnic patients with CHC [8,11,18]. However, data on this issue remain limited and controversial in U.S. patients. More importantly, it remains unknown whether a higher grade of steatosis is more associated with a
higher stage of hepatic fibrosis. The present study assessed a large cohort of U.S. patients and found that presence of steatosis, especially a higher grade of hepatic steatosis, was significantly associated with stage III/IV fibrosis. Patients
with grade II/III steatosis had significantly higher mean fibrotic scores and percentage of stage III/IV fibrosis. In addition, patients with grade II/III steatosis had significantly higher frequencies of hypoalbuminemia, thrombocytopenia,
and splenomegaly, the clinical evidence of portal hypertension and advanced hepatic fibrosis. After adjusting for serum levels of ALT and albumin, platelet count, ALT pattern, and HAI, multivariate analysis revealed that presence of grade
II/III steatosis was independently associated with stage III/IV hepatic fibrosis. Taken together, our results indicate that the presence of grade II/III steatosis may accelerate progression of fibrosis in U.S. patients with CHC.
In conclusion, this study reveals a high prevalence of hepatic steatosis in the U.S. patients with CHC, that is independently associated with being overweight/obese as defined by BMI ≥25 kg/m2. The present study also indicates that in patients with CHC, grade II/III steatosis may accelerate activity and progression of the disease, and is associated with a significantly higher frequency of stage
III/IV fibrosis.
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