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Original Studies |
Department of Surgery, Laval Hospital, Laval University, Ste-Foy G1V 4G5, Quebec, Canada; the Department of Hepato-Pathology, Mount Sinai Medical Center (S.N.T.), New York 10029; and the Department of Surgery, State University of New York Health Science Center at Brooklyn (J.G.K.), Brooklyn, New York 11203
Address all correspondence and requests for reprints to: John G. Kral, M.D., Ph.D., State University of New York Health Science Center at Brooklyn, 450 Clarkson Avenue, Box 40, Brooklyn, New York 11203.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Fatty liver is most prevalently associated with obesity and diabetes through unknown mechanisms. Syndrome X, the metabolic syndrome of obesity, linking noninsulin-dependent diabetes mellitus (NIDDM), dyslipidemia, and hypertension to a male or visceral distribution of adipose tissue, is a more important risk factor for most comorbidities of obesity than obesity per se (4). It is not clear whether the effects of obesity on the liver can be separated from those of impaired glucose tolerance (IGT) or NIDDM or whether they have any relationship to the pathogenesis of inflammation in NASH. Although several components of the metabolic syndrome have separately been correlated with fatty liver, no study seems to have explored the possible pathogenetic role of metabolic syndrome X in liver disease.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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From January 1984 to March 1993, among 580 consecutive patients
who underwent biliopancreatic diversion for severe obesity (5), 551
(95%) had routine wedge biopsy of the liver. Most of the 551 (439
women and 112 men) severely obese patients (mean weight, 124 ± 27
kg; mean height, 169 ± 9 cm) were self-referred without any
particular screening process in the recruitment. Their mean age was 36
yr (range, 16–62 yr). Among the 439 women, 55 were menopausal, and 39
used oral contraceptives (Table 1
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A total of 87 patients were taking antihypertensive medication. Blood pressure on admission to the hospital was recorded by nursing staff using Life Sign (Welch Allyn Co., Skaneateles, NY) with a large cuff while the patient was recumbent. In 162, systolic blood pressure was 140 mm Hg or higher, and 95 patients had diastolic blood pressure of 90 mm Hg or higher. In all, 41% (216 of 527) were either treated for hypertension or were defined as hypertensive because they had elevated systolic or diastolic blood pressure as described.
Dyslipidemia was defined as the presence of any one of the following: serum cholesterol (CHOL) of 7 mmol/L or more, low density lipoprotein CHOL of 5.5 mmol/L or more, high density lipoprotein (HDL) CHOL of 0.8 mmol/L or more, CHOL/HDL ratio of 5, or serum triglycerides of 3.0 mmol/L or more.
None of the 551 patients had any history of hepatitis, and it was not suspected clinically in any patient. Serology to rule out hepatitis was not available. Patients with a history of use of hepatotoxic medication or significant exposure to solvents or similar toxic substances were excluded. Alcohol consumption was assessed from the standard medical history and the anesthesiologists’ preoperative evaluation and thus reflects common medical- surgical practice rather than specialized psychiatric or hepatological assessment. No special test was performed to insure the quality of the information. Consumption was graded as: never, occasional, frequent, or daily. Thirty percent (n = 139) of the 461 patients with available information were smokers.
Blood chemistry
Laboratory data include hemoglobin, and serum albumin, alkaline
phosphatase (ALP), prothrombin time, aspartate aminotransferase (AST),
alanine aminotransferase (ALT), 
-glutamyl transferase, CHOL, HDL,
low density lipoprotein CHOL, serum tryglycerides, and fasting blood
sugar, determined by routine methods.
Anthropometry
On admission to the hospital all patients were weighed in a light gown to the nearest 0.1 kg on a Detectomedic scale when weight was 136 kg or less and on an electronic Toledo scale when weight exceeded 136 kg. Height in centimeters was measured using a scale-integrated stadiometer. Body mass index (BMI) was calculated as weight (kilograms) divided by height (meters) squared. The percent ideal body weight was defined as actual weight divided by ideal weight times 100, where ideal weight = 45.5 kg at a height of 152 cm, adding or subtracting 0.9 kg for each 1 cm of height above or below 152 cm (7).
Between 1990 and 1993, waist/hip circumference ratio (WHR) as a measure of fat distribution was obtained routinely at the widest circumferences at the umbilical (= waist) and gluteal (= hip) level with the patient standing. WHR values were thus available for 126 (22 men) patients.
Liver biopsies
All 551 knife biopsies were wedges taken from the edge of the left lobe of the liver at the start of the operation. They were stained with hematoxylin-eosin and Trichrome (Masson). All slides were graded in Quebec by two investigators blinded to the identity of the patient. In cases of conflicting grades, a third examiner made the final determination. Steatosis was graded: 0 = no steatosis, I = steatosis in less than 30% of hepatocytes, II = 30–60%, and III = more than 60% of hepatocytes.
For expert validation of fibrosis, inflammation, and cirrhosis, a subset of 93 coded slides was sent to the liver pathologist (S.N.T.), who was blinded to the clinical data of the patients. These slides were obtained from 41 patients who subsequently had had random repeat biopsies as part of a follow-up study and 41 additional patients matched for age, sex, and BMI as controls (8). Eleven additional biopsies were sent from patients with unsuspected cirrhosis discovered during surgery.
Fibrosis was graded semiquantitatively on a 6-point scale: grade 0 = no fibrosis, grade 1 = fibrosis of portal tracts and/or perivenular or pericellular fibrosis, grade 2 = formation of short septa, grade 3 = fibrous septa connecting portal tracts or terminal hepatic venules, grade 4 = occasional nodule formation, and grade 5 = cirrhosis. Inflammation, glycogenated nuclei, fat granulomas, and Mallory bodies were noted.
The hepatopathologist also graded steatosis. The agreement with the
Quebec data was assessed by correlation, revealing r = 0.79;
P < 0.0001 with a 
agreement of 44%. For
statistical analysis of steatosis, our own grading for 551 patients was
used, whereas for fibrosis, inflammation, and cirrhosis, the liver
pathologist’s grading was used.
Informed written consent was obtained from all patients, and the study was conducted in conformance with the Helsinki Declaration.
Statistics
Results were expressed as the mean ± SD, as data were normally distributed. Categorical variables, expressed as percentages, were evaluated using Fisher’s exact test. Continuous variables were analyzed with unpaired Student’s t tests if Leavine’s test for homogeneity of variance was not significant; otherwise, Wilcoxon rank sum tests were used. Pearson correlation coefficients were calculated. Logistic regression analysis was performed using steatosis or fibrosis as the dependent variable. The odds ratio (OR) represents the ratio of the odds for those with compared to those without the risk factor. Comparisons of means between groups with different components of the metabolic syndrome and grade of steatosis was performed using one-way ANOVA (Tukey). All reported P values are two sided and were significant at a level of P < 0.05. Despite the large number of correlations Bonferroni’s correction was not used, given the power of our analyses. We have chosen to present the actual P values, recognizing that significance levels above 0.005 can be challenged.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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With the exception of ALP mean serum liver function tests were within the reference range of the hospital laboratory. Individual levels were elevated in 4.0–20.5% of patients in agreement with other published data (9). The mean CHOL/HDL ratio was elevated, to values more than 5 in 46.4% of the patients. Twenty-eight percent of all subjects had fasting blood sugar levels greater than 6 mmol/L, whereas 14% had serum triglycerides more than 3 mmol/L.
Histopathology
Steatosis was found in 86% of the patients. The risk of having steatosis was 2.6 times greater in men than in women (OR = 2.6; P < 0.0001). Fibrosis was present in 74% (61 of 82) of the subgroup of patients analyzed separately, with the majority having grade 1. Inflammation, which was lymphocytic infiltration of portal tracts, was mild and present in only 24%. Glycogenated nuclei, fat granuloma, and Mallory bodies were found in 43%, 27%, and 6% respectively, of patients without cirrhosis. Among the 11 patients with cirrhosis, 8 had well developed cirrhosis, and 3 had early cirrhosis.
Correlations (Table 2)
Steatosis. Relative weight, expressed as BMI, was inversely related to serum albumin levels in both sexes (r = -0.28; P < 0.001) and revealed positive correlations with serum liver function tests (not shown). BMI also correlated positively with fasting blood sugar, but inversely with both total and HDL CHOL, with no relationship to serum triglycerides. It correlated weakly, but positively, with the degree of steatosis.
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-glutamyl transferase, ALP, or prothrombin
time (not shown). The ratio of ALT to AST (10) was 1.28 ± 0.45
(range, 0.32–3.0). It correlated with the degree of steatosis (r
= 0.22; P < 0.0001), but was not associated with
alcohol consumption or diabetes.
All four components of the metabolic syndrome, fat distribution,
impaired glucose tolerance, hypertension, and dyslipidemia, were highly
significantly correlated with the grade of fatty infiltration. In the
cohort of 104 women with WHR measurements there was significant
interaction among fasting blood sugar, WHR, and the relative risk of
steatosis hepatis (Fig. 1). Furthermore,
Table 3 demonstrates the additive effects
of 3 of the 4 components of syndrome X on degree of fatty infiltration
in 371 women.
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Fibrosis. Fibrosis was highly correlated with steatosis (r = 0.56; P < 0.0001) and with similar factors as steatosis. Thus, fasting blood sugar (r = 0.43; P < 0.0004), WHR (r = 0.60; P < 0.02), BMI (r = 0.32; P < 0.003), and the presence of diabetes all correlated with fibrosis. Fibrosis was also related to age, but not to the use of alcohol, tobacco, or oral contraceptives. As with steatosis there was no relationship between fibrosis and the presence of inflammation or glycogenated nuclei.
Cirrhosis. The presence of diabetes was the strongest predictor of cirrhosis (P < 0.001), followed by steatosis (P < 0.003) and age (P < 0.01), in the stepwise regression analysis. The level of serum triglycerides was not an independent predictor of cirrhosis.
Inflammation. Age was the only statistically significant predictor of inflammation in stepwise logistic analysis. There were no relationships between degree of steatosis or fibrosis and the presence of inflammation. Women taking oral contraceptives and men had more inflammation, accounting for a relationship with WHR (P < 0.05). None of the other components of the metabolic syndrome was related to inflammation.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Hyperinsulinemia, although not measured here, is considered to be the most important component in the association between intraabdominal fat accumulation and the abnormalities of the metabolic syndrome, but the etiology of hyperinsulinemia itself is not known. We did not determine insulin levels in these patients, but insulin levels are highly correlated with glucose in similar patients (12, 13). Blood glucose is the best predictor of NIDDM, primarily tracking the progression of IGT, whereas insulin cotracks with glucose via hyperinsulinemia until pancreatic ß-cell exhaustion occurs (14).
Previously we have shown relationships among central fat distribution, radiologically determined fatty liver, and impaired glucose disposal in mildly obese and in normal weight subjects (15, 16), demonstrating that the associations between syndrome X and fatty liver are not limited to the severely obese and are valid across ethnic groups. Taken together with our findings here of robust correlations between the degree of steatosis and blood glucose in the normal range before the appearance of IGT or NIDDM, it is reasonable to hypothesize a central role for glucose in the etiology of the metabolic syndrome and fatty liver. Hepatic glucose toxicity in this context may be mediated through excessive flux through the hexosamine pathway, a mechanism of insulin resistance (17). Indirect evidence for such glucose toxicity on the subcellular level is provided in studies demonstrating the influence of oral glucose on mitochondrial redox tolerance and energy metabolism (18). Fatty liver in itself is associated with impaired ATP synthesis (19).
FFA have been implicated in the insulin resistance of the metabolic syndrome through elevated delivery from intraabdominal adipose tissue via the portal vein to the liver (20). The mechanism of the insulin resistance is interference by FFA with glucose metabolism (21, 22). Alternatively, as with glucose toxicity, it is possible that FFA has a toxic effect on the liver via lipid peroxidation causing fibrogenesis and progression to cirrhosis (23). Indeed, antioxidants, such as vitamin E, have recently been demonstrated to normalize serum liver function tests in obese children (24).
Because of the interdependence of glucose, insulin, and FFA (25), it is difficult to determine the primacy of any one factor. However, energy intake is the governing principle of survival, and glucose has at least temporal primacy among ingested sources of energy, as evidenced through preabsorptive cephalic phase responses (26) and the rapidity of absorption and metabolism of glucose. The rate of eating (27) and meal size (28) are determinants of substrate delivery. We hypothesize that eating behavior is the key factor driving the metabolic syndrome of obesity with its many corollaries, including steatosis hepatis. Treatments aimed at decreasing the rate of eating and increasing the number of small meals, as has already been demonstrated in NIDDM (28), should effectively treat and prevent steatosis hepatis. Drugs that delay gastric emptying are also effective at improving glucose tolerance (29) and thus may improve fatty liver with its attendant hyperinsulinemia.
In the controversy over the role of fatty infiltration in fibrosis, cirrhosis, and ultimately liver failure, several researchers have asserted the importance of inflammatory mechanisms as in NASH (3). Cytokines are present in alcoholic liver disease (30), where they may contribute to an inflammatory component. Recent findings of elevated serum leptin levels in alcoholic cirrhosis occurred mainly in women and were only indirectly related to body fat (31). We found signs of only mild inflammation in a minority of our patients, and men had more liver changes than women. Thus, we do not believe that cytokines or leptin are determinants of fatty liver in our population, contrary to a recent proposal by Kaplan (32). There were no correlations between inflammation and fasting blood sugar or the presence of diabetes. These findings lead us to believe, in agreement with Bacon et al. (1), that NASH is a separate disease entity that should be differentiated from (benign) "pure" steatosis (2, 33). Steatosis of obesity, on the other hand, which is linked to metabolic syndrome X, is a more serious form of steatosis that should be distinguished from benign fatty liver as well as from NASH. Studies of insulin, cytokines, steroids, and leptin in progress may help to further elucidate these relationships.
In conclusion, through a large cross-sectional study of severely obese patients having routine liver biopsies at the time of antiobesity surgery we show for the first time a relationship between the metabolic syndrome X and liver pathology. Furthermore, we identify risk factors distinguishing benign or pure fatty liver from steatosis-related progressive liver disease separate from NASH. These findings are relevant to the etiology of the metabolic syndrome as well as fatty liver-related fibrosis and cirrhosis and have implications for the prevention and treatment of these prevalent conditions.
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Acknowledgments |
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Received November 24, 1998.
Revised January 26, 1999.
Accepted January 28, 1999.
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References |
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