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HepC Newsletter
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Dema-@aol.com
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Jul 14, 2009 07:08 PDT
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NATAP http://natap.org/
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Association between dietary nutrient composition and the incidence of
cirrhosis or liver cancer in the united states population
Hepatology July 2009
George N. Ioannou 1 2 3 *, Olivia B. Morrow 2, Marah L. Connole 2, Sum P.
Lee 1 2 3
1Division of Gastroenterology, Department of Medicine, Veterans Affairs
Puget Sound Health Care System, Seattle, WA
2Research Enhancement Award Program, Veterans Affairs Puget Sound Health
Care System, Seattle, WA
3Division of Gastroenterology, Department of Medicine, University of
Washington, Seattle, WA
Abstract
Little is known about the impact of dietary factors on the progression of
liver disease. Our aim was to determine whether dietary intake was
associated with the risk of cirrhosis-related or liver cancer-related death or
hospitalization in the U.S. population. Participants included 9221 persons aged
25-74 years without evidence of cirrhosis at entry into the study or
during the first 5 years of follow-up, who were subsequently followed for a mean
of 13.3 years as part of the first National Health and Nutrition
Examination Survey. Dietary intake was ascertained at baseline using a 24-hour
dietary recall questionnaire. During follow-up, 123 of 9221 participants had a
diagnosis of cirrhosis (n = 118) or liver cancer (n = 5) in hospitalization
records or death certificates, including 36 who were diagnosed only on the
basis of death certificates.
Participants who reported a diet high in protein were at a higher risk of
hospitalization or death due to cirrhosis or liver cancer (P = 0.001),
whereas those who reported a diet high in carbohydrates were at a lower risk (P
= 0.003), after adjusting for potential confounders (daily consumption of
protein, carbohydrate, fat, tea or coffee, and alcohol, gender, race, age,
educational attainment, U.S. geographical region, diabetes, body mass
index, and subscapular-to-triceps skinfold ratio).
Although total fat consumption was not significantly associated with the
risk of cirrhosis or liver cancer, cholesterol consumption was associated
with higher risk (P = 0.007), whereas serum cholesterol level was not
associated with risk of cirrhosis or liver cancer. Conclusion: Diet may be an
important and potentially modifiable determinant of liver disease.
Dietary factors are likely to be important determinants of the development
of hepatic steatosis and its progression to steatohepatitis for the
following reasons: (1) Dietary factors are important and probably causative risk
factors for obesity, insulin resistance, and diabetes, which are the most
important, known risk factors for hepatic steatosis. (2) Dietary lipid
composition influences both the quantity and composition of lipids that are
delivered to the liver and incorporated into hepatocyte lipid droplets. This is
important because recent data derived primarily from animal models suggest
that specific lipid molecules, such as saturated fatty acids, may promote
lipotoxicity,[1][2] whereas others, such as n-3 polyunsaturated fatty acids
(PUFAs), may actually have beneficial effects.[3][4] Therefore, it is
possible that the quantity and composition of dietary lipid can either promote
or protect against the development or progression of hepatic steatosis. (3)
In rabbits[5][6] and mice[7] a high cholesterol diet has been shown to
induce profound steatosis, inflammation, and centrilobular fibrosis.
Hepatic steatosis is the defining feature of nonalcoholic fatty liver
disease (NAFLD) but it is also a common and probably pathogenetic feature of
hepatitis C virus (HCV) infection and alcoholic liver disease. Although HCV
infection and alcohol consumption can cause hepatic steatosis by themselves,
obesity-related steatosis also occurs in the setting of HCV infection and
alcoholic liver disease.[8] Therefore, if dietary composition affects the
development or progression of hepatic steatosis, it is likely to play a part
in the natural history of the three most important liver conditions in the
U.S.: NAFLD, HCV infection, and alcoholic liver disease.
Dietary nutrients may also cause hepatic injury through pathways that do
not involve the development or progression of hepatic steatosis.
Carbohydrates, proteins, and lipids are all extensively metabolized in the liver and
it is conceivable that they may influence the progression of chronic liver
disease, either positively or negatively. In hepatitis B virus (HBV)
transgenic mice, a diet low in animal protein was associated with decreased liver
injury and decreased incidence of hepatocellular carcinoma.[9][10] In the
presence of oxidative stress, dietary cholesterol may be oxidized in the
liver to oxysterols, which can induce cell damage and malignant transformation
and regulate signal transduction pathways.
Our aim was to investigate whether dietary nutrient composition was
associated with the subsequent development of cirrhosis or liver cancer in a
representative sample of the U.S. population.
Abbreviations
BMI, body mass index; HBV, hepatitis B virus; HCV, hepatitis C virus;
ICD-9, International Classification of Diseases, 9th Revision; NAFLD,
nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; NHANES,
National Health and Nutrition Examination Survey; NHEFS, NHANES I Epidemiologic
Follow-up Study; PUFA, polyunsaturated fatty acid.
Results
During an average follow-up time of 13.3 years, 123 out of 9,221
participants had a new diagnosis of cirrhosis (n = 118) or liver cancer (n = 5) in
hospitalization records or death certificates, including 36 who were
diagnosed only on the basis of death certificates (Table 1). Patients who
developed cirrhosis or liver cancer were older, more obese with more central fat
distribution, had lower educational attainment and higher alcohol
consumption, and were more likely to be male, diabetic, and nonwhite.
The total number of calories and the total quantity of fat consumed were
not associated with the incidence of cirrhosis or liver cancer in univariate
or multivariate analyses (Table 2). Increasing carbohydrate consumption
was associated with significantly reduced incidence of cirrhosis or liver
cancer in unadjusted and adjusted analyses in both percent and absolute energy
models (adjusted hazard ratio of 0.42, 95% confidence interval [CI]
0.2-0.8, comparing the top to the bottom quartile). In contrast, protein
consumption was associated with a significantly increased risk of cirrhosis or
liver cancer after adjusting for potential confounders in absolute energy
models, but not in percent energy models.
Although total fat consumption was not significantly associated with
cirrhosis or liver cancer, we identified associations with specific lipid
components (Table 3). In particular, higher consumption of cholesterol was
associated with a higher risk of cirrhosis or liver cancer in both unadjusted and
adjusted analyses. Persons in the top quartile of cholesterol consumption
were more than twice as likely to develop cirrhosis or liver cancer
compared to persons in the bottom quartile of cholesterol consumption. Consumption
of saturated fatty acids, oleic acid, or linoleic acid was not associated
with the risk of cirrhosis or liver cancer. In contrast, consumption of
fatty acids other than the ones quantified by the NHANES I investigators was
associated with a reduced risk of cirrhosis or liver cancer in total energy
models (but not in percent energy models). Given that saturated fatty
acids, oleic acid (the most common dietary monounsaturated fatty acid), linoleic
acid (an n-6 PUFA), and cholesterol were quantified by NHANES I
investigators, the other fats consist mostly of n-3 and n-6 PUFAs (other than
linoleic acid).
Exploratory subgroup analyses by BMI and alcohol consumption are shown in
Table 4. The most significant associations that we observed in the entire
population (that is, with cholesterol, carbohydrate, and protein intake)
were only observed among persons with elevated BMI (>/=25 kg/m2) and not among
persons with normal BMI (<25 kg/m2). In contrast, the associations between
dietary nutrients and cirrhosis or liver cancer were similar among persons
with or without excessive alcohol consumption.
In the analyses presented in Tables 2 we excluded the first 5 years of
follow-up, reasoning that cirrhosis or liver cancer that was present and
undiagnosed at entry into the cohort would have led to hospitalization or death
within 5 years. We also varied the number of years from entry into the
cohort that were excluded from analysis from 0 to 6 and found in each analysis
that protein and cholesterol consumption were associated with higher risk
of cirrhosis or liver cancer, whereas carbohydrate and other fat consumption
were significantly associated with lower risk of cirrhosis or liver
cancer. When we repeated our analyses using only the 7032 participants who were
hospitalized at least once or who died during follow-up, we found
near-identical results. Dietary content of protein, carbohydrate, total fat,
saturated fatty acid, oleic acid, linoleic acid, cholesterol, or other fat was not
independently associated with the number of hospitalizations during
follow-up.
Because dietary cholesterol consumption was so strongly associated with
the incidence of cirrhosis or liver cancer, we evaluated whether serum
cholesterol levels were also associated with cirrhosis or liver cancer, but we
found no such association in either univariate or multivariate analyses.
Therefore, ingested, dietary cholesterol was associated with cirrhosis or liver
cancer, but hepatically synthesized cholesterol, which is the main
determinant of serum cholesterol, was not associated with cirrhosis or liver
cancer.
Finally, we used NHANES III data collected between 1988-1994 (Table 5) to
investigate the association between dietary composition and the presence of
HCV infection (which was not ascertained in NHANES I). There was no
association between any measure of dietary composition and HCV infection after
adjusting for the same confounders that we adjusted for in our NHANES I
analyses. Therefore, it is extremely unlikely that the significant associations
that we present in Tables 2 and 3 would have changed if we could have
adjusted for HCV infection. Also, the lack of association between HCV infection
and dietary composition strongly suggests that the presence of underlying
liver disease does not cause a change in dietary intake and, instead, makes
it more plausible that differences in dietary intake of proteins,
carbohydrates, cholesterol, and perhaps other lipid components contribute to the
development of cirrhosis or liver cancer.
Discussion
Our results show for the first time that dietary nutrient composition is a
strong predictor of hospitalization or death due to cirrhosis or liver
cancer in the U.S. population. In particular, we identified that protein and
cholesterol consumption were associated with elevated risk, whereas
consumption of carbohydrates was associated with reduced risk of hospitalization or
death related to cirrhosis or liver cancer. We also observed a weaker
association between consumption of PUFAs and reduced risk of cirrhosis or liver
cancer, although PUFA consumption was not ascertained well in NHANES I.
The strong association between cholesterol intake and cirrhosis or liver
cancer is potentially our study's most important finding. In rabbits[5][6]
and mice[7] a high cholesterol diet has been shown to induce profound
steatosis, inflammation, and centrilobular fibrosis. It was postulated that the
hepatic steatosis, which was predominantly microvesicular, was the result of
a cholesterol-induced reduction in mitochondrial beta oxidation of fatty
acids.[5] Some dietary cholesterol is already oxidized to oxysterols and it
is also possible for dietary cholesterol to be converted in the liver to
oxysterols, which promote cytotoxic and carcinogenic effects. Hepatic
oxidative stress is a prominent feature of nonalcoholic steatohepatitis (NASH),
HCV infection, and alcoholic liver disease, and could lead to generation of
oxysterols from dietary cholesterol. Despite the profound importance of
cholesterol in nonhepatic diseases such as atherosclerosis, dietary cholesterol
and oxysterols have received little attention as potential lipotoxic
molecules in the human liver. We are not aware of any other human studies
linking cholesterol intake to human liver disease. Our finding that dietary
cholesterol but not serum cholesterol was associated with cirrhosis or liver
cancer could have profound implications if confirmed by other studies. For
example, it would suggest that drugs blocking intestinal cholesterol
absorption could have more beneficial effects to the liver than drugs blocking
hepatic cholesterol synthesis, which lower serum cholesterol levels by
up-regulation of hepatic low-density lipoprotein receptors.
We did not have strong a priori hypotheses as to the direction of
associations between protein or carbohydrate consumption and cirrhosis or liver
cancer. Thus, our findings of a positive association of protein consumption
and a negative association of carbohydrate consumption with hospitalization
or death related to cirrhosis or liver cancer should be considered with
caution. High protein intake in humans, in particular, animal protein, has been
associated with hepatocellular carcinoma in an ecological study from rural
China.[17] In HBV transgenic mice, a diet low in animal protein was
associated with decreased liver injury and decreased incidence of hepatocellular
carcinoma.[9][10] (We did not have information on whether ingested protein
was of animal or plant origin.) Twenty-five patients with biopsy-proven
NASH had diets richer in protein (as well as saturated fat and cholesterol and
poorer in PUFAs and fiber) than 25 age-, BMI-, and gender-matched healthy
controls.[18] We are not aware of any studies investigating the effects of
carbohydrate intake on the progression of liver disease in humans. Contrary
to our findings, a recent study found that patients with NAFLD consumed
2-3 times more fructose than controls, which may be linked to the development
of steatosis because the hepatic metabolism of fructose favors de novo
lipogenesis.[19] Our data did not allow us to determine the specific fructose
intake; we speculate that fructose intake was much lower in the period of
our study (1971-1992) than it is now due to the dramatic increase in the
consumption of soft drinks containing high fructose corn syrup.
Although hepatic steatosis is defined by excessive deposition of lipid
within hepatocytes, little is known about the exact nature of these lipids in
humans. Evidence is emerging from cell culture and animal model experiments
that specific lipid molecules, such as saturated fatty acids, may exert
lipotoxicity,[1][2] whereas others, such as n-3 PUFAs, may actually have
beneficial effects.[3][4] In human studies, hepatic levels of n-3 PUFAs were
shown to progressively decrease from control patients to patients with NAFLD
to NASH.[20][21] In a randomized controlled trial, n-3 PUFA supplementation
reduced ultrasonographic steatosis, alanine aminotransferase levels, and
insulin resistance in patients with suspected NAFLD.[22] We did not find any
association between dietary intake of saturated fatty acids or the
monounsaturated fatty acid oleic acid and cirrhosis or liver cancer. Although we
did not have direct estimates of dietary PUFAs, especially n-3 PUFAs, we
approximated PUFA intake by subtracting the intake of saturated fat, oleic
acid, linoleic acid, and cholesterol from total fat intake. Using this
approximation, we identified that persons in the top quartile of PUFA intake were
half as likely to develop cirrhosis or liver cancer than persons in the
bottom quartile in absolute energy models, but not in percent energy models;
however, the test of trends across quartiles of other fat intake was just
short of statistical significance (P = 0.05) even in the absolute energy
models. Future studies should investigate these associations with more specific
ascertainment of n-3 and n-6 PUFA intake.
Subgroup analyses showed that the significant associations of protein,
carbohydrate, and cholesterol intake with cirrhosis or liver cancer that we
described in the entire study population, were limited to overweight or obese
persons (BMI 25 kg/m2) (Table 4). No such associations were observed in
normal-weight persons. In contrast, alcohol consumption did not appear to
modify substantially the associations between dietary nutrients and cirrhosis
or liver cancer. This suggests that high protein and cholesterol and low
carbohydrate intake are more likely to mediate their hepatic effects through
obesity-related fatty liver disease.
Our study has some limitations, including the absence of data on HCV
infection, which is a major cause of cirrhosis and liver cancer in the U.S.
However, we have shown that in the more recent NHANES III study, HCV infection
was not associated with any of the dietary components that we investigated;
hence, HCV infection is unlikely to be an important source of uncontrolled
confounding. It is possible that our results are subject to
misclassification because a 24-hour dietary recall may not reflect long-term dietary
intake accurately. However, such inaccuracies in the assessment of dietary
intake using a 24-hour dietary recall are expected to be random and to have no
relation to the study's outcome, that is, the development of cirrhosis or
liver cancer. It is well described that such random, nondifferential
misclassification of exposure does not lead to spurious associations, but, rather,
tends to reduce real associations toward the null.[23] Therefore, we
believe that the associations that we describe between cholesterol, protein, and
carbohydrate intake and the development of cirrhosis or liver cancer are
likely to be true and the magnitude of these associations is likely to be
even greater than what we report. Multiple studies have used the NHANES
24-hour dietary recall data to study the associations between baseline dietary
factors and the subsequent development of disease or mortality as we
did.[24-26] The quality of the NHANES 24-hour dietary recalls is considered very
good because the National Center for Health Statistics employed specially
trained, experienced interviewers who performed more than 20,000 24-hour
dietary recalls as part of NHANES I.
Although we simultaneously adjusted for all the dietary components that we
investigated, it is possible that these dietary components may be
surrogate markers for the intake of other known or unknown nutrients that could
have important effects on the liver, such as dietary antioxidants. We could
not determine from the available 24-hour dietary recall data whether the
protein intake that was associated with increased risk of cirrhosis-related
death or hospitalization was animal protein or plant protein. The associations
that we describe could occur if an underlying chronic liver disease were
to influence taste, smell, and food preference before the development of
cirrhosis. However, in the NHANES III study there was no association between
the presence of a chronic liver disease (HCV infection) and dietary intake.
Our study measures hospitalizations and deaths due to cirrhosis or liver
cancer, not the actual incidence. Thus, patients with undiagnosed cirrhosis,
or diagnosed cirrhosis that did not lead to hospitalization or death, were
not captured.
At the same time, our study has some important strengths. Dietary intake
was ascertained prospectively in a large, nationally representative sample
of the U.S. population with 13 years of prospective follow-up (after
excluding from analysis the first 5 years following entry into the study).
Hospitalizations or deaths due to cirrhosis were ascertained prospectively by
specially trained personnel without any knowledge of baseline dietary intake.
Many determinants of liver disease progression are currently unknown, as
evidenced by the fact that we cannot predict accurately which patients with
any of the major liver diseases (HCV, HBV, NAFLD, and alcoholic liver
disease) will progress to cirrhosis and which ones will have a relatively benign
course. Our study raises the possibility that dietary factors may be
important, modifiable, and hitherto unrecognized determinants of liver disease
progression.
Patients and Methods
Study Design.
Data were derived from the first National Health and Nutrition Examination
Survey (NHANES I) performed by the National Center for Health Statistics.
NHANES I is a cross-sectional study of a nationwide probability sample from
the civilian, noninstitutionalized population of the coterminous United
States conducted between 1971-1975.[11] The survey included 14,407
participants aged 25-74 years who completed extensive dietary questionnaires and
underwent physical examinations and laboratory investigations. The NHANES I
Epidemiologic Follow-up Study (NHEFS)[12] sought to locate these 14,407
individuals in the years 1982-1984, 1986, 1987, and 1992 and collected data on
specific health conditions that they developed in the intervening period
through personal interviews, hospitalization records, and death certificates.
We merged together NHANES I and NHEFS to form a nationally representative
cohort of 14,407 persons with about 20 years of follow-up. We used the NHANES
I-NHEFS cohort to determine whether dietary composition at baseline is
associated with the subsequent incidence of death or hospitalization related
to liver cancer or cirrhosis.
Study Population.
Among 14,407 NHANES I participants aged 25-74 years, 13,861 were
successfully traced in at least one of the four follow-up occasions (that is
1982-1984, 1986, 1987, or 1992). In order to limit our analysis to incident cases
of cirrhosis and liver cancer, we attempted to exclude participants who
suffered from these conditions at the time of entry into the study.
Specifically, we excluded participants who reported at baseline ever being told by a
physician that they had jaundice (n = 886), hepatitis (n = 47), or a
malignant tumor (n = 47), who had hepatomegaly or splenomegaly at baseline
examination (n = 237), or whose level of serum albumin was less than 3 g/dL (n =
10). Serum bilirubin levels and platelet counts, which may be abnormal in
advanced cirrhosis, were available only in a small minority of participants
and therefore could not be used to identify participants with possible
cirrhosis. Because cirrhosis and liver cancer may be present for a long time
before they are clinically diagnosed, we also excluded participants who were
diagnosed with these conditions within the first 5 years of follow-up, or
who had less than 5 years of follow-up (n = 687). We excluded 46 participants
with missing values in any of the following potential confounding
variables included in our models: age, gender, race, alcohol consumption, body mass
index (BMI), subscapular-to-triceps skinfold ratio, geographical location,
and educational attainment. The 24-hour dietary recall questionnaire, as
well as questions on diabetes and coffee consumption, were administered only
to the subsample of NHANES participants recruited at locations 1-65. This
subsample was designed so that it would still constitute a random sample of
the U.S. population. An additional 2,680 NHANES I participants did not
complete a 24-hour dietary recall questionnaire and did not answer questions
on diabetes or coffee consumption because they were not recruited at
locations 1-65, leaving 9221 participants in the current analyses.
Ascertainment of Baseline Dietary Intake.
A dietary interview was conducted by professional staff at entry into the
study in 1971-1975, including a 24-hour dietary recall questionnaire. The
24-hour recall provides information on specific food items and their
quantities ingested for all regular meals and between-meal foods or snacks
consumed from midnight to midnight on the day preceding the interview. A Nutrient
Composition Data Bank was then used to calculate the grams of protein,
carbohydrate, and fat consumed during the 24-hour period. In addition, the
24-hour intake of the following specific fats was calculated: cholesterol,
saturated fatty acids, oleic acid (a monounsaturated fatty acid), and linoleic
acid (an n-6 PUFA). The estimated dietary intake of other lipids of
interest such as n-3 PUFAs or n-6 PUFAs other than linoleic acid was not provided
by the NHANES I investigators.
Hospitalizations and Deaths Due to Liver Cirrhosis or Liver Cancer During
Follow-up.
Deaths and hospitalizations due to liver cirrhosis or liver cancer that
occurred during follow-up were ascertained from hospitalization records and
death certificates. Specially trained NHEFS personnel abstracted the
diagnoses in these documents into International Classification of Diseases, 9th
Revision (ICD-9) diagnosis codes. We used the ICD-9 code 155.0 for liver
cancer and the following ICD-9 codes for cirrhosis: alcoholic cirrhosis 571.2;
cirrhosis without mention of alcohol 571.5; pigmentary cirrhosis 275.0;
esophageal varices 456.0-456.2; hepatic coma 572.2; portal hypertension 572.3;
and hepatorenal syndrome 572.4. Esophageal varices, hepatic coma, portal
hypertension, and hepatorenal syndrome have been included in the diagnosis
of liver cirrhosis because the overwhelming majority of these conditions in
the U.S. are the result of liver cirrhosis. If acute necrosis of the liver
(ICD-9 code 570.0) was diagnosed together with hepatic coma or hepatorenal
syndrome, then the person was considered not to have cirrhosis. Other
complications of cirrhosis such as ascites or peritonitis have not been included
as evidence of cirrhosis because they are commonly caused by other
conditions. The date of the first hospital admission for each condition was used
as the date of incidence. For subjects who had a death certificate recording
one of these conditions but did not have a hospitalization for any of them,
the date of death was used as the date of incidence. Henceforth we use the
term incidence of cirrhosis or liver cancer for brevity, but what we have
ascertained is the incidence of hospitalizations and deaths related to
cirrhosis or liver cancer.
Ascertainment of Potential Confounding Variables.
We considered the following baseline characteristics, which may be
associated with both dietary intake and development of cirrhosis or liver cancer
as potential confounders: age; BMI; subscapular to triceps skinfold ratio (a
measure of central as opposed to peripheral subcutaneous fat); race,
categorized as white (n = 7644) and nonwhite (n = 1638, of whom 1545 were black
and only 93 of other race, too small a number for additional racial
categories); gender; alcohol consumption over the previous 12 months, categorized
as none, >0 to <1 drink/day, 1 to <2 drinks/day, and >/=2 drinks/day;
coffee or tea consumption categorized into <1, 1-2, and >2 cups/day; educational
attainment, categorized as completion of high school or not; self-reported
diabetes mellitus; and geographical area of residence in the U.S.,
categorized into Northeast, Midwest, South, and West.
Viral hepatitis B and C testing was not available in 1971-1974 when the
NHANES I participants were recruited. We wanted to ensure that viral
hepatitis C, an important cause of cirrhosis in the U.S., was not associated with
the dietary consumption of carbohydrates, proteins, and fats (including
cholesterol, saturated fatty acids, oleic acid, and linoleic acid) in order to
exclude the possibility that viral hepatitis was an important source of
unmeasured confounding in our NHANES I cohort. To do this, we used data from
NHANES III, a cross-sectional study conducted between 1988-1994 that
included measurements of viral hepatitis serologies.
Statistical Analysis.
The Cox proportional-hazards model[13] was used to determine the hazard
ratio comparing persons within different quartiles of a dietary nutrient
intake with respect to the risk for cirrhosis or liver cancer with or without
adjusting for the potential confounders listed above. For each macronutrient
we present results from two statistical models, corresponding to percent
energy and absolute energy.[14] In percent energy models each macronutrient
is modeled as the percent of total energy that it provides calculated as
the number of calories from each macronutrient divided by the total number of
calories consumed (for alcohol, models will use categorized drinks per
day); total energy is included as a linear covariate, with or without
adjusting for the potential confounders listed above. Percent energy models can be
interpreted as the effect of substituting energy from each specific
macronutrient for other macronutrients, thus keeping the total dietary energy
intake constant. In absolute energy models, each macronutrient is modeled as
the absolute energy that it provides, adjusted for the energy provided by
each of the other macronutrients, with or without adjusting for potential
confounders. Absolute energy models can be interpreted as increasing energy
from a specific macronutrient while keeping the energy from each other
macronutrient constant. All dietary components were categorized into quartiles and
modeled either as dummy variables (where each quartile is compared to the
lowest quartile) or as a single variable to give a test of trends for
increasing quartile. The date 5 years from ascertainment of dietary intake was
used as time zero for the Cox proportional-hazards models because any cases
occurring within the first 5 years were excluded. We performed sensitivity
analyses in which we varied the number of years following entry into the
cohort that we excluded from analysis from 0 to 6 years.
We performed additional analyses limited to persons (n = 7032) who were
hospitalized at least once or who died during follow-up, such that all had
hospitalization records or death certificates available to look for the
diagnosis of cirrhosis or liver cancer. We also determined whether dietary
composition was independently associated with the number of hospitalizations
during follow-up.
Due to the importance of obesity and alcohol consumption in liver disease,
especially as causes of hepatic steatosis, we performed subgroup analyses
stratifying persons into obese (BMI >25 kg/m2) or nonobese, and into
persons with excessive alcohol consumption or not. Alcohol consumption was
considered excessive in women who consumed 1, and in men who consumed 2 alcoholic
drinks/day.[15][16]
Using the NHANES III cross-sectional data (1988-1994), we investigated
whether there was an association between quartiles of dietary carbohydrate,
protein, or fat intake and the presence of HCV infection, with or without
adjusting for the confounders listed above by logistic regression. HCV
infection was defined by the presence of HCV RNA.
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