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Obesity and Its Nurturing Effect on Hepatitis C
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“The microbe is nothing; the terrain is everything.”
—Louis Pasteur
W
hen this great 19th century scientist made this
statement, he was emphasizing the importance of the interaction between the microbe
and the environment in which the microbe resides on
processes such as fermentation, silk worm infestation, as
well as the effects of the great fire of 1666 on the eradication of the plague in London. These words seem equally
appropriate today in regard to chronic hepatitis C (HCV)
infection and two important clinical issues: progression to
cirrhosis and viral eradication in HCV. The relevant “terrain” for HCV appears to be body fat mass and hepatic
steatosis, now recognized as cofactors for both the presence1-3 and progression1 of fibrosis in HCV, along with
alcohol use, male gender, age, and duration of infection.4
The nurturing effect of these two inter-related host factors3— body fat mass and hepatic steatosis—may have
implications in HCV beyond fibrogenesis but may also
protect HCV from antiviral therapy.
In the current issue of HEPATOLOGY, Bressler et al.5
report that body fat mass, as estimated by body mass index
(BMI) (calculated by the body weight in kilograms divided by the height in meters squared), influenced viral
eradication in response to antiviral treatment for HCV.
Using standard statistical techniques in a retrospective
analysis of 174 patients who received 3 different interferon (IFN)-based treatment regimens (while controlling
for the confounding variables of alcohol use, gender, genotype, and cirrhosis at baseline), these investigators
found that obesity defined as a BMI greater than 30 was a
negative predictor of response to HCV treatment. In addition, this BMI effect was independent of hepatic steatosis. Before discussing the potential mechanisms and
clinical implications of these observations, it is important
Abbreviations: HCV, hepatitis C virus; BMI, body mass index; IFN, interferon.
From the Division of Gastroenterology and The Schwartz Center for Metabolism
and Nutrition at MetroHealth Medical Center, Case Western Reserve University,
Cleveland, OH.
Address reprint requests to: Arthur J. McCullough, M.D., Division of Gastroenterology and The Schwartz Center for Metabolism and Nutrition at MetroHealth
Medical Center, 2500 Metrohealth Dr., Cleveland, OH 44109-1998. E-mail:
[email protected].
Copyright © 2003 by the American Association for the Study of Liver Diseases.
0270-9139/03/3803-0005$30.00/0
doi:10.1053/jhep.2003.50413
to revisit a number of issues, previously discussed in this
journal,6 that relate to the accuracy and interpretation of
studies involving body composition.
The first is the accuracy of the methodology used to
measure body fat mass and hepatic steatosis. Bressler et al.
are to be commended for their attempts to estimate body
fat mass in 3 different ways: BMI, body surface area, and
body weight by quartiles. However, all 3 of these related
measurements are potentially inaccurate due to fluid retention in cirrhosis even in the absence of ascites and
edema. Therefore, it would have been beneficial if the
fluid status and number of patients with cirrhosis had
been reported. Another estimate of body fat mass, such as
anthropometry, would have supplied additional support
for the conclusions based on BMI. In contrast to these
limitations, liver biopsy was used to estimate hepatic fat, a
parameter that is more reliable and whose pathologic interpretation is accurate and reproducible. However, hepatic fat is not uniformly distributed, and the possibility
of sampling error exists.
The second issue is based on the notion of fat distribution being more important than the total body fat mass.
Visceral fat has been shown to be a predictor of hepatic
steatosis in HCV patients1 and obesity.6 Therefore, waist
circumferences (not likely to be available in retrospective
study) would have been of interest to compare with BMI.
An additional issue is the limitations innate to a retrospective design. In view of such nascent observations
made by Bressler et al., this study design was logistically
unavoidable. Nonetheless, it would have been preferable
to observe the effect of BMI on viral response to a single
uniform treatment rather than 3 different therapies used
over the 12-year epoch of this study. This study design is
also of concern because it cannot account for potential
changes in body composition that may have occurred
prior to and during the study period.6 Other specific criticisms can be raised. Although it is understandable why
only patients who completed 80% of their medications
were included in the analysis, a sensitivity analysis could
have been performed even if all patients were included in
the study in conjunction with available information on all
subjects. In addition, it is unclear why age, race, and viral
load (other factors thought to influence HCV treatment
response rates) were not included in the univariate and
multivariate analyses. Additional information also would
have been helpful, such as the BMI in the 3 different
treatments and the treatment effect of BMI in relapsers.
Regardless of these considerations, the two important
observations in the current study appear valid. The first is
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MCCULLOUGH
that obesity is an independent factor that diminishes the
eradication rate of IFN-based treatment. This confirms
previous studies7-9 that suggested obesity to be an independent negative predictor of HCV response to treatment. Although the mechanism by which obesity
diminishes the efficacy of antiviral treatment in the HCV
patients remains to be elucidated, there are at least 3 likely
possibilities.
The first possibility is related to fixed dosing and decreased bioavailability. The efficacy of both IFN and ribavirin is dose related. Therefore, obese patients may simply
be getting subtherapeutic doses of drug when fixed rather
than weight-based dosing is given, such as in studies performed by Bressler et al.5 and others.8,9 In fact, previous
work10 showed that obese patients with HCV had lower
concentrations of IFN than nonobese patients when
given a fixed dose of IFN. A larger body size may result in
more extensive drug distribution and lower serum concentrations. Not surprisingly, this explanation may be too
simplistic. As the size of the IFN molecule increases with
pegylation, the decrease in the volume of distribution results in factors such as obesity and variations in body
weight exerting a less profound effect on IFN pharmacokinetics. However, studies using larger pegylated interferons8,9 still found obesity to be an independent negative
predictor for HCV viral response to treatment. Alternatively,
obesity may decrease the bioavailability of IFN from its subcutaneous administration because of abnormal lymphatic
drainage,11 an abnormality that may be dependent on both
the size and site of the macromolecule injected.12
The second possible mechanism is a diminished hepatic response to IFN due to hepatic steatosis associated
with obesity. In their study, Bressler et al. found these 2
factors to be independent from each other. However, hepatic fat deposits may cause altered hepatic function,13
distort the normal architecture, and decrease the contact
area between drug and hepatic membranes. In support of
this possibility, a recent report found decreased serum
levels of 2⬘-5⬘ oligoadenylate synthetase (a marker of endogenous IFN activity) in response to IFN in obese HCV
patients.10 The significance of this potential mechanism is
somewhat diminished because HCV patients with genotype 3 (which has the most hepatic fat) have high response
rates to treatment. It is possible, however, that the hepatic
steatosis mechanism may be more important in genotype 1.
The third possible mechanism is altered immune function associated with obesity,14 in part mediated by leptin
resistance. A rigorous Th-1 response stimulated by antiviral treatment improves HCV clearance with abnormalities in helper T cells and Th1/Th2 ratios being more
common in nonresponders to therapies.15 Leptin is a
pleiotropic molecule that regulates T-cell response, polar-
HEPATOLOGY, September 2003
Fig. 1. This hypothesis proposes that obesity causes hepatic steatosis
and that each independently diminishes HCV response to treatment.
Obese patients have decreased IFN bioavailability and impaired immune
response to HCV. Hepatic steatosis causes fibrosis (itself a predictor of
a poor virologic response) and inhibits the biologic response of IFN on
the liver. Whether the effects of obesity and hepatic steatosis on HCV
response rates are completely independent, additive, or synergistic
remains to be determined.
izing Th cells toward a Th1 phenotype. However, in
states of leptin resistance (such as obesity), disordered
T-cell function may prevent viral clearance. It should be
emphasized that leptin resistance is just one aspect in the
mosaic of obesity-induced immunologic abnormalities
that may play a role in HCV resistance to treatment.
The second observation made by Bressler et al. was that
the negative effect of obesity on viral clearance was independent from hepatic steatosis. This implies that these 2
intertwined factors act independently on viral clearance in
a fashion suggested in a simplified, testable hypothesis
provided in Fig. 1 and discussed in the legend.
While understanding the mechanisms of the observations by Bressler et al. may provide new approaches to
future therapies, the clinical relevance of this important
report is clear. Weight loss in obese patients may improve
the efficacy of HCV treatment. A recent study16 suggests
this strategy may, in fact, be beneficial. So, it appears that
Pasteur’s concept is still relevant and that HCV’s resistance to treatment is being nurtured by obesity, a “terrain” that reflects the excesses of an affluent society.
ARTHUR J. MCCULLOUGH, M.D.
Division of Gastroenterology and
The Schwartz Center for Metabolism and
Nutrition at MetroHealth Medical Center
Case Western Reserve University
Cleveland, OH
References
1. Adinolfi LE, Gambardella M, Adreana A, Tripodi MF, Utili R, Ruggiero
G. Steatosis accelerates the progression of liver damage of chronic hepatitis
C patients and correlates with specific HCV genotype and visceral obesity.
HEPATOLOGY 2001;33:1358-1364.
HEPATOLOGY, Vol. 38, No. 3, 2003
2. Ortiz V, Berenguer M, Rayon JM, Carrasco D, Berenguer J. Contribution
of obesity to Hepatitis C related fibrosis progression. Am J Gastroenterol
2002;97:2408-2414.
3. Hourigan LF, MacDonald GA, Purie D, Whitehall VH, Shorthouse C,
Clouston A, Powell EE. Fibrosis in chronic Hepatitis C correlates significantly body mass index and steatosis. HEPATOLOGY 1999;29:1215-1219.
4. Poynard T, Ratziu V, Charlotte F, Goodman Z, McHutchison J, Albrecht
J. Rates and risk factors of liver fibrosis progression in patients with chronic
Hepatitis C. J Hepatol 2001;34:730-739.
5. Bressler BL, Guindi M, Tomlinson G, Heathcote J. High body mass index
is an independent risk factor for non-response to antiviral treatment in
chronic Hepatitis C. HEPATOLOGY 2003;38:639-644.
6. McCullough AJ, Falck-Ytter Y. Body composition and hepatic steatosis as
precursors for fibrotic disease. HEPATOLOGY 1999;29:1328-1330.
7. Camps J, Crisostomo S, Garcia-Granero M, Riezu-Boj JE, Civeira MP,
Prieto J. Prediction of the response of chronic hepatitis C to interferon alfa:
a statistical analysis of pretreatment variables. Gut 1999;34:1714-1717.
8. Zeuzem S, Feinman SV, Rasenack J, Heathcote EJ, Lai MY, Gane E,
O’Grady J, et al. Peg interferon alfa-2a in patients with chronic hepatitis C.
N Engl J Med 2000;343;1666-1672.
9. Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL
MCCULLOUGH
10.
11.
12.
13.
14.
15.
16.
559
Jr, Haussinger D, et al. Peg interferon alfa-a plus ribavirin for chronic
hepatitis C virus infection. N Engl J Med 2002;347:975-982.
Lam NP, Pitrak D, Speralakis R, Lau AH, Wiley TE, Layden TJ. Effect of
obesity on pharmakinetics and biologic effect of interferon-␣ in hepatitis
C. Dig Dis Sci 1997;42:178-185.
Banerjee D, Williams EV, Ilott J, Monypenny IJ, Webster DJT. Obesity
predisposes to increased drainage following axillary node clearance: a prospective audit. Ann R Coll Surg Engl 2001;83:268-271.
Porter CJH, Charman SA. Lymphatic transport of proteins after subcutaneous administration. J Pharm Sci 2000;89:297-310.
Taliani G, Duca F, Lecce R, Livoli D, Pasquazzi C, DeBac C. Hepatic
liodocaine metabolism in chronic hepatitis C virus hepatitis with or without steatosis. HEPATOLOGY 1995;21:1760-1761.
Marti A, Marcos A, Martinez JA. Obesity and immune function relationships. Obesity Reviews 2001;2:131-140.
Masaki N, Fukushima S, Hayashi S. Lower Th-1/TH-2 ratio before interferon therapy may favor long-term virological responses in patients with
chronic hepatitis C. Dig Dis Sci 2002;47:2163-2169.
Hickman JJ, Clouston AD, MacDonald GA, Purdie DM, Prins JB, Ash S,
Jonsson JR, et al. Effect of weight reduction on liver histology and biochemistry in patients with chronic hepatitis C. Gut 2002;51:89-94.