Showing posts with label vitamin D. Show all posts
Showing posts with label vitamin D. Show all posts

Tuesday, March 13, 2018

Higher levels of vitamin D is associated with a lower risk of liver cancer

Study found higher levels of vitamin D is associated with a lower risk of liver cancer
In a large case-cohort study published this week in the journal BMJ, researchers at the National Cancer Center, Tokyo suggest a higher concentration of vitamin D in men and women is associated with a lower risk of overall cancer, including liver cancer.

However, the lower risk associated with higher levels of vitamin D seemed to show a ceiling effect, suggesting exceeding vitamin D levels beyond an optimal level may provide no additional benefit; A potential ceiling effect observed in our study may suggest that no additional benefit would accrue when a certain concentration of 25-hydroxyvitamin D is exceeded.

Quick Links
Link to the full-text BMJ article, read a patient fact sheet all about vitamin D from the National Institutes Of Health, finally a nice summary is over at Healio, and an in-depth look at the study for patients is available over at NHS; Vitamin D may reduce the risk of some cancers, additional coverage can be found in the media as well.

Full-Text Article
Sanjeev Budhathoki, staff scientist1, Akihisa Hidaka, staff scientist1, Taiki Yamaji, section head,1, Norie Sawada, section head1, Sachiko Tanaka-Mizuno, associate professor2, Aya Kuchiba, section head3 4, Hadrien Charvat, staff scientist1, Atsushi Goto, section head1, Satoshi Kojima, manager5, Natsuki Sudo, researcher5, Taichi Shimazu, section head1, Shizuka Sasazuki, division chief1, Manami Inoue, division chief1, Shoichiro Tsugane, director1, Motoki Iwasaki, division chief1 for the Japan Public Health Center-based Prospective Study Group
BMJ 2018; 360 doi: https://doi.org/10.1136/bmj.k671
(Published 07 March 2018)
Cite this as: BMJ 2018;360:k671
Abstract
Objective
To evaluate the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of overall and site specific cancer in a large cohort study.

Design
Nested case-cohort study within the Japan Public Health Center-based Prospective Study cohort.

Setting
Nine public health centre areas across Japan.

Participants
3301 incident cases of cancer and 4044 randomly selected subcohort participants.

Exposure
Plasma concentration of 25-hydroxyvitamin D measured by enzyme immunoassay. Participants were divided into quarters based on the sex and season specific distribution of 25-hydroxyvitamin D among subcohorts. Weighted Cox proportional hazard models were used to calculate the multivariable adjusted hazard ratios for overall and site specific cancer across categories of 25-hydroxyvitamin D concentration, with the lowest quarter as the reference.

Main outcome measure Incidence of overall or site specific cancer.
Results
Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend=0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend=0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios.

Conclusions
In this large prospective study, higher vitamin D concentration was associated with lower risk of total cancer. These findings support the hypothesis that vitamin D has protective effects against cancers at many sites.
Full- Text Article: http://www.bmj.com/content/360/bmj.k671

National Institutes Of Health 
Vitamin D Fact Sheet for Consumers
In general, young people have higher blood levels of 25-hydroxyvitamin D than older people and males have higher levels than females. By race, non-Hispanic blacks tend to have the lowest levels and non-Hispanic whites the highest. The majority of Americans have blood levels lower than 75 nmol/L (30 ng/mL).

Higher vitamin D concentration lowers risk for overall, liver cancer
Free registration may be required to view article

Sunday, January 28, 2018

Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review

Also On This Blog
Tuesday, March 13, 2018
Higher levels of vitamin D is associated with a lower risk of liver cancer:
https://hepatitiscnewdrugs.blogspot.com/2018/03/higher-levels-of-vitamin-d-is.html

World J Gastroenterol. Jan 28, 2018; 24(4): 445-460
Published online Jan 28, 2018. doi: 10.3748/wjg.v24.i4.445

Review
Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review 
Nghiem Xuan Hoan, Hoang Van Tong, Le Huu Song, Christian G Meyer, Thirumalaisamy P Velavan

Core tip: Vitamin D deficiency is common and associated with chronic liver diseases. Several studies have ascribed a strong association of vitamin D insufficiency with unfavorable clinical courses and progression of liver disease in hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. However, any causal relation is so far not fully understood. In addition, there are inconsistent results with regard to the impact of vitamin D supplementation on the virological response to IFN-based therapy; this applies particularly to HCV infections. The present review addresses general aspects of vitamin D deficiency and focuses on its association with HBV and HCV infection. Furthermore, the effects of vitamin D supplementation in combination with IFN-based therapy on the virological response in HBV and HCV infected patients are reviewed.

Tuesday, April 25, 2017

Vitamin D does not prevent cardiovascular disease

Vitamin D does not prevent cardiovascular disease
Monday 24 April 2017

Previous research has suggested that cardiovascular disease might be more common in people with low levels of Vitamin D.

But trials using Vitamin D as a supplement haven't shown any benefit - and it's been argued that this is because they were using too low a dose.

And now, The Vitamin D Assessment Study - a large trial of monthly, high dose supplementation - has found no benefit in preventing cardiovascular disease.

Read - Transcript

Guest
Professor Robert Scragg
School of Population Health, The University of Auckland
(view full episode)

Monday, February 27, 2017

Vitamin D decreases HCV cell replication, aids virologic response

Vitamin D decreases HCV cell replication, aids virologic response

Huang JF, et al. Hepatol Res. 2017;doi:10.1111/hepr.12878.

February 27, 2017
Vitamin D decreased hepatitis C cell replication and appeared significantly associated with rapid virologic response in anti-viral therapy, according to study results published in Hepatology Research.

“Liver has long been regarded as the key player manipulating complex biochemical metabolism, which is essential to maintenance of homeostasis,” the researchers wrote. “[Vitamin] D, the secosteroid hormone with pleiotropic effects, is an important physiological regulator contributed into various biological, immunological and metabolic functions in liver diseases. These non-skeletal effects are relevant in the pathogenesis of many causes of chronic liver disease.”
Continue Reading @ Healio

Related On This Blog
A collection of research articles investigating a possible role of vitamin D in hepatitis C.

Sunday, February 26, 2017

Hepatitis C infected patients need vitamin D3 supplementation in the era of direct acting antivirals treatment 

Useful Link
Vitamin D2 and/or Vitamin D3
Vitamin D: A Rapid Review
Vitamin D2 is the form of D that is found in fortified foods like milk, juices or cereals, and D3 is the form that is synthesized by the skin when it's exposed to the sun or (ultraviolet light/UVB). 
UVB light from the sun strikes the skin, and humans synthesize vitamin D3, so it is the most "natural" form. Human beings do not make vitamin D2, and most healthy fish contain vitamin D3.

On This Blog
Is There A Natural Way To Improve Liver Fibrosis?
On this page the goal is to explore published data on natural alternatives and dietary supplements to fight or curtail liver damage.  

Hepatitis C infected patients need vitamin D3 supplementation in the era of direct acting antivirals treatment 
Yasuteru Kondo

World J Gastroenterol. Feb 28, 2017; 23(8): 1325-1327
Published online Feb 28, 2017. doi: 10.3748/WJG.v23.i8.1325

Abstract
It has been reported that the serum level of vitamin D3 (VitD3) could affect the natural course of chronic hepatitis C (CH-C) and the response to treatment with pegylated interferon (Peg-IFN) and ribavirin. Although several mechanisms for the favorable effects of VitD3 supplementation were reported, the total effect of VitD3 supplementation remains unclear. Previously, we reported that supplementation with 1(OH)VitD3 could enhance the Th1 response inducing not only a favorable immune response for viral eradication but also HCC control. Recently, the main treatment of CH-C should be direct acting antivirals (DAAs) without Peg-IFN. Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients with severe fibrosis lacking sufficient amounts of VitD3.


Core tip: Although several mechanisms for the favorable effects of vitamin D3 (VitD3) supplementation were reported, the total effect of VitD3 supplementation remains unclear. Recently, the main treatment of chronic hepatitis C should be direct acting antivirals (DAAs) without pegylated interferon (Peg-IFN). Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients with severe fibrosis lacking sufficient amounts of VitD3.

INTRODUCTION
It has been reported that the serum level of vitamin D3 (VitD3) could affect the natural course of chronic hepatitis C (CH-C) and the response to treatment with pegylated interferon (Peg-IFN) and ribavirin (RBV)[1,2]. Although several mechanisms for the favorable effects of VitD3 supplementation were reported, the total effect of VitD3 supplementation remains unclear. It has been reported that VitD3, as synthesized in the skin by photolysis from 7-dehydrocholesterol, is transported in the blood to the liver where it is hydroxylated at the C-25-position. Then, it is hydroxylated at the C-1α-position to form the active metabolite 1,25(OH)2VitD3 in the kidney. 1,25(OH)2VitD3 is known to regulate calcium and phosphorus metabolism in skeletal homeostasis. Moreover, 1,25(OH)2VitD3 could affect various kinds of immune cells via vitamin D receptor[3,4]. Several groups reported that the amount of 25(OH)VitD3 affects the progression of CH-C and response to Peg-IFN/RBV treatment. Moreover several mechanisms for the favorable effects of VitD3 supplementation in CH-C patients have been reported[5]. Dr. Azza reported that the serum level of 25(OH)VitD3 in CH-C children was significantly lower than that in healthy children. In addition to the treatment response, the deficiency of VitD3 could affect bone density. Therefore, we should consider supplementation with VitD3 for CH-C patients even in the era of direct acting antivirals (DAAs).

DISCUSSION
After a sustained virological response, the risk of hepatocarcinogenesis remains. Previously, we reported that supplementation with 1(OH)VitD3 could enhance the Th1 response inducing not only a favorable immune response for viral eradication but also HCC control[5]. The induction of a favorable immune response by adding VitD3 might be able to suppress the hepatocarcinogenesis after achieving SVR, especially in children and elderly patients lacking sufficient amounts of VitD3. Another group reported that 1,25(OH)2VitD3 could inhibit HCC development through reducing secretion of inflammatory cytokines from immune-related cells[6]. Moreover, it has been reported that reduced 25(OH)VitD3 serum levels were found to be associated with HCV-related HCC[7]. In addition to the risk of HCC development, 25(OH)VitD3 deficiency could be associated with advanced stages of HCC and it could be a prognostic indicator for a poor outcome[8]. In Japan, hepatocarcinogenesis after achieving SVR is an important issue since many CH-C patients are old and have severe fibrosis. Especially, CH-C patients with severe fibrosis might not have sufficient VitD3 since hepatocytes are necessary to metabolize VitD3. Moreover, it has been reported that there might be a relationship between carcinogenesis and insufficient VitD3[6,9]. Therefore, we should analyze the effect of VitD3 supplementation on hepatocarcinogenesis after achieving SVR[7]. Additionally, the immunological effect of VitD3 might differ between DAAs with and without Peg-IFN.

CONCLUSION
Recently, the main treatment of CH-C should be DAAs without Peg-IFN. Peg-IFN is a strong immune-modulator. Therefore, an immunological analysis should be carried out to understand the effect of VitD3 after treatment of DAAs without Peg-IFN.

References
1. Petta S, Cammà C, Scazzone C, Tripodo C, Di Marco V, Bono A, Cabibi D, Licata G, Porcasi R, Marchesini G. Low vitamin D serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51:1158-1167.  [PubMed]  [DOI]
2. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina AR, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World J Gastroenterol. 2011;17:5184-5190.  [PubMed]  [DOI]
3. Chun RF, Liu PT, Modlin RL, Adams JS, Hewison M. Impact of vitamin D on immune function: lessons learned from genome-wide analysis. Front Physiol. 2014;5:151.  [PubMed]  [DOI]
4. Ryynänen J, Carlberg C. Primary 1,25-dihydroxyvitamin D3 response of the interleukin 8 gene cluster in human monocyte- and macrophage-like cells. PLoS One. 2013;8:e78170.  [PubMed]  [DOI]
5. Kondo Y, Kato T, Kimura O, Iwata T, Ninomiya M, Kakazu E, Miura M, Akahane T, Miyazaki Y, Kobayashi T. 1(OH) vitamin D3 supplementation improves the sensitivity of the immune-response during Peg-IFN/RBV therapy in chronic hepatitis C patients-case controlled trial. PLoS One. 2013;8:e63672.  [PubMed]  [DOI]
6. Guo J, Ma Z, Ma Q, Wu Z, Fan P, Zhou X, Chen L, Zhou S, Goltzman D, Miao D. 1, 25(OH)2D3 inhibits hepatocellular carcinoma development through reducing secretion of inflammatory cytokines from immunocytes. Curr Med Chem. 2013;20:4131-4141.  [PubMed]  [DOI]
7. Lange CM, Miki D, Ochi H, Nischalke HD, Bojunga J, Bibert S, Morikawa K, Gouttenoire J, Cerny A, Dufour JF. Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. PLoS One. 2013;8:e64053.  [PubMed]  [DOI]
8. Finkelmeier F, Kronenberger B, Köberle V, Bojunga J, Zeuzem S, Trojan J, Piiper A, Waidmann O. Severe 25-hydroxyvitamin D deficiency identifies a poor prognosis in patients with hepatocellular carcinoma - a prospective cohort study. Aliment Pharmacol Ther. 2014;39:1204-1212.  [PubMed]  [DOI]
9. Fedirko V, Duarte-Salles T, Bamia C, Trichopoulou A, Aleksandrova K, Trichopoulos D, Trepo E, Tjønneland A, Olsen A, Overvad K. Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case-control study. Hepatology. 2014;60:1222-1230.  [PubMed]  [DOI]

Sunday, February 19, 2017

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data 

Systematic Review
World J Hepatol. Feb 18, 2017; 9(5): 278-287
Published online Feb 18, 2017. doi: 10.4254/WJH.v9.i5.278

Influence of vitamin D on liver fibrosis in chronic hepatitis C: A systematic review and meta-analysis of the pooled clinical trials data
Alia S Dadabhai, Behnam Saberi, Katie Lobner, Russell T Shinohara, Gerard E Mullin

Core tip: Vitamin D levels are associated with more advanced fibrosis in chronic hepatitis C

Abstract
AIM
To investigate the relationship between vitamin D and liver fibrosis in hepatitis C-monoinfected or hepatitis C virus (HCV)-human immunodeficiency virus (HIV) co-infected patients.

METHODS
Pertinent studies were located by a library literature search in PubMed/Embase/Cochrane/Scopus/LILACS by two individual reviewers. Inclusion criteria: (1) studies with patients with HCV or co-infected HCV/HIV; (2) studies with patients ≥ 18 years old; (3) studies that evaluated liver fibrosis stage, only based on liver biopsy; and (4) studies that reported serum or plasma 25(OH)D levels. Studies that included pediatric patients, other etiologies of liver disease, or did not use liver biopsy for fibrosis evaluation, or studies with inadequate data were excluded. Estimated measures of association reported in the literature, as well as corresponding measures of uncertainty, were recorded and corresponding odds ratios with 95%CI were included in a meta-analysis.

RESULTS
The pooled data of this systematic review showed that 9 of the 12 studies correlated advanced liver disease defined as a Metavir value of F3/4 with 25(OH) D level insufficiency. The meta-analysis indicated a significant association across studies.

CONCLUSION
Low vitamin D status is common in chronic Hepatitis C patients and is associated with advanced liver fibrosis.

INTRODUCTION
Hepatitis C virus (HCV) infection remains one of the most common etiologies of liver disease worldwide. A number of epidemiological papers have addressed the global prevalence of Hepatitis C. Lanini et al[1] reported that 100 million people globally have serological evidence of current or past HCV infection causing 700000 deaths annually while others suggest that the actual occurrence is double[2]. HCV remains the most common indication for liver transplantation in the United States[3]. Chronic infection with HCV can lead to liver inflammation, liver fibrosis, cirrhosis, and hepatocellular carcinoma.

Liver fibrosis is a result of excessive accumulation of extracellular matrix proteins, as part of the wound healing response to chronic injury and chronic inflammation[4]. Various factors have been associated with progression of fibrosis including duration of infection, age, male sex, diabetes, alcohol consumption and human immunodeficiency virus (HIV) co-infection[5].

Vitamin D is a hormone that has numerous biological properties that influence host physiology by regulating epigenetic regulation of more than 2000 genes throughout the body. Vitamin D is best known for its role in maintaining bone mineralization but has diverse and profound influences which can determine disease development and outcome. Although referred to as a vitamin, this steroid hormone is synthesized in the body by a series of hydroxylation reactions that occur in skin (7-hydroxylation), the liver (25-hydroxylation) and the kidney (1-hydroxylation)[6] (Figure 1). Reduction of the enzymatic conversion of 7-dehydrocholesterol to 1.25 hydroxy vitamin D at any of the three conversion steps can result in suboptimal vitamin D status[7].

Vitamin D has a number of influences on innate and adaptive immunity which are pertinent to study in conditions that are driven by chronic inflammation and maladaptive tissue injury[8,9]. Given the ubiquitous distribution of vitamin D receptors in virtually every cell in the body-suboptimal vitamin D status has been studied for its relationship to numerous diseases[10].

For example, there is substantial evidence that vitamin D benefits rheumatoid arthritis, due to its immunomodulatory effect[11]. The role of vitamin D in various cancers has been established linked to its antiproliferative action mediated through vitamin D nuclear receptor[12]. There have been numerous reports on lower serum vitamin D levels in patients with chronic liver disease from various etiologies[13]. In chronic HCV, Low vitamin D levels have been reported in 46% to 92% of patients[10] raising suspicion of its potential contribution to disease pathogenesis.

There is growing evidence from various groups, that vitamin D levels are inversely correlated with liver inflammation and stage of liver fibrosis in patients with HCV; however, the studies are heterogeneous with occasionally the results are conflicting. Additionally, the methods of reporting liver fibrosis were variable.


Figure 1 Vitamin D metabolism.
Vitamin D has diverse influences throughout the body as vitamin D receptors present on virtually every cell. The actions of vitamin D can be subdivided into two larger categories: Calcemic and non-calcemic actions. The non-calcemic actions of vitamin D are legion and have been reviewed elsewhere[6,54-58]. Reproduced with permission[6].

The aim of this study was to evaluate the relationship between vitamin D status and hepatic fibrosis based on histopathological staging in patients with chronic HCV mono-infection or co-infected HIV-HCV infection, by performing a systematic review of the scientific literature followed by a meta-analysis.

View Full Text ...

Of Interest
January 9, 2017
Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?
This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection.

Results
Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03±9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699) nor with the degree of liver fibrosis (P=0.269).

Conclusion
In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C.
View full text article..

Monday, January 9, 2017

Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?

Arq. Gastroenterol. vol.54 no.1 São Paulo Jan./Mar. 2017
Original Article
Download Full Text PDF

Is there an association between vitamin D and liver fibrosis in patients with chronic hepatitis C?
Kalinca da Silva OLIVEIRA1, Caroline BUSS1,2 and Cristiane Valle TOVO1,3

Abstract
Background
Vitamin D is known for its immunomodulatory, anti-inflammatory and antifibrotic properties, which are quite relevant in the pathogenesis and treatment of many causes of chronic liver disease.

Objective
This study aimed to evaluate the association between serum vitamin D levels and the histopathological findings in patients with chronic hepatitis C virus infection.

Methods
Cross-sectional study composed of patients with chronic hepatitis C. All patients underwent vitamin D 25 dosage and anthropometric data analysis. Liver biopsy was performed in a maximum 36-month period before inclusion in the study.

Results
Of the 74 patients included in the study, 45 (60.8%) were women, mean age was 57.03±9.24 years, and 63 (85.1%) were white. No association was observed between the serum levels of vitamin D and inflammatory activity (P=0.699) nor with the degree of liver fibrosis (P=0.269).

Conclusion
In this study, no association was observed between vitamin D and inflammatory activity, as well as the degree of liver fibrosis, in patients with chronic hepatitis C.

Discussion Only
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No association between the vitamin D serum levels and the different degrees of inflammatory activity or liver fibrosis was found in this study. Some studies examined the relationship between the vitamin D serum level and the progression of the disease in patients with chronic hepatitis C5,10,12, but this is a controversial issue.

It has been suggested that HCV reduces the production of 7-dehydrocholesterol, the precursor of endogenous vitamin D. Most patients presented low vitamin D levels, suggesting that HCV depresses serum levels and changes the lipid metabolism6.

Vitamin D deficiency is closely related to the severity of some chronic liver disease1,2,7,17,23. Vitamin D anti-inflammatory and modulating properties could impact on disease progression especially on HCV chronic liver disease12. Some authors observed that vitamin D might have an impact on other outcomes and in the response to the treatment of patients with chronic hepatitis C 8,18,21,26.

In the present study, 9 (12.2%) patients presented was observed deficiency. Similar results have been shown in the literature9 in the population with HCV, although some reports present a high index of vitamin D deficiency/insufficiency.

A recent study9 showed an inverse relationship between vitamin D levels and viral load, liver fibrosis and treatment outcomes, supporting the hypothesis that the improvement of vitamin D status may have considerable potential to amend the host defense against HCV infection and response to therapy.

An independent association between low vitamin D serum level and higher degree of inflammatory activity has been suggested 4,13. A probable explanation for the association between lower vitamin D levels and lower inflammatory activity in the liver would be the decrease of 25-hydroxylase activity, promoting decrease in vitamin D hydroxylation activity and, hence, lower serum levels13. However, this association was not observed in this study, corroborating Petta et al.'s findings 20, putting in question this potential mechanism.

Some studies show that vitamin D serum levels are inversely related to liver fibrosis, showing a relationship between the anti-inflammatory effects10,14,20. Thus, vitamin D deficiency could contribute to a more advanced liver fibrosis and the use of supplementation should have an antifibrotic effect on HCV carriers5. On the other hand, Kitson et al.13) and Bitetto et al.4 did not find association between vitamin D serum levels and the degree of liver fibrosis in their studies, in which the contribuiting factors were not clear, with chances of being racial, genetic or methodological differences used in vitamin D analysis.

It should be questioned if vitamin D deficiency increases with age and the patients included in the present study should be quite young to assess this relationship. Vitamin D concentration was evaluated in individuals in the city of São Paulo belonging to different age groups15. A total of 591 individuals were included. The authors hypothesized that there would be cyclic patterns for the vitamin D and the UV radiation values that repeat every 12 months. They concluded that there was seasonal variation in the vitamin D concentration for all the groups studied; however, the amplitude of the variation was higher for the groups of young and physically active people, possibly due to the higher level of sunlight exposure for these groups. The lowest vitamin D concentration was detected in the spring. In the present study, however, this variable was analyzed and there was no association between age and vitamin D level when we considered the cutoffs for sunny countries established by Holick et al.11.

The fact that this study does not present data on the potential confounders that may influence vitamin D serum levels (sunlight exposure, use of medications or osteoporosis prevalence) can be considered as a limiting factor, although all patients collected the blood in the same season of the year.

Some authors reported that some drugs used for diabetes, for reducing cholesterol or diuretics may interfere lowering serum levels of vitamin D 24. This may be an interesting observation, however, this was not evaluated in the present study.

In conclusion, there was no association between vitamin D serum levels and inflammatory activity or the degree of liver fibrosis in the patients with chronic HCV infection.

Continue reading ...

Thursday, April 24, 2014

Vitamin D – should you take it?

Egg yolks contain a small amount of vitamin D istockphoto.comVitamin D – should you take it? 
By Lindsay Kobayashi
Posted: April 24, 2014

Egg yolks contain a small amount of vitamin D
iStockphoto.com

My hunch is that it depends. Vitamin D is a nutrient that helps our bodies regulate the metabolism of calcium and phosphate (1). Most vitamin D comes from sunlight, while it is also found in certain foods including fatty fish, mushrooms, egg yolks, vitamin-D fortified foods. For example, milk in many countries is always fortified with vitamin D, and some brands of breakfast cereals and orange juice are fortified as well (2).  Vitamin D can also be obtained through taking vitamin D supplements found at your local grocery or health food store. The classic health consequences of inadequate vitamin D are rickets in children, and low bone mineral density and osteoporosis in older adults (3). Low vitamin D has also been associated with increased risk for many other health conditions including breast, prostate, and colorectal cancer, multiple sclerosis, and cardiovascular disease (4-6). However, the quality of scientific evidence for these relationships varies because it is actually quite challenging methodologically to study the cause-effect relationship of vitamin D on health.

Because definitive high-quality evidence is lacking, the actual beneficial effect of vitamin D on health has been heavily debated in recent years. Like many other dietary or lifestyle factors that have been linked to health outcomes with scientific uncertainty (examples: coffee, alcohol, vitamin C, herbal supplements), the available information about whether to take vitamin D supplements can be very confusing. Here is where we stand right now:

In 2011, the American Institute of Medicine released an expert report on the dietary reference intakes for vitamin D (3). They stated that, for people aged 1 to 70 years old including pregnant and lactating women, the recommended dietary allowance (RDA) is 600 IU per day of vitamin D. For adults aged over 70 years the RDA is 800 IU per day. Intake should not exceed 4000 IU per day for people aged 9 years and over. The full RDA guidelines can be found here. Interestingly, their expert panel concluded that current scientific evidence is insufficient to conclude that vitamin D plays a causal role in non-bone-related health conditions (3). Now, this statement may or may not mean that vitamin D has no effect on health aside from bone conditions, simply that our current knowledge is insufficient.

Supplements can be a good source of vitamin D
iStockphoto.com
Supplements can be a good source of vitamin D istockphoto.comFast forward to today, and it doesn’t seem like our evidence base has evolved much. An ‘umbrella’ review of evidence on the link between blood plasma concentrations of vitamin D and 137 unique health outcomes was published in the British Medical Journal earlier this month (7). The review was the largest synthesis of knowledge to date, and the authors unfortunately had to conclude that:
“Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable”
The authors concluded that vitamin D supplementation is probably linked to decreased dental caries (cavities) in children, reduced parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis, and to an increase in maternal vitamin D concentrations at term, and an increase in birth weight (7). These are very specific conditions that apply only to children, pregnant mothers, and chronic kidney disease patients. The authors also concluded that the evidence is ‘suggestive’ for a correlation between higher blood vitamin D concentrations and a lower risk of several conditions including colorectal cancer, non-vertebral fractures, cardiovascular diseases, depression, high body mass index, and type 2 diabetes (7). However, a major point to note is that these are correlations, which means that although vitamin D has been associated with these health conditions, it may not cause them. Because of the limitations of current research, including the difficulty in measuring the actual vitamin D intake of people, and how much of this actually gets absorbed and has a biological effect, the timing between vitamin D intake and disease onset, and determining the actual dose of vitamin D that may protect against disease, we don’t have definitive answers right now.

So, what should we do about our own health? It is clearly too soon to make any strong recommendations about population-level vitamin D supplementation. Following the current RDA for vitamin D is good, and achieving this level for yourself may include supplementation if you don’t eat many foods containing vitamin D. Always talk to your family physician if you have any concerns about your own health or vitamin D intake. And finally, as always, keep yourself informed with high quality information to make decisions for your own health.

References
1)      National Health Service. Vitamins and minerals – vitamin D. http://www.nhs.uk/Conditions/vitamins-minerals/Pages/Vitamin-D.aspx (accessed 21 April 2014).
2)      National Institutes of Health. Vitamin D: Fact sheet for consumers. http://ods.od.nih.gov/factsheets/VitaminD-QuickFacts/#h3 (accessed 21 April 2014).
3)      Committee to Review Dietary References Intakes for Vitamin D and Calcium, Institute of Medicine: Dietary Reference Intakes for Calcium and Vitamin D. Edited by Ross AC, Taylor CL, Yaktine AL, Del Valle HB. Washington, DC: The National Academies Press; 2011.
4)      Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266-81.
5)      Munger KL, Zhang SM, O’Reilly E, Hernán MA, Olek MJ, Willett WC, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology 2004;62(1):60-5.
6)      Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation 2008;117:503-11.
7)      Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JPA. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ2014;348:g2035

Source PLOS Blogs

Saturday, August 24, 2013

Metabolic factors and chronic hepatitis C: a complex interplay

Biomed Res Int. 2013;2013:564645. doi: 10.1155/2013/564645. Epub 2013 Jul 17.

Metabolic factors and chronic hepatitis C: a complex interplay.

Macaluso FS, Maida M, Minissale MG, Li Vigni T, Attardo S, Orlando E, Petta S.

Source
Section of Gastroenterology, DiBiMIS, University of Palermo, Piazza delle Cliniche 2, 90127 Palermo, Italy.

View Article - BioMed Research International

Abstract

In the last years, several lines of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C. Chronic HCV infection is able to perturb the metabolic homeostasis of the host, in a context of complex interactions where pre-existent metabolic status and genetic background play an important role, allowing us to state that HCV infection is a systemic disease. In this review, we discuss the most recent lines of evidence on the main metabolic factors that are known to be associated with CHC, namely, insulin resistance/type 2 diabetes, steatosis, visceral obesity, atherosclerosis, vitamin D, menopause, fructose and coffee intake, lipoproteins, methylenetetrahydrofolate reductase status, and hyperuricaemia. In particular, we focus on the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and non-liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features. In this setting, the importance of a multifaceted evaluation of CHC patients and a prompt correction of modifiable metabolic risk factors should be emphasized.

Introduction

Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide, and it has reached a pandemic spread []. The risk of progression from chronic HCV infection to cirrhosis and its clinical outcomes is highly variable, and many factors are believed to accelerate disease progression and to impact the likelihood of sustained virological response (SVR) after pegylated interferon/ribavirin therapy. In this line, a considerable amount of evidence showed how metabolic factors may influence the natural history of patients with chronic hepatitis C (CHC) and affect the outcome of antiviral therapies, particularly insulin resistance (IR) and steatosis []. This correlation is not unidirectional [], since chronic HCV infection is able to influence glucose and lipid metabolism and thus to perturb the metabolic homeostasis of the host leading to extrahepatic consequences (Figure 1). The result of this complex interaction is the conceptual translation of CHC from a localized to a systemic disease and, therefore, the need for the clinician to evaluate a patient with CHC focusing on liver disease and on associated metabolic conditions.

The interplay between metabolic factors and chronic HCV infection.

We discussed the most recent lines of evidence on the role of the main metabolic factors that are known to be associated with CHC, the pathophysiological mechanisms underlying the correlation between HCV infection and metabolic disorders, the impact of metabolic factors on the progression of liver and liver-related diseases, and, on the contrary, the possible influence of chronic HCV infection on metabolic features.

Insulin Resistance

IR is defined as the condition in which higher insulin concentrations are required to achieve a normal metabolic response, otherwise not reached by normal insulin levels, and wherein the alterations mainly belong to postreceptorial transduction mechanisms []. IR is correctly regarded as the pathophysiological keystone of metabolic syndrome (MS), which represents a major cause of morbidity and mortality and whose prevalence is increasing worldwide []. Given the high spreads of MS and CHC, the chances of coexistence of these two conditions in a single patient are elevated. Nevertheless, this overlap is not simply coincidental: in subjects with CHC, the presence and severity of IR are related to host factors, mostly visceral obesity [], but in addition, many experimental [] and clinical [] studies suggested how HCV infection itself seems to be able to perturb glucidic homeostasis, leading to hepatic and extrahepatic IR. In this line, several lines of evidence are currently available on the ability of HCV to induce IR. Cross-sectional studies showed that the prevalence of diabetes in patients with CHC is superior to the one reported in other cohorts, such as subjects with other chronic liver diseases, human immunodeficiency virus-infected patients or drug users []. IR, evaluated through the homeostasis model assessment (HOMA-IR), is associated with HCV genotypes 1 and 4 and their viral load, which is higher than that in matched patients with chronic hepatitis B [], is increased even at early stages of liver fibrosis [] and, finally, may decrease across followup after SVR achievement []. In patients with CHC, mechanisms of IR can be found not only in liver, where they are expressed by an increased endogenous glucose production, but also in muscle tissue, resulting in a reduced glucose uptake in muscle []. Conversely, glucidic function of adipose tissue is not affected in HCV-associated IR, unlike what is commonly described in the course of “pure” IR conditions. This has prompted speculation that HCV may be able to affect insulin signalling inducing both hepatic and peripheral IR [] via several direct or indirect mechanisms (downregulation of suppressor of cytokine signalling (SOCS) and protein phosphatase PPA2, upregulation of tumour necrosis factor-α and induction of proinflammatory cytokines or other unknown soluble mediators). Excellent reviews described molecular pathways of HCV-induced IR [, ].

The relevance of IR in patients with CHC appears of great interest considering its potential influence on severity and progression of chronic liver disease, where IR can act both directly and indirectly, by inducing steatosis. A large population-based study [] on patients with chronic liver disease of various etiology showed that IR and T2D were independent predictors of overall mortality, with the remarkable exception of CHC patients; nevertheless, both T2D and IR were independently associated with liver-related mortality in patients with CHC. In this line, both cross-sectional and prospective studies repeatedly highlighted how IR and/or steatosis are associated with the severity and the progression of hepatic fibrosis and thus with the clinical progression of liver disease [, ]. While steatosis acts via collagenous deposition, generation of lipid peroxides, and finally stellate cell activation [], IR seems to be a powerful promoter of fibrogenesis via direct hepatic stellate cell stimulation, tumor necrosis factor-α and connective growth factor production, and ductular reactions induction []. In addition, several studies also suggested that full-blown T2D may further increase fibrogenesis and thus the risk of severe fibrosis in a context of IR []. This latter observation has been recently questioned by an interesting retrospective paper by Giordanino and colleagues []: even if diabetic patients had a higher number of diabetes- and liver-related events and higher mortality than nondiabetics, diabetes was not an independent factor for liver-related events, and diabetes-related events were lower in the HCV-positive group. Nevertheless, considering the high prevalence of cirrhosis and non-SVR among diabetic CHC patients, these data could however suggest an indirect role of diabetes in liver disease progression and in lack of SVR []. Finally, IR was found to be associated with the presence ofoesophageal varices in patients with HCV-related compensated cirrhosis []. This suggests the ability of insulin to modulate dynamic components of portal hypertension, for example, the endothelial synthesis of nitric oxide and endothelin [, ], other than induce architectural disturbances through the promotion of fibrogenesis.

As obesity and T2D are well-known risk factors for the development of many types of cancer, many experimental and observational studies on a potential increase of hepatocellular carcinoma (HCC) development in patients with CHC and IR were performed. A population-based study [] revealed that the presence of T2D was associated with a 3-fold increase risk of HCC occurrence and that this risk was higher in patients with both HCV and T2D and even higher in presence of obesity. In addition, in a recent prospective study by Nkontchou et al., IR itself was an independent risk factor for HCC development in HCV-related cirrhosis and, at the same time, a predictor of liver-related death or transplantation []. A vast literature exists on potential molecular mechanisms and mediators underlying the processes of liver carcinogenesis, including IR and hyperinsulinaemia, oxidative stress, and imbalances between proinflammatory and anti-inflammatory cytokines, even if further data are needed [].

While lines of evidence supporting the association between IR and progression of CHC appear overall to be solid, controversial data exist on the role of IR as a predictor of both rapid (RVR) and SVR in CHC patients treated with pegylated interferon/ribavirin. Recent studies in European [], Caucasian-American, and African-American [] patients infected with genotype 1 HCV showed that IR is associated with a lower likelihood to achieve an SVR after antiviral treatment with peg-interferon and ribavirin. The same results were recorded for genotypes 2, 3 [], and 4 []. Such data have been emphasized by a recent meta-analysis [], which quantified in a difference approximately equal to 20% the likelihood of SVR between patients with and without IR. In addition, lower HOMA-IR levels have been associated with RVR achievement in non-diabetic, noncirrhotic genotype 1 HCV patients, thus suggesting a relevant role of IR in the early phase of viral kinetics []. The roots of these phenomena may be sought in the mutual interference between insulin and interferon signalling via SOCS-3 liver expression []. Nevertheless, other authors [] did not observe an association between IR and SVR, showing that only moderate/severe steatosis, but not IR, was negatively associated with SVR. Overall, these observations may lead to hypothesize that both IR and steatosis could impact the likelihood of SVR and that the different results among studies may be related to pre-existent differences in metabolic dysfunctions and genetic backgrounds in the examined cohorts. In this line, interesting findings emerged through analysis of the interaction between interleukin-28B (IL-28B) genotype, an important host factor for SVR achievement after antiviral therapy, and IR. In white patients with genotype 1 CHC, the IL28B rs12979860 CC genotype was associated with reduced IR, and the same polymorphism and IR were associated with SVR at multivariate analysis, but not steatosis []. Finally, new data are currently emerging on the impact of IR on new direct acting antiviral-based treatments. In naïve genotype 1 CHC patients, baseline HOMA-IR was not correlated with virological response to telaprevir-based therapy, even if SVR was associated with improved HOMA-IR []; in experienced patients, baseline HOMA-IR correlated with SVR in univariate but not multivariate analysis []. Even if these results could suggest that HOMA-IR may not have a direct causal relationship with virological response to telaprevir-based therapy, caution is warranted because data analysis did not take into account the role of IL28B polymorphisms and steatosis (assessed in a fraction only of naïve patients and not evaluated in experienced subjects).

Steatosis

Steatosis is an extremely common histological finding in patients with CHC, with a prevalence ranging from 40 to 80% [], superior to the rate reported in chronic liver diseases of different etiology []. This high variability is probably due to a different distribution of known risk factors for steatosis, such as obesity, T2D, alcohol, and dyslipidemia, in the examined cohorts. However, even when these prevalence data are adjusted for metabolic risk factors, the proportion of patients with HCV and intrahepatic fat accumulation remains high (30–40%) []. Consequently, although NAFLD and CHC are both common conditions in the general population, the rate of steatosis observed in CHC is 2.5 times bigger than the expected value on the basis of a simple random coexistence []. These data suggest that not only host but also viral factors may participate in steatosis induction in CHC. A direct effect of HCV on steatogenesis is particularly relevant in genotype 3 patients, where steatosis is more frequent and severe [], due to specific genomic sequences of HCV genotype 3 favoring lipids accumulation in the liver. The core protein may be sufficient to induce steatosis, the genotype 3a being the most efficient [], although sequences outside the core seem to concur []. HCV is able to (in)directly promote the intracytoplasmic accumulation of fat in the liver increasing the hepatic synthesis of fatty acids and reducing the mechanisms of secretion and degradation of lipids []. Molecular details can be found in excellent reviews [, , ]. In this line, HCV-induced overexpression of an adipocytokine which takes part in steatogenesis, retinol binding protein 4 (RBP4) [], has been recently advocated as a possible expression of a virus-linked pathway to steatosis in CHC, largely unrelated to IR [, ]. Interestingly, steatosis may decrease after SVR [] and has been related to HCV viral load []. All these events are more noticeable in patients with genotype 3 HCV, in which steatosis has been referred as “viral.” Conversely, in non-3 genotypes infections, steatosis is regarded as “metabolic,” since it seems to be correlated more strictly with age and metabolic variables []. Of note, many mechanisms accounting for HCV-related steatosis can also promote IR. On the other hand, patients with high degrees of viral steatosis do not steadily present high levels of IR, and vice versa: studies reported that HOMA score is higher in patients with genotypes 1 and 4 HCV [], while HOMA levels are the lowest in patients with genotype 3 []. However, these findings are not univocal and likely dependent on different baseline metabolic features of analyzed cohorts.

The clinical relevance of steatosis in CHC patients lies in the fact that numerous studies have identified in liver fat accumulation a potential risk factor for progression of fibrosis, HCC occurrence, and lower likelihood of SVR achievement after antiviral therapy. Both cross-sectional and prospective papers identified steatosis as a predictor of liver fibrosis [], with a major role related to metabolic rather than virus-induced steatosis, even if data are sometimes discordant. Interestingly, a longitudinal French study showed that worsening of steatosis was the only independent factor associated with the progression of liver fibrosis in untreated patients with CHC []. In this line, the presence of steatosis has been related to possible increased oxidative stress and to phenomena of lipid peroxidation [, ] which may assist in fibrogenesis promotion. Other works highlighted how steatosis seems correlated with higher levels of proinflammatory cytokines, which are able to activate stellate cells [, ]. The same condition of IR has been invoked as a link between steatosis and fibrosis through the capability of insulin, glucose, and leptin, whose receptors are expressed on stellate cells, to induce the production of connective tissue growth factor [, ]. A further possible mechanism of steatosis-induced fibrogenesis could be related to the evidence that liver fat accumulation is associated with increased apoptotic cell phenomena, which are able to
activate stellate cells [, ].

About steatosis and carcinogenesis, several clinical papers have repeatedly found an association between fatty liver and HCC development in patients with CHC []. Indeed, in vitro and in vivo studies showed that HCV core protein expression promotes liver fat accumulation and, at the same time, may contribute to carcinogenesis [, ], even if molecular pathways are not yet fully understood. A persistent activation of PPARα was highlighted in mice models [], but this observation was not confirmed in HCV-infected humans []. Furthermore, many studies reported that hepatic steatosis is negatively correlated with SVR rates after peg-interferon and ribavirin treatment [, ]. This association may be explained through mechanisms that involve IR-induced SOCS, which in turn are responsible for a reduced activation of STAT, proteins involved in interferon signalling []. This association seems more specific of metabolic steatosis rather than viral one, since steatosis observed in genotype 3 patients has not been related to decreased likelihoods of SVR []. Finally, interesting findings relating steatosis and steatosis-induced liver complications with specific single nucleotide polymorphisms are emerging. The patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 C>G single nucleotide polymorphism is a genetic determinant of liver fat accumulation [] able to influence fibrosis severity in NAFLD patients [], and it has been associated with severe steatosis, fibrosis stage, treatment response, and HCC occurrence in subjects with CHC []. In genotype 1 CHC patients, CC polymorphism of IL28B was associated with higher levels of total and low-density lipoprotein cholesterol, lower levels of triglycerides, and a lower prevalence of IR and moderate-severe steatosis compared to patients with different genotypes [].


Visceral Obesity

Originally considered a simple passive depot for calories storage, visceral adipose tissue is now regarded as an endocrine site producing several substances able to regulate energetic metabolism, immunity, and inflammation and thus to influence the pathogenesis of cardiovascular disease, IR, and diabetes [, ]. In addition, visceral adiposity, evaluated through magnetic resonance, has been associated with liver fat accumulation in healthy subjects [, ] and with severity of necroinflammation, and fibrosis in patients with NASH []. In a CHC setting, an association between visceral obesity, steatosis and fibrosis was initially found using waist circumference and body mass index (BMI) [, ], which may be considered surrogate markers of visceral adipose tissue, even if not entirely accurate. In a more precise way, visceral adiposity index (VAI) is a marker of adipose distribution and dysfunction reflecting nonclassic cardiometabolic risk factors such as altered production of adipocytokines/cytokines, increased lipolysis, and plasma-free fatty acids [] that has been independently associated not only with steatosis but also with necroinflammatory activity, in patients with genotype 1 CHC []. This index was also related to viral load, a finding consistent with several papers that have already suggested a direct association between viral load and BMI [] and between HCV RNA status and obesity []. Overall, these aspects may lead to speculate that, on one hand, adipose tissue could offer fatty substrates and a proinflammatory status promoting HCV replication and that, on the other hand, HCV could molecularly interfere with adipocyte function indirectly, by increasing the inflammatory status and, directly, by colonizing adipocytes or immune cells infiltrating adipose tissue. In this line, interesting findings were also derived from the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial cohort []; authors found an association between several weight-related features and increased rates of histological or clinical progression of CHC: not only IR and histologic features of fatty liver disease at baseline but also weight change during the trial were strongly associated with progressive liver disease.

Finally, new data on a potential role of obesity in affecting SVR rates after treatment with protease inhibitors are emerging; a recent paper by Poordad and colleagues highlighted how, in previously untreated patients, baseline predictors of good response after peg-interferon, ribavirin, and boceprevir treatment included not only IL-28B genotype, low baseline viral load, and absence of cirrhosis but also lower BMI; in addition, BMI was associated with interferon responsiveness (defined as ≥1 log10 HCV-RNA decline at week 4) and with SVR adjusted for log10 HCV-RNA decline at week 4 []. In this regard, further evidences are urgently needed.
 
Atherosclerosis

In view of the complex overlap between CHC and MS and its features, several recent studies aimed to evaluate if an increased risk of atherosclerosis, cardiovascular events, and related mortality in patients with CHC exist. However, the presence of such an association is not as obvious, at least theoretically, if we consider the typical low-risk lipid profile of most patients with CHC.

In a large population study from Northern Europe, HBV and HCV infections were not associated with an increased risk for cardiovascular events, including carotid atherosclerosis, myocardial infarction, and stroke []. Conversely, a recent long-term prospective study revealed that chronic HCV-infected subjects have higher mortality from both hepatic and extrahepatic diseases, with a hazard ratio of 1.50 for circulatory diseases []. In this line, other studies [] showed that atherosclerosis, assessed by carotid artery plaques and/or intima-media thickness (IMT), was increased in patients with CHC compared to healthy controls. In a large prospective study, our group recently reported that the prevalence of asymptomatic carotid atherosclerosis is elevated in CHC patients compared to matched controls and highlighted an association between carotid vascular damage and severity of fibrosis []. These findings are clearly in line with other surveys showing that clinical diagnosis of HCV infection is per se an independent risk factor for increased carotid IMT [] and for cerebrovascular deaths []. The pathophysiological mechanisms which may explain this correlation are not clear, but it can be speculated that the proinflammatory mechanisms underlying liver fibrogenesis could be systemically activated, promoting atherosclerosis []; in addition, experimental lines of evidence have demonstrated the presence of HCV genomic material within carotid plaques in HCV-infected patients, assuming a possible viral direct action []. In this line, Adinolfi and colleagues recently observed that also viral load and hepatic steatosis are associated with the presence of carotid atherosclerosis in CHC subjects, thus assuming that HCV infection could be a relevant risk factor for carotid atherosclerosis occurrence via viral load and steatosis []. In contrast to these findings, Mostafa and colleagues recently demonstrated that IMT was associated with classical cardiovascular risk factors, such as systolic blood pressure and LDL cholesterol, while HCV infection was not associated []; a recent population-based Japanese study showed a paradoxically lower risk of atherosclerosis in CHC patients compared with healthy controls, even if an increased prevalence of IR in patients with HCV infection is confirmed []; Younossi and colleagues found that chronic HCV infection is independently associated with the presence of metabolic conditions (IR, T2D and hypertension) and, interestingly, with the presence of congestive heart failure, but not with increased rates of ischaemic heart disease and stroke []. Overall, the results of these studies highlight the presence of ambiguous data on the possible association between HCV infection and cardiovascular risk and the need for further studies in order to obtain external validation of these data in different, for example, per se “metabolic” and “nonmetabolic,” populations.

Vitamin D

Pleiotropic extraskeletal effects of vitamin D are exerted through the modulation of transcription of over 200 genes involved in immune response, inflammation, cell differentiation, and fibrogenesis and have been recently investigated in settings of chronic liver diseases, including CHC []. Our group firstly reported that genotype 1 CHC subjects show a higher prevalence of 25-hydroxyvitamin D (25[OH]D) deficiency compared to a matched control population, also in patients with minimal liver damage, and found an independent inverse relationship between 25(OH)D serum levels and severity of liver fibrosis []. Even if other papers observed no associations between vitamin D status and fibrosis stage [, ], these findings were further confirmed by other authors [, ] and supported by experimental studies showing that vitamin D interacts with its nuclear vitamin D receptor protecting against oxidative stress production [], influencing the migration, proliferation, and gene expression of fibroblasts [, ] and reducing the inflammatory and fibrogenic activity of liver stellate cells [, ]. In addition, several studies [] reported a correlation between low 25(OH)D levels and higher necroinflammatory activity, a link that has been suggested to be related to a decreased liver expression of the 25-hydroxylase CYP27A1, enzyme involved in vitamin D3 liver hydroxylation, caused by HCV infection itself []. In addition, on the basis of a recent genome-wide study which identified genetic variants affecting 25(OH)D serum levels in healthy populations [], our group recently reported that GG homozygosis for rs12785878 DHCR7 gene (one of the polymorphism linked to lower serum levels of [25(OH)D], near dehydrocholesterol reductase), together with lower 25(OH)D levels, is independently associated with the severity of liver fibrosis in patients with genotype 1 CHC, thus suggesting that DHCR7 genotype could also prompt fibrogenesis by itself via other direct/indirect mechanisms [].

While the role of vitamin D status in treatment regimens that include protease inhibitors is yet to be studied, its weight has been extensively investigated in dual therapy with peg-interferon plus ribavirin. First, vitamin D serum levels have been related to RVR achievement, thus assuming a role complementary to IL28B polymorphisms in enhancing the correct prediction of SVR [, ]. In addition, Vitamin D deficiency has been associated with failures in achieve an SVR after antiviral therapy in genotypes 1 [, ], 2, and 3 [] HCV infection in some cohorts, but not in others ([, ] for genotype 1; [] for genotype 2-3). Interestingly, prospective data from two small randomized clinical trials found that vitamin D3 supplementation improves SVR in genotypes 1, 2, and 3 HCV infections treated with peg-interferon plus ribavirin [, ]. Even if these results are sometimes discordant, the rationale for an immunomodulator capability of vitamin D can be found in experimental studies which show the potential ability of vitamin D signalling to interfere with T cells function and immune response [, ]. Consequently, further investigations on the relationship between vitamin D supplementation and SVR may be advisable, even in the rapidly evolving era of direct acting antivirals-based therapy.

Reproductive Status and Menopause

Studies performed on large cohorts have shown that high levels of estrogens, as typically observed during pregnancy [], are associated with a reduced necroinflammatory activity in HCV-infected women and that the rate of fibrosis progression in CHC is twice as fast in men than in women [, ]. Similarly, menopause has been associated with an accelerated liver fibrosis in women with CHC, an event that may be prevented by long-term hormonal replacement therapy []. It has been speculated that this aspect may be secondary to menopause-induced alterations in hormonal balance, in particular the reduction of estrogen levels and the decrease of estradiol/testosterone ratio. These changes result in a disequilibrium in proinflammatory and anti-inflammatory cytokines levels with a subsequent increase in necroinflammatory activity and thus faster fibrosis progression [].
Reproductive status could affect the response to pegylated interferon/ribavirin therapy, even if the relationship between gender and SVR is still controversial. While some papers showed that the percentages of SVR did not differ between men and women [], other authors have identified in female gender an independent factor for SVR achievement []. A recent study showed that, after stratifying the female population for pre- and postmenopausal status, postmenopausal women have similar progression of liver damage and equal SVR rates than in males but lower than in women in reproductive age []; in addition, early menopause was the only factor independently associated with lack of SVR in women with genotype 1 chronic HCV infection []. This phenomenon may be related to the alterations of inflammatory factors induced by estrogens deprivation, particularly the decrease of hepatic expression of tumor necrosis factor-α and of circulating levels of IL-6, imbalances that may interfere with the response to peg-interferon and ribavirin antiviral therapy []. In this line, it should be also mentioned that in postmenopausal women peg-interferon α-2B plus ribavirin seems to be more effective than peg-interferon α-2A plus ribavirin []. The reasons for this phenomenon are not completely understood, but different pharmacokinetics of the two peg-interferons may be theorized. In fact, in postmenopausal women there is an increase in body weight and a different fat distribution induced by hormonal changes; in this context, peg-interferon α-2A has a predominant distribution in plasma and liver and thus it may have a lower bioavailability compared to peg-interferon α-2B, which also distributes within extrahepatic tissues, such as cytokine-producing visceral fat tissue.

Interestingly, while menopause may affect the progression and outcome of therapy in CHC, chronic HCV infection in turn may influence the postmenopausal status and its clinical presentation. A recent work demonstrated that HCV infection is independently associated with natural menopause, controlling for age, and that HCV women have a higher prevalence of vasomotor symptoms. The mechanisms by which HCV infection impacts on menopause are not clear, but they may be related to an impaired estrogen metabolism in the liver [].

Surely, more data are needed to better define the reciprocal interaction between menopause and HCV infection and to evaluate the possible influence of reproductive hormonal status on response to new treatments with protease inhibitors and interferon-free regimens. In this line, an ongoing study in naïve and experienced CHC patients is assessing the impact of menopause on a boceprevir-based antiviral therapy.

Fructose and Coffee Intake, Lipoproteins, Methylenetetrahydrofolate Reductase Status and Hyperuricaemia

During the last decades, dietary fructose intake has increased worldwide []. Several studies on mice showed potential deleterious metabolic effects of fructose, including systemic inflammation, increased lipogenesis and worsening of IR, and obesity [, ]. In this line, clinical studies observed that a diet rich in fructose is able to reduce insulin sensitivity [] and to promote obesity in healthy subjects [, ], and it is linked to features of MS and to severity of liver fibrosis in patients with NAFLD []. Nowadays, there are few data on a potential role of fructose in the progression of CHC. Tyson and colleagues [] performed a cross-sectional study on HCV-infected male subjects, finding no significant associations between dietary fructose intake and fibrosis risk, assessed by Fibro-SURE Actitest, even if a significant association between a moderate fructose intake (30 to 48 g/d) and severe necroinflammation was observed. Conversely, preliminary data from our group on a cohort of genotype 1 CHC patients (Petta S. et al., unpublished data) show that only industrial, but not fruit fructose, would be associated with liver injury. Obviously, additional evidences are needed to fully clarify the potential role of fructose intake on hepatic inflammation and fibrosis in CHC subjects.

Several past works have linked coffee drinking with a protective role on serum liver function tests, specifically ALT, AST, and gamma-glutamyltransferase levels []. More recently, in a large prospective cohort derived from of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) trial, regular coffee consumption was a predictor of less severe steatosis on liver biopsy and of lower rates of histological and clinical progression []. In addition, an increased consumption of coffee seems to be able to reduce the risk of liver cancer, as stated by a recent meta-analysis [], and it has been associated with improved SVR rates after peg-interferon plus ribavirin therapy in CHC, even if the pathophysiological pathways through which coffee may influence liver diseases are not fully understood [].

A number of lines of evidence suggested a relationship between lipoproteins and HCV cell cycle []. In particular, it is evident that CHC patients show lower serum low-density lipoproteins (LDL) [], which in turn are inversely associated with the severity of liver fibrosis [] and, directly, with the likelihood to achieve RVR and SVR after pegylated interferon/ribavirin therapy [, ]. These aspects have been related, on one hand, to a competition for LDL receptor sites which prevents viral entry into hepatocytes and thus to an increased exposure of HCV to the host serum immune response [] and, on the other hand, to the association between higher total and LDL- cholesterol levels with the rs12979860 CC IL-28B polymorphism []. In this line, also hyperhomocysteinemia and methylenetetrahydrofolate reductase (MTHFR) C677T point mutation have been investigated in order to evaluate their potential role in CHC. Clinical studies found a link between higher homocysteine levels, MTHFR status, and severity of both steatosis and fibrosis progression in patients with CHC [, ]. In addition, other works also identified hyperhomocysteinemia as a negative risk factor for SVR achievement after standard antiviral therapy []. In this regard, our group reported a remarkable increase of homocysteine serum levels in genotype 1 CHC patients, not related to MTHFR status, and an independent association between MTHFR C677T homozygosis and higher total and LDL-cholesterol levels, a link which could suggest a possible indirect interference of MTHFR status, via modulation of cholesterol levels, on liver fibrosis and response to antiviral therapy [].

On the basis of several evidences observing an independent relationship between uric acid serum levels and ultrasonographic diagnosis of NAFLD [], histological severity of NAFLD [] and development over time of cirrhosis or death because of cirrhosis [], some studies recently investigated uric acid uric serum levels in patients with CHC. Whereas Pellicano and colleagues linked higher acid serum levels to poor responses to peg-interferon and ribavirin-based therapy [], a recent paper of our group [] stated that hyperuricaemia is associated with severity of steatosis, even if not directly associated with lower SVR percentages, representing, via steatosis induction, a potential indirect factor affecting liver damage and poor response to therapy. These findings are supported by experimental data which showed that uric acid may be able to induce IR and others important events involved in steatogenesis, such as systemic inflammation, endothelial dysfunction, and oxidative stress [, ], but they obviously need to be confirmed through prospective studies.

Conclusions

This overview on main metabolic factors associated with CHC allows us to firmly state that HCV infection is a systemic disease, leading to metabolic consequences due to the interaction of HCV with glucose and lipid homeostasis. This results in IR/T2D and steatosis induction and in the other metabolic features previously discussed, and commonly observed in these patients. Overall, metabolic factors strongly affect the natural history not only of chronic liver disease but also of not liver-related diseases, in a context of complex interplays where pre-existent metabolic disorders and genetic backgrounds play a relevant role.

In the future, some points should be particularly focused on. The suspected role of IR in increasing the rate of cardiovascular events deserves further prospective analysis to rule out confounders, such as coexistent NAFLD; given the potential weight of IR on SVR achievement, lines of evidence on efficacy of insulin sensitizer therapy are inconclusive yet, and the impact of new pharmacological supports, such as STAT-C agents, should be carefully investigated; the clinical relevance of “minor” metabolic factors, such as vitamin D status or visceral obesity, should be further evaluated in prospective studies, especially to assess their impact on the four-week sensitivity to pegylated interferon/ribavirin; finally, single nucleotide polymorphisms of PNPLA and IL28B genes should be further investigated, since they are currently giving a genetical-pathophysiological key to a better understanding of the mechanisms behind the interactions between metabolic dysfunctions, HCV infection, and viral clearance []. Anyway, considering the accelerated progression of liver disease and the cardiometabolic risks, two imbricated and equally important aspects in patients with CHC, lifestyle modification, for example, physical activity and healthful diet, seem mandatory

Conflict of Interests
No conflict of interests exists.

References
1. Lavanchy D. The global burden of hepatitis C. Liver International. 2009;29(1):74–81. [PubMed]
2. Petta S. Insulin resistance and diabetes mellitus in patients with chronic hepatitis C: spectators or actors? Digestive and Liver Disease. 2012;44(5):359–360. [PubMed]
3. Bugianesi E, Salamone F, Negro F. The interaction of metabolic factors with HCV infection: does it matter? Journal of Hepatology. 2012;56(supplement 1):S56–S65. [PubMed]
4. Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology. 2005;42(5):987–1000. [PubMed]
5. Zimmet P, Alberti KGMM. Global and societal implications of the diabetes epidemic. Nature. 2001;414(6865):782–787. [PubMed]
6. Petta S, Cammà C, Marco VD, et al. Insulin resistance and diabetes increase fibrosis in the liver of patients with genotype 1 HCV infection. American Journal of Gastroenterology. 2008;103(5):1136–1144. [PubMed]
7. Shintani Y, Fujie H, Miyoshi H, et al. Hepatitis C virus infection and diabetes: direct involvement of the virus in the development of insulin resistance. Gastroenterology. 2004;126(3):840–848. [PubMed]
8. Moucari R, Asselah T, Cazals-Hatem D, et al. Insulin resistance in chronic hepatitis C: association with genotypes 1 and 4, serum HCV RNA level, and liver fibrosis. Gastroenterology. 2008;134(2):416–423. [PubMed]
9. Negro F. Abnormalities of lipid metabolism in hepatitis C virus infection. Gut. 2010;59(9):1279–1287. [PubMed]
10. Hui JM, Sud A, Farrell GC, et al. Insulin resistance is associated with chronic hepatitis C virus infection and fibrosis progression. Gastroenterology. 2003;125(6):1695–1704. [PubMed]
11. Arase Y, Suzuki F, Suzuki Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology. 2009;49(3):739–744. [PubMed]
12. Vanni E, Abate ML, Gentilcore E, et al. Sites and mechanisms of insulin resistance in nonobese, nondiabetic patients with chronic hepatitis C. Hepatology. 2009;50(3):697–706. [PubMed]
13. Parvaiz F, Manzoor S, Tariq H, Javed F, Fatima K, Qadri I. Hepatitis C virus infection: molecular pathways to insulin resistance. Virology Journal. 2011;8, article 474 [PMC free article] [PubMed]
14. Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ. Hepatitis C virus infection: molecular pathways to metabolic syndrome. Hepatology. 2008;47(6):2127–2133. [PubMed]
15. Stepanova M, Rafiq N, Younossi ZM. Components of metabolic syndrome are independent predictors of mortality in patients with chronic liver disease: a population-based study. Gut. 2010;59(10):1410–1415. [PubMed]
16. Cua IHY, Hui JM, Kench JG, George J. Genotype-specific interactions of insulin resistance, steatosis, and fibrosis in chronic hepatitis C. Hepatology. 2008;48(3):723–731. [PubMed]
17. Cammà C, Bruno S, Di Marco V, et al. Insulin resistance is associated with steatosis in nondiabetic patients with genotype 1 chronic hepatitis C. Hepatology. 2006;43(1):64–71. [PubMed]
18. Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. Journal of Clinical Investigation. 2004;114(2):147–152. [PMC free article] [PubMed]
19. Svegliati-Baroni G, Ridolfi F, Di Sario A, et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: differential effects on signal transduction pathways. Hepatology. 1999;29(6):1743–1751. [PubMed]
20. Giordanino C, Ceretto S, Bo S, et al. Type 2 diabetes mellitus and chronic hepatitis C: which is worse? Results of a long-term retrospective cohort study. Digestive and Liver Disease. 2012;44(5):406–412. [PubMed]
21. Cammà C, Petta S, Di Marco V, et al. Insulin resistance is a risk factor for esophageal varices in hepatitis C virus cirrhosis. Hepatology. 2009;49(1):195–203. [PubMed]
22. Vincent MA, Montagnani M, Quon MJ. Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium. Current Diabetes Reports. 2003;3(4):279–288. [PubMed]
23. Iwakiri Y, Groszmann RJ. Vascular endothelial dysfunction in cirrhosis. Journal of Hepatology. 2007;46(5):927–934. [PubMed]
24. Chen C-L, Yang H-I, Yang W-S, et al. Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology. 2008;135(1):111–121. [PubMed]
25. Nkontchou G, Bastard J-P, Ziol M, et al. Insulin resistance, serum leptin, and adiponectin levels and outcomes of viral hepatitis C cirrhosis. Journal of Hepatology. 2010;53(5):827–833. [PubMed]
26. Petta S, Craxì A. Hepatocellular carcinoma and non-alcoholic fatty liver disease: from a clinical to a molecular association. Current Pharmaceutical Design. 2010;16(6):741–752. [PubMed]
27. Romero-Gómez M, Del Mar Viloria M, Andrade RJ, et al. Insulin resistance impairs sustained response rate to peginterferon plus ribavirin in chronic hepatitis C patients. Gastroenterology. 2005;128:636–641. [PubMed]
28. Conjeevaram HS, Kleiner DE, Everhart JE, et al. Race, insulin resistance and hepatic steatosis in chronic hepatitis C. Hepatology. 2007;45(1):80–87. [PubMed]
29. Poustchi H, Negro F, Hui J, et al. Insulin resistance and response to therapy in patients infected with chronic hepatitis C virus genotypes 2 and 3. Journal of Hepatology. 2008;48(1):28–34. [PubMed]
30. De Nicola S, Aghemo A, Grazia Rumi M, et al. Interleukin 28B polymorphism predicts pegylated interferon plus ribavirin treatment outcome in chronic hepatitis C genotype 4. Hepatology. 2012;55(2):336–342. [PubMed]
31. Deltenre P, Louvet A, Lemoine M, et al. Impact of insulin resistance on sustained response in HCV patients treated with pegylated interferon and ribavirin: a meta-analysis. Journal of Hepatology. 2011;55(6):1187–1194. [PubMed]
32. Grasso A, Malfatti F, Leo PD, et al. Insulin resistance predicts rapid virological response in non-diabetic, non-cirrhotic genotype 1 HCV patients treated with peginterferon alpha-2b plus ribavirin. Journal of Hepatology. 2009;51(6):984–990. [PubMed]
33. Franceschini L, Realdon S, Marcolongo M, Mirandola S, Bortoletto G, Alberti A. Reciprocal interference between insulin and interferon-alpha signaling in hepatic cells: a vicious circle of clinical significance? Hepatology. 2011;54(2):484–494. [PubMed]
34. Fattovich G, Svegliati Baroni G, Pasino M, et al. Post-load insulin resistance does not predict virological response to treatment of chronic hepatitis C patients without the metabolic syndrome. Digestive and Liver Disease. 2012;44(5):419–425. [PubMed]
35. Petta S, Amato M, Cabibi D, et al. Visceral adiposity index is associated with histological findings and high viral load in patients with chronic hepatitis C due to genotype 1. Hepatology. 2010;52(5):1543–1552. [PubMed]
36. Poynard T, Ratziu V, McHutchison J, et al. Effect of treatment with peginterferon or interferon alfa-2b and ribavirin on steatosis in patients infected with hepatitis C. Hepatology. 2003;38(1):75–85. [PubMed]
37. Petta S, Rosso C, Leung R, et al. Effects of IL28B rs12979860 CC genotype on metabolic profile and sustained virologic response in patients with genotype 1 chronic hepatitis C. Clinical Gastroenterology and Hepatology. 2013;11:311–317. [PubMed]
38. Serfaty L, Forns X, Goeser T, et al. Insulin resistance and response to telaprevir plus peginterferon α and ribavirin in treatment-naïve patients infected with HCV genotype 1. Gut. 2012;61:1473–1480. [PubMed]
39. Younossi Z, Negro F, Serfaty L, et al. The homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial. Hepatology. 2013
40. Adinolfi LE, Gambardella M, Andreana A, Tripodi M-F, 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(6):1358–1364. [PubMed]
41. Thomopoulos KC, Arvaniti V, Tsamantas AC, et al. Prevalence of liver steatosis in patients with chronic hepatitis B: a study of associated factors and of relationship with fibrosis. European Journal of Gastroenterology and Hepatology. 2006;18(3):233–237. [PubMed]
42. Lonardo A, Adinolfi LE, Loria P, Carulli N, Ruggiero G, Day CP. Steatosis and hepatitis C virus: mechanisms and significance for hepatic and extraepatic disease. Gastroenterology. 2004;126(2):586–597. [PubMed]
43. Mihm S, Fayyazi A, Hartmann H, Ramadori G. Analysis of histopathological manifestations of chronic hepatitis C virus infection with respect to virus genotype. Hepatology. 1997;25(3):735–739. [PubMed]
44. Abid K, Pazienza V, De Gottardi A, et al. An in vitro model of hepatitis C virus genotype 3a-associated triglycerides accumulation. Journal of Hepatology. 2005;42(5):744–751. [PubMed]
45. Piodi A, Chouteau P, Lerat H, Hézode C, Pawlotsky J-M. Morphological changes in intracellular lipid droplets induced by different hepatitis C virus genotype core sequences and relationship with steatosis. Hepatology. 2008;48(1):16–27. [PubMed]
46. Negro F. Mechanisms and significance of liver steatosis in hepatitis C virus infection. World Journal of Gastroenterology. 2006;12(42):6756–6765. [PubMed]
47. Larter CZ, Farrell GC. Insulin resistance, adiponectin, cytokines in NASH: which is the best target to treat? Journal of Hepatology. 2006;44(2):253–261. [PubMed]
48. Petta S, Cammà C, Di Marco V, et al. Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis C virus genotype 1. Hepatology. 2008;48(1):28–37. [PubMed]
49. Petta S, Tripodo C, Grimaudo S, et al. High liver RBP4 protein content is associated with histological features in patients with genotype 1 chronic hepatitis C and with nonalcoholic steatohepatitis. Digestive and Liver Disease. 2011;43(5):404–410. [PubMed]
50. Mihm S. Hepatitis C virus, diabetes and steatosis: clinical evidence in favor of a linkage and role of genotypes. Digestive Diseases. 2010;28(1):280–284. [PubMed]
51. Patton HM, Patel K, Behling C, et al. The impact of steatosis on disease progression and early and sustained treatment response in chronic hepatitis C patients. Journal of Hepatology. 2004;40(3):484–490. [PubMed]
52. Leandro G, Mangia A, Hui J, et al. Relationship between steatosis, inflammation, and fibrosis in chronic hepatitis C: a meta-analysis of individual patient data. Gastroenterology. 2006;130(6):1636–1642. [PubMed]
53. Fartoux L, Chazouillères O, Wendum D, Poupon R, Serfaty L. Impact of steatosis on progression of fibrosis in patients with mild hepatitis C. Hepatology. 2005;41(1):82–87. [PubMed]
54. Castéra L, Hézode C, Roudot-Thoraval F, et al. Worsening of steatosis is an independent factor of fibrosis progression in untreated patients with chronic hepatitis C and paired liver biopsies. Gut. 2003;52(2):288–292. [PMC free article] [PubMed]
55. Okuda M, Li K, Beard MR, et al. Mitochondrial injury, oxidative stress, and antioxidant gene expression are induced by hepatitis C virus core protein. Gastroenterology. 2002;122(2):366–375. [PubMed]
56. Lerat H, Honda M, Beard MR, et al. Steatosis and liver cancer in transgenic mice expressing the structural and nonstructural proteins of hepatitis C virus. Gastroenterology. 2002;122(2):352–365. [PubMed]
57. Kitase A, Hino K, Furutani T, et al. In situ detection of oxidized n-3 polyunsaturated fatty acids in chronic hepatitis C: correlation with hepatic steatosis. Journal of Gastroenterology. 2005;40(6):617–624. [PubMed]
58. Gochee PA, Jonsson JR, Clouston AD, Pandeya N, Purdie DM, Powell EE. Steatosis in chronic hepatitis C: association with increased messenger RNA expression of collagen I, tumor necrosis factor-α and cytochrome P450 2E1. Journal of Gastroenterology and Hepatology. 2003;18(4):386–392. [PubMed]
59. Hora C, Negro F, Leandro G, et al. Is connective tissue growth factor (CTGF) the missing link between steatosis, insulin resistance and fibrosis in patients with chronic hepatitis C? Journal of Hepatology. 2006;44(supplement 2):p. S199.
60. Aleffi S, Petrai I, Bertolani C, et al. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells. Hepatology. 2005;42(6):1339–1348. [PubMed]
61. Walsh MJ, Vanags DM, Clouston AD, et al. Steatosis and liver cell apoptosis in chronic hepatitis C: a mechanism for increased liver injury. Hepatology. 2004;39(5):1230–1238. [PubMed]
62. Seidel N, Volkmann X, Länger F, et al. The extent of liver steatosis in chronic hepatitis C virus infection is mirrored by caspase activity in serum. Hepatology. 2005;42(1):113–120. [PubMed]
63. Pekow JR, Bhan AK, Zheng H, Chung RT. Hepatic steatosis is associated with increased frequency of hepatocellular carcinoma in patients with hepatitis C-related cirrhosis. Cancer. 2007;109(12):2490–2496. [PubMed]
64. Moriya K, Yotsuyanagi H, Shintani Y, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. Journal of General Virology. 1997;78(7):1527–1531. [PubMed]
65. Moradpour D, Englert C, Wakita T, Wands JR. Characterization of cell lines allowing tightly regulated expression of hepatitis C virus core protein. Virology. 1996;222(1):51–63. [PubMed]
66. Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T. PPARα activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. Journal of Clinical Investigation. 2008;118(2):683–694. [PMC free article] [PubMed]
67. Lim WS, Ng DL, Kor SB, et al. Tumour necrosis factor alpha down-regulates the expression of PPARalpha in human hepatocarcinoma HepG2 cells by activation of NF-kB pathway. Cytokine. 2013;61:266–274. [PubMed]
68. Walsh MJ, Jonsson JR, Richardson MM, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signaling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1. Gut. 2006;55(4):529–535. [PMC free article] [PubMed]
69. Kotronen A, Peltonen M, Hakkarainen A, et al. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology. 2009;137(3):865–872. [PubMed]
70. Valenti L, Al-Serri A, Daly AK, et al. Homozygosity for the patatin-like phospholipase-3/adiponutrin i148 m polymorphism influences liver fibrosis in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(4):1209–1217. [PubMed]
71. Valenti L, Rumi M, Galmozzi E, et al. Patatin-Like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. Hepatology. 2011;53(3):791–799. [PubMed]
72. Shoelson SE, Herrero L, Naaz A. Obesity, inflammation, and insulin resistance. Gastroenterology. 2007;132(6):2169–2180. [PubMed]
73. Després J-P, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–887. [PubMed]
74. Chan DC, Watts GF, Ng TWK, Hua J, Song S, Barrett PHR. Measurement of liver fat by magnetic resonance imaging: relationships with body fat distribution, insulin sensitivity and plasma lipids in healthy men. Diabetes, Obesity and Metabolism. 2006;8(6):698–702. [PubMed]
75. Thomas EL, Hamilton G, Patel N, et al. Hepatic triglyceride content and its relation to body adiposity: a magnetic resonance imaging and proton magnetic resonance spectroscopy study. Gut. 2005;54(1):122–127. [PMC free article] [PubMed]
76. van der Poorten D, Milner K-L, Hui J, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449–457. [PubMed]
77. González-Reimers E, Castellano-Higuera A, Alemán-Valls R, et al. Relation between body fat and liver fat accumulation and cytokine pattern in non-alcoholic patients with chronic HCV infection. Annals of Nutrition and Metabolism. 2009;55(4):351–357. [PubMed]
78. Hourigan LF, Macdonald GA, Purdie D, et al. Fibrosis in chronic hepatitis C correlates significantly with body mass index and steatosis. Hepatology. 1999;29(4):1215–1219. [PubMed]
79. Amato MC, Giordano C, Galia M, et al. Visceral adiposity index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(4):920–922. [PMC free article] [PubMed]
80. Ticehurst JR, Hamzeh FM, Thomas DL. Factors affecting serum concentrations of hepatitis C virus (HCV) RNA in HCV genotype 1-infected patients with chronic hepatitis. Journal of Clinical Microbiology. 2007;45(8):2426–2433. [PMC free article] [PubMed]
81. Chen W, Wong T, Tomlinson G, Krahn M, Heathcote EJ. Prevalence and predictors of obesity among individuals with positive hepatitis C antibody in a tertiary referral clinic. Journal of Hepatology. 2008;49(5):711–717. [PubMed]
82. Everhart JE, Lok AS, Kim H-Y, et al. Weight-related effects on disease progression in the hepatitis C antiviral long-term treatment against cirrhosis trial. Gastroenterology. 2009;137(2):549–557. [PMC free article] [PubMed]
83. Poordad F, Bronowicki JP, Gordon SC, et al. Factors that predict response of patients with hepatitis C virus infection to boceprevir. Gastroenterology. 2012;143:608–618. [PubMed]
84. Völzke H, Schwahn C, Wolff B, et al. Hepatitis B and C virus infection and the risk of atherosclerosis in a general population. Atherosclerosis. 2004;174(1):99–103. [PubMed]
85. Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study. Journal of Infectious Diseases. 2012;206:469–477. [PubMed]
86. Boddi M, Abbate R, Chellini B, et al. HCV infection facilitates asymptomatic carotid atherosclerosis: preliminary report of HCV RNA localization in human carotid plaques. Digestive and Liver Disease. 2007;39(1):S55–S60. [PubMed]
87. Targher G, Bertolini L, Padovani R, Rodella S, Arcaro G, Day C. Differences and similarities in early atherosclerosis between patients with non-alcoholic steatohepatitis and chronic hepatitis B and C. Journal of Hepatology. 2007;46(6):1126–1132. [PubMed]
88. Ishizaka Y, Ishizaka N, Takahashi E, et al. Association between hepatitis C virus core protein and carotid atherosclerosis. Circulation Journal. 2003;67(1):26–30. [PubMed]
89. Ishizaka N, Ishizaka Y, Takahashi E, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intima-media thickening. The Lancet. 2002;359(9301):133–135. [PubMed]
90. Marzouk D, Sass J, Bakr I, et al. Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt. Gut. 2007;56(8):1105–1110. [PMC free article] [PubMed]
91. Petta S, Torres D, Fazio G, et al. Carotid atherosclerosis and chronic hepatitis C: a prospective study of risk associations. Hepatology. 2012;55(5):1317–1323. [PubMed]
92. Lee M-H, Yang H-I, Wang C-H, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. Stroke. 2010;41(12):2894–2900. [PubMed]
93. Boddi M, Abbate R, Chellini B, et al. Hepatitis C virus RNA localization in human carotid plaques. Journal of Clinical Virology. 2010;47(1):72–75. [PubMed]
94. Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis. 2012;221(2):496–502. [PubMed]
95. Mostafa A, Mohamed MK, Saeed M, et al. Hepatitis C infection and clearance: impact on atherosclerosis and cardiometabolic risk factors. Gut. 2010;59(8):1135–1140. [PubMed]
96. Miyajima I, Kawaguchi T, Fukami A, et al. Chronic HCV infection was associated with severe insulin resistance and mild atherosclerosis: a population-based study in an HCV hyperendemic area. Journal of Gastroenterology. 2013;48:93–100. [PubMed]
97. Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Alimentary Pharmacology & Therapeutics. 2013;37:647–652. [PubMed]
98. Kitson MT, Roberts SK. D-Livering the message: the importance of vitamin D status in chronic liver disease. Journal of Hepatology. 2012;57:897–909. [PubMed]
99. Petta S, Cammà C, Scazzone C, et al. Low vitamin d serum level is related to severe fibrosis and low responsiveness to interferon-based therapy in genotype 1 chronic hepatitis C. Hepatology. 2010;51(4):1158–1167. [PubMed]
100. Bitetto D, Fattovich G, Fabris C, et al. Complementary role of vitamin D deficiency and the interleukin-28B rs12979860 C/T polymorphism in predicting antiviral response in chronic hepatitis C. Hepatology. 2011;53(4):1118–1126. [PubMed]
101. Kitson MT, Dore GJ, George J, et al. Vitamin D status does not predict sustained virologic response or fibrosis stage in chronic hepatitis C genotype 1 infection. Journal of Hepatology. 2013;58:467–472. [PubMed]
102. Baur K, Mertens JC, Schmitt J, et al. Combined effect of 25-OH vitamin D plasma levels and genetic Vitamin D Receptor (NR 1I1) variants on fibrosis progression rate in HCV patients. Liver International. 2012;32(4):635–643. [PubMed]
103. Lange CM, Bojunga J, Ramos-Lopez E, et al. Vitamin D deficiency and a CYP27B1-1260 promoter polymorphism are associated with chronic hepatitis C and poor response to interferon-alfa based therapy. Journal of Hepatology. 2011;54(5):887–893. [PubMed]
104. Willheim M, Thien R, Schrattbauer K, et al. Regulatory effects of 1α,25-dihydroxyvitamin D3 on the cytokine production of human peripheral blood lymphocytes. Journal of Clinical Endocrinology and Metabolism. 1999;84(10):3739–3744. [PubMed]
105. Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: mechanisms for inflammatory damage in chronic disorders? Quarterly Journal of Medicine. 2002;95(12):787–796. [PubMed]
106. Cigolini M, Iagulli MP, Miconi V, Galiotto M, Lombardi S, Targher G. Serum 25-hydroxyvitamin D3 concentrations and prevalence of cardiovascular disease among type 2 diabetic patients. Diabetes Care. 2006;29(3):722–724. [PubMed]
107. Cantorna MT, Zhu Y, Froicu M, Wittke A. Vitamin D status, 1,25-dihydroxyvitamin D3, and the immune system. The American Journal of Clinical Nutrition. 2004;80(6):1717–1720. [PubMed]
108. Abu-Mouch S, Fireman Z, Jarchovsky J, Assy N. The beneficial effect of vitamin D combined eg interferon and ribavirin for chronic HCV infection. Hepatology. 2009;50:p. LB20.
109. Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. The Lancet. 2010;376:180–188. [PMC free article] [PubMed]
110. Petta S, Grimaudo S, Di Marco V, et al. Association of vitamin D serum levels and its common genetic determinants, with severity of liver fibrosis in genotype 1 chronic hepatitis C patients. Journal of Viral Hepatitis. 2013;20(7):486–493. [PubMed]
111. Petta S, Ferraro D, Cammà C, et al. Vitamin D levels and IL28B polymorphisms are related to rapid virological response to standard of care in genotype 1 chronic hepatitis C. Antiviral Therapy. 2012;17:823–831. [PubMed]
112. Abu-Mouch S, Fireman Z, Jarchovsky J, Zeina A-R, Assy N. Vitamin D supplementation improves sustained virologic response in chronic hepatitis C (genotype 1)-naïve patients. World Journal of Gastroenterology. 2011;17(47):5184–5190. [PMC free article] [PubMed]
113. Nimer A, Mouch A. Vitamin D improves viral response in hepatitis C genotype 2-3 naïve patients. World Journal of Gastroenterology. 2012;18(8):800–805. [PMC free article] [PubMed]
114. Von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Ødum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nature Immunology. 2010;11(4):344–349. [PubMed]
115. Conte D, Fraquelli M, Prati D, Colucci A, Minola E. Prevalence and clinical course of chronic hepatitis C virus (HCV) infection and rate of HCV vertical transmission in a cohort of 15,250 pregnant women. Hepatology. 2000;31(3):751–755. [PubMed]
116. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The Lancet. 1997;349(9055):825–832. [PubMed]
117. Deuffic-Burban S, Poynard T, Valleron A-J. Quantification of fibrosis progression in patients with chronic hepatitis C using a Markov model. Journal of Viral Hepatitis. 2002;9(2):114–122. [PubMed]
118. Di Martino V, Lebray P, Myers RP, et al. Progression of liver fibrosis in women infected with hepatitis C: long-term benefit of estrogen exposure. Hepatology. 2004;40(6):1426–1433. [PubMed]
119. Villa E, Vukotic R, Cammà C, et al. Reproductive status is associated with the severity of fibrosis in women with hepatitis C. PLoS ONE. 2012;7e44624 [PMC free article] [PubMed]
120. McHutchison JG, Lawitz EJ, Shiffman ML, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. New England Journal of Medicine. 2009;361(6):580–593. [PubMed]
121. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131(2):470–477. [PubMed]
122. Villa E, Karampatou A, Camm C, et al. Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C. Gastroenterology. 2011;140(3):818–829. [PubMed]
123. Villa E, Cammà C, Di Leo A, et al. Peginterferon-Α_2B plus ribavirin is more effective than peginterferon-Α2A plus ribavirin in menopausal women with chronic hepatitis C. Journal of Viral Hepatitis. 2012;19:640–649. [PubMed]
124. Cieloszyk K, Hartel D, Moskaleva G, Schoenbaum EE. Effects of hepatitis C virus infection on menopause status and symptoms. Menopause. 2009;16(2):401–406. [PubMed]
125. Bray GA, Nielsen SJ, Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. American Journal of Clinical Nutrition. 2004;79(4):537–543. [PubMed]
126. Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander-Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high-fructose corn syrup equivalent. American Journal of Physiology. 2008;295(5):G987–G995. [PubMed]
127. Ouyang X, Cirillo P, Sautin Y, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. Journal of Hepatology. 2008;48(6):993–999. [PMC free article] [PubMed]
128. Aeberli I, Hochuli M, Gerber PA, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care. 2013;36:150–156. [PMC free article] [PubMed]
129. Lin WT, Huang HL, Huang MC, et al. Effects on uric acid, body mass index and blood pressure in adolescents of consuming beverages sweetened with high-fructose corn syrup. International Journal of Obesity. 2012;37:532–539. [PubMed]
130. Odegaard AO, Choh AC, Czerwinski SA, Towne B, Demerath EW. Sugar-sweetened and diet beverages in relation to visceral adipose tissue. Obesity. 2012;20(3):689–691. [PMC free article] [PubMed]
131. Abdelmalek MF, Suzuki A, Guy C, et al. Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51(6):1961–1971. [PMC free article] [PubMed]
132. Tyson GL, Richardson PA, White DL, et al. Dietary fructose intake and severity of liver disease in hepatitis C virus-infected patients. Journal of Clinical Gastroenterology. 2013;47(6):545–552. [PMC free article] [PubMed]
133. Arnesen E, Huseby NE, Brenn T, Try K. The Tromso heart study: distribution of, and determinants for, gamma-glutamyltransferase in a free-living population. Scandinavian Journal of Clinical and Laboratory Investigation. 1986;46(1):63–70. [PubMed]
134. Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Unexpected effects of coffee consumption on liver enzymes. European Journal of Epidemiology. 1993;9(3):293–297. [PubMed]
135. Honjo S, Kono S, Coleman MP, et al. Coffee consumption and serum aminotransferases in middle-aged Japanese men. Journal of Clinical Epidemiology. 2001;54(8):823–829. [PubMed]
136. Klatsky AL, Morton C, Udaltsova N, Friedman GD. Coffee, cirrhosis, and transaminase enzymes. Archives of Internal Medicine. 2006;166(11):1190–1195. [PubMed]
137. Ruhl CE, Everhart JE. Coffee and caffeine consumption reduce the risk of elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2005;128(1):24–32. [PubMed]
138. Freedman ND, Everhart JE, Lindsay KL, et al. Coffee intake is associated with lower rates of liver disease progression in chronic hepatitis C. Hepatology. 2009;50(5):1360–1369. [PMC free article] [PubMed]
139. Larsson SC, Wolk A. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007;132(5):1740–1745. [PubMed]
140. Freedman ND, Curto TM, Lindsay KL, Wright EC, Sinha R, Everhart JE. Coffee consumption is associated with response to peginterferon and ribavirin therapy in patients with chronic hepatitis C. Gastroenterology. 2011;140(7):1961–1969. [PMC free article] [PubMed]
141. Mancone C, Steindler C, Santangelo L, et al. Hepatitis C virus production requires apolipoprotein A-I and affects its association with nascent low-density lipoproteins. Gut. 2011;60(3):378–386. [PubMed]
142. Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. Hepatology. 2009;50(4):1030–1037. [PubMed]
143. Ramcharran D, Wahed AS, Conjeevaram HS, et al. Associations between serum lipids and hepatitis C antiviral treatment efficacy. Hepatology. 2010;52(3):854–863. [PMC free article] [PubMed]
144. Harrison SA, Rossaro L, Hu K-Q, et al. Serum cholesterol and statin use predict virological response to peginterferon and ribavirin therapy. Hepatology. 2010;52(3):864–874. [PubMed]
145. Angelico F, Francioso S, Del Ben M, et al. Clinical trial: low plasma cholesterol and oxidative stress predict rapid virological response to standard therapy with peginterferon and ribavirin in HCV patients. Alimentary Pharmacology and Therapeutics. 2009;30(5):444–451. [PubMed]
146. Petta S, Camma C, Di Marco V, et al. Time course of insulin resistance during antiviral therapy in non-diabetic, non-cirrhotic patients with genotype 1 HCV infection. Antiviral Therapy. 2009;14(5):631–639. [PubMed]
147. Li JH, Lao XQ, Tillmann HL, et al. Interferon-lambda genotype and low serum low-density lipoprotein cholesterol levels in patients with chronic hepatitis C infection. Hepatology. 2010;51(6):1904–1911. [PMC free article] [PubMed]
148. Adinolfi LE, Ingrosso D, Cesaro G, et al. Hyperhomocysteinemia and the MTHFR C677T polymorphism promote steatosis and fibrosis in chronic hepatitis C. Hepatology. 2005;41(5):995–1003. [PubMed]
149. Toniutto P, Fabris C, Falleti E, et al. Methylenetetrahydrofolate reductase C677T polymorphism and liver fibrosis progression in patients with recurrent hepatitis C. Liver International. 2008;28(2):257–263. [PubMed]
150. Borgia G, Gentile I, Fortunato G, et al. Homocysteine levels and sustained virological response to pegylated-interferon α2b plus ribavirin therapy for chronic hepatitis C: a prospective study. Liver International. 2009;29(2):248–252. [PubMed]
151. Petta S, Bellia C, Mazzola A, et al. Methylenetetrahydrofolate reductase homozygosis and low-density lipoproteins in patients with genotype 1 chronic hepatitis C. Journal of Viral Hepatitis. 2012;12:465–472. [PubMed]
152. Lonardo A, Loria P, Leonardi F, et al. Fasting insulin and uric acid levels but not indices of iron metabolism are independent predictors of non-alcoholic fatty liver disease. A case-control study. Digestive and Liver Disease. 2002;34(3):204–211. [PubMed]
153. Li Y, Xu C, Yu C, Xu L, Miao M. Association of serum uric acid level with non-alcoholic fatty liver disease: a cross-sectional study. Journal of Hepatology. 2009;50(5):1029–1034. [PubMed]
154. Lee Y-J, Lee H-R, Lee J-H, Shin Y-H, Shim J-Y. Association between serum uric acid and non-alcoholic fatty liver disease in Korean adults. Clinical Chemistry and Laboratory Medicine. 2010;48(2):175–180. [PubMed]
155. Yamada T, Suzuki S, Fukatsu M, Wada T, Yoshida T, Joh T. Elevated serum uric acid is an independent risk factor for nonalcoholic fatty liver disease in Japanese undergoing a health checkup. Acta Gastro-Enterologica Belgica. 2010;73(1):12–17. [PubMed]
156. Xu C, Yu C, Xu L, Miao M, Li Y. High serum uric acid increases the risk for nonalcoholic fatty liver disease: a prospective observational study. PLoS ONE. 2010;5(7)e11578 [PMC free article] [PubMed]
157. Ryu S, Chang Y, Kim S-G, Cho J, Guallar E. Serum uric acid levels predict incident nonalcoholic fatty liver disease in healthy Korean men. Metabolism. 2011;60(6):860–866. [PubMed]
158. Lee JW, Cho YK, Ryan MC, et al. Serum uric acid as a predictor for the development of nonalcoholic fatty liver disease in apparently healthy subjects: a 5-year retrospective cohort study. Gut and Liver. 2010;4(3):378–383. [PMC free article] [PubMed]
159. Petta S, Cammà C, Cabibi D, Di Marco V, Craxì A. Hyperuricemia is associated with histological liver damage in patients with non-alcoholic fatty liver disease. Alimentary Pharmacology and Therapeutics. 2011;34(7):757–766. [PubMed]
160. Afzali A, Weiss NS, Boyko EJ, Ioannou GN. Association between serum uric acid level and chronic liver disease in the United States. Hepatology. 2010;52(2):578–589. [PubMed]
161. Pellicano R, Puglisi G, Ciancio A, et al. Is serum uric acid a predictive factor of response to IFN-treatment in patients with chronic hepatitis C infection? Journal of Medical Virology. 2008;80(4):628–631. [PubMed]
162. Petta S, Macaluso FS, Cammà C, Di Marco V, Cabibi D, Craxì A. Hyperuricaemia: another metabolic feature affecting the severity of chronic hepatitis because of HCV infection. Liver International. 2012;32:1443–1450. [PubMed]
163. Feig DI, Kang D-H, Johnson RJ. Medical progress: uric acid and cardiovascular risk. New England Journal of Medicine. 2008;359(17):1811–1821. [PMC free article] [PubMed]
164. Edwards NL. The role of hyperuricemia in vascular disorders. Current Opinion in Rheumatology. 2009;21:132–137. [PubMed]
165. Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nature Genetics. 2013;45:164–171. [PubMed]