A Hard Day's Night - Cholesterol, Cancer and Selenium

Note: this is a long post, but stay with me; it has some surprising twists. Tell your friends, but don't spoil the ending for them!


Low cholesterol is a risk factor for liver cancer in HBV infection; I wouldn't be surprised if it's the same for HCV, as low cholesterol is a risk factor for fibrosis and non-response.

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http://www.ncbi.nlm.nih.gov/pubmed/8490412


BMJ. 1993 Apr 3;306(6882):890-4.

Prolonged infection with hepatitis B virus and association between low blood cholesterol concentration and liver cancer.

Chen Z, Keech A, Collins R, Slavin B, Chen J, Campbell TC, Peto R.

OBJECTIVE: To determine whether prolonged infection with hepatitis B virus is associated with a lower blood cholesterol concentration.

DESIGN: Cross sectional study.

SETTING: 81 villages in rural China with a high prevalence of chronic infection with hepatitis B virus.

SUBJECTS: 1556 apparently healthy men aged 35-64 years, randomly selected.

MAIN OUTCOME MEASURES: Hepatitis B virus carrier state; plasma concentrations of cholesterol, apolipoprotein B, and apolipoprotein A I.

RESULTS: 238 (15%) of the men were positive for hepatitis B surface antigen, indicating that they were chronic carriers. Plasma concentration of cholesterol was 4.2% (0.11 mmol/l) lower among carriers (that is, positive for hepatitis B surface antigen) than among non-carriers (95% confidence interval 0.6% to 8.0% (0.01 to 0.21 mmol/l), p < 0.05), and apolipoprotein B concentration was 7.0% (0.036 g/l) lower (2.8% to 11.2% (0.014 to 0.058 g/l), p < 0.001). In contrast, no association was observed between plasma concentrations of cholesterol or apolipoprotein and hepatitis B that had been eradicated (that is, patient positive for hepatitis B core antibody but negative for hepatitis B surface antigen).

CONCLUSIONS: Chronic hepatitis B virus infection, which usually starts in early childhood in China, seems to lead not only to a greatly increased risk of death from liver disease but also to a somewhat lower cholesterol concentration in adulthood. This common cause produces an inverse association between cholesterol concentration and risk of death from liver cancer or from other chronic liver diseases.

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Much the same thing happens with Hep C, where low cholesterol is definitely a part of the viral strategy, not just a consequence of liver damage:

J Viral Hepat. 2006 Jan;13(1):56-61.

Serum lipid pattern in chronic hepatitis C: histological and virological correlations.

Siagris D, Christofidou M, Theocharis GJ, Pagoni N, Papadimitriou C, Lekkou A, Thomopoulos K, Starakis I, Tsamandas AC, Labropoulou-Karatza C.

Lipoproteins are closely connected to the process of hepatitis C virus (HCV) infection. The aim of this study was to evaluate the lipaemic profile in patients with chronic HCV infection, and to identify any association between serum lipid levels and viral load, HCV genotype or liver histology. Total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and triglycerides (TG) were measured in the sera of 155 patients with chronic HCV infection and 138 normal subjects, matched for age and sex. Viral parameters and liver histology were evaluated in HCV-infected patients.

Serum TC (P < 0.0005), HDL-C (P < 0.0005) and LDL-C (P < 0.0005) were lower in chronic hepatitis C patients compared with controls. Grading score was positively correlated with TC and LDL-C. Patients with HCV genotype 3a had significantly lower levels of TC, HDL-C, LDL-C, higher viral load and higher frequency of hepatic steatosis than those with other genotypes. Logistic regression analysis identified genotype 3a (OR, 6.96; 95% CI, 2.17-22.32, P = 0.0011) as the only significant predictive variable associated with low serum cholesterol concentration.

HCV infection is associated with clinically significant lower cholesterol levels (TC, LDL and HDL) when compared with those of normal subjects. This finding is more pronounced in patients infected with HCV genotype 3a.[/b] Further studies are necessary to define the pathophysiology of the relationship between lipid metabolism and HCV infection.

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And low cholesterol in Hep C is also associated with an increased risk of liver cancer:



HPB (Oxford). 2010 Nov;12(9):625-36. doi: 10.1111/j.1477-2574.2010.00207.x.

Evidence of aberrant lipid metabolism in hepatitis C and hepatocellular carcinoma.

Wu JM, Skill NJ, Maluccio MA.


OBJECTIVES: Lipids are linked to many pathological processes including hepatic steatosis and liver malignancy. This study aimed to explore lipid metabolism in hepatitis C virus (HCV) and HCV-related hepatocellular carcinoma (HCC).

METHODS: Serum lipids were measured in normal, HCV and HCV-HCC patients. Whole-genome microarray was performed to identify potential signature genes involved in lipid metabolism characterizing normal vs. HCV vs. HCV-HCC conditions.

RESULTS: Serum cholesterol was significantly reduced in HCV and HCV-HCC patients compared with normal controls, whereas there was no difference in glucose and triglycerides. Microarray analysis identified 224 probe sets with known functional roles in lipid metabolism (anova, 1.5-fold, P ≤ 0.001). Gene-mediated fatty acid (FA) de novo synthesis and uptake were upregulated in HCV and this upregulation was further enhanced in HCC. Genes involved in FA oxidation were downregulated in both the HCV and HCC groups**. The abnormality of cholesterol metabolism in HCV was associated with downregulation of genes involved in cholesterol biosynthesis, absorption and transportation and bile acid synthesis; this abnormality was further intensified in HCC.

CONCLUSIONS: Our data support the notion that HCV-related lipid metabolic abnormalities may contribute to hepatic steatosis and the development of cancer. Identification of these aberrations would stratify patients and improve treatment algorithms.

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My conclusions;

dietary cholesterol ought to reverse some of these abnormalities; this would explain the strong protective effect of eggs against viral hepatitis mortality seen in the China Study (note that T C Campbell, author of the controversial China Study*, was one of the authors of the first paper).

Replacing seed oils with animal fats, polyunsaturated fats (other than those in animal fats - AA, EPA and DHA) with monounsaturated and saturated fats, and restricting carbohydrate, especially sugar and grains, will tend to correct HCV-related lipid abnormalities.

[* Controversial because T C Campbell is a vegetarian and misinterpreted some of the China study data selectively to support a vegan bias. Amongst other things, he misinterpreted the effects of a diet of pure casein - which is a selenium-deficient purified milk protein used to produce liver cancer experimentally in rats - to claim that all animal protein is somehow harmful, and vegetable protein is beneficial. For example, soy, gluten and peanuts - yeah right, I don't think so. We'll come back to selenium in a minute.]

**"Genes involved in FA oxidation were downregulated in both the HCV and HCC groups". Very low carbohydrate dieting (and/or fasting) reactivates these fat burning genes, such as PPAR-alpha, which also inhibits HCV replication (the naringenin gene).

Perhaps vitamin E is not very effective (below) because it fails to elevate cholesterol in HCV (it is usually supposed to "improve" lipids somewhat):

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Int J Vitam Nutr Res. 2003 Nov;73(6):411-5.

Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.

Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y, Konaka K, Kabeya K, Kaneko M, Takayama H, Hashimoto Y, Yamada T, Takahashi H, Shimojo H, Nagamine T, Mori M.

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection.

Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years.

The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival.

Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.

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You might remember how the Cochrane Collaboration did a meta-analysis of clinical trials of antioxidant supplements some years back and found most of them increased mortalitity? Apart from selenium and vitamin C, that is.

One finding of the Cochrane Collaboration was that selenium supplements (and only selenium supplements) significantly reduced the occurence of gastrointestinal cancers in all of five trials - an average relative risk of 0.59 (0.46-0.75).

I wonder, was liver cancer considered a GI cancer for the purposes of that analysis?

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Nutrients. 2010 Sep;2(9):929-49. Epub 2010

http://www.ncbi.nlm.nih.gov/pubmed/21699491

Has Selenium a Chemopreventive Effect on Hepatocellular Carcinoma?

http://aje.oxfordjournals.org/content/150/4/367.short


Both experimental and epidemiologic studies have linked a low dietary intake of selenium with an increased risk of cancer. The authors examined the association between plasma selenium levels and risk of hepatocellular carcionoma (HCC) among chronic carriers of hepatitis B and/or C virus in a cohort of 7, 342 men in Taiwan who were recruited by personal interview and blood draw during 1988–1992. After these men were followed up for an average of 5.3 years, selenium levels in the stored plasma were measured by using hydride atomic absorption spectrometry for 69 incident HCC cases who were positive for hepatitis B surface antigen (HBsAg) and/or antibodies against hepatitis C virus (mostly HBsAg positive) and 139 matched, healthy controls who were HBsAg positive. Mean selenium levels were significantly lower in the HCC cases than in the HBsAg-positive controls (p =0.01). Adjusted odds ratios of HCC for subjects in increasing quintiles of plasma selenium were 1.00, 0.52, 0.32, 0.19, and 0.62, respectively. The inverse association between plasma selenium levels and HCC was most striking among cigarette smokers and among subjects with low plasma levels of retinol or various carotenoids. There was no clear evidence for an interaction between selenium and α-tocopherol in relation to HCC risk.
Am J Epidemiol 1999; 150; 367–74.



Anticancer Agents Med Chem. 2010 May;10(4):338-45.

Selenium in the prevention and treatment of hepatocellular carcinoma.
Darvesh AS, Bishayee A.

http://www.ncbi.nlm.nih.gov/pubmed/20380634

Hepatocellular carcinoma (HCC) happens to be one of the most lethal cancers in the world. Even though most cases occur in the developing world, reported cases in Western Europe as well as North America are on a steep rise. Human HCC etiology includes chronic liver disease, viral hepatitis, alcoholism, iron overload as well as dietary carcinogens such as aflatoxins and nitrosoamines. Surgical resection as well as liver transplants, which are currently used to treat HCC, is mostly ineffective. Consequently, there exists a decisive requirement to explore possible alternative chemopreventive and therapeutic strategies for HCC. Both oxidative stress and inflammatory mechanisms have been implicated in the pathophysiology of HCC. The use of dietary antioxidants and micronutrients has been proposed as an effective means for successful management of human HCC. Trace elements such as vanadium and selenium are involved in several major metabolic pathways as well as antioxidant defense systems. Selenium has been shown to be involved in the prevention of numerous chronic illnesses such as several specific cancers and neurodegenerative diseases. This review examines the potential role of selenium in the prevention and treatment of HCC. The in vivo and in vitro effects of selenium and the mechanisms involved in preclinical models of liver cancer are critically reviewed in this article. The chemopreventive and therapeutic effects of selenium are reviewed especially in relation to its antioxidant property. Future directions and potential challenges involved in the advance of selenium use in the prevention and treatment of liver cancer are also discussed.

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And now, for those who've made it this far, a real treat:

http://cancerres.aacrjournals.org/content/63/20/6707.full



Our findings indicate that selenium deficiency induces apoptosis in some “hepatocyte-like” cells. However, most HCC cells, particularly HBV-related ones, tolerate selenium deficiency and escape its deadly consequences. Thus, as demonstrated by the gain of survival capacity of apoptosis-sensitive cell lines with Vitamin E, such malignant cells have acquired a selective survival advantage that is prominent under selenium-deficient and oxidative-stress conditions.

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Hepatocellular cancer cell lines containing HBV virus genes are more resistant to selenium deficiency than other hepatocytes.

I'll bet that exactly the same thing applies to HCV. You won't get it in the genome like HBV as it's an RNA not a DNA virus, but there's the same relationship with selenium deficiency and cancer, so it seems likely.



Brazil nuts = 19mcg selenium each on average.


(Note: most if not all hepatocytes used in HCV cell culture studies are actually hepatoma - i.e. liver cancer - cell lines. Maybe that's why the antiviral drugs they develop don't always work in real livers! And maybe some of what we think we know about HCV is wrong.)



And the final twist, worthy of Roald Dahl:

First, some news from the UK;

Too Much Selenium Can Increase Your Cholesterol

The researchers found in those participants with higher plasma selenium (more than 1.20 µmol/L) there was an average total cholesterol level increase of 8% (0.39 mmol/L (i.e. 15.1 mg/dL). Researchers also noted a 10% increase in non-HDL cholesterol levels (lipoproteins within your total cholesterol that can help predict the risk of someone suffering a heart attack or chest pain). Also, of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements.

A 10% increase in what we might here term "good" cholesterol might be just enough to offset the drop in cholesterol caused by HCV.

(I like the way that 48.2% of these subjects "admitted" to taking supplements that may have elevated their non-HDL cholesterol. Not "reported", "admitted". No doubt they cracked under interrogation, while the other 51.8% successfully denied the allegation.)

US research shows the same trend;

http://www.ncbi.nlm.nih.gov/pubmed/1990681

Atherosclerosis. 2010 Jun;210(2):643-8. Epub 2010 Jan 11.

Serum selenium and serum lipids in US adults: National Health and Nutrition Examination Survey (NHANES) 2003-2004.

Laclaustra M, Stranges S, Navas-Acien A, Ordovas JM, Guallar E.

OBJECTIVE: High selenium has been recently associated with several cardiovascular and metabolic risk factors including diabetes, blood pressure and lipid levels. We evaluated the association of serum selenium with fasting serum lipid levels in the National Health and Nutrition Examination Survey (NHANES) 2003-2004, the most recently available representative sample of the US population that measured selenium levels.

METHODS: Cross-sectional analysis of 1159 adults>or=40 years old from NHANES 2003-2004. Serum selenium was measured by inductively coupled plasma-dynamic reaction cell-mass spectrometry. Fasting serum total cholesterol, triglycerides, and HDL cholesterol were measured enzymatically and LDL cholesterol was calculated.

RESULTS: Mean serum selenium was 136.7 microg/L.
[HTML's inconvenient but understandable dislike of epidemiological data presentations means that you'll have to look at the fulltext for details, sorry]

CONCLUSION: In US adults, high serum selenium concentrations were associated with increased serum concentrations of total and LDL cholesterol. Selenium was associated with increasing HDL cholesterol only at low selenium levels. Given increasing trends in dietary selenium intake and supplementation, the causal mechanisms underlying these associations need to be fully characterized.


full text here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2878899/

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Of course, fatty animal foods - such as pork and bacon - are the best source of selenium besides brazil nuts and supplements, so some of these statistics could be due to the cholesterol-elevating effects of animal fats.

"of the participants with the highest selenium levels, 48.2% admitted they regularly took dietary supplements" in the UK study; it was 75.1% in the US, but surely not all supplements supplied selenium and even fewer supplied a high dose of selenium.

From table 1 the difference in saturated fat intake between quartiles is small but the trend matches selenium.



But still - there's a pattern here.

Enter the virus, cholesterol goes down, cancer goes up;

enter selenium, cholesterol goes up, cancer goes down.

Oh, by the way, lower cholesterol is associated with higher cancer death rates across the board...

This paper summarizes the state of research into selenium and seum lipids and glucose: 

http://www.nutritionandmetabolism.com/content/7/1/38 

"Interestingly, the effects of selenium supplementation on blood lipids are contradictory in animal and human studies. In rats, selenium supplementation increases LDL receptor activity [28,29] but decreases 3-hydroxy 3-methylglutaryl co-enzyme A (HMG-CoA) reductase expression [30], leading to decreased plasma LDL cholesterol and total cholesterol levels. However, one animal study in mice showed a significant increase in plasma cholesterol with the loss of housekeeping selenoprotein expression [31]. In human, selenium supplementation was found to increase total cholesterol and triglyceride levels in French adults [27]. Total cholesterol and LDL cholesterol levels also increased after selenium supplementation in the Chinese population [32]. Another study showed no further decrease in triglyceride or LDL cholesterol concentration but a blunted increment of HDL with selenium supplementation in participants with coronary heart disease receiving simvastatin-niacin treatment [33]. Therefore, the role of selenium supplementation on lipid metabolism in humans deserves further research. Recently, the apoE δ4 gene was found to play a central role between selenium levels and lipid metabolism in rural elderly Chinese [34]. The underlying interactive mechanism between susceptible gene, selenium, and lipids needs further investigation."

It seems the rodent is not such a good model for the interactions we are interested in here, not suprisingly as their lipoprotein regulation diverges from that of humans in many ways.

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Thanks for having followed this investigation to its startling conclusion. Here's a reward: "12,000 Miles", from the beautiful album The Overflow by Humphreys and Keen. If you like this, you can download the entire 13-song album here for only $5US http://humphreysandkeen.bandcamp.com/