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Saturday, 3 June 2017

Gilbert's Syndrome - a user's guide

Last week I received some liver test results from my last follow-up visit to Auckland Clinical Services after clearing HCV genotype 3 in the Phase 3 Epclusa trial mentioned here.

ALT and AST were gratifying low at 12 and 15 U/L respectively, albumin healthy at 45 g/L, but total bilirubin was high at 23 umol/L despite direct bilirubin being low at 3 umol/L. The normal reference range for total bilirubin is 3-21 umol/L.
I've seen this before in LFT results and been told that it's consistent with Gilbert's syndrome, and I know that my brother has been told that he has Gilbert's syndrome. I vaguely remembered something about Gilbert's syndrome being a protective factor for heart disease. This meant nothing to me when I had no way of assessing this sort of health claim, but I thought it was worth looking into. And what I found was surprising - not only is the Gilbert's association real, but bilirubin level across the whole range may be something worth including in risk calculations.

In the first paper I found, the incidence of IHD was 2% in the Gilbert's sample, 12% in the case-matched general population.[1] The Gilbert's population had higher HDL but "According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD." The elevated antioxidant status in the Gilbert's cases would help to explain the higher (and probably more functional) HDL anyway.


Franchini et al have supplied an excellent review of the Gilbert's CVD link; their paper is a model of clarity in writing and layout.[2] Bilirubin is a breakdown product of heme, supposed by some authors to be the lethal ingredient in the toxic food red meat. However I could find no evidence that heme intake relates to meat intake, and have heard of vegans with Gilbert's syndrome. Indeed the Paleo Ketogenic Diet researchers have used an all-meat diet to manage an extreme case of Gilbert's syndrome (there is such a thing as excessive bilirubin, but this is not usually what is meant by Gilbert's Syndrome in adults).[3]

One of the most heartening findings is that not only Gilbert's syndrome but also higher bilirubin within the normal range is associated with independence in the elderly.[4]
"The OR of functional dependence for each standard deviation increment in the serum total bilirubin level was 0.56 (P = 0.002). After additional adjustment, the inverse association remained essentially unchanged. In quartile-based analysis, participants with higher quartiles of serum total bilirubin tended to have lower ORs of functional dependence. The trends of lower likelihood of functional dependence across increasing quartiles of the serum total bilirubin level were statistically significant (P= less than 0.05 for all trends)."
Bilirubin tends to increase with age and is not associated with reduced mortality over the age of 70 (but who cares if you're functionally independent). However, it's likely that survivor bias also applies. Bilirubin might even explain the changing LDL-associated risk in the elderly - because those with lower bilirubin were more likely to have had heart attacks when younger, and bilirubin rises with age, a healthy older population may have a higher % of people with Gilbert's syndrome or higher bilirubin and be protected from oxidised LDL and thrombosis, the two main benefits of higher bilirubin.
That Gilbert's syndrome also protects against platelet hyperactivity and thrombosis supports the various CVD hypotheses of Malcolm Kendrick and Gregory D. Sloop.[5]

Elevated levels of bilirubin are associated with reduced risk of cardiovascular disease especially in Gilbert's syndrome.
- Platelet hyper-activity due to oxidative stress increases the risk of thrombosis, and therefore myocardial infarction.
- Bilirubin may inhibit platelet activity by interacting with collagen and ADP receptors, or by improving resistance to oxidative stress.
- Inhibiting platelet activity may represent one mechanism to explain protection against cardiovascular disease leading to mortality in mildly hyperbilirubinemic individuals.

Bilirubin is a lipid soluble antioxidant which is easily recycled via biliverdin reductase.
"Bilirubin protects polyunsaturated fatty acids from lipid peroxidation, thus preventing damage by reactive oxygen species to cell membranes and proteins."[6]
Gilbert's syndrome is associated with a lean phenotype. Is this because of its inhibitory effect on omega-6 peroxidation? It is also associated with a reduced risk of NAFLD and type 2 diabetes.


However, Gilbert's syndrome has a dark side; the reduction in glucuronidation that results in elevated bilirubin can also alter estrogen metabolism and has been associated with an increased risk of hormone-sensitive breast cancer.[7]
"Patients with Gilbert syndrome have an impaired function of the enzyme UGT1A1, responsible for the degradation of 4-OH-estrogens. These elements are produced by the degradation of estrogens and are well-known carcinogens. In theory, patients with Gilbert syndrome accumulate 4-OH-estrogens and, therefore, might have a higher risk for breast cancer, especially when exposed to higher levels of estrogens."
In fact, because CVD is more of a risk for men, and women can expect longer lives in any case, the benefits of Gilbert's syndrome are probably not spread equally between the sexes. Avoidance of alcohol, which is estrogenic and associated with breast cancer risk, might be more important in women with Gilbert's.

A further risk with Gilbert's syndrome is that impaired function of the enzyme UGT1A1 means that some drugs, including acetaminophen (paracetamol) will be more active and there is theoretically a lower safety margin.[8] However the antioxidant activity of bilirubin may render this point moot with regard to acetaminophen, if not other drugs.

In any case bilirubin, especially if it can be assessed from more than one blood draw, and is not likely to be affected by drugs or liver disease, seems like something that should be used in risk assessment. There is, for example, probably not much point in prescribing a statin to someone with high bilirubin, not that there is any point in prescribing statins to healthy people anyway.


Can bilirubin be hacked? Phycobilin from algae such as spirulina, and phytochrome from green leafy vegetables, are analogous chemicals with similar properties, but will be less effective if they are not recycled by biliverdin reductase.

References



[1] Vítek L, Jirsa M, Brodanová M, Kalab M, Marecek Z, Danzig V, Novotný L, Kotal P. Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis. 2002 Feb;160(2):449-56.

[2] Franchini M, Targher G, Lippi G. Chapter 3 – Serum Bilirubin Levels and Cardiovascular Disease Risk: A Janus Bifrons? Advances in Clinical Chemistry. 2010. 50; 47–63.

https://www.dropbox.com/s/nzhg9llideyg91d/franchini2010.pdf?dl=0

[3] Tóth C, Clemens Z. Gilbert’s Syndrome Successfully Treated with the Paleolithic Ketogenic Diet. American Journal of Medical Case Reports 2015; 3(4): 117-120.
http://pubs.sciepub.com/ajmcr/3/4/9/

[4] Kao TW, Chou CH, Wang CC et al. Associations between serum total bilirubin levels and functional dependence in the elderly. Intern Med J, 2012; 42: 1199–1207. doi:10.1111/j.1445-5994.2011.02620.x
http://onlinelibrary.wiley.com/doi/10.1111/j.1445-5994.2011.02620.x/abstract

[5] Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert's syndrome? Atherosclerosis. 2015; 239(1): 73–84.
http://dx.doi.org/10.1016/j.atherosclerosis.2014.12.042


[6] Läer S, Apel M, Bernhardt J, Kapitulnik J, Kahl R. Interactions between bilirubin and reactive oxygen species in liver microsomes and in human neutrophil granulocytes. Redox Rep. 1997; 3(2):119-24. doi: 10.1080/13510002.1997.11747098.
[7] Astolfi RH, Bugano DD, Francisco AA et al.Is Gilbert syndrome a new risk factor for breast cancer? Medical Hypotheses. 2011; 77(2): 162-164. 
(See also https://www.dropbox.com/s/cfoadvmigzozymw/Breast%20Cancer%20AA.pdf?dl=0 )

[8] de Morais SM, Uetrecht JP, Wells PG. Decreased glucuronidation and increased bioactivation of acetaminophen in Gilbert's syndrome. Gastroenterology. 1992; 102(2):577-86.









2 comments:

Kenneth Strain said...

Interesting. Searching a little further on this topic brought me to "Interaction of bilirubin and biliverdin with reactive nitrogen species" Kaur et al FEBS Letters 543 (2003) 113-119 (open access).

That's intersting for me mainly due to the link with peroxynitrite (due to eNOS problems resulting from a mess of SNPs). That's another link to CVD espacially in those who may have certain methylation SNPs and (so) low tetrahydrobipterin which bias eNOS to ONOO− rather than NO.

Ken

George Henderson said...

Very interesting! Antioxidants with affinity for reactive nitrogen species would tend to sidestep the "ROS as essential messengers" dilemma, being more able to quench the end-products of excessive production. ONOO also inactivates B12; and tetrahydrobiopterin is an antioxidant in its own right.

BH4 is a potent antioxidant, and it may also be possible that these improvements could be due to the anti-oxidant capacity of BH4 rather than its role as an NOS cofactor. This is supported by a study in healthy volunteers which shows that acute beneficial effects of BH4 may be due to scavenging of ROS—this study found no effect of BH4 on acetycholine-mediated dilation at baseline; however, ischemia reperfusion (which is associated with increased ROS)-induced decreases in dilation responses to acetylcholine can be rescued by the infusion of BH4 (500 μg/min). This dilatory response could be restored by both 6R- and 6S-BH4, as well as by amino-BH4 (NH4) that has the same ROS scavenging capacity as BH4 while being unable to catalyze the production of NO, thus indicating that the improvement observed in this study was likely due to the scavenging of ROS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4038990/

When endothelial nitric oxide synthase is 6R-BH4-deplete, it synthesizes superoxide rather than nitric oxide. Reduced nitric oxide bioavailability by interaction with reactive oxygen species is implicated in endothelial dysfunction (ED). 6R-BH4 corrects ED in animal models of ischemia reperfusion injury (IRI) and in patients with cardiovascular risks.

http://atvb.ahajournals.org/content/27/6/1334.long

As folate can increase BH4 synthesis and replace it in some functions, this strengthens my evolutionary hypothesis that Gilbert's is an adaptation to diets without fresh plant foods.
Bilirubin at higher levels replaces or spares much vitamin C and E, and also decreases the need for folate by sparing BH4 and B12.

Ribavirin inhibits BH4 synthesis. A deficiency of BH4 can also result in depression as it is needed for serotonin and dopamine synthesis.