The potential benefits of missing an appendix

Researchers at the Van Andel Insititute in Grand Rapids, Michigan have published a research report that has garnered a lot of media attention. You may have heard about it. It involves Parkinson’s and the appendix. They found – using two independent databases – that the removal of the appendix dramatically reduces one’s risk of developing Parkinson’s. In addition, they also found that the healthy (non-Parkinson’s) human appendix has an abundant supply of the misfolded version of the Parkinson’s-associated protein alpha synuclein. In today’s post, we will look at what the appendix is, what this new research report suggests, and explain why you should not rush out to get your appendix removed just yet.

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Appendix. Source: journalofethics

I recieved a curious email last night.

It read:

Dear Simon,
Should I have my appendix chopped out?
Kind regards,
[Name removed]

Direct and to the point. The way I like things.

Today’s post is my response to that email.

On Wednesday 31st October 2018, this report was published in the prestigeous journal Science Translational Medicine:

Title: The vermiform appendix impacts the risk of developing Parkinson’s disease
Authors: Killinger BA, Madaj Z, Sikora JW, Rey N, Haas AJ, Vepa Y, Lindqvist D, Chen H, Thomas PM, Brundin P, Brundin L, Labrie V.
Journal: Science Translational Medicine, 2018, 10, 465, eaar5280.
PMID: 30381408                        (This report is OPEN ACCESS if you would like to read it)

The report caused a great deal of media activity (for examples, click here, here, here, here, here et al and here). In fact, it has been a while since I have seen such a response to a Parkinson’s-associated research report (I think the Exenatide results was the last such media circus – click here to read more about that).

What has the new study found?

That the human appendix contains an abundance of the misfolded form of alpha synuclein protein and that removal of the appendix decreases the risk of developing Parkinson’s.

Interesting. What is the Appendix?

The human appendix is a small (averaging 9 cm in length) tube attached to the beginning of the large intestine.

Location of the appendix. Source: Healthversed

What does the appendix do?

The appendix was long considered functionless, a bit of an oddity, and by some an mistake or accident of evolution. More recently, however, a new image has started to appear with regards to the appendix.

It is believed to be a ‘storehouse’ for bacteria, which can repopulate the digestive system after illnesses. It also houses an abundance of infection-fighting lymphoid cells, which suggests that it plays an important role in the immune system.

But if we are completely honest, we really don’t know what the appendix does.

Seriously, we really don’t know.

But what happens when people need their appendox removed?

The surgical procedure to remove the appendixn is called an appendectomy. It is generally a emergency surgery, that’s performed to treat appendicitis – which is an inflammatory condition of the appendix.

Appendicitis is typically caused by a blockage of the hollow portion of the appendix.

Appendicitis. Source: msdmanuals

This blockage results in a build up of pressure and decreased blood flow to the appendix, and bacterial growth inside the appendix will cause an inflammatory response. Left untreated, an inflamed appendix will eventually burst spilling its infectious materials into the surrounding abdominal cavity – the consequences of which can be serious: in 2015, 50,000 people around the world died of appendicitis.

So what did the new research report find?

The reseachers began their study by looking for any association between appendectomies and Parkinson’s.

To do this, they used two independent databases:

1. the nationwide Swedish National Patient Registry (started in 1964, this databases registers the diagnoses of the entire population of Sweden; it is an amazing resource for research!)
2. the Parkinson’s Progression Markers Initiative (PPMI – sponsored by the Michael J Fox Foundation).

Their analyses suggested that an appendectomy was associated with a lower risk of developing Parkinson’s.

In the large Swedish database (which included 551,647 individuals who had an appendectomy), there was a 19.3% reduction in the incidence of Parkinson’s. What was particularly interesting in this result is that the researchers noticed that this effect was largely due to people living in rural areas, where an appendectomy decreased the risk even further (a 25.4% reduction). And for people living in urban areas, an appendectomy actually had little effect on reducing one’s risk of developing Parkinson’s.

The investigators concluded that since rural living is generally considered to be associated with a higher risk of developing Parkinson’s “these findings suggest that appendectomy influences environmental risk factors for PD, specifically for individuals living in rural environments“.

In addition, in both of the datasets, they found that the earlier an appendectomy occurred, the longer the age of PD diagnosis was delayed.

Next, the researchers looked for signs of alpha synuclein aggregation in the appendix.

What is alpha synclein?

Alpha synuclein. Source: Wikipedia

Alpha synuclein is one of the most abundant proteins in our brains – making up about 1% of all the proteins floating around in each neuron in your head – and it is a very well studied protein (with over 9700 research reports listed on the Pubmed search engine with the key words ‘alpha synuclein’).

When alpha synuclein protein is produced by a cell, it normally referred as an ‘unfolded protein’, in that is does not really have a defined structure. When it is first produced, alpha synuclein will look something like this:

Alpha synuclein. Source: Wikipedia

In this form, alpha synuclein is considered a monomer – which is a single molecule, just one copy of the protein. It is capable of binding to other molecules, and when it binds to other alpha synuclein proteins, they form what is called an oligomer (a collection of monomers). And these oligomers can have different structures.

In Parkinson’s, alpha synuclein also binds (or aggregates) to form what are called ‘fibrils’.

Microscopic images of monomers, oligomers and fibrils. Source: Brain

And it is believed that these oligomer and fibril forms of alpha synuclein protein may go on to produce the Lewy bodies that characterise the Parkinsonian brain.

Parkinson’s associated alpha synuclein. Source: Nature

Lewy bodies are dense circular clusters of alpha synuclein protein (and other proteins) that are found in specific regions of the brain in people with Parkinson’s (Click here for more on Lewy bodies).

A cartoon of a neuron, with the Lewy body (indicated) within the cell body. Source: Alzheimer’s news

So the researchers looked for this protein alpha synuclein in the appendix?

Exactly.

They collected samples of appendices from normal, healthy individuals, and when they looked for alpha synuclein, they found a lot of the Parkinson’s-associated oligomer form of the protein. This is the aggregated form of the protein – very similar to the form of the protein found in the Parkinsonian brain.

Remarkably, they found alpha synuclein oligomers in nearly all of the cases (46 of 48 subjects examined) – please remember that all of these samples had come from people without Parkinson’s – and this effect was regardless of age – they found the aggregates in samples from people under 20 years of age, and also over 80 years of age.

Interesting. Was that all they found?

No, the researchers took the experiment one step further – they collected tissue from the appendix and the brain of both healthy individuals and people with Parkinson’s. Then the researchers dissociated these samples and exposed the resulting product to a solution containing normal monomeric alpha synuclein. They then left these mixed solutions for up to 48 hours and watched what happened to the normal monomeric alpha synuclein.

Interestingly, the samples from healthy and PD appendix showed an accelerated formation of alpha synuclein oligomers over time when compared to the solutions containing the healthy and PD substantia nigra samples. These results suggest that the appendix contains a most potent form of oligomeric alpha synuclein than the brain.

Is this the first time anyone has looked at the appendix and Parkinson’s?

Actually, no.

There have been a number of studies investigating this.

And what is the consensus regarding an association between the appendix and Parkinson’s?

Well, I’ll let you decide.

It all kicked off in 2014, when one research group looked at tissue of the appendix from normal people and they found something interesting.

Title: Alpha-synuclein in the appendiceal mucosa of neurologically intact subjects.
Authors: Gray MT, Munoz DG, Gray DA, Schlossmacher MG, Woulfe JM.
Title: Mov Disord. 2014 Jul;29(8):991-8. doi: 10.1002/mds.25779. Epub 2013 Dec 18.
PMID: 24352892

The researchers looked at biopsies of the appendix from 20 normal people (no history of Parkinson’s). In all cases they found high levels of alpha synuclein in the nerve fibres surrounding the appendix. And curiously, when they looked at other areas of the intestinal system, they found little or no alpha synuclein.

Which fits with the findings of new study right?

Indeed.

And then another group of researchers took a large cohort of people with Parkinson’s and asked which of them had ever had an appendectomy (removal of the Appendix).

Title: Appendectomy may delay Parkinson’s disease Onset
Authors: Mendes A, Gonçalves A, Vila-Chã N, Moreira I, Fernandes J, Damásio J, Teixeira-Pinto A, Taipa R, Lima AB, Cavaco S.
Journal: Mov Disord. 2015 Sep;30(10):1404-7.
PMID: 26228745

Of the 295 people with Parkinson’s involved in the study, 34 were found to have had an appendectomy. There was no significant difference in age of onset across the entire group of people involved in the study, but in people with late onset Parkinson’s (after the age of 55 years) the authors found that found evidence that an appendectomy significantly delayed the onset of Parkinson’s symptoms.

Which also fits with the findings of this new study, right?

Indeed.

But before you rush out and order yourself an appendectomy, please note the following research report:

Title: Appendectomy in mid and later life and risk of Parkinson’s disease: A population-based study.
Authors: Marras C, Lang AE, Austin PC, Lau C, Urbach DR.
Journal: Mov Disord. 2016; 31(8):1243-7.
PMID: 27241338

The researchers involved in this study looked at the medical records of the 14 million (that is a big number!) residents of Ontario (Canada) who have health care insurance. They found 42,999 had undergone an appendectomy. When the researchers compared people with appendectomies with people without an appendectomy (the control group) and people who had a cholecystectomy (removal of the gallbladder – a surgical control group), they found no difference what -so-ever in the risk of Parkinson’s. The researchers concluded that their data did not support an association between mid to late life appendectomy and Parkinson’s.

Ok, that’s a big study. 14 Million people. So there is no association then?

If you are a regular reader of this website, you should know by now that nothing in this game is simple.

Shortly after that previous report was released, this study was published:

Title: Appendectomy and risk of Parkinson’s disease: A nationwide cohort study with more than 10 years of follow-up.
Authors: Svensson E, Horváth-Puhó E, Stokholm MG, Sørensen HT, Henderson VW, Borghammer P.
Journal: Mov Disord. 2016 Sep 13.
PMID: 27621223

In this study, the researchers used the Danish medical and administrative registries to assess the question ofwhether there is an association between appendectomies and risk of Parkinson’s. Between 1980-2010, the investigators identified 265,758 cases that had had an appendectomy (as determined by the operation code). They then matched these with 1.3 million cases from the general population (who had not had an appendectomy). When they looked at the number of people in each group who went on to develop Parkinson’s, they found that appendectomies was associated with a subtle INCREASE in Parkinson’s risk 10 or more years after surgery.

What?!?

Yeah, I know. Welcome to the wonderful world of academic research. And just a month or so ago, this study was published

Title: Appendectomy and risk of Parkinson’s disease in two large prospective cohorts of men and women.
Authors: Palacios N, Hughes KC, Cereda E, Schwarzschild MA, Ascherio A.
Journal: Mov Disord. 2018 Sep;33(9):1492-1496.
PMID: 30218460

Using data from the Nurses’ Health Study and the Health Professionals Follow-up Study, these researchers found “limited to no association between appendectomy and Parkinson’s disease risk”.

So there is no association?

I’m not saying that. All I am saying here is that there has been previous research on this topic and the results are mixed.

And the researchers in Michigan acknowledged this in the discussion of their report, highlighting the strengths and weaknesses of the previous reports as well as their own study. But the use of two independent databases in this new study does strengthen their position.

So what does it all mean?

Well, it means that my appendix is staying where it is for now, and I would hope that the individual who emailed me will also not be seeking an appendectomy.

One important thing to remember when reading this new research report is what Dr Rachel Dolhun (movement disorder specialist and VP of Medical Communications at the Michael J Fox Foundation) wrote today:

This is only an association, not a direct causation.

Just because there is a reduction in PD risk in people with appendectomies does not mean that having your appendix removed will decrease your chances of developing Parkinson’s. The data just suggests that there is an association.

The really interesting aspect of the new research report is that misfolded oligomeric alpha synuclein was found to be so abundant in the (non-Parkinsonian) appendix. This finding raises a lot of questions regarding the function and nature of this protein. But it also points towards the use of compounds which limit the accumulation of oligomeric alpha synuclein in the appendix and other areas of the gastrointestinal tract as a potential future therapeutic strategy for PD.

That said, it will be interesting to see the results of the ongoing RASMET study which is a clinical trial evaluating safety and tolerability of ENT-01 – a compound that almost complete suppresses the toxic effect of alpha synuclein. ENT-01 can not enter the brain, so Enterin Inc (the company conducting the trial) are focusing on the gut and constipation.

But until those results are available and we have further association data regarding the appendix, let’s refrain from ordering any appendectomies folks.

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The banner for today’s post was sourced from everydayhealth