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Liver and lipids

My research background, at least as far as my PhD is concerned, is in pharmacology and physiology.  Specifically, I studied the effects of chronic alcohol consumption on signal transduction in the liver. Simply, I explored the ways in which chronic alcohol consumption affects how liver cells “talk” (both to each other, and how individual cells transmit a signal from an extracellular stimulus into an intracellular response).  If I were to go all “alphabet soup” on you, I would talk about my explorations into IP3-Ca2+ signaling, or my real area of expertise, cAMP-PKA signaling and CREB phosphorylation. Luckily (for all of us) that’s not what I want to write about.

 

What I want to write about is the role of various fats (aka lipids) in the development of fatty liver. Before I delve into the land of lipids, a bit of background is in order.

 

Fatty liver is the first phase of a process that in some people ends with cirrhosis and liver failure.  Most people associate this progression (from fatty liver, to fibrosis, and finally to cirrhosis) with chronic alcohol consumption, however recently the prevalence of nonalcoholic fatty liver disease (NAFLD) has grown. In fact, when I first started my PhD research, sources were saying that alcoholic fatty liver disease (AFLD) was the #1 cause of fatty liver. By the time I was writing my thesis (and I didn’t take THAT long), sources were claiming that AFLD had been overtaken by NAFLD. As the name suggests, fatty liver disease (aka liver steatosis) is the accumulation of fat in the liver. Microscopically this is evident as micro or macrovesicular fat accumulations within the cells of the liver (hepatocytes), while grossly a fatty liver appears enlarged, soft, oily, and pale (foie gras anyone?).

 

Fatty liver- both alcoholic and nonalcoholic – is generally asymptomatic, and requires a liver biopsy or radiology (such as CT, MRI, or ultrasonography) for diagnosis, though blood tests for liver markers are used to detect non-specific changes in liver health (you also might notice this while looking around someone’s insides during a surgical procedure, as I noted during a laparoscopic gallbladder removal during my surgery clerkship).  The prevalence of fatty liver is unclear, however the percentage of heavy drinkers that have fatty liver changes is probably quite high, with some studies showing that up to 90% of active drinkers have fatty changes [1]. Again, because of the relative “silent” nature of NAFLD, it’s hard to determine the prevalence of the condition, however it is strikingly (and increasingly) common, with sources suggesting that it may affect 20-30% of the US population [2]. Scarily, it is estimated that over 6 million CHILDREN in the US have this condition today, with this number continuing to grow [3].

 

Fat can accumulate in the liver in five different (though often simultaneous) ways. There can be (1) an increase in uptake and storage of dietary fats, (2) an increased uptake of free fatty acids (FFA) from other stores (from your fat tissue to your liver), (3) increased de novo lipogenesis (making lipids from scratch), (4) decreased consumption (b-oxidation to those in the trade) of fats, or (5) impaired export of triglycerides from the liver [4]. It is likely that a number of these mechanisms work in concert to produce fatty liver disease, but the precise reasons WHY they occur have not yet been determined, nor has the relative importance of each mechanism been teased out. Undoubtedly different mechanisms are of varying importance in different conditions and circumstances.  Indeed, relatively early studies of alcohol-induced liver disease showed that, depending on experimental conditions such as method and length of exposure, hepatic lipids could be derived from dietary, adipose, or de novo hepatic sources [5]. Teasing out what we already know (or think we know), and how each of these mechanisms interact to lead to fatty liver disease is beyond the scope of this blog post (it’s beyond the scope of most medical texts, really), but the role of dietary fats deserves some airtime in this discussion, and is what I wish to talk about here.

 

The research into the pathogenesis of alcoholic fatty liver is long and tortuous (or is that torturous, if you’re a graduate student trying to get a handle on past research?). Without going into too much depth, there has been controversy over the years as to whether alcohol itself causes fatty liver, or whether fatty liver occurs with alcohol consumption as a result of simultaneous nutrient deficiencies. Because chronic alcohol consumption is frequently accompanied by a very poor diet, it was postulated that liver disease occurred primarily as a result of nutrient deficiency, not alcohol consumption. This proved to be partially true in animal models, where a diet deficient in nutrients such as choline and methionine exacerbates the development of alcoholic liver disease.  Alas, nutritional supplementation only diminishes or slows, but does not prevent, alcoholic liver disease development and progression [6, 7]. Steatosis still occurs in the presence of an adequate diet, showing that nutritional deficiencies alone cannot account for the development of fatty liver.

 

Before I delve into the research, here is a quick primer on lipids (skip it if you’re already a pro). For the purpose of this post, there are two important ways to classify fatty acids. The first is length. Here I will discuss both medium chain fatty acids (MCFA), which are 6-12 carbons long, and long chain fatty acids (LCFA), which are greater than 12 carbons in length (usually 14-22; most have 18). Secondly, fatty acids can have varying amounts of saturation (how many hydrogens are bound to the carbons). A fatty acid that has the maximal number of hydrogens is a saturated fatty acid (SAFA), while one which has one double bond is monounsaturated (MUFA) and a fatty acid with more than one double bond is called a polyunsaturated fatty acid (PUFA)*.

 

Most alcohol researchers rely on an isocaloric liquid diet containing 35% of the calories from alcohol in the treatment group with the alcohol replaced by a carbohydrate in the control group. It was discovered pretty early on (in the 1960s) that eliminating dietary fatty acids significantly reduced the amount of fat accumulated in the liver and that you needed at least 25% of calories from fat, and ideally around 40%, to get a good model of alcoholic fatty liver (granted this is in rats, not humans). It didn’t take long for researchers to realize that different types of fatty acids were better (or perhaps more interestingly, worse) at creating fatty liver than others. The first notable realization (at least as far as I’m aware) is that medium chain fatty acids (MCFA) caused much less steatosis than long chain fatty acids (LCFA). Indeed, as early as 1972 researchers were showing that alcoholic fatty liver in rats could be reversed by replacing corn oil (an excellent source of LCFA, especially polyunsaturated fatty acids (PUFAs)) with MCFA. Stunningly (to me at least), there was a more rapid regression of fatty liver when the corn oil was replaced with MCFA than when the alcohol was replaced with sucrose [8]!

 

Another fascinating and interesting piece to this puzzle came in the mid 80s when it was shown that beef fat prevents alcoholic liver disease in rats. This research was conducted after epidemiological studies showed that a high intake of saturated fat was relatively protective against ALD disease while a high intake of polyunsaturated fats promoted ALD.  Researchers took this epidemiological finding to the lab, and showed that rats that were fed an alcohol-containing diet with tallow (beef fat) developed none of the symptoms of alcoholic fatty liver disease, while those fed alcohol with corn oil developed severe pathology [9]. More recent research (which I will explore in an upcoming post) delves into the protective mechanisms of SAFAs.

 

Alas, a high fat model of ALD that doesn’t actually give you liver pathology is not particularly useful for studying fatty liver, so most ALD research uses a diet that combines olive oil, corn oil, and/or soy oil and produces significant fat accumulation in the liver (indeed, this is what my PhD research was based on).  But what can research that has used other sources of fats tell us about alcoholic liver disease, and perhaps more interestingly (as the NAFLD epidemic continues to sweep the nation and the world) what can this research tell us about fatty liver disease that has nothing to do with alcohol consumption?

 

During my time in the lab (and even more so while writing my dissertation), I came to recognize that there are many similarities between fatty liver diseases of apparently very different etiologies. From a cell signaling perspective (my specialty), I was surprised by the parallels of our ALD fatty liver model and the fatty liver caused by protein malnutrition (yes- protein malnutrition leads to fatty liver- bizarre, no?). I have had less time to focus on the parallels between ALD and NAFLD (not caused by protein-malnutrition), however most of the medical information on this topic suggests life-style modification that focuses on the importance of reducing fat, especially (*eye roll*) saturated fat. I have yet to see the smoking gun for saturated fats in the pathogenesis of NAFLD, and if the process is anything like that of alcoholic liver disease (as I much suspect to be the case), minimizing saturated fats for those with NAFLD will likely do more harm than good.

 

I will expound on this statement in an upcoming post.

 

 

*For the lipid lovers in the crowd… Yes- there are significant differences in the effects of various types of PUFAs when it comes to alcoholic liver disease, though there are some interesting complications with the Omega3s depending on what research you look at. For the sake of this post (and most research), when I say PUFA I am generally referring to linoleic acid, the main PUFA in the dietary models of ALD and the modern diet.

 

 

1.            Kondili, L.A., G. Taliani, G. Cerga, M.E. Tosti, A. Babameto, and B. Resuli, Correlation of alcohol consumption with liver histological features in non-cirrhotic patients. Eur J Gastroenterol Hepatol, 2005. 17(2): p. 155-9.

2.            Kim, C.H. and Z.M. Younossi, Nonalcoholic fatty liver disease: a manifestation of the metabolic syndrome. Cleve Clin J Med, 2008. 75(10): p. 721-8.

3.            Jin, R., N.A. Le, S. Liu, M. Farkas Epperson, T.R. Ziegler, J.A. Welsh, D.P. Jones, C.J. McClain, and M.B. Vos, Children with NAFLD Are More Sensitive to the Adverse Metabolic Effects of Fructose Beverages than Children without NAFLD. J Clin Endocrinol Metab, 2012. 97(7): p. E1088-98.

4.            Lim, J.S., M. Mietus-Snyder, A. Valente, J.M. Schwarz, and R.H. Lustig, The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol, 2010. 7(5): p. 251-64.

5.            Lieber, C.S., N. Spritz, and L.M. DeCarli, Role of dietary, adipose, and endogenously synthesized fatty acids in the pathogenesis of the alcoholic fatty liver. J Clin Invest, 1966. 45(1): p. 51-62.

6.            Nieto, N. and M. Rojkind, Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet. J Hepatol, 2007. 46(2): p. 330-9.

7.            Kajikawa, S., K. Imada, T. Takeuchi, Y. Shimizu, A. Kawashima, T. Harada, and K. Mizuguchi, Eicosapentaenoic acid attenuates progression of hepatic fibrosis with inhibition of reactive oxygen species production in rats fed methionine- and choline-deficient diet. Dig Dis Sci, 2011. 56(4): p. 1065-74.

8.            Theuer, R.C., W.H. Martin, T.J. Friday, B.L. Zoumas, and H.P. Sarett, Regression of alcoholic fatty liver in the rat by medium-chain triglycerides. Am J Clin Nutr, 1972. 25(2): p. 175-81.

9.            Nanji, A.A., C.L. Mendenhall, and S.W. French, Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res, 1989. 13(1): p. 15-9.

 

 

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Sorry there’s been a delay in getting anything new out. I’ve had some exams, a quick trip to Colorado, and am now just finding my feet on my surgery clerkship. I have a bunch of things I intend to write about soon, but this paper popped up the other day and it ties in really nicely to some of the things I’ve already written about. I just had to write about it! I promise that in my upcoming posts I will get away from bowels and microbiota (though these subjects are incredibly important!).

You may remember Clostridium difficile from one of my previous posts on the appendix. C. diff is an anaerobic bacterium that frequently resides in the large intestine. After a course of antibiotics, when other gut-inhabitants have been killed, an overgrowth of C. diff can lead to a very nasty spectrum of symptoms ranging from mild diarrhea to death. Because of the frequent use of antibiotics and because of new hyper-virulent strains of C. diff, infection with this bacterium has reached epidemic levels. Alas, this is one of the most common infections found in hospitals, nursing homes, and other medical facilities.

The incidence of C. diff is on the rise, with both the number of cases and the mortality from infection recently doubling. There are approximately 3 million cases of C. diff infection in the US each year, and it’s estimated that care for these cases is in excess of $3.2 billion. C. diff infection leads to a number of discomforts, including abdominal pain, diarrhea, fatigue, and flu-like symptoms. Alas, treatment can be difficult, and symptoms can persist for months or even years.

As I mentioned in a previous post, the usual treatment for C. diff is further antibiotic treatment. C. diff infection usually occurs after all the normal gut flora has been eliminated and further antibiotics (sometimes given with probiotics to encourage the return of commensal bacteria) are targeted at eliminating C. diff (there’s even a new antibiotic (Dificid) specifically targeted at C. diff). The problem, of course, is that IF these antibiotics are effective, you now have a relatively unpopulated gut that is barren and ready for the taking by whatever stray bacteria have survived the courses of antibiotics or whatever quick growing bacteria happens to make their way to the intestines to claim the empty territory- unfortunately C. diff is frequently the victor in this foot race!

Recurrent rates of C. diff infection range from 15-30%, and once you’ve had one recurrence, you’re more likely to have another: a 40% chance of having a second, and a 65% chance of having a third. Obviously antibiotics are of limited efficacy here, so what is an appropriate course of action?

In my previous post, I discussed a paper that showed that having an appendix (and thus having a safe house for normal commensal bacteria that can repopulate your gut after infection or antibiotic treatment), is protective against a recurrence of C. diff [1]. But what if you don’t have that safe house, or if you get a recurrence despite having an appendix? Again, as mentioned in a previous post, a Fecal Microbiota Transplant (FMT) seems to do the trick.

A paper published at the end of March [2], combined data from 5 sites and showed that FMT can provide RESOUNDING cure rates in people suffering from recurrent C. diff infections. Here’s a quick review: 77 patients, with average symptom duration of 11 months (range 1-28) underwent FMT at 1 of 5 medical centers in an attempt to cure their chronic infection. On average, these patients had already undergone 5 treatment regimes to try and cure their infection. FMT (most donors were family members, spouses, partners, or friends) was infused by colonoscopy into the terminal ileum, cecum, and (depending on the site) parts of the colon. Resolution of a number of symptoms- abdominal pain, fatigue, and diarrhea, were recorded.

In 70% of patients, pain resolved with FMT, while it improved in an additional 23%. 42% of patients saw a resolution of fatigue, with an additional 51% reporting an improvement. An astounding 82% saw a resolution of diarrhea and 17% saw an improvement within 5 days of FMT. These are patients, remember, that have been suffering from symptoms for an average of 11 months.

Alas, 7 patients (just under 10%) experienced an early recurrence (less than 90 days after FMT), and required a secondary treatment (either antibiotics targeted at C. diff or another FMT), which successfully treated the recurrence. Thus, the “primary cure rate” (resolution of diarrhea within 90 days of FMT) was 91%, and the “secondary cure rate” (resolution of infection after a further course of antibiotics or a second FMT), brought the cure rate to 98%. (It is worth noting that the one not “cured” patient died in hospice and was not re-treated after failure of a primary cure).

Some patients did have late recurrent infections of C. diff. Not surprisingly, these cases all occurred in patients that took a course (or multiple courses) of antibiotics to treat an unrelated infection. Recurrence occurred in 8 of the 30 patients that took a course of antibiotics. Interestingly, recurrence may also be associated with the use of proton-pump inhibitors (perhaps not a surprise, as PPIs inadvertently affect our microbiota [3])

This paper is excellent evidence to support FMT becoming a first-line therapy for the treatment of C. diff infection (and I will add especially for those that lack an appendix). FMT restores a natural biodiversity to the intestine of someone who has had their own microbiota disturbed by disease and/or antibiotics. For many people (those that experienced a primary cure), the restoration of the biodiversity was enough to overcome C. diff infection. For others, the restored biodiversity gave them the edge to overcome infection with a further targeted antibiotic or a second transplant. Remember- these are patients that had failed MULTIPLE treatments for C. diff and had been experiencing symptoms for an average of 11 months.

While there are definitely risks to FMT (it is important that donors be screened to rule out dangerous transmissible infections such as HIV, hepatitis, and parasitic infections), there are arguably additional benefits. One patient in this study reported a significant decrease in allergic sinusitis and another reported an improvement in arthritis. Both associated the improvement of symptoms with FMT. Indeed, FMT has been reported as a successful treatment for a number of conditions including inflammatory bowel disease (such as ulcerative colitis), irritable bowel disease, idiopathic constipation and insulin resistance [2].

It is important to recognize that some of the patients in this trial did suffer from subsequent disorders that should be further explored. While the conditions were not apparently associated with FMT, 4 patients that received this therapy later developed conditions including peripheral neuropathy, Sjogren’s disease, rheumatoid arthritis, and idiopathic thrombocytopenic purpura. Further studies need to determine if there is an association between FMT and autoimmune or rheumatologic disorders. If associations are found, I would expect that this would call into question the appropriate selection of donors for individual patients.

It is becoming increasingly obvious that an appropriate and diverse microbiome is important for health. When this microbiome is thrown out of whack, be it by an evolutionary-novel lifestyle, infection, or antibiotic treatment, the restoration of this environment should be the focus of medical treatment. Fecal Microbiota Transplant is a rational and effective method of restoring a healthy and diverse intestinal microbiome.

(It is worth mentioning that 97% of the patients in this study stated that they would undergo another FMT if they experienced a recurrence of C. diff, and 53% would choose FMT as their first treatment option before a trial of antibiotics. Yes, the idea of FMT may seem gross, but it is effective. For those that have suffered for upwards of a year, this treatment truly is a life-changing option.).

1.            Im, G.Y., R.J. Modayil, C.T. Lin, S.J. Geier, D.S. Katz, M. Feuerman, and J.H. Grendell, The appendix may protect against Clostridium difficile recurrence. Clin Gastroenterol Hepatol, 2011. 9(12): p. 1072-7.

2.            Brandt, L.J., O.C. Aroniadis, M. Mellow, A. Kanatzar, C. Kelly, T. Park, N. Stollman, F. Rohlke, and C. Surawicz, Long-Term Follow-Up of Colonoscopic Fecal Microbiota Transplant for Recurrent Clostridium difficile Infection. Am J Gastroenterol, 2012.

3.            Vesper, B.J., A. Jawdi, K.W. Altman, G.K. Haines, 3rd, L. Tao, and J.A. Radosevich, The effect of proton pump inhibitors on the human microbiota. Curr Drug Metab, 2009. 10(1): p. 84-9.

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I hope that my last post persuaded you that the appendix is not the pathetic remains of our forbearers’ large cecum, but is in fact a nifty piece of anatomy that maintains a safe house for the normal micro flora of our gut (If you’re interested in gut micro flora, Melissa wrote a great post here). While this little organ seems to work well in developing countries where there are frequent outbreaks of enteric pathogens and minimal hygiene, something seems to have gone awry in the developing world. While appendicitis is exceedingly rare in developing countries, it has been reported that up to 6% of the population in industrialized countries develop appendicitis necessitating appendectomy [1]. Why has our bacterial safe house turned into a ticking time bomb?

As early as 1505, Leonardo da Vinci identified the appendix and recognized that it sometimes became inflamed and burst. Much of his medical knowledge was lost, and it wasn’t recognized again until 1705 when the (then very young) father of clinical case reports, Giovanni Battista Morgagni, dissected a man who had died of appendicitis and subsequent peritonitis. That case actually revolutionized the understanding of medicine, with Morgagni and his mentor Valsalva recognizing that a specific disease was caused by a specific condition in a specific part of the body. This showed that illness was not caused by an imbalance of humors or a generalized malaise, but rather a specific cause. This one case led Morgagni and Valsalva to perform autopsies on all their deceased patients, and their detailed notes of over 700 cases were analyzed and published in the book On the Seats and Causes of Disease as Indicated by Anatomy. This book, and the idea that disease is caused by specific disorders, revolutionized medicine.

While appendicitis was one of the first diseases for which the anatomical source was recognized, we still don’t clearly understand why the condition occurs. It is generally believed that appendicitis occurs when the appendix is obstructed (by obstruction of the opening into the cecum by feces or swelling of the appendix due to proliferation of the tissue of the appendix itself), and the mucinous products of the appendix build up, leading to increased pressure and eventually tissue death. This dead tissue encourages bacterial proliferation (and we’re no longer talking about the friendly house-keeping type). Acute appendicitis is a medical emergency, and one that must be diagnosed and handled quickly. The removal of an inflamed, but intact, appendix is a much easier and neater procedure than trying to manage the aftermath of a ruptured appendix and subsequent peritonitis. If you think you might have appendicitis- get thee to the emergency department!

But why has appendicitis become so common? Appendectomy is sometimes referred to as ‘bread and butter’ for a general surgeon, but in developing countries this condition is almost unheard of. The rate of appendicitis is reported to be about 35-fold higher in the United States than in areas of African unaffected by modern health care and sanitation. Additionally, as communities adopt Western sanitation and hygiene practices, the rate of appendicitis increases [2]. Could appendicitis be another result of the “hygiene hypothesis”- the idea that modern medicine and sanitation can lead to an under-stimulated and over-active immune system?

As discussed in my first post, the appendix is associated with a large amount of gut-associated lymphoid tissue (GALT). While I pointed out that the appendix does secrete some substances that actively encourage the formation of biofilms for friendly bacteria, GALT also plays a role in the more typically recognized ‘keep the bad guys out’ aspect of the immune system. It’s that part of the system that tends to go awry with our modern hygienic world. Our immune system evolved to handle and control a number of different pathogens, including unfriendly bacteria and parasites. In the absence of pathogens, however, the system can go amiss The immune system is primed and looking for a fight, and if nothing appropriate comes along to take a beating, the immune system can start getting self-destructive, going after the body in which it is housed. It’s a classic case of ‘idle hands’ (or an active teenager with no good way to get the energy out!). This may well play a role in the prevalence of appendicitis in the developed world: overactive GALT tissue causes the appendix to swell, plugging the appendix, stopping the secretions from exiting into the cecum, and leading to increased pressure and subsequent necrosis and disease. (This is the condition that tends to occur in young people. In older people, appendicitis tends to be caused by the physical blockage of the appendix by a coprolith).

So is that it? In the past, and in the developing world, the appendix operated as a safe house for commensal bacteria. In the modern/hygienic world the appendix isn’t really needed, and can in fact get a bit out of whack because it doesn’t have anything to direct it’s immune-related functions towards. It definitely seems as though this might be the case, and unfortunately the problem appears to extend beyond the appendix. It turns out that an overactive appendix may also play a role in ulcerative colitis- an inflammatory condition of the large intestine. In some people with ulcerative colitis, an appendectomy improves the symptoms of ulcerative colitis, and in others it can completely cure the condition. The intended purpose of the appendix may shed light on why this pathology occurs. First- in a hyper-immune state, the appendix may house bacteria that the immune system aberrantly attacks. Alternatively (or additionally), the GALT tissue may drive the gut into a hyper-immune state. In either case- understanding the evolutionary purpose of the appendix can help understand and treat the conditions that occur in our modern hygienic world. Furthermore, it offers evidence that we should think about the impact of our uber-hygienic world, and consider how we might best handle the mismatch between our immune system that evolved to keep us safe in a dirty world and our modern clean environment.

(If you’re looking for a scholarly discussion of this topic, I highly recommend The cecal appendix: one more immune component with a function disturbed by post-industrial culture [2].)

1.            Bollinger, R.R., A.S. Barbas, E.L. Bush, S.S. Lin, and W. Parker, Biofilms in the normal human large bowel: fact rather than fiction. Gut, 2007. 56(10): p. 1481-2.

2.            Laurin, M., M.L. Everett, and W. Parker, The cecal appendix: one more immune component with a function disturbed by post-industrial culture. Anat Rec (Hoboken), 2011. 294(4): p. 567-79.

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