Would you like a glass of Sauternes with your fatty liver?

Today I want to turn my attention to non-alcoholic fatty liver disease (NAFLD).

But before I do, let me briefly describe the anatomy of the liver, so we’re all on the same page.

The liver is the largest single internal organ and gland of the human body. It weighs about 3 to 4 pounds and is involved in a whole host of functions: detoxification, protein synthesis, bile production, lipid production, glucose synthesis and breakdown and blood sugar regulation to name a few.

It’s made up of two major sections, the right and left lobe. These lobes in turn are made of lobules. These lobules are made up of plates or sheets of cells called the hepatocytes. These hepatocytes radiate out from multiple central veins. These central veins direct blood from the liver into general circulation.

Blood passes between the hepatocytes by way of channels called sinusoids. This blood is a mixture that comes from both the artery feeding the liver (hepatic artery) and the portal vein. The portal vein contains blood from the spleen, pancreas and the digestive tract. This blood is rich in nutrients and whatever else crosses the gut wall, and it all ends up in the liver.

These sinusoids have immune cells called Kupffer cells whose role is to destroy bacteria and other foreign substances by engulfing and digesting them. These Kupffer cells are extremely important in protecting the liver and body from external threats and are a potential site of inflammatory immune responses.

Between the hepatocytes run small tubes called bile canaliculi that collect bile and direct it to the bile duct for transport to the gallbladder where it is used to help digest fat from the food you eat.

And that, dear reader, is your crash course in the anatomy of a human liver.

So let’s now look at non-alcoholic fatty liver disease (NAFLD).

Non-alcoholic fatty liver disease is exactly what it sounds like: a liver full of fatty hepatocytes in the absence of excessive alcohol intake. The human version of foie gras if you will, but without the berry compote, toast points or vegan protest.

It is the most common liver disease in the world, both in children and adults. The majority of patients who have it are overweight or obese. However, this is not always the case as normal-weight people can also have a fatty liver which goes to show that thinness is no guarantee of health (or longevity). What is common to both groups, nevertheless, is insulin resistance. Insulin resistance is considered a central player in people afflicted with this disorder.

Insulin resistance is characterized by cells outside the body no longer responding to insulin’s signal to absorb glucose from the blood. It also occurs because the liver itself is insulin resistant and continues to produce glucose even when blood sugar levels in the body are elevated.

Most patients with NAFLD have no symptoms at all. Those who do have symptoms report some discomfort in the upper-right-hand side of the abdominal area and perhaps a bit of fatigue. Sometimes patients present with a mild case of jaundice. It’s usually suspected when a doctor does an abdominal exam, and it’s confirmed when either a blood test detects abnormal liver function or an imaging procedure like an ultrasound detects fatty deposits.

While this relatively benign disorder may not progress any further, in some it can morph into a more serious inflammatory condition called non-alcoholic steatohepatitis or NASH. In NASH, inflammation damages the cells of the liver (hepatocytes) leading to scarring or fibrosis. No doubt the Kuppfer cells in the sinusoids are an important cause of this inflammation.

In some people with NASH, the inflammation continues to progress even further to full-blown cirrhosis and loss of liver function. And as chronic inflammation is at the root of cancer formation, the risk of liver cancer is also high.

Dietary factors that I believe predispose to NAFLD include alcohol, gluten, dietary lectins, polyunsaturated fats, especially from omega 6 vegetable oils and fructose. All these substances cause disturbances in intestinal bacterial populations as outlined here and here.

One well-known cause of fatty liver is choline deficiency. Choline is an amino acid abundant in foods like egg yolks and liver. Unfortunately, because of the high-cholesterol content of these foods, many people have been scared away from eating them much to the detriment of their livers.

A series of posts by Chris Masterjohn at the Daily Lipid blog covered this topic a couple of years back. I’m in total agreement with Chris that choline is a very important factor as it’s pretty much impossible to induce fatty liver in a lab rodent in the presence of adequate dietary choline. However, I don’t believe choline deficiency can shoulder the entire blame, especially in regards to explaining insulin resistance.

Choline can be synthesized from the amino acid methionine which is abundant in eggs, meat, wheat (boo hiss) and brazil nuts, but not everyone converts it efficiently. Betaine, folate and B6 are also important in that they spare choline. However, this assumes that you have the digestive capacity to get these important nutrients from your diet.

As my series on small intestinal bacterial overgrowth (SIBO) demonstrated, that assumption is wrong in the great number of people walking around with undiagnosed cases of small intestinal dysbiosis.

So yes, by all means eat foods rich in choline but you better make damn sure you’re able to absorb it. And if you can’t, then the reason is because your digestive cells are unhealthy. And that brings me to the role endotoxemia plays in all of this.

There is compelling evidence that bacterial translocation of endotoxins from the gut is a big factor in initiating the inflammatory response that underlies both insulin resistance and nonalcoholic fatty liver disease. For a quick explanation of what endotoxemia is please read the previous post.

This makes perfect sense. If there is small intestinal dysbiosis, there also, by definition, exists an inability to properly digest nutrients like choline, betaine, folate, B6 and pretty much anything else you care to mention. Dysbiosis also means increased intestinal permeability caused by the inflammation pathogens provoke. You can’t have dysbiosis, either of the small or large intestines and not have some form of leaky gut. And the first stop those pathogens, toxins and foreign substances from the gut go to is the liver.

Let’s review some rodent studies that add credence to this hypothesis.

More than 50 years ago, studies conducted by Broitman, Gottlieb and Zamcheck, showed that rats who were choline-deficient did indeed develop liver cirrhosis. However, if you sterilized the guts of these rats with an antibiotic (neomycin), they didn’t develop cirrhosis even in the presence of a choline deficiency.

When endotoxin was added to the water supply, the neomycin could no longer prevent liver injury even though neomycin kills gram-negative bacteria. Apparently, the amount of endotoxin the rats were getting was too much for the antibiotic to handle.

Further experiments implicating endotoxins have been seen in nine separate rodent studies since then. In these studies, all rodents were fed high-fat rodent pellets deficient in the amino acids methionine and choline to induce rapid fatty liver disease.

What’s fascinating is that when these rodents were given probiotics, there was a marked improvement in liver function even though their diets were purposefully lacking these liver sparing amino acids. In all nine studies, liver function improved. Fatty acid content either went down or insulin resistance in the liver improved or inflammation decreased or cholesterol was lowered or all the above.

This latter effect on cholesterol is very intriguing. Many people are unaware that cholesterol is part of the immune system and that cholesterol, both LDL and HDL, binds to endotoxins and inactivates them so that they can be safely excreted in bile and feces. So it makes sense that the livers of these rodents would make less cholesterol if the level of endotoxin went down.

But why would probiotics have this beneficial effect?

Well, as you recall from my posts on the many functions of friendly gut bacteria, they prevent the colonization of the digestive tract with pathogens, especially nasty gram-negative bacteria and their inflammatory-provoking lipopolysaccharide (LPS) cell-wall remnants.

They also displace pathogens that have already taken up residence in the gut by outcompeting them for space and nutrients and by producing antimicrobial compounds that kill them. And by doing so, they strengthen the barrier defenses of the gut wall preventing intestinal permeability or leaky gut. Remember, any toxin that crosses the gut wall ends up in the portal vein leading to the liver.

Finally, commensal gut flora are vital for proper immune function. A properly functioning gut immune defense kills these pathogens before they have the chance to cross the gut wall and trash your liver.

Are there any indications that this also holds true in humans? Funny you asked!

In a study published in 2000 that followed 22 patients with NASH, it was discovered that these patients had a significantly higher prevalence of SIBO than the general population. Go figure! This doesn’t prove causality, but it is an interesting finding don’t you think?

In another study, 97 patients with liver encephalopathy were given probiotics and prebiotics. Liver or hepatic encephalopathy, by the way, results in confusion, an altered level of consciousness and coma as a result of liver failure. It’s due to the liver’s inability to clear toxic substances.

So what was the result of giving these patients both probiotics and prebiotics? Improvement in their symptoms as well as a decrease in ammonium levels.

A prospective, randomized, double-blind study was conducted with 66 patients after liver transplant. Half the patients were given a combination of four Lactobacillus strains in addition to their enteral nutrition. In the probiotic group, rates of postoperative infection were significantly less–3% vs. 48%–than in the control group. The probiotic group was also able to get off of antibiotics far quicker than the non-probiotic group.

In one pilot study, 10 patients with biopsy-proven nonalcoholic steatohepatitis or NASH were given a mixture of probiotics consisting of both Lactobacillus and Bifidobacterium strains. They were also instructed to take a prebiotic (FOS) and vitamins (B6, B2, B12, D3, C and folic acid). After two months, the 10 patients showed a significant improvement in their liver function. These beneficial results partially persisted even after the treatment was over.

In a second pilot study, four groups of liver disease patients were studied. One group had NAFLD, the second had alcoholic liver disease (ALD) and both the third and fourth groups had hepatitis C but in the hepatitis groups, one group had liver cirrhosis and the other didn’t.

All patients were treated for three months with probiotics. All groups saw improvement in liver function, but only the ALD group experienced reductions in the production of inflammatory cytokines.

It appears, therefore, from studies in rodents and humans that it is endotoxemia that is causing inflammation in the liver and is therefore the root of liver disease. Choline deficiency no doubt plays a role by inhibiting the export of fat from the liver, increasing inflammation and perhaps handicapping the liver’s ability to detoxify these pathogens.

By administering probiotics to correct gut dysbiosis, endotoxemia is stopped or reversed and so is further damage to the liver.

The way endotoxins cause liver damage can be summarized this way:

  • Altered gut flora leads to
  • Increased gut permeability which leads to
  • Increased LPS/gut toxins which leads to
  • Increased activation of the immune system which leads to
  • Increased cytokine (immune signaling protein) production which leads to
  • Liver inflammation and injury which leads to
  • Increased systemic inflammation and organ injury.

In the next post, I’ll write about some interesting findings in regard to probiotics and alcoholic liver disease.



Frazier, T., DiBaise J. K., McClain J. (2011). Gut Microbiota, Intestinal Permeability, Obesity-Induced Inflammation, and Liver Injury. Journal of Parenteral and Enteral Nutrition, http://pen.sagepub.com.

Gropper, S., Smith, J., Groff, J. L. (2009). Advanced Nutrition and Human Metabolism, Fifth Edition. Belmont: Wadsworth.

Iacono A., et al. (2011). Probiotics as an emerging therapeutic strategy to treat NAFLD: focus on molecular and biochemical mechanisms. Journal of Nutritional Biochemistry, 22: 699-711.

Kopacova, M. (2011). Probiotics in hepatology. World Journal of Gastroenterology, 17(24): 2890-2896.

Wiggs A. J., et al. (2000). The role of small intestinal bacterial overgrowth, intestinal permeability, endotoxaemia, and tumour necrosis factor (a) in the pathogenesis of non-alcoholic steatohepatitis. , 48: 206-211.


Comments are closed.

Post Navigation