|Nonalcoholic Fatty Liver Disease|
|Written by Chris Masterjohn|
|Friday, 01 April 2011 17:10|
A Silent Epidemic of Nutritional Imbalance
Over seventy million Americans may have nonalcoholic fatty liver disease.1 The disease begins with the accumulation of fat within the cells of the liver, but can progress to inflammation, the development of scar tissue, and in some cases death from liver failure or cancer.2-4 Simple accumulation of fat within the liver generally proceeds without producing any overt symptoms, but it is not necessarily harmless. The liver regulates blood glucose and blood cholesterol levels, plays a critical role in burning fat for fuel, helps eliminate excess nitrogen, contributes to the metabolism of endocrine hormones, stores vitamin A, protects against infections, and detoxifies drugs and environmental toxins.
Any type of damage to the liver is thus likely to impact whole-body health. Indeed, fatty liver disease increases the risk of cardiovascular disease three-fold in men, fourteen-fold in women, and seven- to ten-fold in type-one diabetics.5-6 Fatty liver is thus a dangerous silent epidemic, and as we will see, it is likely caused by the overabundance of calorie-rich, nutrient-poor refined foods and the banishment of traditional sources of choline like liver and egg yolks from the modern American menu.
Relation to Obesity, Diabetes, and Insulin Resistance
Samuel Zelman, a medical doctor from Topeka, Kansas, published the first human case series connecting fatty liver disease to obesity in 1952.7 Zelman decided to examine a group of obese patients for fatty liver after observing the disease in a hospital aide who drank twenty or more bottles of Coca-Cola per day. This obscene amount of soda provided 1,600 calories of sugar and the caloric equivalent of a pint or more of whisky per day. Obese people were so hard to find at the time that it took Zelman a full year and a half to find twenty obese people who were not alcoholics. All of his subjects showed some degree of liver damage, and about half had a significant degree of fatty liver disease.
Zelman knew that fatty liver occurred in the earliest animal models of obesity involving genetics or surgical damage to the hypothalamus,8-9 and suggested that hypothalamic damage, biological inheritance, and â€śpsychological factorsâ€ť contributed to obesity in humans. He proposed that obesity increased the caloric requirement and led to cravings for energy-dense, nutrient-poor foods that increased the need for choline and B vitamins. These foods then overloaded the liver with energy but failed to provide the nutrients needed to process that energy, resulting in fatty liver.
Zelmanâ€™s obese subjects universally preferred a diet rich in carbohydrate and fat but poor in protein. The one exception was a man who â€śrelated a fantastic story of fondness for the ingestion of huge beefsteaks,â€ť but Zelman distrusted his story because the manâ€™s psychiatrist had accused him of being a pathological liar. Zelman prescribed a diet containing â€śas much protein as possible,â€ť emphasizing beef liver, lean fish, and lowfat dairy products such as skim milk and cottage cheese, as well as extra B vitamins and choline.
Zelman was likely on the right track when he identified nutrient density as an important component of a therapeutic diet, but his opposition to both fat and carbohydrate likely contributed to his regimenâ€™s ultimate lack of success. He reported â€śas much difficulty and discouragement in dealing with the craving for carbohydrate- and fat-rich foods manifested by the obese as with the craving for alcohol of the chronic alcoholic.â€ť Only two of his twenty subjects lost weight. He retested them for fatty liver and found some improvement, but he never reported completely successful resolution of obesity in any of his patients and consequently failed to document the success of his program in treating fatty liver.
Although type-one diabetes is much less common than obesity, it had been connected to fatty liver disease as early as 178410 and the resolution of diabetic fatty liver was an early objective of insulin therapy.11 Physicians identified the connection between alcohol consumption and fatty liver disease in the 1830s,12 however, and in the middle of the twentieth century the connection to obesity and diabetes was lost from mainstream consciousness as alcohol came to be seen as the exclusive cause of the disease. At least as early as the 1970s, this exclusive association of fatty liver with alcoholism had become so ingrained that physicians simply accused their patients of lying if they presented with fatty liver but denied drinking alcohol.13
In 1980, Jurgen Ludwig and other physicians from the Mayo Clinic produced a report of twenty patients with nonalcoholic fatty liver disease.13 Ninety percent of the patients were obese, 35 percent had heart disease, 30 percent had gall bladder problems, and 25 percent had type-two diabetes. These physicians coined the term â€śnonalcoholic steatohepatitis,â€ť to describe the disease and abbreviated it â€śNASH.â€ť The creation of a specific term for the nonalcoholic manifestation of the disease promoted greater awareness of this form, facilitated the organization of an entire research field devoted to its study, prevented doctors from accusing patients of lying about their alcohol intake, and, in the words of the Mayo Clinic physicians themselves, spared doctors â€śthe embarrassment (or worse) that may result from the ensuing verbal exchanges.â€ť
Since the Ludwig groupâ€™s landmark paper, numerous studies have confirmed the relation between fatty liver, obesity and diabetes. Autopsy14-15 and ultrasound16-17 studies have shown that rates of fatty liver are five- to fifteen-fold greater in obese individuals than in lean individuals and that the disease is present in up to three quarters of obese people. Similar studies have shown that 45 percent of type-one diabetics and 70-85 percent of type-two diabetics have fatty liver.6, 18-19 Moreover, even in the absence of diabetes and obesity, those with the lowest insulin sensitivity have the highest accumulation of liver fat.20
Since nonalcoholic fatty liver disease was rarely diagnosed before 198013 and since even today most people with fatty liver are probably not diagnosed,21 there is no way to track its prevalence over time. The prevalence of diagnosed diabetes in the United States, however, has increased from five to eight percent since 1988,22 and the prevalence of obesity has increased from about 15 percent to 35 percent since 1960.23 Given the high prevalence of fatty liver in obese and diabetic populations, we have likely experienced the emergence of a silent epidemic of fatty liver disease as the prevalence of obesity and diabetes has grown over the last few decades to reach epidemic proportions.
Diagnosing Fatty Liver Disease
Biopsy, ultrasound and magnetic resonance spectroscopy (MRS) are all legitimate methods of diagnosing fatty liver,6, 16-19, 21, 24-25 although ultrasound can sometimes fail to detect moderate cases of fat accumulation. Even though physicians often refer patients to biopsy when they have elevated liver enzymes,24 nearly 80 percent of patients with fatty liver have normal levels of these enzymes.21 In fact, in ten women who recently developed liver problems on an experimental diet low in choline, nine developed fatty liver but only one developed elevated liver enzymes.26 Fatty liver should therefore be suspected on the basis of obesity, diabetes and insulin resistance rather than elevated liver enzymes.
Fatty Liver As a Nutritional Imbalance
A well-functioning liver supports our health in many different ways (see sidebar). It is therefore deeply concerning that fatty liver is an independent risk factor for cardiovascular disease,5-6 as this would suggest that the disease may in fact compromise liver function and contribute to other degenerative diseases. Learning how to prevent and treat fatty liver, then, is critical.
In order to understand how our livers get fat, we must first realize that fatty liver disease occurs in two distinct stages (see sidebar for more detail). In the first, called simple steatosis, fat accumulates within the cells of the liver. In the second stage, inflammation, the proliferation of fibrous connective tissue (fibrosis), and eventually the formation of scar tissue (cirrhosis) ensue. In modern terminology, â€śnonalcoholic fatty liver disease (NAFLD)â€ť refers to the full range of these disease states, while â€śNASHâ€ť refers only to the inflammatory stage.27
A number of experimental diets are currently used to study nonalcoholic fatty liver disease in laboratory animals, including diets high in fat, high in fructose, or deficient in choline and methionine. None of these models fully resembles the human situation, probably because they all emphasize single factors carried to extremes, whereas the human situation reflects a combination of several contributing factors (see sidebar).
The totality of the evidence suggests that the initial accumulation of fat in the liver is triggered by nutritional imbalance. As Zelman suggested in the 1950s, fatty liver seems to occur as a result of too much energy flowing through the liver without sufficient nutrients to process it. The accumulation of delicate fats, especially polyunsaturated fatty acids (PUFAs), increases the vulnerability of the liver to oxidative and inflammatory insults in the form of infections, toxins, or poor metabolism. These insults launch the progression from the first stage of simple fat accumulation to the second stage of inflammation.
The key culprits, then, are nutrient-poor refined foods, choline deficiency and polyunsaturated oils. The interaction between these factors can be seen by turning to the history of the development of animal models for fatty liver disease.
The Role of Refined Foods
In 1924, George Burr joined the laboratory of Herbert Evans, where Evans and Katherine Scott Bishop had recently discovered vitamin E.66 Evans and Bishop were having trouble reproducing their vitamin E-deficient diet, and Burr helped them develop a highly purified diet based deficiency that vitamin E could not cure, which Burr and his wife Mildred later identified as essential fatty acid (EFA) deficiency.67-68 Observing the fact that the annual per capita consumption of sugar in the United States had tripled over the preceding decades from 38 pounds to 115 pounds, Clarence Martin Jackson conducted a comprehensive analysis of the anatomy and tissue characteristics of rats fed Burrâ€™s EFA-sufficient, 80 percent sucrose control diet.69 He compared them to rats fed 45 percent sucrose or 45 percent starch. Neither the 45 percent sucrose diet nor the 45 percent starch diet produced fatty liver, but the 80 percent sucrose diet produced moderate to severe cases of the disease. He noted that the liberal provision of cod liver oil, dried yeast and wheat germ satisfied the nutritional needs of the rats in all treatment groups, and that smaller amounts of sucrose may contribute to fatty liver in humans consuming nutritionally deficient diets. Indeed, dietary protein, methionine, and choline were later shown to protect against sucrose-induced fatty liver.12
In 1977, the American Institute of Nutrition (AIN), the principal professional organization for nutritional research scientists in the United States, developed standards for cereal-based, purified and chemically defined rodent diets.70 The purpose of the purified and chemically defined diets was to standardize diets between studies, so that toxicologists could easily make comparisons between one study and another. The days of cod liver oil, yeast and wheat germ were over. The days of purified vitamin and mineral mixes were now ushered in.
The AIN initially designated the purified diet as â€śAIN-76,â€ť but they increased the vitamin K concentration ten-fold three years later in response to reports of excessive bleeding.71 They designated the new diet â€śAIN-76A.â€ť Both of these diets were 50 percent sucrose and 15 percent starch, much lower in sucrose content than the diet that Jackson had used to induce fatty liver just a few decades earlier. Nevertheless, reports quickly began to surface of fatty liver developing spontaneously in rodents fed the AIN-76A diet.72 Reducing the concentration of sucrose from 50 percent to 20 percent resolved the fatty liver. Because of this and several other adverse metabolic effects of sucrose, the AIN released a new diet in 1993 and reduced the sucrose content to 10 percent, with the remainder of the carbohydrate supplied by cornstarch and a small amount of dextrinized cornstarch to aid in pelleting.73-74 As a result of many other problems that had surfaced with the diets, the AIN also increased the amount of vitamins E, K and B12, increased the calcium-to-phosphorus ratio, substituted soy oil for corn oil, and added various trace minerals not yet known to be essential.
Why did sucrose prove so much more harmful in the context of the purified AIN-76 diet than it did when Jackson provided it in combination with cod liver oil, yeast, and wheat germ? In all likelihood, the provision of these unrefined foods supplied a wide variety of interacting vitamins, minerals, and other nutritional substances that aided in the metabolism of the sugar, helping the liver to burn it for energy, store much of the excess as glycogen, and export any fat made from it into the bloodstream. We will never know the exact nutritional composition of Jacksonâ€™s diet. We do know from other studies, however, that supplying extra choline in the diet provides powerful protection against fatty liver, whether induced by sugar, alcohol, or fat.
The Role of Choline
The discovery that choline could prevent the accumulation of fat in the liver was a byproduct of the seminal animal research conducted during the 1920s and 1930s showing that type-one diabetes was a disease of insulin deficiency. Physiologists first identified the role of insulin deficiency in type-one diabetes by studying the disease in dogs. In 1889 they produced diabetes by simply taking out the whole pancreas from these dogs and, after scrambling for a couple decades to identify the active component, they cured the diabetes with insulin in the early 1920s.75
Although cured of diabetes, the insulin-treated dogs nevertheless developed severe fatty liver degeneration and ultimately died of liver failure. Adding raw pancreas to their diet, which was composed of lean meat and sucrose, cured the problem. As researchers attempted to discover what it was in raw pancreas that cured the disease, they found in the early 1930s that egg yolk lecithin, which is abundant in choline, could cure it.76 Then they found that choline alone could cure it.77
It later turned out that the dogs became deficient in choline and methionine without a pancreas because they were not producing the digestive enzymes needed to free up those nutrients from the foods they were eating. Thus, simply providing them with the digestive enzyme trypsin could cure the fatty liver.78
In 1932 a group of researchers decided to replicate the fatty liver seen in the dogs in a nondiabetic rat model. What better way to stuff their livers with fat? Feed them fat! It seemed simple enough and it did indeed work. Although they had trouble reproducing the fatty liver with different colonies of rats or during the summer heat, they produced fatty liver in certain colonies of rats during the winter by replacing 40 percent of their ordinary cereal-based diet with beef drippings. Choline-rich lecithin derived from egg yolk or beef liver or simply choline itself cured the disease.79-80
Another group of researchers, however, tried to replicate this experiment in a group of rats who were consuming sufficient protein to maximize growth.81 They thus fed them 40 percent beef drippings but replaced another 20 percent of their cereal grains with the milk protein casein. This experiment failed miserably (Figure 1a). The researchers suspected that the casein might have been the problem, and they were indeed correct: on a choline-free, 40 percent beef dripping diet, reducing the casein from 20 to 5 percent doubled the level of fat in the liver (Figure 1b).82
We now know that choline is necessary to produce a phospholipid called phosphatidylcholine. This is a critical component of the VLDL particle, which we need to make in order to export fats from our livers. The amino acid methionine can act as a precursor to choline. Thus, the combined deficiency of choline and methionine will severely impair our abilities to package up the fats in our livers and to send them out into the bloodstream.83 This explains why casein was so effective at preventing fatty liver: it provided the rats with methionine that they could use to make choline.
Similarly, in 1949 a group of researchers showed that sucrose and ethanol had equal potential to cause fatty liver, and that increases in dietary protein, extra methionine and extra choline could each completely protect against this effect.12 Over fifty years later, in our own decade, researchers have shown that choline deficiency likewise causes fatty liver in humans.84 Thus, choline eventually proved capable of preventing fatty liver regardless of whether it was induced by feeding sugar, fat, or alcohol. These studies suggested that virtually any form of energy delivered to the liver can cause the accumulation of fat, so long as key nutrients needed to metabolize that energyâ€”such as cholineâ€”were missing.
The Role of Polyunsaturated Oils
The initial experiments showing the protective effect of casein suggested that long-chain saturated fats might be more problematic than unsaturated fats or medium-chain fats (Figure 2a). As it turns out, saturated fats actually increase the need for choline slightly more than polyunsaturated fats (Figure 2b).85 Why this happens is unclear, but it may be that the body is quick to burn polyunsaturated fats for energy, since having them hang around is so dangerous. After all, if they hang around, they are likely to contribute to oxidative damage.
There is some experimental evidence suggesting that polyunsaturated fats may impair the export of fats from the liver by facilitating oxidative damage of the proteins involved.86 This evidence comes from isolated cells and live animals injected with fatty acids. Substituting coconut oil for corn oil prevents steatosis in some,52 but not all,37 studies using choline-deficient diets. Polyunsaturated oils are probably most likely to contribute to the accumulation of liver fat when combined with other factors that favor oxidative stress such as alcohol abuse, iron overload, toxin exposure, and poor metabolism.
There is much stronger evidence that polyunsaturated oils are responsible for the progression from simple steatosis to NASH.37 Substitution of carbohydrate, coconut oil or beef tallow for corn oil all prevent the oxidative damage and inflammation that results from methionine and choline deficiency during this stage of the disease.37 High-fat diets, moreover, only cause overt NASH when they are based on corn oil (see sidebar). These effects may result from a high intake of total PUFA, or may result from a high ratio of omega-6 to omega-3 fatty acids. Both of these factors are likely to play a role.
A Combination of Factors
As nonalcoholic fatty liver disease has emerged over the last several decades, refined foods have become commonplace. Liver has virtually disappeared from the American menu, and eggs have fallen victim to the anti-cholesterol campaign. These foods are the principal sources of choline (see Table 1). Total fructose intake has increased 30 percent, and intakes of linoleic acid, the major omega-6 PUFA, have doubled.56, 60 It is likely that all these factors have conspired to produce the current epidemic.
Each of the experimental diets often used to induce fatty liver in laboratory animalsâ€”diets high in fat, high in fructose, or deficient in choline and methionineâ€”fail to completely capture the picture of human fatty liver disease. When these factors are combined, however, the picture begins to emerge (see sidebar).
The requirement for choline and the propensity to develop fatty liver is influenced by a personâ€™s genetics and background diet. Diets rich in fat or fructose will require more choline than diets rich in starch. Vitamin B6, folate, vitamin B12 and betaine (a nutrient found most abundantly in spinach and to a lesser extent in wheat and beets) all reduce the requirement for choline. A personâ€™s ability to make choline out of the amino acid methionine depends on his genetics, and preliminary studies suggest that Asians are better able to make this conversion than Caucasians.87-91
Figure 2. Left: Predominantly unsaturated or medium-chained fats produced less steatosis than predominantly long-chain saturated fats. Right: A diet containing 30 percent butter produced a choline requirement that was 30 percent higher than a diet containing 30 percent corn oil when fed to rats. From references 81 and 85.
Many other nutritional, metabolic, and lifestyle factors are likely to play a role in fatty liver as well, by influencing the liverâ€™s ability to store carbohydrates as glycogen and to burn carbohydrates and fats for fuel. Thus, while there are special roles for including egg yolks, liver, other organ meats, and spinach in the diet, as well as avoiding polyunsaturated oils and refined foodsâ€”especially sugarâ€”there is likely to be a wide range of different diets that can promote liver health. What they all have in common is that they are ancestral diets, rich in nutrient-dense foods that we are well-adapted to, rather than the displacing foods of modern commerce. The emergence of fatty liver as a silent epidemic in the modern era is a call to nourish our livers with age-old traditional wisdom as we pursue the vibrant health of our ancestors.
TABLE 1. Choline in Selected Foods
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This article appeared in Wise Traditions in Food, Farming and the Healing Arts, the quarterly journal of the Weston A. Price Foundation, Spring 2011.
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written by mwai, Sep 17 2012
Might the mucin accumulation of hypothyroidism be the cause of fatty liver?
written by Jane, Jun 28 2012
|Last Updated on Monday, 02 April 2012 20:39|