Human Foie Gras: The New Plague of Fatty Livers

                                                                                                                                
 “M. Apicius [Marcus Gavius Apicius, a first century AD Roman gourmet] made the discovery, that we may employ the same artificial method of increasing the size of the liver of the sow, as of that of the goose; it consists in cramming them with dried figs, and when they are fat enough, they are drenched with wine mixed with honey, and immediately killed.”

— Pliny the Elder, The Natural History, Book VIII, Chapter 77

For thousands of years, humans have created a tasty delicacy called foie gras from the livers of certain animals. Foie gras, which means “fatty liver” in French, is made by force-feeding animals, usually geese or ducks, a mash consisting of fat-soaked grain. Fatty livers are most easily induced in animals that regularly store extra fat for energy before migration. Humans also store energy easily, and modern lifestyles, including diets heavy in fat-soaked carbohydrates, have inadvertently created an epidemic of fatty livers in people. Some researchers estimate that the problem now affects one-third of the US population. 

Alcoholism was the main cause of fatty livers in the past

Doctors have long been familiar with fatty livers in alcoholics, in whom a combination of the toxicity of alcohol and dietary deficiencies converts liver cells into fat-laden bubbles. This condition is known as alcoholic steatosis and is the first step along a road that can lead to cirrhosis and liver failure. Alcoholic steatosis can be reversed if the patient stops drinking. If not, it can become progressively worse, leading to inflammation of the liver called alcoholic steatohepatitis. Ultimately this inflammatory degeneration can lead to a scarred and shrunken liver (cirrhosis) and to liver failure.

Non-alcoholic fatty liver becomes a new diagnosis

By 1980, the appearance of fatty livers and the kinds of problems that are associated with them in nondrinkers forced doctors to devise a new diagnosis—nonalcoholic fatty liver disease (NAFLD). As in alcohol fueled liver disease, NAFLD can also lead to inflammation, a condition called nonalcoholic steatohepatitis (NASH), and to cirrhosis and liver failure in some patients. Progression from NAFLD to NASH seems to require the additional effects of viral hepatitis or of toxic substances, like certain medications, both of which also play a role in some alcoholic liver disease progression. 
…..and becomes a serious problem

Since the 1980s, the prevalence of NAFLD has been climbing in parallel with the numbers of people affected by the metabolic problems of obesity, insulin resistance, and type 2 diabetes. Like these problems, NAFLD is now affecting younger people, even children. By 2006, NAFLD and NASH were the leading reasons patients were referred to liver specialists. They were also the leading cause behind diagnoses that led to 4 to 10 percent of liver transplants. While it is very difficult to make accurate estimates about the overall prevalence of NAFLD, by now it is clear that it is very common in people who have abdominal obesity, insulin resistance, and type 2 diabetes—perhaps affecting as many as 75 percent of such individuals.  
Why fat in the liver is bad for you

In a state of good health, the liver functions silently. Tucked up under the ribs on the right side of the abdomen, it is the size and shape of a deflated football and is the second largest organ in the body (the skin is the largest). The liver coordinates energy storage and regulation and makes proteins and cholesterol necessary to the health of all cells in the body. It also makes and secretes bile to absorb fats from the intestine and filters toxins from the blood to destroy them or ship them out with bile. The liver also stores vitamins and regulates the blood’s ability to clot in a fine-tuned range.  
 If necessary, the liver stores fat in its cells. Generally, this is a temporary state, and the fats are transported back to the body for use as an energy source or for storage in fat tissue. Obesity, insulin resistance, and diabetes, however, work together to keep fat in liver cells. Despite the stored fat the liver can continue to function well, producing no symptoms, unless other factors produce inflammation and scarring. NALFD is often discovered incidentally, because of abnormal liver function blood tests from inflammation, or a scan of the abdomen for other problems. 

Fat plus inflammation can trigger liver failure

When fat accumulation in the liver is accompanied by inflammation or occurs in someone who already has a scarred liver from other problems, like heavy alcohol use or hepatitis, liver failure and cirrhosis ( shrinkage from scarring) may follow. It is estimated that 20 percent of those with NAFLD have inflammatory changes in their livers, moving them from a diagnosis of NAFLD to a diagnosis of steatohepatitis, or NASH, which increases their risk of developing liver failure and cirrhosis. Unfortunately, there are no easy tests to determine the presence or absence of inflammation in the liver, and patients may have no symptoms. Liver function tests may remain normal, and although liver biopsy provides a definite diagnosis, it carries some risks and thus is not a suitable screening test for patients who have no symptoms or findings. 
Symptoms of liver disease

Symptoms of liver disease can be very vague until liver scarring and failure are well advanced. Fatigue, vague abdominal pain, and digestive complaints, as well as enlargement of the liver are early indicators. Jaundice (yellowing of the skin and eyes), fluid in the abdomen, poor clotting, and bleeding from the intestinal tract are late symptoms. Most people who have fatty livers will not go on to this degree of failure, just as most alcoholics do not, but there is no easy way to know who will and who won’t. 

What can be done?

In the presence of NAFLD it is important to avoid liver toxins such as alcohol and many drugs. With gradual weight loss, it is possible to reverse the accumulation of fat in the liver and to reduce liver inflammation, particularly if the weight loss program includes significant exercise to improve insulin sensitivity. Even in transplanted livers, NAFLD can recur as long as obesity, diabetes, and insulin resistance remain. Obesity surgery appears to reverse some of the liver problems in affected people and may yield new insights into the mechanism of insulin resistance. While researchers are striving to develop drugs that improve insulin resistance and alter fat transport and storage mechanisms, prevention, as always, is the best advice. This will require education, patience, self-discipline, and hard work, and it is particularly important for young people. While foie gras from a goose is tasty, its development in humans is undesirable. 

The Obesity Epidemic: Blame it on Science Too

When I was a child I thought my grandfather and Jackie Gleason were two of the fattest men in the world. Last year I happened on a rerun of The Honeymooners and was taken aback by Mr. Gleason’s modest girth. And an old movie of my grandfather shows, at most, a size 40 waist – practically svelte these days. What’s happened to us? We’ve become accustomed to widespread obesity in men, women and children. Is this one of the prices we pay for our market-driven, entertainment-loving culture?  Look at all the factors conspiring to load the scales: escalating inactivity, a vast snack and soft drink industry, supersizing, frenetic lives, fast food restaurants, the demise of the family-centered, home-cooked meal and its replacement with eating anywhere and everywhere, all the time. There is blame aplenty to go around, but this is a medical column, so we’ll stick to the role of science. Why pick on the medical science? Because we need to know how the expert advice we rely on plays out over time and if well-intentioned advances lead us astray.
Taking fat out of the diet
In the 1950s, medical researchers took on the epidemic of heart disease that had begun around 1900. Fatty streaks in the aortas of young soldiers dead in the Korean War made pathologists think that heart disease actually began early in life. They created an animal model for study, feeding rabbits cholesterol dissolved in vegetable oil instead of lettuce and carrots. When fat showed up in the rabbit arteries, the dietary theory of heart disease came to life. Some scientists quibbled, claiming that the problem was more complex, that other dietary factors like sugar might be equally to blame, but they lost the debate. Dietary cholesterol became the enemy, and over the next half-century the public learned to view the egg as a toxic substance, despite its near perfect protein and yolk full of valuable vitamins.

Along came the observation that Mediterranean populations had little heart disease compared to Americans. They also walked more, ate regular meals in family settings, didn’t snack, doused all but breakfast in olive oil, and scoffed at tasteless, pre-packaged food. But what we saw was lots of pasta, with not an ounce of cholesterol in it. Pasta was the ideal candidate to replace fat. We embraced the carbohydrate age, and turned a blind eye to the fact that, for years, we had managed to turn cattle fat by feeding them carbohydrates.

The national waistline ballooned, but can we at least say that the dietary agenda paid off in terms of heart disease? The answer is murky, because there were other, simultaneous prongs of attack: a fruitful campaign against tobacco use; drug treatment of high blood pressure; drugs that keep the body from absorbing or making cholesterol and drugs that calm the heart. Galloping technological advances allowed doctors to ream out plugged coronary arteries, prop them open with metal struts, or bypass them altogether. Nevertheless, cardiovascular disease remains our leading cause of death and the total number of patients with the disease has increased. Only the death rate from heart attacks has fallen and that statistic  is attributable to the interventions and drugs and declines in smoking.  The effect of the officially sanctioned diet on the epidemiology of heart disease, if any, is hard to discern. Now we face even more cardiovascular disease as epidemic abdominal obesity brings with it more diabetes, high blood pressure, and inhibition of physical activity.

A contribution from chemistry: artificial sweeteners

Science contributes to the obesity epidemic in other, more subtle ways. Through chemistry, we possess the magic of intense sweetness without a caloric price. An enormous rise in artificial sweetener use parallels the obesity epidemic. Well, is that a surprise? Everyone’s trying to lose weight. But what if, in addition to failing to stem the tide of weight gain, non-nutritive sweeteners are contributing to it? A few studies raise this unsettling possibility, and no study shows any significant effect of these chemicals on the process of weight loss, unless they are used in conjunction with a disciplined program of eating and exercise.

How could something with no caloric value contribute to obesity? Perhaps by raising levels of insulin, hormone which promotes fat storage. At least one artificial sugar (Xylitol) stimulates enough insulin release in dogs (who ate the stuff accidentally) to cause profound hypoglycemia and death. Do “non-nutritive” sweeteners cause release of insulin in people as well? This hasn’t been studied well. Artificial sweeteners were developed for Type I diabetics, who lack insulin altogether, so there wasn’t any point in measuring the hormone. But there is an insulin burst from the pancreas within thirty seconds of sweetness arriving in the mouth (the cephalic insulin response), and most people who use non-nutritive sweeteners do make insulin, which efficiently converts any extra calories in the meal accompanying the drink to fat. Some studies do suggest that insulin levels are higher in regular artificial sweetener users than non-users.

Tipping the scales while fixing the mood?

Chemistry also gives us the drugs that make people happy – or at least less unhappy. Over the last 30 years, antidepressant use for life’s inevitable miseries has skyrocketed. We are engaged in the very new practice of using these drugs in children. One side effect, perhaps more common than advertised, is difficulty withdrawing from the drugs. Another is weight gain. Some depression requires drugs, and antidepressants or antipsychotic agents don’t always cause weight gain. But the drugs are in such widespread use that you probably know someone who has packed on 20 pounds in the course of a divorce or other life stress that prompted antidepressant use and someone else who accepts the weight gains because they can’t stop the drugs.

Will science solve the obesity epidemic? 

Should we look to medical science or to the mega-million dollar diet industry to reverse our big obesity problem? To the development of new surgical procedures, more appetite suppressing drugs, sterner diet and exercise prescriptions, or new versions of deprivation diets (which rarely lead to permanent weight loss)?  I think not. And who knows what unexpected consequences might come along for the ride.   For a significant statistical improvement in the obesity problem, the answers will have to come from all of us and from our choices about how we act and what we value – from the culture, not from science. For too long we have treated food as an enemy, taking the joy and taste out of eating, without much to show for our efforts. Heart disease is still the number one killer, obesity is epidemic, and diabetes is hot on its heels. Extra weight comes off for good in the same slow, sneaky way it crept on – a few hundred calories a day out of balance with caloric needs. That’s just one dessert, or a beverage or two. Or a brisk walk instead of an hour of television. Every day we make the choices that determine our energy balance – elevator or stairs? TV or a walk? Coke or water? Vote for the guy who wants to put PE back in school or the one who doesn’t care? Yes, extra weight takes a very long time to lose, but next year will come around before you know it, no matter what you do. The choices will have added up, one way or the other. Every choice counts. In an epidemic, every person counts.

Walking or Running For Fitness? Both.

Karl is a friend who hikes a local trail almost every day. The trail is not easy, ascending 300 feet in the first quarter mile alone. Uphill stretches push the pulse and breathing rates up; downhill stretches require strength, flexibility and balance. Karl is 83 and he has maintained his physical fitness with functional activities like hiking and skiing. His old friends in the valley no longer hike with him.  “It is sad,” he says, shaking his head. “They didn’t need to stop and now they can’t do it anymore.”  He is right – fitness requires doing.

Why bother staying fit?

Physical fitness is worth preserving. It makes aging easier and more enjoyable, prolongs independent living and accessibility to many pleasurable activities, and lessens dementia risk. It raises insulin sensitivity, reduces blood pressure, cuts weight and improves cardiovascular risk factors.  You needn’t be an athlete to be fit and, as Karl demonstrates, fitness does not require gym memberships, classes or travel to and from a sports facility. And as many researchers have demonstrated, simple activities such as walking and running have positive effects on body and mind.

What does running do for you?

Much information about the beneficial effects of running comes from studies done in high level athletes. This sports oriented literature can be bewildering, leading into a thicket of terms like periodization and lactate thresholds and specialized measurements like aerobic capacity and heart rate variability. But buried in the details of these studies are useful facts that, when simplified, provide guidance that will improve the fitness of beginners and people who already have a stable exercise habit.

Why walk too?

While running promotes faster weight loss than walking, both lower blood pressure and improve heart and lung function. Walking requires more of the shin muscles and running more of the gluteals and quadriceps. Both are worth incorporating into a fitness program because of these different patterns of leg muscle use. Balancing the strength of lower and upper leg muscles and improving flexibility of all of them lessens strain on knees.

How much of each?

The balance between walking and running in an exercise plan depends on beginning fitness level and on goals.  For a sedentary individual unaccustomed to exercise, regular walks will be enough to increase fitness, at least in the beginning. For someone who has run in the past but not recently, a combination of walking and running is a good way to start. And for someone who has a good level of fitness and a long running history but is getting older and accumulating aches and pains, the addition of walking balances leg muscle groups.

Short periods of intense effort pay off

For all groups, the introduction of short bouts of more intense walking or running into a regular exercise program is perhaps the most important aspect of maintaining and improving fitness. These “intervals” provide the challenge that the heart and lungs need to stimulate their capacity to provide blood to working muscle more efficiently. A recent study from Denmark provides good evidence that a very small amount of time spent running faster improves fitness. It also decreases blood pressure and makes routine running more efficient. In the study, the addition of an interval program of faster activity, performed twice a week, was not only well tolerated but study subjects stuck with it and benefited more than they did from other seemingly more difficult programs.

In the Danish program, a short warmup is followed by two five minute segments separated by a 2 minute rest, and followed by a short cool-down walk or run. The five minute segments consist of running comfortably for 30 seconds, harder for another 20 and as fast as possible for another 10 seconds, and repeating this pattern 4 more times. A walker could try the same pattern, with effort judged by breathing rate and difficulty and by the ability to complete the 5 minute segments. As improvement occurs the segments cover more distance.

Change the terrain

Other ways to increase effort include walking or hiking uphill and climbing stairs. The important thing is to build in some segments of exercise that require more effort and cause faster breathing into at least two periods of exercise a week. In addition, going “off-road” on dirt and rock and sand requires use of little balancing muscles and improves strength and balance.

How much is enough?

How much weekly exercise is necessary? One figure quoted frequently is 150 minutes – less than half an hour a day. The payoffs though, depend on demanding more of the heart and lungs during those times than during routine life. Ambling up the street at the same pace as you walk between the couch and the TV will have less effect than but walking briskly, to the point of feeling slightly short of breath.

Can people who have arthritis walk and run for exercise? For the most part stiff joints feel better with movement. If walking or running gets easier as the joint is “warmed up,” the joint stiffness and discomfort are most likely related to shortened muscles and tension on their tendons, not to joint pathology that will get worse with activity.

Make sure you remain able to get up and down from the ground

For overall fitness, some time also needs to be devoted to strength and flexibility exercises. Pilates exercises, yoga practices, weight lifting and core muscle strengthening exercises like the TRX programs all improve muscle strength and flexibility, enhance walking and running ability and contribute to improving balance. The ability to get up and down from the ground indicates a lot about these non-cardiovascular aspects of fitness, and every effort should be made to make certain this ability is preserved over time.

Mind over matter

The most difficult part of beginning or sticking to an exercise plan is often in the mind rather than the muscles. When Karl says his friends didn’t need to stop hiking, he means that they stopped pushing themselves before there were any compelling physical reasons to stop, and then one day they no longer had the ability which he has so far maintained. His example is inspiring.

Alzheimer’s Disease: A Power Failure?

Like Willy Sutton, the bank robber famed for his explanation of why he robbed banks (because that’s where the money is),  Alzheimer’s disease researchers have aimed most of their efforts at the well-known, visible pathology of the disease, the collections of debris scattered among the dying cells in the brains of patients suffering from the dementing illness.  Made of a protein known called beta-amyloid, these plaques are the cause of the progressive death of brain cells and consequent loss of mental function – or so it has been thought.  Research focus on amyloid plaques has been disappointing, though, yielding neither effective treatments nor preventive strategies.  Moreover, the dramatic rise in the incidence of Alzheimer’s disease (AD), from 2% of people over age 85 in 1960 to 50% in 2000 indicates that something else is in play, something other than bad genetic luck that supposedly causes beta-amyloid to accumulate and nerve cells to die.

Energy production in the brain

As attention has turned to other potential causes of AD, older research findings seemingly unrelated to AD have assumed new importance, particularly discoveries related to brain energy metabolism. The preferred fuel for the brain is glucose. Until the 1980s, researchers thought that the brain, unlike other organs, did not need use the hormone insulin to allow glucose to enter its cells. But in the 1970s insulin receptors were discovered in brain cells and insulin was found in the spinal fluid, implying that the brain did indeed use the hormone. Because progressive resistance to insulin and difficulty getting glucose into cells to provide energy are the hallmarks of type 2 diabetes, and because the rise in AD incidence paralleled rising rates of type 2 diabetes in the last few decades, researchers began to wonder if AD might be rooted in insulin resistance and impaired energy production in brain cells. Insulin resistance in the brain might also explain the results of glucose metabolism studies in the brains of people at high genetic risk for AD, showing as much as 25% decrease in the use of glucose in areas concerned with memory and learning – long before any symptoms suggestive of AD have appeared.

Insulin resistance

By 2005, the idea that insulin resistance in the brain plays a significant role in the development of AD gained traction. Since not all type 2 diabetics get AD and not all AD patients have type 2 diabetes, insulin resistance cannot be the sole cause of AD. But a high blood insulin level is one of the two biggest risk factors for the disease. The other is a genetic factor – the gene for the E4 version of a protein called apolipoprotein B (apoB). Like insulin, apoB’s function is moving the building blocks for energy production into place in the various cells of the body.  ApoB is like a delivery vehicle, packed with fats and cholesterol which are necessary for building the cellular machinery in the brain and providing fatty fuel for use when glucose is unavailable.

The tie between glucose, insulin and amyloid

Does impairment of glucose metabolism in the brain have any relationship to the classic pathological components of the disease – the amyloid plaques littering the brain, the destruction of nerve cell architecture, and the non-specific inflammatory changes? There are tantalizing clues.  In the brain amyloid protein is a normal waste product. What is not normal is its accumulation in clumps around nerve cells. Beta-amyloid is usually broken down by an enzyme called IDE, insulin destroying enzyme. IDE breaks down insulin much more readily than it does amyloid proteins and when insulin is present in high amounts, the amyloid waits longer to be cleaned up and precipitates out of solution, forming clumps.  Uncleared amyloid also prevents insulin from attaching to nerve cells to let more glucose in, depriving them of fuel.

Competition for IDE may not explain beta-amyloid accumulation completely, but it is a link between insulin, glucose metabolism and AD. In addition, high levels of glucose in all parts of the body prompt the development of abnormal collections of proteins/glucose combinations called advanced glycation products which trigger inflammatory damage to tissues in all organs. The brain is no exception.

A link between poor sleep and AD?

Sleep is another subject beginning to gain attention in the prevention and treatment of AD. Lack of good sleep contributes to the development of the metabolic syndrome, including type 2 diabetes, though disruption of normal hormonal rhythms.   In normal people and in people with sleep apnea, sleep deprivation produces measurable impairments in working memory, thinking speed, attention, vigilance, and higher cognitive functions – the same functions affected by dementing illnesses such as AD.

Reasons for optimism 

Do changing theories about AD have any practical consequences?  Indeed. First, there is more reason for optimism about the future. If AD rates have risen because of changing dietary habits and lifestyles, we can change them again. The factors known to produce the metabolic syndrome are weight gain, lack of exercise and poor diet. Regular exercise is recognized as a deterrent to the development of AD. Some people are beginning to feel that the low fat dietary recommendations must also be changed since they have resulted in diets high in processed foods and carbohydrates, and low in foods with high amounts of antioxidants which counter inflammation. Fat metabolism, abnormal in the metabolic syndrome, is also important in the brain, which contains 25% of the body’s cholesterol. It needs sufficient healthy fats in the diet for normal function.

The second practical implication of the changing view of AD is the application of known drug treatments for type 2 diabetes, both for attempted prevention and for treatment of AD. Clinical studies in AD patients are already under way, using medications that improve insulin resistance.  Intranasal insulin has also been tried. It is delivered directly into the brain, without fear of lowering body glucose levels and has shown some promise in improving AD symptoms. These approaches are entirely new and evidence of shifting focus in research. If Willy Sutton were an AD researcher he would be changing his targets.

    Terminal Lucidity and Lucid Intervals

    Caregivers of Alzheimer’s patients have long reported episodes of the patient returning briefly to “themselves,” for periods of hours to days. Some dramatic cases  of such returns have been reported in the terminal phases of life. All of these cases have fallen into the “we don’t know why that happens” category of clinical observations.  The concept of brain cells failing to function because of lack of energy is one that fits the appearance of lucid intervals better than a theory of the disease that implicates cellular destruction alone as the underlying cause of symptoms.

Arch Gerontol Geriatr. 2012 Jul-Aug;55(1):138-42. doi: 10.1016/j.archger.2011.06.031. Epub 2011 Jul 20. Terminal lucidity: a review and a case collection.
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