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LE Magazine February 2004
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The “Hidden” Liver Disease
By Penelope Hamil

Most people take liver health for granted. After all, the liver is one of the body’s most resilient organs and the only one capable of regenerating itself. Regrettably, most doctors are unaware of a liver ailment that strikes a significant portion of the population.

It is called nonalcoholic fatty liver disease. Researchers say it has become the most common liver disorder in the United States, affecting an estimated 24% of us, according to a recent study at Johns Hopkins University School of Medicine.1 What’s even more frightening is that, like diabetes and hypertension, this usually silent liver condition sneaks up and can cause life-threatening health problems years down the line.

If staying alive were easy, everyone would be doing it. People usually associate liver disorders with alcoholism or viral hepatitis. The facts reveal that nonalcoholic fatty liver disease is the villain that will most likely attack your liver
The only encouraging piece of news is that this common killer is largely preventable, and can even be reversed if caught in time. In this article, we enlighten members to the destructive effects of nonalcoholic fatty liver disease and innovative steps they can take to prevent or reverse this common hepatic disorder.

The words “nonalcoholic fatty liver disease” describe this condition well: an accumulation of fat in the liver, making up at least 10% of the organ2—in people who drink little or no alcohol. The latter distinction is an important one, say experts, because in the past, fat buildup in the liver has typically been associated with alcohol abuse. Nonalcoholic fatty liver disease is the name given to a broad spectrum of liver disease that encompasses several stages of hepatic pathologies.

The Three Basic Stages
of Nonalcoholic
Fatty Liver Disease

1. simple fatty liver (also called steatosis), which was formerly considered a benign condition characterized by a buildup of fat in the liver, but now has been determined to be a prognostic indicator for the treatment of hepatitis C.

2. nonalcoholic steatohepatitis, in which the fatty buildup in the liver has progressed and developed inflammation (hepatitis) of the liver, as well as scarring (fibrosis).

3. cirrhosis, in which the scarring of the organ is advanced, irreversible, and even life threatening.

Who’s at Risk?
The typical person with nonalcoholic fatty liver disease is in his or her fifties, but the disease strikes people of all ages, including children.3-5 A new study finds that 65% of people over 80 years of age have nonalcoholic fatty liver disease. In this octogenarian population, gender, body weight, and lipid profile did not significantly affect the disease’s incidence. The authors suggest that nonalcoholic fatty liver disease “may reach a point of being irreversible in the elderly, despite an age-associated decline in weight and lipid levels.”6

Nonalcoholic fatty liver disease is much more prevalent in obese and diabetic people than in the general population. An estimated 90% of obese people are at risk for the development of chronic liver injury.7 Moreover, about half of the estimated 16 million Americans with type II diabetes have nonalcoholic fatty liver disease.8 Combine obesity and diabetes, and a person’s risk climbs even higher: just about all of those with both conditions have some degree of nonalcoholic fatty liver disease,9 almost half have nonalcoholic steatohepatitis, and 20% suffer from cirrhosis.8

Even more important than the fact that a person is obese is where excess fat is stored on the body. Research has shown that people who carry excess weight around their middle (abdomen or waist) are most prone to developing insulin resistance. And recent studies have revealed that the majority of people with nonalcoholic fatty liver disease have central (abdominal) obesity.10,11

What’s Behind the Problem?
Nonalcoholic fatty liver disease is known by its acronym, NAFLD. It is a condition characterized by steatosis (fatty liver), inflammation, insulin resistance, and the presence of fibrosis. NAFLD can evolve into cirrhosis, liver failure, and cancer.

The pathogenesis of NAFLD is not well understood. Production of tumor necrosis factor-alpha (TNF-a) has been reported to be one of the early events in the many types of liver injury, and together with other TNF-a-dependent cytokines (inflammatory messengers), it may mediate a process of chronic liver injury.

During chronic liver injury, proliferation and migration of activated hepatic stellate cells are involved in the pathogenesis of hepatic fibrosis. Recent studies have demonstrated that oxidative stress stimulates production of collagen, which drives the development of fibrosis. Hepatic stellate cells are the main source of the abnormal collagen-derived extracellular matrix material that represents the biochemical hallmark of the disease process.
In recent years, a nutrient called polyenylphosphatidylcholine (PPC), a polyunsaturated phospholipid extract from soybean that inhibits stellate cell proliferation, has emerged as a promising agent for the treatment and prevention of liver cirrhosis and steatosis.12

Hepatitis, inflammation of the liver, showing disarray of the hepatocytes or liver cells.

Dyslipidemia (high LDL and triglycerides; low HDL), insulin resistance, and other components of the metabolic syndrome (see sidebar, on p.56, “The Syndrome X Connection”) increasingly are recognized as being associated with NAFLD. Adding weight to the theory that insulin resistance plays a leading role in the development of a fatty liver is that high insulin levels have been shown to block the oxidation (burning off) of fat in liver cells (hepatocytes), contributing to the buildup of harmful fatty acids and triglycerides in the organ.13-15 In fact, triglyceride fat is the very type of fat stored in tiny sacs inside a fatty liver.7 High concentrations of fatty acids (which help produce the triglycerides that can build up in the liver) are not only toxic to liver cells, but also may be directly tied to the oxidative stress that leads to the inflammation and scarring in the second stage of NAFLD.13,16 A recent study shows that 58% of patients with severe hypertriglyceridemia had elevated liver enzymes indicative of nonalcoholic steatohepatitis.17 Intriguingly, as we will see later, PPC has shown potent triglyceride reductions in human clinical studies.

A new study shows that insulin resistance is associated not merely with NAFLD, but with its more serious form, nonalcoholic steatohepatitis. The study employed a measure of insulin resistance known as the homeostatic model assessment (HOMA), which is calculated as the fasting insulin level times the fasting glucose level, divided by 405 (for blood tests reported in US numerical units; for European numerical units, divide by 22.5 instead of 405). A HOMA level greater than 2.2 indicates insulin resistance. Patients with simple fatty liver (steatosis) had an average HOMA level of 1.61, whereas patients with nonalcoholic steatohepatitis averaged 3.67 and were therefore insulin resistant.18 As noted earlier, dyslipidemia, including elevation of triglyceride levels, insulin resistance, and other components of the metabolic syndrome increasingly are recognized as being associated with NAFLD.

Micrograph of tissue showing cirrhosis of the liver, in which fibrous septa (membranes) divide the hepatic parenchyma into nodules and regenerative nodules develop in the surrounding hepatocytes.

Signs, Symptoms, and Complications
Most people with NAFLD have no obvious symptoms, even when the disease has progressed to non- alcoholic steatohepatitis.8 Doctors report that in some cases, patients may raise very bland or general complaints such as fatigue and malaise that could be attributed to any number of common ailments. A minority of people with NAFLD may experience an occasional sensation of fullness or a vague, dull pain on the right side of the abdomen, just below the rib cage.

If the disease progresses to the more-advanced cirrhosis stage, however, a patient can suffer any number of symptoms, including blotchy red palms, prominent veins on the abdomen, star-shaped spider veins on the upper torso, thinning hair, swelling of the legs (edema), abdominal fluid retention (ascites), and even mental confusion, as well as irregular or absent menstrual periods in premenopausal women and enlarged breasts (gynecomastia) in men.7 Studies show that as many as 20% of patients with nonalcoholic steatohepatitis may progress to cirrhosis within a 10-year period,19,20 and 3% may progress to liver failure, eventually requiring liver transplantation.21 Because cirrhosis is typically diagnosed so late in NAFLD patients compared to those with other chronic liver diseases, it is more likely to be fatal.22 And compared to simple fatty liver sufferers, patients with advanced nonalcoholic steatohepatitis are more than 10 times more likely to die from the disease.23,24

Most worrisome is mounting evidence that nonalcoholic steatohepatitis can progress to hepatocellular cancer (liver cancer). A new study finds that Ki-67 staining, a marker of liver cell proliferative activity, is virtually absent in the normal liver but is seen in 54% of fatty liver patients and in 100% of nonalcoholic steatohepatitis patients. In nonalcoholic steatohepatitis, the Ki-67 index correlates with grades of necro-inflammation in the liver.25

How Is NAFLD Diagnosed?

Because NAFLD is usually asymptomatic, a doctor generally will first suspect NAFLD when liver function tests during routine blood work show that a patient’s liver enzymes (in particular, alanine aminotransferase, or ALT) are mildly to moderately elevated. Studies show that as many as 29% of adults fall into this category.43 But because people who do not have NAFLD may have elevated ALT levels, and because the disease also may be present whether or not a person has elevated enzyme levels44—NAFLD is found in as many as 30% of people with normal ALT levels45—further laboratory testing is always necessary.

The next step in the diagnosis process usually is to screen the liver by ultrasound (sonography), which uses harmless sound waves to show images of the organ. When a large amount of fat has accumulated in the liver, it may show up as enlarged and will appear “brighter” than the kidneys on the ultrasound screen;46however, moderate amounts of fat may not be detected by an ultrasound screening. A computed tomography (CT) or magnetic resonance imaging (MRI) scan also may be used, but most doctors opt for ultrasound, as it is less expensive and does not expose the patient to radiation. Although these tests can suggest that a patient has NAFLD—mainly by excluding other liver diseases and conditions (such as biliary tract disease and focal liver disease) that also can elevate levels of liver enzymes—they cannot give a definitive diagnosis or determine the stage of the disease.33,47,48

The only way to confirm a diagnosis of NAFLD—and to gauge the severity of inflammation, fibrosis, or cirrhosis—is a liver biopsy,33,3,21 in which a needle is inserted into the liver to remove a sample of tissue that is then examined under a microscope. (In a fatty liver, numerous large round white sacs, or fat vacuoles, will be visible to the lab technician.) Yet many doctors are reluctant to recommend biopsy as a mean of diagnosing or assessing the degree of NAFLD, because like any surgical procedure, it carries the risk of complications, including bleeding and infection. Moreover, as there is no proven specific treatment for the disease, having a definitive diagnosis via biopsy is not very likely to affect the management of the disease in a particular patient.49

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