The “Hidden” Liver DiseaseFebruary 2004
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 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.
Who’s at Risk?
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?
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.
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.
Signs, Symptoms, and Complications
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