Knowing the score: Identifying patients at high risk of liver fibrosis from Non-Alcoholic Fatty Liver Disease (NAFLD)

Bass, Nathan M., MD, PhD
Professor Emeritus of Medicine
Former Medical Director, UCSF Liver Transplantation Service
Division of Gastroenterology
UCSF Medical Center and School of Medicine Also by this Author 

Non-alcoholic fatty liver disease (NAFLD) affects up to a third of the general population. Patients with its more severe form, nonalcoholic steatohepatitis (NASH), are at significant risk for developing end-stage liver disease. Strongly associated with obesity and type 2 diabetes, the prevalence of NAFLD is increasing in the United States and constitutes a growing health concern.

Dr. Nathan M. Bass, Professor Emeritus of Medicine, Division of Gastroenterology, UCSF Medical Center and School of Medicine, discusses the pathology and clinical significance of NAFLD, approaches to identifying the disease and the clinical utility of the NAFLD fibrosis score to identify those with more advanced fibrosis, most in need of close monitoring and intervention.

Defining NAFLD

“The first notable thing about NAFLD,” says Dr. Bass, “is that it’s defined by what it isn't.  This reflects how the disease was initially recognized, when physicians at the Mayo Clinic observed a cohort of patients who presented with liver disease. Liver biopsies from these patients had the appearance typically associated with a very severe liver lesion that can result from heavy alcohol abuse, called alcoholic hepatitis.  When the liver biopsies were examined under a microscope they exhibited particular features: fat in the liver cells; inflammation; evidence of damage to liver cells.  In addition, there was a varying amount of fibrosis, from very mild or absent, to very advanced, or even cirrhosis.”

“So this is clearly a disease that looked very much like the lesion of severe alcohol abuse. It clearly could progress to the most advanced stages of the disease and, as we also recognize now, it can also advance to liver cell cancer.  But the surprising thing was that the cohort of individuals were largely middle-aged women who were obese, with a high prevalence of type 2 diabetes, but their alcohol consumption was zero to negligible.  So they recognized this is a liver disease that is associated with obesity and type 2 diabetes in the absence of significant alcohol exposure, and hence the name non-alcoholic fatty liver disease.”

Distinguishing the Two Forms of NALFLD – NAFL and NASH

The majority of patients with NAFLD only have accumulation of fat in their liver. This represents the most benign end of the NAFLD spectrum and is sometimes referred to as non-alcoholic fatty liver or NAFL. Most patients with NAFL retain this histological pattern for most, if not all, of their lifespan. “In a smaller group of patients,” notes Dr. Bass, “fat in the liver is associated with inflammation and liver cell damage – what is referred to as a necroinflammatory lesion. The appearance of this lesion is very similar to that seen in alcoholic hepatitis. This condition is therefore termed non-alcoholic steatohepatitis or NASH.”

Disease Progression

“Who will ultimately develop a more severe manifestation of NAFLD (i.e., NASH) is one of the most important questions to address,” says Dr. Bass. “The current estimate is that disease will progress in up to 30% of patients with NAFLD. Some individuals with a particular risk profile, typically including obesity and diabetes, will go on to develop the necroinflammatory condition of NASH from the outset.”

The progression of NAFLD to fibrosis, cirrhosis, and the complications of cirrhosis, including liver cell cancer, portal hypertension, liver failure, and indications for liver transplantation, are thought to occur in about 20% of patients with NASH. So, the greatest concern with NAFLD is that there is a sub-group who can develop a necroinflammatory lesion, which can, in turn, progress to cirrhosis and is attended by serious medical consequences and mortality.

Risk Factors and Prevalence

The key risk factors for NAFLD - obesity and type 2 diabetes - are linked to the metabolic syndrome, sometimes also referred to as the insulin resistance syndrome. Insulin resistance plays a central role in the pathogenesis of a number of complications of obesity, including type 2 diabetes, cardiovascular mortality, higher risk for the development of a variety of cancers, and a higher risk for the development of fatty liver disease. 

Because of the rising incidence of obesity in the U.S. it’s estimated that 30% of the general population may have NAFLD, and that between 5% to 15% have NASH. “In a clearly obese population NAFLD will be present in at least double that number - in 60%,” notes Dr.Bass.  “Proportionally, the risk of NASH appears to be higher in this group, so half of that population will have a more severe lesion of NASH. The same applies to those with type 2 diabetes, in whom the prevalence of NAFLD is thought to be around 75%, with half of those having NASH.  So the obese and diabetic populations are not only at much higher risk for the development of NAFLD, but also for progressing to NASH.”

There are some other, less common, associations to recognize. These include polycystic ovarian syndrome, hypothyroidism, hypopituitarism and hypogonadism.  Sometimes obstructive sleep apnea is included in this group, but this is a complex association.  Obstructive sleep apnea is associated with obesity and it's associated with insulin resistance, so it forms part of a complex pattern of associations in which the liver is commonly found to be affected with NAFLD.

NAFLD, Cardiovascular Disease and Type 2 Diabetes. Cause and Effect?

“There's one more association that I think is very important to understand,” notes Dr. Bass. “NAFLD clearly has a very strong association with two complications of the metabolic syndrome: the risk of cardiovascular disease, and the risk of developing type 2 diabetes. The question is whether this is a predictive association.”

Recent studies have established that there are strong and independent associations of NAFLD with a variety of factors that are predictive of cardiovascular risk and of the risk of cardiovascular incidents.  What is unclear at this point is the nature of this association - is it actually causative? This is a very important question because firstly, it clearly shows that patients with NAFLD need to be particularly followed and investigated for cardiovascular risk and require at least some counseling with respect to that. Secondly, there is a possibility that improvement in NAFLD may, in fact, positively benefit patients in terms of cardiovascular outcomes in the future.”

“There are similar questions relating to the association between NAFLD and type 2 diabetes.  Is there a cause and effect between the non-alcoholic fatty liver and the risk of diabetes? Clearly patients with NAFLD appear to have more severe type 2 diabetes which is often also more difficult to treat in the presence of NAFLD.” 

Identifying NAFLD

Identifying NAFLD can be a challenge, as very often the condition is silent from a clinical standpoint, explains Dr. Bass.  Liver disease very typically does not manifest itself until a very advanced stage when the symptoms are those of a complication.  NAFLD may be suspected in patients who are overweight to obese, particularly if they also have type 2 diabetes. If they have evidence of the metabolic syndrome, the risk of NAFLD increases, and if those patients meet true criteria for metabolic syndrome they are often more likely to have the histological lesion of NASH as opposed to simply fat in their liver cells.  Patients who have fatty liver disease often complain of non-specific symptoms which may be associated as much with their obesity, as with NAFLD itself, such as fatigue.

NAFLD may be identified during routine liver function tests or as a result of an abdominal imaging study. In women, it can be picked up during an ultrasound examination performed as a part of a gynecological examination. In terms of actual findings on physical examination, the liver may be enlarged; one may see dermatological lesions associated with insulin resistance on the skin examination.

For the most part, however, the suspicion of NAFLD is going to depend upon initial laboratory tests, an imaging study, usually an ultrasound, and an exclusion of other causes of liver diseases.  The first and most important of these is the patient’s alcohol history. It's also important to take a drug history because medication can certainly result in liver injury and abnormal liver tests, and some can even give rise to a liver histology pattern that appears very much like steatohepatitis.

Laboratory Testing

“The standard laboratory test abnormalities in NAFLD correspond to a liver panel that evidences what is usually a very mild injury pattern,” notes Dr. Bass. “In other words, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) will be elevated, but usually to a very modest degree. The alkaline phosphatase is almost always normal in uncomplicated NAFLD.  In fact it’s increasingly recognized that there are a lot of individuals with NAFLD who have liver function tests, specifically ALT and AST, that are within the laboratory normal range. The second set of laboratory tests which are useful at this point are those used to exclude other causes of liver disease. The most important of these would include the chronic viral hepatitis suspects - hepatitis B and hepatitis C, -and excluding genetic hemochromatosis. There are also certain autoimmune liver diseases that one can readily exclude on the basis of the pattern of liver function test abnormalities and also the presence of autoantibodies and abnormal immunoglobulin patterns.” 

NAFLD Fibrosis Score

Following a diagnosis of NAFLD, it is most important to assess its severity, to determine which individuals are at risk for developing cirrhosis and its complications.  These are the patients to follow more closely and in whom some intervention may be important. Patients who have more severe liver disease, particularly those who have developed more advanced fibrosis, are at the highest risk for death, not only from liver related causes, but from cardiovascular disease as well.

A liver biopsy is the gold standard for providing detailed histological information about the liver but it is impractical and costly to perform biopsies on all those with NAFLD, and there are associated risks. “So the search has been on for quite some time now for a non-invasive means for determining the stage of fibrosis in a patient's liver,” says Dr. Bass.

The current recommendation of American Association for the Study of Liver Diseases (AASLD), American College of Gastroenterology (ACG), and the American Gastroenterological Association (AGA) is to obtain a fibrosis score to identify patients at risk for having more advanced fibrosis. “The NAFLD fibrosis score is one of many fibrosis scores that use a variety of variable inputs,” explains Dr. Bass. “Its advantage is that it uses some fundamental, simple variables for input: age, body mass index, fasting blood glucose, platelet count, albumin, AST and ALT.  Results from these tests are entered into a formula that yields a score that then indicates the probability of an individual having more advanced fibrosis. It uses easily obtainable clinical and laboratory variables, which are available as a panel. Other benefits of the score are that it is the most extensively validated, non-invasive fibrosis score available for NAFLD. This is reflected in the fact that the AASLD, ACG and AGA guidelines, recommend it as a routine assessment.”

The fibrosis score helps to identify those patients to refer for specialist evaluation that may include using a radiological technique, such as sonographic transient elastography,  or a liver biopsy to confirm or complement the assessment of the patient's risk of having advanced fibrosis. This is the population at highest risk of developing complications of liver disease that needs to be identified for closer follow-up and further evaluation.

“There have also been some recent studie showing that the score is not only a useful assessment of the risk for advanced fibrosis, and by that we really mean bridging fibrosis (stage 3), or cirrhosis (stage 4),” continues Dr. Bass.  “But it also has a very strong correlation with the risk of death in this patient population. We do recognize that the stage of fibrosis is probably the most important predictor of future mortality from liver disease in this population, and so, as may be expected, the NAFLD fibrosis score is a predictor of mortality in the NALFD population as well, and probably one of the better ones that has become available over the past few years. It’s established itself as the preferred assessment tool because it’s convenient, accurate, extensively validated, cost-effective and completely safe. It’s a useful tool to help clinicians identify the patients with more severe disease in whom intervention may be important.”