The Challenge of Diagnosing NASH

One of the most frustrating parts of the NASH pandemic is that most people suffering from it have no symptoms and absolutely no idea there is even an issue.  Part of the reason for this lack of awareness is because there is no truly definitive way to diagnose NASH other than an invasive biopsy of the liver.

A primary goal of many biopharma companies working on NASH today is not only to find a cure but also to develop non-invasive tests that can conclusively diagnose the disease.  This is important because even with everything that is known about the widespread precedence of the disease routine screening is still not recommended due to uncertainty and costs.  It’s vital that we reach a point where an effective screen for NAFLD/NASH is in widespread use to combat the incidence of the disease.

So how do doctors today determine if someone has NAFLD or NASH?  Here’s everything you need to know.

Physical exams:

There are distressingly few physical symptoms or indicators of NALFD or NASH in early stages (aside from general obesity, which is by no means a guarantee of NAFLD/NASH).  Upper right abdominal pain (pain in the location of the liver) is the most common symptom, but only a small portion of patients ever report it.  Indicators of insulin resistance similar to Type II Diabetes have also been observed; this is darkening of skin over knuckles, knees, and elbows.  Jaundice (yellowing of the skin and eyes) is another symptom, but often not present until later stages where irreversible damage is already present.

None of these symptoms are uniquely correlated to NAFLD/NASH.  You may have all of them and have a perfectly fine liver, or you may have none of them and have cirrhosis.  If you do have any of these indicators and display other risk characteristics such as obesity, your doctor may proceed to more conclusive forms of diagnosis.

Imaging Tests:

ct scan
Fatty vs healthy liver CT Scans. Note the visible dark bumps on the lower left that represent fat deposits

Various types of standard imaging tests such as ultrasound, CT scan, and MRI, can tell with relatively high levels of confidence if there is fat in the liver, but cannot detect other symptoms such as inflammation or fibrosis.  As such, they can generally detect NAFLD but cannot easily differentiate NASH.  They can in some cases detect very advanced NASH where cirrhosis is present.

A type of test known as MRE (magnetic resonance elastography) is a better diagnostic tool for detecting fibrosis.  It combines an MRI with a tool that introduces sheer waves via vibration into the body to accurately measure stiffness and hardiness of various organs.  It is increasingly being used to diagnose NASH.

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Fibroscan uses a combination of ultrasound and vibrations to determine if fibrosis is present, and how severe it is

A newer ultrasound technique called transient elastography is similar to a MRE and can be reliably used to detect fibrosis and cirrhosis of the liver and is easy to administer in a doctor’s office.  Commonly known as Fibroscan after the device used to perform the test, it is a simple non-invasive procedure that uses a combination of ultrasound and low frequency tissue vibration to detect liver stiffness (check out this cool explanatory video).  It has become an increasingly valuable tool in liver diagnosis and the results can be interpreted using the scoring scale below.

fibroscan score

The challenge with all of these methods, even the newer Fibroscan, is that they are not part of any normal screening process.  They would only be administered if a doctor has sufficient reason to suspect liver disease.

Blood Tests:

While there is currently no single “NASH test” (though many companies are working on it), there are a number of different blood tests that can be used to assist with diagnosing NASH.  I’m not a doctor so I will simplify the concepts below, and point you to this comprehensive medical overview of all of the non-invasive tests currently available for more information.

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Generally, blood tests are used to detect a combination of general diagnostics, NASH-specific biomarkers, and other lab work in order to make a predictive model that is used to determine whether a biopsy is required.  There are dozens of such models but the problem is that while all show promise they still have higher inaccuracy rates than desired.

Liver enzymes such as AST, ALT, and bilirubin are commonly measured.  Analysis of the AST/ALT ratio is commonly used as a means to refer patients for more intensive screening, but the preponderance of the evidence shows that they are less than reliable and prone to false-positives.  Elevated bilirubin levels are frequently associated with advanced liver disease, but there are also many instances where no liver disease was present.  In children, there is even evidence that lower bilirubin levels are an indicator of NASH.

There are a number of biomarkers (see definition here) that are associated with NASH, especially when used in combination with other types of tests to produce a composite predicative model.  The most common ones are certain cytokines, adipokines, and keratins (specifically K18).  Collectively these biomarkers are grouped into categories such as markers of inflammation, oxidative stress, and apoptosis (cell death).  They are not indicative of any specific result by themselves.

Grouping these types of results together with other risk factors and secondary causes of NASH is known as a predicative test, and there are more than a dozen of them under research.  Some of the most popular tests are known as HAIR, BARD, NFS, FIB4, and Fibrotest, but there are many others and more being introduced all of the time.

Unfortunately, none of these tests by themselves are conclusive without a follow-on biopsy, which is not without risk.  While they are useful diagnostic tools they do not fulfill the promise of a true definitive non-invasive test for NASH.

Liver Biopsy:

If a doctor suspects that NASH may exist based on any of the aforementioned methods of diagnosis, they will order a liver biopsy.   In this procedure a small amount of liver tissue is removed from the body and physically examined to make a diagnosis.

Liver-Biopsy4

This procedure has many drawbacks; it is invasive and can be painful, it can cause serious complications in 1 to 3% of patients, and even death in 0.01% of cases.  Furthermore, while considered the gold standard for NASH diagnosis, it is not infallible and in fact some studies show that it can miss diagnosing NASH in up to 25% of samples.  Even when it does detect NASH it can misdiagnose the degree of fibrosis severity up to a third of the time.  This is largely due to the fact that the liver is a very large organ, and NASH symptoms do not always present uniformly throughout it.  Therefore when taking a relatively tiny sample for biopsy there exists a higher than desired chance that the sample will not be indicative of the larger mass.

The holy grail:

The ultimate goal of ongoing research into NASH diagnosis is a simple blood-drawn test that can diagnose NASH effectively enough to be placed into routine screening for anyone considered at risk.  This could then be paired with the results of the current race to discover the first medical treatment for NASH to provide for early detection and treatment of NASH.

With potentially 30 million mostly-unaware American’s living with NASH today, the race can not end quickly enough.

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