WHAT IS KNOWN ABOUT NASH

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INVENTORY


All the experts of liver disease agree that there is a rapid development of this disease, but they are not all agreed on its exact definition nor on the criteria to be used to formally identify the disease. Furthermore, there is debate about the protocol for diagnosis. Indeed some would recommend widespread testing to track the evolution of the disease  more accurately whereas others argue on the utility of tracking the disease disease when no treatment currently exists.

Moreover, the causes of the disease, even if they are strongly correlated to obesity and excessive consumption of sugar are, as often in metabolic diseases, multi-factorial. Genetic or epi-genetic predisposition are obvious and certain ethnic groups such as Hispanics are clearly more exposed to it.

Similarly, the consequences in terms of morbidity of the disease are not fully understood. Cardiovascular diseases appear by far to be the leading cause of death in the NASH population although it has not been established that such deaths are a direct consequence of NASH or that of a common clinical pathology.

In light of recent published studies, it seems that the truth is somewhere in between. The fertile ground for the development of NASH is also clearly conducive to the occurrence of cardiovascular disease, which may explain the correlation. But in terms of arteriosclerosis, it appears that metabolic disorders induced by NASH also have a direct effect on the increase in coronary deposits which increases the risk of cardiovascular events.

Liver fibrosis and end-stage cirrhosis is  one of the other well-documented consequences of the disease. It can lead to a cessation of liver function which requires a transplant or can lead to liver cancer, a process already well known in the case for viral or alcoholic cirrhosis.

But again this mechanism is not the only one. It appears that 40% of patients with NASH who develop liver cancer do not have cirrhosis, so there would be an unsolved mechanism where NASH leads directly to cancer  without passing by the fibrosis box …


MECHANISMS ET DIAGNOSIS

To try to translate what I understand of the disease and its mechanisms (please note that I am not a researcher or physician) I will quickly summarize the disease mechanism as I understood it.

Following a number of factors, environmental, genetic, nutritional, etc, a significant portion of the world population has started to develop what is called a NAFLD (Non alcoholic fatty Liver disease), a fatty liver that stresses liver cells and disrupts the metabolism of the liver. This disease is clearly associated with a significant increase in cardiovascular risk.

Here is the based supposed prevalence of NAFLD in the general adult population regarding last publications.



Of these patients, a proportion will develop a more advanced pathology, NASH (nonalcoholic steatohepatitis), this condition is the result of inflammation of the liver cells due to stress-induced NAFLD. This inflammation leads to degeneration of liver cells (ballooning), to portal inflammation and then in a second stage, to fibrosis, which is  the appearance of scar tissue replacing dead liver cells. When this fibrosis increases, we can reach an almost irreversible stage of scar tissue which occupies so much of the liver that it can no longer function properly. This is cirrhosis that has a very serious prognosis for the patient.

It is important to note that we are dealing with a cascade of consequences of the same disease that begins with NAFLD and progressively gets worse though evolution to the next stage.

NAFLD -> NASH -> Fibrosis -> Cirrhosis

Another factor not described here is the intimate relation between the described pathologies and type 2 diabetes which can be one of the causes of fat accumulation in the liver but also a consequence of the increase of insulin resistance tissue induced by the metabolic disorder of the liver as a result of NASH.

This all adds up to a vicious circle where diabetes worsens the NASH which in turn aggravates the diabetes itself... It is the complexity of the metabolic syndrome in all its splendor.

To try to define from when NAFLD becomes NASH, a score system called the NAS score has been initially proposed (it is worth noting that this scoring system was established for untreated patients)

This score is based on a histological analysis of liver biopsy studied microscopically. In this evaluation, three parameters are considered:
Steatosis on a score of 0 to 3
The lobular inflammation with a score of 0 to 3
The ballooning (cell degeneration) on a score of 0 a2


The NAS score (on a scale of 0 -8) is the sum of these 3 notations.  NASH was considered positive when the NAS score is greater than or equal to 3 with at least one count in each of its three sections.

This scoring system is not perfect. During NASH symposium, when the inventor of the NAS score was questioned on what would be his priority to qualify for NASH he answered “ballooning and portal inflammation”. However only one of these parameters is considered directly in the NAS score.

This seems logical to me.. Obviously steatosis is a prerequisite for NASH but as is common in the previous stage that is the NAFLD, it is not a discriminating factor between NAFLD and NASH.

Ballooning (or cellular degeneration) seems to be one of the central factors of markers of the disease
The portal inflammation does not appear to systematically correlated with lobular inflammation according to some studies that I have read. It is the sign of an advanced phase of the disease and should therefore be specifically monitored.

During the AADSL meeting  mid November 2015 the evolution of the consensual definition of NASH  was confirmed. The definition integrate now balloning  scores  and inflammation scores .

NASH is now characterized by:

balloning score> 0

inflammation score> 1




stricto sensu we could imagine a NASH without steatosis . 

One consequence of NASH is the appearance of liver fibrosis which in turn is measured by a score (fibrosis score) that goes from F0 (no fibrosis) to F4 (cirrhosis).

The best graphic explanations of the mechanism of NASH are on the site of Tobira Therapeutics and reversed below.

what is NASH


mechanisms of NASH


(The two graphics are extracted from the Tobira Therapeutics web site)



TREATMENT STRATEGIES

All of these factors have an impact on the expectations of the scientific community concerning medication for the treatment of NASH. 

In the light of the previous diagrams we can outline the ideal drug profile
- it must be active at the origin of each of the links in the chain since each link is a complication of the previous link
- it must not aggravate the risks known to be directly related to the disease (CVD, diabetes)
- it must block the progression to fibrosis for patients that have not yet reached this stage
- on the most seriously affected patients, it must stop the causes of the evolution of fibrosis to allow the liver to repair itself and regress fibrosis

However if the mechanism described above is right, the ideal solution would be :

1. Use dietary changes and exercise to reduce NAFLD.
2. Once NASH is diagnosed, act on all the metabolic parameters to suppress inflammation induced by NAFLD.

Logically the rest should follow since stopping inflammation will stop cell degeneration which thereby prevent the production of further scar tissue and hence stop fibrosis.

To support the latter, in an article published in April 2015 in the "Journal of Hepatology ».

  « Current efforts and trends in the treatment of NASH » written by  Vlad Ratziu, Zachary Goodman, Arun Sanyal  - we find:

« An ideal drug candidate for NASH should reduce hepatic inflammation and liver cell injury, should correct the underlying insulin resistance and should have antifibrotic effects. However, primarily ‘‘anti-NASH’’ drugs that have no direct antifibrotic effect could, theoretically, result in a subsequent reduction of fibrosis if a sustained resolution of NASH is achieved. »

The reversion of fibrosis should be the indirect effect of successful treatment of NASH without requiring that the treatment has a direct antifibrotic effect.

The controversy on whether or not to develop a drug specifically targeted to reduce levels of fibrosis seems to me to be irrelevant, except in the case of fibrosis caused by factors other than NASH itself. Successful NASH treatment  will most probably halt and lead to the regression of fibrosis while the reverse is not true. Curing fibrosis alone will not cure NASH.

The actual mechanism of the disease is of course extremely complex because human metabolism is a delicate balance of many parameters, so this will not necessarily work for all forms of disease, or for all patients to the same degree, but we can imagine that the this description gives the big picture of the disease and how best it can be cured.

For a another good panorama of the disease you can also read this excellent article on Seeking Alpha.


A very good video is presenting NASH from the  

The Nash Education Program


You should read also :

AGA

The Diagnosis and Management of Non-alcoholic Fatty Liver Disease: Practice Guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology 




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