Subject: FW: NATAP: NAFLD Review
From: Robert Gish <[email-masked]>
Date: Wed, 19 Feb 2020 10:31:14 +0000

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Robert G. Gish MD

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Subject: NATAP: NAFLD Review

www.natap.org

Past, present and future perspectives in nonalcoholic fatty liver disease

April 2019 Arun Sanyal

Fibrosis is widely recognized as the hallmark of disease progression in NASH, and the mechanisms underlying fibrogenic progression are currently an area of intense research. Although hepatic stellate cells are widely considered to be the
primary cellular source of collagenous matrix in NASH, observations that portal inflammation is associated with fibrosis progression suggest a role for portal myofibroblasts as well43.

In those who have developed cirrhosis, the rates of clinical decompensation have been reported to be ~3–4% annually96.
In 2017, two rigorously performed controlled trials of simtuzumab involving 219 and 258 individuals provided prospective data on the rates of progression from bridging fibrosis to cirrhosis, and from cirrhosis to decompensation in patients with NASH, respectively97.
Over a duration of 24 months, 21% of patients with NASH with bridging fibrosis developed cirrhosis and 19% of those with compensated cirrhosis due to NASH developed clinical decompensation. Approximately two-thirds of the patients included in the trial in
those with cirrhosis had clinically significant portal hypertension defined by a hepatic venous pressure gradient >10 mmHg (ref.98).
This finding might explain the higher rate of portal hypertensive complications than those reported in prior studies96.

Numerous studies have reported a very high prevalence of NAFLD in the general population, and it is estimated that ~25% of adults and 10% of children have NAFLD in the USA68,69.

One less controversial aspect of NAFLD progression is the linkage between the disease and HCC. HCC can develop in the absence of cirrhosis, although the absolute risk is low (0.44 per 1,000 person-years of exposure)1,92,93.
Overall, NASH is increasing as an aetiology for HCC and is the second most common cause for HCC requiring transplantation evaluation in the USA94.
Of note, whereas the incidences of several obesity-associated cancers such as breast cancer and colon cancer have remained stable or declined over the past 10 years, the incidence of HCC has increased by 3% annually for the past 10 years95.
The growing prevalence of NASH is probably related to this phenomenon95.

A high prevalence of NAFLD has also been reported in those of Hispanic origin, in elderly individuals and in those with diabetes71,72.

The early descriptions of NASH led to efforts to identify the biological basis of NAFLD. It was quickly noted that steatosis could be induced by a high-fat diet or by leptin receptor deficiency in the
ob/ob mouse14.
Although these models did not produce steatohepatitis, it was observed that injections of bacterial lipopolysaccharide could induce inflammation along with steatosis and that steatotic hepatocytes developed heightened susceptibility to injury from TNF15.
This work led Day and James to postulate the ‘two-hit’ hypothesis of NASH in 1998, in which steatosis was the first hit and exposure to inflammatory cytokines was the second hit, causing cell death and inflammation in NASH16.
They considered fat accumulation to be fairly benign, although studies have since found fibrosis to develop even in those with steatosis alone17.

Using euglycaemic–hyperinsulinaemic clamps in humans, it was then demonstrated that, even in the absence of T2DM, glucose disposal was progressively impaired from healthy controls to those with histologically confirmed nonalcoholic fatty
liver (NAFL) and then NASH with both low-dose and high-dose insulin infusions19.

Early studies were accompanied by a description of hepatic oxidative stress associated with NAFLD in humans19,
which occurred with the development of NAFL and increased further in NASH. Mitochondrial injury and both morphological and functional changes in mitochondria in the liver in humans with NASH were described in 1999 and confirmed in 2001, raising the
possibility that these changes were involved in driving the oxidative stress in the liver19,22.

Lipidomic studies in humans with NAFLD further revealed widespread perturbations in multiple lipid classes such as triglycerides, cholesterol and eicosanoids29,30.
Additional studies demonstrated that hepatic cholesterol synthesis is inappropriately increased in NASH despite an accumulation of free cholesterol, suggesting a defect in intracellular lipid sensing31.

Another landmark in the evolution of knowledge on NASH pathogenesis was the observation of an activated innate immune system in this condition. With the discovery of Toll-like receptors (TLRs) in the 1990s and the recognition of increased
inflammation in response to their activation by bacterial lipopolysaccharide or intracellular products associated with cellular injury, increased TLR signalling was noted in murine models of NAFLD34,35.
It was further shown that palmitic acid could activate TLRs such as TLR2 and activate the inflammasome in NASH36.

NASH has also been associated with increased systemic bacterial lipopolysaccharide levels, which are known to activate TLR4.

It is now recognized that inflammatory and pro-fibrogenic macrophages probably play a key part in disease progression41,42,
but gaps remain in our knowledge of what drives macrophage infiltration, whether liver-resident macrophages serve similar roles as bone-marrow-derived macrophages and what leads to a switch from a pro-inflammatory to a pro-fibrogenic macrophage profile.

Introduction

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common form of chronic liver disease in most regions of the world1.
It is a growing cause of end-stage liver disease globally and is recognized as an aetiology of hepatocellular cancer (HCC), even in the absence of underlying cirrhosis2.
The prevalence of NAFLD is almost one-third of the general population in Western nations and is linked to excess body weight and type 2 diabetes mellitus (T2DM)3.
The prevalence of the disease is also particularly high in the Middle East1
and is growing in countries of the Asian subcontinent and the Far East4.
It is estimated that the burden of end-stage liver disease will increase 2–3-fold in both Western nations as well as in several Asian countries by 2030 (refs2,5).
Over the past two decades, substantial progress has been made in understanding the spectrum of NAFLD, its clinical course and the biological factors (for example, lipotoxic stress) underlying its development and progression to cirrhosis, which has led to several
therapeutic agents that are now in pivotal clinical trials. In this Perspective, I discuss the past accomplishments, present perspectives and future trends in NAFLD research from a translational perspective (Fig. 1).

A key finding in the past few years is that NASH, atherosclerosis and T2DM share many common pathogenic features such as ectopic fat deposits, inflammation, cell stress and death and fibrosis in affected organs, which are expected to drive
common diagnostic tools that will inform the assessment of all of these diseases. Therapies that will beneficially affect all of these end-organ diseases will emerge as the first-line treatments of the condition.

Finally, it is becoming clear that weight loss, specifically reduced adiposity, is an important driver of histological improvement133.
The benefits of weight loss will extend beyond those expected from drug treatment of high-risk NASH to include decreased cardiovascular and metabolic outcomes and potentially even cancer. Public health strategies will need to recognize the common elements
driving the growing health consequences of T2DM, NAFLD, heart failure and several obesity-related cancers to reduce the burden of disease related to all of these conditions in the future.

In the past 5 years, the potential to halt disease progression by the use of
specific anti-inflammatory and anti-fibrotic agents has been tested. The 1-year findings from a 2-year trial of the
CC-chemokine receptor 2 (CCR2)–CCR5 antagonist cenicriviroc, which was designed to reduce NASH fibrosis, has demonstrated a significant (P < 0.01) improvement in one-stage or greater fibrosis reduction in patients with NASH without changing upstream
aspects of the disease, such as steatosis and hepatocyte ballooning injury127.
This trial further demonstrated that improvement in inflammation as defined by biochemical and molecular analyses is not recapitulated by traditional histological methods of inflammation assessment, raising questions about the validity of these conventional
methods. Unfortunately, trials to inhibit fibrosis with the use of direct anti-fibrotics such as simtuzumab have been disappointing, suggesting that either more potent anti-fibrotic therapies are needed or that anti-fibrotic strategies should be combined with
more metabolically targeted therapeutics. The current evidence, to date, supports the need for a metabolic anchor for the treatment of NASH.

Conclusions

NAFLD currently occupies centre stage in terms of research and therapeutic development in the area of liver diseases. Although the field is relatively young, it is an area of intense
research given its public health implications. Early studies provided seminal information on its linkage to insulin resistance and the metabolic syndrome, and, over the past few years, the core elements of pathogenesis have been worked out along with the identification
of several therapeutic targets, some of which have already been translated to treatment trials. Several agents are in pivotal trials and a regulatory pathway for drug approval has been established. Future studies are expected to identify specific disease drivers
in individuals and subpopulations on the basis of molecular drivers of disease. The current efforts to develop and qualify specific biomarkers for NASH are expected to enable all health-care providers to rapidly assess the presence and severity of the underlying
disease. Together with ongoing drug development efforts, these efforts will permit both identification of those at greatest risk of outcomes and potentially the reversal of the disease. Ultimately, from a societal perspective, it will be essential to attack
the root cause of NAFLD, T2DM and cardiovascular disease to reduce the burden of diseases related to caloric excess and disordered metabolism. This goal will require a broad effort of all stakeholders to address the social, economic, cultural and medical underpinning
of obesity and its related conditions, including NAFLD.