Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)—The Overlooked Complications of Type 2 Diabetes
Presented by:
Elisabetta Bugianesi, MD, PhD
University of Turin, Italy Zobair Younossi, MD, MPH
Inova Fairfax Medical Campus, Falls Church, VA, USA Kenneth Cusi, MD
University of Florida, Gainesville FL, USA
Nonalcoholic fatty liver disease (NAFLD) and diabetes are common comorbid metabolic disorders. Proper dietary and pharmacological treatment is essential for preventing NAFLD progression. Among many proposed treatments, weight reduction is the only approved option for NAFLD to date. However, it is not easy to maintain weight loss by lifestyle modification alone, and pharmacological treatments are helpful in this regard. Attention should be paid to the management of NAFLD and diabetes and efforts should be made to intervene early and individualize treatment of NAFLD in patients with diabetes.
NAFLD is a spectrum of pathologies ranging from fatty liver to NASH to cirrhosis.
The condition is more prevalent in patients with type 2 diabetes compared to the general population, being present in over 50% of patients with diabetes in the US and almost 70% in Europe.
NAFLD is a significant contributor to increased mortality.
Clinical predictors of NAFLD include advanced age, race (the prevalence is greater in Hispanic, Asian, and black patients), and hypertension.
NAFLD is also associated with CV disease, and in particular for both fatal and non-fatal CV events, and is also independent predictor of future CV events in type 2 diabetes.
Considering hepatic complications, diabetes is a strong and independent risk factor for hepatocellular carcinoma (HCC) and increases the risk of HCC by 2-3 fold.
Indeed, NAFLD is now the most rapidly growing indication for liver transplantation in the US.
Considering all the above, screening has been advocated by some management guidelines in selected patients, but there is still some debate on the need for screening due to the high direct and indirect costs of testing, low predictive value of non-invasive tests, risks of liver biopsy, and lack of effective treatments.
However, there appears to be general consensus that routine screening should not be employed in all patients.
Lastly, according to the EASL-EASD-EASO joint guidelines, clinicians need to find common ground where all the major players in the metabolic field can cooperate, and share resources and clinical data, to best define which patients do and do not need screening to avoid the reality or perception of “disease mongering” and assure an effective way forward for patients and healthcare systems.
NAFLD can be diagnosed using clinical data, but this method is both non-specific and imprecise.
Diagnostic exams include clinical/lab tests, imaging (ultrasound, MRI, spectroscopy, CT), biomarkers (e.g. FIBROSpect) and liver biopsy, with the latter being the most sensitive and specific.
In NAFLD, fibrosis is the most important predictor of long-term outcomes.
Although liver biopsy is the current imperfect gold standard for NASH diagnosis, a number of non-invasive tests are being developed.
Considering imaging biomarkers, fibrosis has no molecular signature that is detectable by current imaging techniques, and as such imaging attempts to detect fibrosis indirectly.
Many biomarkers have been proposed: stiffness, diffusion, perfusion, metabolites, and image texture.
The leading biomarker is likely “liver stiffness measurement or LSM” (elasticity) and related parameters with the rationale that fibrotic collagen deposition imparts parenchymal rigidity.
LSM can be used as a non-invasive marker to predict survival.
Vibration-controlled transient elastography (VCTE; FibroScan) is widely used, while shear wave elastography (SWE) and acoustic radiation force impulse (ARFI) measure liver stiffness in a single region of interest (ROI), and magnetic resonance elastography (MRE) measures stiffness across multiple ROIs.
Regardless, patients with NASH, and especially those with fibrosis, will urgently need treatment and should be identified.
It seems apparent that the future use of combination tools (fibrosis scores, LSM and serum fibrosis tests) may improve the clinical utility in a cost-effective manner.
Lastly, it is clear that future management of NASH will require multidisciplinary care.
Management of NAFLD merits a call to action considering that there are several barriers to therapy and lack of unequivocal treatment targets.
Steatosis should be used to identify and guide treatment of hepatic fibrosis.
For prevention of hepatic cirrhosis, two approaches are being used, an “antifibrotic” (downstream) approach and an “insulin-sensitizer” (upstream) approach.
Current treatments include weight loss, vitamin E, GLP-1 RAs, and pioglitazone.
For weight loss, 3%-5% is needed to improve steatosis, but 7%-10% is considered minimal to improve the majority of the histopathological features of NASH, including fibrosis.
Exercise alone may prevent or reduce steatosis, but its ability to improve other aspects of liver histology remains unknown.
Bariatric surgery can be considered in some patients, but this is not an established therapeutic option.
Pioglitazone has been shown to improve liver histology in patients with and without diabetes with biopsy-proven NASH.
More recently, GLP-1 RAs have been investigated in patients with diabetes and NAFLD, and both liraglutide and dulaglutide have shown promising results.
In addition, future strategies may combine different therapies.
Possible options include use of an insulin-sensitizer (novel agent or low-dose pioglitazone) plus a “downstream” agent such as pioglitazone with vitamin E.
Tropifexor + cenicriviroc (chemokine receptor type 2/5 antagonist), cilofexor + firsocostat + semaglutide are some examples of combination therapy.
Another additional option may be to combine pioglitazone with agents that promote weight loss and reduce CV disease such as a GLP-1 RA or SGLT2 inhibitor.
Such an approach may be useful in light of the adverse CV consequences of NAFLD.
In summary, pioglitazone will be to NAFLD what metformin is to type 2 diabetes.
There are several new agents in the pipeline, and combination therapy will likely be the standard of care in the future.
Fibrosis is the most important predictor of long-term outcomes.
Pioglitazone will be to NAFLD what metformin is to type 2 diabetes.
There are several new agents in the pipeline, and combination therapy will likely be the standard of care in the future.
Key messages/Clinical Perspectives
Patients with NAFLD, especially those with fibrosis, need urgent treatment and should be identified.
Present disclosure: E. Bugiansi and E. Lammert: none. Z. Younossi: Gilead. K. Cusi: Allergan, AstraZeneca, Genertech, Novo Nordisk, Poxel, ProSciento, Cirius Therapeutics, Echosens, Eli Lilly, Inventive Pharma, Janssen, Novartis.
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