Evolving Management Strategies for Nonalcoholic Fatty Liver Disease–Targeting Primary Care Physicians

Importance of Problem

Nonalcoholic Fatty Liver Disease (NAFLD) has become one of the most prevalent causes of liver disease in the world. The overall NAFLD prevalence is ∼25% in the general population, with the highest prevalence reported in South America (31%) and Middle-East (32%), followed by Asia (27%), the U.S. (24%), and Europe (23%), whereas NAFLD is less common in Africa (14%). NAFLD can progress to nonalcoholic steatohepatitis (NASH).¹ Increased fibrosis can lead to cirrhosis and the need for liver transplantation. Primary care physicians and endocrinologists need to consider using biomarkers and imaging modalities to diagnose and stage the disease better, follow disease progression closely, and initiate appropriate management strategies for this global health problem.

Risk Factors and Comorbidities

Many patients seen in metabolic/endocrine clinics have NAFLD/NASH. Patients with type 2 diabetes mellitus (T2DM) who are obese or who have dyslipidemia, metabolic syndrome, or polycystic ovarian syndrome are at risk for NAFLD. The American Association for the Study of Liver Diseases (AASLD) guidance for patients with T2DM suggests that one should suspect NAFLD and NASH and determine risk of advanced fibrosis.² The greater the number of metabolic diseases that patients have, the higher their risk of NASH. The European Association for the Study of the Liver (EASL), the European Association for the Study of Diseases (EASD), and the European Association for the Study of Obesity (EASO) guidelines recommend screening for NAFLD in patients at high cardiovascular disease risk, including those with T2DM or metabolic syndrome.³ This is important for primary care doctors and endocrinologists because these patients are frequently seen at these clinics.

Sometimes the clinicians focus solely on treating the endocrine condition and NAFLD/NASH is missed. Other conditions that may be associated with NAFLD are hypothyroidism, obstructive sleep apnea, hypopituitarism, hypogonadism, pancreatoduodenal resection, and psoriasis. There is a high burden of metabolic comorbidities associated with NAFLD and NASH, creating implications for clinical management of the disease. Obesity is present in 51% of individuals with NAFLD and 82% of NASH patients. T2DM was identified in 23% of NAFLD cases and 47% of NASH cases. The prevalence of metabolic syndrome among NAFLD patients was 43% and 71% in NASH, with hyperlipidemia/dyslipidemia (NAFLD, 69%; NASH 72%) common as well.^1,4 These are clinically relevant because cumulative studies suggest that the presence of NAFLD/NASH may independently increase the risk of cardiovascular events, and may also increase the risk of incident T2DM and worsen glycemic control.^5,6

Diagnosing Strategies

The diagnosis of NAFLD (Table 1) requires that there is no significant alcohol consumption, presence of hepatic steatosis by imaging or histology without any other competing etiologies and no other coexisting causes of chronic liver diseases. It is important to identify the patients at low or high risk for advanced fibrosis (bridging fibrosis or cirrhosis).²

Table 1.

Noninvasive Diagnostic Strategies for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Serum-based score	Components
APRI	AST, platelet count
FIB-4	Age, ALT, AST, platelet count
NAFLD fibrosis score	Age, ALT, AST, platelet count, BMI, albumin, impaired fasting glucose/diabetes
BARD	ALT, AST (AST/ALT ratio), BMI, diabetes

Imaging	Comments
VCTE—FibroScan	Can be point of care
	Can grade steatosis and fibrosis
2D shear wave elastography	May require radiology referral but can be point of care with minimal training
MRE/MRS/liver multiscan	Requires radiology referral
	Expensive
	Limited to certain centers only
Ultrasound	Inexpensive and accessible
	Cannot distinguish fibrosis/steatosis
CT without contrast	Useful in morbidly obese
	Affected by iron and fibrosis
	Reduced accuracy in patients with minimal steatosis

ALT, alanine aminotransferase; AST, aspartate aminotransferase; APRI, AST to platelet ratio index; BARD, BMI, AST to ALT ratio and diabetes; CT, computed tomography; MRE, magnetic resonance elastography; MRS, magnetic resonance spectroscopy; NAFLD, non-alcoholic fatty liver disease; VCTE, vibration-controlled transient elastography.

Liver enzymes

The absolute values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are inadequate in assessing NAFLD/NASH. In fact, ALT levels are often normal in up to 80% of patients with NAFLD and >50% of patients with NASH.⁷ Age is another confounder since ALT levels fall with age. Therefore a normal or elevated ALT is neither predictive nor indicative of severity of NASH. Consequently, normal levels of ALT do not indicate absence of NASH.^7–9 When patients are followed longitudinally over time, improvement in liver enzymes is often indicative of worsening disease (fat in the liver converted to fibrous tissue).¹⁰ The AST:ALT ratio can provide important diagnostic clues. The normal AST:ALT ratio is ∼0.8. An AST:ALT ratio of 2.0 or higher or ALT level exceeding 300 U/L may be indicative of alcoholic liver disease. However, the AST:ALT ratio is usually 1.0 or less in NAFLD but when fibrosis becomes advanced, the AST:ALT ratio may become reversed.¹¹ Aminotransferase levels and AST/ALT are not reliable predictors for NASH.¹²

Guidelines do not currently exist to specify cutoff point and maximum concentration of ALT and AST for different genders. However, some studies have shown that risk of NAFLD increases as ALT rises to more than 19 U/L and 30 U/L in women and men, respectively.¹³

Imaging

To diagnose suspected liver disease, imaging is commonly performed at clinics. Unfortunately, the standard ultrasound or cross-sectional imaging with computed tomography (CT) scans or magnetic resonance imaging (MRI) cannot identify or distinguish the stages of NAFLD or NASH.

Ultrasound is inexpensive, easily accessible, and quick to perform. It can identify hepatic steatosis and hepatic fat beyond 20% or 30% with fairly high sensitivity; however, it has very low sensitivity to detect hepatic fat <20%.¹⁴ CT scan without contrast has 79% sensitivity and 97% specificity to detect steatosis >30%, but this technique is still unable to distinguish stages of NAFLD or NASH.¹⁵

These modalities can identify advanced cirrhosis with portal hypertensive changes such as esophageal varices, ascites, and splenomegaly, but cannot differentiate between steatosis/NASH, fibrosis, or early cirrhosis.

Liver biopsy

Liver biopsy is the current gold standard test to stage fibrosis in patients with NAFLD, but is invasive. It also helps exclude any other chronic liver disease, such as α1-antitrypsin deficiency or iron overload. Liver biopsy confirms the diagnosis of NASH, characterized by fat inflammation and cell death, and the stage of fibrosis, which leads to a prognostic value. There are concerns about bleeding, pain, and variations in sampling. The liver biopsy samples 1 out of 50,000 parts of the liver. Fatty liver disease is sometimes heterogenous, and nearly one quarter of patients with liver disease could have a missed diagnosis (or understaging of disease severity) owing to variations in sampling.^16–18 The cost and potential complications of biopsy have led to considerable interest in the development of novel, noninvasive methods for use in clinical practice.

According to AASLD guidelines, a liver biopsy should be performed in patients with metabolic syndrome who are at increased risk of NASH.² The current American Diabetes Association practice guidelines for 2019 also state “Patients with type 2 diabetes or prediabetes and elevated liver enzymes (alanine aminotransferase) or fatty liver on ultrasound should be evaluated for presence of NASH and liver fibrosis.”¹⁹

Noninvasive staging predictors of advanced fibrosis in NAFLD

Because of the limitations of utilizing liver enzymes or imaging modalities such as ultrasound, CT scans, or invasive liver biopsy alone in predicting advanced fibrosis, better strategies and diagnostic tools are being developed. Currently, there are numerous diagnostic scores to assess liver damage. APRI is the AST to platelet ratio index. FIB-4 uses age, ALT level, AST level, and platelet count. The NAFLD fibrosis score (NFS) uses simple serum blood test scoring with parameters such as age, BMI, AST to ALT ratio, platelets, albumin level, and the presence or absence of impaired glucose tolerance and diabetes.^20,21 The BARD score stands for BMI, AST to ALT ratio, and diabetes. Enhanced liver fibrosis score uses parameters such as age, hyaluronic acid, aminoterminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1.

Among these diagnostic tools, NFS and FIB-4 scores are better predictors than BARD and APRI.²² These scoring methods have good negative predictive values for ruling out fibrosis, and the calculators are freely available online making them easy to use.^22,23 The NFS and FIB-4 index are widely used in the veteran population and in clinics in the United States. NFS is derived from and validated in a NAFLD cohort. It has a low cutoff <1.455 that excludes advanced disease (∼90% negative predictive value) and a high cutoff >0.676 that indicates advanced disease. FIB-4 score was derived originally from HCV/HIV cohorts and then was validated in a NAFLD cohort. If the score is <1.3, it excludes advanced disease with a 95% negative predictive value. Patients with scores >2.67 are likely to have advanced fibrosis. There are some caveats to these scores; no method is perfect. It is well known that ALT level and platelet count fall with age, that is, when a patient is older than 65 years, hence scoring systems need to account for this age-related decline, which can reduce specificity of the tests.

There are also some studies that suggest that these tools may be less useful in certain ethnic groups. De Sliva et al. found that NAFLD noninvasive test scoring in people from South Asia may be less accurate. Hence, more studies should be done to confirm this finding.²⁴ Also, Bertot et al. demonstrated that the diagnostic and prognostic accuracy of widely used noninvasive fibrosis models in NAFLD are significantly impacted by the presence of diabetes.²⁵ Among patients with diabetes, NFS, APRI, and FIB-4 were not reliable at excluding risk of future events such as liver decompensation, mortality, and hepatocellular carcinoma, but the scores were highly accurate among patients without diabetes.²⁵ AASLD guidelines recommends using NFS or FIB-4 to identify those at low or high risk for bridging fibrosis or cirrhosis.²

Noninvasive staging of NASH by imaging

Vibration-controlled transient elastography (VCTE), commonly called FibroScan, allows point-of-care measurement of liver stiffness and controlled attenuation parameter (CAP) score with good negative predictive value for excluding advanced fibrosis and liver fat. It can also help identify those likely to have advanced disease, meaning stage 3 to 4 fibrosis. VCTE is the best validated and commonly used type of elastography worldwide.^26,27 The CAP score is measured in decibels per meter (dB/m). It ranges from 100 to 400 dB/m. A CAP score higher than 290 dB/m is S3 steatosis and signifies >67% fat in the liver. Fibrosis scores are measured in kilopascals and range from F0 to F4 with F0 indicating mild liver scarring and F4 as advanced liver scarring (cirrhosis). The FibroScan is a relatively cost-efficient way to monitor patients in the primary care or endocrinology office setting without involving radiology/hepatology.

Shear wave elastography is another technology that is based in radiology departments; hence, it's more difficult to use at the point of care. There are a few centers in the United States that perform point-of-care 2D shear wave elastography, so accessibility to the technology presents a barrier. However, physicians can use this modality with minimal training.²⁶

Magnetic resonance elastography (MRE) and magnetic resonance spectroscopy require an advanced center with appropriate scanners and more training in interpretation of the test. The imaging is very accurate, but these modalities require much more in terms of resources to set up. MRE is the most expensive noninvasive technique, but better than VCTE for detection of early fibrosis and of fibrosis stages F3–F4.²⁸

To summarize, imaging studies can help stratify a patient's probability of having significant fibrosis.²⁹ These tests have high negative predictive value but are not so definitive in terms of ruling in or diagnosing a specific stage of the disease. However, the new imaging modalities such as elastography are also accurate. These noninvasive tests can be used by endocrinologists and primary care physicians to assess risk of fibrosis but referral to a liver specialist and a liver biopsy may be required for definitive diagnosis.

Management Strategies

Whom to treat

The management of NAFLD should consist of treating liver disease and associated metabolic comorbidities, such as obesity, hyperlipidemia, insulin resistance (IR), and type 2 diabetes. Dietary and lifestyle modification, with aims of achieving sustained weight loss, should be the first line therapy for patients with NASH. Pharmacotherapies aimed primarily at improving liver disease should generally be limited to those with biopsy-proven NASH and fibrosis.

Dietary and lifestyle modification

Diet and lifestyle modification is the basis of any management strategy for those with NAFLD/NASH, but it is challenging for many patients to achieve and maintain. Weight loss generally reduces steatohepatitis, achieved either by hypocaloric diet alone or in conjunction with increased physical activity. There have been numerous studies looking at the effect of weight loss on fatty liver disease.^30–33

A hypocaloric diet (daily reduction by 500–1000 kcal) combined with moderate intensity exercise is the best strategy for sustaining weight loss over time.³⁴ Weight loss of at least 3%–5% of body weight appears necessary to improve steatosis, but a greater weight loss (7%–10%) is needed to improve the majority of histopathological features of NASH, including fibrosis. Resolution of fibrosis has been noted with ≥10% loss of body weight, however, this is only achieved in <10% of persons in a year.^30,31,33 Exercise alone in adults with NAFLD may prevent or reduce steatohepatitis, but its ability to improve other aspects of liver histology remains unknown.²

Mardinoglu et al. conducted a short-term intervention trial with an isocaloric low-carbohydrate diet in obese subjects with NAFLD and showed a rapid and dramatic lowering of liver fat and other cardiometabolic risk factors as evidenced by a decrease in hepatic de novo lipogenesis.³⁴ Liver transcriptomic analysis on biopsy samples taken from a second cohort in this same study revealed downregulation of the fatty acid synthesis pathway and upregulation of folate-mediated one-carbon metabolism and fatty acid oxidation pathways.²⁴ These results highlight the potential of exploring diet-microbiota interactions for treating NAFLD.³⁴ In patients with prediabetes, diet rich in monounsaturated fatty acids has shown to decrease hepatic fat and improve both hepatic and total insulin sensitivity.³⁵

Hence, weight loss and maintenance of weight loss in many patients is an important consideration. A reduction of calorie intake and increased physical activity are extremely important for maintenance of cardiovascular health and weight loss on fatty liver disease. It needs to be the cornerstone of therapy, as it is with type 2 diabetes.

Surgical/Endoscopic Procedures

Bariatric surgery has shown positive results. Mathurin et al., studied patients 5 years after bariatric surgery. They were able to demonstrate that the percentage of patients with steatosis decreased from 37.4% at baseline to 16% at the end, the NAFLD score from 1.97 to 1, ballooning from 0.2 to 0.1, whereas inflammation remained unchanged.³⁶ Fibrosis worsened at 5 years, although >95% of patients had a fibrosis score ≤F1 at 5 years.

Foregut bariatric surgery can be considered in eligible obese individuals with NAFLD or NASH. However, it is premature to consider it as an established option to specifically treat NASH. In otherwise eligible patients with compensated NASH or cryptogenic cirrhosis, bariatric surgery may be considered on a case-by-case basis by an experienced bariatric surgery program.² In addition to surgery, endoscopic methods such as intragastric balloon placement and endoscopic sleeve gastroplasty have also been developed to enhance weight loss, although none of these has (yet) been approved for the specific treatment of NAFLD/NASH.^37,38

Medical treatment

Looking more specifically at medications used along the spectrum, from a healthy liver to cirrhosis, there are a number of pathophysiologic defects that can be targeted with different medications (Table 2).

Table 2.

Pharmacotherapy for Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis

Compound	Mechanism of action	Trial	Primary endpoint(s)	AASLD recommendation for NASH
Pioglitazone	PPARγ agonist	PIVENS Multiple studies	Improvement in NAS ≥2 without worsening fibrosis	May be used in patients with biopsy-proven NASH
Liraglutide	GLP-1 receptor agonist	LEAN	Resolution of NASH without worsening fibrosis	Premature to consider GLP-1 receptor agonists
Vitamin E	Antioxidant	PIVENS TONIC	Improvement in NAS ≥2 without worsening fibrosis	May be used in nondiabetic adults with biopsy-proven NASH
Lack of beneficial effect on NAFLD

Compound	NAFLD benefit	Hypoglycemia	Weight
SGLT-2 inhibitors	Neutral	Neutral	Loss
DPP-4 inhibitors	Neutral	Neutral	Neutral
α-glucosidase inhibitors	Neutral	Neutral	Neutral
Colesevelam	Neutral	Neutral	Neutral
Bromocriptine	Neutral	Neutral	Neutral
Sulfonylureas	Neutral	Moderate-severe	Gain
Glinides	Neutral	Mild-moderate	Gain
Insulin	Neutral	Moderate-severe	Gain
Pramlintide	Neutral	Neutral	Loss

AASLD, American Association for the Study of Liver Diseases; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; NASH, nonalcoholic steatohepatitis; PPAR, peroxisome proliferator-activated receptor; NAS, NAFLD Activity score.

Metformin

Metformin is a biguanide that works by decreasing hepatic glucose production and increasing glucose uptake in muscle. Although it has low risk of hypoglycemia and can promote modest weight loss, it has not been shown to improve histological features of NASH. As such, while it remains a useful treatment for T2DM, it is not recommended as a treatment for NASH, per se.²

Dipeptidyl peptidase-4 inhibitors

This group of drugs works primarily by blocking the enzyme (dipeptidyl peptidase-4 [DPP-4]) that degrades glucagon-like peptide-1 (GLP-1). A few small clinical trials have reported reduction of plasma ALT levels with sitagliptin.³⁹ Patients when treated with vildagliptin for 6 months, saw a clinically significant decrease in hepatic triglyceride levels unrelated to change in body weight, but there was no change in their peripheral insulin sensitivity.⁴⁰ To date, no studies have examined the change in liver histology following DPP-4 treatment in NASH. As such, DPP-4 inhibitors are not recommended for treatment of NAFLD/NASH at the present time.

Thiazolidinedione

Thiazolidinediones are a class of antidiabetic oral agents that increase glucose uptake in muscle and fat and also decrease hepatic glucose production. They are ligands for the nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPARγ). Pioglitazone may be used to treat patients with and without type 2 diabetes with biopsy-proven NASH because it improves liver histology in these patients.^2,41 Risks and benefits should be discussed with each patient before starting therapy. It is currently not recommended to treat NAFLD patients without biopsy-proven NASH. The most common undesirable side effects of this drug are edema, weight gain (∼2–3 kg over 2–4 years),⁴² risk of osteoporosis in women,⁴³ bladder cancer risk.^44–46

GLP-1 receptor agonists

GLP-1 is a gut-derived incretin hormone that increases glucose-dependent insulin secretion and decrease glucagon secretion. In the Lean trial (NCT01237119), 1.8 mg Liraglutide when administered subcutaneously once daily for 48 weeks, was associated with greater resolution of steatohepatitis and less progression of fibrosis.² Semaglutide is currently in a phase II trial (NCT02970942) for NASH to investigate efficacy and safety. Side effects may include low blood sugar, headache, acid reflux, indigestion, nausea, vomiting, diarrhea, constipation, and skin problems at the injection site.

SGLT-2 inhibitors

This class of drugs acts by decreasing the renal glucose absorption with marked reduction in plasma glucose levels. Treatment with canagliflozin and dapagliflozin has shown to decrease plasma aminotransferases levels, but there are no studies assessing their effect on liver histology.³⁹ Hence, they are not currently recommended for the treatment of NASH/NAFLD.

Vitamin E (rrr α-tocopherol)

Vitamin E is an antioxidant that prevents liver damage from oxygen radicals. It also protects against mitochondrial toxicity and blocks intrinsic apoptotic pathways. It improves liver histology in nondiabetic adults with biopsy-proven NASH and can be used for these group of patients at a dose of 800 IU/day, after counseling them on risks associated with increased hemorrhagic stroke,⁴⁷ increased risk of prostate cancer,⁴⁸ and benefits such as reduced risk of ischemic stroke.⁴⁷ It is currently not recommended for the treatment of NASH in diabetic patients, NAFLD without liver biopsy, NASH cirrhosis, or cryptogenic cirrhosis due to lack of evidence.²

Ursodeoxycholic acid

Ursodeoxycholic acid offers no histologic benefit over placebo in NASH and is not recommended for the treatment of NAFLD or NASH.² These drugs have many undesirable side effects, including nausea, rash, itching, bladder pain.

Omega-3 fatty acids

They may be considered for treating hypertriglyceridemia in patients with NAFLD. Omega-3 fatty acids should not be used as a specific treatment of NAFLD or NASH because they have failed to show convincing therapeutic benefit in NAFLD.² Although omega 3 fatty acids are relatively safe for consumption, adverse effects include an upset stomach, fishy breath, loose stools, or nausea.

Novel Agents

Four drugs (obetocholic acid [OCA], elafibranor, selonsertib and cenicriviroc [CVC]) have entered phase 3 clinical trials.^49,50

Farnesoid X receptor agonists

Farnesoid X receptor (FXR) controls glucose and lipid metabolism through regulation of insulin sensitivity in skeletal muscle and adipose tissue, and regulation of gluconeogenesis and glycogenolysis in the liver, while also decreasing circulating triglycerides. In a recent phase 3 study (REGENERATE), OCA was shown to reduce liver fibrosis by at least one stage without worsening of NASH after 18 months of therapy, and may soon be available for the treatment of NASH (these data were presented at the International Liver Congress 2019, the Annual Meeting of the EASL). Data on 931 participants showed that once daily dose of OCA 25 mg met the primary endpoint of fibrosis improvement (≥1 stage) with no worsening of NASH in 23% of patients (P = 0.002 vs. placebo). The primary endpoint for resolution of NASH, however, was not met. OCA is approved by the US FDA as a second-line therapy for primary biliary cirrhosis (PBC).

In 2018, FDA had sent out a black box warning concerning the dose of OCA in cirrhotic PBC patients. A secondary analysis of CONTROL trial found that OCA doses up to 25 mg daily were safe in patients with NASH without cirrhosis and with compensated cirrhosis. Safety and efficacy for OCA dosage is being tested in phase III REVERSE study (NCT03439254).

Other FXR agonists such as tropifexor and GS-9674 are in phase 2 clinical trials.

C-C chemokine receptor types 2 and 5 antagonists

The activation of C-C chemokine receptor types 2 (CCR2) and 5 (CCR5) promotes recruitment and migration of monocytes to the liver, which maturate into proinflammatory macrophages that activate Kupffer cells and stimulate hepatic stellate cells (the key cell type responsible for secreting extracellular matrix in the liver) to deposit collagenous matrix. CVC is a potent CCR2 and CCR5 antagonist that is currently being evaluated for its anti-inflammatory and antifibrotic activity in a phase 3 clinical trial (AURORA study). CVC treatment in a phase IIb clinical study (CENTAUR; NCT02217475) resulted in sustained antifibrotic benefit in adults with NASH and stage 3 liver fibrosis. Most CVC-treated F3 subjects achieved improvement of ≥1 stage of fibrosis after year 1 and maintained this benefit after year 2 as well. Subjects well tolerated the treatment with CVC; adverse event with severity ≥2 (diarrhea: 2.1%, fatigue: 2.8%) was seen in ∼2% of patients.

PPAR agonists α/δ

PPARα activation leads to control of lipid flux and, in the liver, inhibition of inflammatory genes induced by nuclear factor-κB and improvement of necroinflammatory activity. In addition, active PPARδ improves glucose homeostasis and inhibits hepatic lipogenesis, and has anti-inflammatory activity in macrophages and Kupffer cells. GOLDEN-505 study was a phase 2b, randomized, placebo-controlled trial that included 274 patients with no cirrhosis who were randomized to either elafibranor 80 or 120 mg/day, or placebo, for 52 weeks. In the intention-to treat analysis, there was no significant difference between the elafibranor and placebo groups in the protocol-defined primary outcome. However, there was resolution of NASH without worsening of fibrosis in a higher proportion of patients in the 120-mg elafibranor group versus the placebo group (19% vs. 12%), based on a post hoc analysis for the modified definition.⁵¹ Elafibranor is currently being evaluated in an ongoing phase 3 clinical trial (RESOLVE-IT) (NCT02704403) that has a planned recruitment of 2000 participants.

Apoptosis signal-regulating kinase 1 inhibitor

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase involved in transduction of apoptotic signals under oxidative stress conditions. ASK1 pathway is activated in NASH and correlates with fibrosis stage. Inhibition improves steatosis, inflammation, and fibrosis. Selonsertib is currently tested in a phase 3 trial of patients with stage 3 fibrosis (STELLAR 3 study). Among those with NASH cirrhosis (STELLAR 4 study), selonsertib was not found to improve fibrosis stage (i.e., STELLAR 4 did not meet predetermined 48-week primary endpoint; press release in Feb 2019 by Gilead).

Other drugs under investigation

Aramchol (arachidyl amido cholanoic acid), is an stearoyl COA desaturase (SCD1) inhibitor. It blocks a rate-limiting step in the production of monounsaturated fatty acids in the liver. MGL-3196 is a specific thyroid receptor ß-agonists. GR-MD-02 is the Galectin-3 inhibitor that could have an effect on fibrogenesis. NGM282 is an FGF19 analog and GS-0976 is an acetyl-coA carboxylase inhibitors that unblocks the rate-limiting step and de novo lipogenesis in the liver. These drugs are currently under investigation for NAFLD/NASH.

Summary

Better diagnostic and management strategies for NAFLD and NASH are critical at this time. Overall, worldwide prevalence of NAFLD and NASH is 25% and 7%, with type 2 diabetes as the most significant risk factor. Common comorbidities of NASH include obesity, type 2 diabetes, hyperlipidemia/dyslipidemia, hypertension, and metabolic syndrome. Histologic assessment remains the gold standard for diagnosis. There should be a high index of suspicion for NAFLD/NASH in patients with type 2 diabetes. The lack of liver enzyme elevation and the level of increase in liver enzymes is not helpful in identifying those with NASH and/or liver fibrosis. As to diagnostic tools, liver fibrosis stage is the strongest predictor for disease-specific mortality in NASH.

Management of biopsy-proven NASH should begin with lifestyle modifications with diet, exercise, and if otherwise indicated, bariatric surgery to control obesity. Cardiovascular risk reduction would require treatment for hypertension and dyslipidemia. For example, if the patient presents with biopsy-proven NASH and bridging fibrosis at stage 3, and does not have type 2 diabetes, one could use vitamin E. Pioglitazone would probably be a reasonable choice in a patient with diabetes as one could treat the diabetes as well as the fatty liver disease. Although not recommended by AASLD based on lack of data, a GLP-1 receptor agonist also would be an excellent choice.

New molecules targeting different pathways, such as liver metabolic homeostasis, inflammation, oxidative stress, and fibrosis, are being tested for the treatment of NASH in ongoing clinical trials, but we await determination of their effectiveness. Given that the pathophysiology of NASH is multifactorial, combination regimens may prove to be helpful for management of this condition.

Author Disclosure Statement

No competing financial interests exist.