CURRENT MANAMGEMENT OF NON-ALCOHOLIC STEATOHEPATITIS

Abstract

NASH is the most common cause of liver disease in Western populations, and its prevalence is increasing rapidly. It is part of a multi-system disease affecting other organs such as the kidneys, heart and blood vessels, and is closely associated with components of the metabolic syndrome. Physicians managing patients with NASH should not only focus on the management of NASH, but also on associated comorbidities in individual patients.

The approaches to treatment of NASH include either limiting energy surplus alone, or in combination with targeting of downstream pathways of inflammation and fibrosis. In this mini-review, we discuss the currently available treatment options for NASH, as well as those in late stage clinical trials. We discuss the challenges of managing these patients with a limited number of approved therapies, as well as managing advanced stage patients with NASH and cirrhosis.

We also discuss the specific management of comorbidities in NASH patients, in particular diabetes, hypertension, dyslipidemia and cardiovascular diseases.

Finally, we present the screening protocols for both hepatocellular carcinoma and extrahepatic malignancies in these patients.

Introduction

Despite the rising prevalence of non-alcoholic steatohepatitis (NASH) and the increasing burden of disease, the efficacy of current drug therapies for NASH are limited, and there are no existing FDA-approved drugs. However, besides the liver, NASH is part of a multi-system disease that affects other organs such as the kidneys, the heart, the arteries, and can precede the onset of both diabetes and the metabolic syndrome. Narrowly focusing on the liver may limit overall improvement in outcomes, especially considering that the top two causes of mortality in NAFLD patients are cardiovascular and malignancy-related¹. This review describes our current approach to the management of NASH patients, including screening for and managing comorbidities.

NASH occurs when the liver is overwhelmed by chronic energy surplus. This energy surplus leads to lipotoxicity, cell death, inflammation, and fibrosis. The two main approaches to the treatment of NASH include either targeting the root cause of energy surplus and excess adiposity, or specific anti-inflammatory and antifibrotic therapies.

Weight loss with lifestyle measures

By limiting energy surplus, weight loss has been shown to be a cornerstone in the management of NASH patients, with ≥7% weight loss improving histology. Not only can weight loss improve liver histology, but it also improves the cardio-metabolic profile of these patients and their glucose homeostasis.

Dietary weight loss can be achieved by caloric restriction, leading to improvements in liver fat. Various diets have been proposed to aid in weight loss, including Atkins, Biggest Loser, Jenny Craig, Nutrisystem, and Volumetrics. Newer diets such as the Ketogenic Diet and Intermittent Fasting have also shown to have potential benefits for weight loss. Despite the various strategies and nutrient compositions of these diets, the key factor to their effectiveness is a reduction in energy intake, with a proposed reduction of 500kcal/day below energy requirements to help achieve weight loss². More important than the composition of nutrients in these diets is the recommendation of a diet plan that an individual patient can adhere to. Independent from weight loss, adherence to the Mediterranean diet, coffee consumption, and increasing the proportion of omega-3 polyunsaturated fatty acids in the diet have been shown to be beneficial to NASH patients³. Despite these recommendations, acceptance of dietary interventions is challenging because of the close association between dietary habits, culture and ethnicity. In addition, many patients with NASH cirrhosis have a caregiver with NASH, probably due to shared lifestyle-related risk factors⁴. Ideally, dietary interventions should be applied to the entire household. This can help with adherence to the diet as well as potentially benefit caregivers at risk of the metabolic syndrome and its associations. Patients and their families should receive advice from trained nutrition professionals on dietary intervention strategies to achieve weight loss.

Exercise has also been shown to help with weight loss and NASH. No obvious benefit has been demonstrated between aerobic and resistance exercises, or between high intensity and low intensity exercise. Resistance exercises may be more feasible in NASH patients who cannot tolerate aerobic exercise, while high intensity exercises may increase adherence to exercise programs with the reduced time commitment. Guidelines recommend >30min/day of exercise, for at least 5 days in a week². Given the frequency of multiple comorbidities in these patients, safety must be emphasized when recommending physical activity, with supervised exercise programs initially in those with significant comorbidities. A combination of diet and exercise appears to be synergistic, resulting in greater weight reduction and liver fat reduction ⁵.

The key to implementing these lifestyle changes is initiation and adherence to these changes. Only a minority of patients can achieve this and both patients and providers are often disappointed during clinical visits. Even when patients do achieve weight loss most return to their baseline weight within 3–5 years⁶ for multi-factorial reasons, including socioeconomic and psychological. Unfortunately, many physicians do not have the experience or time to unravel these complex issues during a regular clinic visit. We recommend a holistic lifestyle intervention plan incorporating diet, exercise, and physical activity modifications, provided by appropriately trained professionals.

Medical interventions for weight loss

Because very few patients manage to achieve and sustain weight loss with lifestyle measures alone, other options have to be considered to limit the chronic energy surplus in the liver. A number of pharmacological agents have been approved by the US FDA for long term weight loss (Table 1). These medications function by impairing the absorption of calories, supressing the appetite, or acting as a stimulant. Medications are indicated in patients who cannot achieve >5% loss of total body weight with lifestyle interventions, who cannot sustain weight loss, patients with a BMI ≥27 kg/m² and at least 1 metabolic comorbidity, or those with a BMI >30 kg/m² whatever the comorbidities². Most of these medications have not clearly been shown to be beneficial to liver histology in NASH patients. Only Liraglutide, a glucagon-like peptide-1 (GLP-1) agonist, has been found to improve liver histology in NASH patients in a phase II study⁷.

Table 1:

US Food and Drug Administration approved weight loss medications approved for long term use

Medication	Mechanism of action	Reported benefits to the liver	Notable side effects
Orlistat	Pancreatic lipase inhibitor – impairs fat absorption	Possible improvements in histology	Fat malabsorption, diarrhoea, liver failure
Lorcaserin	Serotonin 2C agonist – appetite suppressant	Reductions in liver enzymes	Constipation, migraine, neurological side effects, serotonin syndrome
Phentermine-topiramate	Sympathomimetic – induces satiety		Constipation, tachycardia, insomnia, neurological side effects
Naltrexone-bupropion	Dopamine agonist and opioid receptor antagonist	Reductions in liver enzymes	Tachycardia, hypertension, headache, insomnia, seizure, suicidal thoughts
Liraglutide	GLP-1 agonist	Phase II trial demonstrating improvements in histology	Gastrointestinal side effects

Medications currently approved by the US FDA for long term use for weight loss. GLP-1: glucagon-like peptide-1

Weight loss medications combined with lifestyle measures can help patients achieve and sustain 5–10% total body weight loss, thus, it has become increasingly clear that to sustain weight loss, long-term administration of these medications may be necessary. Thus patients are exposed to a longer period of side effects from these medications. Lifestyle measures should be the first option, and should be continued when pharmacological agents are being taken. Patients should be closely monitored, and medications should be discontinued if patients do not achieve ≥5% weight loss. In addition to these medications, sodium-glucose cotransporter-2 (SGLT2) inhibitors have also been shown to be effective for weight loss, and may thus be beneficial in NASH. However, further studies are needed before they can be recommended for use.

Bariatric surgery has also been shown to have clear benefits for weight loss and was associated with improved cardiometabolic profiles in these patients. Although several studies have confirmed improvements in liver histology after bariatric surgery, the largest prospective study to date demonstrated a possible worsening of fibrosis, with more severe fibrosis in almost 20% of patients one-year after surgery⁸. The potential benefits must be weighed against the risks of bariatric surgery, especially in patients with more advanced NASH, advanced fibrosis and cirrhosis.

Certain novel, non-invasive mechanical devices have been developed to help weight loss by limiting energy surplus, with fewer side effects than pharmacological or surgical options. Gelesis 100, a hydrogel-based matrix was recently FDA approved for weight loss⁹. This compound works by occupying space in the stomach thus reducing the appetite. It is not associated with the side effects of other drugs such as nausea and vomiting with GLP-1 agonists. Other minimally invasive mechanical devices such as intra-gastric balloons and duodenal mucosal resurfacing may help with weight loss by limiting energy surplus. However, other than Gelesis 100, the use of these therapies for NASH are in the early stages, and further studies are needed to determine their efficacy and safety for the treatment of overweight.

Targeting downstream pathways in NASH

Although they are not FDA approved, both Vitamin E and pioglitazone (a PPAR-γ agonist) benefit patients with NASH. They have both been shown to improve disease activity scores, and fibrosis in certain cases ¹⁰. Vitamin E reduces oxidative stress in the liver due to its powerful antioxidant properties. Despite the potential benefits, vitamin E has also been associated with increased all-cause mortality, increased intracranial bleeding and prostate cancer. However NASH patients who might have benefited from histological improvement from vitamin E were not included in these studies. In addition, the higher mortality rates may have been due to the higher proportion of men, the failure to take into consideration smoking, as well as other drugs and supplements¹¹. These risks must be balanced with the potential benefit in NASH patients, who have no options for treatment other than lifestyle measures. Certain subgroups of NASH patients have been shown to respond better to vitamin E, and individualized therapy may be a possible strategy ¹². Pioglitazone has been shown to benefit NASH patients without diabetes, pre-diabetes or overt diabetes^10,13. This agent improves insulin sensitivity and enhances adipocyte fat storage. Pioglitazone causes weight gain, which discourages patients who are already struggling to adhere to weight loss interventions. In addition, it may cause congestive cardiac failure and bone loss. As with vitamin E, the benefits of the drug must be balanced against the reported risks.

Other than these two medications, a number of new drugs targeting downstream NASH pathways are in the late stage clinical trials. These drugs treat the disease by inhibiting excess lipid delivery to the liver, de novo lipogenesis, apoptosis, inflammation, or fibrogenesis. A number of these drugs act as farnesoid X receptor (FXR) agonists, inhibiting de novo lipogenesis, improving insulin sensitivity, and regulating the link between de novo lipogenesis and bile acid metabolism. Fibroblast growth factor (FGF) analogues can also provide a similar effect. Another class of drugs increases β oxidation of fatty acids in the mitochondria and modulates the uptake of fatty acids in the liver via thyroid hormone receptors. The drugs currently in phase IIb and phase III trials and their mechanisms of action have been listed in Table 2.

Table 2:

List of drugs currently being evaluated in phase 2b and phase 3 clinical trials

Drug(s)	Mechanism of action	Phase in clinical trial	Trial identification
Obeticholic acid	FXR agonist	III	NCT02548351
Cenicriviroc	CCR2/CCR5 inhibitor	III	NCT03028740
Elafibranor	PPAR-α/δ agonist	III	NCT02704403
Belapectin	Galectin-3 inhibitor	III	4th quarter 2019
Resmetirom	THR-ß agonist	III	NCT03900429
Aramchol	SCD1 inhibitor	III	3rd quarter 2019
Tropifexor	FXR agonist	IIb	NCT02855164
Pegbelfermin	FGF21 analogue	IIb	NCT03486899
NGM282	FGF19 analogue	IIb	NCT03912532
Seladelpar	PPAR-δ agonist	IIb	NCT03551522
Lanifibranor	PPAR-α agonist	IIb	NCT03008070
MSDC-0602K	MPC inhibitor	IIb	NCT02784444

List of medications currently in late stage clinical trials (phase 2b and phase 3) for NASH. FXR: farnesoid X receptor, CCR: C-C chemokine receptor, PPAR: peroxisome proliferator-activated receptor, THR- ß: thyroid hormone receptor ß, SCD-1: Stearoyl-CoA desaturase 1, FGF: fibroblast growth factor, MPC: mitochondrial pyruvate carrier

The benefit of these drugs has not yet been confirmed in NASH, but prospects are good for an FDA approved drug for this indication in the near future. The FDA has created an alternative pathway for approving drugs, known as the Accelerated Approval Pathway (subpart H for drugs). This enables drug companies to apply for approval with trials using surrogate endpoints, shortening the time needed for FDA approval. In addition, drugs that have failed earlier clinical trials are being evaluated in combination with other drugs. All of these efforts will probably result in an FDA approved drug in the near future.

We recommend carefully explaining the risks, benefits and limitations of lifestyle measures compared to currently available pharmacotherapy and allowing patients to make a choice based on an informed decision. The use of vitamin E or pioglitazone for NASH is considered “off-label”, and this must be clearly explained to patients. Participation in clinical trials can be offered to eligible patients.

Managing patients with cirrhosis and NASH

The progression of NASH from significant fibrosis to cirrhosis is associated with a exponentially poorer prognosis. Once the patients develop cirrhosis, the only good treatment option is liver transplantation. Patients may require a liver transplant once they develop decompensated cirrhosis, hepatocellular carcinoma, or certain other complications of cirrhosis. NASH patients with cirrhosis may also develop sarcopenia and frailty, which can worsen their waiting list mortality¹⁴. After liver transplantion, these patients must take diabetogenic medications such as steroids, tacrolimus, and mammalian target of rapamycin (mTOR) inhibitors to prevent allograft rejection due to their increased metabolic risk. Cardiovascular mortality has been shown to be a significant cause of post liver transplant mortality, which may be increased in these patients¹⁵. A new strategy including sleeve gastrectomy at the time of liver transplantion was recently reported. Patients with a BMI ≥35 kg/m² who underwent a sleeve gastrectomy during transplantation maintained greater weight loss and had fewer components of the metabolic syndrome¹⁶. Although this study did not specifically evaluate NASH patients, the predominant liver disease in this study was NASH, and almost 50% of the patients had NASH cirrhosis. Further studies are needed before this can be recommended in routine practice.

Managing diabetes in patients with NASH

NASH can precede diabetes and potentially increase the risk of incident type 2 diabetes. A prospective study reported that patients with NAFLD can have an up to twofold increased risk of subsequent incident diabetes¹⁷. Patients with NASH who are not previously diagnosed with diabetes should be screened for type 2 diabetes. If not present, screening should be repeated at regular intervals in these patients. Fasting plasma glucose levels can be measured during routine follow-up to monitor for the development of diabetes or pre-diabetes in these patients.

Once a patient has diabetes, the management of type 2 diabetes in NASH patients must be evaluated in relation to his/her co-morbidities. Metformin should be the first line treatment in diabetes¹⁸. If the HbA1c is still not sufficiently controlled, we recommend GLP-1 agonists, SGLT2 inhibitors, or thiazolidinediones. GLP-1 agonists have been shown to improve cardiovascular and all-cause mortality in high risk patients with type 2 diabetes. They have been shown to reduce heart failure and the progression of chronic kidney disease (CKD) in certain patients, and are recommended in these patients by the American Diabetes Association clinical practice recommendations¹⁸. In addition, these agonists are associated with significant weight loss, and a phase 2 study reported improvement in liver histology in patients with NASH⁷. SGLT2 inhibitors can also improve weight loss, cardiovascular outcomes, and reduce the progression of CKD¹⁸. Finally, there is emerging evidence that these agents are beneficial to patients with NASH. Pioglitazone has been shown to improve steatohepatitis, disease activity scores, and possibly fibrosis in non-diabetic patients. A recent trial has also demonstrated histological benefits in NASH patients with type 2 diabetes¹³. However, these results must be balanced against the weight gain, fluid retention, and possible worsening of heart failure associated with this drug.

NASH patients with cirrhosis and diabetes who are eligible for liver transplantation must often reach glycemic and weight loss targets to be listed on national transplant waiting lists. Insulin is commonly prescribed to achieve the glycemic targets in these patients. This presents a management dilemma, as the associated weight gain with insulin may prevent patients from achieving weight loss targets. In addition, these patients are sarcopenic, and thus severely insulin resistant and metabolically inflexible. They often require much higher doses of insulin to achieve the glycemic targets, further increasing weight gain and adiposity. We recommend the use of GLP-1 agonists or SGLT-2 inhibitors even in these patients, as they have been shown to help with weight loss, to improve survival and to stabilize CKD in this group¹⁸. Ideally, insulin should be used in cirrhotic NASH patients when glycemic control is difficult with the above-mentioned medication combinations.

Managing hypertension in patients with NASH

NASH is associated with hypertension and the severity of NASH tends to increase in patients with hypertension ¹⁹. The association with NASH does not appear to be as strong as that with diabetes. The benefits of weight loss, especially via lifestyle measures are also true for hypertension. Given the association of NASH with diabetes and CKD, many patients with NASH may need to receive an angiotensin converting enzyme inhibitor (ACE-i)/angiotensin receptor blocker (ARB). There is a theoretical rationale for the use of ACE-i and ARB in NASH patients, as the latter can inhibit the activation of hepatic stellate cells and target pathways involved in the pathophysiology of portal hypertension. However, data on the comparative benefit of anti-hypertensive agents in NASH are limited. Thus we recommend management based on current guidelines. Additionally, given the relative ease and low cost of checking blood pressure, we recommend that NASH patients get regular blood pressure checks during clinical visits, with specific thresholds for intervention according to current guidelines. NASH patients may need to discontinue ACE-I or ARBs once they develop decompensated cirrhosis.

Atherogenic dyslipidemia in NASH patients

Patients with NASH have poorer atherogenic profiles than non-NASH patients, with higher plasma concentrations of VLDL, LDL, and sdLDL. Patients with NASH should undergo screening for dyslipidemia at regular intervals. Studies evaluating statin use in NASH patients have demonstrated improvements in biochemistry. A Greek study reported a histological improvement in NASH in patients receiving rosuvastatin²⁰. However, these findings were not consistent with others. Thus, with the still unproven efficacy for NASH, the main aim of treatment of dyslipidemia is the prevention of cardiovascular events, in particular atherosclerotic cardiovascular disease (ASCVD). Based on current evidence and guidelines, patients with increased LDL levels should have treatment based on their risk profiles. Statins can be safely used in patients with NASH, and should be the first line treatment of LDL to prevent ASCVD. If the response to statins are insufficient, ezetimibe or a PCSK9 inhibitor can be added²¹. Fibrates can be considered in patients with concomitant hypertriglyceridemia.

Many patients with NASH and dyslipidemia are not prescribed statins, despite studies showing their safety in this population²². This is probably due to a fear of liver injury in this group. Withholding statins in these patients with an increased risk of cardiovascular disease can result in worse outcomes. Educating providers, especially non-hepatologists, is a key to allow NASH patients with elevated liver enzymes to continue to receive statins if needed to reduce ASCVD.

Cardiovascular disease in NASH patients

NAFLD is associated with cardiovascular disease and worsening disease severity resulting in a higher rate of incident fatal and non-fatal cardiovascular events. NAFLD is a predictor of atherosclerosis, which has been shown to be independent of traditional cardiovascular risk factors²³. In addition, NAFLD is associated with diastolic dysfunction, impaired ventricular relaxation and increased myocardial thickness, causing reduced exercise tolerance. Exercise tolerance lowers as liver fibrosis worsens²⁴.

The main intervention in these patients should be aggressive risk factor modification, including smoking cessation and control of associated comorbidities in addition to the diet and lifestyle measures discussed above. Physicians managing patients with NASH should regularly evaluate the patient’s cardiovascular risk profile with tools such as the ASCVD risk calculator. There is no firm evidence to recommend aggressive routine screening such as coronary artery calcium scoring in these patients.

Hepatocellular carcinoma (HCC) in NASH patients

Although it was traditionally believed to only occur after the onset of cirrhosis, studies have now demonstrated that between 13–20% of patients with NAFLD-related HCC do not have cirrhosis²⁵. Due to the rapidly increasing prevalence of this disease, NAFLD-related HCC is the second most common indication for HCC transplants in the USA, and may become the first indication. Patients with NAFLD-related HCC also tend to be diagnosed at a more advanced tumor stages compared to other causes of HCC.

While there is still insufficient evidence to recommend screening in non-cirrhotic NASH patients, those with NASH cirrhosis should undergo regular screening for HCC. A retrospective study showed that patients with NASH cirrhosis were inadequately screened, and those who did undergo screening had smaller tumors at diagnosis²⁶. Physicians should identify patients who qualify for screening, especially those with early, well compensated cirrhosis and minimal biochemical abnormalities.

Extrahepatic malignancy screening in NASH patients

The second most common cause of mortality in patients with NASH is extra-hepatic malignancies¹. Increased rates of colon and breast cancer have been reported in male and female patients, respectively. It is unclear if this is due to NASH, or to the shared comorbidities in NASH, obesity, and the metabolic syndrome. Current recommendations for cancer screening should be followed in this population. In particular, biennial screening mammograms for women aged 50–74, and colon cancer screening in patients age 50–75 are important²⁷.

There are certain practical challenges when performing colorectal screening in NASH patients. A study from Hong Kong reported an increased incidence of adenomas and advanced neoplasms in NASH patients, with a higher rate of proximal colonic lesions²⁸ while proximal/right colon lesions are the most commonly missed lesions during colonoscopy. In addition to the increased risk of sedation and endoscopy in obese patients, diabetic patients tend to have more difficulty achieving adequate bowel preparation. This may further increase the rates of missed lesions in NASH patients, especially those with diabetes.

Vaccinations in NASH patients

The Centers for Disease Control and Prevention recommends vaccinations for patients with liver disease. Influenza, Tdap, pneumococcal, hepatitis B, hepatitis A, varicella, and MMR are recommended in patients with chronic liver disease including NASH²⁹. Physicians managing these patients should follow a vaccination schedule. However, rates of vaccination, even for hepatitis A and B have been shown to be suboptimal in patients with chronic liver diseases managed by hepatologists³⁰.

Conclusion

Despite the limited number of pharmacological agents available for the treatment of NASH, the key to management is also effective treatment of comorbidities. The physicians caring for these patients should look beyond the liver to achieve good outcomes in this group, and preferably work with trained ancillary healthcare providers to provide care. In addition, because of this rapidly changing field, physicians should keep abreast of the current literature and emerging pharmacological agents when managing this group.

Key Points.

• Despite the high prevalence and potential consequences of NASH, there are currently no FDA approved treatments for this disease

• NASH should be managed as a multi-system disease in conjunction with the metabolic syndrome and its features

• Weight loss by lifestyle measures, or aided by medical interventions help limit energy surplus

• Specific medications can potentially be used to target inflammation and fibrosis

• Management of other features of the metabolic syndrome must be taken into account in relation to the individual patient and his or her comorbidities

Abbreviations

NASH

non-alcoholic steatohepatitis

FDA

food and drug administration

NAFLD

non-alcoholic fatty liver disease

BMI

body mass index

GLP-1

glucagon-like peptide-1

SGLT2

sodium glucose co-transporter 2

PPAR

peroxisome proliferator-activated receptor

FXR

farnesoid X receptor

FGF

fibroblast growth factor

mTOR

mammalian target of rapamycin

HbA1c

hemoglobin A1c

CKD

chronic kidney disease

ACE-i

angiotensin converting enzyme inhibitor

ARB

angiotensin receptor blocker

VLDL

very low density lipoprotein

LDL

low density lipoprotein

sdLDL

small dense low density lipoprotein

ASCVD

atherosclerotic cardiovascular disease

PCSK9

proprotein convertase subtilisin / kexin type 9

HCC

hepatocellular carcinoma

Tdap

tetanus, diphtheria and pertussis

MMR

measles, mumps and rubella