|Year : 2021 | Volume
| Issue : 4 | Page : 243-248
Fatty liver - Current and future treatment: A narrative review
Arka De, Ajay Duseja
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
|Date of Submission||29-Oct-2021|
|Date of Decision||27-Oct-2021|
|Date of Acceptance||17-Nov-2021|
|Date of Web Publication||23-Dec-2021|
Department of Hepatology, Post Graduate Institute of Medical Education and Research, Chandigarh - 160 012
Source of Support: None, Conflict of Interest: None
A holistic approach is required for managing patients with nonalcoholic fatty liver disease (NAFLD). Lifestyle interventions and medical management of metabolic risk factors currently form the cornerstone of NAFLD management. A target weight loss of approximately 7%–10% in overweight/obese patients is recommended with the help of dietary calorie restriction and exercise. None the less, attaining and sustaining the target weight loss is a major challenge with lifestyle interventions. Exercise alone has also been shown to be beneficial even in the absence of weight loss and may be the modality of choice in patients with lean NAFLD. Currently, pioglitazone and Vitamin E are recommended by most of the scientific societies in patients with biopsy proven, noncirrhotic nonalcoholic steatohepatitis (NASH). Recently, saroglitazar has been approved by the drug controller general of India for management of NAFLD with comorbidities or NASH with F1-F3 fibrosis. Although not recommended as a primary modality to treat NAFLD per se, bariatric surgery is an alluring option in otherwise eligible obese patients without cirrhosis. A lot of research is being carried out in the field of NASH pharmacotherapy and many new drugs are in the pipeline.
Keywords: Cryptogenic cirrhosis, insulin resistance, liver transplantation, metabolic dysfunction-associated fatty liver disease, metabolic syndrome, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis
|How to cite this article:|
De A, Duseja A. Fatty liver - Current and future treatment: A narrative review. Apollo Med 2021;18:243-8
| Introduction|| |
“Foie gras” or fatty liver refers to the excessive accumulation of fat in the liver. There are a multitude of causes of fatty liver [Table 1] and the most common are nonalcoholic fatty liver disease (NAFLD) and alcohol. In the ensuing review, we will be discussing the current and future therapeutic options for NAFLD and will not discuss other etiologies of fatty liver.
Globally, one in every four individuals has underlying NAFLD. The burden of NAFLD in India is alarmingly high with a prevalence of 9%–53% with possible geographic variations and a rural-urban divide. This burden is expected to increase over time due to increasing urbanization, adoption of western lifestyles, and easy access to calorie-dense foods. NAFLD is characterized by hepatic steatosis in the absence of significant alcohol intake or alternate etiologies of fatty liver.
NAFLD incorporates a spectrum of histologic findings that includes nonalcoholic fatty liver (NAFL) or simple steatosis, nonalcoholic steatohepatitis (NASH), steato-fibrosis or NASH with fibrosis, NASH-cirrhosis, and NASH-hepatocellular carcinoma (HCC). In contrast to NAFL, NASH which is characterized by hepatocyte ballooning and lobular inflammation with or without fibrosis is usually considered to be the progressive form of the disease which requires specific pharmacotherapy.,,,
Earlier data from India had suggested a mild liver histology in patients with NAFLD presenting to the hepatologists., Recent data from India, however, suggest that histological NASH is present in more than 60% of patients and advanced fibrosis (≥F3) in 35% of patients.
Similarly, recent data based on noninvasive assessment in Indian patients show the presence of significant fibrosis in 19%, 21% and 29% of patients as assessed by Fibrosis-4 (FIB-4), AST platelet ratio index, and FibroScan respectively. The presence of metabolic risk factors and data on explant pathology also suggests NAFLD to be the predominant etiology of cryptogenic cirrhosis and cryptogenic HCC in India. Similar to data from the West, recent Indian data shows a trend of NASH as the increasing etiology of HCC and an emerging indication for liver transplantation.
Since the diagnosis of NAFLD requires exclusion of alcohol and other secondary causes of hepatic steatosis and the definition does not mention the metabolic dysfunction which is so common in these patients, some experts consider it to be a negative definition and have recently proposed the new term metabolic dysfunction-associated fatty liver disease (MAFLD) in place of NAFLD. However, the attempt to give a positive definition of MAFLD is causing confusion as experts are also suggesting that under the umbrella of MAFLD, there is no need to distinguish steatohepatitis and no-steatohepatitis Furthermore, the perception that the word “non-alcoholic” is probably trivializing and stigmatizing the disease is premature and does not make a solid ground for this change in nomenclature. Further, around 10%–20% of patients with NAFLD are lean and a substantial proportion of them do not have diabetes mellitus. These patients may be missed using the proposed MAFLD criteria. Hence, we would be restricted to the standard definition of NAFLD in this review article.
The current understanding of the complex pathophysiology of NAFLD involves multiple hits and is beyond the scope of this review. We will focus on the current pharmacological management of NAFLD and will give a brief overview of the future of NASH therapy.
Current management of NAFLD
A holistic approach is required to optimize the management of NAFLD. Diagnosis and adequate management of metabolic comorbidities such as type 2 diabetes mellitus (T2DM), hypertension (HTN), dyslipidemia, and obesity is of paramount importance. Currently, lifestyle interventions including dietary modifications and exercise form the cornerstone of NAFLD management.,, Pharmacologic options for the treatment of NAFLD per se remain limited and are usually restricted to a select group of patients as discussed below.
There is a clear dose-response relationship between the magnitude of weight loss and the degree of histologic improvement. Thus, while weight loss of 3%–5% can improve hepatic steatosis, higher degrees of weight loss are required for improvement in features of NASH (≥7%) and fibrosis (≥10%). A weight-loss target of 7%–10% is recommended in current international guidelines for overweight or obese individuals with NAFLD. Rapid weight loss (>1 kg/week) should, however, be avoided as this can lead to a worsening of liver functions.
Physical exercise is a key lifestyle intervention in the management of NAFLD. Improvement in hepatic steatosis with exercise was shown in 2.3 lakh volunteers over 5 years of follow-up. Importantly, recent evidence suggests that exercise can have beneficial effects beyond weight loss. Indeed, evidence suggests that exercise can lead to improvements in insulin resistance and hepatic steatosis even in the absence of weight loss. This is particularly relevant for patients with “lean” NAFLD who already have a normal body mass index.
The type, intensity, and duration of exercise required in NAFLD is a field of ongoing research and the available data are scanty. Limited evidence suggests that the degree of reduction in steatosis may not depend on the intensity of exercise. Exercise usually consists of aerobic exercises, such as brisk walking, jogging, running, swimming, or cycling for 45–60 min, at least 5 days in a week to achieve a target heart rate of 60%–70% of maximal heart rate. Resistance exercises can complement aerobic exercises and are particularly relevant for patients with poor cardio-respiratory fitness or who cannot otherwise partake in aerobic exercises.
Dietary caloric restriction should go hand-in-hand with exercise. Reduction of calorie intake by 30% or 500–1000 kcal/day is usually recommended.,, There is much hue and cry in the popular media about the putative benefits of specific types of named diets. The Mediterranean diet has been shown to decrease cardiovascular disease (CVD), cancer, obesity, T2DM, and associated mortality., However, some of the proposed diets (including the Mediterranean diet) are difficult to incorporate with usual Indian food habits and dietary choices. With the available evidence, a negative calorie balance appears to be more important than the specific form of diet. Indeed, a dietary plan that the patient is comfortable is more likely to be complied with over a sustained period of time. Data on the utility of intermittent fasting in patients with NAFLD is also evolving.
There has been a lot of debate about the putative benefits of mild-moderate alcohol consumption in NAFLD. Contrary to evidence from previous cross-sectional studies, recent longitudinal studies have demonstrated worsening of histology and noninvasive markers in NAFLD with modest alcohol consumption. Further, the risk of various malignancies like breast and colon carcinoma are increased with even limited alcohol consumption. Thus, alcohol use in any amount should be discouraged in patients with NAFLD.
Pharmacotherapy for weight loss
An important caveat is that while a proportion of patients can attain weight loss by lifestyle interventions alone, the weight loss is sustainable in only a fraction of the patients (3%–6%). With the passage of time various physiologic adaptations lead to a decrease in satiety, increased hunger, and decreased energy expenditure leading to weight gain. Drugs that are currently approved by the Food and Drug Administration (FDA) for weight loss include orlistat, liraglutide, phentermine-topiramate combination, and naltrexone–bupropion. However, pharmacologic interventions for weight loss are generally not recommended in patients with NAFLD including those with cirrhosis.
Bariatric and endoscopic therapies for weight loss
Bariatric surgery has been shown to decrease weight by 14%–25% after 10 years of follow-up with a reduction in mortality, CVD, and improved control of DM. Resolution of NASH may be attainable in almost 85%–90% of patients' postbariatric surgery. Bariatric surgery is an important option in otherwise eligible obese patients with NAFLD, but it is not recommended for the treatment of NAFLD per se. However, due caution and vigilance should be ensured to rule out cirrhosis prior to proceeding for bariatric surgery. Postbariatric surgery mortality in cirrhosis ranges from 1% to 2.45% in compensated disease to as high as >15% in patients with decompensated cirrhosis. Various endoscopic bariatric devices and procedures have been described for weight loss. This is an evolving area, and more data is required in patients with NAFLD.
Management of other metabolic risk factors
The presence of metabolic syndrome is the predominant pathophysiological driver of hepatic steatosis, inflammation, and fibrosis in the vast majority of patients with NAFLD. The management of metabolic comorbidities such as DM, HTN, and dyslipidemia is part and parcel of the holistic management of NAFLD.,, It is worthwhile to remember that the commonest cause of mortality in patients with NAFLD is CVD. Statins, when indicated, can be safely used in patients even with elevated transaminases. However, caution is required in patients with cirrhosis particularly in those with CTP class B or C.
Glycemic worsening has been associated with hepatocyte ballooning and fibrosis. DM in patients with NAFLD should be managed as per guidelines for the general population. Various anti-diabetic medications have also been evaluated for the treatment of NAFLD per se. Although metformin improves insulin resistance and liver biochemistry, improvement in histologic parameters was not demonstrated with its use. There is encouraging phase 2 data about the use of glucagon-like peptide-1 (GLP-1) analogs in NAFLD. Liraglutide has been shown to improve NASH resolution and decrease fibrosis progression in the LEAN trial. In a recent trial including 320 patients with biopsy-proven NASH, higher rates of histologic resolution of NASH were reported with Semaglutide compared with placebo. However, there was no improvement in fibrosis. Both liraglutide and Semaglutide have also been shown to decrease body weight. Further phase 3 trials on these GLP-1 analogs in NASH are eagerly awaited. Encouraging data are also available with the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with NASH. However, the largest body of evidence for histologic improvement in NASH with the use of an anti-diabetic agent is for pioglitazone which is discussed in detail below. Endoscopic treatment of metabolic diseases is an emerging field and improvement in metabolic profile and hepatic steatosis has been reported in patients with T2DM and NAFLD using endoscopic duodenal mucosal resurfacing., However, a lot more evidence is needed before endoscopic therapies can be incorporated in the routine therapeutic armamentarium for managing metabolic risk factors in NAFLD.
Current pharmacotherapy for managing nonalcoholic fatty liver disease
International guidelines recommend pharmacotherapy only in patients who have underlying NASH on liver biopsy.,, However, biopsy is not feasible option in routine clinical practice. With the emergence of excellent noninvasive serum biomarkers and elastography for ascertaining the severity of underlying fibrosis, the key determinant of clinical and histologic outcomes, biopsy is being largely restricted to patients with diagnostic confounders in most Indian centers outside of clinical trial settings. Although not recommended, in patients where biopsy is not feasible, it may be prudent to proceed with pharmacotherapy in those with clinical or noninvasive predictors of severe disease.
The current pharmacotherapeutic options for NAFLD are limited. These are summarized in [Table 2]. Various international guidelines recommend Vitamin E or pioglitazone although these are not approved for use in NAFLD by regulatory agencies like US-FDA.,, In 2020, the drug controller general of India (DCGI) has approved saroglitazar for use in NAFLD with comorbidities (obesity, DM, dyslipidemia, or metabolic syndrome) and NASH with F1-F3 fibrosis.
|Table 2: Current pharmacological options in nonalcoholic fatty liver disease|
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Pioglitazone is a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist which decreases insulin resistance and hepatic steatosis primarily by upregulation of adiponectin. In the pivotal PIVENS trial, 247 biopsy-proven NASH patients without DM were randomized to either pioglitazone (30 mg/day), Vitamin E (800 IU/day), or placebo for 96 weeks. Patients on pioglitazone did not achieve the primary endpoint of “improvement in NAS by 2 points with at least 1-point improvement in hepatocellular ballooning and 1-point improvement in either the lobular inflammation or steatosis score and no increase in the fibrosis score.” However, significantly, more patients in the pioglitazone group attained a resolution of NASH as compared to placebo. Significant benefit with pioglitazone regarding NASH resolution has also been demonstrated in biopsy-proven NASH patients with prediabetes or T2DM. Current guidelines recommend the use of pioglitazone in patients with biopsy-proven NASH with or without T2DM.,, However, pioglitazone may lead to weight gain which may potentially off-set the benefits of therapy. Osteoporosis has also been reported. A debatable association with urinary bladder cancer has also been suggested.,
Vitamin E is an antioxidant. In the aforementioned PIVENS trial, Vitamin E was shown to decrease hepatic steatosis, inflammation, and ballooning with an improvement in NAFLD activity score (NAS) and increased NASH resolution. The beneficial effects of Vitamin E on liver biochemistry and various histologic parameters including steatosis, inflammation, and ballooning but not fibrosis have been corroborated in multiple studies and meta-analysis. NASH resolution has also been demonstrated in pediatric patients in the TONIC trial. Current guidelines recommend Vitamin E (800 IU/day) in nondiabetic patients with biopsy proven NASH.,, Although well-tolerated concerns there are concerns about a possible increased risk of prostate cancer with long-term use of Vitamin E. Previous concerns regarding increased all-cause mortality appear unwarranted as was shown in recent meta-analyses.,
Saroglitazar is a dual PPAR agonist with a predominant PPAR-α effect and moderate PPAR-γ effect. Thus, it is helpful for dyslipidemia and insulin resistance, without being associated with typical glitazone side effects. There is a lot of data on the use of Saroglitazar in diabetic dyslipidemia for which it has been approved in India since 2013. In the recently published phase II EVIDENCES IV trial from the USA, Saroglitazar significantly improved liver biochemistry, hepatic steatosis, insulin resistance, and dyslipidemia in NAFLD patients. Data from the multicentric, EVIDENCES II study from India, further showed a of decrease in NAS by ≥2 points without worsening of fibrosis in significantly more patients with saroglitazar compared to placebo (52.3% vs. 23.5%; P = 0.04) in 102 patients with biopsy-proven noncirrhotic NASH. Overall, saroglitazar is well tolerated and the predominant adverse effects are gastrointestinal including flatulence, dyspepsia, and bloating. Saroglitazar in a dose of 4 mg/day has now been approved by the DGCI for use in with NAFLD with comorbidities (obesity, DM, dyslipidemia, or metabolic syndrome) and NASH with F1-F3 fibrosis.
Future pharmacotherapy in noncirrhotic nonalcoholic steatohepatitis
Based on encouraging phase II data, various drugs such as obeticholic acid (OCA), resmetirom (thyroid hormone beta-agonist), cenicriviroc (chemokine inhibitor), and aramchol (bile acid/fatty acid conjugate) are being evaluated in phase III studies. OCA, a farnesoid-X-receptor (FXR) agonist is approved for the management of primary biliary cholangitis at a dose of 5 mg and has been recently marketed in India. Interim analysis of the phase 3 study with OCA in patients with NASH (Regenerate trial) showed that the primary outcome of ≥1 stage improvement in fibrosis without worsening of NASH was significantly more common in patients treated with 25 mg (23.1%, P = 0.0002) of OCA as compared to placebo (11.9%). However, almost half of the patients who received 25 mg of OCA complained of pruritus and 13% of patients discontinued treatment. Further, elevated LDL was also seen in 17% patients although this appears to be responsive to statins. It should be emphasized that OCA is currently neither approved by any regulatory agency nor recommended by current guidelines for the treatment of patients with NAFLD/NASH.
Current therapeutic strategies in patients with NASH target one of three axes: Metabolic dysfunction, inflammation, and fibrogenic pathways. Given the complex pathophysiology of NASH, combining drugs with different mechanisms of action (e.g., cilofexor [a nonsteroidal FXR agonist and firsocostat [an acetyl-Co A carboxylase inhibitor], combination of tropifexor [a FxR agonist] and Licogliflozin [SGLT-2 inhibitor]) is a rational approach and is being evaluated in phase 2 clinical trials. The role of gut microbiota and its modulation is also being studied in NASH. Fecal microbiota transplantation is being evaluated in patients with NASH-related decompensated cirrhosis (NCT02868164). In a recent, proof-of-concept study in biopsy-proven NAFLD patients, a high-potency, multistrain probiotic was shown to improve ballooning, inflammation, and NAS on histology along with significant improvements in ALT, cytokine, and endotoxin levels.
Management of noncirrhotic nonalcoholic steatohepatitis related cirrhosis and hepatocellular carcinoma
The management of NASH-related cirrhosis and HCC is done along similar lines as for other etiologies. Currently, there are no recommended or approved therapeutic options for NASH cirrhosis with the use of Vitamin E, pioglitazone, or saroglitazar being restricted to noncirrhotic patients. Recent retrospective studies suggest that Vitamin E and metformin may reduce the risk of decompensation and improving the transplant-free survival in NASH cirrhosis., Further, metformin may also decrease the risk of HCC. However, pending further evidence, NASH-specific pharmacotherapy should not be used routinely in patients with NASH-cirrhosis. Liver transplantation remains the treatment of choice for those with decompensated cirrhosis. Posttransplant graft and patient survival outcomes at 1, 3, and 5 years are comparable to liver transplants done for other etiologies. However, close attention should be given to pretransplant cardiovascular and renal evaluation to unravel overt or silent cardiovascular and renal disease which is common in these patients. Post liver transplant recurrent or de-novo NAFLD is a major challenge and should be managed with lifestyle interventions and modifications of the culprit immunosuppressive drugs if possible. Data on the use of drugs such as Vitamin E, pioglitazone, and saroglitazar are not available in post liver transplant patients with NAFLD/NASH.
| Conclusions|| |
The therapeutic armamentarium for the management of NAFLD continues to remain limited. Current management primarily entails adequate medical management of metabolic comorbidities and lifestyle interventions targeting weight loss. Exercise and dietary modifications are of paramount importance. Saroglitazar is approved by DCGI for use in patients with NASH having F1-3 fibrosis. Pioglitazone and Vitamin E are also recommended in biopsy-proven noncirrhotic patients with NASH.
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Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]