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 Table of Contents  
REVIEW ARTICLE
Year : 2018  |  Volume : 20  |  Issue : 1  |  Page : 57-62

Recent update: Nonalcoholic steatohepatitis


1 HOD, Medicine and Gastroenterology, Department of Medicine, INHS Asvini, Mumbai, Maharashtra, India
2 Resident (Retd), Department of Medicine, INHS Asvini, Mumbai, Maharashtra, India
3 Consultant Radiology, Breach Candy Hospital, Mumbai, Maharashtra, India

Date of Web Publication9-Jul-2018

Correspondence Address:
Jnanaprakash B Karanth
Department of Medicine, INHS Asvini, Near R C Church, Colaba, Mumbai - 400 005, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jmms.jmms_75_17

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  Abstract 

Nonalcoholic fatty liver disease has been traditionally conceptualized as a histological disease spectrum which progresses from simple steatosis or pure fatty liver through liver fibrosis or Nonalcoholic Steatohepatitis (NASH) to cirrhosis and eventually hepatocellular carcinoma (HCC). NASH can progress to cirrhosis, has very high cardiovascular mortality and is a leading cause of HCC worldwide. Recently, the role of various genetic and environmental factors in pathogenesis and progression of the disease have evolved. The lifestyle modifications such as weight reduction, dietary changes, and few drugs with sensitization or antioxidant are available as treatment options. Several newer pharmacological agents are in different stages of clinical trial, and individualized therapy might be a reality in the near future. In view of increasing prevalence of NASH, even in a developing country like ours, a literature search was conducted in PubMed and EMBASE to identify recent publications. We intend to present the epidemiology, and recent inroads made into the pathogenesis, and management of NASH.

Keywords: Hepatocellular Carcinoma, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis


How to cite this article:
Hande V, Karanth JB, Hande P C. Recent update: Nonalcoholic steatohepatitis. J Mar Med Soc 2018;20:57-62

How to cite this URL:
Hande V, Karanth JB, Hande P C. Recent update: Nonalcoholic steatohepatitis. J Mar Med Soc [serial online] 2018 [cited 2018 Dec 14];20:57-62. Available from: http://www.marinemedicalsociety.in/text.asp?2018/20/1/57/236263


  Introduction Top


NonAlcoholic Fatty Liver Disease (NAFLD), worldwide is one of the most common liver diseases. NAFLD encompasses NAFL, NonAlcoholic Steatohepatitis (NASH), NASH-related cirrhosis, and NASH-related hepatocellular carcinoma (HCC). It is increasingly being considered as one of the strong cardiovascular risk factor.[1]

The term “NASH” was first introduced in 1980 to describe histological changes in liver, in the patients with no or insignificant (<20 g/day) alcohol intake, indistinguishable from that of alcoholic hepatitis by Ludwig et al.[2] It is predicted to be one of the main indications for liver transplantation by 2020.[3] An extensive literature search was conducted to identify recent publications available in various journals with the help of PubMed and EMBASE. We intend to present the epidemiology, recent advances made in understanding the pathogenesis and management of NASH.

Epidemiologic features

The recent meta-analysis study on epidemiology of NAFLD by Younossi et al.[4] involving a large population from 22 countries had revealed a significant rise in the prevalence of NAFLD to 25%–30% in 2010 globally from 15% in 2005. The prevalence of NAFLD in Asia and Europe was reported to be similar to that in United States (around 10%–30%).

NAFLD is being perceived as the liver disease component of metabolic syndrome. The metabolic syndrome prevalence was 41% in NAFLD patients whereas the same in patients with NASH was found to be 71%. The prevalence of hyperlipidemia/dyslipidemia was observed to be on the higher side at 69% in patients with NAFLD and 72% in patients with NASH. In view of high prevalence of metabolic syndrome and dyslipidemia in patients of NAFLD, these patients require aggressive treatment and risk stratification to control the risk of cardiovascular disease.[5] Compared to the general population, a higher prevalence of obesity (51% of individuals with NAFLD and 82% of NASH patients) and diabetes mellitus (23% of NAFLD patients and 47% of NASH patients) was observed.[4],[5]

In India, the prevalence of NAFLD is around 9%–32% in the general population and is found to be higher among those with metabolic syndrome as suggested in few epidemiological studies.[6]

There is an increase in the incidence of metabolic syndrome being observed in serving personnel, veterans and their dependents. In view of the above, large numbers of patients are being diagnosed as NASH. However, no data could be found on the epidemiology in the Armed Forces during our extensive literature search.


  Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis Top


NAFLD is defined as hepatic fat accumulation (triglycerides) <5% of the liver weight or hepatocytes histologically (assessed by liver biopsy) as per World Gastroenterology Organization global guidelines June 2012 on NAFLD and NASH. However, other causes (significant alcohol intake, viral hepatitis, autoimmune liver disease, Wilson's disease, hemochromatosis, and α 1 - antitrypsin deficiency) of fat infiltration in the liver should be excluded.[7] NAFLD has been traditionally conceptualized as a histological disease spectrum which progresses from simple steatosis or pure fatty liver through liver fibrosis or NASH to cirrhosis and eventually HCC.

The American Association for the Study of Liver Diseases classifies patients of NAFLD into “not steatohepatitis, with steatosis” and NASH. Around 33% of patients with not steatohepatitis, with steatosis, develop NASH on disease progression which turns into a phenomenal large number. Unlike isolated hepatic steatosis, NASH is strongly associated with histological findings of liver inflammation, cellular ballooning, focal necrosis and fibrosis.[8] The liver fibrosis as been classified into stages from F0 to F4 as follows: F0: no fibrosis, F1: portal fibrosis without septa, F2: portal fibrosis with few septa, F3: bridging septa between central and portal veins, and F4: cirrhosis. F2 stage corresponds to NASH. A total of around 2% patients with NASH can progress to fibrosis stage F4 resulting in increased risk of cirrhosis and primary liver cancer.[8] The sequential liver-biopsy study in patients of NAFLD indicates progression of fibrosis to next stage is around 10 years though it may vary from person to person. Hence, F2 fibrosis will progress to F4 (cirrhosis) within two decades. In this review article, we present the recent advances in pathogenesis and management of NASH.


  Pathogenesis Top


The traditional belief is that NASH is a continuum from simple steatosis. Based on the above belief, Day and James in 1998 proposed “Two-Hit” theory for the pathogenesis of NASH.[9] According to the Two-Hit theory, the first hit is steatosis (i.e., pure fatty deposition) which leads to hepatocyte injury. Cytokines, endotoxin, adipokines or oxidative stress injury are the second hit resulting in NASH.[10] With further research over the years, the initial “Two-Hit” theory was replaced by the “Multiple-Hit” model for explaining the pathogenesis of NASH. It introduced the concept of insulin resistance in the pathogenesis of NASH. Insulin resistance results in hyperinsulinemia that causes an imbalance between cytokines (tumor necrosis factor alpha), adipokines, and adiponectin (those secreted by adipose tissue) and proinsulin.[11] This results in increased lipogenesis in liver leading to hepatic fatty acid infiltration. In this model, the first hit is insulin resistance and its associated metabolic disturbance, whereas reactive oxygen species-induced oxidative damage, deregulation of hepatocyte apoptosis, and multiple adipokines are multiple hits that can result in NASH in preexisting steatosis.[12]

After further research, an alternative “Distinct-Hit” model for the pathogenesis of NAFLD was proposed. The role of genetic and environmental factors in the pathogenesis and progression of NAFLD spectrum evolved [Figure 1].
Figure 1: Schematic diagram of Pathophysiology of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis; distinct Hit Model. (Patatin - like phospholipase domain-containing protein 3 and transmembrane 6 superfamily, member 2, triglyceride)

Click here to view


Genetic and environmental factors

Patatin - like phospholipase domain-containing protein 3 (PNPLA3) and transmembrane 6 superfamilies member 2 (TM6SF2), genetic polymorphisms that are involved in regulation of hepatocyte lipid content have been strongly associated with NASH.[13],[14],[15] PNPLA3 is a multifunctional protein expressed in hepatocytes and adipocytes and has both lipogenic and lytic (triacylglycerol lipase) actions. TM6SF2 polymorphism results in lipotoxicity by decreasing the very low-density lipoproteins secretion from hepatocyte. Both the above gene polymorphisms have been strongly associated with pathogenesis NASH, and significant ethnic variability in expression has been found.[16]

The Hedgehog pathway induction involved in signal cascade results in hepatic fibrosis. Its role in NASH pathogenesis was described by Syn et al.[17] It is emerging as another major genetic discovery in the pathogenesis of NASH.

Any disturbance in circadian rhythm and alteration in gut microbiota has been associated with metabolic syndrome and NAFLD. Both these propositions had been initially studied in mice, and presently, they have been proved in human beings. However, studies and research are still ongoing to determine and manipulate the gut microbiota to either treat or prevent NASH [18],[19] Studies on disturbance of circadian rhythm in mice had revealed dysregulation of farnesoid X receptor (FXR) and constitutive androstane receptor (CAR) activity results in NASH. Inactivation of FXR results in decreased insulin sensitivity, increased lipogenesis, decreased fatty acid beta-oxidation and increased bile acid accumulation in liver cell which leads to overactivation of CAR and hepatic fibrosis.[20] However, further research in this field is in progress.

Clinical features

Patients with NASH are generally asymptomatic. Most patients are diagnosed incidentally during routine workup or their annual medical check-ups. At that time, they are detected to have raised liver enzymes and/or fatty liver on imaging. Some patients are detected to have above findings during evaluation for other illness or while being evaluated for symptoms such as dyspepsia and generalized weakness. The only clinical sign that is elicited in patients with NASH may be hepatomegaly. Signs of hepatocellular failure are seen as the disease progress to cirrhosis or HCC. There are no specific or the diagnostic test for NASH. Most patients may have mild elevation (<03 times of specified upper limits) in aspartate aminotransferase and alanine aminotransferase (ALT) levels with ALT slightly higher than the former.

Definitive diagnosis is made histologically by liver biopsy. The disadvantage is it is invasive and to convince an asymptomatic patient to undergo liver biopsy is not easy. Hence, any patient who is obese or with metabolic syndrome, and no significant history of alcohol consumption presenting with raised liver enzymes after exclusion of other causes of liver ailments must be suspected to have NASH.

Imaging in nonalcoholic steatohepatitis

Ultrasonography (USG) is well established for the detection of fatty liver. Diffuse increase in echogenicity is seen usually in diffuse hepatic steatosis. This is because of higher reflectivity of the ultrasound waves from the liver tissue, most likely due to accumulation of fat within the hepatocytes.[21] This is termed simply as “bright liver.” However, the echo texture is usually homogeneous and is not coarse. The extent of hepatic fatty infiltration can be expressed more objectively as grades.[21],[22] which indicate the severity:

  • Grade I (mild) – increased echogenicity with portal vein walls visualized well and echogenic diaphragm
  • Grade II (moderate) – increased echogenicity with reduced portal vein wall echogenicity, without obscuration of the diaphragm
  • Grade III (severe) – increased echogenicity with imperceptible portal vein wall echogenicity and obscuration of the diaphragm.


However, instead of diffuse infiltration, there may be patchy fatty deposition which is seen as focal hyperechogenic areas known as focal fatty infiltration. Focal fat sparing is localized areas lacking the fatty change and appear hypoechoic as compared with the rest of the bright liver parenchyma. These may be confused with focal liver lesions or masses but have no evidence of mass effect. These areas are generally geographic appearing in typical locations in segment IV, near the gallbladder, or subcapsular region.

Even though USG is operator dependent and lacks objective quantification, it is cost-effective, cheaper, and widely available, thus making it suitable for screening a larger population. USG detects moderate-to-severe hepatic steatosis that can progress to NASH with reasonable accuracy. However, it is less accurate for detecting mild hepatic steatosis.[22]

Ultrasound elastography – Acoustic radiation force impulse (ARFI) evaluates liver stiffness by measuring the shear wave velocities through the parenchyma which is an indicator of hepatic fibrosis.[23] Higher ARFI velocities are suggestive of increased stiffness due to fibrotic changes as in cirrhosis [Figure 2], [Figure 3], [Figure 4], [Figure 5].
Figure 2: Liver acoustic radiation force impulse elastography: shear wave velocity of 1.07 m/s in segment 5 is suggestive of simple Grade I fatty infiltration

Click here to view
Figure 3: Liver acoustic radiation force impulse elastography: shear wave velocity of 1.40 m/s in segment 5 is suggestive of Grade II fatty infiltration

Click here to view
Figure 4: Liver acoustic radiation force impulse elastography: shear wave velocity of 1.89 m/s in segment 5 is suggestive of Grade III fatty infiltration with higher velocity

Click here to view
Figure 5: Liver acoustic radiation force impulse elastography: shear wave velocity of 3.22 m/s in segment 5 is very high and is suggestive of increased stiffness indicative of fibrosis of the liver parenchyma

Click here to view


Computed tomography has a role in specific clinical situations, such as liver donor in liver transplantation.

Magnetic resonance imaging and magnetic resonance spectroscopy are now regarded as the most accurate practical methods of measuring liver fat in clinical practice, especially for longitudinal follow-up of patients with NAFLD.

Management

The wide range of treatment modalities including lifestyle modification, the plethora of pharmacological agents and even surgical interventions such as bariatric surgery have been proposed or evaluated as treatment options for management of NAFLD. The volume and quality of available evidence on efficacy and safety of these interventions are also quite variable. The basic principles used in the treatment of NASH are to target the three major processes involved in pathogenesis insulin resistance, inflammation, and fibrosis.

Lifestyle modification

Lifestyle modification, including dietary modification and physical activity, has been proved to be efficacious in reversing the steatohepatitis, reducing the fibrosis, and fat content in the liver in NASH patients. Recently, the Asia-Pacific working party on NAFLD fatty liver disease guidelines have recommended lifestyle modification in all patients with NAFLD (level A1 evidence). However, the exact intensity, duration, and type of physical activity to be prescribed in these patients is still being debated.[24]

Pharmacological agents

A wide range of pharmacological agents have been evaluated for their therapeutic potential in preventing the progression of and improving reversal of pathological processes in NAFLD. These agents include anti-oxidants (Vitamin E and D), oral hypoglycemic agents (metformin, thiazolidinedione, glucagon-like peptide-1 agonists, and dipeptidyl peptidase-4 inhibitors, Saroglitazar dual peroxisome proliferator-activated receptor [PPAR] agonist) lipid-lowering agents (including statins and fibrates), pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, synbiotics, and probiotics. These agents have shown some beneficial effects in NASH patients and are under evaluation for approval in the treatment of NASH. Currently, only pioglitazone and Vitamin E are recommended for the treatment of NASH as per international guidelines. Statins are also recommended in patients with NAFLD who have a mild elevation of transaminases or compensated cirrhosis.[25],[26]

Thiazolidinediones are PPAR-γ agonists with an insulin-sensitizing effect. Pioglitazone also acts as a PPAR-α agonist.[27] The first European NAFLD clinical practice guidelines published in 2016 recommended its use for the treatment of patients with NASH and Type 2 diabetes mellitus. The recommendation was made at an evidence level of B2, mainly based on evidence from the Pioglitazone versus Vitamin E versus Placebo for the Treatment of Non-Diabetic Patients with Nonalcoholic Steatohepatitis (PIVENS) trial and few other small randomized controlled trials (RCTs).[26]

Vitamin E has been recommended for treating patients with NASH in the 2016 European guidelines. Short-term therapy is well tolerated and safe (evidence level B2). The evidence comes mainly from two large RCTs, PIVENS, and Treatment of nonalcoholic fatty liver disease in children (TONIC) studies.[28]

In a recently published network meta-analysis, Lombardi et al.[29] have reviewed clinical trials comparing the effect of various groups of pharmacological interventions mentioned above with no treatment. As per this review, none of the pharmacological interventions have demonstrated significant differences in mortality at long-term follow-up or drug adverse effects, morbidity, and quality of life of patients. The available quality of evidence also was very poor as reported by the reviewers to make clear clinical recommendations.

Chavez-Tapia et al.[30] have assessed the efficacy of Bariatric surgery for NASH in obese patients, but could not find a sufficient number of randomized controlled trials or quasi-randomized clinical studies to make any clear conclusions on benefits and harms of bariatric surgery as a therapeutic approach for patients with NASH.

Newer therapies

Obeticholic acid, liraglutide, cenicriviroc, elafibranor, and aramchol are few of the emerging drugs for the treatment of NASH. They have either completed trials or are being tested in ongoing trials.[25]

A meta-analysis to evaluate the efficacy of ezetimibe in treating NAFLD and NASH was done by Nakade et al.[31] The study demonstrated improvement in hepatocyte ballooning, but not in hepatic inflammation and fibrosis in patients with NASH.

Polyzos et al.[32] assessed the combined effect of low-dose spironolactone plus Vitamin E versus Vitamin E monotherapy. It was found to result in significant reduction of NAFLD liver fat score (a noninvasive indicator of steatosis) in the combined therapy group. However, ALT-to-platelet ratio index, which is an index of fibrosis, had shown no significant reduction.

Tabrizi et al.[33] have conducted a systematic review to summarize the evidence on the effect of Vitamin D supplementation on metabolic profiles in patients with NAFLD. As per the study findings, Vitamin D supplementation had no effect on fasting blood sugar, insulin resistance, lipid profile, body mass index, and liver enzyme values in NAFLD patients.

Hameed et al.[34] have tested the efficacy of obeticholic acid (OCA) and weight loss in NASH, as compared to placebo (weight loss alone). OCA had led to weight loss in up to 44% of patients with NASH. An additive positive impact of OCA treatment with weight loss was observed on liver histology and serum aminotransferases.

Gao et al.[35] have proposed acupuncture as a useful therapeutic application in NAFLD and proposed possible mechanisms of action in steps. These mechanisms were regulating lipid metabolism, improvement in insulin resistance, increasing the antioxidant levels inhibiting the expression of inflammatory cytokines, and improving the morphology and structure of hepatocyte. However, there is no controlled trial documenting the efficacy of this intervention.

To summarize, even though many treatment modalities have suggested; only lifestyle modifications and Vitamin E have been proved to be effective in altering the histology of liver changes. Pioglitazone is used for treatment in patients with diabetes, but has not been recommended for the general population with NASH. Even though the other therapeutic agents such as obeticholic acid, and bariatric surgery have demonstrated a change in histological findings, there is insufficient evidence to recommend them to treat NAFLD/NASH. The safety and efficacy of other newer therapeutic agents are yet to be tested by a sufficient number of controlled trials.


  Conclusion Top


NASH is one of the most common causes of chronic liver disease worldwide and is emerging as one of the causes of primary HCC as well as the liver transplant. Various genetic and environmental factors have been recently found to have the role in pathogenesis and progression of the disease. Lifestyle modifications such as weight reduction, dietary changes, and few drugs with insulin sensitization or antioxidants are available as treatment options. However, in the management of NASH for the near future are: sensitizing asymptomatic patients on the disease progression, discovery of biomarkers, or imaging modalities for diagnosing and monitoring the progression of the disease and developing a pharmacologic agent that has some direct effect in treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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