Nonalcoholic steatohepatitis (NASH)




Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD).

It  is associated with disease progression, development of cirrhosis, and need for liver transplant. 

NASH is a progressive form of NAFLD and has superseded hepatitis  as the main cause of cirrhosis and the main reason for liver transplantation.

A progressive liver disease characterized by the presence of 5% or greater hepatic steatosis with hepatocellular damage and inflammation.

NASH diagnosis is established by liver biopsy that shows steatosis, lobular inflammation and hepatocellular ballooning.

NASH is classified into five stages on the basis of the extent of fibrosis: F0 indicates no fibrosis, F1 portal fibrosis, F2 periportal fibrosis, F3 bridging fibrosis, and F4 cirrhosis.

Once NASH progresses to clinically meaningful fibrosis-stages F2 and F3, the risk of adverse clinical outcomes markedly increases, especially among patients with type two diabetes.

Fibrosis stages F3 and F4 are associated with death do to liver disease.

A condition that results from a combination of adipose tissue Insuline resistence, adipocytokine imbalance, and systemic inflammation.

Up to 1/3 of NASH population will develop fibrosis, and 20% cirrhosis as part of disease progression.

The presence of NASH and advanced fibrosis impacts mobility and mortality.

The development of clinically significant fibrosis in NASH is associated with worse liver related outcomes with progression to cirrhosis and complications, including hepatocellular carcinoma, cardiovascular events, and death.

Patient with NASH have significantly decreased survival times, increase liver and non-liver related mortality compared with controls.

An underrecognized process.


A major worldwide cause of chronic liver disease, associated with cirrhotic  morbidity, hepatocellular carcinoma and liver transplantation, worsening cardiovascular disease, and metabolic dysfunction.


NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing.

Worldwide prevalence of NAFLD at about 5.3%

The prevalence among middle-aged adults in the US is 14% and increasing.


NAFLD has become the most common cause of chronic liver disease in adults, even in children, and it is the second leading indication for liver transplantation behind hepatitis C disease.


NASH In patients with diabetes will be responsible for 65,000 liver transplants 1.37 million cardiovascular related deaths, 812,000 liver related deaths, and will cost about $55.8 billion to the healthcare system.

NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, cardiovascular disease and metabolic syndrome. 

Risk factors for NASH and advanced fibrosis include: older age, abnormal aminotransferase levels, metabolic syndrome, this rule obesity, and hypertension.


NASH prevalence of metabolic syndrome is 71% and for NAFLD 43%.


Liver biopsy is the only accepted method for diagnosis of NASH. 


NASH-specific therapies are lacking.


 The main treatment are lifestyle modification which include: dietary changes, exercise, and weight loss


Liver histology outcomes, including fibrotic changes, are directly related to weight loss. 


Bariatric surgery may be indicated to achieve and maintain weight loss necessary for therapeutic affect.


Approximately 20% of patients with NASH will develop cirrhosis.


NASH is predicted to become the leading indication for liver transplants in the US. 

Pharmacotherapy in patients with NASH has been associated with failures, and is difficult to establish efficacy.

Therapy is divided into those agents targeting weight loss and those targeting more specific aspects of the lipotoxicity – fibroinflammatory cascade.

Fibroblast growth factor 21 (FGF 21) has metabolic affects mediated in part by adiponectin that improves insulin sensitivity, reducesinflammation, improves vascular function, and acts directly on various tissues, including the liver, adipose tissue, and the pancreas.

These effects modulate, lipogenesis, ketogenesis and energy expenditures, and FGF 21 analogues, such as pegozafermin have demonstrated improved metabolic effects with NASH.

The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years.

Nonalcoholic fatty liver disease (NAFLD) is one of the most commonly encountered liver disorders worldwide.

In  NAFLD the accumulation of triglyceride in hepatocytes, develops in the absence of secondary causes such as medications, excessive alcohol consumption, or certain heritable conditions.

Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of NAFLD, with steatosis as well as evidence of inflammation, with or without fibrosis.


Over time NASH can progress to cirrhosis, end- liver disease, and the need for a liver transplant.


Simple steatosis has a low rate of progression with only about 4% of patients developing cirrhosis


More than 20% of patients with NASH will develop cirrhosis in their lifetime.


NASH is now the leading indication for liver transplant listing for women and is expected to overtake alcoholic liver disease as the leading liver transplant indication for all patients within the next few years.


There is an increased risk of hepatocellular carcinoma among patients with NASH.


NASH has significant geographic variability, with highest rates in the Middle East and South America (>30%) and lowest rates in Africa (13%). 


20% to 30% of the US population meet criteria for NAFLD.


Prevalence appears to be increasing, with an estimated 3.6 million new cases annually.


Both NAFLD and NASH are more prevalent among males.


NAFLD prevalence is highest among Hispanic and lowest among black populations.


Ina  series of clinic outpatients or living donors for liver transplants biopsy results found NASH in 1.4% to 15% of patients.


Population prevalence estimates extrapolated from liver biopsy case series and from voluntary or referred biopsies studies involving patients with NAFLD suggest about 20% of all patients with NAFLD are expected to demonstrate NASH histology.


Estimates suggest that 3% to 6% of adults have NASH.


The proportion of NAFLD patients with NASH is expected to increase over the next decade. 


NASH and NAFD  are strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome.


Patients with NASH are more likely to be obese or exhibit metabolic derangements than patients with only NAFLD or the general population.


THE prevalence of NAFLD in patients undergoing bariatric surgery exceeds 90%.

Among patients with NASH and obesity, bariatric surgery compared with non-surgical management was associated with significant lower risk of major adverse liver outcomes and major adverse cardiovascular events (Amiinian A).

NASH outcomes are strongly associated with degree of hepatic fibrosis.


The severity of fibrosis is predictive of long-term outcomes including overall mortality in patients with NAFLD.


 A higher proportion of patients with NASH have evidence of fibrosis on biopsy than patients with uncomplicated NAFLD.


NASH may regress to NAFLD over time.


About 25% of patients� fibrosis is staged at F2 or greater at the time of NAFLD diagnosis.


Around 40% of NASH patients have progression of their fibrosis over time, at a rate of about 1 stage per decade.


Patients with NASH develop hepatocellular carcinoma at higher rates than the general population and have an annual rate that is 12 times higher than patients with NAFLD.


Patients with NAFLD have higher overall and liver-specific mortality.


NASH has an annual mortality 1.7 times higher than NAFLD (25.56 vs 15.44 events per 1000 person-years), and liver-specific mortality is 15 times higher than in NAFLD (11.77 vs 0.77 events per 1000 person-years).


Despite increased liver-related mortality, cardiovascular disease is the primary cause of death for patients with both diagnoses.


Patients with NASH are asymptomatic or have nonspecific symptoms such as fatigue or vague abdominal pain. 


Most commonly, patients with NASH are diagnosed  after workup for unrelated conditions.


An ultrasound or computed tomographic (CT) scan that demonstrates steatosis or laboratory testing that shows elevated transaminases may prompt further workup for either NAFLD or NASH. 


Liver ultrasound is the initial imaging study for patients with abnormal liver function test results and clinical concern about hepatic steatosis. 


Patients with steatosis, those who are obese or who have prediabetes or type 2 diabetes, hypertension, hypertriglyceridemia, or metabolic syndrome are at higher risk of NASH . 


Older patients are also more likely to have NASH than younger patients. 


NAFLD diagnosis requires either radiographic or histologic demonstration of more than 5% hepatic steatosis in the absence of excessive alcohol consumption. 


NASH diagnosis requires a biopsy with histologic examination demonstrating hepatic steatosis of more than 5%, hepatocyte ballooning degeneration, and hepatic lobular inflammation.


Alcohol consumption threshold of less than 21 standard drinks each week for men and 14 drinks per week for women to characterize steatohepatitis as nonalcoholic.


Standard drink defined as being 1 oz [30 mL] of hard liquor, 4 oz [120 mL] of wine, or 12 oz [.36 L] of beer).


Liver biopsy is currently the only accepted method to reliably differentiate NASH from simple steatosis, ie, uncomplicated NAFLD.


No NASH-specific therapies are currently approved, and lifestyle modifications are generally recommended for all patients with NAFLD, regardless of whether they have NAFLD or NASH.



Currency guidelines recommend biopsy for patients with NAFLD who are at increased risk of steatohepatitis and/or advanced fibrosis and for patients in whom coexisting liver diseases cannot be ruled out.


High-risk patients include: those with coexisting metabolic diseases, elevated LFTs, particularly elevated alanine aminotransferase, and Hispanic ethnicity. 


Liver biopsy may be helpful in providing prognostic information to patients. 


Liver biopsy limitations: Can be painful and carry morbidity such as bleeding, infection, bile leak, damage to other organs, and rare mortality risk (<0.01%).


Fibrosis is the most important prognostic factor for the long-term outcomes of NASH.


Fibrosis is a requirement for diagnosis of NASH.


Improvement or worsening of disease activity may be associated with the regression or progression of fibrosis, respectively, in NAFLD.


NAFLD is common and, when uncomplicated, typically asymptomatic, so hepatic steatosis is often incidentally diagnosed on imaging studies such as ultrasound or CT scan. 


A biopsy-controlled study involving patients with NASH showed that ultrasound missed 22% of steatosis diagnoses.


Steatosis detection  on noncontrast CT, has similarity or lower sensitivity than ultrasound.


MRI  is the most sensitive modality for the evaluation of hepatic steatosis, with a92%-100% sensitivity, 92%-97% specificity.


Lover MRI can detect as little as 3% steatosis.


No imaging modalities can differentiate NAFLD from NASH.


Imaging studies have limited ability to discern advanced fibrosis.


Noninvasive imaging evaluation for fibrosis measures elastic shear wave propagation through liver parenchyma, with stiffer fibrotic tissue propagating waves faster.


The best methods are transient elastography using ultrasound and magnetic resonance elastography.


Elastography using ultrasound has a sensitivity of advanced fibrosis of 85%


 and 92% for detecting cirrhosis.


Magnetic resonance elastography 


has a sensitivity of 86% for identifying patients with advanced fibrosis.


While an elevated ALT level is a commonly cited marker of progressive NAFLD or NASH, a normal ALT level does  not preclude a diagnosis of NASH. 


The conventional ALT cutoff for further testing is 1.5 times the upper limit of normal; however, at this level, ALT has only 72% sensitivity and 51% specificity for the diagnosis of NASH.


11% to 30% of patients with biopsy-proven NASH have normal ALT levels.


When elevated, the AST:ALT ratio is typically less than 1.40.


Aminotransferase  elevation  does not correlate with the diagnosis of NASH, severity of fibrosis, or severity of inflammation.


Elevated ALT levels have been associated with insulin resistance and degree of hepatic steatosis in patients with NASH, but patients with severe NASH may have normal liver enzymes.


The NAFLD fibrosis score uses commonly available clinical parameters including patient age, body mass index, diagnosis of impaired fasting glucose or diabetes, AST:ALT ratio, albumin level, and platelet count.


The score may be useful for excluding advanced fibrosis, with a 90% sensitivity and 64% specificity for stages F0 through F2 fibrosis if the score is less than 1.455 and 60% sensitivity and 97% specificity for stages F3 and F4 fibrosis if the score is more than 0.675. 

F0 indicates no fibrosis, F1 portal fibrosis, F2 periportal fibrosis, F3 bridging fibrosis, and F4 cirrhosis.

The FIB-4 index, which predicts fibrosis based on age, ALT, AST, and platelet count, has been validated in NAFLD and NASH.


 The FIB-4  index performed as well as or better than the NAFLD fibrosis score for advanced fibrosis.




No approved therapy for NASH is available. 


Currently, the primary treatment for NASH is lifestyle modification through diet and exercise, the ultimate goal is weight loss.


No specific macronutrient diet has been shown to have a benefit for NASH. 


Caloric restriction is the most appropriate recommendation.


Fructose consumption should be limited.


Fructose is associated with NASH development in patients with NAFLD and fibrosis progression.


Patients with NASH should also abstain from or significantly limit alcohol consumption, as it is associated with hepatic injury and decreased chance of NASH resolution with treatment.


Exercise decreases hepatic fat content independent of weight loss.

Exercise reduces insulin resistance, and may modify de novo synthesis of free fatty acids, all of which may have an effect on NASH.


 Vigorous exercise appears to limit the progression of NAFLD to NASH.


Weight loss has the strongest association with histologic improvement in NASH. 


Weight loss of at least 5% is required  for improvement of NASH.


All patients who lost more than 10% of their weight had reductions in their NAFLD activity score, and 90% had complete resolution of their NASH.


Weight  loss of more than 10% may be associated with fibrosis regression, with this effect seen in 45% of patients. 


Modest weight loss  of 5% stabilizes fibrosis.


Risk of death from cardiovascular causes, the most common cause of death in NASH, is reduced after bariatric surgery.


Bariatric surgery have shown substantial improvements in liver histology and NAFLD activity score, including decreased prevalence of NASH.

With bariatric surgery trial 85% no longer had NASH on biopsy 1 year after bariatric surgery, and 33% had fibrosis regression.


Vitamin E (an antioxidant) and pioglitazone (a thiazolidinedione insulin sensitizer acting through peroxisome proliferator-activated receptor [PPAR] have shown some benefit in randomized trials. 


The utility of vitamin E and pioglitazone for the treatment of NASH is uncertain.


liraglutide, a synthetic long-acting glucagon-like peptide 1 (GLP-1) agonist currently available for treatment of type 2 diabetes and obesity, found the drug effective for patients with NASH in terms of weight loss, resolution of steatohepatitis, and less progression of fibrosis than placebo, although gastrointestinal adverse effects were seen, including diarrhea, constipation, and appetite loss.


Semaglutide Treatment resulted in significant high percentage of patients with NASH resolution than placebo, but did not show significant difference in the percentage of patients with improvement in fibrosis stage.


Statin therapy is safe for patients with liver disease and should be prescribed for all high-risk patients.


Weight loss agents may benefit some patients as an adjunct to other therapies.


Lanifibranir, A pan-PPAR (peroxisome proliferator-activated receptor [PPAR] ) agonist that modulates key metabolic, inflammatory, and fibrogenic pathways in the pathogenesis of NASH has demonstrated decreased disease activity without worsening fibrosis.

Resmetirom is an oral, liver-directed, thyroid hormone receptor beta selective agonist for the treatment of NASH with liver fibrosis.

Resmetirom is superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage (MAESTRO-NASH investigators).





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