High score review: non-alcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is an inflammatory subtype of non-alcoholic fatty liver disease (NAFLD), accompanied by liver steatosis and evidence of liver cell damage (ballooning) and inflammation, with or without liver fibrosis.

Over time, NASH may progress to cirrhosis, end-stage liver disease, or require liver transplantation.

This review will mainly discuss the epidemiology, clinical outcomes, and current methods of diagnosis and treatment of NASH.

1.
A recent meta-analysis of epidemiology estimates that the global prevalence of NAFLD is approximately 25%.

Its prevalence seems to have been increasing, with an estimated 3.
6 million new cases each year.

Both NAFLD and NASH are closely related to obesity, dyslipidemia, type 2 diabetes and metabolic syndrome.

Compared with those with NAFLD alone or the general population, NASH patients are more likely to be obese or have metabolic disorders.

Paired biopsy (before and after treatment) studies have shown that NASH may be reversed to NAFLD over time; patients without NASH but whose biopsy results suggest fibrosis may represent that they have had NASH but have reversed.

At the time of non-alcoholic fatty liver diagnosis, about 25% of NAFLD patients have fibrosis stage F2 or above (Table 1).

Table 1 NAFLD Activity Score As time goes by, about 40% of NASH patients will continue to experience fibrosis at a rate of about one stage every ten years.

The probability of NASH patients suffering from hepatocellular carcinoma is significantly higher than that of the general population, and its annual incidence is 12 times that of NAFLD (5.
77 vs.
0.
44 persons/1000 persons).

Long-term studies have shown that compared with the general population, NASH patients have higher overall mortality and liver-related mortality.

The annual mortality rate of NASH patients is 1.
7 times higher than that of NAFLD patients (25.
56 vs.
15.
44 persons/1000 persons), and the liver-related mortality rate is 15 times higher than that of NAFLD patients (11.
77 vs.
0.
77 persons/1000 persons).

Although liver-related mortality is increasing, cardiovascular disease is still the main cause of death in patients with NASH and NAFLD.

2.
Clinical manifestations Most patients with NASH are asymptomatic or have only non-specific symptoms, such as fatigue or mild abdominal pain.

Ultrasound or CT scan showed steatosis in the upper right quadrant or laboratory examination showed elevated transaminase, which may indicate NAFLD or NASH, and further examination is required.

If the patient has not progressed to cirrhosis, the physical examination is usually normal or only central obesity.

3.
The diagnosis of NASH The diagnosis of NAFLD requires imaging or histological evidence of more than 5% of liver steatosis without excessive alcohol consumption.

In contrast, the diagnosis of NASH requires biopsy and histological examination, showing liver steatosis of more than 5%, accompanied by ballooning degeneration of hepatocytes and liver lobule inflammation.

4.
Treatment of NASH 1.
Lifestyle changes.
For NASH, the ideal therapeutic effect is to effectively reverse liver injury and fibrosis, and improve other metabolic indicators or cardiovascular complications (or at least not worsen the latter).

Although a lot of progress has been made in the research on the pathogenesis of NASH in the past 10 years, there is still no approved treatment for NASH.

Currently, the main treatment for NASH is to change lifestyle through diet and exercise, with the ultimate goal of losing weight.

Although the diet does have a certain effect on liver fat accumulation, there is no evidence that a specific macronutrient diet is beneficial to NASH.

Therefore, calorie restriction is the most suitable recommendation for these patients.

The intake of fructose should be restricted because fructose is associated with the progression of NASH and fibrosis.

In addition, patients with NASH should also avoid alcohol (or limit appropriately).

Regardless of weight loss, exercise can reduce liver fat content, at the same time can improve insulin resistance, and inhibit the de novo synthesis of free fatty acids, these can have an impact on NASH.

Regardless of how it is achieved, weight loss is most closely related to the histological improvement of NASH.

A weight loss of 7%-10% should be the first treatment goal for patients with NASH.

However, less than 50% of patients can achieve this goal through lifestyle changes.

2.
The degree of weight loss required for histological improvement of bariatric surgery NASH is difficult to achieve and difficult to maintain.

And bariatric surgery is the most effective weight loss therapy.

Paired biopsy studies before and after bariatric surgery showed significant improvements in liver histology and non-alcoholic fatty liver disease activity scores, including a reduction in the prevalence of NASH.

A prospective study involving 109 patients found that 85% of patients no longer had NASH in a biopsy one year after bariatric surgery, and 33% of patients had fibrosis reversal.

Although the histology of NASH has improved, in clinical work, only NASH patients with obesity-related comorbidities are eligible for bariatric surgery.

The 2018 AASLD guidelines pointed out that it is too early to use bariatric surgery exclusively for NASH treatment.

3.
Existing drugs that can improve NASH Although there is still no approved drug for NASH.

In a phase 3 trial, 247 NASH patients without diabetes were randomized to receive pioglitazone 30 mg, vitamin E 800 IU, or placebo (for 96 weeks).

Compared with placebo, vitamin E treatment significantly improved the subjects’ histological lesions without worsening the degree of fibrosis (the NAFLD activity score was reduced by more than 2 points; 43% vs.
19%, P = 0.
001) , While the efficacy of pioglitazone did not reach statistical significance (34% vs.
19%, P = 0.
04). However, when assessing whether there is a ballooning change, there are differences between the reports, and the pioglitazone group has the most patients with errors in the assessment.

Whether the primary endpoint is reached depends on the improvement of hepatocyte ballooning, so the heterogeneity in the histological evaluation may be the reason why pioglitazone failed to reach the endpoint.

In addition, in this study, neither vitamin E nor pioglitazone improved fibrosis in patients compared with placebo.

It is worth noting that 47% of patients treated with pioglitazone and 36% of patients treated with vitamin E experienced improvement in steatohepatitis, compared with 21% of patients treated with placebo alone.
This time The primary endpoint led AASLD to conclude that pioglitazone or vitamin E can be used to treat patients with NASH diagnosed by biopsy.

However, studies in recent years have found that vitamin E supplementation can increase the risk of hemorrhagic stroke and prostate cancer, and its safety is worrying.

In general, the efficacy and safety of vitamin E and pioglitazone in the treatment of NASH are uncertain.

A small phase 2 trial (n=52) evaluating liraglutide (a GLP-1 agonist that can be used to treat type 2 diabetes and obesity) in patients with NASH found that the drug is reducing weight and improving Steatohepatitis and fibrosis were significantly better than placebo, while subjects only experienced some gastrointestinal side effects, including diarrhea, constipation, and loss of appetite.

Before liraglutide is recommended for the treatment of NASH, further research is needed.

Some evidence suggests that statins can be used to treat NASH.

Weight loss drugs have not been widely used in NASH research, but considering that there is a strong correlation between the degree of weight loss and the improvement of liver histology, these drugs can benefit some patients as adjuncts to other treatments.

Yimaitong compiled and compiled from: Sheka AC, Adeyi O, Thompson J, Hameed B, Crawford PA, Ikramuddin S.
Nonalcoholic Steatohepatitis: A Review.
JAMA.
2020;323(12):1175–1183.
doi:10.
1001/jama.
2020.
2298