"The Lancet" Sub-Journal reviews the risk, diagnosis and treatment of extrahepatic complications

Non-alcoholic fatty liver disease (NAFLD, commonly known as "fatty liver") affects the health of approximately 30% of adults worldwide, leading to a considerable number of liver-related and extrahepatic diseases, and related deaths

NAFLD includes a series of disease processes: from non-alcoholic simple liver steatosis (NAFL) to non-alcoholic steatohepatitis (NASH), which gradually leads to liver fibrosis, and eventually may develop into cirrhosis, liver failure or even Liver cancer

Recently, "The Lancet Gastroenterology & Hepatology" published a review that elaborated on the epidemiological evidence that NAFLD is a multi-system disease, the pathophysiological mechanism behind it, and extrahepatic diseases.

NAFLD is closely related to a variety of extrahepatic complications

The main cause of death in NAFLD patients is cardiovascular disease, followed by extrahepatic cancers (such as colorectal cancer) and liver-related complications

Cardiovascular diseases

A meta-analysis that included 16 observational studies, enrolled approximately 34,000 people (36% of whom had NAFLD), and an average follow-up of nearly 7 years showed that compared with non-NAFLD populations, NAFLD patients have cardiovascular diseases (including fatal and non- Fatality) risk increased by 64%, and the more severe the NAFLD condition, the higher the incidence of cardiovascular events

Some cohort studies have found that NAFLD is associated with the risk of progression of coronary or carotid atherosclerosis, and the improvement or regression of NAFLD is associated with a decrease in the risk of carotid atherosclerosis

A meta-analysis covering nearly 615,000 individuals (40% of whom have NAFLD) showed that NAFLD is associated with a 19% increase in the risk of atrial fibrillation, which is independent of other cardiovascular disease risk factors

Type 2 diabetes

A meta-analysis of 33 studies covering more than 500,000 individuals (30.

However, some studies have observed that as NAFLD improves or subsides, the risk of type 2 diabetes will gradually decrease, and this benefit has nothing to do with weight changes

Chronic kidney disease

A large meta-analysis covering more than 1.

However, whether improvement of NAFLD will reduce the risk of progression of chronic kidney disease still needs further research to better clarify

Risk of colorectal tumors and other extrahepatic cancers

A meta-analysis of data from approximately 91,000 asymptomatic adults (mainly Asians) undergoing colonoscopy screening found that NAFLD patients have a 28%-61% increase in the risk of colorectal adenoma and a 56% increase in the risk of colorectal cancer.

In an American population study with a median follow-up time of 8 years, data from 4,722 NAFLD patients and 14,441 control healthy individuals (matched by age and gender) showed that NAFLD is associated with a doubling of cancer risk, and this cancer risk mainly affects Liver, digestive tract and uterus

In another study of about 54,000 Chinese men, NAFLD was associated with a slight increase in the risk of all cancers, especially thyroid cancer and lung cancer

There are also studies suggesting that NAFLD increases the risk of colorectal cancer and lung cancer in smokers, and the risk of kidney cancer in men with non-type 2 diabetes

In a cohort study with a median follow-up time of 14 years, data from 10,568 biopsy-proven NAFLD patients and 49,925 matched healthy individuals showed that all histological stages of NAFLD were associated with a significant increase in overall mortality, and this This risk gradually increases with the deterioration of NAFLD histology:

Simple steatosis: the total mortality rate is 1.

Excess mortality mainly comes from extrahepatic cancer, followed by cirrhosis, cardiovascular disease and hepatocellular carcinoma
.

The inextricable metabolic syndrome

Metabolic syndrome is more common in NAFLD patients (occurring in more than 50% of patients), so this may increase the risk of comorbid diseases such as type 2 diabetes, cardiovascular disease and chronic kidney disease, which have similar heart conditions Metabolic risk factors
.

For NAFLD patients, the health of the liver itself is an independent risk factor for type 2 diabetes and cardiovascular disease (and potentially chronic kidney disease); and in metabolic syndrome, the liver also plays a key role, including the role of atherogenic The influence of dyslipidemia, elevated blood pressure, abnormal blood sugar, type 2 diabetes, and central obesity in the form of sclerosis
.

Pathophysiology of NAFLD

The review pointed out that the pathophysiology of NAFLD is very complex, involving metabolic disorders, lipotoxicity, insulin resistance, chronic inflammation, fibrosis, intestinal function, and intestinal microbiome
.

NAFLD and related complications are often accompanied by low-grade metabolic inflammation.
Low-grade metabolic inflammation is also a feature of obesity-related diseases, type 2 diabetes and NAFLD, and inflammatory mediators may cause liver abnormalities and extrahepatic complications of NAFLD
.

▲The relative impact of NAFLD on cardiovascular diseases, type 2 diabetes and extrahepatic diseases (picture source: reference [1]; translation: new medical perspectives)

In addition, in the past 4-5 years, some research advances have deepened our understanding of NAFLD genetics.
Many genome-wide association studies have shown that NAFLD is associated with genes such as PNPLA3 and TM6SF2
.

Diagnosis and management of extrahepatic complications

In NAFLD patients, if metabolic syndrome and traditional cardiovascular disease risk factors coexist, then clinicians need to be aware that these patients may have type 2 diabetes, cardiovascular disease, or chronic kidney disease
.
Traditional cardiovascular disease risk factors include age> 65 years, smoking, high blood pressure or atrial fibrillation, and elevated LDL-C (low-density lipoprotein cholesterol)
.

The review pointed out that it is easy to screen for type 2 diabetes by detecting glycosylated hemoglobin (HbA1c)
.
The American Diabetes Association (ADA) recommends that all people ≥45 years of age receive HbA1c tests.
If they are overweight/obese and have any risk factors for type 2 diabetes, they should receive HbA1c tests regardless of age; HbA1c tests should be performed at least every 3 Conducted once a year
.
HbA1c has also been included in the diagnostic criteria for type 2 diabetes in China, with HbA1c≥6.
5% as the cut-off point to assist in the diagnosis of diabetes
.
Chronic kidney disease can be assessed by measuring eGFR (normal ≥90mL/min/1.
73m²) and urinary albumin excretion (normal <30mg/g)
.
When chronic kidney disease progresses to stage 3-5 (eGFR is reduced), the patient's 10-year risk of cardiovascular disease will further increase (at least 50%)
.
The cardiovascular disease risk assessment can be calculated based on existing models
.
According to the follow-up data of the general population for more than 15 years, the coronary artery calcification score (CACS) is a powerful predictor of cardiovascular disease events
.

For NAFLD patients with liver cirrhosis and portal hypertension, hepatocellular carcinoma needs to be monitored regularly by ultrasound
.

For most NAFLD patients with less severe liver disease, although the risk of developing hepatocellular carcinoma is not completely ruled out, regular monitoring of this group is not currently recommended
.
Similarly, screening for extrahepatic cancer in NAFLD patients is not recommended
.

In terms of treatment, for NAFLD patients with increased risk of cardiovascular disease, statin therapy is recommended to reduce the risk.
If hypertension is present, antihypertensive therapy is required at the same time
.
If cardiovascular disease is diagnosed, consider using low-dose aspirin and angiotensin-converting enzyme inhibitor (ACEI) drugs or angiotensin receptor blocker (ARB) drugs, and refer to a cardiologist
.

For NAFLD patients with type 2 diabetes and chronic kidney disease, it is recommended to consider metformin and GLP-1 analogs, or pioglitazone (if there are no previous contraindications) and SGLT2 inhibitors
.
Despite being a first-line treatment, there is a lack of convincing evidence that metformin is beneficial for liver disease in patients with NAFLD
.
There is evidence that pioglitazone can help resolve the pathology of NASH and improve the fibrosis score of NASH patients
.
It has also been recommended for NASH patients by multiple guidelines .

Life>
.
Increasing physical activity and reducing weight can effectively improve early liver disease in patients with NAFLD, and improve blood sugar control, cardiovascular disease and chronic kidney disease risk factors
.
Histological liver improvement depends on the degree of weight loss, not intervention
.
Weight loss of 10% or more can induce pathological resolution of NASH and improve at least one histological stage of liver fibrosis; if it is difficult to achieve the 10% goal, weight loss of 5%-10% can also improve liver steatosis and NASH
.
It is worth noting that non-obese NAFLD patients can also improve liver disease by losing 3%-10% of their body weight
.

In addition, NAFLD patients should also avoid alcohol, hepatotoxic drugs, smoking, and intake of drinks and foods high in sucrose or fructose
.

summary

In short, the existence and severity of NAFLD are closely related to the risk of a variety of extrahepatic complications
.
The review research team suggested that all patients with NAFLD should receive a screening program similar to those of the same sex and similar age for cardiovascular disease, type 2 diabetes, chronic kidney disease, and extrahepatic cancer
.
Note: The original text has been deleted

Reference

[1] Giovanni Targher, et al.
, (2021).
Non-alcoholic fatty liver disease: a multisystem disease requiring a multidisciplinary and holistic approach.
The Lancet Gastroenterology & Hepatology, DOI: https://doi.
org/10.
1016/S2468 -1253(21)00020-0