Classification of NAFLD
According to the etiology, NAFLD is divided into two categories: primary and secondary, the former being related to insulin resistance and genetic susceptibility, and the latter being caused by some specific reasons. The former is related to insulin resistance and genetic susceptibility, while the latter is caused by some specific causes. Excessive weight gain and overweight due to overnutrition, fatty liver associated with metabolic syndrome such as obesity, diabetes, hyperlipidemia, and cryptogenic fatty liver all belong to the category of primary NAFLD; fatty liver due to malnutrition, total parenteral nutrition, rapid weight loss after bariatric surgery, and poisoning by drugs/environmental and industrial toxins belong to the category of secondary NAFLD. The general term NAFLD often refers to primary NAFLD.
According to the pathological changes, NAFLD is divided into three stages: (non-alcoholic) simple fatty liver, nonalcoholic steatohepatitis (NASH), and (non-alcoholic) fatty cirrhosis.
Pathogenesis
The pathogenesis of NAFLD is unclear. The “2-strike” hypothesis is accepted by most scholars. The first strike is related to fat accumulation and insulin resistance. The accumulation of fat in the liver and the decrease of insulin clearance can cause insulin resistance. Insulin resistance in turn leads to an increase in free fatty acids in serum, and high fatty acid uptake by hepatocytes leads to oxidative overload of mitochondria and increases fatty acid storage in hepatocytes. Hyperinsulinemia increases glycogen degradation and fatty acid synthesis, and decreases Apo-100 synthesis to increase the accumulation of diglycerides. This results in “Strike 1”.
”Strike 2″ refers to oxygen stress and abnormal cytokines that lead to necroinflammation and fibrosis in the liver. The oxygen stress state refers to the production of free radicals or reactive oxides and their metabolites from molecular oxygen that exceed the ability to defend or detoxify them. Mitochondria and microsomes are the main sites of reactive oxidant production. Lipid peroxide induces membrane protein mutations, acetaldehyde covalently binds to abnormal liver proteins and enzymes to form aldehyde adducts, Mallory vesicles are antigenic; lymphocyte phenotypic alterations such as increased CD4/CD8, CD56/CD8 and CD25/CD2; increased endotoxin and TNFα; insulin resistance related hormones such as leptin, estrogen, cortisol, growth hormone, glucagon and insulin-like growth factor, as well as cytokines such as TNFα, TGFβ1, γ-IFN and IL-12 and IL-18 mediating metabolic and immune dysfunction.
In addition, iron overload, genetic, environmental, immune and drug factors may be involved in the development of NAFLD.
Diagnostic criteria
I. Clinical diagnostic criteria
NAFLD can be diagnosed by having any of the following items 1~4 and item 5 or 6
1. No history of alcohol consumption or consumption of alcohol containing <40 g of ethanol per week;
2.Excluding viral hepatitis, total parenteral nutrition and other specific diseases that can lead to fatty liver;
3.In addition to the clinical manifestations of the original disease, symptoms such as weakness, abdominal distension, vague pain in the liver area, etc. may be accompanied by hepatosplenomegaly;
4.Serum aminotransferase may be elevated, mainly alanine aminotransferase, often accompanied by increased levels of gamma-glutamate transpeptidase and triglyceride;
5.The liver imaging performance conforms to the diagnostic imaging criteria of diffuse fatty liver;
6. Histological changes of the liver conform to the pathological diagnostic criteria of fatty liver disease.
II. Clinical typing criteria
For those who meet the clinical diagnostic criteria of non-alcoholic fatty liver disease, their clinical typing is as follows.
(i) Non-alcoholic simple fatty liver disease can be diagnosed if any of the following items 1-2 and 3 or 4 are present: 1. clinical diagnostic criteria 1-3; 2. liver function tests are basically normal; 3. imaging manifestations meet the diagnostic criteria of fatty liver; 4. liver histological manifestations meet the diagnostic criteria of simple fatty liver.
(2) Non-alcoholic steatohepatitis can be diagnosed by having any of the following items 1-2 and 3 or 4: 1. having clinical diagnostic criteria 1-3; 2. serum ALT level higher than 2 times the upper limit of normal value for more than 4 weeks; 3. imaging manifestations conform to the diagnostic criteria of steatohepatitis; 4. liver histological manifestations conform to the diagnostic criteria of steatohepatitis.
(3) Non-alcoholic fatty cirrhosis can be diagnosed by having any of the following items 1 and 2 or 3: 1. clinical diagnostic criteria 1-3; 2. imaging suggests fatty liver with cirrhosis; 3. histological changes in the liver meet the diagnostic criteria of fatty cirrhosis.
Imaging diagnosis
Fatty liver: ultrasound diagnosis based on.
(1) Diffuse point-like hyperechogenicity in the near field of the liver, with higher echogenicity than the spleen and kidneys, with a few focal hyperechogenicity;
(2) Echo attenuation in the far field with sparse dots;
(3) Intrahepatic ductal structures are poorly visualized;
(4) Mild or toxic liver with blunting of the anterior hepatic margin.CT diagnosis based on: liver density generally lower than spleen or liver/spleen CT ratio ≤ 1. Mild if liver density is reduced, CT value slightly lower than spleen, liver/spleen CT ratio ≤ 1.0; moderate if liver/spleen CT ratio ≤ 0.7 and intrahepatic vessels are not clearly visible; significantly reduced or even negative liver density, liver/spleen CT ratio ≤ 0.5. Intrahepatic vessels are clearly visible as severe.
Cirrhosis: The diagnosis of cirrhosis is based on widening of the liver fissure, increased thickness of the liver envelope, irregularity of the liver surface, inhomogeneous echogenicity/density/signal in the liver, mismatch of the ratio of the liver lobes, thickening of the portal vein trunk diameter, increase in the parameters of portal blood flow per minute, increase in the volume index of the spleen, thickening of the gallbladder wall or change in the morphology of the gallbladder, etc.
Treatment
The main principles of treatment for NAFLD are.
(1) Improve lifestyle, such as diet, exercise, weight loss, alcohol, smoking cessation, and caution in the use of hepatotoxic drugs;
(2) actively search for and remove possible causes and triggers;
(3) Manage the primary underlying disease or concomitant disease;
(4) Apply hepatoprotective drugs to halt the progression of chronic liver disease in those with hepatic impairment;
(5) Recommend liver transplantation for patients with end-stage liver disease.
1. Management of primary underlying disease
Weight control For NAFLD patients with overweight/obesity, the target body mass index is <25 kg/m2. 1 to 2 kg of weight loss per month is appropriate. For patients with moderate to severe obesity or obesity combined with diabetes, dyslipidemia, hypertension and other concomitant diseases, weight loss drugs such as osteoporosis (Xenical) can be added or even gastroplasty surgery can be performed.
Improving insulin resistance and controlling blood glucose In addition to weight loss through lifestyle changes and medications, metformin and rosiglitazone (Vindial) can be added to improve insulin resistance, and patients with impaired glucose tolerance and diabetes need to receive insulin therapy.
Adjustment of dyslipidemia For patients with moderate to severe primary hyperlipidemia. Patients with hyperlipidemia combined with coronary heart disease or with more than 2 risk factors for coronary heart disease, who are still ineffective in 3-6 months for measures such as weight loss and improvement of insulin resistance, may use beta or tartan lipid-regulating drugs.
2.Hepatoprotective drug therapy
Generally choose one to two drugs, the course of treatment for more than six months, or until the serum transaminase normalization, imaging examination suggests that fatty liver regression.
(1) Reduce reactive oxygen species and antagonize lipid peroxidation, such as glutathione and its precursors (reduced glutathione, beta betaine, N-acetyl cysteine, S adenosine methionine), vitamin E, silymarin, diisopropylamine dichloroacetate;
(2) Anti-inflammatory, choleretic, and hepatic lipid reducing agents such as ursodeoxycholic acid;
(3) Protect and repair biofilm, improve liver lipid metabolism, antioxidant, anti-fibrosis, such as essential phospholipids (polyunsaturated phosphatidylcholine);
(4) Improving intestinal flora disorders, preventing and treating enterogenic endotoxemia and related liver injury, such as Lactobacillus, anti-TNFα antibody or TNFα receptor antagonist;
(5) Chinese herbal medicine, such as cholinergic tablets.
(6) Application of adipocytokines: the application of leptin and adiponectin is still in the stage of drug clinical trials.
3.Iron therapy is suitable for those with excessive iron load in the liver.
4.Management of end-stage liver disease It is necessary to prevent and control portal hypertension and liver failure and its complications. Liver transplantation is often the only option to save life in the late stage of the disease, but the recurrence rate of steatohepatitis after liver transplantation is high.