I. Preface
The liver has strong synthesis, storage, secretion and metabolism capabilities, and when liver function is damaged, its functional evaluation indexes appear to varying degrees. At present, the evaluation of liver function is divided into static tests and dynamic tests. Static tests include indicators such as albumin and coagulation factors in response to synthesis, transaminases in response to hepatocyte integrity, bilirubin in response to secretion, and alkaline phosphatase and glutamyl transpeptidase in response to cholestasis. Dynamic tests include indocyanine green (ICG) clearance test, monoethylglycinophthalide xylenolamine (MEGX) test, aminopyrine breath test (ABT), etc. At present, static tests are more commonly carried out.
II. Static test indicators
Albumin is produced by the liver and its level can reflect the synthesis function of hepatocytes. However, due to the long half-life of albumin (21 days), changes in acute liver function are often not reflected in it, and its level is easily influenced by treatment and other factors, so it does not reflect the actual level in the body. Thrombospondin is a protein synthesized in the liver and its activity can be a sensitive reflection of hepatocyte function. When hepatocytes are damaged, the impaired entry, binding and secretion of bilirubin by hepatocytes can cause an increase in blood bilirubin levels. As liver injury worsens, bilirubin tends to show a progressive increase, while prothrombin activity progressively decreases. Serum pre-albumin is a glycoprotein synthesized by the liver and belongs to a group of serum fast converting proteins with a short half-life of about 1.9 days. It is a more sensitive and accurate indicator than albumin, bilirubin and Y-globulin. When the liver parenchyma is damaged, the synthesis of cholinesterase by the liver is reduced and the release into the blood is decreased, so the measurement of serum cholinesterase helps to evaluate the synthetic function of the liver. In acute hepatitis, the damage to hepatocytes is slight and the structure of liver lobules is not damaged, so there is no significant decrease in the activity of cholinesterase at this time. In patients with chronic hepatitis and cirrhosis, the decrease in cholinesterase activity is greater. If the decrease persists, it indicates a poor prognosis and is significantly lower in liver failure. Cholinesterase roughly parallels the decrease in serum albumin and is more sensitive to changes in disease than albumin, with cholinesterase rising rapidly as disease improves and albumin recovering more slowly. Because of the wide range of cholinesterase reference values, many patients with acute hepatitis levels are not necessarily lower than the lower limit of the reference value for normal subjects, but with treatment, cholinesterase has a tendency to gradually increase, so as with other liver markers, continuous observation of changes in cholinesterase levels is of greater significance for the prognostic evaluation of liver disease.
III. Dynamic test index
Indocyanine green (ICG) clearance test, ICG is a non-toxic pigment with infrared absorption, and is also the only FDA-approved intravenous injection of the color dye drug. After its intravenous injection, it rapidly binds with protein in blood, is selectively taken up by hepatocytes and then gradually excreted into bile in free form and later excreted with feces, without intestinal and hepatic circulation, and is not excreted through the kidneys, which is an ideal method for quantitative response to liver reserve and has been widely carried out internationally. The ICG retention rate (1CGR15) or ICG clearance rate (ICG K) in blood at 15 min is usually used as an indicator. It is the only method in the world to achieve real-time dynamic testing of liver function at the bedside. ICG clearance is useful as an early and timely test of liver function in the transplanted liver after liver transplantation. ICG plasma clearance has been significantly reduced when there is no change in some routine tests, thus enabling rapid diagnosis of the condition. It is generally accepted that the earliest significant difference in liver function after living liver transplantation is the 24th hour after surgery, and the critical value of ICG K at this point that predicts a good or bad outcome is 0.18/min, above which transplant patients have a good prognosis with a two-year survival rate of 100%, and below which a high incidence of transplant liver dysfunction is predicted. Another report showed that the prognosis of cirrhotic patients with ICG R15 greater than 60% was extremely poor, with 80% dying within 3 months, while those with ICG R15 between 35% and 45% had a mortality rate of only 15% within 3 months.ICC plasma clearance can also guide the treatment of artificial liver, and the ICG plasma clearance test is an important prognostic method. The main factors affecting Icc clearance are effective hepatic blood flow, degree of biliary patency, and number of functioning hepatocytes; therefore, it is important to exclude this influencing factor when doing the ICG clearance test.
The MEGX test is a method based on the intrahepatic conversion of lidocaine to MEGX, which is related to the P450 cytochrome enzyme (CPY), which drives the continuous oxidative N-mono-dehydrocarbon reaction of lidocaine to MEGX in the liver. due to the action of CYP3A4, interactions between lidocaine and other substances or drugs may be triggered. For example, antibiotics or antidepressants may inhibit the formation of MEGX by inhibiting CYP isoenzyme action, and in addition, other drugs may induce the action of CYP3A4, thereby promoting the production of MEGX. Notably, the median value of MEGX varied between the sexes (67 ng/ml in men and 49 ng/m1 in women). In women taking birth control pills, it has been reported that this value may decrease to 25 ng/m1. In conclusion, all substances affecting the action of CYP3A4 may affect the results of the MEGX assay. In addition, the quantitative assay of MEGX serum concentration requires the use of immunoassay, HPLC or gas chromatography, so its not possible to perform the test at the bedside.
14C aminopyrine aminopyrine is metabolized primarily in hepatocyte microsomes, via the cytochrome P450 isoenzyme system, with little exclusion in its original form. The test is time consuming, typically taking several hours, requires specialized laboratory instrumentation, and may be radioactive and not easily performed in general wards. 14c exhalation (radioactive element determination) may be affected by a variety of factors, including a combination of factors, gastrointestinal motility or basal metabolic rate. Because of the limited clinical results, further studies are needed for aspects such as the reliability of liver function assessment.
IV. Commonly used liver function evaluation models
Single liver function indexes have limited role in evaluating liver prognosis, and the combined application of multiple indexes will be more valuable. CTP scoring and grading are quite widely used both at home and abroad. The specific scoring and grading methods are shown in Table 1.
Table 1 CTP score and grading
Variables 1 2 3
Hepatic encephalopathy grading None 1-2 3-4
Ascites None Mild or can be controlled with diuretics Moderate or above, with or without diuretics
Diuretic control Diuretic
Albumin (g/L) >35 28-35 <28
Prolonged prothrombin time (sec) <4 or 4-6 >6
INR 1.7-2.3 1.7 ＞2.3
Bilirubin ＜2 times 2-3 times ＞3 times
Bilirubin (cholestatic) <4 times 4-10 times >10 times
A: 5-6 points, B: 7-9 points C: 10-15 points
The CTP scoring system reflects the liver reserve function well, and thus is widely used in several aspects such as evaluation of prognosis of portal vein surgery, prognosis of cirrhotic patients, assessment of liver function before lobectomy, and preoperative prediction of cirrhotic patients undergoing surgery for non-hepatic reasons. However, in the process of application, it was found that CTP itself has certain shortcomings: (i) it is mainly applied to patients with cirrhosis, and the scores of two of the five indicators – ascites and hepatic encephalopathy – are susceptible to subjective factors and treatment, which are difficult to standardize; (ii) it cannot distinguish the significance of abnormal and significantly abnormal laboratory indicators (e.g., total bilirubin 3 mg and 30 mg of patients with the same score); ③ objective indicators such as albumin and prothrombin time can also have errors in different laboratories, especially PT, which is affected by a variety of factors such as different sources of tissue thromboplastin, instruments and operating techniques, making the test results vary greatly within and between laboratories; ④ the scores are too concentrated, with only 8 points difference between the lowest and highest scores. Many patients have different conditions with the same score: conversely, patients with the same score have different severity of disease; ⑤ all indicators have the same weight, i.e., they are considered to have the same degree of prognostic impact, e.g., albumin 34 g/L and hepatic encephalopathy grade II score are both 2, while the clinical significance signified by the two is very different in the clinical setting. Despite the obvious shortcomings of the CTP and the significant differences in index selection with the model of end-stage liver disease to be described later, several comparative studies have shown that the CTP score is one of the best systems for grading liver function and determining prognosis.
In foreign countries, acute liver failure is mostly caused by drugs, alcohol and other hepatotoxic substances, especially acetaminophen (paracetamol). In order to determine whether patients with liver failure need emergency liver transplantation, the Royal College of Physicians of the University of Edinburgh, UK, proposed the criteria for emergency liver transplantation (see Table 2), which is widely used and recognized in western countries. It divides patients into two parts according to the etiology: those caused by acetaminophen and those not caused by acetaminophen. If a single indicator meets the criteria, such as PH < 7.3 or H+ > 50, or PT > 100s (INR > 6.5), the patient requires emergency liver transplantation to save his life. When the patient is treated with N-acetylcysteine (NAC), the specific antidote for acetaminophen, the PH criteria can be relaxed to 7.25. If the condition is not yet severe enough to be described above, the patient is evaluated according to the criteria at the bottom of the table. Obviously, for acute liver failure, the application of this criterion is of high value, however, for our patient population with predominantly chronic severe hepatitis, the scope of application is small.
Table 2: King’s college criteria, University of Edinburgh, UK
Acetaminophen-induced Non-acetaminophen-induced
Arterial blood PH <7.3 or H+ >50 Prothrombin time >100 s (INR >6.5)
(PH <7.25, if treated with NAC)
Or (none of the above)
With all 3 of the following
Any 3 of the following 5 conditions
1.PT>100s
2.Serum creatinine >300umol/L
3.Hepatic encephalopathy grade III-IV
1, Adverse etiology (drug or non-A non-B hepatitis)
2, hepatic encephalopathy (stage III) before jaundice more than 7 days
3, age less than 10 years or more than 40 years
4., PT > 50 seconds (INR > 3.5)
5., TBil>300umol/L
In 2000, the Mayo clinic4 group proposed a prognostic prediction model for patients with cirrhosis treated with TIPS (MayoTIPS model), which identified four indicators that better predicted survival at 3 months after surgery: serum creatinine, bilirubin, INR and etiology. 2001 Karnath et al. slightly modified the formula of the “MayoTIPS model” by multiplying each factor by 10 to become: R=3.8*ln bilirubin+11.2*lnlNR+9.6*ln creatinine+6.4*cause of disease (0 for biliary or alcoholic, 1 for other, bilirubin and creatinine in mg). creatinine are in mg/dL). Unlike previous empirical models, it is calculated using the natural logarithm approach, which reduces the influence of extreme data and improves accuracy. Accurate evaluation of liver reserve function in patients with end-stage liver disease facilitates clinicians in selecting individualized treatment plans for patients, especially since the development of liver transplantation technology in recent years urgently requires a precise, simple and objective standard. Compared with CTP grading, MELD score has the following advantages: ① All three indicators in MELD score are based on objective laboratory tests, without subjective indicators such as ascites and hepatic encephalopathy, and the only thing that needs artificial interpretation is etiology. However, the removal of etiology has no significant effect on the predictive function of the MELD score. ② The MELD score is more accurate in evaluating the condition of end-stage liver disease. In the MELD score without “bottom value” and “top value” phenomenon, the range of evaluation of the disease is widened, and the score is continuous, so that the severity of the disease can be better distinguished. ⑧ MELD score in the use of three indicators in the laboratory is not very different, easy to obtain, can be repeatedly measured. ④MELD score is obtained using statistical methods, according to the importance of each parameter to give the appropriate weight, and thus have a better predictive effect, while CTP classification is based on clinical experience summed up. However, MELD also has some problems, mainly in: ①Serum creatinine is affected by many factors, such as when diuretics are used, serum creatinine may increase in a short period of time, while its liver disease itself may not change significantly. ②Serum bilirubin can fluctuate due to factors such as starvation and systemic infections, and INR can be prolonged by malabsorption of vitamin K due to cholestasis. ⑧ Although statistical analysis shows that complications of cirrhotic portal hypertension such as ascites, ruptured variceal bleeding, spontaneous peritonitis and hepatic encephalopathy have no significant effect on the judgment function of the MELD score, clinical evidence shows that all of the above complications pose a direct risk to the lives of patients with cirrhosis and may not be consistent with the actual prognosis of the patients. the MELD score is based on the European and American with alcoholic liver disease and viral hepatitis C Therefore, whether the MELD score is applicable to China and whether it can be used as a standard for liver transplantation in China needs to be further validated.
V. Summary and outlook
The above models were established on foreign case data, and it is necessary to use multicenter studies to explore the application of foreign models in China and further develop liver function evaluation and prognosis judgment systems suitable for Chinese conditions. Since the existing clinical and laboratory tests are still inadequate in accurately predicting prognosis, there is still a need to find and evaluate other biomarkers that can reflect the degree of liver injury or hepatocyte regeneration ability as prognostic indicators. These include the removal of actin released from necrotic hepatocytes. Liver failure occurs when large necrotic hepatocyte surfaces consume large amounts of Gc protein, and low levels of Gc protein are associated with more severe disease and a poorer prognosis. Some recent studies have shown some promise by finding that indicators such as serum troponin I, phosphate, arterial blood lactate, and soluble CDl63 are also associated with prognosis in patients with severe liver disease. The improvement of existing prognostic evaluation models depends on the continuous discovery of new indicators with better prognostic judgment value.