Be wary of drug-induced liver injury! "Asia Pacific Association for Liver Research" released the latest consensus guidelines

Only for medical professionals to read this article to understand the guide ~ Drug-induced liver injury (DILI) is one of the important drug-induced diseases, and it is also the main cause of clinically unexplained liver injury and unexplained liver disease, and its incidence is on the rise .

Recently, the Asia Pacific Association for Liver Research (APASL) issued a consensus guideline for DILI, focusing on specific DILI.

The strength of the recommendations reflects the quality of the underlying evidence, which is classified into one of three levels according to the hierarchy: high (A), medium (B), or low (C).

The GRADE system provides two recommended levels: strong (1) and weak (2).

 (Scan the QR code of the picture to get the original text of the guide.
) The recommendations are as follows: 1.
Risk factors for DILI 1.
Age may be a risk factor for the higher incidence of cholestatic DILI in the elderly (level B evidence, review Sex cohort study).

2.
Women are generally considered to be a risk factor for the development of DILI (C-level evidence, case studies).

3.
Hepatocellular DILI in women and young patients is more likely to progress to acute liver failure and higher liver transplantation rates (level B evidence, retrospective cohort study).

4.
Race (including human leukocyte antigen and non-human leukocyte antigen polymorphism) is an important risk factor for the development of DILI (level A evidence, large multi-ethnic cohort study).

5.
For DILI caused by acetaminophen, isoniazid, halothane and methotrexate, long-term alcohol consumption may be an important risk factor (level C evidence, case series study).

6.
Pregnancy as a risk factor for the development of DILI is controversial with the current level of evidence (level of evidence C, case series studies).

7.
Certain drugs, such as tamoxifen and methotrexate, pre-existing metabolic syndrome and obesity increase the risk of DILI (level A evidence). 8.
Potential liver disease increases the risk of DILI development, and at the same time increases the risk of adverse outcomes and mortality (level A evidence).

2.
Diagnosis and causality assessment: 6 recommendations.
Recommendation 1: We should comprehensively evaluate patients with suspected drug-induced liver injury, including obtaining a complete history of drug intake, evaluating liver injury patterns based on serum biochemical tests, and excluding liver diseases caused by other causes.

Understanding the potential drug-related adverse effects on the liver and a high degree of understanding of DILI will improve the accuracy of medical history collection (evidence level: A recommendation level; 1: strong).

Recommendation 2: Three DILI models based on the baseline serum alanine aminotransferase and alkaline phosphatase ratios based on the first biochemical results help to classify DILI as hepatocellular injury, cholestatic injury or mixed injury.

The R value is a standard and reliable tool that correlates DILI biochemical damage and pathological damage patterns (evidence level: B recommendation level; 1: strong recommendation).

Recommendation 3: Drug-induced autoimmune hepatitis is not uncommon, and a comprehensive investigation is needed, including a simplified scoring system, serological testing, and liver biopsy in the AIH group (level of evidence: recommendation level A; 1: strong recommendation).

Recommendation 4: Drug-related fatty liver is an uncommon disease, which may be caused by specific drugs, especially hormone drugs.

These drugs should be considered as risk factors for fatty liver; appropriate investigations should be conducted to rule out other possible causes of liver disease (evidence level: B recommendation level; 1: strong recommendation).

Recommendation 5: In the process of monitoring DILI patients, the measurement and evaluation of serum albumin, INR, bilirubin, and alanine aminotransferase levels should be used as standard tools for assessing the severity of liver injury (evidence level: C recommendation level; 1: strong recommendation ).

Recommendation 6: Anti-HAV antibody, HBsAb, anti-HCV-Ab, HEV-Ab antibody, anti-nuclear antibody, anti-smooth muscle antibody and serum antibody levels should be tested in all patients with suspected DILI diagnosis.

This is especially important when they have hepatocytes or mixed liver damage (level of evidence: recommended level B; 1: strong recommendation).

3.
Imaging For all patients suspected of DILI, abdominal ultrasonography should be routinely performed.

If there are clinical indications, computer tomography, magnetic resonance imaging, magnetic resonance cholangiopancreatography and positron emission tomography can be considered (evidence level: B recommended level; 1: strong recommendation).

4.
Liver biopsy: 2 recommendations.
Recommendation 1: Only consider liver biopsy if the diagnosis needs to be ruled out (level of evidence: level B, level of recommendation: not recommended).

Recommendation 2: When patients stop responding to suspicious drugs or Chinese herbal medicines, liver biopsy may be considered (level of evidence: level B, level of recommendation: not recommended).

5.
Causality assessment methods and scales The RUCAM/CIOMS scale is the preferred causality assessment method, used to guide the systematic and objective assessment of patients suspected of DILI (level of evidence: C level, inferred from the level 2b study, with good results Reference standard exploratory cohort study).

6.
Genetic testing.
Human leukocyte antigen genotyping should be used in selected clinical scenarios.
In these scenarios, genetic testing is helpful for accurate diagnosis and management of patients (quality of evidence: A, strength of recommendation: weak).

7.
New biomarkers Verification of new biomarkers for early detection and evaluation of the prognosis of idiosyncratic DILI.

(Evidence level: C, strongly recommended).

8.
Prognosis and natural history: 7 recommendations 1.
Early diagnosis of DILI, timely discontinuation of the drug, and avoidance of repeated use of illegal drugs are very important.

2.
Cholestyramine is recommended in DILI induced by leflunomide to accelerate the elimination of drug effects (quality of evidence: B, strength of recommendation: weak).

3.
L-carnitine is an antidote for valproic acid-induced hepatotoxicity and/or valproic acid-induced hyperammonemia (quality of evidence: B, strength of recommendation: weak).

4.
Deacetylcysteine ​​(NAC) is an antidote for hepatotoxicity caused by acetaminophen (quality of evidence: A, strength of recommendation: strong).

Prednisolone and NAC can improve the liver biochemistry and function of flupirtine-induced DILI (quality of evidence: B, strength of recommendation 1: strong).

5.
Ursodeoxycholic acid (UDCA) may improve liver enzymes in patients with cholestasis.
However, it is uncertain whether it helps to improve liver injury (quality of evidence: C, strength of recommendation: weak).

6.
Except for the above, there is insufficient evidence to recommend cholestyramine, carnitine, NAC and UDCA for DILI (quality of evidence: C, strength of recommendation: weak).

7.
DILI-ALF urgently needs to consider liver transplantation (quality of evidence: B, strength of recommendation: weak).

Adult DILI-ALF patients are advised to inject NAC intravenously (quality of evidence: A, strength of recommendation: strong).

8.
Large-volume plasma exchange may be an option for DILI-ALF, especially when liver transplantation is not feasible or timely.

9.
DILI prevention statement: In the case of long-term use of potentially hepatotoxic drugs (such as isoniazid/combined anti-tuberculosis drugs), it is recommended to monitor liver function, and there is a significant increase in transaminase and/or jaundice, nausea, abdominal pain and other symptoms ( In the case of Level A evidence), the drug should be considered to be discontinued.

10.
Statement of category effect and cross-reactivity: It is very important to understand category effect and cross-reactivity when choosing alternative treatments for patients without DILI (level A evidence).

11.
Traditional Chinese medicine/Chinese herbal medicine-induced liver injury: 8 recommendations 1.
When diagnosing traditional Chinese medicine/Chinese herbal medicine-induced liver injury, it is very important to understand the medical history and obtain information on the use of traditional Chinese medicine/Chinese herbal medicine-induced liver injury (Evidence C , Recommended level 1).

2.
The diagnostic strategy of traditional Chinese medicine/Chinese herbal medicine to induce DILI is mainly to exclude other possible causes, which are the same as liver damage caused by conventional drugs (evidence C, recommendation level 1).

3.
Patients who are suspected of inducing DILI by traditional Chinese medicine/Chinese herbal medicine should stop suspicious products immediately.

Monitoring is necessary until the liver injury has recovered (1C).

In China, magnesium isoglycyrrhizinate is an effective drug approved by the China National Medical Products Administration for the treatment of acute liver cell injury.

In the absence of public sector, industry cooperative investigations and pharmacovigilance, the prevalence of combined herbal medicines and the incidence of DILI related to combined Chinese medicines in the general population and patient populations are still unknown (level of evidence B).

4.
The RUCAM system, objective clinical and research evaluation, requires the reporting of the minimum elements of DILI, and can be used to assess the causality between patients with liver injury suspected of allied herbal medications (AHM) (evidence B, recommendation 2).

5.
DILI related to AHM presents different symptoms and signs.

Whether it is new or underlying chronic liver disease, the patient may be completely asymptomatic or present with similar symptoms of acute and chronic hepatitis, autoimmune hepatitis, cholestatic hepatitis, granulomatous hepatitis, or sinus obstructive syndrome (evidence B).

6.
Drug-induced liver damage related to AHM is a diagnosis of exclusion, which is strengthened by time correlation and causality, even if it is difficult to determine the actual drug or component or interaction that causes liver damage, especially a combination of multiple herbs Polymer preparations.

(Evidence B, recommendation level 2) 7.
The diagnosis of AHM-DILI does not require liver biopsy, but it is recommended whenever possible.
At the same time, herbal preparations are searched and analyzed to eliminate competing causes and determine potential chronicity.
And make predictions.

The retrieval and analysis of herbal preparations is ideal.

(Evidence B, recommendation level 2) 8.
The management of DILI related to AHM starts with the discontinuation of related drugs, providing supportive and targeted symptomatic treatment, identifying clinical factors that predict poor prognosis, and it is important to recognize the need for liver early Transplanted patients with ALF or ACLF.

(Evidence C, recommendation level 1) 12.
Chronic liver disease and non-alcoholic fatty liver disease combined with DILI: 7 recommendations 1.
Before starting antiviral, all patients should undergo baseline hepatitis B surface antigen, anti-hepatitis C virus and liver biochemical tests, and Ultrasonography of the abdomen (evidence level B, recommendation level 1).

2.
Unless symptoms appear, it is not recommended to conduct routine liver biochemical monitoring for patients without risk factors for hepatic artery embolism during treatment (level of evidence A, level of recommendation 1). 3.
For patients with risk factors, monitor liver biochemical examinations every 2 weeks for the first 8 weeks.

Thereafter, monthly liver biochemical tests can be performed until the end of treatment, especially for individuals with risk factors for drug-induced hepatitis (evidence level B, recommendation level 2).

4.
The anti-tuberculosis treatment must be closely monitored.
From the beginning of the treatment, the clinical symptoms and liver biochemical testing and evaluation must be carefully monitored, and then regularly monitored until the end of the treatment.

Most liver toxicity occurs in the first 2 months of treatment (evidence level A, recommendation level 1).

5.
Some drugs, such as aminodone, methotrexate and tamoxifen, may cause fatty liver and chronic liver disease (evidence level B, recommendation level 1).

6.
More and more people realize that patients with chronic liver disease are prone to drug-induced liver injury (evidence level B; recommendation level 2).

7.
Patients with underlying liver disease have an increased risk of death (evidence level B, recommendation level 1).

Want to see more guidelines, go to the doctor’s station~References: [1]Devarbhavi H,Aithal G,Treeprasertsuk S,et al.
Drug-induced liver injury:Asia Pacific Association of Study of Liver consensus guidelines[J].
Hepatol Int.
2021 Feb 27.