You can assess this by measuring the liver function parameters like AST

SmPC or USPI or FDA drug labels are standard references to check for all the detailed information of the drug including adverse effects.

Livertox is a similar database by NIH to check the hepatotoxic drug, including its mechanism and extent of damage and it seems much better as compared to the above mentioned labels because drug labels are made by the information obtained from the clinical trials but sometimes they are not sufficient.

Few drugs may turn out to be hepatotoxic when used commonly in community.

The easiest way is to monitor the serum aminotransfereases levels and if they are above 3 times the normal limits we call it a liver injury and take a call to stop the drug.

About clindamycin, it is a drug being metabolised by liver and has a propensity to cause hepatotoxicity.

Transient elevation of aminotransfereases are seen and even in few cases acute liver injury is also seen.

One should be cautious and monitor liver enzymes if in doubt.

Severity of liver disease should be graded according to presence or absence of impairment of function, which is

mild if no elevation of bilirubin or INR occurs

moderate, when Bilirubin is elevated.

severe when INR is elevated in addition to Bilirubin being elevated.

and more severe when hepatic encephalopathy occurs.

Clinically, as the stage if INR elevation, especially if not immediately improving of cessation of implicated drug, I would contact a transplant center for referral, as Liver failure due to DILI is very poor prognosis. Importantly this may include herbal and dietary supplements.

Milena Miljkovic ([email protected])

To see the type of liver effect that the concrete medication can exhibit, you should review the product information (SmPC, USPI). For example, liver effect can be manifested only as transient increased ALT and AST (liver enzymes/transaminases) or as transient liver function test (LFT) increased. Such events are usually not considered as serious and occur with common or uncommon frequency. However, liver effect of some medicines can be manifested also as very serious events, such as jaundice or hepatitis or even as life-threatening fulminant hepatitis, whereby such events usually occur rarely or very rarely.

Measures are/should be also included in the product information (SmPC, USPI). For example, these measures include recommendation to determine liver enzymes before the initiation of the therapy and also during the therapy, and if ALT, AST values are higher than 3-5 x ULN, the dose of that medicine can be reduced, but if accompanied with specific symptoms, that medicine should be discontinued. Based on the FDA (Guidance for Industry - Drug-Induced Liver Injury: Premarketing Clinical Evaluation, 2009), discontinuation of treatment should be considered if:

• ALT or AST >8 x ULN (transient increase)

• ALT or AST >5 x ULN (for more than 2 weeks)

• ALT or AST >3 x ULN (and TBL >2 x ULN or INR >1.5)

• ALT or AST >3 x ULN (with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, and/or eosinophilia >5%).

To check the mechanism of hepatotoxicity, and to see further information about the medication effect on the liver (described in scientific literature), you can review Livertox database.

For the last question related to clindamycin use, the approach should be that “the use of clindamycin must have far greater benefits for the patient than the potential harm to the liver”. It is known that clindamycin can cause liver function test abnormal (common event), as well as that this antibiotic can also cause jaundice (frequency unknown, but rare based on scientific literature data). However, in a case of severe infection with certain anaerobe bacteria resistant to other available antibiotics, clindamycin should be used (as there is no other option), and if the therapy with clindamycin is prolonged, liver function tests should be performed.

Thank you all!

Mostafa Elsersy The CIOMS/RUCAM scale is a tool to predict whether liver damage can be attributed to a particular medication.

http://www.pmidcalc.org/?sid=8229110&newtest=Y

For causality RUCAM remains the standard in the absence of Expert Opinion Panels. In the future we likely will see more phenotype based causality as we presented as AASLD in 2016 and outlined in a recent review Tillmann HL, Barnhart HX, Serrano J, Rockey DC. Novel approaches to Causality Adjudication in Drug-Induce Liver Injury. curt Hepatology rep. 2018.

I agree with the above comments.

For your example clindamycin, risk of idiosyncratic DILI is documented. As with most drugs causing idiosynratic DILI, only very few susceptible patients are affected. Unfortunately, occurrence of idiosyncratic DILI in agiven patient cannot be predicted (in contrast to intoxication as in acetaminophen-overdose).

It might be worthwhile (if possible) to check the patients history not only for drug allergies, but also for potential prior DILI episode and avoid these drugs.

In addition to controls of liver parameters it might be helpful to inform the patient to seek medical attention in case of symptoms like nausea, fatigue, abdominal pain and of course jaundice.

In case of liver injury, exclusion of other possible causes (viral hepatitis, choölestasis etc.) is necessary to confirm the diagnosis (cf RUCAM above).

The risk to develop idiosyncratic DILI seens not to be higher in patients with chronic liver disease in general. However, if DILI occurs in such patients, liver injury might be more severe due to pre-existing liver damage.