Toxicology – ClinCaseQuest

Interactive Checklist of differential diagnoses of DILI and HILI

Nataliia Lopina — Thu, 03 Feb 2022 07:55:00 +0000

Differential diagnoses of drug-induced and herb-induced liver disease: Checklist of differential diagnoses of DILI and HILI.

This tabular listing, although not comprehensive, is to be used as a guide and in connection with the updated RUCAM, derived from a previous publication.

Register on our website right now to have access to more learning materials!

Subscribe to our pages:

See also:

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

Child-Pugh Score for Cirrhosis Mortality: online calculator

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

King’s College Criteria for Acetaminophen Toxicity

MELD Score (Model For End-Stage Liver Disease) (12 and older): Online calculator

MELD Score stratifies severity of end-stage liver disease, for transplant planning. NB! MELD Score can…

Interactive Checklist of differential diagnoses of DILI and HILI

Differential diagnoses of drug-induced and herb-induced liver disease: Checklist of differential diagnoses of DILI and…

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

The RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the likelihood of drug-induced…

R-value for Liver Injury Online calculator

Can be used in patients with suspected drug induced liver injury (DILI) with abnormal liver…

Child-Pugh Score for Cirrhosis Mortality: online calculator

The Child-Pugh Score can be useful in the prognosis of patients with cirrhosis, but more…

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

Identification of patients who should be immediately referred for liver transplant. INR > 6.5 (Prothrombin…

Сообщение Interactive Checklist of differential diagnoses of DILI and HILI появились сначала на ClinCaseQuest.

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

Nataliia Lopina — Tue, 01 Feb 2022 07:15:00 +0000

The RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the likelihood of drug-induced liver injury (DILI), as well as the assessment of the likelihood of herb-induced liver injury (HILI). Previous name CIOMS (Council for International Organizations of Medical Sciences).

Causality assessment by the updated RUCAM requires prior evaluation of liver injury criteria and its pattern in each suspected case

Respective criteria are readily assessable by initial measurement of ALT (alanine aminotransferase) and ALP (alkaline phosphatase).

Updated RUCAM for the Hepatocellular Liver Injury of DILI and HILI.

Drug-induced liver injury is a diagnosis of exclusion, even in cases where the liver injury is likely to be drug-related, the doctor needs to perform a detailed analysis according to certain parameters given in the rating scale.

To assess the causality of drug-induced liver injury (DILI) on the RUCAM scale, it is necessary to select the variant of liver injury (hepatocellular or cholestatic/mixed) and evaluate the indicators corresponding to the variant of liver damage, after the assessment, it is necessary to sum the scale indicators and interpret the scores.

Evaluation of causality using the updated RUCAM requires a preliminary assessment of the criteria for liver injury and its nature in each suspected case.

Appropriate criteria are easily assessed by initially measuring ALT (alanine aminotransferase) and ALP (alkaline phosphatase).

Liver injury is defined by increased serum activities of ALT of at least 5N and/or of ALP of at least 2N, best assessed simultaneously on the day of first presentation (N – upper limit of normal). These thresholds will increase the specificity of the hepatotoxicity causality assessment, eliminates false positive cases, and substantiates hepatotoxicity causality at a high level of probability. They are also in line with a recent consensus on DILI. However, when ALT is within the normal range, ALP increases should be paralleled by increased γ-glutamyltranspeptidase or better 5’ nucleosidase to rule out isolated increases of ALP activities due to bone or another origin rather than hepatobiliary disease

In accordance with the original RUCAM, the updated RUCAM takes into account divergent laboratory constellation of the liver injury and provides two different subscales: one for the hepatocellular type of injury and the other one for the cholestatic or mixed type of injury. These types can be differentiated using the ratio R, calculated as the ALT/ ALP activity measured at the time liver injury is suspected, with both activities expressed as multiples of N.

The liver injury is hepatocellular if ALT > 5N and ALP ≤ N, or if both ALT and ALP are elevated, R ≥ 5;
the liver injury is cholestatic if ALP > 2N and ALT ≤ N, or if both ALT and ALP are elevated, R ≤ 2;
the liver injury is mixed if ALT > 5N and ALP > N and 2 < R < 5.

This classification of liver injury pattern clearly assigns each DILI or HILI case to the updated RUCAM, either for the hepatocellular injury (Table Hepatocellular Liver Injury) or the cholestatic and mixed liver injury (Table Cholestatic or Mixed Liver injury).

Pregnancy is a risk factor only for the cholestatic and mixed liver injury, not for the hepatocellular injury (Table Cholestatic or Mixed Liver injury).

RUCAM scale online calculator

Evaluation of the relationship between liver injyry and taking the drug by the number of points:

Each element of the updated RUCAM is assigned an individual score, and the sum of the individual scores gives the final score for the case. From +14 to -9 points, there is a wide range of final grades.Total score and resulting causality grading:

≤0 points – excluded
1-2 points – unlikely
3-5 points – possible
6-8 points – probable
>9 points – highly probable

What should be considered when using this rating scale?

Operational Information on the Updated RUCAM

RUCAM affords prospective use, since retrospective scoring is less accurate.
RUCAM is to be calculated individually for each co-administered product.
RUCAM is conceptualized primarily for idiosyncratic, not for intrinsic reactions.
RUCAM excludes cases with onset of hepatic injury before start of product use.
RUCAM is applicable only for acute liver injury, not for preexisting chronic liver disease.
RUCAM cannot correctly assess when ALP is elevated for non-hepatic reasons.
Concomitant use of drugs and herbs is a crucial item that is best inquired and documented at first presentation when liver injury is suspected. Details of a temporal association and potential hepatotoxic features of the used product are to be assessed and documented. For reasons of comparison and transparency, each comedicated drug or herb requires a separate analysis by the complete updated RUCAM. In patients with use of multiple drugs or herbs, the final causality should be attributed primarily to the product with the highest score achieved with the updated RUCAM.

Previous Hepatotoxicity

Hepatotoxicity listed in the product information sheet (e.g., Summary of product characteristics in the EU or product information in the US) must be checked, although the terms used to express the liver injury may vary and usually do not refer to specific definitions. If it is mentioned, then the hepatotoxicity is considered as known for that compound. If this toxicity is not mentioned, a quick literature search in PubMed and the well documented NIH LiverTox website are recommended to determine whether the product has already been involved in published DILI and HILI.

Response to Unintentional Reexposure

A positive reexposure test result is a hallmark and gold standard in DILI cases and recognized by respective scores. To classify a reexposure test as positive, few criteria are required, as specified. The respective criteria were based on the conclusions of International Consensus Meetings in 1988 and 1990, as reviewed previously and recently. For the hepatocellular type of injury, the defining criteria are ALT levels before reexposure (designated as baseline ALT or ALTb), and reexposure ALT levels (designated as ALTr). The reexposure test is positive if ALTb is <5N and ALTr is ≥2ALTb, negative if one or both criteria are not fulfilled, and uninterpretable if data are lacking for one or both criteria. For the cholestatic or the mixed liver injury, the assessment criteria and interpretation of results are similar, with ALT replaced by ALP (Table).

Conditions of unintentional reexposure tests in suspected DILI and HILI cases.

Reexposure Test Result	Hepatocellular Injury		Cholestatic or Mixed Liver Injury
	ALTb	ALTr	ALPb	ALPr
● Positive	<5N	≥2ALTb	<2N	≥2ALPb
● Negative	<5N	<2ALTb	<2N	<2ALPb
● Negative	≥5N	≥2ALTb	≥2N	≥2ALPb
● Negative	≥5N	<2ALTb	≥2N	<2ALPb
● Uninterpretable	<5N	n.a.	<2N	n.a.
● Uninterpretable	n.a.	≥2ALTb	n.a.	≥2ALPb
● Uninterpretable	n.a.	n.a.	n.a.	n.a.

The original RUCAM was tested for its validity with the use of DILI cases confirmed by positive rechallenge taken as the gold standard and DILI cases where there was strong evidence that drugs were not the culprit drugs. As the updated RUCAM does not change fundamentally the structure and the weights of the original method there is no reason to consider a change in its validity. Presently, all relevant clinical diagnostic parameters are included in the updated RUCAM and in the checklist. There is little evidence that liver histology adds substantially to the diagnosis of DILI or HILI, as these lack specific histopathological features since they mimic all primary hepatic and biliary diseases. Therefore, liver histology is not part of the diagnostic program of the updated RUCAM. However, it is possible to take into account the results of a liver biopsy examination to exclude an alternative cause but certainly not to confirm DILI or HILI.

Search for Alternative Causes

In this domain, the updated RUCAM scale considers the clinically most relevant alternative causes and complications of underlying disease(s). Antibodies are important tools but require assessment and approval by regulatory agencies. Problems of diagnosing infections by hepatitis E virus (HEV) are evident in the US with anti-HEV antibody tests that are not FDA approved. Most importantly, titer changes of antibodies in suspected hepatic viral infections are to be evaluated in the further clinical course to confirm or disprove an ongoing virus infection.

Rare alternative causes are included in a checklist of differential diagnoses as a reminder for the clinician that many diagnoses exist as alternatives to DILI and HILI. These other diagnoses are to be considered, excluded or verified in the context of clinical data and importance, financial resources, and benefit for the patient. Establishing alternative causes contributes to the accuracy of the updated RUCAM and often provides clues to possible specific therapies.

Checklist of differential diagnoses of DILI and HILI

Checklist of differential diagnoses of DILI and HILI. This tabular listing, although not comprehensive, is to be used as a guide and in connection with the updated RUCAM, derived from a previous publication.

Differential Diagnosis	Diagnostic Parameters	Diagnostic Exclusion Done for Patient’s Assessment
		Yes	No	Partial
● Hepatitis A virus (HAV)	Anti-HAV-IgM	□	□	□
● Hepatitis B virus (HBV)	HBV-DNA, anti-HBc-IgM	□	□	□
● Hepatitis C virus (HCV)	HCV-RNA, anti-HCV	□	□	□
● Hepatitis E virus (HEV)	HEV-RNA, titer change for anti-HEV-IgM/anti-HEV-IgG	□	□	□
● Cytomegalovirus (CMV)	CMV-PCR, titer change for anti-CMV-IgM/anti-CMV-IgG	□	□	□
● Epstein Barr virus (EBV)	EBV-PCR, titer change for anti-EBV-IgM/anti-EBV-IgG	□	□	□
● Herpes simplex virus (HSV)	HSV-PCR, titer change for anti-HSV-IgM/anti-HSV-IgG	□	□	□
● Varicella zoster virus (VZV)	VZV-PCR, titer change for anti-VZV-IgM/anti-VZV-IgG	□	□	□
● Other virus infections	Specific serology of Adenovirus, Coxsackie-B-Virus, Echovirus, Measles virus, Rubella virus, Flavivirus, Arenavirus, Filovirus, Parvovirus, HIV, and others	□	□	□
● Other infectious diseases	Specific assessment of bacteria, fungi, parasites, worms, and others	□	□	□
● Autoimmune hepatitis (AIH) type I	Gamma globulins, ANA, SMA, AAA, SLA/LP, Anti-LSP, Anti-ASGPR	□	□	□
● Autoimmune hepatitis (AIH) type II	Gamma globulins, Anti-LKM-1 (CYP 2D6), Anti-LKM-2 (CYP 2C9), Anti-LKM-3	□	□	□
● Primary biliary cholangitis (PBC)	AMA, Anti PDH-E2	□	□	□
● Primary sclerosing cholangitis (PSC)	p-ANCA, MRC	□	□	□
● Autoimmune cholangitis (AIC)	ANA, SMA	□	□	□
● Overlap syndromes	See AIH, PBC, PSC, and AIC	□	□	□
● Non alcoholic steatohepatitis (NASH)	BMI, insulin resistance, hepatomegaly, echogenicity of the liver	□	□	□
● Alcoholic liver disease (ALD)	Patient’s history, clinical and laboratory assessment, other alcoholic disease(s)	□	□	□
● Drug induced liver injury (DILI) or herb induced liver injury (HILI)	Patient’s history, clinical and laboratory assessment, sonography, use of the updated RUCAM	□	□	□
● Cocaine, ecstasy and other amphetamines	Toxin screening	□	□	□
● Rare intoxications	Toxin screening for household and occupational toxins	□	□	□
● Hereditary hemochromatosis	Serum ferritin, total iron-binding capacity, genotyping for C2824 and H63D mutation, hepatic iron content	□	□	□
● Wilson disease	Copper excretion (24 h urine), ceruloplasmin in serum, free copper in serum, Coombs-negative hemolytic anemia, hepatic copper content, Kayser-Fleischer-ring, neurologic-psychiatric work-up, genotyping	□	□	□
● Porphyria	Porphobilinogen in urine, total porphyrines in urine	□	□	□
● α₁—Antitrypsin deficiency	α₁—Antitrypsin in serum	□	□	□
● Biliary diseases	Clinical and laboratory assessment, hepatobiliary sonography, MRC	□	□	□
● Pancreatic diseases	Clinical and laboratory assessment, sonography, CT, MRT	□	□	□
● Celiac disease	TTG antibodies, endomysium antibodies, duodenal biopsy	□	□	□
● Anorexia nervosa	Clinical context	□	□	□
● Parenteral nutrition	Clinical context	□	□	□
● Cardiopulmonary diseases	Cardiopulmonary assessment of congestive heart disease, myocardial infarction, cardiomyopathy, cardiac valvular dysfunction, pulmonary embolism, pericardial diseases, arrhythmia, hemorrhagic shock, and various other conditions	□	□	□
● Addison’s disease	Plasma cortisol	□	□	□
● Thyroid diseases	TSH basal, T4, T3	□	□	□
● Grand mal seizures	Clinical context of epileptic seizure (duration > 30 min)	□	□	□
● Heat stroke	Shock, hyperthermia	□	□	□
● Polytrauma	Shock, liver injury	□	□	□
● Systemic diseases	Specific assessment of sarcoidosis, amyloidosis, metastatic tumor, sepsis, and others	□	□	□
● Other diseases	Clinical context	□	□	□

Abbreviations: AAA, Anti-actin antibodies; AMA, Antimitochondrial antibodies; ANA, Antinuclear antibodies; ASGPR, Asialo-glycoprotein-receptor; BMI, Body mass index; CT, Computed tomography; CYP, Cytochrome P450; PDH, Pyruvate dehydrogenase; HAV, Hepatitis A virus; HBc, Hepatitis B core; HBV, Hepatitis B virus; HCV, Hepatitis C virus; HEV, Hepatitis E virus; HILI, Herb induced liver injury; HIV; human immunodeficiency virus; LKM, Liver kidney microsomes; LP, Liver-pancreas antigen; LSP, Liver specific protein; MRC, Magnetic resonance cholangiography; MRT, Magnetic resonance tomography; p-ANCA, Perinuclear antineutrophil cytoplasmic antibodies; PCR, Polymerase chain reaction; RUCAM, Roussel Uclaf Causality Assessment Method; SLA, Soluble liver antigen; SMA, Smooth muscle antibodies; TSH, Thyroid stimulating hormone; TTG, Tissue transglutaminase

Thus, the updated RUCAM can be used based on:

Type of the damage to the liver (hepatocellular, cholestatic, mixed type);
Detailing of the main elements of assessments (table hepatocellular, cholestatic/mixed type of damage);
Differential diagnosis (checklist table)
Reexposure criteria (table).

Correct Diagnoses

Results based on the updated RUCAM are quickly available for trained physicians with substantial clinical experience who then have to decide whether DILI or HILI is the most like diagnosis in their patients or any other differential diagnoses. Their decision is crucial, as DILI and HILI require discontinuation of the offending product whereas other diagnoses may require specific therapeutic modalities. The patient will immediately profit from the correct diagnosis achieved after using the updated RUCAM and the checklist.

Missed Diagnoses

Unrecognized alternative causes to the liver injury are a real clinical problem when caring for patients with initially assumed but later not confirmed DILI or HILI; the long list of missed diagnoses in the setting of initially assumed injury cases is indeed threatening. More recent evidence suggests that the problem of missed diagnoses is multifaceted and caused by incomplete case data collection, poor case data analysis, problems of appropriate case data transfer from medical files to the manuscript, and unjustified upgrading of causality scores. Missing the correct diagnosis may cause legal considerations that are better avoided by prior sophisticated clinical and regulatory approaches. Effective treatments would have been available for some patients with missed diagnoses, a critical situation in the clinical context.

Abbreviations: CMV, Cytomegalovirus; EBV, Epstein Barr virus; HSV Herpes simplex virus; LKM, Liver kidney microsomes; SMA, Smooth muscle antibodies; VZV, Varicella zoster virus.

Missed diagnoses in cases of initially suspected hepatotoxicity by synthetic drugs or herbs. Adapted from previous reports, which provide the respective references for each missed diagnosis listed above.

Historical background

Previous synonym of RUCAM were CIOMS (Council for International Organizations of Medical Sciences) or CIOMS/RUCCAM.

The updated RUCAM is as good as physicians and assessors are handling this method and consider basic liver tests for the liver injury classification, the specific operational information, details of core elements and their scoring, differential diagnoses, and the reexposure criteria. RUCAM has not been designed for chronic DILI and HILI or when a suspected injury occurs on pre-existing liver disease, both complex conditions where an expert panel of hepatologists would provide a more accurate approach especially for the timing of the events and the exclusion of alternative causes.

Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report.

Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. The authors presented the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.

RUCAM was not designed for chronic DILI and HILI, or when damage is suspected in pre-existing liver disease.

RUCAM scoring can help establish a clinical diagnosis, which can be useful for further choice of therapy.

Register on our website right now to have access to more learning materials!

Subscribe to our pages:

Literature

Danan G., Bénichou C. Causality assessment of adverse reactions to drugs—I. A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries. J. Clin. Epidemiol. 1993;46:1323–1330. doi: 10.1016/0895-4356(93)90101-6. [PubMed]
Andrade RJ, Robles M, Fernández-Castañer A, López-Ortega S, López-Vega MC, Lucena MI (2007).
“Assessment of drug-induced hepatotoxicity in clinical practice: a challenge for gastroenterologists.” World J. Gastroenterol. 13 (3): 329–40.
Danan G, Teschke R. RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2015;17(1):14. Published 2015 Dec 24. doi:10.3390/ijms17010014
Teschke R., Eickhoff A., Schwarzenboeck A., Schmidt-Taenzer W., Genthner A., Frenzel C., Wolff A., Schulze J. Clinical review: Herbal hepatotoxicity and the call for systematic data documentation of individual cases. J. Liver Clin. Res. 2015;2:1008. (Google Scholar)

See also:

Child-Pugh Score for Cirrhosis Mortality: online calculator

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

King’s College Criteria for Acetaminophen Toxicity

MELD Score (Model For End-Stage Liver Disease) (12 and older): Online calculator

MELD Score stratifies severity of end-stage liver disease, for transplant planning. NB! MELD Score can…

Interactive Checklist of differential diagnoses of DILI and HILI

Differential diagnoses of drug-induced and herb-induced liver disease: Checklist of differential diagnoses of DILI and…

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

The RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the likelihood of drug-induced…

R-value for Liver Injury Online calculator

Can be used in patients with suspected drug induced liver injury (DILI) with abnormal liver…

Child-Pugh Score for Cirrhosis Mortality: online calculator

The Child-Pugh Score can be useful in the prognosis of patients with cirrhosis, but more…

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

Identification of patients who should be immediately referred for liver transplant. INR > 6.5 (Prothrombin…

Сообщение RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator появились сначала на ClinCaseQuest.

R-value for Liver Injury Online calculator

Nataliia Lopina — Wed, 19 Jan 2022 14:30:28 +0000

Can be used in patients with suspected drug induced liver injury (DILI) with abnormal liver chemistries.

R-value= (patient’s ALT / upper limit of normal ALT ) / ( patient’s ALP / upper limit of normal ALP )

Note: Normal values may vary by lab.

R-value calculation allows clinicians to collectively identify and describe the pattern of liver injury in an objective manner.
R-value calculation allows clinicians suspecting a diagnosis of DILI to formulate an organized diagnostic strategy to rule out other causes of acute liver injury and to narrow the list of possible culprit drugs based on the pattern of liver injury.
Recommended by guidelines.

Parameters that required for the assessment:

Patient’s ALT, U/L
Upper limit of normal ALT According to your lab, U/L
Patient’s ALP, U/L
Upper limit of normal ALP According to your lab, U/L

Interpretation:

R-value range	The type of the liver injury	Conclusion and Advise
<2	Cholestatic pattern of liver injury.	• Pancreatic malignancy, cholangiocarcinoma, primary malignancy of the gallbladder, choledocholithiasis, sepsis, TPN, heart failure, PSC, and PBC should be ruled out as causes • Commonly used drugs that can cause this pattern of liver injury include: amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, azathioprine, and anabolic steroids • Recommend imaging studies (e.g. abdominal ultrasound)
2-5	Mixed pattern of liver injury.	Recommend acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)
>5	Hepatocellular pattern of liver injury.	• Acute viral hepatitis, ischemic liver injury, Budd-Chiari syndrome, autoimmune hepatitis, and Wilson’s disease (in younger patients) should be ruled out as causes • Commonly used drugs that can cause this pattern of liver injury include: isoniazid, macrolides, nitrofurantoin, minocycline, anti-epileptics, NSAIDs, green tea extract, and inhaled anesthetics • Recommend acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)

Futher diagnostic approach:

R Factor	Injury type	Recommended 1st line tests*
>5	Hepatocellular	Acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)
2–5	Mixed	Acute viral hepatitis serologies, HCV RNA and autoimmune hepatitis serologies, imaging studies (e.g. abdominal ultrasound)
<2	Cholestatic	Imaging studies (e.g. abdominal ultrasound)

*From Chalasani 2014

The R-value (also known as the R ratio or R factor) was introduced after an international consensus meeting in 1989 aimed at preparing definitions and criteria related to drug related liver injury. At the request of the Council for International Organizations of Medical Sciences (CIOMS), a pilot program led by pharmaceutical company Roussel Uclaf was initiated to help classify different patterns of acute liver injury, introducing the R-value.

The R-value itself has not been validated, but remains commonly used in clinical practice to objectively define different patterns of liver injury. The American College of Gastroenterology (ACG) has incorporated the R-value in its guidelines for diagnosis and management of idiosyncratic drug-induced liver injury.

Recommendations for workup based on R Factor, adapted from Chalasani 2014

The pattern of acute liver injury (and therefore the R-value) can vary throughout the clinical course of the illness.
Identifying the pattern of liver injury can guide diagnostic approach to DILI, including appropriate further diagnostic testing necessary to rule out other causes of liver injury.
Calculating the R-value is the first step in calculating the Roussel Uclaf Causality Assessment Method (RUCAM) when determining if liver injury is related to a specific drug.
Because the pattern of liver injury can evolve over time, the time point at which liver chemistries are used to calculate the R-value can alter the final result. It is recommended that the initial liver chemistries suggesting liver injury be used, but ultimately left to the clinician to decide what set of liver chemistries to use when making an assessment.
The use of upper limit of normal (ULN) in the equation creates some room for variability. The ULN varies among different laboratories.
While not validated, the R-value is widely used and has been incorporated into guideline recommendations for assessing liver injury.
Though the R Factor does not incorporate coagulopathy (INR) and mental status, these two factors should always be immediately assessed in all cases of acute liver injury to rule out acute liver failure.

Register on our website right now to have access to more learning materials!

Subscribe to our pages:

Literature

Bénichou C. Criteria of drug-induced liver disorders. Report of an international consensus meeting. J Hepatol. 1990 Sep;11(2):272-6. doi: 10.1016/0168-8278(90)90124-a. PMID: 2254635.
Chalasani NP, Hayashi PH, Bonkovsky HL, Navarro VJ, Lee WM, Fontana RJ; Practice Parameters Committee of the American College of Gastroenterology. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul;109(7):950-66; quiz 967. doi: 10.1038/ajg.2014.131. Epub 2014 Jun 17. PMID: 24935270.
Danan G, Teschke R. RUCAM in Drug and Herb Induced Liver Injury: The Update. Int J Mol Sci. 2015;17(1):14. Published 2015 Dec 24. doi:10.3390/ijms17010014

MELD Score (Model For End-Stage Liver Disease) (12 and older): Online calculator

May 16, 2022

MELD Score stratifies severity of end-stage liver disease, for transplant planning. NB! MELD Score can…

Interactive Checklist of differential diagnoses of DILI and HILI

February 3, 2022

Differential diagnoses of drug-induced and herb-induced liver disease: Checklist of differential diagnoses of DILI and…

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

February 1, 2022

The RUCAM score (Roussel Uclaf Causality Assessment Method) helps to assess the likelihood of drug-induced…

Child-Pugh Score for Cirrhosis Mortality: online calculator

January 12, 2022

The Child-Pugh Score can be useful in the prognosis of patients with cirrhosis, but more…

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

January 4, 2022

Identification of patients who should be immediately referred for liver transplant. INR > 6.5 (Prothrombin…

King’s College Criteria for Acetaminophen Toxicity

December 19, 2021

Identification of patients who should be immediately referred for liver transplant. Arterial pH < 7.30:…

Сообщение R-value for Liver Injury Online calculator появились сначала на ClinCaseQuest.

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

Nataliia Lopina — Tue, 04 Jan 2022 10:07:00 +0000

Identification of patients who should be immediately referred for liver transplant.

Patient’s score	Result	Comment
0	0	0

Patients with acute liver failure should be treated in centers that specialize in the care of such patients. The King’s College criteria can help identify patients who require liver transplantation.

Criteria for non-acetaminophen-induced acute liver failure include:

1 big criterion – International normalized ratio (INR)> 6.5; and
5 small criteria:
1. the patient’s age is <11 or> 40 years;
2. the level of bilirubin in serum is more than 300 μmol per liter;
3. More than seven days have passed from the onset of jaundice to the development of encelopathy;
4. INR (international normalized ratio)> 3.5 (prothrombin time> 50 seconds);
5. etiology – the absence of hepatitis A and B or the presence of an idiosyncratic reaction to a drug.

Interpretation of results:

A patient’s survival prognosis is poor if he has at least 1 major criterion or any 3 minor criteria.

The King’s College criteria are recommended by the American Association for the Study of Liver Diseases (AASLD) for determining the need for liver transplantation in patients with acute liver failure.

Register on our website right now to have access to more learning materials!

Subscribe to our pages:

References

O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. doi: 10.1016/0016-5085(89)90081-4. PMID: 2490426. https://pubmed.ncbi.nlm.nih.gov/2490426/
Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002 Feb 16;359(9306):558-63. doi: 10.1016/S0140-6736(02)07743-7. PMID: 11867109. https://pubmed.ncbi.nlm.nih.gov/11867109/
Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003 Jan;31(1):299-305. doi: 10.1097/00003246-200301000-00048. PMID: 12545033. https://pubmed.ncbi.nlm.nih.gov/12545033/
Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002; 36(3):659–665. doi: 10.1053/jhep.2002.35069. https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jhep.2002.35069
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 Aug 14;337(7):473-9. doi: 10.1056/NEJM199708143370707. PMID: 9250851. https://pubmed.ncbi.nlm.nih.gov/9250851/

Baseline Cardiovascular Risk Assessment in Cancer Patients Scheduled to Receive Cardiotoxic Cancer Therapies (Anthracycline Chemotherapy) – Online Calculator

July 3, 2023

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies (Anthracycline Chemotherapy)…

National Institutes of Health Stroke Scale (NIHSS) – Online calculator

June 22, 2023

The National Institutes of Health Stroke Scale (NIHSS) is a scale designed to assess the…

Charlson Comorbidity Index (CCI) Online Calculator

May 10, 2023

Charlson Comorbidity Index predicts 10-year survival in patients with multiple comorbidities.

VariablePointsAge <50…

Multiple Myeloma Diagnostic Criteria – Online Calculator

February 5, 2023

Email (indicate if you want the results to be sent to your email)

Date of assessment

≥1 of the following (A or B)

A. Clonal bone marrow plasma cells ≥10%

B. Biopsy-proven bony or extramedullary plasmacytoma

≥1 myeloma defining event (C1 or C2)

• C1. End organ damage attributable to underlying plasma cell disorder (≥1 of the following): *

o Hypercalcemia (Serum calcium >1 mg/dL (>0.25 mmol/L) higher than upper limit of normal or >11 mg/dL (>2.75 mmol/L))

o Renal insufficiency (Creatinine clearance<40 mL per min or serum creatinine >2 mg/dL (177 μmol/L))

o Anemia (Hemoglobin >2 g/dL (20 g/L) below lower limit of normal

o Bone lesions (≥1 osteolytic lesion on skeletal x-ray

• C2. ≥1 of the following biomarkers of malignancy: *

o Clonal bone marrow plasma cells ≥60%

o Involved:uninvolved sFLC ratio ≥100

o >1 focal lesion on MRI

Result

Diagnostic result

Negative. Not positive for multiple myeloma by IMWG criteria

Diagnostic result

Positive for multiple myeloma by IMWG criteria

Details:

* Required

For Multiple Myeloma Diagnostic Criteria assessment necessary to provide selection of the…

Revised Multiple Myeloma International Staging System (R-ISS) Online Calculator

January 17, 2023

Revised Multiple Myeloma International Staging System (R-ISS) – prognostication tool for myeloma patients based on…

Multiple Myeloma International Staging System (ISS) Online Calculator

January 16, 2023

Multiple Myeloma International Staging System (ISS) prognosticates the severity of multiple myeloma based on routinely…

Сообщение King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure появились сначала на ClinCaseQuest.

King’s College Criteria for Acetaminophen Toxicity

Nataliia Lopina — Sun, 19 Dec 2021 07:42:00 +0000

Identification of patients who should be immediately referred for liver transplant.

Patient’s score	Result	Comment
0	0	0

Patients with acute liver failure should be managed in centers with expertise in caring for these patients. King’s College Criteria for Acetaminophen Toxicity could help identify patients that required liver transplantation.

The presence of one of the following should prompt a referral/transfer to a liver transplantation center:

Arterial pH < 7.30

INR > 6.5 (PT > 100 sec)

Creatinine > 3.4 mg/dL (300 µmol/L)

Grade III or IV hepatic encephalopathy
• Grade – III hepatic encephalopathy – Marked confusion, incoherent speech, sleeping most of the time but arousable to vocal stimuli
• Grade – IV hepatic encephalopathy – Comatose, unresponsive to pain; decorticate or decerebrate posturing

Lactate > 3.5 mmol/L after fluid resuscitation (<4 hrs) OR lactate > 3 mmol/L after full fluid resuscitation (12 hours)

Phosphate > 3.75 mg/dL (1.2 mmol/L) at 48-96 hours

Acidosis (admission arterial pH < 7.30) OR
Hepatic encephalopathy (grade III or IV), AND coagulopathy (PT > 100 s), AND acute kidney injury (creatinine > 3.4 mg/dL), OR
Hyperlactatemia (4-hour lactate > 3.5 mmol/L, or 12-hour lactate > 3.0 mmol/L), OR
Hyperphosphatemia (48-96 hour phosphate > 3.7 mg/dL) in patients with acetaminophen-induced fulminant hepatic failure.

The King’s College Criteria (KCC) was derived from a retrospective review of 588 patients with fulminant hepatic failure (FHF) over 13 years. The predictors are slightly different based on the etiology of the FHF (acetaminophen versus other causes).

The arterial pH, hepatic encephalopathy (HE), prothrombin time, and creatinine predictors were derived from 310 acetaminophen-induced FHF patients and retrospectively validated on a separate 121 acetaminophen-induced FHF patients.

There were establish the next Sensitivity, Specificity, Predictive Accuracy for mention above indicators in predictive the necessity of the liver transplantation.

Criteria	PPV	Sensitivity	Specificity	Predictive Accuracy
Arterial pH < 7.30	0.95	0.49	0.99	0.81
HE + PT + Cr	0.67	0.45	0.94	0.83
Lactate*		0.81	0.95	0.92
Phosphate**	1	0.89	1	0.98

PPV = Positive predictive value; HE = Hepatic encephalopathy stage III/IV; PT = prothrombin time > 100 s; Cr = creatinine > 3.4 mg/dL
* Either lactate > 3.5 mmol/L after early resuscitation, or > 3.0 mmol/L after full resuscitation.
** Phosphate > 3.7 mg/dL between 48 – 96 hours.

Patients were transferred to King’s College Hospital at a relatively late stage (median time of 51 hours after acetaminophen ingestion) and were the most severely ill (the majority of patients were admitted with HE stages III or IV). This may have affected the predictive values of the test criteria.

In a systematic review of 14 eligible studies, the estimated overall sensitivity and specificity of the KCC for predicting mortality were 58% and 95%, respectively.

The search for earlier prognostic indicators with a higher sensitivity for poor prognosis led to investigations of α-fetoprotein, coagulation factor V, ketone body ratio, lactate and phosphate.

Lactate and phosphate concentrations were initially found to have improved predictive ability to the KCC. Subsequent studies have shown slightly inferior predictive ability compared to the KCC.

The addition of lactate or phosphate to the KCC may improve sensitivity and negative predictive value.

Serum aminotransferases and bilirubin should be monitored daily. Frequent monitoring should be performed for coagulation parameters, complete blood counts, metabolic panels, blood gases, and blood glucose. Patients should be monitored and treated for hypoglycemia, hypokalemia, and hypophosphatemia.

All patients with acetaminophen-induced hepatotoxicity should be prescibed N-acetylcysteine.

Fresh frozen plasma (FFP) is indicated only in the setting of active hemorrhage or prior to invasive procedures in coagulopathic patients. Prophylactic administration of FFP is not recommended since it does not improve mortality and can interfere with assessments of liver function.

Register on our website right now to have access to more learning materials!

Subscribe to our pages:

References

O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug;97(2):439-45. doi: 10.1016/0016-5085(89)90081-4. PMID: 2490426. https://pubmed.ncbi.nlm.nih.gov/2490426/
Bernal W, Donaldson N, Wyncoll D, Wendon J. Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet. 2002 Feb 16;359(9306):558-63. doi: 10.1016/S0140-6736(02)07743-7. PMID: 11867109. https://pubmed.ncbi.nlm.nih.gov/11867109/
Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med. 2003 Jan;31(1):299-305. doi: 10.1097/00003246-200301000-00048. PMID: 12545033. https://pubmed.ncbi.nlm.nih.gov/12545033/
Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology. 2002; 36(3):659–665. doi: 10.1053/jhep.2002.35069. https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1053/jhep.2002.35069
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 Aug 14;337(7):473-9. doi: 10.1056/NEJM199708143370707. PMID: 9250851. https://pubmed.ncbi.nlm.nih.gov/9250851/

Baseline Cardiovascular Risk Assessment in Cancer Patients Scheduled to Receive Cardiotoxic Cancer Therapies (Anthracycline Chemotherapy) – Online Calculator

July 3, 2023

Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies (Anthracycline Chemotherapy)…

National Institutes of Health Stroke Scale (NIHSS) – Online calculator

June 22, 2023

The National Institutes of Health Stroke Scale (NIHSS) is a scale designed to assess the…

Charlson Comorbidity Index (CCI) Online Calculator

May 10, 2023

Charlson Comorbidity Index predicts 10-year survival in patients with multiple comorbidities.

Email (indicate if you want the results to be sent to your email)

Date of assessment

Myocardial infarction *

History of definite or probable MI (EKG changes and/or enzyme changes)

Yes

Congestive heart failure *

Exertional or paroxysmal nocturnal dyspnea and has responded to digitalis, diuretics, or afterload reducing agents

Yes

Peripheral vascular disease *

Intermittent claudication or past bypass for chronic arterial insufficiency, history of gangrene or acute arterial insufficiency, or untreated thoracic or abdominal aneurysm (≥6 cm)

Yes

Cerebrovascular accident or Transient ischemic attack *

History of a cerebrovascular accident with minor or no residua and transient ischemic attacks

Yes

Dementia *

Chronic cognitive deficit

Yes

Chronic obstructive pulmonary disease *

Yes

Connective tissue disease *

Yes

Peptic ulcer disease *

Any history of treatment for ulcer disease or history of ulcer bleeding

Yes

Liver disease *

Severe = cirrhosis and portal hypertension with variceal bleeding history, moderate = cirrhosis and portal hypertension but no variceal bleeding history, mild = chronic hepatitis (or cirrhosis without portal hypertension)

None

Mild

Moderate to severe

Diabetes mellitus *

None or diet-controlled

Uncomplicated

End-organ damage

Hemiplegia *

Yes

Moderate to severe chronic kidney disease *

Severe = on dialysis, status post kidney transplant, uremia, moderate = creatinine >3 mg/dL (0.27 mmol/L)

Yes

Solid tumor *

None

Localized

Metastatic

Leukemia *

Yes

Lymphoma *

Yes

AIDS *

Yes

Charlson Comorbidity Index

10-year survival

VariablePointsAge <50…

Multiple Myeloma Diagnostic Criteria – Online Calculator

February 5, 2023

Email (indicate if you want the results to be sent to your email)

Date of assessment

≥1 of the following (A or B)

A. Clonal bone marrow plasma cells ≥10%

B. Biopsy-proven bony or extramedullary plasmacytoma

≥1 myeloma defining event (C1 or C2)

• C1. End organ damage attributable to underlying plasma cell disorder (≥1 of the following): *

o Hypercalcemia (Serum calcium >1 mg/dL (>0.25 mmol/L) higher than upper limit of normal or >11 mg/dL (>2.75 mmol/L))

o Renal insufficiency (Creatinine clearance<40 mL per min or serum creatinine >2 mg/dL (177 μmol/L))

o Anemia (Hemoglobin >2 g/dL (20 g/L) below lower limit of normal

o Bone lesions (≥1 osteolytic lesion on skeletal x-ray

• C2. ≥1 of the following biomarkers of malignancy: *

o Clonal bone marrow plasma cells ≥60%

o Involved:uninvolved sFLC ratio ≥100

o >1 focal lesion on MRI

Result

Diagnostic result

Negative. Not positive for multiple myeloma by IMWG criteria

Diagnostic result

Positive for multiple myeloma by IMWG criteria

For Multiple Myeloma Diagnostic Criteria assessment necessary to provide selection of the…

Revised Multiple Myeloma International Staging System (R-ISS) Online Calculator

January 17, 2023

Revised Multiple Myeloma International Staging System (R-ISS) – prognostication tool for myeloma patients based on…

Multiple Myeloma International Staging System (ISS) Online Calculator

January 16, 2023

Multiple Myeloma International Staging System (ISS) prognosticates the severity of multiple myeloma based on routinely…

Сообщение King’s College Criteria for Acetaminophen Toxicity появились сначала на ClinCaseQuest.

Toxicology – ClinCaseQuest

Interactive Checklist of differential diagnoses of DILI and HILI

Differential Diagnosis / Diagnostic Parameters

RUCAM scale to estimate the probability of the drug-induced liver injury (DILI) and herb induced liver injury (HILI) online calculator

RUCAM scale online calculator

Select the type of liver injury: hepatocellular or cholestatic/mixed:

1. Time to onset from the beginning of the drug/herb

2. Course of ALT after cessation of the drug/herb

2. Course of ALP after cessation of the drug/herb

3. Risk factors

4. Concomitant use of drug(s)/herb(s)

5. Search for alternative causes

6. Previous hepatotoxicity of the drug/herb

7. Response to unintentional reexposure

What should be considered when using this rating scale?

Previous Hepatotoxicity

Response to Unintentional Reexposure

Search for Alternative Causes

Checklist of differential diagnoses of DILI and HILI

Differential Diagnosis / Diagnostic Parameters

Correct Diagnoses

Missed Diagnoses

Historical background

R-value for Liver Injury Online calculator

Futher diagnostic approach:

Recommendations for workup based on R Factor, adapted from Chalasani 2014

King’s College Criteria for Non- Acetaminophen Toxicity acute hepatic failure

≥1 of the following (A or B)

≥1 myeloma defining event (C1 or C2)

King’s College Criteria for Acetaminophen Toxicity

≥1 of the following (A or B)

≥1 myeloma defining event (C1 or C2)