AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury

In the paper

“In countries in which the over‐the‐counter sale of APAP has been restricted, the incidence of serious APAP toxicity has fallen.”

In the paper

“A focused analysis of GTE cases enrolled in the DILIN has led to recognition of the typical presentation of GTE as being hepatocellular and sometimes fatal, with a strong genetic association with HLA‐B*35:01.72”

What the sources say

• Not checked yetcites [72] Hoofnagle JH Bonkovsky HL Phillips EJ Li YJ Ahmad J Barnhart H. HLA‐B*35:01 and green tea‐induced liver injury. Hepatology. 2021; 73: 2484– 93. 32892374 PMC8052949

In the paper

“Based on DILIN Registry data, HDS comprise approximately 20% of all cases of liver injury encountered in adults.28”

What the sources say

• Not checked yetcites [28] Navarro VJ Barnhart H Bonkovsky HL Davern T Fontana RJ Grant L. Liver injury from herbals and dietary supplements in the U.S. drug‐induced liver injury network. Hepatology. 2014; 60: 1399– 408. 25043597 PMC4293199

In the paper

“The coagulopathy can be severe, and a prolonged INR is a bad prognostic sign.168”

What the sources say

• Not checked yetcites [168] Koch DG Tillman H Durkalski V Lee WM Reuben A. Development of a model to predict transplant‐free survival of patients with acute liver failure. Clin Gastroenterol Hepatol. 2016; 14: 1199– 206. 27085756 PMC6055510

In the paper

“The apoptotic index, which incorporates full‐length serum cytokeratin 18 (CK18) and caspase‐cleaved CK18 levels, may also be more sensitive than serum ALT in detecting liver injury and also be of prognostic value.212,213”

What the sources say

• Not checked yetcites [212] Thulin P Nordahl G Gry M Yimer G Aklillu E Makonnen E. Keratin‐18 and microRNA‐122 complement alanine aminotransferase as novel safety biomarkers for drug‐induced liver injury in two human cohorts. Liver Int. 2014; 34: 367– 78. 24118944
• Not checked yetcites [213] Rutherford A King LY Hynan LS Vedvyas C Lin W Lee WM. Development of an accurate index for predicting outcomes of patients with acute liver failure. Gastroenterology. 2012; 143: 1237– 43. 22885329 PMC3480539

In the paper

“The DILIN tested a multiplex lymphocyte proliferation assay but did not obtain informative results.217”

What the sources say

• Not checked yetcites [217] Whritenour J Ko M Zong Q Wang J Tartaro K Schneider P. Development of a modified lymphocyte transformation test for diagnosing drug induced liver injury associated with an adaptive immune response. J Immunotoxicol. 2017; 14: 28– 31. PMC5505862 28121193

In the paper

“Rarely, ICI‐related sclerosing cholangitis can present with a cholestatic pattern of liver test elevations.”

In the paper

“Fatalities arise in < 1% of patients with IMH and almost exclusively occur in those with jaundice.207”

What the sources say

• Not checked yetcites [207] Schneider BJ Naidoo J Santomasso BD Lacchetti C Adkins S Anadkat M. Management of immune‐related adverse events in patients treated with immune checkpoint inhibitor therapy: ASCO guideline update. J Clin Oncol. 2021; 39: 4073– 126. 34724392

In the paper

“In general, statins are safe to administer, but myalgias and myopathy may lead to early dose reduction or termination in up to 10% of treated patients.197”

What the sources say

• Not checked yetcites [197] Zhang H Plutzky J Skentzos S Morrison F Mar P Shubina M. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013; 158: 526– 34. 23546564 PMC3692286

In the paper

“Although many medications have been associated with liver‐related fatalities, only a minority carry a black box warning for hepatotoxicity.”

In the paper

“Underreporting and poor adherence to American Thoracic Society guidelines are common in cases of isoniazid hepatotoxicity and are associated with hospitalization, death, and liver transplantation.187,188”

What the sources say

• Not checked yetcites [187] Singanayagam A Sridhar S Dhariwal J Abdel‐Aziz D Munro K Connell DW. A comparison between two strategies for monitoring hepatic function during antituberculous therapy. Am J Respir Crit Care Med. 2012; 185: 653– 9. 22198973
• Not checked yetcites [188] Hayashi PH Fontana RJ Chalasani NP Stolz AA Talwalkar JA Navarro VJ. Under‐reporting and poor adherence to monitoring guidelines for severe cases of isoniazid hepatotoxicity. Clin Gastroenterol Hepatol. 2015; 13: 1676– 82.e1. 25724701 PMC4653068

In the paper

“Other groups are exploring the development of in vitro test systems derived from circulating macrophages and human liver organoids, but further validation is needed.218,219”

What the sources say

• Not checked yetcites [218] Benesic A Rotter I Dragoi D Weber S Buchholtz ML Gerbes AL. Development and validation of a test to identify drugs that cause idiosyncratic drug‐induced liver injury. Clin Gastroenterol Hepatol. 2018; 16: 1488– 94. 29723689
• Not checked yetcites [219] Shinozawa T Kimura M Cai Y Saiki N Yoneyama Y Ouchi R. High‐fidelity drug‐induced liver injury screen using human pluripotent stem cell‐derived organoids. Gastroenterology. 2021; 160: 831– 46.e10. 33039464 PMC7878295

In the paper

“Although the incidence of severe DILI appears to be lower than previously appreciated,180 isoniazid continues to be a leading cause of DILI‐related ALF in the United States and worldwide (Table 2).181–184”

What the sources say

• Not checked yetcites [180] Jiang F Yan H Liang L Du J Jin S Yang S. Incidence and risk factors of anti‐tuberculosis drug induced liver injury (DILI): large cohort study involving 4652 Chinese adult tuberculosis patients. Liver Int. 2021; 41: 1565– 75. 33866661
• Not checked yetcites [181] Nolan CM Goldberg SV Buskin SE. Hepatotoxicity associated with isoniazid preventative therapy. A 7‐year survey from a public health tuberculosis clinic. JAMA. 1999; 281: 1014– 8. 10086436
• Not checked yetcites [182] Sotgiu G Matteelli A Getahun H Girardi E Sañé Schepisi M Centis R. Monitoring toxicity in individuals receiving treatment for latent tuberculosis infection: a systematic review versus expert opinion. Eur Respir J. 2015; 45: 1170– 3. 25700378 PMC4391659
• Not checked yetcites [183] Saukkonen JJ Cohn DL Jasmer RM Schenker S Jereb JA Nolan CM. An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med. 2006; 174: 935– 52. 17021358
• Not checked yetcites [184] Joint Tuberculosis Committee of the British Thoracic Society. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Thorax. 1998; 53: 536– 48. 9797751 PMC1745276

In the paper

“Recent studies suggest that bona fide DILI is only responsible for 30% of cases of demonstrable liver injury in patients with advanced cancer, whereas hepatic metastases, sepsis, and other causes of liver disease account for the remainder, emphasizing the importance of contrast‐enhanced CT and MR scanning in evaluation of these patients.205”

What the sources say

• Not checked yetcites [205] Tsung I Dolan R Lao CD Fecher L Riggenbach K Yeboah‐Korang A. Liver injury is most commonly due to hepatic metastases rather than drug hepatotoxicity during pembrolizumab immunotherapy. Aliment Pharmacol Ther. 2020; 50: 800– 8. 31309615

In the paper

“They are prescribed to more than 50% of oncology patients with advanced solid organ tumors.8,203”

What the sources say

• Not checked yetcites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985
• Not checked yetcites [203] Haslam A Prasad V. Estimation of the percentage of us patients with cancer who are eligible for and respond to checkpoint inhibitor immunotherapy drugs. JAMA Net Open. 2019; 2: e192535. PMC6503493 31050774

In the paper

“DILI biomarkers in development are currently being directed toward improved DILI diagnosis and prognosis as well as to provide mechanistic insight into DILI pathogenesis.”

In the paper

“Currently available serum markers of liver injury (i.e., AST, ALT, ALP) are neither sensitive nor specific enough to detect early DILI, nor are they able to reliably predict clinical outcomes.”

• Also stated in: § DILI biomarkers · plain

  “Currently available serum markers of liver injury such as serum AST, ALT, and ALP levels are not sensitive or specific enough to detect early DILI.”

In the paper

“In addition, other studies have suggested that statins in patients with compensated chronic liver disease and cirrhosis may even reduce the risk of hepatocellular cancer and decompensation.201”

What the sources say

• Not checked yetcites [201] Athyros VG Boutari C Stavropoulos K Anagnostis P Imprialos KP Doumas M. Statins: an under‐appreciated asset for the prevention and treatment of NAFLD and NASH and the related cardiovascular risk. Cur Vasc Pharmacol. 2018; 16: 246– 53. 28676019

In the paper

“For example, the incidence appears to be higher in exposure‐based studies using electronic medical records (32.8 per 100,000 adult patients who received one of the top implicated drugs in the United States and 40 per 100,000 patients at a pediatric hospital).11,12”

What the sources say

• Not checked yetcites [11] Shin J Hunt CM Suzuki A Papay JI Beach KJ Cheetham TC. Characterizing phenotypes and outcomes of drug‐associated liver injury using electronic medical record data. Pharmacoepidemiol Drug Saf. 2013; 22: 190– 8. 23258383
• Not checked yetcites [12] Sandritter TL Goldman JL Habiger CJ Daniel JF Lowry J Fischer RT. An electronic medical records‐based approach to identify idiosyncratic drug‐induced liver injury in children. Sci Rep. 2019; 9: 18090. 31792283 PMC6888850

In the paper

“DILI can be mechanistically classified as being either direct (i.e., dose‐dependent, intrinsic, and predictable) or idiosyncratic (largely dose‐independent, idiosyncratic, and unpredictable) (Table 1).”

In the paper

“A third mechanism of hepatotoxicity is called indirect DILI, which arises when the biological action of the drug affects the host immune system, leading to a secondary form of liver injury.”

What the sources say

• Not checked yetcites [7] Loomba R Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017; 152: 1297– 309. 28219691 PMC5501983
• Not checked yetcites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985

In the paper

“Examples of indirect hepatotoxicity include the immune‐mediated hepatitis (IMH) observed with immune checkpoint inhibitors (ICIs) and reactivation of HBV infection following rituximab infusions.7,8”

What the sources say

• Not checked yetcites [7] Loomba R Liang TJ. Hepatitis B reactivation associated with immune suppressive and biological modifier therapies: current concepts, management strategies, and future directions. Gastroenterology. 2017; 152: 1297– 309. 28219691 PMC5501983
• Not checked yetcites [8] Lombardi A Mondelli MU. Review article: immune checkpoint inhibitors and the liver, from therapeutic efficacy to side effects. Aliment Pharm Ther. 2019; 50: 872– 84. 31378985

In the paper

“The incidence of idiosyncratic DILI is even higher in hospitalized patients, being reported as high as 1.4% among medical inpatients.13–16”

What the sources say

• Not checked yetcites [13] Meier Y Cavallaro M Roos M Pauli‐Magnus C Folkers G Meier PJ. Incidence of drug‐induced liver injury in medical inpatients. Eur J Clin Pharmacol. 2005; 61: 135– 43. 15726344
• Not checked yetcites [14] Xu H Chen Y Xu J Zhou Q. Drug‐induced liver injury in hospitalized patients with notably elevated alanine aminotransferase. World J Gastroenterol. 2012; 18: 5972– 8. 23139615 PMC3491606
• Not checked yetcites [15] Björnsson HK Olafsson S Bergmann OM Björnsson ES. A prospective study on the causes of notably raised alanine aminotransferase (ALT). Scand J Gastroenterol. 2016; 51: 594– 600. 26653080
• Not checked yetcites [16] Sistanizad M Peterson GM. Drug‐induced liver injury in the Australian setting. J Clin Pharm Ther. 2013; 38: 115– 20. 23350857

In the paper

“Like idiosyncratic DILI, indirect hepatotoxins are generally independent of the dose of medication administered and have a latency of weeks to months with varying clinical manifestations.”

In the paper

“Idiosyncratic DILI is uncommon, with an estimated annual incidence in the general population of 14 to 19 events per 100,000 inhabitants or 60,000 cases per year in the general US population.9,10”

• Also stated in: § Leading causes of idiosyncratic DILI worldwide · hedged

  “The estimated annual incidence of idiosyncratic DILI in the general population is low (14–19/100,000) but higher in exposure‐based studies using electronic medical record data (33–40/100,000).”

What the sources say

• Not checked yetcites [9] Björnsson ES Bergmann OM Björnsson HK Kvaran RB Olafsson S. Incidence, presentation, and outcomes in patients with drug‐induced liver injury in the general population of Iceland. Gastroenterology. 2013; 144: 1419– 25. 23419359
• Not checked yetcites [10] Sgro C Clinard F Ouazir K Chanay H Allard C Guilleminet C. Incidence of drug‐induced hepatic injuries: a French population‐based study. Hepatology. 2002; 36: 451– 5. 12143055

In the paper

“For instance, HDS products surpass pharmaceuticals in China, Korea, and Singapore, accounting for 27%–62% of their DILI cases.22,25,26”

What the sources say

• Not checked yetcites [22] Shen T Liu Y Shang J Xie Q Li J Yan M. Incidence and etiology of drug‐induced liver injury in mainland China. Gastroenterology. 2019; 156: 2230– 41.e11. 30742832
• Not checked yetcites [25] Suk KT Kim DJ Kim CH Park SH Yoon JH Kim YS. A prospective nationwide study of drug‐induced liver injury in Korea. Am J Gastroenterol. 2012; 107: 1380– 7. 22733303
• Not checked yetcites [26] Wai CT. Presentation of drug‐induced liver injury in Singapore. Singapore Med J. 2006; 47: 116– 20. 16435052

In the paper

“Histologic features typically observed in AIH, such as interface hepatitis, emperipolesis (the presence of an intact cell within the cytoplasm of another), and rosette formation, are also observed among DILI cases (89%, 34%, and 40%, respectively, in DILI cases) and are not pathognomonic for AIH.89”

What the sources say

• Not checked yetcites [89] Suzuki A Brunt EM Kleiner DE Miquel R Smyrk TC Andrade RJ. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury. Hepatology. 2011; 54: 931– 939. 21674554 PMC3192933

In the paper

“Although DILI is often attributed to repeated exposure to an oral agent, it is important to recognize that exposure to an intravenous agent, such as monoclonal antibodies, may also cause DILI.”

In the paper

“Insufficient data exist to confirm subject age, sex, and race and ethnicity as reliable risk factors for DILI susceptibility. However, some drugs are more likely to cause DILI in older individuals (e.g., amoxicillin‐clavulanate, isoniazid), whereas others are more commonly implicated in children (valproate, minocycline).”

In the paper

“DI‐AIH may show more portal neutrophilic infiltrates and be accompanied by cholestasis, whereas sporadic AIH may show a chronic “hepatitis” pattern, and the interface hepatitis will be dominated by plasma cells.89”

What the sources say

• Not checked yetcites [89] Suzuki A Brunt EM Kleiner DE Miquel R Smyrk TC Andrade RJ. The use of liver biopsy evaluation in discrimination of idiopathic autoimmune hepatitis versus drug‐induced liver injury. Hepatology. 2011; 54: 931– 939. 21674554 PMC3192933

In the paper

“However, topical formulations of medications to the skin, eyes, or ears rarely, if ever, cause DILI because of the low dose of medication absorbed.”

In the paper

“Patients with recent hypotension, sepsis, or heart failure are at risk for ischemic liver injury, usually characterized by rapid and a marked increase in serum aminotransferase values followed by rapid decline with normal or near‐normal bilirubin levels.”

In the paper

“Noticeable differences also exist between sexes, with women experiencing more frequent and severe hepatotoxicity.44,45”

What the sources say

• Not checked yetcites [44] Zopf Y Rabe C Neubert A Gassmann KG Rascher W Hahn EG. Women encounter ADRs more often than do men. Eur J Clin Pharmacol. 2008; 64: 999– 1004. 18604529
• Not checked yetcites [45] George N Chen M Yuen N Hunt CM Suzuki A. Interplay of gender, age and drug properties on reporting frequency of drug‐induced liver injury. Regul Toxicol Pharmacol. 2018; 94: 101– 7. 29407200

In the paper

“Although standardized DILI incidence increases with patient age, this may be explained, in part, by greater medication use with increasing age.9”

What the sources say

• Not checked yetcites [9] Björnsson ES Bergmann OM Björnsson HK Kvaran RB Olafsson S. Incidence, presentation, and outcomes in patients with drug‐induced liver injury in the general population of Iceland. Gastroenterology. 2013; 144: 1419– 25. 23419359

In the paper

“The Drug‐Induced Liver Injury Network (DILIN) has demonstrated that trimethoprim‐sulfamethoxazole is the most common suspect drug among African Americans, whereas amoxicillin‐clavulanate is the leading cause in White populations.”

What the sources say

• Not checked yetcites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
• Not checked yetcites [49] Chalasani N Reddy KRK Fontana RJ Barnhart H Gu J Hayashi PH. Idiosyncratic drug induced liver injury in African‐Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol. 2017; 112: 1382– 8. 28762375 PMC5667647

In the paper

“In some instances, dose escalation may also increase the risk of developing idiosyncratic DILI as seen with azathioprine, whereas dose reduction or increasing the dosing interval may improve tolerability.35–37”

What the sources say

• Not checked yetcites [35] Carrascosa MF Salcines‐Caviedes JR Lucena MI Andrade RJ. Acute liver failure following atorvastatin dose escalation: is there a threshold dose for idiosyncratic hepatotoxicity? J Hepatol. 2015; 62: 751– 2. 25463547
• Not checked yetcites [36] Seki N Uematsu K Shibakuki R Eguchi K. Promising new treatment schedule for gefitinib responders after severe hepatotoxicity with daily administration. J Clin Oncol. 2006; 24: 3213– 5. 16809744
• Not checked yetcites [37] Otani K Kaneko S Tasaki H Fukushima Y. Hepatic injury caused by mianserin. BMJ. 1989; 299: 519. PMC1837346 2507056

In the paper

“In contrast, hypersensitivity reactions can have very short latency periods of only 24–72 h.”

In the paper

“In addition, African Americans were more likely to have adverse outcomes and develop chronic DILI.48,49”

What the sources say

• Not checked yetcites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
• Not checked yetcites [49] Chalasani N Reddy KRK Fontana RJ Barnhart H Gu J Hayashi PH. Idiosyncratic drug induced liver injury in African‐Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol. 2017; 112: 1382– 8. 28762375 PMC5667647

In the paper

“Patients with pre‐existing liver disease are at increased risk of developing liver injury with selected drugs (e.g., methotrexate, anti‐TB therapy). In addition, subjects with pre‐existing liver disease are at increased risk of poor outcomes with a DILI episode.”

In the paper

“The predominant histological pattern in ICI DILI is hepatocellular injury, with approximately 70% showing panlobular hepatitis and approximately 20% with centrilobular coagulative necrosis on liver biopsy.95–97”

What the sources say

• Not checked yetcites [95] Sawada K Hayashi H Nakajima S Hasebe T Fujiya M Okumura T. Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020; 35: 1042– 8. 31752049
• Not checked yetcites [96] Zen Y Yeh MM. Checkpoint inhibitor‐induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019; 36: 434– 440. 31358424
• Not checked yetcites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

In the paper

“In general, the identified HLA alleles have low positive predictive value, because of the low incidence of DILI in the general population, but a high negative predictive value.”

In the paper

“Antimicrobials, central nervous system agents, and anti‐inflammatory agents are the most commonly implicated agents in the DILI series worldwide. However, HDS are most commonly implicated in some Asian countries and are increasingly implicated in Western countries as well.”

In the paper

“Furthermore, there are limited data exploring the impact of diet, tobacco use, and coffee consumption on DILI susceptibility.”

In the paper

“In contrast, HDS products represent only a minority of cases in Japan, the United States, and Spain but with an increasing incidence over time.23,27–31”

What the sources say

• Not checked yetcites [23] Takikawa H Murata Y Horiike N Fukui H Onji M. Drug‐induced liver injury in Japan: an analysis of 1676 cases between 1997 and 2006. Hepatol Res. 2009; 39: 427– 31. 19207579
• Not checked yetcites [27] Andrade RJ Medina‐Caliz I Gonzalez‐Jimenez A Garcia‐Cortes M Lucena ML. Hepatic damage by natural remedies. Semin Liver Dis. 2018; 38: 21– 40. 29471563
• Not checked yetcites [28] Navarro VJ Barnhart H Bonkovsky HL Davern T Fontana RJ Grant L. Liver injury from herbals and dietary supplements in the U.S. drug‐induced liver injury network. Hepatology. 2014; 60: 1399– 408. 25043597 PMC4293199
• Not checked yetcites [29] Stephens C Robles‐Diaz M Medina‐Caliz I Garcia‐Cortes M Ortega‐Alonso A Sanabria‐Cabrera J. Comprehensive analysis and insights gained from long‐term experience of the Spanish DILI registry. J Hepatol. 2021; 75: 86– 97. 33539847
• Not checked yetcites [30] Chalasani N Bonkovsky HL Fontana RJ Lee W Stolz A Talwalkar J. Features and outcomes of 899 patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology. 2015; 148: 1340– 52.e7. 25754159 PMC4446235
• Not checked yetcites [31] Devarbhavi H Joseph T Kumar NS Rathi C Thomas V Singh SP. The Indian network of drug‐induced liver injury: etiology, clinical features, outcome and prognostic markers in 1288 patients. J Clin Exp Hepatol. 2021; 11: 288– 98. 33994711 PMC8103312

In the paper

“Medical comorbidities such as obesity and diabetes are associated with increased incidence and severity of DILI with specific drugs. However, the role of alcohol, tobacco, and diet in DILI susceptibility is not established.”

In the paper

“However, DILI caused by anti‐TB therapy has been associated with abnormal baseline serum aminotransferases, showing a stronger dose‐dependent association with the severity of liver enzyme elevation than older age.55”

What the sources say

• Not checked yetcites [55] Gray EL Goldberg HF. Baseline abnormal liver function tests are more important than age in the development of isoniazid‐induced hepatoxicity for patients receiving preventive therapy for latent tuberculosis infection. Intern Med J. 2016; 46: 281– 7. 26648478

In the paper

“Therefore, pretreatment HLA testing will likely not prove useful in most circumstances to prevent DILI, but HLA testing may be helpful in DILI diagnosis and causality assessment.59,60”

What the sources say

• Not checked yetcites [59] Kullak‐Ublick GA Andrade RJ Merz M End P Benesic A Gerbes AL. Drug‐induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017; 66: 1154– 64. 28341748 PMC5532458
• Not checked yetcites [60] Koido M Kawakami E Fukumura J Noguchi Y Ohori M Nio Y. Polygenic architecture informs potential vulnerability to drug‐induced liver injury. Nat Med. 2020; 26: 1541– 8. 32895570 PMC8482794

In the paper

“Moreover, a given drug may be associated with more than one clinical profile.”

In the paper

“Although DILI may present with lower levels of laboratory abnormalities, up to 20% of individuals in the general population have mildly increased liver biochemistries because of NAFLD, alcohol, and other common conditions.74”

What the sources say

• Not checked yetcites [74] Fontana RJ Watkins PB Bonkovsky HL Chalasani N Davern T Serrano J. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32: 55– 68. 19132805 PMC3637941

In the paper

“The LiverTox website provides a brief synopsis of the clinical features of idiosyncratic DILI due to more than 1000 prescription drugs and 60 HDS that are culled from the world's literature.”

What the sources say

• Not checked yetcites [5] Björnsson ES Hoofnagle JH. Categorization of drugs implicated in causing liver injury: critical assessment based on published case reports. Hepatology. 2016; 63: 590– 603. 26517184

In the paper

“In addition, LiverTox provides a likelihood scale summarizing how many reports of bona fide hepatotoxicity have been attributed to a product as follows: category A, 50 or more reports; category B, 12–49 cases; category C, 4–11 cases; category D, 1–3 plausible cases; category E, no reports of liver injury; and category X, newly approved agents.”

In the paper

“Amoxicillin‐clavulanate is the most frequently implicated individual agent in many western countries, whereas anti‐tuberculosis (TB) agents dominate in Asian countries (Table 2).”

In the paper

“In addition, older subjects appear to be at increased risk of isoniazid and amoxicillin‐clavulanate hepatotoxicity, whereas younger individuals are more prone to develop DILI from anticonvulsants and minocycline.45,46”

What the sources say

• Not checked yetcites [45] George N Chen M Yuen N Hunt CM Suzuki A. Interplay of gender, age and drug properties on reporting frequency of drug‐induced liver injury. Regul Toxicol Pharmacol. 2018; 94: 101– 7. 29407200
• Not checked yetcites [46] Fountain FF Tolley E Chrisman CR Self TH. Isoniazid hepatotoxicity associated with treatment of latent tuberculosis infection: a 7‐year evaluation from a public health tuberculosis clinic. Chest. 2005; 128: 116– 23. 16002924

In the paper

“The R‐value is best calculated at the time of presentation, but the pattern of injury can change as the condition progresses.77”

What the sources say

• Not checked yetcites [77] Benichou C Danan G Flahault A. Causality assessment of adverse reactions to drugs. Part II: an original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993; 46: 1331– 6. 8229111

In the paper

“Typically, DILI appears within 6 months of starting a new medication, although certain drugs have longer latency periods (e.g., nitrofurantoin, methotrexate).”

• Also stated in: § Competing causes of liver injury · plain

  “Most hepatotoxic drugs cause liver injury within the first 6 months of use but occasionally have longer latency intervals or may even present after drug discontinuation (e.g., amoxicillin‐clavulanate).”

In the paper

“A French population‐based study showed that the standardized DILI incidence was more than 2 times higher in women than men older than 50 years, although no sex differences were noted under age 50.9,10”

What the sources say

• Not checked yetcites [9] Björnsson ES Bergmann OM Björnsson HK Kvaran RB Olafsson S. Incidence, presentation, and outcomes in patients with drug‐induced liver injury in the general population of Iceland. Gastroenterology. 2013; 144: 1419– 25. 23419359
• Not checked yetcites [10] Sgro C Clinard F Ouazir K Chanay H Allard C Guilleminet C. Incidence of drug‐induced hepatic injuries: a French population‐based study. Hepatology. 2002; 36: 451– 5. 12143055

In the paper

“Being overweight, having diabetes, alcohol use, and chronic viral hepatitis have also been associated with progressive fibrosis in methotrexate‐treated patients.51,52”

What the sources say

• Not checked yetcites [51] Laharie D Seneschal J Schaeverbeke T Doutre MS Longy‐Boursier M Pellegrin JL. Assessment of liver fibrosis with transient elastography and FibroTest in patients treated with methotrexate for chronic inflammatory diseases: a case‐control study. J Hepatol. 2010; 53: 1035– 40. 20801541
• Not checked yetcites [52] Rosenberg P Urwitz H Johannesson A Ros AM Lindholm J Kinnman N. Psoriasis patients with diabetes type 2 are at high risk of developing liver fibrosis during methotrexate treatment. J Hepatol. 2007; 46: 1111– 8. 17399848

In the paper

“The Maria‐Victorino Clinical Diagnostic Scale (CDS)109 uses similar variables to the RUCAM but excludes concomitant medications and includes points for extrahepatic manifestations.”

What the sources say

• Not checked yetcites [109] Maria VA Victorino RM. Development and validation of a clinical scale for the diagnosis of drug‐induced hepatitis. Hepatology. 1997; 26: 664– 9. 9303497

In the paper

“Notwithstanding, RECAM has yet to be tested in regions of the world where the spectrum of DILI agents differs from that seen in the United States and Spain (Table 2) or in cases with more than a single suspect drug.”

In the paper

“This semiautomated, computerized platform has a dynamic range of −6 to +20 points and performs at least as well as the RUCAM in independent data sets.113”

What the sources say

• Not checked yetcites [113] Hayashi PH Lucena MI Fontana RJ Bjornsson E Aithal GP Barnhart H. A revised electronic version of RUCAM for the diagnosis of drug induced liver injury. Hepatology. 2022; 76: 18– 31. 35014066 PMC9233102

In the paper

“Although the DDW‐J was shown to be superior to the original RUCAM in Japanese patients, it is not currently used outside of Japan because of the lack of widely available and reproducible DLST assays.112”

What the sources say

• Not checked yetcites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

In the paper

“The updated RUCAM also provides more specific guidance in ascertaining the hepatotoxicity profile of the suspect drug”

In the paper

“specifies criteria for rechallenge”

What the sources say

• Not checked yetcites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744
• Not checked yetcites [119] Teschke R Frenzel C Schulze J Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013; 19: 2864– 82. 23704820 PMC3660812

In the paper

“In the acute cholestatic type, cholestasis without accompanying inflammation (so‐called bland cholestasis) may be the sole histological presentation and manifests as bile present in dilated canaliculi and within the hepatocyte cytoplasm.98”

What the sources say

• Not checked yetcites [98] Zhang X Ouyang J Thung SN. Histopathologic manifestations of drug‐induced hepatotoxicity. Clin Liver Dis. 2013; 17: 547– 64. 24099017

In the paper

“The RECAM is a newly developed, computerized causality assessment instrument”

In the paper

“contemporary HDS are commonly multi‐ingredient products that are marketed under the guise of delivering some improvement in appearance, performance, or sense of well‐being.124”

What the sources say

• Not checked yetcites [124] Huang YS Chang TT Peng CY Lo GH Hsu CW Hu CT. Herbal and dietary supplement‐induced liver injury in Taiwan: comparison with conventional drug‐induced liver injury. Hepatol Int. 2021; 15: 1456– 65. 34382132

In the paper

“Advantages of expert opinion include the ability to account for atypical cases, interrupted drug exposure, and synthesis of subtle clues including liver histology in relationship to published literature.”

In the paper

“Overall, jaundice and liver failure are rare in DILI because of ICI, and approximately a third of those with severe grades of DILI may even regress spontaneously.97”

What the sources say

• Not checked yetcites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

In the paper

“The RECAM is currently available online.”

In the paper

“Structured expert opinion: The semiquantitative scale developed by DILIN categorizes the likelihood of DILI into five probability groups that vary from < 25% to > 95% probability (Table 6).74,116,117”

What the sources say

• Not checked yetcites [74] Fontana RJ Watkins PB Bonkovsky HL Chalasani N Davern T Serrano J. Drug‐induced liver injury network (DILIN) prospective study: rationale, design and conduct. Drug Saf. 2009; 32: 55– 68. 19132805 PMC3637941
• Not checked yetcites [116] Tillmann HL Suzuki A Barnhart HX Serrano J Rockey DC. Tools for causality assessment in drug‐induced liver disease. Curr Opin Gastroenterol. 2019; 35: 183– 90. 30865042 PMC6452904
• Not checked yetcites [117] Hayashi PH Barnhart HX Fontana RJ Chalasani N Davern TJ Talwalkar JA. Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the drug‐induced liver injury network (DILIN). Liver Int. 2015; 35: 1623– 32. 24661785 PMC4305346

In the paper

“and its interrater and intrarater reliability needs to be determined.”

In the paper

“Peliosis hepatis appears as blood‐filled lacunar spaces, and its development is associated with androgens and oral contraceptive agents.102”

What the sources say

• Not checked yetcites [102] Tsirigotis P Sella T Shapira MY Bitan M Bloom A Kiselgoff D. Peliosis hepatis following treatment with androgen‐steroids in patients with bone marrow failure syndromes. Haematologica. 2007; 92: e106– 10. 18024386

In the paper

“Causality assessment by expert opinion addresses the unique clinical features of a particular patient along with knowledge of the hepatotoxic potential of the suspect agent versus other causes of liver injury.122”

What the sources say

• Not checked yetcites [122] Rochon J Protiva P Seeff LB Fontana RJ Liangpunsakul S Watkins PB. Reliability of the Roussel Uclaf causality assessment method for assessing causality in drug‐induced liver injury. Hepatology. 2008; 48: 1175– 83. 18798340 PMC3618289

In the paper

“more than 50% of adults over the age of 20 used dietary supplements in the preceding 30 days in a 2017–2018 study.123”

What the sources say

• Not checked yetcites [123] Mishra S Stierman B Gahche JJ Potischman N. Dietary supplement use among adults: United States, 2017–2018. NCHS Data Brief. 2021; 399: 1– 8. 33663653

In the paper

“The Digestive Disease Week–Japan 2004 (DDW‐J) score is a modification of the RUCAM with the inclusion of drug‐lymphocyte stimulation test (DLST) results and peripheral eosinophilia.111,112”

What the sources say

• Not checked yetcites [111] Takikawa H Takamori Y Kumagi T Onji M Watanabe M Shibuya A. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the international consensus meeting. Hepatol Res. 2003; 27: 192– 5. 14585395
• Not checked yetcites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

In the paper

“The semiquantitative expert opinion causality assessment scale developed by the DILIN is frequently used in clinical practice and in prospective research studies”

In the paper

“The updated RUCAM has improved user instructions and more complete diagnostic evaluation compared with the original RUCAM”

In the paper

“Intentional suspect drug rechallenge is rarely undertaken in clinical practice”

In the paper

“There are five likelihood categories, but the dynamic range of possible scores is more compressed compared with the RUCAM and the Revised Electronic Causality Assessment Method (RECAM).”

In the paper

“The updated RUCAM score was published in 2016 and has several modifications that generates a score ranging from −9 to +14 points with the same five likelihood categories.108”

What the sources say

• Not checked yetcites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744

In the paper

“In contrast, a liver biopsy defines chronic liver disease when there is significant fibrosis or even cirrhosis noted on histology.104”

What the sources say

• Not checked yetcites [104] Kleiner DE. Liver histology in the diagnosis and prognosis of drug‐induced liver injury. Clin Liver Dis (Hoboken). 2014; 4: 12– 6. 30992912 PMC6448725

In the paper

“The updated RUCAM has improved user instructions and more complete diagnostic evaluation compared with the original RUCAM”

In the paper

“According to DILIN, chronic DILI is the perpetuation of liver damage after 6 months from DILI onset, independent of the pattern of liver injury, whereas the Spanish DILI Group considers 1 year as the best cutoff point.48,106”

What the sources say

• Not checked yetcites [48] Fontana RJ Hayashi PH Gu J Reddy KR Barnhart H Watkins PB. Idiosyncratic drug‐induced liver injury is associated with substantial morbidity and mortality within 6 months from onset. Gastroenterology. 2014; 147: 96– 108.e4. 24681128 PMC4285559
• Not checked yetcites [106] Medina‐Caliz I Robles‐Diaz M Garcia‐Munoz B Stephens C Ortega‐Alonso A Garcia‐Cortes M. Definition and risk factors for chronicity following acute idiosyncratic drug‐induced liver injury. J Hepatol. 2016; 65: 532– 42. 27184533 PMC7458366

In the paper

“It provides a score varying from −10 to +14 points and groups the scores into five likelihood categories with stratification by hepatocellular versus cholestatic/mixed injury.”

What the sources say

• Not checked yetcites [75] Danan G Benichou C. Causality assessment of adverse reactions to drugs. Part I: a novel method based on the conclusions of international consensus meetings: application to drug‐induced liver injuries. J Clin Epidemiol. 1993; 46: 1323– 30. 8229110
• Not checked yetcites [77] Benichou C Danan G Flahault A. Causality assessment of adverse reactions to drugs. Part II: an original model for validation of drug causality assessment methods: case reports with positive rechallenge. J Clin Epidemiol. 1993; 46: 1331– 6. 8229111

In the paper

“HDS are used widely around the world on a daily basis.”

In the paper

“NRH and OPV may clinically present insidiously, whereas SOS may manifest as either acute or chronic disease.”

In the paper

“Structured causality assessment instruments incorporate the dose, duration, and timing of suspect drug and other concomitant drug or HDS product use; an assessment of the laboratory, radiological, and histological features at presentation; and exclusion of competing causes of liver injury.”

In the paper

“Although most marketed supplements are safe”

In the paper

“Steatosis may be purely microvesicular, which is primarily related to mitochondrial injury, mixed microvesicular and macrovesicular, or purely macrovesicular.100”

What the sources say

• Not checked yetcites [100] Rabinowich L Shibolet O. Drug induced steatohepatitis: an uncommon culprit of a common disease. Biomed Res Int. 2015; 2015: 168905. 26273591 PMC4529891

In the paper

“but retains risk factors of age, alcohol, and pregnancy that are of unclear value.”

In the paper

“The RECAM removed several risk factors and has an expanded list of competing causes to exclude, and diagnostic testing is categorical and menu‐driven to reduce interobserver variability.”

In the paper

“This approach has been shown to be as useful as the RUCAM, although expert opinion is rarely available in routine clinical practice.117”

What the sources say

• Not checked yetcites [117] Hayashi PH Barnhart HX Fontana RJ Chalasani N Davern TJ Talwalkar JA. Reliability of causality assessment for drug, herbal and dietary supplement hepatotoxicity in the drug‐induced liver injury network (DILIN). Liver Int. 2015; 35: 1623– 32. 24661785 PMC4305346

In the paper

“Phospholipidosis is another form of DILI seen as hepatocytes with foamy granular cytoplasm. Similar to induction hepatocytes, phospholipidosis represents an adaptive response to cationic amphophilic drugs like amiodarone and antimalarial agents, via the inhibition of lysosome‐specific phospholipase A2.100,101”

What the sources say

• Not checked yetcites [100] Rabinowich L Shibolet O. Drug induced steatohepatitis: an uncommon culprit of a common disease. Biomed Res Int. 2015; 2015: 168905. 26273591 PMC4529891
• Not checked yetcites [101] Bessone F Dirchwolf M Rodil MA Razori MV Roma MG. Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease—a physiopathological and clinical integrated view. Aliment Pharmacol Ther. 2018; 48: 892– 913. 30194708

In the paper

“but is not intended for use in patients with chronic liver disease.”

In the paper

“The presence of eosinophils and granulomas on a liver biopsy in a patient with suspected DILI is associated with a more favorable outcome, whereas those who have necrosis or fibrosis have poorer outcomes.”

In the paper

“Generic causality assessment models include the World Health Organization Collaborating Center for International Drug Monitoring system by the Uppsala Monitoring Center, which have not gained traction in DILI research or clinical practice because of their lack of liver specificity.114,115”

What the sources say

• Not checked yetcites [114] The use of the WHO–UMC system for standardised case causality assessment. 2021. [cited 2021 Sep 29]. Available from: http://www.who‐umc.org/graphics/4409.pdf
• Not checked yetcites [115] Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981; 30: 239– 45. 7249508

In the paper

“Scores range from −5 to +17 points.”

What the sources say

• Not checked yetcites [111] Takikawa H Takamori Y Kumagi T Onji M Watanabe M Shibuya A. Assessment of 287 Japanese cases of drug induced liver injury by the diagnostic scale of the international consensus meeting. Hepatol Res. 2003; 27: 192– 5. 14585395
• Not checked yetcites [112] Hanatani T Sai K Tohkin M Segawa K Kimura M Hori K. A detection algorithm for drug‐induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of medical sciences/the Roussel Uclaf causality assessment method scale. Pharmacoepidemiol Drug Saf. 2014; 23: 984– 8. 24596340

In the paper

“Currently there are three commonly used causality assessment methods”

In the paper

“and each has its own strengths and limitations.”

In the paper

“Unlike AIH, plasma cell infiltration is not predominant, and the inflammatory infiltrate consists mostly of T lymphocytes, with CD8+ cells being greater in number than CD4+ cells.”

What the sources say

• Not checked yetcites [95] Sawada K Hayashi H Nakajima S Hasebe T Fujiya M Okumura T. Non‐alcoholic fatty liver disease is a potential risk factor for liver injury caused by immune checkpoint inhibitor. J Gastroenterol Hepatol. 2020; 35: 1042– 8. 31752049
• Not checked yetcites [96] Zen Y Yeh MM. Checkpoint inhibitor‐induced liver injury: a novel form of liver disease emerging in the era of cancer immunotherapy. Semin Diagn Pathol. 2019; 36: 434– 440. 31358424
• Not checked yetcites [97] Zen Y Chen YY Jeng YM Tsai HW Yeh MM. Immune‐related adverse reactions in the hepatobiliary system: second‐generation check‐point inhibitors highlight diverse histological changes. Histopathology. 2020; 76: 470– 80. 31550390

In the paper

“In chronic cholestasis, the cholestasis persists and may have severe bile duct injury or progress to bile duct loss.88”

What the sources say

• Not checked yetcites [88] Kleiner DE Chalasani NP Lee WM Fontana RJ Bonkovsky HL Watkins PB. Hepatic histological findings in suspected drug‐induced liver injury: systematic evaluation and clinical associations. Hepatology. 2014; 59: 661– 70. 24037963 PMC3946736

In the paper

“A broad spectrum of histological patterns has been reported in patients with DILI, and a given drug may be associated with more than a single histopathological signature.”

In the paper

“Of note, microvesicular steatosis usually does not lead to increased echogenicity on ultrasound, nor does it manifest with hepatomegaly, and only liver biopsy can confirm its presence.101”

What the sources say

• Not checked yetcites [101] Bessone F Dirchwolf M Rodil MA Razori MV Roma MG. Review article: drug‐induced liver injury in the context of nonalcoholic fatty liver disease—a physiopathological and clinical integrated view. Aliment Pharmacol Ther. 2018; 48: 892– 913. 30194708

In the paper

“Cholestatic DILI histology includes acute cholestasis, chronic cholestasis, and acute cholestatic hepatitis.”

In the paper

“Marketed supplements comprise single‐ingredient products as well as mixtures of many different ingredients that may be both natural and synthetic.”

In the paper

“which stratifies causality assessment by the R‐value”

What the sources say

• Not checked yetcites [108] Danan G Teschke R. RUCAM in drug and herb induced liver injury: the update. Int J Mol Sci. 2016; 27: 14– 30. PMC4730261 26712744
• Not checked yetcites [119] Teschke R Frenzel C Schulze J Eickhoff A. Herbal hepatotoxicity: challenges and pitfalls of causality assessment methods. World J Gastroenterol. 2013; 19: 2864– 82. 23704820 PMC3660812

In the paper

“The degree of necrosis and presence of prominent ductular reaction are associated with poor outcome, whereas the presence of eosinophils and granulomas is associated with better outcome.104”

What the sources say

• Not checked yetcites [104] Kleiner DE. Liver histology in the diagnosis and prognosis of drug‐induced liver injury. Clin Liver Dis (Hoboken). 2014; 4: 12– 6. 30992912 PMC6448725

In the paper

“Genetic polymorphisms in the HLA region and the conditions under which a product is consumed may influence the likelihood of an individual patient developing HDS hepatotoxicity.”

In the paper

“In some instances, a short course of corticosteroids (i.e., 1–3 months) with rapid tapering may be of benefit in patients with autoimmune features on biopsy as well as for patients with DILI from ICIs and tyrosine kinase inhibitors (Table 9).153,154”

• Also stated in: § Medical management of idiosyncratic patients with DILI · hedged

  “Corticosteroids given for 1–3 months may be of benefit in selected patients with idiosyncratic DILI, including those with severe hypersensitivity features, DRESS, and autoimmune features on liver biopsy.”

What the sources say

• Not checked yetcites [153] Hu PF Wang PQ Chen H Hu XF Xie QP Shi J. Beneficial effect of corticosteroids for patients with severe drug‐induced liver injury. J Dig Dis. 2016; 17: 618– 27. 27426618
• Not checked yetcites [154] Wree A Dechêne A Herzer K Hilgard P Syn WK Gerken G. Steroid and ursodesoxycholic acid combination therapy in severe drug‐induced liver injury. Digestion. 2011; 84: 54– 9. 21304237

In the paper

“An example is the inclusion of sildenafil in products marketed for sexual performance.”

In the paper

“the composition of HDS may change over time as a result of varying growing conditions, leading to batch‐to‐batch variability.”

In the paper

“Recent data suggest that APAP hepatotoxicity may occur even when therapeutic doses are used, but particularly in association with these other cofactors.165”

What the sources say

• Not checked yetcites [165] Louvet A Wandji LCN Lemaître E Khaldi M Lafforgue C Artru F. Acute liver injury with therapeutic doses of acetaminophen: a prospective study. Hepatology. 2021; 73: 1634– 6. 33306215

In the paper

“latency of exposure to a product before the onset of injury can be quite variable because of the accumulation of product within the body.”

In the paper

“it is well known that supplements are vulnerable to intentional or inadvertent inclusion of ingredients.”

In the paper

“Ursodeoxycholic acid may improve symptoms of pruritus and hasten DILI recovery, but large, randomized controlled trials are needed to determine the optimal dose and duration.155”

What the sources say

• Not checked yetcites [155] Lang SM Ortmann J Rostig S Schiffl H. Ursodeoxycholic acid attenuates hepatotoxicity of multidrug treatment of mycobacterial infections: a prospective pilot study. Int J Mycobacterol. 2019; 8: 89– 92. 30860185

In the paper

“Another randomized trial of 102 patients with antitubercular DILI also demonstrated a shorter length of stay but no survival benefit with NAC.149”

What the sources say

• Not checked yetcites [149] Moosa MS Maartens G Gunter H Allie S Chughlay MF Setshedi M. A randomized controlled trial of intravenous N‐acetylcysteine in the management of anti‐tuberculosis drug‐induced liver injury. Clin Infect Dis. 2021; 73: e3377– 83. 32845997

In the paper

“More recently, detection of serum APAP‐protein adducts has been proposed as a more specific way to diagnose APAP hepatotoxicity particularly in patients presenting late or with an unintentional overdose, but this assay is not commercially available.166”

What the sources say

• Not checked yetcites [166] James LP Letzig L Simpson PM Capparelli E Roberts DW Hinson JA. Pharmacokinetics of acetaminophen‐protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009; 37: 1779– 84. 19439490 PMC2712440

In the paper

“Most adults and children with idiosyncratic DILI present with a drug latency of 2–24 weeks, although some drugs have an ultrashort (< 7 days) latency.30”

What the sources say

• Not checked yetcites [30] Chalasani N Bonkovsky HL Fontana RJ Lee W Stolz A Talwalkar J. Features and outcomes of 899 patients with drug‐induced liver injury: the DILIN prospective study. Gastroenterology. 2015; 148: 1340– 52.e7. 25754159 PMC4446235

In the paper

“when the veracity of a report is verified, regulatory actions can be taken against the manufacturer”

What the sources say

• Not checked yetcites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

In the paper

“in the European Union, the allowance of a product on the market requires a demonstrated history of safe use, along with periodic chemical verification of the labeled ingredients.”

What the sources say

• Not checked yetcites [127] Food supplements. European Commission website. 2021. [cited 2021 Sep 19]. Available from: https://ec.europa.eu/food/safety/labelling‐and‐nutrition/food‐supplements_en

In the paper

“The reason for this widespread toxicity is that, unlike drugs associated with idiosyncrasy, APAP is a dose‐related hepatotoxin, with all mammalian species susceptible to liver injury in doses only 2 to 3 times therapeutic dosing.161”

What the sources say

• Not checked yetcites [161] Rumack BH. Acetaminophen hepatotoxicity: the first 35 years. J Toxicol Clin Toxicol. 2002; 40: 3– 20. 11990202

In the paper

“Botanical ingredients include plant parts and other herbs that are not listed on the product label.”

In the paper

“American consumers spent more than $9.6 billion on herbal products in 2019.125”

What the sources say

• Not checked yetcites [125] US herbal supplement sales increase by 8.6% in 2019, record‐breaking sales predicted for 2020. 2020. [cited 2021 Sep 19]. Available from: http://herbalgram.org/news/press‐releases/2020/us‐herbal‐supplement‐sales‐2019/

In the paper

“Nonbotanical ingredients include chemicals, pesticides, and heavy metals.”

In the paper

“This may be due to delayed recognition of the product as the cause of liver injury or reluctance of HDS consumers to seek medical care.”

In the paper

“The regulatory environment in non‐US markets varies, as summarized in a recent review.127”

What the sources say

• Not checked yetcites [127] Food supplements. European Commission website. 2021. [cited 2021 Sep 19]. Available from: https://ec.europa.eu/food/safety/labelling‐and‐nutrition/food‐supplements_en

In the paper

“A diagnosis of APAP hepatotoxicity relies on a history of excessive APAP ingestion, detection of an elevated serum APAP level following single‐time‐point ingestion, and exclusion of competing causes of acute hepatocellular liver injury.”

In the paper

“HDS are commonly used worldwide”

In the paper

“including withdrawal of a product from the market in the most extreme circumstance.”

What the sources say

• Not checked yetcites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

In the paper

“the lack of knowledge and awareness of potential liver injury from these widely used, over‐the‐counter supplements may cause the injury to go unrecognized by patients and providers.”

In the paper

“The incidence of chronic DILI in 598 subjects enrolled into the DILIN was 21% at 6 months, with African Americans and patients with a cholestatic liver injury at presentation being at increased risk.147”

What the sources say

• Not checked yetcites [147] Fontana RJ Hayashi PH Barnhart H Kleiner DE Reddy KR Chalasani N. Persistent liver biochemistry abnormalities are more common in older patients and those with cholestatic drug‐induced liver injury. Am J Gastroenterol. 2015; 110: 1450– 9. 26346867 PMC4784423

In the paper

“Supplements can cause severe hepatotoxicity that can have variable clinical, laboratory, and histological phenotypes.”

In the paper

“Intentional adulteration usually results from the inclusion of substances, usually pharmaceuticals, to achieve some pharmacodynamic effect in keeping with the supplement's marketed purpose for use.”

In the paper

“The polyphenolic backbone of the catechins is exploited for its antioxidant potential but is likely also responsible for liver injury.”

In the paper

“Several cases of liver injury due to GTE have been published, with the most convincing cases being those in which injury recurred following rechallenge.131,132”

What the sources say

• Not checked yetcites [131] Bonkovsky HL. Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis). Ann Intern Med. 2006; 144: 68– 71. 16389263
• Not checked yetcites [132] Oketch‐Rabah HA Roe AL Rider CV Bonkovsky HL Giancaspro GI Navarro V. United States Pharmacopeia (USP) comprehensive review of the hepatotoxicity of green tea extracts. Toxicol Rep. 2020; 7: 386– 402. 32140423 PMC7044683

In the paper

“Allegations of injury attributable to a dietary supplement can be reported by consumers and providers to the US Food and Drug Administration (FDA), through the MedWatch passive reporting system.128”

What the sources say

• Not checked yetcites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

In the paper

“The DILIN's current efforts are being directed to understand the toxicity that may result from specific ingredients that are sold individually or as ingredients in product mixtures (Table 7).”

In the paper

“These reports are investigated by the FDA's Center for Food Safety and Applied Nutrition”

What the sources say

• Not checked yetcites [128] MedWatch: the FDA safety information and adverse event reporting program. US Food and Drug Administration. [cited 2021 Sep 19]. Available from: https://www.fda.gov/safety/medwatch‐fda‐safety‐information‐and‐adverse‐event‐reporting‐program

In the paper

“Other risk factors for APAP toxicity include fasting and malnutrition, which can lead to depletion of intrahepatic glutathione stores, as well as use of alcohol and other medications that can induce the cytochrome P‐450 system and lead to enhanced production of the toxic metabolite, N‐acetyl‐p‐benzoquinone imine.164”

What the sources say

• Not checked yetcites [164] Whitcomb DC Block GD. Association of acetaminophen hepatotoxicity with fasting and ethanol use. JAMA. 1994; 272: 1845– 50. 7990219

In the paper

“HLA‐B 35:01 has been associated with hepatotoxicity attributed to GTE in White populations and P. multiflorum hepatotoxicity in Asian populations.”

In the paper

“The 1994 Dietary Supplement Health and Education Act provides the current regulatory framework for supplement manufacturing and distribution in the United States.126”

What the sources say

• Not checked yetcites [126] Roytman MM Poerzgen P Navarro V. Botanicals and hepatotoxicity. Clin Pharm Ther. 2018; 104: 458– 69. 29920648

In the paper

“The key to preventing clinically significant liver injury from DILI is early detection of the signal event before it becomes symptomatic or severe.”

In the paper

“DILI biomarkers in development broadly fall into four categories: (A) dynamic liver injury markers that quantify the extent or severity of hepatocyte damage; (B) mechanistic biomarkers that aim to elucidate the intracellular pathways of liver injury; (C) prognostic biomarkers; and (D) diagnostic biomarkers including single‐nucleotide polymorphisms.”

In the paper

“International Classification of Diseases, Tenth Revision codes and natural language processing algorithms may help identify DILI cases from administrative databases, but further refinement is needed.208,209”

What the sources say

• Not checked yetcites [208] Yeboah‐Korang A Louissant J Tsung I Prabhu S Fontana RJ. Utility of computerized ICD‐10 algorithm to identify idiosyncratic drug‐induced liver injury cases in the electronic medical record. Drug Saf. 2020; 43: 371– 7. 31916081 PMC8487619
• Not checked yetcites [209] Heidemann L Law J Fontana RJ. A text searching tool to identify patients with idiosyncratic drug‐induced liver injury. Dig Dis Sci. 2017; 62: 615– 25. 26597192 PMC4877288

In the paper

“In the United States, an estimated 13 million individuals have latent TB, but > 10,000 individuals are treated for active TB each year.179”

What the sources say

• Not checked yetcites [179] Talwar A Tsang CA Price SF Pratt RH Walker WL Schmit KM. Tuberculosis– United States 2018. MMWR Morb Mortal Wkly Rep. 2019; 68: 257– 62.30897076

In the paper

“Whereas the treatment for active TB still consists of isoniazid, rifamycin, pyrazinamide, and ethambutol, alternative strategies are now available that depend on various individual patient characteristics.186”

What the sources say

• Not checked yetcites [186] Nahid P Dorman SE Alipanah N Barry PM Brozek JL Cattamanchi A. Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America clinical practice guidelines: treatment of drug‐susceptible tuberculosis. Clin Infect Dis. 2016; 63: e147– 95. 27516382 PMC6590850

In the paper

“Over the past 40 years, various recommendations for laboratory monitoring while receiving isoniazid have been proposed that begin with baseline liver assessments for all patients.”

In the paper

“In contrast, the 2020 Academy of Dermatology guidelines for managing psoriasis recommends fibrosis‐4 serologic testing and transient elastography at baseline and annually while on methotrexate therapy in patients with risk factors for hepatotoxicity.196”

What the sources say

• Not checked yetcites [196] Menter A Gelfand JM Connor C Armstrong AW Cordoro KM Davis DMR. Joint American Academy of Dermatology–National Psoriasis Foundation guidelines of care for the management of psoriasis with systemic nonbiologic therapies. J Am Acad Dermatol. 2020; 82: 1445– 86. 32119894

In the paper

“The 2008 American College of Rheumatology guidelines for the treatment of rheumatoid arthritis advises laboratory monitoring at baseline and then every 2–4 weeks with the first 3 months, every 8–12 weeks for 3–6 months, and then every 12 weeks beyond 6 months of treatment.194”

What the sources say

• Not checked yetcites [194] Saag KG Teng GG Patkar NM Anuntiyo J Finney C Curtis JR. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease‐modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008; 59: 762– 84. 18512708

In the paper

“Areas of unmet need in DILI clinical care include the need for improved diagnostic and prognostic biomarkers, accurate and reliable causality assessment instruments, and studies of the epidemiology of DILI.”

In the paper

“In addition, improved understanding of the molecular pathogenesis of DILI is needed to minimize future morbidity and mortality and identify therapeutic targets for intervention.”