Rolf Teschke

The diagnosis of immune idiosyncratic drug-induced liver injury (iDILI) by immune checkpoint inhibitors (ICIs) is blurred by the heterogeneity of causality attribution in cancer patients; this requires information gaps to be filled through the collection of cases evaluated for causality by the Roussel Uclaf Causality Assessment Method (RUCAM). RUCAM was used in 8/11 reports (73%), providing a rather homogeneous study cohort for the following manifestation specifics: (1) consensus among the eight RUCAM-based reports that iDILI by ICIs has an immune basis; (2) age of most patients > 60 years; (3) male gender dominated by a factor ranging from 1.5- to 4.0-fold; (4) clinical manifestations at admission included weakness, vomiting, epigastric pain, and itching but not necessarily jaundice; (5) serum activities of ALT up to 3,111 U/L, with ALP up to 2,459 U/L and total bilirubin up to 300 μmol/L; (6) RUCAM-based ratio (R) revealing a pattern of hepatocellular liver injury (42%), cholestatic (39%), and mixed liver injury (19%); (7) therapeutic options require a case-by-case decision, as the natural course is variable among the cancer patients; (8) although treatment with steroids and/or ursodeoxycholic acid was commonly effective, a therapy decision has to consider whether the use of the implicated ICI should be stopped or continued; (9) prognosis depends largely on disease severity; (10) among the cancer patients with DILI by ICIs, 22% died during follow-up, mostly after progress of underlying disease. In brief, RUCAM use allows for the correct description of clinical manifestations, but more diagnostic efforts are needed for iDILI by ICIs if associated with the novel autoimmune pancreatitis type AIP-3, reflecting pancreatic involvement with possible secondary sclerosing cholangitis.

Autoimmune pancreatitis (AIP) represents a rare multifaceted disorder group with currently three types that were recently supplemented by a newly described AIP type causally related to sunlight exposure, not previously reported in any of the AIP publications. The internet search disclosed that the new AIP type was different from three existing AIP types: the AIP-1 or AIP-2 types, both featured by idiopathy, and the AIP-3 type, triggered by immune checkpoint inhibitors. Accordingly, it seemed appropriate to classify the novel AIP as the AIP-4 type, with typical features such as a clear culprit of sunlight exposure, ascertained by a positive result of an unintentional re-exposure and considered a diagnostic gold standard; coexisting secondary sclerosing cholangitis without progression to vanishing bile duct syndrome; and ultimately unavoidable pancreatic atrophy with clinical exocrine insufficiency despite long-term treatment with immunosuppressive drugs. Thus, the recent description of a new AIP type, now classified as the AIP-4 type, is strongly associated with significant sunlight exposure and calls for a reclassification of AIP types that includes AIP-4, whereby additional efforts are essential to identify the causative factors of the AIP-1 and AIP-2 types, including drugs commonly used in the respective cohorts, which also comprise older patients with comorbidities.

Heavy metals (HMs) were originally formed in the universe long before human evolution and are now ubiquitous in the environment, where some HMs are good as essential elements for human health while others are not. The purpose of this analytical review is to provide an updated clinical overview on health risks attributable to drinking water containing specific HMs and to discuss new aspects of molecular steps leading to disrupted diseases. This approach was favored because the study cohorts were homogeneous, since exposed individuals lived in households where all members had access to the same drinking water of constant quality. Among the HMs under consideration, aluminum, arsenic, cadmium, chromium, copper, iron, lead, manganese, and mercury were detected in drinking water and represented a health risk if levels were above thresholds recommended by national and international regulatory authorities. For example, (1) aluminum increased the risk of dementia and Alzheimer’s disease; (2) arsenic was associated with the development of bladder cancer; (3) cadmium increased the no-carcinogenic, as well as the carcinogenic, health risk; (4) chromium was considered as a risk factor for liver and kidney injury, as well cancer development; (5) copper contributed to cognitive impairment in the aging population and Alzheimer’s disease; (6) iron increased the non-carcinogenic health risk; (7) lead impaired neurodevelopmental functions in children; (8) manganese increased the risk of attention-deficit hyperactivity disorder (ADHD); and (9) mercury was causally related to chronic kidney disease. In contrast, for nickel and zinc, no overt health risks have been reported, likely due to low levels in the drinking water, attributable to their low water solubility. Of note is the good news that some HMs represent essential elements for human health. In essence, many HMs were detected in drinking water and exerted non-carcinogenic or carcinogenetic health risks, requiring proactive management of national and international regulatory authorities.

Heavy metals are integral parts of our environment, originating initially from the universe and used in the industry, which may contribute to pollution. This book chapter aims to address the impact of heavy metals on the ecosystem and human health. Among the 32 heavy metals, eight belong to the group of essential ones: cobalt, copper, iron, manganese, molybdenum, nickel, selenium, and zinc. They were necessary in physiological amounts for the evolution of flora and fauna, including humans on earth, and are still needed to sustain their wellbeing. For these, however, non-physiological amounts of essential heavy metals are deleterious and have a negative impact similar to that of the 26 non-essential heavy metals if exposed to high or even small amounts. They can disrupt plant growth and yield due to reduced photosynthesis and impair the health of animals, as well as their reproductive properties. To combat hazardous heavy metals, protective measures aimed at improving the ecosystem are mandatory. These measures start with reducing heavy metal release during metallic fabrication processes and are followed by the remediation of soils contaminated with heavy metals. At the human level, precautionary measures are recommended to reduce occupational exposures to heavy metals and to verify the consumption of food and drinking water with normal amounts of heavy metals. In conclusion, essential heavy metals are beneficial to flora and fauna, including humans, when exposed to physiological amounts. In contrast, high amounts are deleterious, as are non-essential heavy metals in both low and high amounts.

Drug-induced autoimmune hepatitis (DIAIH) is a rare and complex disorder caused by drugs that are commonly metabolized by hepatic microsomal cytochrome P450 (CYP) pathways. Whereas DIAIH presents generally with a single clinical flare, in rare cases its clinical course shows two different, consecutively emerging flares. The aim of this report was to analyze details of this rare but interesting phenomenon and to help improve appropriate causality evaluation in patients with suspected iDILI or DIAIH to provide better insight into the pathomechanistic steps leading the diseases. A clinical course with two flares was found in a DIAIH patient treated with varenicline, a smoking cessation drug, and in another patient experiencing DIAIH following intravenous application of infliximab used to treat ankylosing spondylitis. In both patients, the first flare was determined as a typical liver injury with increased serum activities of alanine aminotransferase (ALT) and normal titers of serum autoimmune parameters, classified as an acute liver injury analogous to idiosyncratic DILI (iDILI), with verified causality using a modified version of RUCAM (Roussel Uclaf Causality Assessment Method). After an interval of around two months from the cessation of varenicline use, the second flare emerged, as evidenced by increased serum ALT values now associated with newly increased serum autoimmune titers of antinuclear antibodies (ANAs), classifying this flare as hepatic autoimmune injury with verified causality for varenicline using the simplified autoimmune hepatitis (AIH) score. A similar clinical DIAIH course of a continuous disease with two flares was described for the second patient, who received infliximab and experienced an interval of one month between the first and second flare. Interestingly to note, neither varenicline nor infliximab is degraded via a CYP pathway, and the metabolic disposition of both drugs is low. In sum, DIAIH can develop with two consecutive flares caused by two drugs not metabolized by CYPs and with slow drug disposition, raising the question of whether this phenomenon of two flares can occur in additional cases of DIAIH due to other drugs metabolized by CYPs or non-CYPs, a question to be resolved by DILI experts in future cases of iDILI and DIAIH.

Acute liver failure (ALF) is a disorder with various etiologies. Although the causes leading to this disruptive condition are well documented in published ALF cohorts, there is significant concern among patients who experience ALF with indeterminate causes, an issue requiring thorough analysis. This review aimed to analyze cohort studies on ALF with a focus on unknown causes leading to classification as indeterminate ALF. The analysis revealed that, among 67 worldwide adult and pediatric ALF cohorts, indeterminate causes of ALF ranged from 2% to 100%, with an average of 30%. Among the 13 pediatric ALF cohorts, the corresponding range was 22% to 100%, with an average of 47%, while among the 55 adult ALF cohorts, the range was 2% to 78%, with an average of 26%. The percentage values were higher in pediatric cohorts due to the higher incidence of rare genetic causes compared to adult patients. Notably, higher rates of indeterminate causes were found in cohorts studied before the availability of diagnostic serologic screening parameters and polymerase chain reaction techniques for various hepatitis virus infections. Patients with indeterminate ALF may not have received a specific treatment that, if effective, could have helped prevent liver transplantation. It is concluded that, in future cases, all efforts must be undertaken to clearly establish the cause of severe liver injury, enabling effective therapy when available and helping reduce the risk of progression to ALF and the need for liver transplantation.

Wilson disease, a well-established genetic disorder characterized by impaired copper excretion and toxic copper accumulation in the liver, has clear clinical presentations and diagnostic criteria. However, the metabolic and molecular pathways leading to liver injury - a critical hallmark of the disease - remain largely cryptic and require new analytical approaches to elucidate underlying mechanisms. In Wilson disease, supraphysiological and toxic amounts of hepatic copper arise due to genetically reduced biliary excretion. Interestingly, hepatic iron accumulation of unknown etiology is also observed. Both metals contribute to the production of reactive oxygen species (ROS), including singlet oxygen, superoxide anions, and highly disruptive hydroxyl radicals generated via the Haber-Weiss and Fenton reactions. Historically, liver injury has been attributed to copper-induced toxicity (cuproptosis) without sufficient consideration of ROS involvement, neglecting the significant ROS burden in hepatic tissue. A revised concept of cuproptosis incorporates ROS, particularly hydroxyl radicals, which convert copper ions into reactive intermediates such as copper peroxyl, copper hydroperoxyl, and copper superoxyl species. These intermediates induce mitochondrial oxidative stress by covalently binding to mitochondrial constituents including lipoylated dihydrolipoamide S-acetyltransferase (DLAT), leading to its aggregation and triggering regulated cell death via cuproptosis. Thus, copper ions must first be converted into reactive intermediates to initiate cuproptosis effectively. Furthermore, singlet oxygen and superoxide anion hydroxyl radicals generated by hepatic iron ions may promote regulated cell death via ferroptosis. This process involves the accumulation of lipid peroxides derived from polyunsaturated fatty acids in mitochondrial membranes, with malondialdehyde (MDA) serving as a diagnostic marker. Consequences include enhanced mitochondrial membrane rigidity, disruption of plasma membrane integrity, and ultimately cell death. This mechanistic pathway requires the activity of iron-dependent enzymes such as lipoxygenases, ferroptosis suppressor protein 1, glutathione peroxidase 4, dihydroorotate dehydrogenase, and lysosomal iron release from ferritin stores. To sum up, the definition of cuproptosis requires refinement to incorporate its mechanistic dependence on ROS, and its quantitative contribution to liver injury should be reassessed alongside hepatic iron and ferroptosis.

Drug-induced autoimmune hepatitis (DIAIH) is a relatively new subtype of idiosyncratic drug-induced liver injury (iDILI), but the features of DIAIH have been variably described due to the inhomogeneity of assessed study cohorts. The aim of this analysis is to harmonize DIAIH cohorts by unifying causality assessments, which may help characterize the features of DIAIH. Methods: Published reports of DIAIH cases were evaluated for the causality assessment methods used to verify the diagnosis of DIAIH. This disorder consists of two parts, i.e., the iDILI part and the autoimmune (AIH) part, whereby each part needs a specific diagnostic algorithm. The validated and scoring Roussel Uclaf Causality Assessment (RUCAM) is privileged for assessing the iDILI part, and the validated, simplified AIH score is the perfect choice for evaluating the AIH part. The analysis of DIAIH publications revealed that 12/20 reports (60%) presented cases assessed by both the RUCAM and the simplified AIH score, providing 49 drugs and drug combinations as causative drugs in up to 25 cases of DIAIH. Serum alanine aminotransferase activities of up to 3489 UL and high titers of autoimmune parameters such as anti-nuclear antibodies, anti-smooth-muscle antibodies, and soluble liver antigen antibodies supported DIAIH diagnosis. In contrast, 4/20 reports (20%) applied only RUCAM, and 2/20 reports (10%) used only the simplified AIH score; these 6 reports therefore provided insufficient criteria for a valid DIAIH diagnosis. Moreover, 2/20 reports (10%) did not use any causality algorithm, providing elusive features of DIAIH. While DIAIH is clearly restricted to drugs as responsible agents, this term is erroneously used to refer to disease induced by non-drugs such as herbs, green tea, dimethoate (an organophosphate insecticide), dietary supplements, biologics, herbal remedies, different viruses, and bacteria, as well as vaccines. For diseases induced by these agents, a better term could be, for instance, non-drug-induced autoimmune hepatitis. Drug cessation and immunotherapy with corticosteroids and azathioprine comprise the treatment of choice. The characteristics of DIAIH can best be described if both the RUCAM and the simplified AIH score are used concomitantly.

Liver transplantation (LT) can be the only option for patients with acute liver failure (ALF) where medical approaches are ineffective. Causes of ALF are multiple and commonly easily detectable, but uncertainty remained on the role of drug-induced liver injury (DILI) within the published ALF cohorts. Therefore, an analysis was undertaken to clarify which drugs may have caused the DILI and how the diagnosis of the liver injury was established. Using the PubMed database and Google Science, the search term of acute liver failure combined with drugs provided 36 publications of ALF cohorts, which included 21,709 DILI cases. Whereas non-drug causes were detectable by specific diagnostic biomarkers, the diagnosis of DILI among the ALF cohorts was neglected, as evidenced by the lacking use of a validated diagnostic algorithm like the Roussel Uclaf Causality Assessment Method (RUCAM), best qualified to verify causality for individual drugs or combined drugs. This lack of firm diagnosis leads to a long list of drugs with highly questionable causality of suspected DILI, prevents calculation of incidence or prevalence data of DILI among ALF cohorts, and cannot help find an appropriate therapy for selected cases of drug-induced autoimmune hepatitis (DIAIH) or overdosed N-acetyl-para-aminophenol (APAP) also known as paracetamol, aiming to prevent LT. Under discussion is also the high rate of indeterminate cases of up to 78% among the published cohorts, which confounds any quantitative approach in this setting. In conclusion, there is much room for improvement in future ALF cohorts, requiring the application of validated tools.

Conventionally, drug-induced liver injury (DILI) exists in two types: idiosyncratic and intrinsic. Both types are classified as non-immune disorders, thereby ignoring that some iDILI cases may have an immune or autoimmune background that requires a different therapeutic approach because steroids may be helpful. The purpose of this analysis was to analyze and classify the subtypes of iDILI which, indeed, show autoimmune or immune features among four cohorts, namely idiosyncratic DILI type 1: idiosyncratic drug-induced autoimmune hepatitis (DIAIH), to be differentiated from the classic drug-unrelated idiosyncratic autoimmune hepatitis (AIH); idiosyncratic DILI type 2: human leucocyte antigen-based idiosyncratic drug-induced autoimmune hepatitis; idiosyncratic DILI type 3: anti-cytochrome P450-based idiosyncratic drug-induced autoimmune hepatitis; and idiosyncratic DILI type 4: immune-based idiosyncratic drug-induced liver injury associated with Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). In conclusion, the traditional non-immune and non-autoimmune iDILI, as well as the four immune or autoimmune iDILI subtypes, are now well classified and clinically characterized by the broadly applied Roussel Uclaf Causality Assessment Method (RUCAM), facilitating additional immunology and therapy studies for the four subtypes, all of which could benefit from steroid treatment.