Uclaf Causality Assessment Method Score Research Articles

Association between the Treatment Pattern of Drug-Induced Liver Injury and Clinical Outcomes: A Retrospective Study

What is Known and Objective? In China, patients with drug-induced liver injury (DILI) are commonly treated with one or more types of hepatoprotective drugs, despite a lack of evidence. We performed this study to investigate the association between the treatment pattern of DILI, including withdrawal of suspected drugs and use of hepatoprotective drugs, and recovery following DILI. Methods. A retrospective study was conducted at a tertiary hospital in Central China. Data of patients with a diagnosis of DILI hospitalized between January 2015 and December 2020 were collected through the Electronic Medical Records System. We excluded cases that did not meet the biochemical criteria of DILI and had a Roussel Uclaf Causality Assessment Method score of less than 3. Univariate and multivariate logistic regression models were used to analyze the association between treatment patterns and clinical outcomes. Results and Discussion. In total, 699 patients were included. Suspected drugs were discontinued in 619 patients (88.6%). 693 patients (99.1%) were treated with hepatoprotective drugs, among whom only 14.7% patients received monotherapy with hepatoprotective drugs. Recovery following DILI was seen in 593 cases (84.8%). By multivariate analysis, the number of hepatoprotective drugs combined did not show significance ( p = 0.363 ), while the withdrawal of suspected drugs was associated with recovery following DILI ( p = 0.015 ). What is New and Conclusion. The withdrawal of suspected drugs is associated with the recovery following DILI, and hepatoprotective drug combinations do not contribute to better outcomes than monotherapy. The findings indicate that DILI patients should stop suspected drugs as soon as possible and the combination therapy of hepatoprotective drugs is unnecessary.

Mifepristone induced liver injury in a patient with Cushing syndrome: a case report and review of the literature

BackgroundMifepristone, also known as RU-486, is an anti-progestational steroid with similar chemical structure to anabolic steroids. Given as a single dose in conjunction with misoprostol, mifepristone is used to induce medical abortion. Mifepristone administered chronically at a higher dose is also approved for the management of hypercortisolism. There have been only 2 reported cases of mifepristone associated liver injury, in both cases, in the setting of Cushing syndrome. We report a third patient with Cushing syndrome with mifepristone induced liver injury with unique histological findings that provide insight to the pathophysiology of liver injury in mifepristone and anabolic steroids.Case presentationPatient is a 63-year-old Caucasian female Cushing disease with no prior history of liver disease. She was started on mifepristone and semaglutide. Ninety days after initiating mifepristone, she developed deep jaundice, severe pruritus, fatigue, and nausea. Liver tests revealed a mixed hepatocellular/cholestatic pattern. Viral and autoimmune serologies were negative and there was no biliary dilatation on imaging. Liver biopsy showed severe cholestasis but no bile duct injury. Focal endothelialitis was present within a central venule. Cholestatic symptoms persisted for one month after presentation before slowly subsiding. Four months after stopping mifepristone, the patient’s symptoms completely resolved, and liver tests became normal. Compilation of Roussell Uclaf Causality Assessment Method score indicated probable causality.ConclusionsMifepristone shares a similar chemical structure as synthetic anabolic/androgenic steroids and there are many similarities in the clinical presentation of liver injury. This case and the 2 other reported cases share similar clinical characteristics. The observation of endothelialitis in our patient may provide a mechanistic link between mifepristone, or anabolic steroids in general, and the development of vascular complications such as peliosis.

Drug-induced severe liver injury due to Sterculia versicolor: a case report with causality assessment from possible to probable.

Sterculia gum, the dry exudate of Sterculia versicolor and other members of the same genus, is used as a thickener and emulsifier in foods. It is generally considered safe as a food or drug, and its adverse reactions, such as Sterculia-induced liver injury, have never been reported. A 46-year-old woman was admitted to hospital with fatigue, nausea, abdominal distension, jaundice and a >16-fold increase in transaminase and bilirubin level. The patient had used Sterculia gum prior to the onset of her symptoms. Her symptoms and clinical indicators improved after treatment. The possibility of acute viral hepatitis, autoimmune hepatitis, and metabolic liver disease was excluded. After discharge from hospital, the patient had a severe liver injury again when re-exposed to Sterculia gum. And the Roussel Uclaf Causality Assessment Method score was updated from 5 to 7, which was consistent with probable drug-induced liver injury. This is the first report of Sterculia-induced liver injury. Clinicians need to be aware of the potential hepatotoxicity of Sterculia.

Zanubrutinib-induced liver injury: a case report and literature review

BackgroundZanubrutinib is a Bruton’s tyrosine kinase inhibitor that has been recently licensed in refractory mantle cell lymphoma and under assessment in phase 3 clinical trials for other B cell malignancies. To date, there are no reported cases of hepatotoxicity secondary to zanubrutinib. We report the first case of severe liver injury due to zanubrutinib.Case presentationA 56-year-old Caucasian male with a history of relapsed lymphoplasmacytic lymphoma was admitted to the hospital with new-onset jaundice, choluria, and pruritus for 10 days. He had been on zanubrutinib as part of a clinical trial for 30 months. His blood profile showed a severe hepatocellular injury with jaundice (alanine transaminase 2474 IU/L and total bilirubin 141 umol/L with mild coagulopathy). He had an extensive work-up including virology, autoimmune, and metabolic profiles in addition to abdominal ultrasound with no alternative explanation found for his liver injury. Zanubrutinib-induced liver injury was suspected, and causality assessment by the updated Roussel Uclaf Causality Assessment Method score showed a probable causal relationship with zanubrutinib. His liver histology was also consistent with drug-induced liver injury. His liver biochemistry improved following cessation of zanubrutinib and normalised after 8 weeks.ConclusionWe report the first case of severe liver injury secondary to zanubrutinib after 30 months of treatment. This case raises clinical awareness regarding zanubrutinib-induced liver toxicity and the importance of drug withdrawal in the event of liver injury.

An unusually impressive atorvastatin-induced elevation of serum alkaline phosphatase

A 90-year-old woman is referred six months after a transient ischaemic attack (TIA) with asymptomatic cholestatic liver function test (LFT) derangement. Following the TIA, atorvastatin and clopidogrel therapy are initiated....

Acute severe hepatitis with alemtuzumab and rechallenge after a year

Alemtuzumab is a monoclonal antibody used as a disease modifying agent in relapsing and remitting multiple sclerosis. It has not previously been associated with drug induced liver injury.Here we present a case of a 49 year old female developing drug induced liver injury secondary to alemtuzumab, confirmed upon rechallenge. Our patient developed severe hepatitis within two days of starting alemtuzumab, both initially and upon rechallenge. The alanine aminotransferase peaked at 577 units per litre and 426 units per litre after initial dose of alemtuzumab and rechallenge respectively. The patient’s liver function tests improved significantly between doses of alemtuzumab and again normalised within three months of the second dose, with no clinical manifestations of acute hepatic failure. A full hepatitis screen ruled out alternative causes of hepatitis, including autoimmune hepatitis and hepatotoxicity relating to other medications.Deliberate rechallenge with a medication thought to be associated with drug induced liver injury is uncommonly performed but provides substantial evidence for causality in the appropriate clinical context. The Roussel Uclaf Causality Assessment Method score was calculated as nine, indicating that drug induced liver injury due to alemtuzumab is highly probable.Drug induced liver injury is a potentially serious condition that should be monitored for during alemtuzumab treatment of relapsing and remitting multiple sclerosis. The role of a rechallenge should be weighed up on a case by case basis.

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature.

Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

A Case of Acute Liver Failure Following Initiation of Valproic Acid

Introduction: Valproic acid (VPA), an anticonvulsant used in the treatment of seizure disorders, migraines, and bipolar disorder, has been shown to cause drug-induced liver injury (DILI) in 5-10% of individuals. Effects can range from subclinical transaminase elevations to acute liver failure and death. Herein, we report a case of acute liver failure 18 days following initiation of VPA. Case Report: A 39 year-old woman with a history of a seizure disorder and schizophrenia treated with olanzapine presented to an outside hospital with breakthrough seizures. She was successfully treated with an anti-epileptic regimen including phenytoin, levetiracetam, VPA and lacosamide and discharged. Two days later she was readmitted to our institution with altered mental status and incontinence. Physical exam revealed orientation only to self, flat affect, and icteric sclera. Labs were significant for pH 7.1, lactate 7.1, AST 282, ALT 343, total bilirubin 2.2 and INR 1.1. A non-contrast head CT was normal. She was treated with IV fluids and IV bicarbonate, and was admitted to the medical ICU. By hospital day 5, her labs revealed AST 2129, ALT 1625 and INR 2.4. Initial serologic testing, including levels for acetaminophen, salicylates, alcohol and carbamazepine, a viral hepatitis panel, toxicology screen, anti-mitochondrial antibody, anti-smooth muscle antibody, HIV, CMV, EBV, HSV, RPR, VZV, and AFP, was negative. A transjugular liver biopsy (Figure) was consistent with VPA induced hepatotoxicity. Despite discontinuing all anti-epileptic medications and initiating IV carnitine, the patient developed ventilator-dependent respiratory failure and acute kidney injury requiring hemodialysis and was listed for liver transplantation. Several weeks following the termination of VPA, the patient's liver associated enzymes and renal function normalized. The patient experienced a recurrent seizure and was restarted on levetiracetam prior to being discharged on hospital day 83. Discussion: The absence of other risk factors, the livery biopsy histology, and the timing of liver injury and recovery are all consistent with VPA-induced acute liver failure. A Roussel Uclaf Causality Assessment Method score of 8 was calculated. The mechanism of toxicity is thought to be due to impairment of liver mitochondrial function. Treatment with VPA requires a high index of suspicion for DILI and early discontinuation of this medication may spare patients from liver transplantation or death.Figure 1

Elevation of serum cytokines preceding elevation of liver enzymes in a case of drug-induced liver injury

A 50-year-old man who was being treated for both pneumonia and type 2 diabetes mellitus complained of abdominal distention on the 16th hospital day. Liver enzyme elevation without symptoms was detected on the 17th hospital day. Based on a Roussel Uclaf Causality Assessment Method score of 10 and a Japan Digestive Disease Week score of 9, we diagnosed the patient as having drug-induced liver injury (DILI). Simultaneous assays of the levels of cytokines revealed that the elevation of the levels of interleukin (IL)-1β, IL-10, IL-12, IL-13 and tumor necrosis factor-α preceded the elevation of the serum liver enzymes. This case suggests that some cytokines or related molecules are potentially useful as early-phase biomarkers for DILI.

A Case of Drug-Induced Autoimmune Hepatitis after Glucosamine Ingestion

글루코사민은 흔하게 사용되며 각광받는 건강 보조식품 중 하나로 항산화 효과 등이 보고되어 있으나 독성, 특히 간염에 대해서는 아직 잘 알려지지 않았다. 저자들은 글루코사민 섭취 후 간독성이 발생한 67세 여자 환자를 경험하였다. 상기 식품을 한 달 이상 섭취 후 약제 유발성 급성 자가면역 간염이 발생하였으며 간손상이 발생할 만한 다른 원인은 관찰되지 않았다. 12주간의 보존적인 치료와 자가면역 간염에 대한 치료(prednisolone과 azathioprine의 병합요법) 후 증상과 생화학적 이상 소견이 호전되었다.

Voriconazole hepatotoxicity in severe liver dysfunction

There are no studies regarding to these effects in patients with severe liver dysfunction. The aims of this study were to characterize voriconazole hepatotoxicity in patients with severe liver dysfunction and to compare it with a matched cohort treated with liposomal amphotericin B. This is an observational study, in which adults patients treated with at least 4 doses of voriconazole were included. Patients treated with liposomal amphotericin B were used as control group. Sixty nine percent of patients treated with voriconazole showed changes in liver function tests (LFTs) during therapy. They showed elevated transaminases in 35%, cholestasis in 15% or a combination of both in 45%. According to the CTC classification, all patients with hepatotoxicity had a severe reaction. The Roussel Uclaf Causality Assessment Method score in all patients with hepatotoxicity was greater than 8. There was a correlation between initial loading dose greater than 300 mg (4.5 mg/kg) and the risk of hepatotoxicity (p < 0.001). The control group developed alterations in the LFTs in only 10.3% of patients. Voriconazole should be used with caution in patients with severe liver dysfunction and following liver transplantation, with frequent monitoring of LFTs or using liposomal amphotericin B instead.

Two cases of toxic hepatitis caused by arrowroot juice

Herbal remedies and health foods are widely used, and their side effects have been reported. We describe two cases of symptomatic toxic hepatitis that developed in middle-aged women after ingesting arrowroot juice. The clinical manifestations were nausea, vomiting, and jaundice. The diagnosis of toxic hepatitis was made using the Roussel Uclaf Causality Assessment Method score on the basis of the patient's history and laboratory data. After supportive care, the patients showed rapid improvements of clinical symptoms, laboratory findings, and liver stiffness. Clinicians should be aware that the consumption of arrowroot juice can cause toxic hepatitis.

Hepatotoxicity Associated with Acarbose Therapy

To report a case of acarbose-induced hepatotoxicity and compare other reported cases from the literature. A 57-year-old woman with type 2 diabetes mellitus for about 10 years had been treated with insulin glargine 20 units/day since December 19, 2002. Acarbose 100 mg 3-times-daily add-on therapy for inadequate glycemic control was started on June 5, 2003. Six months later, the woman complained of gastrointestinal discomfort; the acarbose dose was decreased to 50 mg 3 times daily thereafter. Laboratory examination later revealed alanine aminotransferase (ALT) 640 U/L (upper reference value 55). To elucidate the possibilities of adverse reactions caused by concurrent use of nutritional supplements and medication, we discontinued propolis extract, Ginkgo biloba, placeta extract, and estrogen. Although no remarkable symptoms were noted thereafter, the abnormal ALT values persisted, and no definite viral or autoimmune etiologies were identified. Acarbose was discontinued in August 2004; aspartate aminotransferase and ALT values returned to normal in October 2004. In addition to ruling out other possible etiologic factors, we assessed the probability of acarbose-induced hepatotoxicity by observing the close time relationship between drug administration and the development of signs and symptoms, as well as the close time relationship between drug withdrawal and the normalization of abnormal liver function test values. An objective causality assessment revealed that an adverse drug reaction was probable as determined by both the Naranjo probability scale and the Roussel Uclaf Causality Assessment Method score. Although acarbose-induced hepatotoxicity appears to be uncommon, diabetic patients receiving long-term acarbose therapy should be closely monitored for this adverse effect.