Abnormal Liver Function Tests Research Articles

Four-Year Report of Iatrogenic Bile Duct Injury Repair from a Referral Hepatobiliary Center.

Iatrogenic bile duct injury (BDI) is one of the most common complications that challenge surgeons performing laparoscopic cholecystectomy (LC). As the number of LC surgeries increases, a pattern of BDI is emerging, but little is known about this matter. The purpose of this study was to assess the pattern of post-LC BDIs directed in a referral center in Iran. Post-BDI patients referred to a hepatobiliary center were studied. Demographic data, clinical status, diagnostic examinations, referral time, post-referral management, and morbidity were analyzed. Nine out of 68 patients had Charcot's cholangitis triad featuring right upper quadrant abdominal pain, fever, and icter. Fever, icter, and itching were the most frequent symptoms. Increased bilirubin, leukocytosis, and abnormal liver function test (LFT) were the most common laboratory abnormalities. 30 patients experienced hepatic artery injury. Out of them, six patients experienced hepatectomy due to hepatic ischemia. Two patients were re-admitted and re-operated, and four patients died. Early and correct treatment by a hepatobiliary surgeon experienced in the management of these types of injuries prevents further complications in patients suffering from iatrogenic BDI. Postoperative complications of bile duct repair, such as anastomosis stricture, are possible; thus, patients need long-term and thorough postoperative observation.

Liver involvement with Langerhans cell histiocytosis in adults.

Liver involvement portends poor prognosis in adults. We aimed to characterize the clinical features, liver function tests, radiologic findings, molecular profiles, therapeutic approaches and outcomes of adults patients with Langerhans cell histiocytosis (LCH) with liver involvement. We conducted a retrospective analysis of all adults with LCH (≥ 18 years) seen at Peking Union Medical College Hospital (Beijing, China) between January 2001 and December 2022. Among the 445 newly diagnosed adults with LCH, 90 patients had liver involvement at diagnosis and 22 patients at relapse. The median age was 32 years (range, 18-66 years). Of 112 evaluable patients, 108 had full liver function testing, including alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), and total bilirubin and albumin. Elevated ALP was seen in 63.0% and GGT in 86.1%; 14.8% had elevated bilirubin. Next-generation sequencing of 54 patients revealed frequent BRAFN486_P490 (29.6%), BRAFV600E (18.5%), and MAP2K1 (14.8%). After a median 40 months' follow-up (range 1-168 months), 3-year progression-free survival (PFS) and overall survival were 49.7% and 86.6% respectively. In multivariable analyses, ≥3 abnormal liver function tests (HR 3.384, 95% CI 1.550-7.388, P = .002) associated with inferior PFS; immunomodulatory drug therapy (HR 0.073, 95% CI, 0.010-0.541, P = .010) correlated with superior PFS versus chemotherapy. In summary, elevated GGT and ALP were common in adults with LCH liver involvement. Greater than equal to 3 abnormal liver function tests predicted poor outcomes. Immunomodulatory drug therapy was associated with favorable progression-free survival compared to chemotherapy.

Genetic issues in ICP.

Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disorder with variable global incidence. Genetic susceptibility, combined with hormonal and environmental influences, contributes to ICP aetiology. Adverse pregnancy outcomes linked to elevated serum bile acids highlight the importance of comprehensive risk assessment. ABCB4 and ABCB11 gene variants play a significant role in about 20% of severe ICP cases. Several other genes including ATP8B1, NR1H4, ABCC2, TJP2, SERPINA1, GCKR and HNF4A have also been implicated with ICP. Additionally, ABCB4 variants elevate the risk of drug-induced intrahepatic cholestasis, gallstone disease, gallbladder and bile duct carcinoma, liver cirrhosis and abnormal liver function tests. Genetic variations, both rare and common, intricately contribute to ICP susceptibility. Leveraging genetic insights holds promise for personalised management and intervention strategies. Further research is needed to elucidate variant-specific phenotypic expressions and therapeutic implications, advancing precision medicine in ICP management.

Probing liver function test patterns in COVID-19 pneumonia: Implications for disease severity assessment.

To explore the incidence of liver function test derangement, the precise patterns of derangement, and their relationship with coronavirus disease-2019 pneumonia severity. The retrospective study was conducted at the Dow University Hospital and the Ojha Institute of Chest Diseases, Karachi, and comprised consecutive data from December 16, 2020, to March 16, 2021, of adults of either gender who had nasal swabs positive for coronavirus disease-2019 on real-time reverse transcriptase-polymerase chain reaction. Data regarding patients' demographics, co-morbidities, addictions, laboratory results, and standard information was retrieved from electronic and manual records. The severity of the disease was determined based on World Health Organisation protocols. Data was analysed using SPSS 23. Of the 344 patients, 235(68.3%) were males and 109(31.7%) were females. The overall mean age was 54.58±14.75 years, 187(54.4%) had severe coronavirus disease-2019 pneumonia and 157(45.6%) had non-severe disease at the time of admission. There was a significant prevalence of both mixed and cholestatic patterns of liver function test abnormality among the cases (p=0.046). The presence of a mixed pattern was linked to the disease severity (p<0.05). Advanced age and hypertension were significant risk factors for the development of severe coronavirus disease-2019 pneumonia (p<0.001 and p=0.002). Liver function test abnormality and coronavirus disease-2019 pneumonia severity were fund to have a significant relationship.

Successful Steroid Therapy in a Child with Suspected Autoimmune Hepatitis

Introduction: Autoimmune Hepatitis (AIH) is an unexplained cause of chronic and progressive liver inflammation. The incidence of AIH is about 4.82/per 100,000 people in Korea, but based on global research the incidence is increasing and it should be taken more seriously. Laboratory and imaging tests were performed which led to the diagnosis of AIH but to diagnose AIH is difficult. Steroid therapy is an option for this patient by considering the side effects that are well-monitored. A favourable outcome was shown and this report is expected to highlight the importance of early diagnosis and treatment in AIH cases. Case presentation: A 6-year-old, 5-month-old girl presented to Dr. Soetomo General Academic Hospital, Surabaya with jaundice for 2 weeks. She had been unable to walk for the past 1 month due to pain in both legs, nausea and vomiting, anorexia, right-sided abdominal pain, and an enlarged abdomen. She has had a history of fever for the past 1 month. Laboratory parameters showed cholestasis, abnormal liver function test (aspartate aminotransferase (AST) 1406 U/L, alanine aminotransferase (ALT) 1392 U/L, and prolonged coagulation factor), and positive antinuclear antibody (ANA) test (79.10 AU/mL). Hepatitis markers were negative. Liver biopsy and autoantibodies examination (LKM and SMA) was not done due to limited facilities. Hepatitis, cholecystitis, and ascites were noted on abdominal ultrasonography. Ascites and cholecystitis were seen on an abdominal CT scan. Steroid therapy was administered and there was improvement in clinical condition and laboratory results following two weeks duration of treatment. Conclusion: This case report illustrates that steroid treatment for a child with AIH results in a good improvement and provides achievement of treatment goals following existing guidelines. The use of steroid therapy in suspected cases of AIH, without further diagnostic modalities, may be of value in the prevention of further liver damage, especially in healthcare settings with limited resources.

ALT in Preeclampsia

Background: Preeclampsia is the most frequent cause of abnormal liver function test in pregnancy. Women with preeclampsia and raised serum alanine aminotransferase (ALT) have chance of greater proteinuria and more maternal complications than those with normal liver function. Objective: The present study was designed to assess the association of serum ALT with preeclampsia. Materials and method: A case control study was conducted in the Department of Biochemistry, Dhaka Medical College,Dhaka, Bangladesh, from July 2010 to June 2011. From the pregnant women in third trimester of pregnancy attending in Obstetrics and Gynecology Department of Dhaka Medical College Hospital, 50 diagnosed cases of preeclampsia were selected purposively as cases and 50 normal healthy pregnant women as controls. Serum ALT concentration was measured in all the study subjects. Results: The mean serum ALT concentration in cases and controls were 57.92±20.99 U/L and 15.46±2.66 U/L respectively. The level was significantly higher in cases than that of controls (p=0.001). Conclusion: The study revealed that increased serum ALT concentration is associated with preeclampsia. Delta Med Col J. Jan 2021;9(2): 65-68

Case of Tigecycline Induced Liver Injury: A Cautionary Tale

Tigecycline, the inaugural glycylcycline antibiotic in clinical use, is experiencing rising global utilization owing to its effectiveness against multidrug-resistant (MDR) bacteria. Although gastrointestinal side effects like nausea and vomiting are more prevalent, it is important to recognize that tigecycline can also lead to liver injury. The manufacturer has issued a warning regarding tigecycline's potential to elevate total bilirubin (TB) and transaminase levels. [1] We present the case of a 74-year-old female with a history of multiple comorbidities who developed severe hepatotoxicity following tigecycline therapy for a complicated intra-abdominal infection. The patient shows an abnormal liver function test with hyperbilirubinemia. Later on she developed jaundice. This case underscores the importance of considering TILI in patients receiving tigecycline, particularly those with preexisting liver disease or receiving other potentially hepatotoxic medications.

Beyond diagnosis: exploring coeliac disease incidence alongside clinical and laboratory characteristics of newly diagnosed children in Slovenia.

Coeliac disease is characterized by a wide array of clinical presentations. The focus of our study was to comprehensively assess the clinical manifestations of coeliac disease in newly diagnosed children in Slovenia. Our objectives include estimating the incidence of the disease in children in 2022. In this prospective study, Slovenian paediatric gastroenterologists were invited to provide patient data using medical records of children under 19 diagnosed with coeliac disease from March 2021 to October 2023. Patient data were collected through a dedicated web-based form adapted from the CD SKILLS project, including data on clinical manifestations and laboratory results. Furthermore, the study included an estimation of the incidence of coeliac disease in children and adolescents in Slovenia in 2022. Analysis involved data from 160 children and adolescents (median age: 8 years; 61.9% female). Overall, 16.9% were asymptomatic at diagnosis and 29.4% belonged to a high-risk group for coeliac disease. Among symptomatic cases ( N = 133), abdominal pain was the leading symptom (44.4%), followed by anaemia (12.0%) and diarrhoea (10.5%). Malabsorption symptoms were more prevalent in very young children. Anaemia was found in 22.8 and 10.7% had abnormal alanine aminotransferase levels. The estimated incidence of coeliac disease in Slovene children in 2022 was 17.5/100 000. Abdominal pain emerged as the primary symptom of coeliac disease in children and adolescents, except in very young children where malabsorption symptoms were predominant. Our observation of a lower prevalence of abnormal liver function tests suggests subclinical coeliac disease may be less common in children. Moreover, the calculated coeliac disease incidence in Slovenia aligns with existing data.

Diagnosis and management approach of acute cholangitis with sepsis complications in a peripheral hospital: a case report

Acute cholangitis is a systemic, life-threatening condition that develops as a result of obstruction and infection of the bile ducts. The two main processes leading to acute cholangitis include obstruction of the biliary tract and the growth of bacteria in the bile. A case of acute cholangitis has been reported at Rote Ndao public hospital, Rote Ndao district, East Nusa Tenggara, in a 57-year-old woman, with the main complaint of right upper abdominal pain, jaundice, and fever. The diagnostic approach is based on anamnesis, physical examination, and supporting examinations. Based on the Tokyo guideline 2018 (TG18) the patient met a suspected diagnosis, with A criteria that was evidence of systemic inflammation in the form of fever (body temperature 38.7o C), evidence of an inflammatory response with increasing leukocyte count (26,200/cm3), and for the B criteria that was evidence of cholestasis in the form of jaundice, increasing of total bilirubin (19.8 mg/dL), abnormal liver function tests (SGOT 135 IU/L, SGPT 74 IU/L), while C criteria cannot be performed due to limited hospital imaging facilities. Limitations of investigations should not limit the diagnosis and initial management so it can give the good prognosis. Even though there were complications of sepsis, the patient did not experience signs of shock which could lead to mortality.

Association between COVID-19 severity with liver abnormalities: A retrospective study in a referral hospital in Indonesia.

Coronavirus disease 2019 (COVID-19) is characterized by an acute respiratory infection with multisystem involvement and the association of its severity to liver function abnormalities is not well characterized. The aim of this study was to assess the association between the severity of COVID-19 patients and liver function abnormalities. This retrospective study included adult patients with confirmed COVID-19, which were classified as non-severe or severe according to World Health Organization guidelines. Liver function test results were compared between the severity groups. A total of 339 patients were included of which 150 (44.25%) were severe cases. The male-to-female ratio was 0.9:1 and 3:2 in the non-severe and severe groups, respectively (p=0.031). Aspartate aminotransferase (AST), alanine transaminase (ALT), and total bilirubin levels and acute liver injury (ALI) incidence were significantly higher in the severe group compared to non-severe group (p<0.001, p<0.001, p=0.025, p=0.014, respectively). In contrast, albumin levels were significantly lower (p=0.001). Multivariate analysis showed that ALI was significantly associated with human immunodeficiency virus (HIV) infection (odds ratio (OR): 5.275; 95% confidence interval (CI): 1.165-23.890, p=0.031), hemoglobin level (OR: 1.214; 95%CI: 1.083-1.361, p=0.001), and hypoalbuminemia (OR: 2.627; 95%CI: 1.283-5.379, p=0.008). Pre-existing liver diseases were present in 6.5% of patients. No significant differences were observed between the groups based on COVID-19 severity and ALI presence. Liver function test abnormalities, including ALI, are more prevalent in patients with severe COVID-19 infection. HIV infection, high hemoglobin levels, and hypoalbuminemia may be potential risk factors for ALI.

Association Between Cardiovascular Health and Cirrhosis and Mortality: Insights From a Comprehensive Cross-sectional Study.

We aim to explore the relationship between the newly introduced CVH indicator "Life's Essential 8 (LE8)" and cirrhosis. The global burden of cirrhosis is increasing, with a rising number of deaths, leading to significant societal and economic challenges. Cardiovascular health (CVH) has been found to have potential associations with liver diseases. All participants aged 20 and older from National Health and Nutrition Examination Survey 2005 to 2018 were included. CVH was accessed by LE8, consisting of 4 health behaviors (diet, physical activity, nicotine exposure, and sleep health) and 4 health factors (body mass index, lipid levels, blood sugar, and blood pressure). Cirrhosis was determined based on abnormal liver function test results, with an aspartate aminotransferase to platelet ratio index >2. Participants' mortality status was obtained by matching with the National Death Index and all-cause mortality served as the follow-up endpoint. This extensive cross-sectional study reveals that LE8 was not associated with cirrhosis. A higher health behaviors score was associated with lower cirrhosis. Moreover, there is an inverse U-shaped relationship between the LE8 score and all-cause mortality in participants with cirrhosis, signifying a decrease in all-cause mortality when LE8 surpasses 60. A greater health behaviors score is linked to a decreased proportion of all-cause mortality in cirrhosis patients. Maintaining better health behaviors may be beneficial for cirrhosis, especially through a balanced diet, regular exercise, smoking cessation, and quality sleep.

Overall Summery of Gulf Country Employees from Bangladesh, Preliminary Evaluation for Abnormal Kidney Liver and Virally Infected Individuals Using Low-cost Tests Like CBC Parameters

Hepatitis B Viruses antigen (HBsAg), Hepatitis C Virus (HCV), Human Immunodeficiency Virus (HIV) and Syphilis is a major public concern because of shared route of transmission. Alanine transaminase (ALT) and Aspartate Aminotransferase (AST) and Bilirubin is measured for abnormal liver function test and Abnormal Kidney function is measured by creatinine. The complete blood count (CBC) is the most common examination used to monitor overall health in clinical practice as well as cheap in Bangladesh. Radiological Image could have cheap but HBsAg, HCV, HIV and Syphilis test is cost effective. The main aim to this study is to determine the viral positive, abnormal Kidney, Liver function patient’s detection by doing cheap CBC test parameters. In this study, we have calculated normal patients CBC parameter and same HBsAg, HCV and syphilis patients, abnormal kidney and liver functions patients CBC parameters have been assembled. We also find out the relation with radiological image of chest X-ray for viral positive patients. The result of the study indicated that all CBC parameter of positive HBsAg, HCV and syphilis, abnormal kidney and liver patients approximately same. But only Mean Platelet Volume (MPV) and Platelet number have significant value. Abnormal Kidney and liver patients have high MPV 11.94x10^3 and HCV, HBsAg positive patients 9.9x10^3 whereas normal patients value is 9.7x10^3. This study proves that there is significant effect for MPV value with normal and viral infected patients. This finding could have used early detection for overseas health checkup.

Hepatotoxicity and Its Impact on Mortality in COVID-19 Patients

Objective: "COVID-19-related liver damage" can occur frequently in course of COVID-19 disease and cause significant problems. Our study aimed to investigate prevalence of liver damage due to COVID-19, its risk variables, and the effect of liver damage on course of COVID-19 and mortality. Method: One hundred patients over eighteen years of age who were hospitalized between 01.08.2021-01.03.2022 and had positive RT-PCR tests were included in our study. Impaired liver function tests were identified as having alanine aminotransferase(ALT) and aspartate aminotransferase(AST) levels exceeding upper laboratory limits. Results: The mean age of patients included in study was 57.9 ± 14.9 years, with 49% of them being male. In our study, we had an 8% death rate and 37% of patients had abnormal liver function tests. The presence of severe disease(p&lt;0.001), anorexia symptoms(p=0.027), and abdominal pain(p=0.010) were significant for mortality. A prolonged hospital stay was significantly associated with death(p=0.029), with the mean length of hospital stay being 11.8 ± 4.6 days. Favipiravir use for longer than five days was associated with a substantial risk of liver damage(p=0.044) and mortality(p=0.020), while use of antibiotics in carbapenem group was associated with a significant risk of death(p=0.001). Conclusions: It is noteworthy that a considerable proportion of COVID-19 patients may exhibit increased liver tests, which could serve as a significant predictor and risk factor, particularly with regard to mortality. In order to properly monitor and manage COVID-19 patients, particularly those who are at risk, comprehensive measurements, including liver tests, should be carried out on a regular basis.

Real-world outcomes comparison between the MET inhibitors (METi) capmatinib and tepotinib in patients with stage IV non-small cell lung cancer (NSCLC) with MET exon 14 skipping mutation.

e20588 Background: MET exon 14 skipping mutations are seen in about 3% of patients (pts) with NSCLC, with 2 FDA approved METi for pts with stage IV NSCLC harboring it. Besides the original clinical trials, there is a paucity of real-world data about their outcomes, and adverse events (AE). Our aim was to compare and analyze the utilization of capmatinib (cap) and tepotinib (tep) in this population. Methods: We performed a retrospective chart review of the electronic medical records of all pts with stage IV NSCLC treated with METi between the date of FDA-accelerated approval of these drugs, 5/6/20 for cap and 2/3/21 for tep, and 12/1/23. All pts were treated at the Mayo Clinic Health System. We collected data about baseline characteristics, diagnosis, AE, and outcomes. Chi-squared test was used to compare the frequency of AE, while Kaplan-Meier method was used to calculate median progression free survival (mPFS). Results: A total of 49 pts were treated with METi. Cap was used in 45 pts, 14 received tep, and 10 pts received both, with tep following cap. In the cap group, median age of diagnosis was 74 years (y), 42.22% were male, and the median number of previous lines of therapy (mPLT) was 0. In the tep group, median age of diagnosis was 72 y, 21.43% were male, and the mPLT was 2. Median ECOG at the time of diagnosis was 1 in both groups. There was no statistically significant difference between AE in both groups. Peripheral edema occurred in 75.56% pts who received cap, and in 64.29% with tep (p = 0.41). Pneumonitis happened in 4.44% with cap, and 7.14% with tep (p = 0.69). Creatinine elevation was seen in 37.78% with cap, while 42.86% with tep (p = 0.73), grade 3 elevation was seen in 5.88% and 16.67% respectively. Abnormality in liver function tests occurred in 35.56% of pts in the cap group, and 28.57% in the tep group (p = 0.63), grade 3/4 abnormality occurred in 31.25% and 0% respectively. Finally, pancreatic enzymes elevation was seen in 33.33% of patients in each group (p = 0.67), with none being grade 3/4. Cap was discontinued in 20% of pts due to AE, while it happened in 28.57% of pts with tep. Dose reduction happened in 64.44% of pts who received cap, and 42.86% who received tep. The mPFS was 12.03 months (m) in the cap group, and 8.94 m in the tep group, which was not statistically significant (p = 0.18). Similarly, the mPFS in those treated with tep following cap was 8.94 m. Conclusions: We performed the first real-word comparison between cap and tep. The results demonstrated similar outcomes with both drugs, and no significant differences in AE, suggesting these agents can be employed equivalently. Importantly, rates of therapy discontinuation and dose reduction were high with both, indicating the importance of closely monitoring these pts. The retrospective nature and small sample size are initial limitations that can be overcome with future multi-centric prospective studies.

Symptoms and Conditions in Children and Adults up to 90 Days after SARS-CoV-2 Infection: A Retrospective Observational Study Utilizing the Common Data Model.

Background/Objectives: There have been widespread reports of persistent symptoms in both children and adults after SARS-CoV-2 infection, giving rise to debates on whether it should be regarded as a separate clinical entity from other postviral syndromes. This study aimed to characterize the clinical presentation of post-acute symptoms and conditions in the Korean pediatric and adult populations. Methods: A retrospective analysis was performed using a national, population-based database, which was encoded using the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). We compared individuals diagnosed with SARS-CoV-2 to those diagnosed with influenza, focusing on the risk of developing prespecified symptoms and conditions commonly associated with the post-acute sequelae of COVID-19. Results: Propensity score matching yielded 1,656 adult and 343 pediatric SARS-CoV-2 and influenza pairs. Ninety days after diagnosis, no symptoms were found to have elevated risk in either adults or children when compared with influenza controls. Conversely, at 1 day after diagnosis, adults with SARS-CoV-2 exhibited a significantly higher risk of developing abnormal liver function tests, cardiorespiratory symptoms, constipation, cough, thrombophlebitis/thromboembolism, and pneumonia. In contrast, children diagnosed with SARS-CoV-2 did not show an increased risk for any symptoms during either acute or post-acute phases. Conclusions: In the acute phase after infection, SARS-CoV-2 is associated with an elevated risk of certain symptoms in adults. The risk of developing post-acute COVID-19 sequelae is not significantly different from that of having postviral symptoms in children in both the acute and post-acute phases, and in adults in the post-acute phase. These observations warrant further validation through studies, including the severity of initial illness, vaccination status, and variant types.

Psoriasis Area and Severity Index and its Correlation with Liver Function Test

Objective: To determine Psoriasis Area and Severity Index score and its association with LFT values in patients of psoriasis. Methodology: This cross-sectional study, was done on patients visiting the skin OPD of LUMHS Jamshoro/Hyderabad. Diagnosed patients of Psoriasis, aged between 18 and 50 years and both genders were included. A 5cc blood sample was collected from each individual to evaluate the LFT. Psoriasis Area and Severity Index (PASI) scores was defined based on the percentage of body surface area affected by psoriasis lesion. All the information was entered and analyzed using SPSS version 26. Results: The mean age of the patients was 44.81±11.10 years. Out of the total 102 patients, 74.5% were male patients and 25.5% were female. The mean duration of psoriasis was 6.46 ± 4.49 years. Out of all 32.4% had mild psoriasis (PASI &lt; 7), 40.2% had moderate psoriasis (PASI 8-12), and 27.5% had severe psoriasis (PASI &gt; 12). Regarding LFT values, 73.5% had elevated alanine transaminase (ALT), 32.4% had elevated aspartate transaminase (AST), 70.6% had elevated alkaline phosphatase (ALP), 68.6% had elevated bilirubin, and 67.6% had elevated gamma-glutamyl transferase (GGT). AST and GGT levels rise significantly linked to PASI (p- &lt;0.05). Conversely, for ALP and Bilirubin levels, there is no significant difference across severity of PASI (p- &gt;0.05). Conclusion: Patients with severe psoriasis exhibit a predisposition to hepatic dysfunction. Study observed abnormalities in liver function tests (LFT) among psoriatic patients, suggesting a potential link to liver disease development.

Abnormal liver function tests in patients with graves' disease

Abnormal liver function tests in patients with graves' disease

Intelligent Liver Function Testing (iLFT): An Intelligent Laboratory Approach to Identifying Chronic Liver Disease.

The intelligent Liver Function Testing (iLFT) pathway is a novel, algorithm-based system which provides automated laboratory investigations and clinical feedback on abnormal liver function test (LFT) results from primary care. iLFT was introduced to NHS Tayside, Scotland, in August 2018 in response to vast numbers of abnormal LFTs, many of which were not appropriately investigated, coupled with rising mortality from chronic liver disease. Here, we outline the development and implementation of the iLFT pathway, considering the implications for the diagnostic laboratories, primary care services and specialist hepatology clinics. Additionally, we describe the utility, outcomes and evolution of iLFT, which was used over 11,000 times in its first three years alone. Finally, we will consider the future of iLFT and propose areas where similar 'intelligent' approaches could be used to add value to laboratory investigations.

Abstract PO4-04-11: Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer

Abstract BACKGROUND Giredestrant (GIR) is a highly potent, nonsteroidal, oral, selective estrogen receptor antagonist and degrader (SERD). The Phase Ia/b GO39932 study (NCT03332797) investigated GIR ± palbociclib (palbo) and ± a luteinizing hormone-releasing hormone agonist for patients with ER-positive, HER2-negative, locally advanced or metastatic breast cancer who had disease progression on prior endocrine therapies. In the single-agent dose-escalation stage, patients received 10, 30, 90, or 250 mg of once-daily (QD) GIR. In the dose-expansion stage, patients received 30, 100, or 250 mg of QD GIR. Safety and tolerability of 100 mg GIR + 125 mg palbo was also explored in the dose-escalation and -expansion stages. Results showed that GIR was well tolerated and potentially clinically active as a single agent and in combination with palbo, including in patients with ESR1-mutated tumors. To inform the selection of the clinical dose for GIR late-stage development based on risk–benefit considerations, exposure–response (E–R) analyses for efficacy and safety endpoints were conducted using single-agent GIR data. METHODS Exposure metrics included maximum concentration at steady state and area under the concentration–time curve at steady state. The association between the exposure metrics and efficacy endpoints (objective response rate [ORR] and clinical benefit rate [CBR]) or safety endpoints (all adverse events [AEs], Grade ≥ 3 AEs, selected AEs of interest [sAEIs], including all-grade hepatotoxicity, and bradycardia) were evaluated. RESULTS Data cutoff was September 17, 2021. A total of 111 patients were enrolled in the single-agent GIR cohort. Of these 111 patients, 107 were pharmacokinetic-evaluable and included in the analysis. ORR in patients with measurable disease at baseline was 20% (16/81 patients) and CBR was 49% (54/111). No significant associations were observed between exposure and ORR or CBR, including in patients with ESR1-mutated tumors and those with no mutation detected (p &amp;gt; 0.05). There were 92/107 patients (86%) with AEs of any grade, overall. Seventy-two (67%) had sAEIs, 19 (18%) experienced hepatotoxicity (all events were reported as liver function test abnormalities), 11 (10%) had bradycardia, and 20 (19%) had Grade ≥ 3 AEs. Increasing exposure did not significantly increase the incidence of all AEs, Grade ≥ 3 AEs, sAEIs, or bradycardia at the dose range of 10 to 250 mg (p &amp;gt; 0.05). For hepatotoxicity, the analysis suggested that higher exposure may lead to a higher probability of events (p = 0.0065); however, at the clinically relevant exposure range for the 30 mg dose, the incidence of hepatotoxicity was low and the predicted exposures were at the shallower slope of the relationship. CONCLUSIONS Single-agent GIR did not exhibit a significant association between exposure and efficacy endpoints at a dose range of 10 to 250 mg, regardless of ESR1 mutation status, indicating that the efficacy of GIR might have reached a plateau at low dose levels. At the clinically relevant exposure range of the 30 mg dose, GIR exposure was not associated with an appreciable increase in the incidence of AEs. The Phase Ia/b study design and subsequent E–R results enabled dose selection to be based on risk–benefit considerations, rather than the traditional maximum tolerated dose paradigm, in line with the United States Food and Drug Administration’s oncology dose optimization recommendations. The E–R results also indicate that GIR may have a relevant wide therapeutic window. Overall, these data support the 30 mg clinical dose of GIR that was selected, with a favorable risk–benefit profile, for further clinical studies. Citation Format: Komal Jhaveri, Yi Ting (Kayla) Lien, Nicholas Turner, Elgene Lim, Maureen Cannon, Richard Anziano, Jurgen Langenhorst, Kenta Yoshida, Vikram Malhi, Mary Gates, Jennifer Eng-Wong, Chunze Li, Mona Shah, Pablo Perez-Moreno, Jiajie Yu, Aditya Bardia. Exposure–response analyses of GO39932: a Phase Ia/b study of giredestrant in estrogen receptor-positive, HER2-negative, locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-04-11.

Leptospirosis in a patient with cardiac manifestation: A case report study and literature review

Key Clinical MessageCommon cardiac arrhythmias seen in patients with leptospirosis are usually atrial fibrillation or first‐degree atrioventricular block, with bradyarrhythmia being rare in this group. It is essential to prioritize the examination of the patient's medical background, clinical symptoms, and comprehensive physical evaluation in order to promptly identify and address the patient's condition.AbstractLeptospirosis, a zoonotic disease that is widespread worldwide, has a significant impact on tropical areas and can affect various organs throughout the infection. During the initial stage, symptoms are typically non‐specific. Although cases of all three cardiac layers being affected have been reported, issues with the conduction system are especially significant in the early phase of the disease. The most frequent discoveries in these patients are atrial fibrillation or first‐degree atrioventricular block, with bradyarrhythmia being rare. We describe a 37‐year‐old male farmer who initially sought medical attention for general symptoms that had been deteriorating despite receiving outpatient treatment for 3 days for a presumed diagnosis of influenza. During his initial assessment, he exhibited sinus bradycardia, anemia, leukocytosis, elevated levels of direct and total bilirubin, and abnormal liver function test results. Through thorough history‐taking, physical examination, and laboratory analyses, a diagnosis of leptospirosis was conclusively established for him. Focusing on the patient's medical history, clinical manifestations, and thorough physical assessment is crucial for promptly diagnosing and treating patients. This becomes particularly significant for individuals who exhibit atypical symptoms, exemplified by our patient presenting with nonspecific indications and cardiac issues manifested as bradycardia.