Liver Enzyme Disturbances Research Articles

FRI456 Endocrine and Non-Endocrine Causes of Fatigue in Adults With Turner Syndrome: Cohort Study and Review of the Literature

Abstract Disclosure: A.G. Rosenberg: None. V.D. Dingemans: None. A.G. Bos-Roubos: None. S. Luijks: None. A.B. Dessens: None. R. Dykgraaf: None. J.W. Roos-Hesselink: None. E.F. van Rossum: None. A.J. van der Lely: None. L.C. de Graaff: None. Background: Turner syndrome (TS) is a rare genetic developmental disorder characterized by gonadal dysfunction, short stature and heart defects, among others. Women with TS often suffer from severe fatigue, for which they are typically referred to endocrinologists. The diagnostic work-up is generally time-consuming and invasive, but it rarely solves the problem. To prevent the personal and financial burden of unnecessary diagnostic procedures, it is crucial to understand fatigue in TS. Therefore, in this study, we explored the association between fatigue and endocrine and non-endocrine comorbidities in a - for rare disorders - large group of TS women. Design: Cross-sectional study. Methods: 170 genetically confirmed TS women who attended the TS reference center underwent a systematic health screening, including a structured interview, complete physical examination, biochemical measurements, perceived stress and fatigue questionnaires and additional tests when indicated. Results: Median age was 32.6 years (IQR 23.9 - 41.4 years) and median BMI was 25.4 kg/m2 (IQR 22.6 - 28.5 kg/m2). One in three TS women experienced severe fatigue. Liver enzyme disturbances and body mass index were significantly associated with higher fatigue scores, while childhood growth hormone treatment was associated with lower fatigue scores. Perceived stress was highly correlated with fatigue (ρ = 0.71; P < 0.001). Conclusions: There was no association between fatigue and most endocrine and non-endocrine disorders, which implies that fatigue is only partly explained by somatic disorders. The high correlation between perceived stress and fatigue suggests that TS-specific neuropsychological processes may play an important role in the etiology of fatigue in TS women. We provide a practical algorithm for the endocrine, non-endocrine and psychological approach to fatigue in TS women. Presentation Date: Friday, June 16, 2023

Associations Between Fatigue and Endocrine and Non-endocrine Health Problems in Turner Syndrome: Cohort Study and Review.

Turner syndrome (TS) is a rare chromosomal disorder characterized by gonadal dysfunction, short stature, and heart defects, among other features. Women with TS often suffer from severe fatigue, for which they are typically referred to endocrinologists. The diagnostic work-up is generally time-consuming and invasive, and it rarely solves the problem. To prevent the personal and financial burden of unnecessary diagnostic procedures, it is crucial to understand fatigue in TS. To explore the association between fatigue and endocrine and non-endocrine comorbidities in a-for rare disorders-large group of women with TS. 170 genetically confirmed women with TS who attended the TS Reference Center underwent a systematic health screening, including a structured interview, complete physical examination, biochemical measurements, perceived stress and fatigue questionnaires, and additional tests when indicated. Median (interquartile range) age was 32.6 (23.9-41.4) years. Severe fatigue was experienced by 1 in 3 women with TS. Liver enzyme disturbances and body mass index were significantly associated with higher fatigue scores. Perceived stress was highly correlated with fatigue. There was no association between fatigue and most endocrine and non-endocrine disorders, which implies that fatigue is only partly explained by somatic disorders. The high correlation between perceived stress and fatigue suggests that TS-related neuropsychological processes may play an important role in the etiology of fatigue in women with TS. We provide a practical algorithm for the endocrine, non-endocrine, and psychological approach to fatigue in women with TS.

Antioxidant, Antigenotoxic, and Hepatic Ameliorative Effects of Quercetin/Zinc Complex on Cadmium-Induced Hepatotoxicity and Alterations in Hepatic Tissue Structure

Applications of medicinal uses of metals and their complexes have been gaining major clinical significance, especially during the COVID-19 pandemic. The ligation behavior of quercetin (Q), a flavonoid, and Zn metal, i.e., the Zn/Q complex, was fully characterized based on molar conductance, infrared (IR) spectra, elemental analysis, electronic spectra, thermogravimetric analysis, proton nuclear magnetic resonance (1H-NMR), and transmission electron microscopy (TEM) in our lab. Hepatotoxicity was induced by cadmium (CdCl2). A total of 40 male albino rats were randomly distributed into the following four groups: Control, hepatotoxic group (CdCl2), Zn/Q-treated group, and group treated with a combination of CdCl2 and Zn/Q. Serum hepatic enzymes (AST, ALT, and LDH), total protein, and enzymatic and nonenzymatic antioxidant levels were determined. Histology and TEM for hepatic tissues, in addition to the gene expression of SOD as an antioxidant enzyme in the hepatic tissues, were evaluated. The Q/Zn treatment demonstrated potent protective effects against CdCl2-induced sever oxidative stress and suppressed hepatic toxicity, genotoxicity, liver enzyme disturbances, and structural alterations. In conclusion, the Zn/Q complex produced a high potent antioxidant effect against the oxidative injury and genotoxicity induced by CdCl2 and could be considered to be a potent ameliorative hepatoprotective agent against CdCl2 hepatotoxicity, which could be beneficial during the COVID-19 pandemic.

Human Growth Hormone Induced Cholestatic Hepatitis in a Growth Hormone Deficient Patient with Short Stature

We report a patient with growth hormone deficiency that developed cholestatic hepatitis during treatment with recombinant human growth hormone (HGH). The patient developed jaundice and pruritus during treatment with growth hormone. She did not use any other medications. Her jaundice and pruritus were disappeared and liver enzyme disturbances were normalized after HGH discontinuation. Clinician should be aware of this potential adverse drug reaction and frequent checking of liver enzymes is recommended in patients treating with HGH.

Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10(9) CAR T cells. CTC grade 2-4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10(9) T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed "on-target" toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.

A life-threatening dichlorophen poisoning case: clinical features and kinetics study

Background. Human dichlorophen poisoning is rare. We aim to report a case of dichlorophen poisoning resulting in complete recovery despite life-threatening multiorgan failure and huge serum dichlorophen concentrations. Methods. Description of features and management in one dichlorophen-poisoned patient. After liquid–liquid extraction, dichlorophen concentrations in the urine and the serum were measured using liquid chromatography-heated electrospray ionization–tandem mass spectrometry (LC-HESI-MS/MS). Case report. A 74-year-old female self-ingested an anti-moss dichlorophen solution (360 g/L) in a suicidal attempt. She rapidly developed caustic esophageal and gastric mucosal injuries, confusion, profuse diarrhea, and electrolyte disturbances. Initial elevation in serum aminotransferase and γ-glutamyltransferase concentrations resolved over 6 days. Serum dichlorophen concentration measured was 708.1 μg/L on admission, and its elimination was prolonged (serum apparent elimination half-life: 35.5 h), peaking in urine on day 2. Mild elevation in serum creatine phosphokinase concentration (peaking 48 h post-ingestion) and acute renal failure (requiring hemodialysis on day 8) occurred. The final outcome was favorable with supportive management. Conclusion. Dichlorophen ingestion results in life-threatening multiorgan dysfunction including rapid onset of caustic digestive lesions, diarrhea, liver enzyme disturbances, as well as acute kidney injury and rhabdomyolysis. Recovery can be complete if prompt supportive management is provided.

Burden and outcome of HIV infection and other morbidities in health care workers attending an Occupational Health Program at the Provincial Hospital of Tete, Mozambique

To investigate the burden and outcome of HIV infection and other morbidities amongst a Mozambican hospital staff. Within an occupational health service set up in April 2008 in the provincial hospital of Tete, Mozambique, we offered to all staff members an initial clinical, laboratory and radiological screening and followed them up prospectively until April 2010. A total of 47.5% of 423 health workers attended the program. The cohort (female-to-male ratio: 2.2; mean age: 39 years) consisted mostly of auxiliary staff (43%) and nurses (29.8%). At initial screening, 71% were asymptomatic. HIV infection (28.4%) and tuberculosis (TB) (21%) were the main reported antecedent illnesses. Laboratory screening revealed anaemia (haemoglobin level <10 mg/dl) in 9% participants, abnormal liver enzymes in 23.9% and a reactive non-treponemal syphilis test in 5%. Of 145 performed chest X-rays, 13% showed abnormalities. All 113 health workers not recently tested for HIV were screened, and 31 were newly diagnosed with HIV infection (resulting in an overall HIV prevalence of 43.8%). Nine cases of TB were diagnosed at screening/during follow-up. In April 2010, all but one of the participants were alive. All HIV-infected health workers under antiretroviral therapy were actively followed-up. Serious conditions were frequently diagnosed in health workers, in particular HIV infection. Mid-term outcome was favourable within this program. Creation of screening and care services dedicated to caregivers should be of highest priority in similar African settings.

CHR-2845, a Monocyte/Macrophage Targeted Histone Deacetylase Inhibitor In a First In Man Clinical Trial In Subjects with Advanced Haematological Malignancies

AbstractAbstract 3279CHR-2845 is a novel type of histone deacetylase inhibitor (HDACi) for use in cancer, which is targeted specifically to cells of the monocyte-macrophage lineage. CHR-2845 is a cell-permeant ester that is cleaved to an active acid, CHR-2847, by an intracellular esterase (human carboxylesterase-1, hCE-1) that is primarily found in cells of the monocyte lineage including macrophages, monocytes and Kupffer cells, and also hepatocytes. CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE-1-expressing cells, resulting in a 20–100 fold increase in anti-proliferative potency of CHR-2845 for monocytic over non-monocytic tumour cells. This selectivity should lead to an increased therapeutic window in haematological malignancies involving cells of the monocyte lineage (AML-M4, AML-M5 and CMML). In addition, there is increasing evidence that macrophages associated with progressive, solid tumours (tumour-associated macrophages (TAMs)) and lymphomas are involved in supporting the growth and spread of the tumour. Circulating monocytes differentiate into resident tissue macrophages and, depending on the local microenvironment, acquire specialised phenotypic characteristics and diverse functions. In tumours, macrophages are reprogrammed by neighbouring tumour cells to induce immune suppression of host defences, facilitating progressive tumour growth and tumour cell dissemination. Targeting TAMs with CHR-2845 could, therefore, also have a beneficial effect in non-monocyte derived tumours. The CHR-2845-001 trial recruited patients with advanced haematological malignancies, who are either refractory to standard therapy or for whom no standard therapy exists. This study is a first in man, open label, dose escalating, multi-centre, phase I study of oral CHR-2845 given once a day over a 28 day course of treatment, with the next cycle started at day 29. Cohorts of 3 to 6 patients were treated at increasing dose levels to establish the MTD. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were taken from all patients in all cohorts. The PD evaluation consisted of a FACS-based assay to compare histone acetylation in monocytes, granulocytes and lymphocytes. 18 patients, 7 F:11 M, median age 73 yrs (51 - 80) were enrolled at doses of 20 (n=3), 40 (n=3), 80 (n=3), 160 (n=3), 320 (n=3) and 640 mg (n=3). Intra-subject dose escalations were allowed, with 2 patients receiving 3 dose levels, and 3 patients receiving 2 different dose levels. The median number of cycles administered was 3 (1 – 9). One patient with AML M2 was treated for 7 cycles, a patient with NHL is ongoing at 7 cycles, and a patient with CMML was on treatment for 9 cycles and achieved a bone marrow response and symptomatic relief, although no impact on peripheral monocytes was seen. Dose limiting toxicities (DLT) have not been observed at any dose, possibly due to the targeted nature of CHR-2845. Dose escalation has been halted at 640 mg. Of 197 AEs reported to date, 54 were considered at least possibly related to CHR-2845. Most were grade 1/2, with only 3 grade 3 (anorexia, asthenia, acute confused state). The most frequent drug-related AEs were nausea (11), anorexia (6) and fatigue (5). No liver enzyme disturbances have been noted. PK analysis of CHR-2845 distribution revealed rapid absorption (Tmax 0.9 – 2.1h) and mean elimination plasma half-life of 2.5 hrs. Cmax and AUC(0-t) increased dose proportionally, although there was high variability between patients. There was no substantial accumulation of CHR-2845 observed on Day 28. Preliminary analysis of histone acetylation in PBMCs shows a pattern of monocyte-specific increases in histone acetylation, with no increase in histone acetylation in granulocytes and lymphocytes. Evaluation of PD samples is continuing and an updated analysis will be presented at the meeting. Conclusions:CHR-2845 is well tolerated, with very few of the drug-related adverse events (like nausea, fatigue, diarrhea) commonly seen with HDACi. Plasma concentrations of CHR-2845 achieved in this trial exceed those required for in vitro anti-proliferative activity in the absence of significant toxicity. Updated results will be presented at the meeting, including an assessment of histone acetylation as a pharmacodynamic biomarker in a FACS based assay which can distinguish between targeted acetylation in monocytes versus granulocytes and lymphocytes. Disclosures:Debnam:Chroma Therapeutics: Employment, Equity Ownership. Needham:Chroma Therapeutics: Employment, Equity Ownership. Bawden:Chroma Therapeutics: Employment, Equity Ownership. Hooftman:Chroma Therapeutics: Employment, Equity Ownership.

Long-Term Efficacy and Safety of Combined Treatment of Somatostatin Analogs and Pegvisomant in Acromegaly

We previously reported the efficacy of a combined treatment of active acromegaly with both long-acting somatostatin analogs (SSA) and pegvisomant (PEG-V). Our objective was to assess long-term efficacy and safety in a larger group of acromegalic patients after a period of 138 (35-149) wk [median (range)]. PEG-V was added to high-dose SSA treatment in 32 subjects (13 females) who had not shown a normalization in serum IGF-I concentrations during SSA monotherapy. PEG-V dosage was increased until IGF-I concentration normalized. The maximal dose was 80 mg twice weekly. After dose finding, IGF-I remained within the normal range in all subjects with PEG-V administered once (n = 24) or twice (n = 8) weekly, on a total weekly dose of 60 (40-160) mg. Baseline IGF-I levels were positively correlated with the required dosage of PEG-V (r = 0.48; P = 0.006). PEG-V-dependent liver enzyme disturbances were observed in 11 (6 diabetic) subjects, of which symptomatic gallstones explained two cases. These liver enzyme disturbances were transient in all subjects without discontinuation or dose adaptation of PEG-V. In our series, diabetic patients had a 5.1 times (odds ratio) (confidence interval, 1.02-25.54; P < 0.05) higher risk for developing liver enzyme disturbances. These liver enzyme disturbances seemed to occur earlier. Pituitary adenoma size decreased in four patients. No increase in tumor size was observed in any of the patients. Long-term combined treatment with long-acting SSA and (twice) weekly PEG-V for active acromegaly seems to be effective and safe. Patients with acromegaly and diabetes seem to have a higher risk of developing transient liver enzyme disturbances.

Acute hepatic injury in four children with Dravet syndrome: Valproic acid, topiramate or acetaminophen?

We describe four children with Dravet syndrome treated with the combination of valproic acid (VPA) and topiramate (TPM) who developed transient liver toxicity. The time-interval between fever, administration of acetaminophen, epileptic status and liver enzyme disturbances in our four cases suggests that accumulation of toxic acetaminophen-metabolites is possibly responsible for liver toxicity. If acetaminophen and its metabolites cause those liver problems in children treated with the combination of VPA and TPM, the advice to use acetaminophen for treating fever in children using this combination, should be changed. Only future clinical observations and research can solve this clinical dilemma.

Omega-3 Fatty Acid Supplementation Prevents Hepatic Steatosis in a Murine Model of Nonalcoholic Fatty Liver Disease

Prolonged use of total parenteral nutrition can lead to nonalcoholic fatty liver disease, ranging from hepatic steatosis to cirrhosis and liver failure. It has been demonstrated that omega-3 fatty acids are negative regulators of hepatic lipogenesis and that they can also modulate the inflammatory response in mice. Furthermore, they may attenuate hepatic steatosis even in leptin-deficient ob/ob mice. We hypothesized that omega-3 fatty acid supplementation may protect the liver against hepatic steatosis in a murine model of parenteral nutrition in which all animals develop steatosis and liver enzyme disturbances. For testing this hypothesis, groups of mice received a fat-free, high-carbohydrate liquid diet ad libitum for 19 d with enteral or i.v. supplementation of an omega-3 fatty acid emulsion or a standard i.v. lipid emulsion. Control mice received food alone or the fat-free, high-carbohydrate diet without lipid supplementation. Mice that received the fat-free, high-carbohydrate diet only or supplemented with a standard i.v. lipid emulsion developed severe liver damage as determined by histology and magnetic resonance spectroscopy as well as elevation of serum liver function tests. Animals that received an i.v. omega-3 fatty acid emulsion, however, showed only mild deposits of fat in the liver, whereas enteral omega-3 fatty acids prevented hepatic pathology and led to normalization of liver function tests. In conclusion, whereas standard i.v. lipid emulsions fail to improve dietary-induced steatotic injury to the liver, i.v. supplementation of omega-3 fatty acids partially and enteral supplementation completely protects the liver against such injury.

Intraperitoneal recombinant interferon gamma in ovarian cancer patients with residual disease at second-look laparotomy.

The purpose of this study was to evaluate the efficacy and tolerance of recombinant human interferon gamma (rIFN-gamma) as second-line treatment in patients with persistent disease at second-look laparotomy. One hundred eight patients with residual disease at second-look laparotomy were treated with rIFN-gamma (20 x 10(6) IU/m2) administered intraperitoneally (IP) twice a week for 3 to 4 months. In the absence of clinically assessable disease, response to rIFN-gamma was assessed with a third-look laparotomy. Of 98 assessable patients, 31 (32%) achieved a surgically documented response, including 23 patients (23%) with a complete response (CR). The age and size of residual tumor were significant prognostic factors for the response to rIFN-gamma. A 41% CR rate was observed in 41 patients younger than 60 years and with residual tumor less than 2 cm. The probability of response was independent of previous response to first-line chemotherapy. The median duration of response was 20 months and the 3-year survival rate in responders was 62%. Response to rIFN-gamma was the most significant prognostic factor for survival of patients with residual disease. Adverse events included fever, flu-like syndrome, neutropenia, and liver enzyme disturbances. No significant peritoneal fibrosis was noted. These results support the potential interest of IP rIFN-gamma as adjuvant treatment in ovarian cancer. Controlled prospective trials are required to determine its place in the therapeutic strategy of this malignancy.

The effects of local and systemic interferon beta (Fiblaferon) on supratentorial malignant cerebral glioma — A phase II study

In contrast to the highly promising and, with rates up to 40%, surprisingly high response rates of malignant supratentorial brain gliomas to post-operative adjuvant IFN beta therapy, we were unable to demonstrate any definite anti-proliferative, anti-tumor or immunomodulatory effects of interferon in a phase II study in 13 patients. We used high doses of an IFN beta, Fiblaferon, whose potency was repeatedly confirmed by pharmacokinetic investigations, for local and systemic administration, and the times of administration were those used in the Japanese comparative studies. The side effects observed proved to be related to the amount of IFN beta administered and its duration in our patients as well. In this context, the neurotoxic disturbances require particular attention. These resolved completely after discontinuation of IFN treatment, as do the haematological and liver enzyme disturbances after suspension of medication. We did not observe any improvement in the post-operative quality of life, nor, above all, any improvement in long-term prognosis resulting from a prolonged tumor-free remission period and prolongation of the actual post-operative survival time.

Effects of short‐term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey

Polychlorotrifluoroethylene (polyCTFE--primarily oligomers with 3-4 monomer units), a non-flammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg-1. The administered dose was at a level that had caused toxicity in rats. Steady-state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion.

Liver enzyme disturbances during isoniazid chemoprophylaxis in children.

In 25 of 369 children (6.8 per cent) receiving isoniazid for tuberculosis chemoprophylaxis, serum glutamic oxaloacetic transaminase (SGOT) increased to a concentration greater than 50 units 2 months after medication was begun. There was no other evidence of hepatotoxicity. Isoniazid was discontinued in 4 children with SGOT of more than 95 units. Three of these 4 later resumed and completed isoniazid treatment with smaller, reversible changes in SGOT. The fourth child did not resume medication for nonmedical reasons. In the remaining 21 children with smaller increases of SGOT (50 to 95 units), the SGOT concentration soon decreased during uninterrupted isoniazid administration. None of the 7 children with increases in SGOT who were phenotyped for isoniazid inactivation were rapid inactivators. It is possible that giving a lower dose of isoniazid to slow acetylators might decrease the incidence of hepatotoxicity in programs using isoniazid for the prophylaxis of tuberculosis.