Changes In Liver Tests Research Articles

Review article: Recommendations for detection, assessment and management of suspected drug‐induced liver injury during clinical trials in oncology patients

SummaryBackgroundDrug‐induced liver injury (DILI) is a major concern for oncology drugs in clinical practice and under development. Monitoring cancer patients for hepatotoxicity is challenging as these patients may have abnormal liver tests pre‐treatment or on‐study for many reasons including liver injury due to past oncology treatments, hepatic metastases, medical co‐morbidities such as heart failure, and concomitant medications. At present, there are no regulatory guidelines or position papers that systematically address best practices pertaining to DILI detection, assessment and management in oncology patients.AimsThe goals of this review are (1) to examine and interpret the available evidence and (2) to make recommendations for detection, monitoring, adjudication, and management of suspected hepatocellular DILI during oncology clinical trials.MethodsThis manuscript was developed by the IQ Consortium (International Consortium for Innovation and Quality in pharmaceutical development) DILI Initiative that consists of members from 17 pharmaceutical companies, in collaboration with academic and regulatory DILI experts. The manuscript is based on extensive literature review, expert interpretation of the literature, and several rounds of consensus discussions.ResultsThis review highlights recommendations for patient eligibility for clinical trials with or without primary/metastatic liver involvement, as well as changes in liver tests that should trigger increased monitoring and/or discontinuation of study drug. Guidance regarding causality assessment for suspected DILI events, rechallenge and dose‐modification is provided.ConclusionsThis review brings together evidence‐based recommendations and expert opinion to provide the first dedicated consensus for best practices in detection, assessment, and management of DILI in oncology clinical trials.

The effectiveness of hepatotropic complex Lesil in prevention hepatotoxic effects of anti-helicobacter therapy

Objective — to evaluate the effectiveness of the hepatotropic complex Lesil® for the prevention of the development of drug‑induced liver damage in patients receiving anti‑Helicobacter therapy (AHT). Materials and methods. Observation involved the main (I) and control (II) groups of 40 people in each. Patients with gastroduodenal diseases were included in the study if Helicobacter pylori (H. pylori) infection was first detected. A 14‑day course of 4‑component AHT was administered: pantoprazole, amoxicillin, clarithromycin, colloidal bismuth subcitrate. The main group additionally received Lesil® (Propharma Plant LLC, Ukraine) in a dose of 2 capsules a day for 6 weeks. Patients’ satisfaction with therapy was assessed using a visual analog scale. Statistical processing of the obtained results was carried out using standard methods. Results. After the course of treatment, eradication of H. pylori was achieved in 76 subjects (95%). After the end of AHT in the I group, no changes in liver tests were registered, whereas in the II group, an increase in the activity of ALT and AST in 2.4 (p<0.05) and 2.9 times (p<0.01) was revealed, as well as an increase in the levels of γ‑glutamyltranspeptidase (p<0.01) and alkaline phosphatase (p<0.01), and increase in the fraction of direct bilirubin. Patients of the II group were less satisfied with the treatment: the indicators of the visual analog scale were 4.97±068, compared to the I group (8.43±1.21, p<0.05). Conclusions. Against the background of AHT (PPI in a standard dose, amoxicillin, clarithromycin, colloidal bismuth subcitrate) for 14 days, signs of drug‑induced liver damage were detected, which persisted for 4 weeks after the end of therapy. Hepatocomplex Lesil® is an effective means to prevent drug damage to the liver. This is confirmed by the absence of signs of cytolytic and cholestatic syndromes in the group of patients who received Lesil® 2 capsules per day for 6 weeks in addition to the AHT. Hepatocomplex Lesil® demonstrated safety and good tolerance by patients who were satisfied with AHT in combination with Lesil®.

Longitudinal effects of elexacaftor/tezacaftor/ivacaftor on liver tests at a large single adult cystic fibrosis centre

BackgroundElexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking. MethodsPatients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD. Results255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy. ConclusionsE/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.

Long-term Follow-up of Hepatitis C Patients Who Achieved Sustained Virologic Response in the Pragmatic PRIORITIZE Study

Multiple real-world studies have confirmed the safety and efficacy of hepatitis C (HCV) direct-acting antivirals (DAAs); however, few studies have provided data on long-term outcomes of patients without cirrhosis after achieving sustained virologic response (SVR).1-3 The aims of this analysis were to describe, among individuals in the PRIORITIZE Study achieving SVR: (1) the frequency of laboratory testing and imaging during long-term follow-up (LTFU), (2) changes in liver tests, (3) occurrence of hepatic decompensation or hepatocellular carcinoma (HCC) and deaths, and (4) durability of SVR.

Influence of coronavirus infection on the course of psoriasis

A new SARS-CoV-2-associated coronavirus infection pandemic began in late 2019. The present article is devoted to the analysis of the mechanisms of COVID-19 impact on the course of psoriasis and its consequences. According to the scientific literature, patients with psoriasis are somewhat more likely to be infected with coronavirus infection than the healthy population, but tolerate it in a milder form. At the same time, cases of psoriatic process exacerbation during the active phase of the disease and after COVID-19 have been described. The negative effect of infection on skin disease can be explained by the common genome of the two nosologies, the «cytokine storm» and the prescription of COVID-19 drugs. In addition, both COVID-19 and psoriasis can cause liver dysfunction related to the specific pathogenesis of the diseases as well as the prescribed therapy. The article describes our own experience of monitoring patients with exacerbation of psoriasis against the background of coronavirus infection with pathological changes in liver tests. Inclusion of a fixed combination of glycyrrhizic acid and essential phospholipids in the complex treatment allowed to stop the exacerbation of the psoriatic process more effectively, to reduce the activity of liver enzymes without worsening the clinical conditions associated with COVID-19. Thus, in particular, a clinically significant improvement of the skin condition was recorded. In patient B., alanine aminotransferase activity decreased to 44.4 U/L and aspartate aminotransferase activity to 18.2 U/L. In turn, in patient M. the activity of liver enzymes decreased to 37.8 U/L and 34.7 U/L, respectively. The prescription of this drug can be considered pathogenetically justified, given the effect of glycyrrhizic acid on the production of key cytokines involved in the inflammatory process in psoriasis, coronavirus infection and liver pathology. In addition, the hypothesis of the ability of glycyrrhizic acid to prevent the entry of SARS-CoV-2 into the cell by reducing the expression of angiotensin-converting enzyme 2 is of interest.

COMPARISON OF BIOCHEMICAL PARAMETERS OF PATIENTS WITH LIVER CIRRHOSIS WITH AND WITHOUT COVID-19

There have been many published studies on how COVID-19 can affect the liver and how the severity of liver damage can influence the clinical course of COVID-19. The article describes the features of the biochemical parameters of the liver in different age groups developing with a new coronavirus infection using the example of observations in the department of gastroenterology. In patients under 60 years of age with liver cirrhosis in combination with Covid-19, along with deeper changes in liver tests, a decrease in hemoglobin, leukopenia and thrombocytopenia was observed.

S3531 Acute Hepatitis a Causing Severe Hemolysis and Renal Failure in a Glucose-6-Phosphate Dehydrogenase Deficient Patient

INTRODUCTION: Hepatitis A virus infections are usually self-limited illness that rarely causes fulminant liver failure. Hemolysis is a known complication of viral hepatitis and is typically mild. Severe hemolysis is uncommon; however, it has been reported in patients with Glucose-6-phosphate dehydrogenase (G6PD) deficiency. We report the first case in the United States with undiagnosed G6PD deficiency who presented with hyperbilirubinemia, severe hemolysis, and renal failure due to acute hepatitis A infection. CASE DESCRIPTION/METHODS: A 55-year-old male with a past medical history significant for HIV, presented with complaints of jaundice, fatigue, weakness, and abdominal pain for two weeks. The patient denies any history of alcohol, illicit drug use, or family history of liver disease. On examination, he was hemodynamically stable with scleral icterus. On admission laboratory test showed creatinine 6.38 mg/dL (0.7–1.3) , BUN 48 mg/dL (7–18), total bilirubin 51.8 mg/dL (0.2–1), direct bilirubin 40.4 mg/dL (< =0.2), Lactate dehydrogenase 2678 unit/L (87–241), Haptoglobin < 7.7 mg/dL, Alkaline phosphatase 195 unit/L, AST 4,216 unit/L (15–37), ALT 6,244 unit/L (16–61), Lactic acid 5.5 mmol/L(0.4–2), WBC 16.6 thou/mcL (4.2–10.2), Hemoglobin 7.5 g/dL (12.8–16.4), Platelet 344 thou/mcL (150–400), and INR 1.6 (0.8–1). His combs test was negative. He underwent extensive workup for etiology for his jaundice, including viral hepatitis (HSV, EBV, CMV, HAV, HBV, HCV, HEV), Autoimmune (ANA, SMA, AMA, Immunoglobins), obstructive process (CT abdomen/pelvis). All these tests were negative except for a positive for Hepatitis A IgM. His peripheral blood smear showed hemolysis. He was treated empirically with antibiotics, intravenous fluids, and hemodialysis for renal failure. He underwent liver and kidney biopsies, which showed cholestatic hepatitis and acute tubular injury with bile and hemoglobin casts, respectively (Figures 1 and 2). His G6PD level was low 6.2 U/g Hgb (7–20.5), confirming the diagnosis. With supportive measures, the patient clinically improved, and he was discharged home on day 25 with a total bilirubin of 13 (Figure 3). DISCUSSION: Our patient had acute hepatitis A, which precipitated hemolysis and renal failure in the setting of undiagnosed G6PD deficiency. In conclusion, intravascular hemolysis due to G6PD deficiency should be considered in patients with acute hepatitis A infection who presenting with marked hyperbilirubinemia and renal failure.Figure 1.: A. Liver biopsy (H&E, x40) shows bridging necrosis and collapse of parenchyma with cholestasis and sparse inflammatory infiltrate rich in lymphocytes and plasma cells (B. inset x200). C. A trichrome stain (x20) shows lack of fibrosis supporting acute nature of the illness.Figure 2.: A. Renal biopsy shows tubular casts comprising of hemoglobin (hemoglobin immunostained in B) and bile pigment (Fauchet stain in C). Glomeruli and vasculature were within normal limits.Figure 3.: Changes in liver tests during hospitalization are plotted from admission at day 1 to day 25.

Short-term changes in liver tests predict long-term mortality.

To determine whether short-term changes in liver tests (bilirubin, albumin, gamma glutamyl transferase, alkaline phosphatase, alanine aminotransferase (ALT) and aspartate aminotransferase) predict 12-month mortality and, if so, which test is most informative. Retrospective review of general medicine inpatients at a tertiary hospital (2005-2012) identified non-elective admissions of minimum 7 days' duration. Patients with liver disease, malignancy, admission to the intensive care unit or inpatient mortality were excluded. Linear spline modelled the vector of intra-admission change from admission. The association between 12-month mortality and admission and intra-admission changes in liver tests was assessed by logistic regression modelling, adjusted for age, gender, comorbidity index and heart failure. 12-month mortality was 17% in 4160 patients analysed. 12-month mortality for patients with abnormally low albumin at admission was 5% higher per 1 g/L below 34 g/L (OR 0.95, 95% CI 0.93 to 0.98, p<0.001). Albumin and ALT were the only tests for which an intra-admission change significantly predicted mortality; the predictive effects were additive. 12-month mortality was greater by 4% per 1 g/L intra-admission decrement in albumin (OR 1.04, 95% CI 1.02 to 1.06, p<0.001) and 6% per 100 IU/L intra-admission increment in ALT (OR 1.06, 95% CI 1.02 to 1.1, p=0.005). Intra-admission changes were superior to admission values in predicting mortality. Changes in liver tests predict long-term mortality better than a single value and provide prognostic information more quickly than long-term monitoring. In the absence of known liver disease, albumin predicts long-term mortality better than transaminases. The patient whose albumin decreases in the short term is at high risk of death within 1 year, even from a normal baseline.

Abstract 16993: An Antisense Inhibitor of Apolipoprotein C-III Significantly Decreases Nonesterified Fatty Acid Levels in Severe Hypertriglyceridemic Patients

Background: Apolipoprotein C-III (apoC-III), a CV risk factor, plays a pivotal role in regulating plasma triglyceride (TG) levels. Elevated TG and its nonesterified fatty acid (NEFA) derivatives are associated with insulin resistance and type 2 diabetes. ISIS-APOCIII Rx selectively inhibits apoC-III protein synthesis in the liver and studies show it may improve insulin sensitivity in patients with type 2 diabetes. Treatment with ISIS-APOCIII Rx results in significant dose-dependent decreases in apoC-III and TG levels (Table) in patients with severe hypertriglyceridemia (SHTG) as monotherapy or add on to a stable dose of fibrate. The present study assessed the potential resulting change in NEFA levels in these patients. Methods: Adult patients with SHTG treated or untreated with fibrate were enrolled in a double-blind Phase 2 study to receive ISIS-APOCIII Rx (up to 300 mg) or placebo as weekly SC injections for 13 weeks. Baseline and end-of-treatment fasting serum samples were analyzed for NEFA levels. Results: Results show significant reductions in NEFA levels in line with reductions in TG levels at the 300 mg/week dose (the Phase 3 dose) of ISIS-APOCIII Rx (Table). ISIS-APOCIII Rx was generally safe and well tolerated. There were no clinically meaningful changes in liver tests or other laboratory values. Conclusions: Treatment with ISIS-APOCIII Rx reduces NEFA levels together with decreases in TG in patients with treated or untreated SHTG suggesting the potential for improvement in peripheral insulin sensitivity in these patients.

Clinical and Laboratory Features in Acute Generalized Pustular Psoriasis

Acute generalized pustular psoriasis (AGPP) is a rare variant of psoriasis that can be lethal without proper treatment. It can be caused by the withdrawal of corticosteroids and, among its extra-cutaneous manifestations, liver abnormalities are frequently under-reported or attributed to drugs. The aim of this study was to assess the clinical and laboratory data, treatment options, and disease outcome in patients with AGPP and to search for significant differences between subgroups of these patients. This was a retrospective analysis of the clinical files from inpatients with AGPP observed in our department between 1973 and 2008. Statistical tests were performed at a significance level of 5%. This was an inpatient, single-center study. Outcome measures were a previous history of psoriasis, corticosteroid use before admittance, mortality rate, white blood cell count, absolute neutrophil count, and abnormalities in liver enzymes. A total of 34 patients fulfilled the inclusion criteria, of whom 61% were men and 65% had a previous history of psoriasis vulgaris. Topical corticosteroids were applied by 50% of patients before admittance. Skin lesions remitted with methotrexate, etretinate, or acitretin treatment in all but two patients who died of sepsis. Abnormalities in liver enzymes were present in 47% of patients. Patients without a previous history of psoriasis had a significantly younger age at the first episode of AGPP. In the comparison between the groups of patients with and without liver abnormalities, a male preponderance and higher leukocyte counts were found in the former, with a positive correlation between the absolute neutrophil count and total bilirubin also being observed. Previous use of retinoids or methotrexate was not associated with these hepatic alterations. Limitations of the data were that this was a single-center, retrospective study with a small sample size. Withdrawal of systemic or topical corticosteroids can precipitate or worsen AGPP and these agents should not be used in these patients. Liver abnormalities can be considered an extra-cutaneous manifestation of AGPP. As in other series, no association between the use of drugs and changes in liver tests was found and therefore the deleterious withdrawal of efficient drugs, namely acitretin and methotrexate, should be avoided.

Conversion of daily pegvisomant to weekly pegvisomant combined with long-acting somatostatin analogs, in controlled acromegaly patients

The efficacy of combined treatment in active acromegaly with both long-acting somatostatin analogs (SRIF) and pegvisomant (PEG-V) has been well established. The aim was to describe the PEG-V dose reductions after the conversion from daily PEG-V to combination treatment. To clarify the individual beneficial and adverse effects, in two acromegaly patients, who only normalized their insulin like growth factor (IGF-I) levels with high-dose pegvisomant therapy. We present two cases of a 31 and 44 years old male with gigantism and acromegaly that were controlled subsequently by surgery, radiotherapy, SRIF analogs and daily PEG-V treatment. They were converted to combined treatment of monthly SSA and (twice) weekly PEG-V. High dose SSA treatment was added while the PEG-V dose was decreased during carful monitoring of the IGF-I. After switching from PEG-V monotherapy to SRIF analogs plus pegvisomant combination therapy IGF-I remained normal. However, the necessary PEG-V dose, to normalize IGF-I differed significantly between these two patients. One patient needed twice weekly 100 mg, the second needed 60 mg once weekly on top of their monthly lanreotide Autosolution injections of 120 mg. The weekly dose reduction was 80 and 150 mg. After the introducing of lanreotide, fasting glucose and glycosylated haemoglobin concentrations increased. Diabetic medication had to be introduced or increased. No changes in liver tests or in pituitary adenoma size were observed. In these two patients, PEG-V in combination with long-acting SRIF analogs was as effective as PEG-V monotherapy in normalizing IGF-I levels, although significant dose-reductions in PEG-V could be achieved. However, there seems to be a wide variation in the reduction of PEG-V dose, which can be obtained after conversion to combined treatment.

Changes in liver tests during 1‐year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide

Patients with Type 2 diabetes are at increased risk of liver damage. Therefore, it is of particular importance to investigate the hepatic effects of drugs used to treat such patients. Liver testing results performed in four 1-year, randomized, double-blind studies comparing effects of pioglitazone, metformin or a sulphonylurea, gliclazide, in the treatment of over 3700 patients with Type 2 diabetes have been analysed. Pioglitazone caused reductions in mean levels of hepatic enzymes of between 3 and 18%, whilst gliclazide caused small increases of between 3 and 13%. Metformin treatment showed either small mean increases or decreases. More patients receiving pioglitazone had liver tests within the normal range at the end of treatment (> or = 87%) compared with patients receiving metformin (> or= 80%) or gliclazide (> or = 75%). Slightly fewer patients with pioglitazone than with comparators showed a large increase (> 3 upper limit of normal) in alanine aminotransferase levels at any time during treatment (pioglitazone 0.9%, metformin 1.9%, gliclazide 1.9%). During pioglitazone treatment there is a reduction in liver enzyme levels. Although the mechanism of this effect is not clear, the results demonstrate potential beneficial effects on the liver during treatment of patients with Type 2 diabetes with pioglitazone.

Oral budesonide in the treatment of primary sclerosing cholangitis

OBJECTIVE: This study was designed to evaluate the safety and estimate the efficacy of oral budesonide in patients with primary sclerosing cholangitis (PSC). METHODS: Twenty-one patients with PSC were treated with 9 mg daily of oral budesonide for 1 yr. RESULTS: Significant, but marginally important, improvement in serum alkaline phosphatase (1235 ± 190 vs 951 ± 206 U/L, p = 0.003) and AST levels (119 ± 14 vs 103 ± 19 U/L, p = 0.02) was noted at the end of the treatment period. Serum bilirubin levels increased significantly in the 18 patients who completed 1 yr of treatment (1.1 ± 0.1 vs 1.4 ± 0.3, p = 0.01) and no significant changes in liver tests were noted 3 months after budesonide was discontinued. The Mayo risk score did not change significantly, and although a significant improvement in the degree of portal inflammation was noted at the end of the treatment period, the degree of fibrosis and stage of disease were not significantly affected. There was a marked loss of bone mass of the femoral neck (0.851 ± 0.02 vs 0.826 ± 0.02 g/cm 2, p = 0.002) and lumbar spine (1.042 ± 0.02 vs 1.029 ± 0.02 g/cm 2, p = 0.09) at 1 yr of treatment with budesonide. Two patients required evaluation for liver transplantation during treatment, and two patients developed cosmetic side effects. CONCLUSIONS: Oral budesonide appears to be of minimal, if any, benefit and it is associated with a significant worsening of osteoporosis in patients with PSC.

Ursodeoxycholic acid-induced changes of plasma and urinary bile acids in patients with primary biliary cirrhosis

Ursodeoxycholic acid treatment of patients with primary biliary cirrhosis may lead to relief of pruritus and improvement of biochemical liver tests. The changes in serum and urinary bile acids induced by ursodeoxycholic acid treatment were studied. After 29 patients with primary biliary cirrhosis were treated with ursodeoxycholic acid (750 to 1,000 mg/day) for 6 to 12 mo because of an increase in ursodeoxycholic acid, total plasma bile acids increased from 30.5 +/- 6 mumol/L (mean +/- S.E.M.) to 52.7 +/- 11.7 mumol/L (p less than 0.01). The increase in total plasma bile acids correlated significantly with concentrations of plasma bile acid before treatment (p less than 0.01). The concentrations of endogenous bile acids decreased, mainly because of a decrease of cholic acid. During treatment, glycine conjugation increased and taurine conjugation decreased, whereas sulfation and glucuronidation of bile acids were unchanged. In 10 patients with primary biliary cirrhosis in stages III and IV, urinary excretion of bile acids was also studied. After treatment, ursodeoxycholic acid and its 3-beta isomer and C-1-hydroxylated and C-6-hydroxylated derivatives were also excreted. During treatment, urinary excretion of endogenous bile acids decreased. The increase of ursodeoxycholic acid and the decrease of endogenous bile acids may both be related to the improvement of biochemical liver tests in precirrhotic stages of the disease. In cirrhosis, endogenous bile acids in plasma remained high and changes in liver tests were small.