Biochemical Markers Of Cholestasis Research Articles

Prolonged jaundice after previous SARS-CoV-2 infection: a clinical case report

The hepatobiliary system can be affected by a new coronavirus infection (COVID-19), in addition to the respiratory organs. Vanishing bile duct syndrome (VBDS) is a rare cause of jaundice that usually develops as a result of drug-induced liver injury or possibly due to the combined effect of several etiological factors.Clinical case. A 77-year-old patient was hospitalized due to jaundice, skin itching and dark urine. Symptoms first appeared 1 month after COVID-19 treated with ceftriaxone and were accompanied by an increase in biochemical markers of cholestasis. Both extra- and intrahepatic bile ducts injuries were excluded. Liver histology revealed VBDS. Treatment with ursodeoxycholic acid for 11 months led to complete resolution of jaundice, regression of pruritus and a decrease in biochemical markers of cholestasis.Discussion. This clinical case is of interest in connection with the development of VBDS in a patient after coronavirus pneumonia treated with ceftriaxone. VBDS is rarely included in the differential diagnosis of cholestatic syndrome, which is partly due to the lack of awareness of physicians about the complications that develop after COVID-19 and drug therapy.

A phase II, randomized, open-label, 52-week study of seladelpar in patients with primary biliary cholangitis

We examined the efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-delta agonist, in adults with primary biliary cholangitis (PBC) at risk of disease progression (alkaline phosphatase [ALP] ≥1.67xupper limit of normal [ULN]) who were receiving or intolerant to ursodeoxycholic acid. In this 52-week, phase II, dose-ranging, open-label study, patients were randomized (1:1) to seladelpar 5mg/day (n=53) or 10mg/day (n=55) or assigned to 2mg/day (n=11; United Kingdom sites after interim analysis) for 12 weeks. Doses could then be uptitrated to 10mg/day. The primary efficacy endpoint was ALP change from baseline to Week8. Mean baseline ALP was 300, 345, and 295U/L in the 2mg, 5mg, and 10mg cohorts, respectively. Twenty-one percent of patients had cirrhosis, 71% had pruritus. At Week 8, mean±standard error ALP reductions from baseline were 26±2.8%, 33±2.6%, and 41±1.8% in the 2mg (n=11), 5mg (n=49), and 10mg (n=52) cohorts (all p≤0.005), respectively. Responses were maintained or improved at Week 52, after dose escalation in 91% and 80% of the 2mg and 5mg cohorts, respectively. At Week 52, composite response (ALP <1.67xULN, ≥15% ALP decrease, and normal total bilirubin) rates were 64%, 53%, and 67%, and ALP normalization rates were 9%, 13%, and 33% in the 2mg, 5mg, and 10mg cohorts, respectively. Pruritus visual analog scale score was decreased in the 5mg and 10mg cohorts. There were no treatment-related serious adverse events, and 4 patients discontinued due to adverse events. Seladelpar demonstrated robust, dose-dependent, clinically significant, and durable improvements in biochemical markers of cholestasis and inflammation in patients with PBC at risk of disease progression. Seladelpar appeared safe and well tolerated and was not associated with any increase in pruritus. NCT02955602 CLINICALTRIALSREGISTER. 2016-002996-91 LAY SUMMARY: Current treatment options for patients living with primary biliary cholangitis (PBC) are not optimal due to inadequate effectiveness or undesirable side effects. Patients with PBC who took seladelpar, a new treatment being developed for PBC, at increasing doses (2, 5, or 10mg/day) for 1 year had clinically significant, dose-dependent improvements in key liver tests. Treatment appeared safe and was not associated with any worsening in patient self-reported itch scores.

Factors Associated With Recurrence of Primary Biliary Cholangitis After Liver Transplantation and Effects on Graft and Patient Survival

Primary biliary cholangitis (PBC) frequently recurs after liver transplantation. We evaluated riskfactors associated with recurrence of PBC and its effects onpatient and graft survival in a multicenter, international cohort (the Global PBC Study Group). We collected demographic and clinical data from 785 patients (89% female)with PBC who underwent liver transplantation (mean age, 54 ± 9 years) from February 1983 through June 2016, among 13 centers in North America and Europe. Results frombiochemical tests performed within 12 months of liver transplantation were analyzed to determine whether markers of cholestasis could identify patients with recurrence of PBC(based on histologic analysis). Patients were followed for amedian 6.9 years (interquartile range, 6.1-7.9 years). PBC recurred in 22% of patients after 5 years and 36% after 10 years. Age at diagnosis <50 years (hazard ratio [HR], 1.79; 95% CI, 1.36-2.36; P < .001), age at liver transplantation <60 years (HR, 1.39; 95% CI, 1.02-1.90; P= .04), use of tacrolimus (HR, 2.31; 95% CI, 1.72-3.10; P < .001), and biochemical markers of severe cholestasis (bilirubin ≥100 μmol or alkaline phosphatase >3-fold the upper limit of normal) at 6 months after liver transplantation (HR, 1.79; 95% CI, 1.16-2.76; P= .008) were associated with higher risk of PBCrecurrence, whereas use of cyclosporine reduced risk of PBC recurrence (HR, 0.62; 95% CI, 0.46-0.82; P= .001). In multivariable Cox regression with time-dependent covariate, recurrence of PBC significantly associated with graft loss (HR, 2.01; 95% CI, 1.16-3.51; P= .01) and death (HR, 1.72; 95% CI, 1.11-2.65; P= .02). Younger age at the time of diagnosis with PBC or at liver transplantation, tacrolimus use, and biochemical markers of cholestasis after liver transplantation are associated with PBC recurrence. PBC recurrence reduces odds of graft and patient survival. Strategies are needed to prevent PBC recurrence or reduce its negative effects.

CHOLELITHIASIS IN INFANTS – CONSERVATIVE OR SURGICAL TREATMENT?

The aim of the research: to optimize the treatment strategy of cholelithiasis in infants by studying the conservative therapy and surgical treatment effectiveness.Children with cholelithiasis were divided into three groups: 60 children received conservative treatment; 14 children were not treated; 22 children underwent cholecystectomy. Conservative treatment was carried out by administration of Ursofalk suspension (Dr. Falk Farma, Germany) on the daily dose basis – 20 mg/kg of body weight per day once a day – at bedtime. Duration of litholysis ranged from 6 to 24 months. The therapeutic effect was controlled every 3 months by ultrasound examination of the bile ducts and biochemical analysis of blood serum.Results. Contractile function of the gallbladder normalized after 6 months, biochemical markers of cholestasis after 3 weeks, lipidogram by the end of the second year of conservative treatment. All children tolerated therapy well. No side effects were found. No spontaneous dissolution of gallstones was observed in 14 children who did not receive litholytic therapy. In 22 children, who underwent surgery, morphological changes in the gallbladder wall were reversible, but most of them formed post-cholecystectomy syndrome. In view of the aforesaid, conservative therapy should be considered the priority method of cholelithiasis treatment in children under 3 years of age. Surgical treatment should be performed only according to vital indications.

Pregnancy course in patients with intrahepatic cholestasis of pregnancy treated with very low doses of ursodeoxycholic acid

Objective. Ursodeoxycholic acid (UDCA) has been proposed as the optimal pharmacological treatment for intrahepatic cholestasis of pregnancy (ICP). The lowest effective dosage of UDCA in women with ICP has not been established. The objective is to determine the risk of adverse pregnancy outcomes resulting from ICP and to measure changes in liver function parameters and pruritus severity in ICP patients treated with low doses of UDCA. Material and methods. ICP was diagnosed in 203 patients on the basis of pruritus and elevated liver biochemical parameters. Patients with total bile acids (TBA) ≥10 μmol/l (n = 157) received UDCA (300–450 mg/day; 4–6 mg/kg/day) until delivery. Maternal and fetal outcomes of women with ICP were compared with 100 patients without cholestasis. Patients with ICP were hospitalized for treatment and fetal surveillance. Results. There was no correlation between fetal and neonatal complication rates in ICP patients and biochemical markers of cholestasis. Significant declines in serum TBA (p = 0.003), bilirubin concentration (p = 0.026) and aminotransferase activity (p < 0.001) were observed during treatment with low doses of UDCA. Moreover, severity of pruritus was ameliorated during the 2 weeks of therapy (p = 0.037). A total of 17 patients (10.9%) did not respond to treatment. Conclusions. UDCA at low doses improved biochemical markers and clinical symptoms in almost 90% of ICP patients.

CORRELATION BETWEEN INFLAMMATORY PARAMETERS AND MARKERS OF CHOLESTASIS IN PATIENTS WITH CHOLEDOCHOLITHIASIS

6The aim of this research was to examine the relationship between inflammatory parameters and markers of cholestasis in patients with choledocholithiasis. All subjects underwent clinical, laboratory and ultrasound examination at the Department of Internal Medicine, Military Hospital Nis, Serbia. Inflammatory parameters and biochemical markers of cholestasis were measured by standard biochemical methods. Most of cholestasis markers showed no significant correlation with inflammatory parameters in blood, except for a weak significant correlation between the number of monocytes with the activity of aspartate aminotransferase (AST) (r=0.37, p<0.05). Hyperbilirubinemia was significantly correlated with the fibrinogen values (r=0.42, p<0.05), while albumin positive values were positively associated with alanine aminotransferase (ALT) activity (r=0.5, p<0.05), and negatively with the alkaline phosphatase (AP) (r=-0.43, p<0.05). In patients with choledocholithiasis, there was a positive correlation between the number of monocytes and the activities of AST, hyperbilirubinemia, and fibrinogen, albumin and ALT, while a negative correlation between albumin and AP was present. Acta Medica Medianae 2014;53(2):28-32.

Connection between markers of cholestasis and intensity of oxidative modification of proteins in patients with choledocholithiasis

The aim of this study was to examine the connection between cholestatic markers and the oxidative protein modification intensity in patients with choledocholithiasis. All the participants were subjected to clinical, laboratory and ultrasonic check-up at the Internal Department of the Military Hospital in Nis, Serbia. The parameters of oxidative stress: carbonyl groups, a measure of oxidative protein modification, and biochemical markers of cholestasis were determined by standard biochemical methods. The concentration of total (r=0.41, p<0.05), direct (r=0.49, p<+0.01) and indirect (r=0.41, p<0.05) bilirubin was in statistically significant positive linear correlation with the intensity of oxidative modification of proteins, while the other biochemical markers of cholestasis did not show such correlation. Total, direct and indirect bilirubins showed a significant positive correlation with oxidative protein modification, assessed through the levels of carbonyl groups in patients with choledocholithiasis. Acta Medica Medianae 2014;53(1):10-14.

Correlation of inflammation parameters and biochemical markers of cholestasis with the intensity of lipid peroxidation in patients with choledocholithiasis

During choledocholitiasis inflammatory oxidant stress involves the promotion of mitochondrial dysfunction through an intracellular oxidant stress in hepatocytes leading mainly to necrosis and less to apoptosis. The product of oxidative stress, malondialdehyde (MDA), is extremely cytotoxic and damages cell membranes and intracellular macromolecules. The toxicity of MDA is based on its ability to act as a mutagenic agent in a cell. Therefore, the aim of this prospective study was to establish correlation of the parameters of inflammation and biochemical markers of cholestasis with the intensity of oxidative stress in pathogenesis of liver function disorders. Seventy adult subjects of either sex included in the study were devided into two groups: I--40 patients with obstructive icterus caused by choledocholithiasis, and II--30 healthy individuals. All the participants were subjected to a clinical, laboratory and ultrasonic check-up at the Internal Department of the Military Hospital in Nis. The parameters of oxidative stress: MDA, a measure of lipid peroxidation, and inflammation parameters: C-reactive protein (CRP), fibrinogen, albumins, number of leukocytes (Leu), granulocytes (Gr), lymphocytes (Ly) and monocytes (Mo) and biochemical markers of cholestasis: activity of gamma-glutamyltransferase (gamma-GT) and alkaline phosphatase (AP) enzymes, the level of total, direct and indirect bilirubin were determined by standard biochemical methods. Lower values of albumin (p < 0.001), and significantly higher values of fibrinogen (p < 0.05) and CRP (p < 0.001) were found in the blood of the patients with cholestasis due to choledocholithiasis in relation to the controls. Significantly higher values of Leu (p < 0.01) and Gr (p < 0.001) with decreasing number of Ly (p < 0.001) and Mo (p < 0.001) were found in blood of the patients with cholestasis due to choledocholithiasis in relation to the control. Similarly, higher values of gamma-GT, and AP (p < 0.001), as well as the level of total, direct and indirect bilirubin (p < 0.001) were found in blood of the patients with cholestasis due to choledocholithiasis in relation to the controls. The concentration of MDA (p < 0.001) was increased in the patients with choledocholithiasis in relation to the controls. There was a significant positive linear correlation of the number of leukocytes (r = 0.51, p < 0.05) and the concentration of total (r = 0.87, p < 0.01), direct (r = 0.85, p < 0.01) and indirect (r = 0.88, p < 0.01) bilirubin with the concentration of MDA in the group of patients with choledocholithiasis. Neutrophils and the levels of total, direct and indirect bilirubin have a significant positive linear correlation with the level of lipid peroxidation in patients with choledocholithiasis. Neutrophilia and hiperbilirubinemia observed in this way represent important parameters in estimating the level of liver tissue damage in choledocholithiasis.

Expression of Cytokeratin 7 as a Histological Marker of Cholestasis and Stages of Primary Biliary Cirrhosis

The aim of this study was to estimate cytokeratin 7 (CK-7) expression in biopsy specimens of patients with different stages of primary biliary cirrhosis and clinicopathological patterns (cholestatic and hepatitic) and its correlation with some biochemical and pathological parameters and to examine a diagnostic value of CK-7 expression. A total of 82 biopsy specimens of patients with primary biliary cirrhosis were analyzed. CK-7 expression was graded by 4 grades depending on the extent into parenchymal areas and bile duct epithelium. The correlations of CK-7 expression grade with copper deposition, bile duct/portal tract ratio, bilirubin concentration, and activity of alkaline phosphatase and gamma-glutamyl transpeptidase were studied. CK-7 expression was evaluated as a marker of cholestasis (cholestatic pattern) and inflammation (hepatitic pattern). A positive correlation of CK-7 expression grade with copper-binding protein grade (r=0.698, P<0.0001; OR=6.199, P<0.0001), serum bilirubin level (r=0.375, P=0.001), and alkaline phosphatase activity (r=0.276, p=0.014) was found. CK-7 expression grades correlated positively with histological stages of primary biliary cirrhosis (r=0.639, P<0.000) and negatively with granulomas (r=-0.432, P<0.0001; OR=0.173, P=0.0011). CK-7 expression is a sensitive marker of bile duct injury, which correlated well with histological stages of primary biliary cirrhosis, copper deposits, and biochemical markers of cholestasis: serum bilirubin level and alkaline phosphatase activity. Evaluation of CK-7 expression may improve the diagnosis of this serious and progressive disease. It is recommended to evaluate copper staining together with cytokeratin 7 expression in liver biopsy specimens for more precise diagnostic evaluation of asymptomatic primary biliary cirrhosis.

Colestasis asociada a la nutrición parenteral prolongada en el período neonatal: posible eficacia del ácido ursodesoxicólico

Introduction The morbidity associated with prematurity occasionally leads to the use of prolonged parenteral nutrition, with the subsequent development of cholestasis being one of its complications. Patients and methods This is a two year retrospective study which compared biochemical markers of liver damage and cholestasis in premature babies who received or did not receive urso-deoxycholic acid for parenteral nutrition associated cholestasis. Results Of a total of 24 recruited patients 17 received urso-deoxycholic acid and 7 did not. In the treated group significant decreases ( P<0.05) in gamma-glutamyltranspeptidase and conjugated bilirubin were found after four and five weeks of treatment, respectively. Moreover, a significant correlation ( P<0.01) between conjugated bilirubin and duration of total parenteral nutrition was established. Conclusions Patients who were promptly treated with urso-deoxycholic acid showed a more rapid decrease in biochemical markers of cholestasis, but not of cytotoxicity in the hepatobiliary complications secondary to prolonged parenteral nutrition. However, the present study has limitations derived from its design and therefore it would be desirable launch a randomized trial with sufficient power to evaluate the benefits derived from prophylactic or therapeutic use of urso-deoxycholic acid in the hepatobiliary conditions associated with the prolonged use of parenteral nutrition in the premature infants.

Methotrexate therapy for the symptomatic treatment of primary biliary cirrhosis patients, who are biochemical incomplete responders to ursodeoxycholic acid therapy

Ursodeoxycholic acid is widely used as the standard therapy for the treatment of primary biliary cirrhosis and other cholestatic liver diseases. Although it has been shown to improve biochemical markers and delay disease progression, its effect upon fatigue and pruritus, is at best uncertain. To assess the safety and efficacy of methotrexate for treating symptomatic primary biliary cirrhosis patients who were biochemical partial responders or non-responders to ursodeoxycholic acid therapy. We treated eight consecutive primary biliary cirrhosis patients with methotrexate who were followed in a single hepatology clinical practice, who were symptomatic, and who had had an incomplete biochemical response to ursodeoxycholic acid therapy. Pruritus and fatigue were assessed at each clinic visit and graded from 0 (asymptomatic) to 4 (incapacitating). The median dose of methotrexate was 13.75 mg/week (range 7.5-15) and the mean duration of methotrexate therapy was 49 months (range 11-126). At the end of follow-up pruritus in six of seven patients had improved, and fatigue in all patients had improved with the addition of methotrexate therapy (pruritus: baseline 2.9 +/- 1.1 vs. end of treatment 0.6 +/- 1.5, P < or = 0.0175, and fatigue: baseline 3.0 +/- 0.8, vs. end of treatment 1.0 +/- 0.8, P < or = 0.0023). Improvement in symptoms was associated with a significant improvement in biochemical markers of cholestasis. No significant adverse effects of methotrexate were documented. Methotrexate should be considered as a potential additive treatment for symptomatic primary biliary cirrhosis patients who are incomplete biochemical responders to ursodeoxycholic acid therapy.

The natural history of asymptomatic primary biliary cirrhosis

Appreciation of the spectrum of clinical features of primary biliary cirrhosis (PBC) has evolved considerably over the past few decades. Although the substantial female predominance documented in early series remains true today, it has become clear that other so called ‘classical’ clinical features, such as symptoms of jaundice, pruritis and fatigue, and even biochemical markers of cholestasis, need not necessarily be present. Only a small minority of patients nowadays present with liver failure and most are even identified while asymptomatic, with up to 80% of patients in recently reported series having no PBC-related symptoms at the time of diagnosis, compared to only 4% some 30 years ago (Table 1).1–7 The diagnosis of PBC in asymptomatic patients is usually established after the chance finding of an abnormal physical sign, such as hepatomegaly, or, more often, an elevated serum alkaline phosphatase level during the course of an unrelated illness. Alternatively, patients may be diagnosed after biochemical or autoantibody, including anti-mitochondrial antibody (AMA), screening is carried out either as part of a routine health check or following the documentation of one of the many extrahepatic, predominantly autoimmune, disorders known to be associated with PBC. Crucial to the validity of diagnosing PBC on the basis of a positive AMA test in the latter circumstance is the finding that over 93% of AMA-positive yet asymptomatic patients with no biochemical evidence of cholestasis nonetheless have histological changes compatible with (or diagnostic of) PBC at liver biopsy.8 View this table: Table 1 Prevalence of symptoms at diagnosis of PBC Recognition of the extended clinical spectrum of PBC has resulted in a substantial increase in its reported prevalence, at least in some areas. Far from the historical view of PBC as an uncommon condition,9 recent studies from the north-east of England and Olmstead County in the US indicate that … Address correspondence to A/Professor S.M. Riordan, Gastrointestinal and Liver Unit, The Prince of Wales Hospital, Barker Street, Randwick 2031, New South Wales, Australia. email: riordans{at}sesahs.nsw.gov.au

Intrahepatic cholestasis of pregnancy: A randomized controlled trial comparing dexamethasone and ursodeoxycholic acid

Intrahepatic cholestasis of pregnancy (ICP) is characterized by troublesome maternal pruritus, elevated serum bile acids (> or =10 micromol/L) and increased fetal risk. Recently we determined a cutoff level of serum bile acids, > or =40 micromol/L, to be associated with impaired fetal outcome. We have now studied the effects of ursodeoxycholic acid (UDCA) and dexamethasone on pruritus, biochemical markers of cholestasis, and fetal complication rates in a double-blind, placebo-controlled trial. For this purpose, 130 women with ICP were randomly allocated to UDCA (1 g/day for three weeks), or dexamethasone (12 mg/day for 1 week and placebo during weeks 2 and 3), or placebo for 3 weeks. Pruritus and biochemical markers of cholestasis were analyzed at inclusion and after 3 weeks of treatment. Fetal complications (spontaneous preterm delivery; asphyxial events; and meconium staining of amniotic fluid, placenta, and membranes) were registered at delivery. An intention-to-treat analysis showed significant reduction of alanine aminotransferase (ALT) (P = .01) and bilirubin (P = .002) in the UDCA group only. In a subgroup analysis of ICP women with serum bile acids > or =40 micromol/L at inclusion (n = 34), UDCA had significant effects on pruritus (-75%), bile acids (-79%), ALT (-80%), and bilirubin (-50%) as well, but not on fetal complication rates. Dexamethasone yielded no alleviation of pruritus or reduction of ALT and was less effective than UDCA at reducing bile acids and bilirubin. In conclusion, 3 weeks of UDCA treatment improved some biochemical markers of ICP irrespective of disease severity, whereas significant relief from pruritus and marked reduction of serum bile acids were only found in patients with severe ICP.

Management of primary biliary cirrhosis

Primary biliary cirrhosis (PBC) is a presumed autoimmune disease of the liver, which predominantly affects women once over the age of 20 years. Most cases are diagnosed when asymptomatic (60%). The antimitochondrial antibody is present in serum in most, but not in all, patients with PBC. The disease generally progresses slowly but survival is less than an age- and gender-matched general population. The symptomatic patient may have fatigue, generalized pruritus, portal hypertension, osteoporosis, skin xanthomata, fat soluble vitamin deficiencies, and/or recurrent asymptomatic urinary tract infections. Many nonhepatic autoimmune diseases are found in association with PBC and may prompt initial presentation. To date, immunosuppressive therapy has not been shown to prolong survival in PBC. The hydrophilic bile acid, ursodeoxycholic acid (UDCA), has been shown when given in a dose of 13 to 15 mg/kg daily for up to 4 years to delay the time to liver transplantation or death. This therapy also causes a significant improvement of all the biochemical markers of cholestasis but has no beneficial effects on any of the symptoms or associated disorders. Treatment with UDCA does not obviate the need for liver transplantation. Therapies to prevent complications arising from malabsorption, portal hypertension, and/or osteoporosis are required as well. Good control of pruritus can be achieved in most patients. PBC is diagnosed with increasing frequency, but the agent(s) responsible for this slowly progressive destruction of the interlobular bile ducts remains elusive and hence a specific therapy remains unavailable.

Beneficial effect of ursodeoxycholic acid on alterations induced by cholestasis of pregnancy in bile acid transport across the human placenta

Background/Aims: The existence of impairment in bile acid transport across the placenta during intrahepatic cholestasis of pregnancy and the effect of ursodeoxycholic acid treatment (1 g/day) were investigated. Methods: Kinetic parameters were calculated from experiments carried out on membrane vesicles obtained from basal (TPMb, fetal-facing) and apical (TPMa, maternal-facing) trophoblast plasma membranes. Bile acid uptake was measured using varying concentrations of [ 14C]-glycocholate and a rapid filtration technique. Results: The maximal velocity of transport (Vmax), the apparent affinity constant (Kt) and the efficiency (Ef) of transport (Vmax/Kt) of the anion:bile acid exchanger located at the TPMb were reduced in intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid induced a reversal of Vmax, Kt and Ef to normal values. Owing to the 3-fold increase in Vmax, with no change in Kt, intrahepatic cholestasis of pregnancy induced an enhancement in Ef of ATP-independent bile acid transport across TPMa. Both Vmax and Ef were restored to normal values by ursodeoxycholic acid. Finally, in ATP-dependent bile acid transport across TPMa, a reduction in the Ef due to an increase in Vmax together with a more pronounced increase in Kt was found. This impairment was also reversed by ursodeoxycholic acid. Conclusions: These results suggest that placenta bile acid transport systems are impaired in intrahepatic cholestasis of pregnancy. Moreover, together with the confirmed beneficial effect for intrahepatic cholestasis of pregnancy patients, such as the relief of pruritus and the improvement in biochemical markers of cholestasis, ursodeoxycholic acid treatment restores the ability of the placenta to carry out vectorial bile acid transfer.